WO2021074118A1 - Compositions liquides d'acides gras oméga 3 pour une administration orale directe - Google Patents

Compositions liquides d'acides gras oméga 3 pour une administration orale directe Download PDF

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WO2021074118A1
WO2021074118A1 PCT/EP2020/078716 EP2020078716W WO2021074118A1 WO 2021074118 A1 WO2021074118 A1 WO 2021074118A1 EP 2020078716 W EP2020078716 W EP 2020078716W WO 2021074118 A1 WO2021074118 A1 WO 2021074118A1
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fatty acid
omega
liquid composition
composition
polyol ester
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PCT/EP2020/078716
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English (en)
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Gerd Weiss
Verena GARSUCH
Wolfgang Schiemenz
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Hermes Arzneimittel Gmbh
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • omega-3 fatty acids include a-linolenic acid (ALA), eicosapentaenoic acid (EPA; C20, 5 double bonds) and docosahexaenoic acid (DHA; C22,
  • omega-3 fatty acids occur in two forms, triglycerides and phospholipids; however, semisynthetic products such as methyl esters or ethyl esters of the omega-3 fatty acids are commercially available, too; for instance, 'omega-3-acid ethyl esters 90’ (K85EE) by BASF/Pronova Biocare.
  • K85EE 'omega-3-acid ethyl esters 90’
  • the latter is, inter alia, marketed in soft gelatin capsules under the tradename Omacor ® or LovazaTM for the treatment of hypertriglyceridemia and/or post-myocardial infarction.
  • Omega-3 fatty acids play an important role in the human diet and are known to provide a number of health benefits; for instance, reducing blood triglyceride levels, lowering blood pressure; lowering inflammation levels, alleviating certain circulatory problems by stimulating the blood circulation, and assumingly aiding in learning and cognitive development. Therefore, omega-3 fatty acids, and in particular fish oils containing these fatty acids, are commercially available in a variety of 'omega-3 enriched’ food products; for instance, as parenteral nutrition formulations as well as other pharmaceutical or nutraceutical products.
  • omega-3 fatty acids have sensitivity to oxidation and their rather characteristic, often disagreeable, 'fishy’ odor and taste; the latter an issue which increases upon progressing oxidization. Poor taste and/or odor ultimately often lead to decreasing compliance of the consumer, or patient.
  • One approach is to provide the omega-3 fatty acids in (soft) capsule form to a) prevent, or limit, oxidation, and b) to mask the odor and/or taste.
  • Unfortunately quite a number of consumers, or patients, experience difficulties with swallowing capsules or tablet formulations, including elderly people, children, or people suffering from xerostomia (dry mouth due to hyposalivation) or general phobias around swallowing 'foreign’ objects.
  • the issue of swallowability is partially overcome by the provision of drinkable compositions, such as the water-beased, fish oil containing drinking liquids described in US2016/0316810A1 or US20130078362A1.
  • omega-3 fatty acids Another issue is that rather large amounts need to be taken, or ingested, for the omega-3 fatty acids to be effective; with studies suggesting a daily dose of about 4 g omega-3 fatty acids.
  • the semisynthetic products such as the above-mentioned commercially available 'omega-3-acid ethyl esters 90’ (K85EE)
  • K85EE partially address this issue insofar as they are typically more concentrated and highly enriched with the desirable omega-3 fatty acids
  • the high daily doses are still only achieved by ingesting a multitude of capsules per day (e.g. 2-4 Omacor ® capsules).
  • Products such as 'NORSAN Omega-3 KIDS Jelly’ address the swallowability issue for children by providing a chewable, gummi bear-like soft-gel composition comprising water, gelatin, 250 mg omega-3 fatty acids from natural cod fish oil, lecithin as an emulsifier, strawberry-lemon aroma, xylitol and sorbitol as sucrose-free sweeteners, and malic acid as an antioxidant.
  • US9452150B2 suggests jelly compsitions as an alternative to the conventional capsule products, the jelly compsitions containing water, an organic gelling agent, an emulsifying agent, emulsified polyunsaturated fatty acids in an amount greater than 10 wt.-% in order to decrease the amount of a single dose unit of the composition.
  • the jelly compositions of US9452150B2 are manufactured by adding an appropriate amount of a specific gelling agent (preferably, carrageenan and/or locust bean gum) to an oil-in- water emulsion prepared by the addition of a suitable amount of a specific emulsifying agent to a polyunsaturated fatty acid, preferably, eicosapentaenoic acid ethyl esters (EPA-EE) and/or docosahexanoic acid ethyl esters (DHA-EE).
  • a specific gelling agent preferably, carrageenan and/or locust bean gum
  • EPA-EE eicosapentaenoic acid ethyl esters
  • DHA-EE docosahexanoic acid ethyl esters
  • compositions proposed in US9452150B2 are rather complex; for instance, they require the addition of not only water and an emulsifier to ensure sufficiently rapid release of the fatty acids from the jelly, but also a syneresis inhibitor (e.g. carmellose sodium and pullulan) to ensure stability and prevent syneresis of water from the jelly during storage.
  • a syneresis inhibitor e.g. carmellose sodium and pullulan
  • the use of water in the prior art emulsified compositions may be detrimental to their microbial stability.
  • omega-3 fatty acids in their triglyceride form (i.e. tri-esters of the fatty acids with glycerol) at a content of only about 20 %
  • most of the semi-synthetic products are enriched to comprise the desirable omega-3 fatty acids at contents well above 60 wt.-% or more; and while this is desirable in terms of reducing the volume of a single dose to be administered, it also renders the higher concentrated products more sensitive to oxidation and more ’chemical’ in taste and smell than natural fish-oils, making the development of compositons without a capsule shell-type tastemasking, yet palatable to humans, particularly challenging.
  • compositions for direct oral administration which can be easily swallowed without e.g. added liquids, yet providing a pleasant smell, taste and mouthfeel; as well as good stability. It is thus an object of the present invention to provide such compositions, in particular, liquid compositions for direct oral administration which are storage-stable, exhibit a high content of omega-3 fatty acids and a pleasant taste and smell. Further objects of the invention will be clear on the basis of the following description of the invention, examples and claims.
  • the invention relates to to a liquid composition for direct oral administration, the composition comprising:
  • omega-3 fatty acid composition (b) an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid esters, based on the weight of the omega-3 fatty acid composition, and wherein the weight ratio of the C2-C4 polyol ester under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the present invention relates to a process for the preparation of the liquid composition according to the first aspect of the invention, the process comprising the steps of:
  • omega-3 fatty acid composition Providing a C2-C4 polyol ester with one or more C6-C12 medium chain fatty acids; a thickening agent; at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma; and an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid esters, based on the weight of the omega-3 fatty acid composition; and
  • the weight ratio of the C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 10 : 1, and the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the invention relates to the liquid composition according to the first aspect of the invention for use in the treatment and/or prevention of rheumatoid arthritis, hypertriglyceridemia, and/or post- myocardial infarction.
  • composition or dosage form mean that no further components are added to a composition or dosage form other than those listed. Nevertheless, very small amounts of other materials may potentially be present, such as material-inherent impurities. Furthermore, when referring to e.g. 'essentially consisting of A, B, C and optionally D’ this means that no further components are added to a composition or dosage form other than A, B, C and D, with D being an optional component (i.e. not mandatory) in said composition or dosage form.
  • the term 'substantially free of X means that the respective material (e.g. a chemical compound or a composition) contains less than a functional amount of the optional ingredient X, typically less than 5 wt.-%, or less than 1 wt.-%, preferably less than 0.1 wt.-% or even less than 0.01 wt.-%, and also including 0 wt.-% of the respective ingredient X.
  • the expression refers, inter alia, to very small amounts of the respective ingredient X, such as material-inherent impurities or residual moisture, which may potentially be present in (raw) materials despite the aim to render a material completely free of them.
  • 'substantially free of water means that no water is deliberately included in a material but does not exclude the presence of residual moisture.
  • 'synthetic drug substance shall be understood as referring to substances, namely active pharmaceutical ingredient (APIs) which are administered, e.g. ingested, so as to cause an intential therapeutic effect (i.e. an intential change in a subject’s physiology or, in some cases, psychology), and which are commonly produced or obtained by chemical synthesis.
  • APIs active pharmaceutical ingredient
  • 'synthetic drug substances typically do not occur naturally.
  • synthetic drug substances are commonly understood as being distinguished from, for instance, food, dietary supplements, and other substances that provide nutritional support; such as vitamins, minerals, or the omega-3 fatty acids of the present invention.
  • Examples of synthetic drug substances which are not incorporated into the liquid compositions for direct oral administration according of the present invention include statins such as pravastatin, or other HMG-CoA reductase inhibitors (i.e. inhibitors of the cholesterol synthesizing enzyme CSE); cholesterol absorption inhibitors like ezetimibe; 'fibrates’ such as fenofibrate or gemfibrozil; nicotinic acid and its derivatives; ion exchange resins such as colestyramine.
  • statins such as pravastatin, or other HMG-CoA reductase inhibitors (i.e. inhibitors of the cholesterol synthesizing enzyme CSE); cholesterol absorption inhibitors like ezetimibe; 'fibrates’ such as fenofibrate or gemfibrozil; nicotinic acid and its derivatives; ion exchange resins such as colestyramine.
  • 'pharmaceutically acceptable means that a material is useful in preparing a pharmaceutical or nutraceutical composition that is generally safe, non-toxic and exhibits neither biologically nor otherwise undesirable properties which would prevent, or exclude, it from pharmaceutical or nutraceutical use in humans.
  • 'about’, 'approximately’, 'ca.’, 'essentially’, 'substantially are meant to compensate for the variability allowed for in the pharmaceutical industry and inherent in pharmaceutical or nutraceutical products, such as differences in content due to manufacturing variation and/or time-induced product degradation.
  • the terms in connection with an attribute or value include the exact attribute or the precise value, as well as any attribute or value typically considered to fall within a normal range or variability accepted in the technical field concerned.
  • the term 'room temperature’ shall be understood as ranging from 15 °C to 25 °C, as is for instance defined by the European Pharmacopoeia or by the WHO guidance 'Guidelines for the Storage of Essential Medicines and Other Health Commodities” (2003).
  • 'direct oral administration’ or 'direct oral composition' refer to compositions that are intended to be administered directly from a container (e.g. a bottle, vial, sachet, ampoule, or the like) into the mouth and/or onto the tongue of the consumer, and swallowed easily - typically with no or at best moderate chewing - and with an agreeable taste and/or smell, without the need for further additions of, inter alia, further excipients or comestibles (e.g. fluids such as water, juice, semi-solids such as yoghurt or pudding, or the 'spoonful of sugar’).
  • a container e.g. a bottle, vial, sachet, ampoule, or the like
  • further excipients or comestibles e.g. fluids such as water, juice, semi-solids such as yoghurt or pudding, or the 'spoonful of sugar’.
  • the compositions are taken directly 'as is’ and, thus, get in direct
  • compositions for direct oral administration are often intended to be administrable when the consumer is 'on the go’ and/or in areas of restricted access to clean drinking water.
  • direct oral compositions are often packaged and provided in single dose units.
  • omega-3 oils derived from fish, krill, or algae, or prior art capusule-fills of omega-3 fatty acids are inherently liquids, and hence could - in theory - be ingested 'as is’, too, also does not render them 'direct oral compositions’, or suitable for direct oral administration, in the sense of the present invention, since their taste and smell is experienced as being too 'fishy’ or too 'smelly’ for the majority of people, especially if, after swallowing the 'raw’ oil or capsule fill, the mouth and palate cannot be rinsed or otherwise cleaned from the residual oil film.
  • 'sugar refers to water-soluble, sweet-tasting carbohydrates, in particular to monosaccharides, disaccharides, oligosaccharides and polysaccharides.
  • Solubility provisions as used herein, such as 'slightly soluble’, shall be understood as aqueous solubilities at room temperature (15-25 °C) as determined and ranked according to pharmacopoeial standards (e.g. European Pharmacopeia, Ph.Eur.):
  • the invention relates to a liquid composition for direct oral administration, the composition comprising:
  • omega-3 fatty acid composition (b) an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid esters, based on the weight of the omega-3 fatty acid composition, and wherein the weight ratio of the C2-C4 polyol ester under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the expressions 'C 2 -C 4 polyol ester with one or more C6-C12 medium chain fatty acids’ and 'the omega-3 fatty acid composition comprising at least about 80 wt.-% omega-3 fatty acid esters, based on the weight of the omega-3 fatty acid composition’ will herein commonly be referred to shortly as 'the C2-C4 polyol ester’ and as 'the omega-3 fatty acid composition’, respectively.
  • the two components, the C2-C4 polyol ester and the omega-3 fatty acid composition are miscible with each other.
  • the liquid composition according to the first aspect of the invention is clearly not an emulsion product, and thus is not comparable with, nor identical to, for instance, prior art emulsion products comprising omega-3 fatty acids and/or C6-C12 medium chain fatty acids for parenteral, intraperitoneal, or endotracheal administration. Such products would typically not be consumed orally and hence do not have to address palatability issues. And even though some emulsion products exist which may be intended for direct oral consumption (e.g.
  • the water content of said drinkable emulsions is usually pretty high (often 70 wt.-% or higher) so that the taste of the omega-3 fatty acid composition in the thus highly diluted system is far less noticeable, and less of a formulation challenge.
  • administering a daily recommended dose of 2-4 g omea-3 fatty acids is inconvenient and requires consumption of rather large volumes (typically over 500 mL) when using products with a water content over 60 wt.-% or higher.
  • the liquid composition according to the first aspect of the invention predominantly represents an alternative delivery means to e.g. soft capsules filled with an omega-3 fatty acid composition (or similar solid, or semi-solid, dosage forms that require either to be swallowed 'as is’, or the preparation of drinkable liquid therefrom after the addition of water or other comestibles); and more specifically, an alternative delivery means that allows for palatable, direct oral administration as defined herein, while not aiming to change the overall bioavailability of said omega-3 fatty acid composition.
  • an alternative delivery means that allows for palatable, direct oral administration as defined herein, while not aiming to change the overall bioavailability of said omega-3 fatty acid composition.
  • the C2-C4 polyol of said C2-C4 polyol ester i.e. its 'backbone’, is selected from propylene glycol, glycerol, and/or butylene glycol.
  • the C2-C4 polyol ester is selected from mono- and/or di-esters of propylene glycol, mono-, di- and/or tri-esters of glycerol, and/or mono- and/or di-esters of butylene glycol.
  • the one or more C6-C12 medium chain fatty acids of the C2-C4 polyol ester may be of plant origin.
  • the one or more C6-C12 medium chain fatty acids are aliphatic fatty acids. In one embodiment, the one or more C6-C12 medium chain fatty acids are saturated fatty acids. In one embodiment, the one or more C6-C12 medium chain fatty acids are aliphatic, saturated fatty acids (including e.g. hexanoic acid (Ob), caprylic acid (Cs), capric acid (C10) and lauric acid (C12)). In a further embodiment, the C2-C4 polyol ester comprises aliphatic, saturated fatty acid chains with 8 to 12 carbon atoms, or it comprises aliphatic, saturated fatty acid chains with 8 to 10 carbon atoms. In a yet further embodiment, the C2-C4 polyol ester comprises aliphatic, saturated fatty acid chains of plant origin with 8 to 12, or 8 to 10, carbon atoms.
  • the C2-C4 polyol ester comprises not more than 2 wt.-% of either long chain fatty acids with more than 12 carbon atoms, or short chain fatty acids with less than 6 carbon atoms. In a further embodiment, the C2-C4 polyol ester comprises not more than 2 wt.-% of short chain fatty acids with less than 6 carbon atoms. In a yet further embodiment, the C2-C4 polyol ester comprises not more than 2 wt.-% of long chain fatty acids with more than 12 carbon atoms, and not more than 2 wt.-% of short chain fatty acids with less than 6 carbon atoms.
  • the liquid composition comprises a mixture of two or more C2-C4 polyol esters, preferably C2-C4 polyol esters which are miscible with each other.
  • the C2-C4 polyol ester exhibits a mean viscosity of from about 2 mPas to about 50 mPas as measured by capillary viscosimetry at a temperature of 20 ⁇ 0.1 °C; or from about 5 mPas to about 40 mPas; or from about 25 mPas to about 35 mPas.
  • capillary viscosimetry refers to the method as described in the European Pharmacopoeia (Ph.Eur.) monograph "2.2.9. Capillary Viscometer Method”.
  • At least one, optionally all, of the C2-C4 polyol ester in a mixture of two or more C2-C4 polyol esters exhibits a mean viscosity of from about 2 mPas to about 50 mPas as measured by capillary viscosimetry at a temperature of 20 ⁇ 0.1 °C; or from about 5 mPas to about 40 mPas; or from about 25 mPas to about 35 mPas.
  • the mixture of two or more C2-C4 polyol esters exhibits a mean viscosity of from about 2 mPas to about 50 mPas as measured by capillary viscosimetry at a temperature of 20 ⁇ 0.1 °C; or from about 5 mPas to about 40 mPas; or from about 25 mPas to about 35 mPas.
  • the C 2 -C 4 polyol ester is a medium chain triglyceride (MCT), or in other words a triester of glycerol; for instance, a triglyceride with saturated Os to C 12 fatty acids, or a triglyceride with saturated Cs to C 10 fatty acids; e.g. caprylic acid (Cs), capric acid (C 10 ) and lauric acid (C 12 ).
  • MCTs medium chain triglyceride
  • these MCTs exhibit a neutral odor and taste, as well as a favourable mean viscosity of from about 25 mPas to about 35 mPas as measured by capillary viscosimetry at a temperature of 20 ⁇ 0.1 °C.
  • MCTs Due to the very low amounts of water in MCTs (typically ⁇ 0.1 wt.-%), they also contain almost no microorganisms, and hence exhibit good microbial stability. Furthermore, most commercially available MCT-grades are free of additives such as catalyst residues or antioxidants. Examples of commercially available MCTs suitable for the present invention include Miglyol ® 812 or Miglyol ® 810, which are triglycerides comprising fractionated plant-derived Cs and C10 fatty acids, with Miglyol ® 810 having a higher Cio-content compared to Miglyol ® 812.
  • the C2-C4 polyol ester is a monoglyceride, or in other words a monoester of glycerol; for instance, a monoglyceride with saturated Cs to C12 fatty acids, or a monoglyceride with saturated Cs to C10 fatty acids; e.g. caprylic acid (Ce), capric acid (C10) and lauric acid (C12).
  • monoglycerides suitable for the present invention include Capmul ® MCM (glyceryl mo no cap rylo cap rate) and Capmul ® MCM C8 (glyceryl monocaprylate).
  • the C2-C4 polyol ester is a mono- and/or di-ester of propylene glycol or butylene glycol; for instance, a diester of propylene glycol or butylene glycol with saturated Cs to C10 fatty acids (e.g. caprylic acid (Ce) and capric acid (C10)), or a monoester of propylene glycol with saturated Cs to C12 fatty acids (e.g. caprylic acid (Ce), capric acid (C10) and lauric acid (C12)).
  • Examples of commercially available mono- and/or di-esters of propylene glycol or butylene glycol suitable for the present invention include Miglyol ® 840 (propylene glycol dicaprylate/dicaprate),
  • Miglyol ® 8810 butylene glycol dicaprylate/ dicaprate
  • Capmul ® PG-8 propylene glycol monocaprylate
  • Capmul ® PG-12 propylene glycol monolaurate
  • Miglyol ® grades 812, 810, 840 and/or 8810 are favoured over other commercially available Miglyol ® grades (such as Miglyol ® 818 or 829) for the present invention.
  • Miglyol ® 818 and Miglyol ® 829 comprise more than 2 wt.-% of long chain fatty acids with more than 12 carbon atoms and more than 2 wt.-% of short chain fatty acids with less than 6 carbon atoms, respectively; in particular,
  • Miglyol ® 818 comprises about 5 wt.-% of linoleic acid (Cis), and Miglyol ® 829 is combined with succinic acid (C4).
  • Cis linoleic acid
  • C4 succinic acid
  • the presence of unsaturated linoleic acid is less favoured in that it is particularly sensitive to oxidation, thus, requiring the addition of an antioxidant to the Miglyol ® 818 grade.
  • the addition of succinic acid is less favoured in that it increases the mean viscosity of the Miglyol ® 829 grade to about 230 mPas at 20 °C, and would thus likely render the liquid composition too viscous to flow.
  • the omega-3 fatty acid composition comprises at least about 90 wt.-% omega-3 fatty acid esters, based on the weight of the fatty acid composition. In a further embodiment, the omega-3 fatty acid composition comprises at least about 80 wt.-%, or at least about 90 wt.-%, esters of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), based on the weight of the fatty acid composition.
  • EPA eicosapentaenoic acid
  • DHA docosahexanoic acid
  • the omega-3 fatty acid composition comprises from about 40 wt.-% to about 60 wt.-% esters of eicosapentaenoic acid (EPA) and from about 25 wt.-% to about 50 wt.-% esters of docosahexanoic acid (DHA), based on the weight of the omega-3 fatty acid composition.
  • EPA eicosapentaenoic acid
  • DHA docosahexanoic acid
  • the omega-3 fatty acid composition comprises from about 43 wt.-% to about 50 wt.-% esters of eicosapentaenoic acid (EPA), and from about 34 wt.-% to about 41 wt.-% esters of docosahexanoic acid (DHA), based on the weight of the omega-3 fatty acid composition.
  • EPA eicosapentaenoic acid
  • DHA docosahexanoic acid
  • the esters of the omega-3 fatty acid composition are selected from alkyl esters, preferably from ethyl esters or methyl esters; for instance, eicosapentaenoic acid ethyl esters (EPA-EE) and/or docosahexanoic acid ethyl esters (DHA-EE).
  • alkyl esters preferably from ethyl esters or methyl esters; for instance, eicosapentaenoic acid ethyl esters (EPA-EE) and/or docosahexanoic acid ethyl esters (DHA-EE).
  • the omega-3 fatty acid composition comprises from about 43 wt.-% to about 50 wt.-% eicosapentaenoic acid ethyl ester (EPA-EE), and from about 34 wt.-% to about 41 wt.-% docosahexanoic acid ethyl ester (DHA-EE), based on the weight of the omega-3 fatty acid composition.
  • EPA-EE eicosapentaenoic acid ethyl ester
  • DHA-EE docosahexanoic acid ethyl ester
  • the weight ratio of the eicosapentaenoic acid ethyl ester (EPA-EE) and the docosahexanoic acid ethyl ester (DHA-EE) in the omega-3 fatty acid composition ranges between about 1 : 1 and about 1.5 : 1, or between about 1.1 : 1 and about 1.4 : 1, or between about 1.2 : 1 and about 1.3 : 1.
  • omega-3 fatty acid composition suitable for the present invention according the first aspect of the invention includes 'omega-3-acid ethyl esters 90’, also called K85EE (BASF/Pronova Biocare), which is also available in soft gelatin capsules (e.g. marketed under the tradename Omacor ® or LovazaTM).
  • K85EE 'omega-3-acid ethyl esters 90
  • This exemplary omega-3 fatty acid composition (K85EE) is suitable for all embodiments described herein, and its EPA-EE to DHA-EE weight ratio is 1.26 : 1.
  • the omega-3 fatty acid compositions according to the invention - and, in particular, compositions such as 'omega-3 -acid ethyl esters 90’ (K85EE) - are semi-synthetic products which are highly enriched with the desirable omega-3 fatty acids. While desirable in terms of e.g. reducing the volume of a single dose unit, this also renders these omega-3 fatty acid compositions more sensitive to oxidation and more 'chemical’ in taste and smell than natural fish-oils. It is, thus, far harder to prepare them in the form of liquid compositions for direct oral administration which are taken without further additions, or dilutions and get in direct contact with the tongue and its taste buds.
  • the weight ratio of the C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 5 : 1, or between about 1 : 1 and about 2 : 1, or between about 1.15 : 1 and about 1.85 : 1, or between about 1.3 : 1 and about 1.7 : 1.
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT), such as the above-mentioned Miglyol ® 810/812; and the weight ratio of the medium chain triglyceride (MCT) and the omega-3 fatty acid composition ranges between about 1 : 1 and about 5 : 1, or between about 1 : 1 and about 2 : 1, or between about 1.15 : 1 and about 1.85 : 1, or between aboutl.3 : 1 and about 1.7 : 1.
  • MCT medium chain triglyceride
  • Blending the C2-C4 polyol ester - and in particular, a medium chain triglyceride such as Miglyol ® 810 or 812 - and the omega-3 fatty acid composition in these ratios yields a liquid composition which offers excellent stability against oxidation, which is flowable enough to allow for easy and sufficient emptying, or discharging, of the liquid composition from its container into the mouth, or onto the tongue, of a consumer, or patient, and which provides a pleasant, favorable taste and mouthfeel (not too viscous, sticky or gooey).
  • the liquid composition exhibits a viscosity which allows to empty out at least 85 wt.-%, preferably at least 90 wt.-%, more preferably at least 93 wt.-% of the liquid composition from its primary packaging within about 5 to 10 seconds after i) briefly shaking the closed primary packaging manually (about 2 to 10 times); ii) removing the lid, or otherwise opening the primary packaging; iii) placing, or holding, it at a pouring angle of about 45° for about 10 seconds; and iv) lightly tapping the still upward-facing bottom end of the primary packaging with a fingertip after the about 10 seconds.
  • the liquid composition exhibits a viscosity such that after this simple test - which resembles the steps and provisions a user would typically undertake, or be instructed to undertake, in order to drink the liquid composition - less than 15 wt.-%, preferably less than 10 wt.-%, more preferably less than 7 wt.-% of the liquid composition remain in the primary packaging.
  • the primary packaging in this test may, for instance, a vial or bottle made from glass or polyethylene terephthalate (PET), optionally equipped with a crimp neck or with a threaded neck.
  • the liquid composition provides stable suspensions of any of the suspended particles comprised therein (e.g. the at least one flavor additive or parts thereof) when blending the C2-C4 polyol ester - and in particular, a medium chain triglyceride such as Miglyol ® 810 or 812 - and the omega-3 fatty acid composition in these ratios.
  • a medium chain triglyceride such as Miglyol ® 810 or 812 - and the omega-3 fatty acid composition in these ratios.
  • the poorly tasting and smelling omega-3 fatty acid composition with the more C2-C4 polyol ester - and, in particular, with a medium chain triglyceride such as Miglyol ® 810 or 812 - of neutral taste and smell also yields an initial reduction in the 'fishy’ smell and/or taste of the resulting blend, though, not enough to render it palatable enough for most human consumers, yet.
  • the liquid composition comprises at least about 40 wt.-% of the C2-C4 polyol ester based on the total weight of the liquid composition; or at least about 45 wt.-%; or at least about 48 wt.-%.
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT; such as the above-mentioned Miglyol ® 810/812), and the liquid composition comprises at least about 40 wt.-% of the medium chain triglyceride (MCT), based on the total weight of the liquid composition; or at least about 45 wt.-%; or at least about 48 wt.-%.
  • MCT medium chain triglyceride
  • the liquid composition comprises at least about 20 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition; or at least about 25 wt.-%; or at least about 28 wt.-%.
  • the omega-3 fatty acid composition is one which comprises from about 43 wt.-% to about 50 wt.-% eicosapentaenoic acid ethyl ester (EPA-EE), and from about 34 wt.-% to about 41 wt.-% docosahexanoic acid ethyl ester (DHA-EE), based on the weight of the omega-3 fatty acid composition (such as the above-mentioned 'omega-3-acid ethyl esters 90’; K85EE), and the liquid composition comprises at least about 20 wt.-% of said omega-3 fatty acid composition based on the total weight of the liquid composition; or at least about 25 wt.-%; or
  • the liquid composition comprises at least about 40 wt.-% of the C2-C4 polyol ester and at least about 20 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition; or at least about 48 wt.-% of the C2-C4 polyol ester and at least about 28 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition.
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT; such as the above-mentioned Miglyol ® 810/812), and the liquid composition comprises at least about 40 wt.-% of the medium chain triglyceride (MCT) and at least about 20 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition; or at least about 48 wt.-% of the medium chain triglyceride (MCT) and at least about 28 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition.
  • MCT medium chain triglyceride
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT; such as the above-mentioned Miglyol ® 810/812) and the omega-3 fatty acid composition is one which comprises from about 43 wt.-% to about 50 wt.-% eicosapentaenoic acid ethyl ester (EPA-EE), and from about 34 wt.-% to about 41 wt.-% docosahexanoic acid ethyl ester (DHA-EE), based on the weight of the omega-3 fatty acid composition (such as the above-mentioned 'omega-3 -acid ethyl esters 90’; K85EE); and the liquid composition comprises at least about 40 wt.-% of the medium chain triglyceride (MCT) and at least about 20 wt.-% of said omega-3 fatty acid composition based on the total weight of the liquid composition;
  • MCT medium chain
  • the thickening agent comprised in the liqid composition according to the first aspect of the invention is capable of forming an oleo-gel, preferably a thixotropic oleo-gel, with at least the C2-C4 polyol ester.
  • the thickening agent is capable of forming an oleo-gel, preferably a thixotropic oleo-gel, with a mixture of the C2-C4 polyol ester and the omega-3 fatty acid composition.
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT; such as such as the above-mentioned Miglyol ® 810/812), and the thickening agent is capable of forming an oleo-gel, preferably a thixotropic oleo-gel, with at least the medium chain triglyceride (MCT).
  • MCT medium chain triglyceride
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT; such as such as the above-mentioned Miglyol ® 810/812), and the thickening agent is capable of forming an oleo-gel, preferably a thixotropic oleo-gel, with a mixture of the medium chain triglyceride (MCT) and the omega-3 fatty acid composition.
  • MCT medium chain triglyceride
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT; such as the above-mentioned Miglyol ® 810/812) and the omega-3 fatty acid composition is one which comprises from about 43 wt.-% to about 50 wt.-% eicosapentaenoic acid ethyl ester (EPA-EE), and from about 34 wt.-% to about 41 wt.-% docosahexanoic acid ethyl ester (DHA-EE), based on the weight of the omega-3 fatty acid composition (such as the above-mentioned 'omega-3 -acid ethyl esters 90’; K85EE); and the thickening agent is capable of forming an oleo-gel, preferably a thixotropic oleo-gel, with the mixture of the medium chain triglyceride (MCT) and said omega-3 fatty
  • MCT medium chain
  • the thickening agent comprised in the liqid composition is an anorganic oleo-gel forming component.
  • the thickening agent is an anorganic oleo-gel forming component selected from the group consisting of fumed silica, precipitated silica, aluminum silicates, bentonite, and mixtures thereof.
  • the thickening agent is fumed silica or precipitated silica.
  • the thickening agent is a hydrophilic fumed silica exhibiting a specific surface area in the range of 50 - 500 m 2 /g, or in the range of 200 - 300 m 2 /g; or a hydrophobic fumed silica treated with dimethyldichlorosilane (DDS).
  • DDS dimethyldichlorosilane
  • examples of commercially available fumed silica grades suitable for the present invention include Aerosil ® 200, Aerosil ® 300, Aerosil ® 380, and Aerosil ® R972.
  • the liqid composition comprises from about 0.1 wt.-% to about 5.0 wt.-% of the thickening agent, based on the total weight of the liquid composition; or from about 0.4 wt.-% to about 4.0 wt.-%; or from about 0.7 wt.-% to about 4.0 wt.-%; or from about 0.9 wt.-% to about 3.5 wt.-%; or from about 0.9 wt.-% to about 3.0 wt.-%; for instance, about 0.9 wt.-% or about 1.8 wt.-% or about 2.7 wt.-%.
  • the liqid composition comprises from about 1.5 wt.-% to about 3.5 wt.-% of a hydrophilic fumed silica exhibiting a specific surface area in the range of 50 - 500 m 2 /g, or in the range of 200 - 300 m 2 /g; or of a hydrophobic fumed silica treated with dimethyldichlorosilane (DDS) based on the total weight of the liquid composition.
  • DDS dimethyldichlorosilane
  • the liqid composition comprises from about 1.5 wt.-% to about 3.5 wt.-% of a hydrophilic fumed silica exhibiting a specific surface area in the range of 200 - 300 m 2 /g, based on the total weight of the liquid composition.
  • Anorganic oleo-gel forming components such as fumed or precipitated silicas, aluminum silicates or bentonite - in particular in the above-mentioned amounts - were found to be most suitable for the present invention, yielding an optimized increase in viscosity and thixotropic gel-formation in the liquid composition which comprises not more than 5 wt.-% of water; - in particular, when employing anorganic oleo gel forming components in the above-mentioned amounts, and/or when blending the C2-C4 polyol ester (e.g. Miglyol ® 810 or 812 ) and the omega-3 fatty acid composition in the above- mentioned ratios.
  • the C2-C4 polyol ester e.g. Miglyol ® 810 or 812
  • the liquid composition exhibits a viscosity which allows to empty out at least 85 wt.-%, preferably at least 90 wt.-%, more preferably at least 93 wt.-% of the liquid composition from its primary packaging within about 5 to 10 seconds after i) briefly shaking the close primary packaging manually (about 2 to 10 times); ii) removing the lid, or otherwise opening the primary packaging; iii) placing, or holding, it at a pouring angle of about 45° for about 10 seconds; and iv) lightly tapping the still upward-facing bottom end of the primary packaging with a fingertip after the about 10 seconds.
  • the liquid composition exhibits a viscosity such that after this simple test - which resembles the steps and provisions a user would typically undertake, or be instructed to undertake, in order to drink the liquid composition - less than 15 wt.-%, preferably less than 10 wt.-%, more preferably less than 7 wt.-% of the liquid composition remain in the primary packaging.
  • the primary packaging in this test may, for instance, a vial or bottle made from glass or polyethylene terephthalate (PET), optionally equipped with a crimp neck or with a threaded neck.
  • the thixotropic properties are in particular useful in that they allow for a shear-thinning (i.e. a reduced viscosity) of the liquid composition during manufacturing steps, primary packaging processes and/or during application by the consumer, while at the same time stabilizing any suspended particles comprised therein, such as the at least on flavor additive, or parts thereof, during storage.
  • a shear-thinning i.e. a reduced viscosity
  • any suspended particles comprised therein such as the at least on flavor additive, or parts thereof, during storage.
  • an optimum balance is obtained for the flow properties of the liquid composition, which facilitates mixing and filling steps during manufacture, as well as easy emptying from the container during consumption, while at the same time keeping the composition viscous enough to prevent undesirable spilling during minor mishaps upon opening the container (e.g.
  • any suspended particles comprised in the liquid composition were found to either not sediment at all, or to be quickly redispersible by simply shaking the bottle or vial in which the liquid composition is provided manually a few times prior to open the lid.
  • the latter gel-forming polymers are too hydrophilic to get sufficiently solubilized in the lipophilic liquid composition of the first aspect of the invention with not more than 5 wt.-% of water; and thus would not be capable to estabish a gel network in the lipophilic composition and/or would require long, inefficient incorporation times for sufficient solublisation and swelling of the more hydrophilic gel forming components; thereby increasing processing times.
  • the liqid composition is substantially free of organic gel forming components.
  • the liquid composition comprises at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma.
  • flavor additive is used broadly and encompasses both taste- and/or smell optimizing additives; in other words, the liquid composition comprises at least one taste- and/or smell optimizing additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma.
  • the addition of one or more flavor additives is deemed necessary to provide an acceptable, preferably even a good, taste and/or smell to the liquid composition.
  • the expression 'flavor additive refers to the entirety of the selected additives, especially where referring to their content in the liquid composition.
  • any contents provided refer to the total of all flavor additives.
  • the liquid composition comprises at least about 10 wt.-% of the flavor additive based on the total weight of the liquid composition; or at least about 15 wt.-%; or at least about 16 wt.-%; or at least about 17 wt.-%. In a specific embodiment, the liquid composition comprises about 17 wt.-%, or about 18 wt.-%, of the flavor additive based on the total weight of the liquid composition. In one embodiment, at least parts of the flavor additive is present in solid, particulate form and suspended in the liquid composition according to the first aspect of the invention.
  • the expression 'at least parts of refers both to quantitative fractions of a single component that may be present in solid, particulate form, and to the qualitative components (e.g. a sugar comprised in the flavor additive being suspended while the aroma component gets solubilized in the liquid composition).
  • flavor additives are deemed necessary in order to provide an acceptable, preferably even a good, palatable taste and/or smell to the liquid composition; and especially additives for improved taste typically need to be water-soluble in order to dissolve in the mouth and/or on the tongue and, thus, allow for proper taste perception.
  • the liquid composition according to the first aspect of the invention comprises not more than 5 wt.-% of water, preferably less, most of these water-soluble flavor additives are considered poorly soluble in the liquid composition (i.e. sparingly soluble or even less soluble), and are thus, at least in parts, present in solid, particulate form. This renders the liquid composition according to the first aspect of the invention a suspension.
  • At least about 50 wt.-% of the flavor additive is present in solid, particulate form and suspended in the liquid composition; or at least about 60 wt.-%; or at least about 70 wt.-%; or at least about 80 wt.-%.
  • the suspended parts of the at least on flavor additive are either held in suspended state within the "resting” gel structure; or - depending on their particle size and particle density - they may sediment to the bottom of the container. In the latter case, and due to the thixotropic gel structure formed throughout the liquid composition, they can easily be re-dispersed by agitation of the container (e.g. shaking of a vial, or squeezing of a foil-lined sachet, or stickpack) right before consumption, leading to a temporary shear-thinning of the liquid composition.
  • agitation of the container e.g. shaking of a vial, or squeezing of a foil-lined sachet, or stickpack
  • the flavor additive comprised in the liquid composition according to the first aspect of the invention comprises a sugar or sugar alcohol.
  • the flavor additive comprises a sugar or sugar alcohol selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof.
  • the flavor additive comprises sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof; preferably xylitol.
  • xylitol, sorbitol and isolmaltitol are particularly suited because they do not only provide a sweet taste to the liquid composition but also offer a cooling effect which is perceived as fresh and more pleasant in taste, and thus is advantageous for addition to the omega-3 fatty acid composition, or the liquid composition comprising it, because it counteracts the somewhat 'fishy’, or 'chemical’, taste notes of the omega-3 fatty acid composition.
  • the flavor additive comprises xylitol.
  • the flavor additive comprises a sweetener.
  • the flavor additive comprises a sweetener selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof.
  • the flavor additive comprises aspartame.
  • the flavor additive comprises an aroma; for instance, natural, semi synthetic and synthetic aromas, such as cherry, orange, citrus, mandarin, lime, strawberry, tropic, or mint aroma etc.
  • Aroma is mostly added to provide a specific taste and/or smell to the liquid composition beyond the mere 'sweet’/’sour’ achieved by the addition of sugars, sugar alcohols, sweeteners and acidifiers; typically, a smell and/or taste of a component which is not actually present in the liquid composition.
  • the aroma may be one with a taste and/or smell resembling cherries (i.e. a cherry aroma) without actual cherry pulp or cherry juice being present in the liquid composition.
  • the aroma may be used alone or in combination; e.g. as a combination of cherry and spearmint aroma, orange and mandarin, or a combination of cherry aroma, peppermint menthol and limonen (preferably (R)-(+)-limonen for its citrusy taste and flavor.
  • the flavor additive comprises an aroma that is volatile; e.g. a liquid peppermint aroma comprising menthol, a liquid orange aroma, or the like.
  • volatile aroma predominantly refers to liquid aroma because liquid aroma typically contain a higher fraction of volatile compounds than solid aroma (the latter often employed more for their taste than their smell). Therefore liquid aroma are more easily perceptible by the nose of a consumer, e.g. upon opening a vial filled with the liquid composition according to the first aspect.
  • volatile aromas and more specifically liquid, volatile aromas, is advantageous for the present invention, in particular for containers which comprise the liquid composition and a gas-filled headspace (e.g. air, or inert gases such as nitrogen or argon).
  • the volatile aroma diffuses into the headspace with the highly beneficial effect that the liquid composition according to the first aspect of the invention does not smell poorly, e.g.
  • the volatile aroma continues to diffuse into the gas-filled headspace withing the consumer’s mouth, so that any air moved towards the nasal cavities by breathing does not smell 'fishy’, or otherwise disagreebale, while the consumer has the liquid compositions, or residues thereof, in the mouth and on the tongue.
  • some of the volatile aroma such as the above mentioned peppermint menthol even have a beneficial cooling effect of their own, and may thus intensify, or as the case may be replace, the cooling effect of flavor additives such as xylitol.
  • Liquid compositions according to the first aspect of the invention comprising a volatile aroma were found to siginificantly improve taste and smell, and in consequence consumer acceptance.
  • the volatile aroma as such is believed to function much alike an inert gas in the gas-filled headspace of e.g. vials or bottles filled with the liquid composition; thereby acting as yet a further means to prevent, or at least limit, oxidation.
  • this preference of volatile flavor additives in particular has not been reported before for pharmaceutical or nutraceutical liquid compositions of omega-3 fatty acids, let alone discussed as a means to provide a composition of omega-3 fatty acids that allows for direct oral administration as defined herein.
  • the flavor additive in the liquid composition comprises an acidifier.
  • the flavor additive comprises an acidifier selected from the group of organic acids, the respective salts thereof, and mixtures thereof.
  • the flavor additive comprises an acidifier in the form of an organic acid selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof.
  • the flavor additive comprises citric acid and/or salts thereof.
  • the flavor additive comprises monosodium citrate.
  • the flavor additive comprises a mixture of citric acid and monosodium citrate, a mixture which is believed to achieve an appropriate acidity both quickly (by the citric acid) and maintaining it for some periode of time (by the more slowly dissolving monosodium salt).
  • this favorable effect of selecting both slow and fast dissolving acidifiers has not been reported before for pharmaceutical or nutraceutical liquid compositions of omega-3 fatty acids, let alone discussed as a means to provide a composition of omega-3 fatty acids that allows for direct oral administration as defined herein.
  • the flavor additive in the liquid composition comprises a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, and aspartame; preferably xylitol and aspartame.
  • the flavor additive in the liquid composition comprises a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, and citric acid and/or salts thereof; preferably xylitol and citric acid and/or salts thereof.
  • the flavor additive in the liquid composition comprises a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, and aspartame, and citric acid and/or salts thereof; preferably xylitol, aspartame, and citric acid and/or salts thereof, and optionally at a content of at least about 15 wt.-% (e.g. 17 wt.-%, or about 18 wt.-%) of the flavor additive based on the total weight of the liquid composition.
  • This combination has been described as one of the most pleasantly and least 'fishy’ tasting ones amongst those tested by the panelists.
  • the flavor additive in the liquid composition comprises a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, and aspartame, citric acid and/or salts thereof, and a volatile aroma; preferably xylitol, aspartame, citric acid and/or salts thereof, and a volatile aroma, and optionally at a content of at least about 15 wt.-% (e.g. 17 wt.-%, or about 18 wt.-%) of the flavor additive based on the total weight of the liquid composition.
  • the liquid composition according to the first aspect of the invention further comprises at least one antioxidant; for instance, an antioxidant selected from lecithin, ascorbic acid or derivatives thereof (e.g. fatty acid esters of ascorbic acid, or sodium erythorbate), tocopherol or derivatives thereof, tertiary butylhydroquinone (TBHQ), carotenoid derivatives, hydroxytoluene, propyl gallate, glycine, rosmarinic acid, or mixtures thereof.
  • the liquid composition according to the first aspect of the invention comprises at least two antioxidants; for instance, two antioxidants selected from the exemplified group.
  • the at least one antioxidant in the liquid composition is provided in the form of an antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid.
  • the fatty acid ester of ascorbic acid in said antioxidant complex is selected from ascorbylstearate, ascorbylpalmitate, or mixtures thereof.
  • the weight ratio of lecithin and ascorbylpalmitate in the antioxidant complex ranges between about 3 : 1 and about 1 : 1, or between about 2.8 : 1 and about 1.2 : 1, or between about 2.7 : 1 and about 1.3 : 1.
  • soy lecithin such as Lipoid ® P45 or P20
  • sunflower lecithin such as Lipoid ® H20
  • lecithin to the antioxidant complex comprising a fatty acid ester of ascorbic acid, e.g. ascorbyl palmitate, was found to be advantageous to sufficiently disperse the oily, viscous fatty acid ester within the liquid composition and thus ensure most efficient stabilization with low amounts of the antioxidant complex.
  • the lecithin serves as a 'wetting agent’ of the solid, suspended components of the flavor additive, or parts thereof.
  • the addition of lecithin to the liquid composition according to the first aspect of the invention does not serve the purpose of rendering the whole liquid composition as such water-dispersible, or enabling its homogeneous emulsification into water or other aquoues media, such as the gastric fluid upon oral administration.
  • the liquid composition when attempting to disperse the liquid composition described herein into water at room temperature, and stirring briefly with a spoon (as a consumer may inadvertently do, for instance, when not realizing that the liquid composition is intended for direct oral administration; i.e. without addition of water, or other comestibles), the liquid composition does not form an emulsion, or micro-emulsion, but instead separates into at least two different phases visible to the naked eye, either floating on the water surface, sedimenting to the beaker bottom, and/or forming large oil-droplets, or 'oil puddles’, depending on intensely the system is stirred.
  • the inventors believe that the oils (omega-3 and e.g. MCT) partially sediment due their thickened texture in which the heavier flavor additive particles, such as xylitol, get enclosed and thus cause a fraction of the oils to get 'weighed down’ in water.
  • This 'non-emulsifiying’ effect of the liquid composition according to the first aspect of the invention is intentional in so far as said liquid composition predominantly represents a delivery means which is an alternative to e.g. soft capsules filled with an omega-3 fatty acid composition, that allows for palatable, direct oral administration while not aiming to change the overall bioavailability of the omega-3 fatty acid composition.
  • the liquid composition according to the first aspect of the invention clearly differs from various prior art compositions in the form of so-called pre-concentrates or self-(micro)emulsifying delivery systems which often exhibit a considerable amount of surfactants and optionally co -surfactants; typically at least about 5 wt.-% or more (and e.g. up to 35 wt.-% or even 50 wt.-%) of (co) surfactants based on the total weight of the pre-concentrate composition.
  • the liquid composition according to the first aspect of the invention contains far less emulsifiers, or surface-active substances, such as the lecithin which may form part of the antioxidant complex.
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-% lecithin, or up to about 0.8 wt.-% lecithin, or up to about 0.5 wt.-% lecithin.
  • the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% lecithin based on the total weight of the liquid composition, from about 0.05 wt.-% to about 0.80 wt.-%, or from about 0.10 wt.-% to about 0.50 wt.-%; for instance, about 0.32 wt.-% lecithin, or about 0.20 wt.-% lecithin.
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-% ascorbylpalmitate, or up to about 0.6 wt.-% ascorbylpalmitate, or up to about 0.3 wt.-% ascorbylpalmitate.
  • the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% ascorbylpalmitate based on the total weight of the liquid composition, from about 0.03 wt.-% to about 0.60 wt.-%, from about 0.06 wt.-% to about 0.30 wt.-%; for instance, about 0.24 wt.-% ascorbylpalmitate, or about 0.08 wt.-% ascorbylpalmitate.
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-% lecithin and up to about 1 wt.-% ascorbylpalmitate, based on the total weight of the liquid composition; or up to about 0.80 wt.-% lecithin and up to about 0.60 wt.-% ascorbylpalmitate; or up to about 0.50 wt.-% lecithin and up to about 0.30 wt.-% ascorbylpalmitate.
  • the liquid composition according to the first aspect of the invention comprises from about 0.01 wt.-% to about 1 wt.-% lecithin and from about 0.01 wt.-% to about 1 wt.-% ascorbylpalmitate, based on the total weight of the liquid composition; or from about 0.05 wt.-% to about 0.80 wt.-% lecithin and from about 0.03 wt.-% to about 0.60 wt.-% ascorbylpalmitate; or from about 0.10 wt.-% to about 0.50 wt.-% lecithin and from about 0.06 wt.-% to about 0.30 wt.-% ascorbylpalmitate.
  • the liquid composition according to the first aspect of the invention comprises about 0.32 wt.-% lecithin and about 0.24 wt.-% ascorbylpalmitate, based on the total weight of the liquid composition. In a specific embodiment, this equals about 0.40 wt.-% lecithin and about 0.30 wt.-% ascorbylpalmitate, based on the weight of the flavor additive-free liquid composition (i.e. without the flavor additive(s)).
  • the liquid composition comprises about 0.20 wt.-% lecithin and about 0.08 wt.-% ascorbylpalmitate, based on the total weight of the liquid composition. In a specific embodiment, this equals about0.25 wt.-% lecithin and about 0.10 wt.-% ascorbylpalmitate, based on the weight of the flavor additive-free liquid composition (i.e. without the flavor additive(s)).
  • the antioxidant complex in the liquid composition according to the first aspect of the invention further comprises a tocopherol selected from alpha tocopherol, beta tocopherol, gamma tocopherol, or delta tocopherol.
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-% tocopherol, or up to about 0.3 wt.-% tocopherol, or up to about 0.2 wt.-% tocopherol.
  • the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% tocopherol based on the total weight of the liquid composition, from about 0.01 wt.-% to about 0.30 wt.-%, from about 0.08 wt.-% to about 0.20 wt.-%; for instance, about 0.12 wt.-% tocopherol, or about 0.13 wt.-% tocopherol.
  • the tocopherol is comprised in, or an integral part of, the omega-3 fatty acid composition under item (b) of the liquid composition according to the first aspect of the invention; for instance, a commercially available omega-3 fatty acid composition.
  • the tocopherol is then added to the liquid composition upon addition of said tocopherol-containing omega-3 fatty acid composition, rather than being a separately added antioxidant.
  • a commercially available omega-3 fatty acid composition comprising such an inherent tocopherol addition, which is suitable for the present invention, includes 'omega-3-acid ethyl esters 90’, also called K85EE (BASF/Pronova Biocare).
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-% lecithin, up to about 1 wt.-% ascorbylpalmitate, and up to about 1 wt.-% tocopherol, based on the total weight of the liquid composition; or up to about 0.80 wt.-% lecithin, up to about 0.60 wt.-% ascorbylpalmitate, and up to to about 0.30 wt.-% tocopherol; or up to about 0.50 wt.-% lecithin, up to about 0.30 wt.-% ascorbylpalmitate and up to about 0.20 wt.-% tocopherol.
  • the liquid composition according to the first aspect of the invention comprises from about 0.01 wt.-% to about 1 wt.-% lecithin, from about 0.01 wt.-% to about 1 wt.-% ascorbylpalmitate and from about 0.01 wt.-% to about 1 wt.-% tocopherol, based on the total weight of the liquid composition; or from about 0.05 wt.-% to about 0.80 wt.-% lecithin, from about 0.03 wt.-% to about 0.60 wt.-% ascorbylpalmitate and from about 0.01 wt.-% to about 0.30 wt.-% tocopherol; or from about 0.10 wt.-% to about 0.50 wt.-% lecithin, from about 0.06 wt.-% to about 0.30 wt.-% ascorbylpalmitate and from about 0.08 wt.-% to about 0.20 w
  • the liquid composition according to the first aspect of the invention comprises about 0.32 wt.-% lecithin, about 0.24 wt.-% ascorbylpalmitate and about 0.12 wt.-% tocopherol, based on the total weight of the liquid composition.
  • the liquid composition according to the first aspect of the invention comprises about 0.20 wt.-% lecithin, about 0.08 wt.-% ascorbylpalmitate, and about 0.12 wt.-% tocopherol, based on the total weight of the liquid composition.
  • soft capsules filled with an omega-3 fatty acid composition as described herein (more specifically, the task of providing an alternative delivery means that allows for palatable, direct oral administration as defined herein, while not aiming to change the overall bioavailability of said omega-3 fatty acid composition) can only be solved in the presence of antioxidants, or only in the presence of the specifically combination(s) of lecithin, ascorbylpalmitate and/or tocopherol.
  • the adjustment of consistency, taste and/or smell of the omega-3 fatty acid composition, or the liquid composition comprising it, so as to render it palatable and pleasant for consumers or patients, is mainly the result of the careful selection of the thickening agent(s), the flavor additive(s), and of the carriers such as the C2-C4 polyol ester(s), as well as their respective amounts and ratios to eachother and to the omega-3 fatty acid composition.
  • Antioxidants, or the antioxidant complex mainly help to maintain this taste/smell adjusting effect upon storage, so that excipients such as said thickening agent(s), flavor additive(s), and carriers can be employed in the smallest amounts required, and thereby keeping the volume of a single-dose unit to a minimum.
  • the liquid composition according to the first aspect of the invention further comprises a gel stabilizer selected from the group of polyhydroxylated compounds, said polyhydroxylated compounds serving as hydrogen bond donors.
  • the gel stabilizer comprises a polyhydroxylated compound selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof.
  • the gel stabilizer comprises the gel stabilizer comprises a polysorbate.
  • the gel stabilizer is polysorbate 80.
  • gel stabilizer Some of these substances, used herein as gel stabilizer, are also known or used as emulsifiers or surfactants in other applications.
  • these gel stabilizers e.g. polysorbates
  • the liquid composition according to the first aspect of the invention contains far less emulsifiers, or surface-active substances (e.g. lecithin, and optional gel stabilizers such as polysorbates) than commonly used in prior art pre-concentrates, and in particular self- (micro) emulsifying pre-concentrates.
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-%, or up to about 0.3 wt.-%, of the gel stabilizer, e.g. polysorbate 80, based on the total weight of the liquid composition.
  • the gel stabilizer e.g. polysorbate 80
  • the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% of the gel stabilizer, or from about 0.05 wt.-% to about 0.3 wt.-% of the gel stabilizer, based on the total weight of the liquid composition. In a specific embodiment, the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% polysorbate 80, or from about 0.05 wt.-% to about 0.3 wt.-% polysorbate 80, based on the total weight of the liquid composition.
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-%, or up to about 0.3 wt.-%, of the gel stabilizer, e.g. polysorbate 80, based on the weight of the mixture of the C2-C4 polyol ester and the omega-3 fatty acid composition (e.g. a mixture of an MCT such as Miglyol ® 812 and K85EE).
  • the gel stabilizer e.g. polysorbate 80
  • the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% of the gel stabilizer, or from about 0.05 wt.-% to about 0.3 wt.-% of the gel stabilizer, based on the weight of the mixture of the C2-C4 polyol ester and the omega-3 fatty acid composition (e.g. a mixture of an MCT such as Miglyol ® 812 and K85EE).
  • the omega-3 fatty acid composition e.g. a mixture of an MCT such as Miglyol ® 812 and K85EE.
  • the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% polysorbate 80, or from about 0.05 wt.-% to about 0.3 wt.-% polysorbate 80 based on the weight of the mixture of the C2-C4 polyol ester and the omega-3 fatty acid composition.
  • the liquid composition according to the first aspect of the invention comprises multiple surface-active substances, such as the gel stabilizer in combination with the lecithin of the antioxidant complex, their total amount shall not exceed 3.0 wt.-% based on the total weight of the liquid composition.
  • the content of surface-active substances is not more than 2.0 wt.-%, or not more than 1.5 wt.-%, or not more than 1.0 wt.-%, or not more than 0.5 wt.-%; e.g. about 0.3 wt.-%, or about 0.4 wt.-%.
  • the liquid composition according to the first aspect of the invention comprises up to about 1 wt.-% of the gel stabilizer (e.g. polysorbate 80), and up to about 1 wt.-% lecithin, based on the total weight of the liquid composition.
  • the liquid composition comprises up to about 0.3 wt.-% of the gel stabilizer (e.g. polysorbate 80), and up to about 0.8 wt.-%, lecithin based, on the total weight of the liquid composition.
  • the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% of the gel stabilizer (e.g.
  • the liquid composition comprises from about 0.05 wt.-% to about 0.3 wt.-% of the gel stabilizer (e.g. polysorbate 80), and from about 0.05 wt.-% to about 0.80 wt.-% lecithin, based on the total weight of the liquid composition.
  • the liquid composition comprises about 0.08 wt.-% of the gel stabilizer (e.g.
  • polysorbate 80 and about 0.32 wt.-% lecithin, based on the total weight of the liquid composition; or about 0.08 wt.-% of the gel stabilizer (e.g. polysorbate 80), and about 0.20 wt.-% lecithin, based on the total weight of the liquid composition.
  • the liquid composition according to the first aspect of the invention comprises:
  • MCT medium chain triglyceride
  • omega-3 fatty acid composition (b) an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • a flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, and
  • liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the liquid composition according to the first aspect of the invention based on its total weight, comprises:
  • omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, and
  • liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to the first aspect of the invention based on its total weight, comprises:
  • omega-3 fatty acid composition comprises at least about 90 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • flavor additives comprising a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, aspartame, citric acid, and aroma; preferably xylitol, aspartame, citric acid, and aroma, and
  • liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to the first aspect of the invention essentially consists of:
  • MCT medium chain triglyceride
  • omega-3 fatty acid composition (b) an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • a flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, and
  • a gel stabilizer selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to the first aspect of the invention based on its total weight, essentially consists of:
  • omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to the first aspect of the invention based on its total weight, essentially consists of:
  • omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, and (e) from about 0.01 wt.-% to about 1.0 wt.-% a gel stabilizer selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to the first aspect of the invention based on its total weight, essentially consists of:
  • omega-3 fatty acid composition comprises at least about 90 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • flavor additives comprising a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, aspartame, citric acid, and aroma; preferably xylitol, aspartame, citric acid, and aroma; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to the first aspect of the invention based on its total weight, essentially consists of:
  • omega-3 fatty acid composition comprises at least about 90 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • flavor additives comprising a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, and aspartame, citric acid, and aroma; preferably xylitol, aspartame, citric acid, and aroma, and
  • the liquid composition according to the first aspect of the invention comprises not more than 4 wt.-% of water as detetermined by Karl Fischer titration; or not more than 3 wt.-%; or not more than 2 wt.-%; not more than 1 wt.-% of water.
  • the liquid composition is substantially free of water; i.e. no water deliberately included while not excluding the presence of potential residual moisture.
  • the liquid composition according to the first aspect of the invention is a suspension.
  • it is mainly the at least on flavor additive, or a part thereof, that is present in solid, particulate form and suspended in the liquid composition.
  • the liquid composition according to the first aspect of the invention is a pharmaceutical, nutraceutical and/or dietary composition.
  • a single dose unit comprises from about 4 g to about 32 g; or from about 8 g to about 24 g; or from about 10 g to about 20 g; or about 16 g, or about 13.6 g, or about 13.2 g of the liquid composition according to the first aspect of the invention; for instance a liquid composition as detailed in the Examples as H01, H02, J01, J02, KOI or K02.
  • a single dose unit essentially consists of from about 4 g to about 32 g; or from about 8 g to about 24 g; or from about 10 g to about 20 g; or about 16 g, or about 13.6 g, or about 13.2 g of said liquid composition; for instance a liquid composition as detailed in the Examples as H01, H02, J01, J02, KOI or K02.
  • a single dose unit of, for instance, from about 10 g to about 20 g of the liquid composition comprises from about 3240 mg to about 5400 mg; e.g. about 4320 mg, or about 3680 mg, or about 3560 mg omega-3 fatty acids in total.
  • these total omega-3 fatty acids preferably from about 2560 mg to about 4320 mg are eicosapentaenoic acid ethyl esters (EPA-EE) and/or docosahexanoic acid ethyl esters (DHA-EE); e.g. about 3440 mg, or about 2960 mg or about 2840 mg.
  • EPA-EE eicosapentaenoic acid ethyl esters
  • DHA-EE docosahexanoic acid ethyl esters
  • omega-3 fatty acids More preferably about 2920 mg to about 4840 mg of these total omega-3 fatty acids are eicosapentaenoic acid ethyl esters (EPA-EE) and/or docosahexanoic acid ethyl esters (DHA-EE); e.g. about 3880 mg, or about 3320 mg, or about 3200 mg.
  • EPA-EE eicosapentaenoic acid ethyl esters
  • DHA-EE docosahexanoic acid ethyl esters
  • An examplary single dose unit of from about 13 g to about 14 g of the liquid composition typically has a volume of about 15 mL and thus fits in a regular screw-cap or snap-fit cap vial with a volume of about 17 to 20 mL, preferably a vial made of glass or PET. Such volumes are both easily ingested in one gulp, and easy to transport, if needed.
  • the daily dose of the liquid composition according to the first aspect of the invention for adults comprises, or is administered as, 1 to 4, preferably 1 to 3, further preferably 1 to 2, and most further preferably 1 single dose unit(s) as described above per day.
  • a single dose unit of the liquid composition according to the first aspect of the invention is provided in bottles, vials, sachets or stickpacks.
  • the packages may be formed from any suitable material; for instance, glass, plastic (e.g. polyethylene terephthalate (PET)), or composite materials such as multi-layered packaging foils.
  • PET polyethylene terephthalate
  • the weight ratio of the medium chain triglyceride (MCT) and the omega-3 fatty acid composition is chosen such as to range between about 1 : 1 and about 5 : 1, and/or such that the liquid composition exhibits thixotrop viscosity characteristics, and a viscosity which allows to empty out at least 85 wt.-%, preferably at least 90 wt.-%, more preferably at least 93 wt.-% of the liquid composition from its primary packaging (e.g.
  • the liquid composition offers both excellent stability against oxidation and compositions which are flowable enough to allow for easy emptying, or discharging, of the liquid composition from its container into the mouth, or onto the tongue, of a subject.
  • Compositions provided in side-sealed bags can typically be formulated a bit 'thicker’, i.e. more viscous, since the sachet or stickpack can be squeezed empty with the help of the fingers.
  • This thicker consistency is beneficial in terms of preventing the at least one flavor additive from sedimentation and 'caking’ during storage.
  • a slightly thicker consistency of the liquid composition provided in sachets or stickpacks helps to prevent, or at least reduce, spilling over the fingers, especially when squeezing closer to the opening of the sachet or stickpack.
  • liquid composition for direct oral administration i.e. intended to be administrable directly from a container and easily swallowed without the need for added fluids
  • spilled composition often causes the finger to smell disagreeably 'fishy’, which in turn would require consumers to find water or other means to clean their hands, and thus at least partially defeat the purpose of these types of liquid compositions.
  • a single dose unit of the liquid composition according to the first aspect of the invention is provided in bottles or vials; for instance, glass bottles, glass vials, or polyethylene terephthalate (PET) bottles.
  • the bottles or vials are overlayered, or flushed, with an inert gas (e.g. nitrogen or argon), closed and hermetically sealed with a cap; optionally with a screw-cap, hinged cap, snap- fit cap, crown cap or a plug made from suited materials such as plastic, metal or rubber.
  • an inert gas e.g. nitrogen or argon
  • the omega-3 fatty acids are considered the active principle to be administered, or the active pharmaceutical/nutraceutical ingredient of the composition.
  • the omega-3 fatty acid composition is not used in the liquid composition according to the first aspect as merely an excipient, or vehicle, for another active principle.
  • the omega-3 fatty acid composition is not added to improve the solubility and/or bioavailability of another active principle, such as active principles of natural, semisynthetic or synthetic origin with lipid regulating properties.
  • the liquid composition for direct oral administration is free of a synthetic drug substance; for instance, free of other antihyperlipidimic (i.e.
  • lipid-lowering drug substances like 'statins’ such as pravastatin, or other HMG-CoA reductase inhibitors (i.e. inhibitors of the cholesterol synthesizing enzyme CSE); cholesterol absorption inhibitors like ezetimibe; 'fibrates’ such as fenofibrate or gemfibrozil; nicotinic acid and its derivatives; ion exchange resins such as colestyramine.
  • 'statins such as pravastatin, or other HMG-CoA reductase inhibitors (i.e. inhibitors of the cholesterol synthesizing enzyme CSE); cholesterol absorption inhibitors like ezetimibe; 'fibrates’ such as fenofibrate or gemfibrozil; nicotinic acid and its derivatives; ion exchange resins such as colestyramine.
  • 'statins such as pravastatin, or other HMG-CoA reductase inhibitors (i.e.
  • the liquid composition for direct oral administration is free of plant extracts which are known to, or at least reported to, exhibit antihyperlipidemic properties; for instance, plant extracts such as amla, moringa, green tea, coffee, cinnamon, garlic, turmeric, artichoke, psyllium, fenugreek, or the like.
  • plant extracts such as amla, moringa, green tea, coffee, cinnamon, garlic, turmeric, artichoke, psyllium, fenugreek, or the like.
  • omega-3 fatty acid composition comprises at least about 80 wt.-%, optionally at least about 90 wt.-%, omega-3 fatty acid esters, based on the weight of the omega-3 fatty acid composition;
  • C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 10 : 1, and the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the at least one flavor additive is added to the liquid composition after combining the C2-C4 polyol ester and the thickening agent.
  • the at least one flavor additive and the thickening agent are combined simultaneously with the C2-C4 polyol ester.
  • the thickening agent is first mixed with the flavor additives, or at least a fraction thereof, prior to combining this pre-mix with the other components.
  • the process according to the second aspect of the invention further comprises the steps of providing and adding an antioxidant.
  • said antioxidant is provided in the form of an antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid to the liquid composition.
  • the lecithin and the fatty acid ester of ascorbic acid are dissolved in the C2-C4 polyol ester, or at least a fraction thereof, prior to combining the resulting antioxidant-pre-mix with the other components.
  • the lecithin and the fatty acid ester of ascorbic acid are dissolved in the C2-C4 polyol ester, or at least a fraction thereof, at elevated temperatures of from about 80 °C to about 120 °C, prior to combining the resulting antioxidant-pre-mix with the other components.
  • the lecithin and the fatty acid ester of ascorbic acid in the C2-C4 polyol ester optionally, first the fatty acid ester of ascorbic acid is dissolved in the C2-C4 polyol ester, or at least a fraction thereof; and subsequently the lecithin is added and dissolved to form the antioxidant-pre-mix.
  • the fatty acid ester of ascorbic acid is dissolved in the C2-C4 polyol ester, or at least a fraction thereof, at a temperature of from about 90 °C to about 120 °C, or from about 100 °C to about 110 °C; and subsequently the lecithin is added and dissolved at a reduced temperature of from about 80 °C to about 100 °C, or from about 90 °C to about 95 °C, to form the antioxidant-pre-mix.
  • the omega-3 fatty acid composition is added to the liquid composition
  • the flavor additive comprises an aroma that is volatile.
  • the volatile aroma is added to the liquid composition
  • the process according to the second aspect of the invention further comprises the steps of providing and adding a gel stabilizer selected from the group of polyhydroxylated compounds to the liquid composition, optionally a polyhydroxylated compound selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof.
  • a gel stabilizer selected from the group of polyhydroxylated compounds to the liquid composition, optionally a polyhydroxylated compound selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof.
  • the gel stabilizer is added to the liquid composition
  • the thickening agent after combining the C2-C4 polyol ester, the thickening agent, the at least one flavor additive, the antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid, and the omega-3 fatty acid composition; - by adding the gel stabilizer to the antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid, or to a pre-mix of said the antioxidant complex with at least parts of the C2-C4 polyol ester; or
  • any liquid flavor additive e.g. to the liquid aroma(s)
  • adding the resulting combined blend to the liquid composition as a final preparation step.
  • the components provided e.g. the raw materials
  • the intermediate or final combinations of said components are degassed. This step, or these steps, are useful in avoiding oxidation of the omega-3 fatty acid composition, with the aim to exclude oxygen as much as possible during processing.
  • the components provided, and/or the intermediate or final combinations of said components are degassed by means of reduced pressure or vacuum.
  • the pressure is reduced to values not higher than 100 mbar; or not not higher than 50 mbar; or not higher than 20 mbar.
  • At least parts of the components provided, and/or at least parts of the intermediate or final combinations of said components are degassed by means of reduced pressure or vacuum; for instance, some components, or blends thereof, may not be degassed or may be degassed by means other than reduced pressure or vacuum, such as by using ultrasound.
  • degassing is performed at least after combining the C2-C4 polyol ester, the thickening agent, and at least one flavor additive.
  • the components provided and/or the combined components are overlayed, or flushed, with an inert-gas atmosphere.
  • at least parts of the components provided, and/or at least parts of the intermediate or final combinations of said components are overlayed, or flushed, with an inert-gas atmosphere.
  • This step, or these steps are also useful in avoiding oxidation of the omega-3 fatty acid composition, with the aim to exclude oxygen as much as possible during processing.
  • the components provided, and/or the intermediate or final combinations of said components are both degassed and overlayed, or flushed, with an inert-gas atmosphere.
  • the inert-gas is selected from nitrogen or argon.
  • the respective pump providing the reduced pressure or vacuum needs to be interrupted at times throughout the process, of course, to allow for the introduction of the inert-gas atmosphere.
  • the process according to second aspect of the invention comprises the steps of:
  • step (ii) Degassing the resulting antioxidant-pre-mix of step (i) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon;
  • step (iii) Adding the thickening agent to the degassed antioxidant-pre-mix of step (ii) under stirring;
  • step (iv) Degassing the resulting thickened antioxidant-pre-mix of step (iii) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon;
  • step (v) Adding at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma to the degassed, thickened antioxidant-pre-mix of step (iv) under stirring;
  • step (vi) Degassing the resulting mixture of step (v) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon;
  • step (vii) Adding the omega-3 fatty acid composition to the degassed resulting mixture of step (vi) under stirring;
  • step (viii) Degassing the resulting mixture of step (vii) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; wherein steps (i) to (viii) are performed such that the weight ratio of the C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 10 : 1, and the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the process a according to second aspect of the invention comprises the steps of:
  • step (iii) Degassing the resulting thickened C2-C4 polyol ester of step (ii) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon;
  • step (v) Degassing the resulting antioxidant-pre-mix of step (iv) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon;
  • step (vi) Adding the degassed antioxidant-pre-mix of step (v) to the degassed, thickened C2-C4 polyol ester of step (iii) under stirring;
  • step (vii) Degassing the resulting thickened antioxidant-pre-mix of step (vi) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon;
  • step (viii) Adding at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma to the degassed, thickened antioxidant-pre-mix of step (vii) under stirring;
  • step (ix) Degassing the resulting mixture of step (viii) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon;
  • step (x) Adding the omega-3 fatty acid composition to the degassed resulting mixture of step (ix) under stirring;
  • step (xi) Degassing the resulting mixture of step (x) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; wherein steps (i) to (xi) are performed such that the weight ratio of the C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 10 : 1, and the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the flavor additive employed in the process according to the second aspect of the invention - and in particular the process according to the two embodiments described above comprising steps (i)-(viii) and (i)-(xi), respectively - comprises an aroma that is volatile; and the volatile aroma is added under stirring after the addition of the omega-3 fatty acid composition.
  • the process according to the second aspect of the invention - and in particular the process according to the two embodiments described above comprising steps (i)-(viii) and (i)-(xi) -further comprises the steps of subjecting the mixture comprising the at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma (either an intermediate mixture, or the ultimately resulting liquid composition) to a high shear mixing step, preferably under vacuum, for reducing the mean particle size of any solid, suspended parts of the at least one flavor additive; optionally using a high shear mixer of the rotor/stator-type (e.g.
  • an UltraTurrax ® or other suitable means such as a colloid mill with defined slit size.
  • Small particle sizes of the at least one flavor additive preferably not more than 150 pm, or not more than 100 pm, or not more than 75 pm, or not more than 50 pm, support a pleasant mouth feel and, at the same time, improve the suspension stability.
  • the at least one flavor additive can be purchased in the desirable particle size range; for instance, xylitol is provided in a quality with a mean particle size of about 90 pm (e.g. Xivia CM90 as available from Dupont Nutrition & Health).
  • the process according to the second aspect of the invention - and in particular the process according to the two embodiments described above comprising steps (i)-(viii) and (i)-(xi) -further comprises the steps of providing and adding a gel stabilizer selected from the group of polyhydroxylated compounds to the liquid composition, optionally a polyhydroxylated compound selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof; wherein the gel stabilizer is either added to the liquid composition under stirring after the addition of the omega-3 fatty acid composition, or added to the antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid first (e.g. the antioxidant-pre-mix of steps (i) or (iv) as described above), and then further processed together with said antioxidant complex.
  • a gel stabilizer selected from the group of polyhydroxylated compounds to the liquid composition, optionally a polyhydroxylated compound
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT).
  • the thickening agent is fumed silica or precipitated silica.
  • the esters of the omega-3 fatty acid composition are selected from alkyl esters, preferably from ethyl esters or methyl esters.
  • the fatty acid ester of ascorbic acid may be selected from ascorbylstearate, ascorbylpalmitate, or mixtures thereof.
  • the process according to second aspect of the invention comprises a further step of packaging a single dose unit of the liquid composition into bottles, vials, sachets or stickpacks.
  • the liquid composition is degassed under reduced pressure prior to packaging; and/or the packaging step is performed in an inert-gas atmosphere.
  • the invention relates to the liquid composition according to the first aspect of the invention as described above for use in the treatment and/or prevention of rheumatoid arthritis, hypertriglyceridemia, and/or post- myocardial infarction.
  • Example 1 Liquid compositions HOI and H02
  • compositions HOI and H02 as listed below in Tables 1 and 2, respectively, are examples of the components and respective amounts provided per single dose of examplary liquid compositions according to the first aspect of the invention.
  • the compositions differ mainly in the amount of the antioxidant complex added, with H01 comprising about 0.32 wt.-% lecithin (L) and about 0.24 wt.-% ascorbylpalmitate (AP), and H02 comprising about 0.20 wt.-% lecithin (L) and about 0.08 wt.-% ascorbylpalmitate (AP), based on the total weight of the liquid composition. This equals about 0.40 wt.-% + 0.30 wt.-% and about 0.25 wt.-% +
  • compositions were prepared, using a process exemplary to the process according to the second aspect of the invention, by dissolving the ascorbylpalmitate in about 10 wt.-% of the MCT at elevated temperatures of about 100-110 °C under stirring, and subsequently adding and dissolving the lecithin under stirring, at elevated temperatures of about 90-95 °C, such as to form an L + AP antioxidant-pre-mix.
  • the thickening agent Aerosil ® 200 was blended with the other about 80 wt.-% of the MCT at a temperature of 20 ⁇ 10 °C, prior to adding the L + AP antioxidant-pre-mix to the MCT-Aerosil ® 200 blend.
  • compositions J01 and J02 as well as KOI and K02 are further examples of the components and respective amounts provided per single dose of examplary liquid compositions according to the first aspect of the invention.
  • These compositions comprise polysorbate 80 as a gel stabilizer and thus reduced amounts of fumed silica (Aerosil ® 200) compared to H01 and H02 of Example 1 above.
  • They also comprise liquid aroma (namely, (R)-(+)-limonen, peppermint-menthol, orange, and mandarin), optionally in addition to solid aroma. This offers the benefit of more pronounced volatility, and hence a more pleasant taste and/or smell experience.
  • compositions were prepared in a similar manner as described in Example 1 above, with the minor differences that
  • the flavor additives comprised not only xylitol, aspartame, citric acid, and the aroma combination cherry /limonen / peppermint menthol (all in powder form), but also monosodium citrate,
  • liquid compositions were subjected to a high-shear mixing step using a rotor/stator-type mixer (UltraTurrax ® ).
  • the gel stabilizer polysorbate 80 can instead be dispersed in a further small aliquot of the total MCT (approx. 3-5 % of the total MCT) at a temperature of about 50 °C to 70 °C, before being adding this polysorbate/MCT-mix to the final liquid composition in a final step.
  • Crimp neck glass vials were weighed empty and then filled with about 10 g of the liquid compositions of Examples 1 and 2. Thereafter, the filled vials were weighed again and then subjected to the following steps: i) briefly shaking the closed vial manually (about 2 to 10 times); ii) removing the lid, or otherwise opening the primary packaging; iii) placing, or holding, it at a pouring angle of about 45° for 10 seconds; and iv) lightly tapping the still upward-facing bottom end of the primary packaging with a fingertip after these 10 seconds. The weight remaining in the vials after steps was determined gravimetrically.
  • a liquid composition for direct oral administration comprising:
  • omega-3 fatty acid composition (b) an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-%, optionally at least about 90 wt.-%, omega-3 fatty acid esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the C2-C4 polyol ester under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to item 1 wherein the C2-C4 polyol ester is selected from mono- and/or di-esters of propylene glycol; mono-, di- and/or tri-esters of glycerol; and/or mono- and/or di-esters of butylene glycol; and/or wherein the C2-C4 polyol ester comprises aliphatic, saturated fatty acid chains with 8 to 12 carbon atoms, or 8 to 10 carbon atoms.
  • omega-3 fatty acid composition comprises at least about 80 wt.-%, or at least about 90 wt.-%, esters of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), based on the weight of the fatty acid composition; and/or wherein the omega-3 fatty acid composition comprises from about 40-60 wt.-%
  • esters e.g. from about 43-50 wt.-%) esters of eicosapentaenoic acid (EPA); and from about 25-50 wt.-% (e.g. from about 34-41 wt.-%) esters of docosahexanoic acid (DHA), based on the weight of the omega-3 fatty acid composition; and wherein optionally said esters are selected from alkyl esters, preferably from ethyl esters or methyl esters.
  • esters are selected from alkyl esters, preferably from ethyl esters or methyl esters.
  • liquid composition according to any one of items 1 to 6, wherein the weight ratio of the eicosapentaenoic acid ethyl ester (EPA-EE) and the docosahexanoic acid ethyl ester (DHA-EE) ranges between about 1 : 1 and about 1.5 : 1, or between about 1.1 : 1 and about 1.4 : 1, or between about 1.2 : 1 and about 1.3 : 1.
  • EPA-EE eicosapentaenoic acid ethyl ester
  • DHA-EE docosahexanoic acid ethyl ester
  • liquid composition according to any one of items 1 to 7, wherein the weight ratio of the C2-C4 polyol ester, optionally a medium chain triglyceride (MCT), and the omega-3 fatty acid composition ranges between about 1 : 1 and about 5 : 1, or between about 1 : 1 and about 2 : 1, or between about 1.15 : 1 and about 1.85 : 1, or between about 1.3 : 1 and about 1.7 : 1.
  • MCT medium chain triglyceride
  • the liquid composition according to any one of items 1 to 8, wherein the composition comprises at least about 40 wt.-% of the C2-C4 polyol ester, optionally a medium chain triglyceride (MCT), based on the total weight of the liquid composition; or at least about 45 wt.-%; or at least about 48 wt.-%; and/or wherein the composition comprises at least about 20 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition; or at least about 25 wt.-%; or at least about 28 wt.-%.
  • MCT medium chain triglyceride
  • the liquid composition according to any one of items 1 to 9, wherein the composition comprises at least about 40 wt.-% of the C2-C4 polyol ester, optionally a medium chain triglyceride (MCT), and at least about 20 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition; for instance, at least about 48 wt.-% of the C2-C4 polyol ester, optionally a medium chain triglyceride (MCT), and at least about 28 wt.-% of the omega-3 fatty acid composition based on the total weight of the liquid composition.
  • MCT medium chain triglyceride
  • MCT medium chain triglyceride
  • the thickening agent is an anorganic oleo-gel forming component, optionally selected from the group consisting of fumed silica, precipitated silica, aluminum silicates, bentonite, and mixtures thereof; preferably a fumed silica or precipitated silica; for instance, a hydrophilic fumed silica exhibiting a specific surface area in the range of
  • liquid composition according to any one of items 1 to 12, wherein the composition comprises at least about 10 wt.-% of the flavor additive based on the total weight of the liquid composition, or at least about 15 wt.-%, or at least about 17 wt.-%; and/or wherein at least parts of the flavor additive is present in solid, particulate form and suspended in the liquid composition; for instance about 50 wt.-%, or at least about 60 wt.-%, or at least about 70 wt.-%, or at least about 80 wt.-%.
  • the flavor additive comprises a sugar or sugar alcohol, optionally a sugar or sugar alcohol selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof; preferably xylitol, sorbitol, isomaltitol, or mixtures thereof; and further preferably xylitol.
  • a sugar or sugar alcohol selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof; preferably xylitol, sorbitol, isomaltitol, or mixtures thereof; and further preferably xylitol.
  • the flavor additive comprises an aroma that is volatile.
  • the flavor additive comprises an acidifier selected from the group of organic acids, the respective salts thereof, and mixtures thereof; optionally, an organic acid selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof; preferably at least citric acid and/or salts thereof.
  • liquid composition according to any one of items 1 to 18, wherein the composition further comprises at least one antioxidant; for instance, an antioxidant provided in the form of an antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid.
  • liquid composition according to item 19 wherein the fatty acid ester of ascorbic acid is selected from ascorbylstearate, ascorbylpalmitate, or mixtures thereof; wherein optionally the weight ratio of lecithin and ascorbylpalmitate in the antioxidant complex ranges between about 3 : 1 and about 1 : 1, or between about 2.8 : 1 and about 1.2 : 1, or between about 2.7 : 1 and about 1.3 : 1.
  • liquid composition according to item 22 wherein the liquid composition comprises from about 0.01 wt.-% to about 1 wt.-% of the gel stabilizer; or from about 0.05 wt.-% to about 0.3 wt.-%; for instance, from about 0.01 wt.-% to about 1 wt.-% polysorbate 80; or from about 0.05 wt.-% to about 0.3 wt.-% polysorbate 80.
  • MCT medium chain triglyceride
  • omega-3 fatty acid composition (b) an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-%, optionally at least about 90 wt.-%, omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • a flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, and
  • liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • a gel stabilizer selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the liquid composition according to any one of items 1 to 24, wherein the composition, based on its total weight, comprises:
  • omega-3 fatty acid composition comprises at least about 80 wt.-%, optionally at least about 90 wt.-%, omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, preferably from about 10 wt.-% to about 39 wt.-% of a flavor additive comprising a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, aspartame, citric acid, and aroma; preferably xylitol, aspartame, citric acid, and aroma, and
  • liquid composition optionally from about 0.01 wt.-% to about 1.0 wt.-% of a gel stabilizer selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof, preferably polysorbate 80; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • a gel stabilizer selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof, preferably polysorbate 80; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the liquid composition according to any one of items 1 to 25, the composition essentially consisting of:
  • omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, preferably from about 10 wt.-% to about 39.5 wt.-% of a flavor additive comprising a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, aspartame, citric acid, and aroma; preferably xylitol, aspartame, citric acid, and aroma; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the liquid composition according to any one of items 1 to 25, the composition, based on its total weight, essentially consisting of:
  • omega-3 fatty acid composition comprises at least about 80 wt.-% omega-3 fatty acid ethyl esters, based on the weight of the omega-3 fatty acid composition, wherein the weight ratio of the medium chain triglyceride under (a) and the omega-3 fatty acid composition under (b) ranges between about 1 : 1 and about 10 : 1,
  • sugar or sugar alcohol is selected from the group consisting of xylitol, sorbitol, isomaltitol, erythritol, trehalose, maltitol, sucrose, fructose, glucose, and inulin, and mixtures thereof,
  • sweetener is selected from the group consisting of aspartame, acesulfame potassium, cyclamate, saccharin, stevia, sucralose, neohesperidin, and thaumatin, and mixtures thereof,
  • the acidifier selected from the group consisting of citric acid, malic acid, ascorbic acid, tartaric acid, the respective salts thereof, and mixtures thereof, preferably from about 10 wt.-% to about 39.49 wt.-% of a flavor additive comprising a sugar alcohol selected from xylitol, sorbitol, isomaltitol, or mixtures thereof, aspartame, citric acid, and aroma; preferably xylitol, aspartame, citric acid, and aroma, and
  • a gel stabilizer selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof, preferably polysorbate 80; wherein the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • liquid composition according to any one of items 1 to 30, wherein said liquid composition exhibits a viscosity which allows to empty out at least 85 wt.-%, preferably at least 90 wt.-%, more preferably at least 93 wt.-% of the liquid composition from its primary packaging within about 5 to 10 seconds after i) briefly shaking the closed primary packaging manually (about 2 to 10 times); ii) removing the lid, or otherwise opening the primary packaging; iii) placing, or holding, it at a pouring angle of about 45° for about 10 seconds; and iv) lightly tapping the still upward-facing bottom end of the primary packaging with a fingertip after the about 10 seconds.
  • a single dose unit comprises, or essentially consists of, from about 4 g to about 32 g; or from about 8 g to about 24 g; or from about 10 g to about 20 g; or about 16 g; or about 13.6 g; or about 13.2 g of said liquid composition; and wherein optionally a single dose unit of said liquid composition is provided in bottles, vials, sachets or stickpacks.
  • a process for the preparation of the liquid composition according to any one of items 1 to 32 comprising the steps of:
  • a C2-C4 polyol ester with one or more C6-C12 medium chain fatty acids a thickening agent; at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma; and an omega-3 fatty acid composition, wherein the omega-3 fatty acid composition comprises at least about 80 wt.-%, optionally at least about 90 wt.-%, omega-3 fatty acid esters, based on the weight of the omega-3 fatty acid composition; and - Combining the components provided, such that the weight ratio of the omega-3 fatty acid composition
  • C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 10 : 1, and the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the process according to item 33 wherein the at least one flavor additive is added to the liquid composition after combining the C2-C4 polyol ester and the thickening agent; or wherein the at least one flavor additive and the thickening agent are combined simultaneously with the C2-C4 polyol ester; wherein optionally the thickening agent is first mixed with at least one flavor additive, or at least a fraction thereof, prior to combining this pre-mix with the C2-C4 polyol ester.
  • omega-3 fatty acid composition is added to the liquid composition after combining the C2-C4 polyol ester, the thickening agent, and the at least one flavor additive.
  • any one of items 33 to 41 wherein the process further comprises the steps of providing and adding a gel stabilizer selected from the group of polyhydroxylated compounds to the liquid composition, optionally a polyhydroxylated compound selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof.
  • a gel stabilizer selected from the group of polyhydroxylated compounds to the liquid composition, optionally a polyhydroxylated compound selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof.
  • the thickening agent after combining the C2-C4 polyol ester, the thickening agent, the at least one flavor additive, the antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid, and the omega-3 fatty acid composition; - by adding the gel stabilizer to the antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid, or to a pre-mix of said the antioxidant complex with at least parts of the C2-C4 polyol ester; or
  • any liquid flavor additive e.g. to the liquid aroma(s)
  • adding the resulting combined blend to the liquid composition as a final preparation step.
  • step (iii) Degassing the resulting thickened antioxidant-pre-mix of step (iii) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; v. Adding at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma to the degassed, thickened antioxidant-pre-mix of step (iv) under stirring; vi. Degassing the resulting mixture of step (v) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; vii. Adding the omega-3 fatty acid composition to the degassed resulting mixture of step (vi) under stirring; viii.
  • step (vii) Degassing the resulting mixture of step (vii) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; wherein steps (i) to (viii) are performed such that the weight ratio of the C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 10 : 1, and the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration.
  • the process according to items 36 to 46 the process comprising the steps of: i.
  • a separate vessel dissolving the antioxidant complex comprising lecithin and a fatty acid ester of ascorbic acid in a second fraction of about 5-20 wt.-% of the amount of the C2-C4 polyol ester at elevated temperatures of from about 80 °C to about 120 °C under stirring to form an antioxidant-pre-mix; v. Degassing the resulting antioxidant-pre-mix of step (iv) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; vi. Adding the degassed antioxidant-pre-mix of step (v) to the degassed, thickened C2-C4 polyol ester of step (iii) under stirring; vii.
  • step (vi) Degassing the resulting thickened antioxidant-pre-mix of step (vi) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; viii. Adding at least one flavor additive selected from the group consisting of sugars, sugar alcohols, sweeteners, acidifiers and aroma to the degassed, thickened antioxidant-pre-mix of step (vii) under stirring; ix. Degassing the resulting mixture of step (viii) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; x. Adding the omega-3 fatty acid composition to the degassed resulting mixture of step (ix) under stirring; xi.
  • step (x) Degassing the resulting mixture of step (x) by means of reduced pressure or vacuum, and overlaying with an inert-gas atmosphere of nitrogen or argon; wherein steps (i) to (xi) are performed such that the weight ratio of the C2-C4 polyol ester and the omega-3 fatty acid composition ranges between about 1 : 1 and about 10 : 1, and the liquid composition comprises not more than 5 wt.-% of water as detetermined by Karl Fischer titration
  • the flavor additive comprises an aroma that is volatile; and wherein the volatile aroma is added under stirring after the addition of the omega-3 fatty acid composition.
  • the process further comprises the steps of providing and adding a gel stabilizer selected from the group of polyhydroxylated compounds to the liquid composition, optionally a polyhydroxylated compound selected from the group of polysorbates, poloxamers, polyethyleneglycols, polyoxyethylen fatty acid glycerides, polidocanol, or mixtures thereof; and wherein the gel stabilizer is added under stirring either after the addition of the omega-3 fatty acid composition; or added to the antioxidant-pre-mix. complex comprising lecithin and a fatty acid ester of ascorbic acid, or to a pre-mix of said the antioxidant complex with at least parts of the C2-C4 polyol ester.
  • the C2-C4 polyol ester is a medium chain triglyceride (MCT); wherein the thickening agent is fumed silica or precipitated silica; and/or wherein the esters of the omega-3 fatty acid composition are selected from alkyl esters, preferably from ethyl esters or methyl esters.
  • the antioxidant complex comprises lecithin and a fatty acid ester of ascorbic acid selected from ascorbylstearate, ascorbylpalmitate, or mixtures thereof.
  • the process comprises a further step of packaging a single dose unit of the liquid composition into bottles, vials, sachets or stickpacks; and wherein optionally
  • the liquid composition is degassed under reduced pressure prior to packaging;
  • the packaging step is performed in an inert-gas atmosphere.

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Abstract

L'invention concerne une composition liquide sensiblement exempte d'eau pour l'administration orale directe d'acides gras oméga 3 qui peut être facilement avalée sans ajout de liquides, par exemple, tout en procurant une odeur, un goût et une sensation en bouche agréables ; ainsi qu'une bonne stabilité. La composition comprend un ester de polyol de C2-C4 avec un ou plusieurs acides gras à chaîne moyenne en C6-C12 et une composition d'acide gras oméga 3 qui comprend au moins environ 80 % en poids d'esters d'acide gras oméga 3 dans un rapport en poids allant d'environ 1:1 à environ 10:1 ; un agent épaississant, et au moins un additif aromatique choisi dans le groupe constitué par les sucres, les alcools de sucre, les édulcorants, les acidifiants, les arômes et éventuellement un stabilisateur de gel.
PCT/EP2020/078716 2019-10-15 2020-10-13 Compositions liquides d'acides gras oméga 3 pour une administration orale directe WO2021074118A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
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US20060034815A1 (en) * 2004-08-06 2006-02-16 Hector Guzman Novel statin pharmaceutical compositions and related methods of treatment
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US20130078362A1 (en) * 2005-07-13 2013-03-28 Abbott Laboratories Liquid nutritional compositions containing unsaturated fatty acids
US20160316810A1 (en) * 2013-12-20 2016-11-03 Abbott Laboratories Nutritional composition containing oxidizable oil and rosmarinic acid
WO2016152054A1 (fr) * 2015-03-26 2016-09-29 備前化成株式会社 Effets de prévention et d'atténuation de la douleur du glycéride d'acide gras ω3

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