WO2015149135A1

WO2015149135A1 - Process of manufacturing a stable dispersion for a dietary supplement

Info

Publication number: WO2015149135A1
Application number: PCT/AU2015/050153
Authority: WO
Inventors: Thomas Yu; Sarah-Louise Jones
Original assignee: Sanofi-Aventis Healthcare Pty Ltd
Priority date: 2014-04-04
Filing date: 2015-04-02
Publication date: 2015-10-08

Abstract

The invention relates generally to a process of manufacturing a dispersion for use as a dietary supplement. More specifically, the present invention relates to a process of preparing a shelf-stable dispersion comprising one or more omega-3 fatty acids, one or more edible oils, one or more minerals and, optionally, one or more viscosity modifying agents. The invention also relates to shelf-stable dietary supplements comprising omega-3 fatty acids and one or more minerals.

Description

PROCESS OF MANUFACTURING A STABLE DISPERSION FOR A DIETARY

SUPPLEMENT

FIELD OF THE INVENTION

[0001 ] The present invention relates generally to a process of manufacturing a dispersion for use as a dietary supplement. More specifically, the present invention relates to a process of preparing a shelf-stable dispersion comprising one or more omega-3 fatty acids, one or more edible oils, one or more minerals and, optionally, one or more viscosity modifying agents. The invention also relates to shelf-stable dietary supplements comprising omega-3 fatty acids and one or more minerals.

BACKGROUND TO THE INVENTION

[0002] The reference in this specification to any prior publication (or information derived from it), or to any matter that is known, is not, and should not be taken as an acknowledgement or admission or any form of suggestion that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0003] The beneficial health effects of dietary supplementation including omega-3 fatty acids have been linked to various human conditions including, but not limited to, cancer, cardiovascular disease, developmental disorders and mental health, cognitive aging, and inflammation. In particular, omega-3 fatty acid supplementation is useful for the prevention and relief of diseases or conditions which result in joint inflammation such as osteoarthritis. Depending on the application, omega-3 fatty acid based supplements can additionally include vitamins, fiber, fatty acids, amino acids, minerals, herbal supplements, combinations thereof or any other nutritionally beneficial additive. [0004] The omega-3 fatty acids, also referred to as ω-3 fatty acids, are a class of polyunsaturated fatty acids (PUFAs). They have a carboxylic acid (-COOH) terminal, considered the 'head' of the chain, and a methyl (-CH₃) terminal, considered the 'tail' of the chain. Omega-3 fatty acids are characterised by a carbon-carbon double bond at the third carbon atom from the tail of the chain.

[0005] Three types of omega-3 fatty acids are beneficial for humans - alpha- linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA is plant derived, while both EPA and DHA are typically derived from marine sources. Common sources of EPA and DHA include, but are not limited to, fish, calamari, caviar, krill, seal, green shell/lipped mussels, oysters, herring, anchovy, cod, salmon, sardine, prawns, red meat, turkey, algae, eggs and oils and/or extracts derived from these sources. Synthetic omega-3 fatty acids also exist with the necessary bioactive characteristics of naturally derived oils.

[0006] Often minerals, particularly those rich in calcium, may be co-formulated with omega-3 fatty acids in dietary supplement formulations. Such minerals may be derived from natural sources including, but not limited to, seaweed, algae, specially cultivated plants, specifically enriched yeast, dark green vegetables, eggs and legumes.

[0007] Formulating dietary supplements so as to be stable during storage, transport, and furthermore, throughout life in a sales environment, is particularly important. The use of oils as and in dietary supplements can lead to sedimentation and phase separation issues particularly when insoluble components such as minerals are present in the formulation. Where the components of the formulation are physically incompatible, or insoluble in each other, formulating the composition so as to be a stable dispersion is important not only for storage and transport but also for the purposes of processing and handling during manufacture of suitable dosage forms, and to ensure the bioactive efficacy of the active ingredients themselves. [0008] In particular, preparing conventional formulations of, for example, a softgel slurry preparation of a mineral and an oil for use as a dietary supplement involves heating and mixing soyabean oil, hydrogenated vegetable oil (HVO), beeswax and lecithin at 65-70°C until the ingredients are melted and appear uniform with no solid masses. Any additional oils and solid components are added into the above mixture and it is stirred as it cools down to room temperature until it appears to be uniform slurry. However experience shows that after 24 hours, the formulation separates into two distinct phases. It is speculated that this is because the soyabean oil, HVO, beeswax and lecithin mixture together do not sufficiently suspend the solids. This lack of stability prevents the commercial, shelf-stable preparation of such formulations.

[0009] There exists a need to develop improved dietary supplement formulations which are stable throughout manufacture, storage and handling and also which provide for optimal delivery, absorbance and metabolisation of bioactive agents in vivo, as well as processes for their preparation.

SUMMARY OF THE INVENTION

[0010] According to one aspect of the invention, there is provided a process of preparing a shelf-stable dispersion of a bioactive agent comprising the step of combining: a first phase comprising one or more edible oils, one or more minerals, and optionally, one or more viscosity modifying agents, and a second phase comprising one or more omega-3 fatty acids, wherein, when combining said phases, there exists a temperature difference of at least 15°C between said first phase and said second phase which promotes the formation of the stable dispersion. [001 1 ] The present invention provides a method in which the manufacture of a shelf-stable dispersion comprising bioactive agents is achieved. The invention particularly provides a stable dispersion in which phase separation and sedimentation are avoided. Such dispersions also ensure ease of further handling, for example during preparation of suitable dosage forms, and the prolonged bioactive efficacy of the active ingredients.

[0012] It has been found that carefully managing the temperature differential at the time that the phase comprising the omega-3 fatty acid is added to the phase comprising the one or more edible oils, one or more minerals, and optionally, one or more viscosity modifying agents can be surprisingly effective in achieving a stable dispersion.

[0013] Preferably the second phase comprising omega-3 fatty acid is in a chilled state relative to ambient temperature at the time of its combination with the first phase. More preferably the phase consists only of omega-3 fatty acid. Even more preferably, the omega-3 fatty acid is chilled to a temperature of about 0°C to 20°C. Even more preferably still the omega-3 fatty acid is chilled to a temperature of about 0°C to 10°C. The cool temperature of this phase, it is believed, helps stabilise the dispersion formed in the first phase, and also preserves the efficacy of the nutritionally active oils which are in the first phase, despite that it is necessary to form the dispersion of the first phase at a relatively high temperature

[0014] Another aspect of the invention provides a process for the preparation of a shelf-stable dispersion comprising a viscosity modifier, at least one edible oil, lecithin, a mineral extract, one or more omega-3 fatty acids, and optionally, one or more further additives, wherein the process of preparing the dispersion comprises the steps of: (i) heating the at least one edible oil and optionally the viscosity modifier to a temperature of between 60°C to 80°C to form a liquid mixture,

(ii) cooling the liquid mixture to a temperature between 45°C to 60°C,

(iii) mixing lecithin with the cooled mixture of step (ii),

(iv) further cooling the mixture of step (iii) to a temperature between 25°C to 45°C,

(v) mixing the mineral extract with the further cooled mixture of step (iv), and

(vi) mixing the one or more omega-3 fatty acids, wherein there is a temperature difference of at least 15°C between the mixture of step (v) and step (vi) upon mixing.

[0015] According to another aspect of the invention, there is provided a shelf- stable dispersion of a bioactive agent prepared by a process comprising combining: a first phase comprising one or more edible oils, one or more minerals, and optionally, one or more viscosity modifying agents, and a second phase comprising one or more omega-3 fatty acids, wherein, when combining said phases, there exists a temperature difference of at least 15°C between said first phase and said second phase, which promotes the formation of the stable dispersion. [0016] Preferably the second phase comprising omega-3 fatty acid is in a chilled state relative to ambient temperature at the time of its combination with the first phase. More preferably the phase consists only of omega-3 fatty acid. Even more preferably, the omega-3 fatty acid is chilled to a temperature of about 0°C to 20°C. Even more preferably still the omega-3 fatty acid is chilled to a temperature of about 0°C to 10°C.

[0017] Preferably, the dispersion prepared according to the process of the invention comprises additional additives, particularly an emulsifier, such as lecithin. Preferably, the dispersion of the invention comprises an emulsifier in an amount of at least 1 % up to about 5% by weight of the dispersion.

[0018] Preferably, in any of the above aspects of the invention the shelf stable dispersion prepared is characterised by having a shelf stability of at least 3 months, preferably of at least 6 months, more preferably of at least 12 months, more preferably still of at least 18 months, and even more preferably still of at least 24 months.

[0019] Preferably, in some embodiments of the above aspects said one or more omega-3 fatty acids includes extracts from, or prepared from marine sources, more preferably from algal, fish or krill oils. Other sources of omega-3 fatty acid may be used. Still more preferably, the dispersion prepared according to the process of the invention comprises one or more omega-3 fatty acids in an amount of at least 30% up to about 70% by weight of the dispersion. Even more preferably, said one or more omega-3 fatty acids include extracts from, or of sources of, omega-3 fatty acids which may also contain impurities and other components, particularly extracts from or sources of omega-3 fatty acids rich in docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA), and more particularly, extracts from or sources of omega-3 fatty acids rich in docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA) which are oils. Preferably the dispersion of the invention comprises one or more omega-3 fatty acids in an amount of at least 30% and up to 70% by weight of the dispersion. [0020] Preferably, in some embodiments of the above aspects said one or more minerals includes mineral extracts, more preferably calcareous mineral extracts, and more particularly the calcareous extract marketed under the trade mark Aquamin® F. Even more preferably still, the dispersion of the invention comprises one or more minerals in an amount of at least 5% up to about 20% by weight of the dispersion.

[0021 ] Preferably, in some embodiments of the above aspects said one or more edible oils includes hydrogenated oils, non-hydrogenated oils and combinations thereof, particularly combinations of soyabean oil and vegetable oil. More preferably, said one or more edible oils are heated prior to combination prepared into the first phase to at least 60°C up to about 80°C. Even more preferably, the dispersion prepared according to the process of the invention comprises one or more edible oils in an amount of at least 5% up to about 50% by weight of the dispersion.

[0022] Preferably, in some embodiments of the above aspects said one or more viscosity modifying agents includes waxes, such as beeswax, castorwax, glycowax, and carnaubawax, and combinations thereof. Preferably, if used, the dispersion prepared according to the process of the invention comprises said one or more viscosity modifying agents in an amount of at least 0.1 % up to about 15% by weight of the dispersion.

[0023] More preferably, the shelf-stable dispersion prepared according to the process of the invention comprises: omega-3 fatty acid 30 to 70% by weight calcareous mineral extract 5 to 20% by weight lecithin 1 to 5% by weight beeswax oil to 15% by weight hydrogenated vegetable oil 5 to 50% by weight soyabean oil 5 to 50% by weight and optionally one or more further additives.

[0024] In this preferred embodiment the dispersion is optionally further downstream processed so as to be in a dosage form suited to use as a dietary supplement, such as in the form of a tablet, a capsule, a softgel, or a softgel capsule.

[0025] In another aspect of the invention, there is provided a shelf-stable dispersion of a bioactive agent comprising one or more edible oils, one or more minerals, one or more omega-3 fatty acids and optionally one or more viscosity modifying agents and further pharmaceutically acceptable excipients.

[0026] Preferably, in this aspect the shelf stable dispersion is characterised by having a shelf stability of at least 3 months, preferably of at least 6 months, more preferably of at least 12 months, more preferably still of at least 18 months, and even more preferably still of at least 24 months.

[0027] More preferably, the shelf-stable dispersion in this aspect of the invention comprises: omega-3 fatty acid 30 to 70% by weight calcareous mineral extract 5 to 20% by weight lecithin 1 to 5% by weight beeswax oil to 15% by weight hydrogenated vegetable oil 5 to 50% by weight soyabean oil 5 to 50% by weight and optionally one or more further additives.

[0028] In this embodiment of the invention the shelf stable dispersion of a bioactive agent is formulated so as to be suited to use as a dietary supplement such as in the form of a tablet, a capsule, a softgel or softgel capsule.

[0029] Preferably, said one or more omega-3 fatty acids includes extracts from, or prepared from marine sources, more preferably from algal, fish or krill oils. Other sources of omega-3 fatty acid may be used. Still more preferably, the dispersion prepared according to the process of the invention comprises one or more omega-3 fatty acids in an amount of at least 30% up to about 70% by weight of the dispersion. Even more preferably, said one or more omega-3 fatty acids are include extracts from or of sources of omega-3 fatty acids which may also contain impurities and other components, particularly extracts from or sources of omega-3 fatty acids rich in docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA), and more particularly, extracts from or sources of omega-3 fatty acids rich in docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA) which are oils. Preferably the dispersion of the invention comprises one or more omega-3 fatty acids in an amount of at least 30% and up to 70% by weight of the dispersion.

[0030] Preferably, said one or more minerals includes mineral extracts, more preferably calcareous mineral extracts, and more particularly the calcareous extract marketed under the trade mark Aquamin® F. Even more preferably still, the dispersion of the invention comprises one or more minerals in an amount of at least 5% up to about 20% by weight of the dispersion. [0031 ] Preferably, said one or more edible oils includes hydrogenated oils non-hydrogenated oils and combinations thereof, particularly combinations of soyabean oil and vegetable oil. More preferably, said one or more edible oils are heated prior to combination prepared into the first phase to at least 60°C up to about 90°C. Even more preferably, the dispersion prepared according to the process of the invention comprises one or more edible oils in an amount of at least 5% up to about 50% by weight of the dispersion.

[0032] Preferably, said one or more viscosity modifying agents includes waxes, such as beeswax, castorwax, glycowax, and carnaubawax, and combinations thereof. Preferably, if used, the dispersion prepared according to the process of the invention comprises said one or more viscosity modifying agents in an amount of at least 0.1 % up to about 15% by weight of the dispersion.

[0033] Preferably, the dispersion prepared according to the process of the invention comprises additional additives, particularly an emulsifier, such as lecithin. Preferably, the dispersion of the invention comprises an emulsifier in an amount of at least 1 % up to about 5% by weight of the dispersion.

[0034] In another aspect of the invention, the shelf-stable dispersion may be used as a dietary or nutritional supplement.

[0035] In another aspect of the invention, the shelf-stable dispersion may be used to treat or prevent one or more of the following diseases, conditions or disorders: circulatory diseases, cardiovascular diseases, hypertension, angina, anxiety disorders, neurosis disorders, panic disorders, brain hemorrhage, cerebrovascular disease, cardiac failure, cerebral vasospasm, coronary heart disease, thrombosis, myocardial ischemia, myocardial infarction, arrhythmia, and related diseases, an asthmatic condition, chronic pulmonary obstructive disease, an arthritis condition or other inflammatory condition. Accordingly, a subject in need may be administered an effective amount of the dispersion of the invention. In one embodiment, the subject can be administered the dispersion of the invention via the oral route.

[0036] Another aspect of the invention provides for the manufacture of a dietary supplement comprising the shelf-stable dispersion and one or more additives.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0038] Except where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term 'about'. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding conventions.

[0039] Additionally, the recitation of numerical ranges within this specification is considered to be a disclosure of all numerical values and ranges within that range. For example, if a range is from about 1 to about 50, it is deemed to include, for example, 1 , 7, 34, 46.1 , 23.7, or any other value or range within the range.

[0040] The word "comprises" or "comprising", and grammatical variations thereof, when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[0041 ] The term "dispersion" is understood to encompass suspensions and emulsions, and particularly semi-liquid mixtures, such as a slurry, in which flowability is maintained allowing for further downstream processing into, for example, tablets or capsules.

[0042] The term "shelf-stable" is understood to mean that the dispersion and/or any dosage form in which the dispersion is presented for ingestion by a patient is stable for transport and storage at ambient temperature. Generally, ambient temperature is understood to be between 20°C to 25°C. A "shelf-stable" dispersion, after transport and storage will maintain its colouration, its viscosity or consistency and its phase continuity, that is, no phase separation will occur.

[0043] In preparing a shelf-stable dispersion the invention provides for the existence of a temperature differential between a first phase comprising one or more omega-3 fatty acids and a second phase comprising one or more edible oils, one or more minerals and, optionally, one or more viscosity modifying agents, when mixed together, which temperature differential between the phases promotes the formation of a stable dispersion. In certain embodiments, the temperature difference between is at least 15°C or at least 20°C or at least 25°C or at least 30°C, or is at least 35°C. Preferably, the temperature difference is between 15°C to 35°C, more preferably between 20°C to 30°C, and even more preferably 25°C to 30°C, or is most preferably about 25°C.

[0044] Generally, management of the viscosity of the phases during preparation of the dispersion of the invention, as well as viscosity of the dispersion itself is desirable. Flowability can be particularly desirable with respect to ensuring the two phases can be homogenously combined, and in downstream processing dependent upon the dosage form of the consequent dietary supplement. [0045] One consideration in managing suitable viscosity of the phases is the temperature of the phase containing said one or more edible oils, one or more minerals and, optionally, one or more viscosity modifying agents which should not be so low as to render it so viscous as to prevent homogenous dispersion of the omega-3 fatty acid into it upon mixing. It will be understood by the skilled person how the temperature of the phase can be modulated.

[0046] Viscosity can also be varied by altering one or more components of the formulation, particularly the amount and/or type of said one or more edible oils, and/or the amount and type of said one or more viscosity modifying agents (when used). Adjusting the quantity of minerals so as to, for example, adjust the dose of bioactive agent will also have an effect on the viscosity of the dispersion. In these embodiments, adjustment of the quantity of edible oils and optional viscosity modifying agents so as to ensure satisfactory viscosity for mixing and downstream processing will be within the skill of those skilled in the art. In alternative embodiments, the amount of minerals in various dispersions of the invention may be maintained at a constant amount, and the quantity of edible oils and optional viscosity modifying agents may be adjusted so as to ensure satisfactory viscosity for mixing and downstream processing.

[0047] The term "omega-3 fatty acid" includes synthetic or naturally occurring omega-3 fatty acids, extracts of or sources of omega-3 fatty acids which may also contain impurities and other components, and particularly extracts of sources of omega-3 fatty acids rich in docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA), and further particularly extracts of sources of omega-3 fatty acids rich in docosahexaenoic acid (DHA) and/or eicosapentaenoic acid (EPA) which are oils.

[0048] Long chain polyunsaturated fatty acids (LCPUFAs), particularly long chain omega-3 fatty acids, are beneficial for humans and include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA is plant derived, while both EPA and DHA are typically derived from marine sources. Omega-3 fatty acids can be conjugated to triglyceride, phospholipid or glycolipid backbones. Common sources of EPA and DHA include, but are not limited to, fish, calamari, caviar, krill, seal, green shell/lipped mussels, oysters, herring, anchovy, cod, salmon, sardine, prawns, red meat, turkey, algae, and oils and/or extracts derived from these sources. Such oils and extracts may comprise additional components including proteins, lipids, saturated fatty acids, hydrocarbons, ketones, aldehydes, esters, antioxidants and pigments. Other natural sources of omega-3 fatty acid include but are not limited to fat, cod liver oil, walnuts and walnut oil, wheat germ oil, rapeseed oil, soyabean lecithin, soyabeans, tofu, common beans, butternuts, eggs, seaweed and flax seed oil. Omega-3 fatty acid may also be derived from genetically engineered sources such as transgenic plants, microbes and fungi. In one embodiment, the invention concerns omega-3 fatty acids beneficial for humans, namely alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and particularly docosahexaenoic acid (DHA), and combinations thereof derived particularly from natural sources including marine sources, and further particularly from algae, fish and krill oil. In another embodiment, the invention concerns omega-3 fatty acids in concentrated form, such as found in high DHA and EPA oils.

[0049] In some embodiments, the dispersion produced according to the process of the invention comprises a DHA-rich omega-3 fatty acid oil derived from algae. In one embodiment, the dispersion comprises a DHA-rich schizochytrium sp. algal oil available under the trade mark Life's DHA®.

[0050] In some embodiments, the invention provides a dispersion comprising one or more omega-3 fatty acids in an amount of at least 30% up to about 70% by weight of the dispersion. Thus, in certain embodiments, the dispersion can comprise one or more omega-3 fatty acids in an amount of at least 30%, at least 40%, at least 50%, at least 60%, and up to about 70%, by weight of the dispersion. Preferably, omega-3 fatty acids of the invention are present in an amount of between 30% to 70% by weight of the dispersion, further preferably 40% to 60%, and even further preferably 45% to 60%. [0051 ] In some embodiments, the omega-3 fatty acids according to the invention are cooled to below room temperature prior to use to protect against heat damage and/or the development of rancidity. Room temperature is understood to encompass a temperature range between about 20°C to about 25°C. Thus, in certain embodiments, the omega-3 fatty acids according to the invention are cooled to a temperature at least below 25°C, at least below 20°C, at least below 15°C, at least below 10°C, or at least below 5°C. Preferably, omega- 3 fatty acids of the invention cooled to between 0°C to 20°C, further preferably 0°C to 15°C, and even further preferably 0°C to 10°C.

[0052] In some embodiments of the invention, the speed at which the omega- 3 fatty acids are added and/or the rate at which the dispersion is cooled once the chilled omega-3 fatty acids are added, may assist in protecting the one or more omega-3 fatty acids against heat exposure and consequently degradation and/or rancidity, and may also assist to prevent phase separation and/or sedimentation. In some preferred embodiments, the rate of cooling of the dispersion may be 0.2°C/min to 5.0°C/min, more preferably 0.2°C/min to 1 .5°C/min.

[0053] The term "edible oils" includes hydrogenated, non-hydrogenated oils and combinations thereof, which, in turn, may include, but are not limited to, canola oil, coconut oil, corn oil, cottonseed oil, flaxseed oil, palm oil, palm kernel oil, peanut oil, safflower oil, sesame oil, soyabean oil, sunflower oil, olive oil and vegetable oil.

[0054] In some embodiments of the invention, suitable edible oils may be heated prior to mixing to at least 60°C up to about 80°C. Thus, in certain embodiments, edible oils may be heated to at least 60°C, at least 65°C, at least 70°C, at least 75°C, and up to about 80°C. Preferably, the edible oils of the invention are heated to between 60°C to 80°C, further preferably 65°C to 75°C, and even further preferably 70°C to 75°C. [0055] In some embodiments, the invention provides a dispersion comprising one or more edible oils in an amount of at least 5% up to about 50% of the dispersion, by weight. Thus, in certain embodiments, the dispersion can comprise one or more edible oils in an amount of at least 5%, at least 10%, at least 20%, at least 30%, or at least 40%, of the dispersion, by weight. Preferably, the dispersion comprises edible oils in an amount of between 15% to 50% by weight of the dispersion, further preferably 20% to 45%, and even further preferably 20% to 40%.

[0056] In some embodiments, dependent on the temperature of preparation of the first phase, a quantity of the edible oils may be replaced by one or more omega-3 fatty acids, or one or more extracts or oils containing omega-3 fatty acids and/or LCPUFAs, so as to provide a boost to the bioactive efficacy of the resultant dietary supplement. In this embodiment, temperature control will be required to prevent degradation and/or rancidity of the omega-3 fatty acid.

[0057] The term "minerals" includes mineral extracts. Minerals suitable for use in the processes and dispersions of some embodiments are those suitable for inclusion in dietary supplements. A non-exhaustive list of minerals includes, but is not limited to, calcium carbonate, reduced iron, calcium chloride, magnesium carbonate, calcium gluconate, magnesium oxide, calcium hydroxide, magnesium sulfate, calcium iodate, manganese acetate, calcium iodobehenate, manganese carbonate, calcium oxide, manganese chloride, calcium sulfate (anhydrous or dihydrate), manganese citrate (soluble), cobalt acetate, manganese gluconate, cobalt carbonate, manganese orthophosphate, cobalt chloride, manganese oxide, cobalt oxide, manganese phosphate (dibasic), cobalt sulfate, manganese sulfate, copper carbonate, monocalcium phosphate, copper chloride, monosodium phosphate, copper gluconate, potassium bicarbonate, copper hydroxide, potassium carbonate, copper orthophosphate, potassium chloride, copper oxide, potassium iodate, copper pyrophosphate, potassium iodide, copper sulfate, potassium sulfate, cuprous iodide, sodium chloride, dicalcium phosphate, sodium bicarbonate, diiodosalicylic acid, sodium iodate, disodium phosphate, sodium iodide, ethylenediamine dihydroiodide, sodium sulfate, ferrous fumarate, sodium tripolyphosphate, iron ammonium citrate, sulfur, iron carbonate, thymol iodide, iron chloride, tricalcium phosphate, iron gluconate, zinc acetate, iron oxide, zinc carbonate, iron phosphate, zinc chloride, iron pyrophosphate, zinc oxide, iron sulfate, and zinc sulfate.

[0058] Minerals may be added in a dose amount suited to provision of a health benefit. In some embodiments, such dosages may be high or low dependent upon the presence of other active ingredients and the health benefit required. The quantity of minerals in the dispersion, and the quantity of solids generally, may require adjustment of the quantity of other ingredients to ensure suitable viscosity of the dispersion for handling and downstream processing. Particularly, where the size of the dosage form is important for patient compliance, for example where the dosage form is a capsule to be swallowed, or a paediatric dosage form, the quantity of minerals and solids in general may need to be adjusted. The solids content of the dispersion correlates generally to size of the dosage form. Preferably, when formulating dispersions so as to optimise viscosity and/or health benefit, the amount of minerals may be maintained at a constant amount, and the quantity of edible oils and optional viscosity modifying agents may be adjusted so as to ensure satisfactory viscosity for mixing and downstream processing.

[0059] In some embodiments, the dispersion comprises one or more minerals in an amount of at least 5% up to about 20% by weight of the dispersion. Thus, in certain embodiments, the dispersion can comprise one or more minerals in an amount of at least 5%, at least 10%, at least 15%, or up to about 20% by weight of the dispersion. Preferably, the dispersion comprises minerals in an amount of between 5% to 20% by weight of the dispersion, more preferably 5% to 15%, and even more preferably 10% to 15%.

[0060] In some embodiments, the dispersions particularly contain calcium. Calcium may be derived from calcium salts which are pharmaceutically acceptable, biologically absorbable and provide bioavailable calcium. Generally, preferred calcium salts are those which are the most absorbable and bioavailable and which have the densest crystalline forms. Suitable calcium salts include calcium carbonate, calcium bicarbonate, calcium citrate, calcium malate, calcium phosphate, calcium oxide, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium lactate, calcium orotate, calcium chloride, calcium hydroxide, calcium sulfate, calcium gluconate, calcium levulinate, calcium hydroxyapatite, calcium caseinate, calcium glubionate, and mixtures thereof. These calcium salts can be obtained synthetically, from mineral sources or from animal sources, such as algae, oyster shells, bone meal and egg shells.

[0061 ] In some embodiments, the dispersion comprises a natural calcareous mineral extract derived from algae, particularly Lithothamnion sp. In one embodiment, the dispersion comprises a calcareous mineral extract available under the trade mark Aquamin® F which is derived from Lithothamnion calcareum, and is preferably Lithothamnion tophiforme.

[0062] Aquamin® F has the following analysis profile:

Calcium 32% min.

Magnesium 2.2% min.

Moisture 5% max.

Lead 0.5ppm max.

Heavy Metals as Lead 10ppm max.

Arsenic 1 ppm max. Cadmium 0.5ppm max. pH (1 % aqueous solution) 9.5 - 10.5

Particle Size 25 m max.

Bulk density 0.7 - 0.9g/cm3

[0063] In some embodiments, viscosity modifying agents may optionally be added to the dispersion. Suitable viscosity modifying agents include, but are not limited to, food grade waxes, complex polysaccharide stabilisers and thickening agents such as alginates, locust bean gum, gellan gum, guar gum, gum arabic, tragacanth, carrageenan, acacia gum, xanthan gums, pectins, cellulose derivatives and other such natural or semi-synthetic polymer materials used in the field of foodstuffs and other dispersions for oral use, including mixtures of one or more thereof.

[0064] The term "waxes" includes naturally derived or synthetic waxes, or combinations thereof, that a person of ordinary skill in the art would know to be suitable in a dietary supplement formulation. Naturally derived waxes can include, but are not limited to, beeswax, castorwax, glycowax, and carnaubawax, and combinations thereof. Beeswax is one preferred wax for use in the processes and dispersions described.

[0065] In some embodiments, "wax" includes one or more wax esters. Generally, there are two types of waxes: hydrocarbon waxes and wax esters. Hydrocarbon waxes are typically petroleum-derived long hydrocarbon chains without any functional group, although some hydrocarbon waxes have natural biological sources. Wax esters are typically plant-derived or animal-derived, and are esters of long fatty acids and long fatty alcohols. [0066] Suitable wax esters can include a major fatty acid chain length of at least 14 carbons to no more than 36 carbons. Thus, in certain embodiments, a suitable wax ester can include a major fatty acid chain length of at least 16 carbons, at least 22 carbons, at least 24 carbons, or at least 26 carbons. Also, in certain embodiments, suitable wax esters can include a major fatty acid chain length of no more than 32 carbons, no more than 26 carbons, or no more than 24 carbons.

[0067] Suitable wax esters can include a major fatty alcohol length of at least 20 carbons and no more than 40 carbons. Thus, in certain embodiments, a suitable wax ester can include a major fatty alcohol length of at least 24 carbons, at least 28 carbons, at least 30 carbons, or at least 32 carbons. Also, in certain embodiments, a suitable wax ester can include a major fatty acid alcohol length of no more than 38 carbons, of no more than 34 carbons, no more than 32 carbons, or no more than 30 carbons.

[0068] Suitable waxes, if used, may have a melting point of at least 60°C up to about 90°C. Thus, in certain embodiments, a suitable wax can have a melting point of, for example, at least 60°C, at least 65°C, at least 70°C, at least 75°C, or at least 80°C. Consequently, in certain embodiments, a suitable wax according the invention, if used, may be heated to at least 60°C, at least 65°C, at least 70°C, at least 75°C, or at least 80°C. Preferably, waxes of the invention, if use, are heated to between 60°C to 80°C, more preferably 65°C to 75°C, and even more preferably 70°C to 75°C.

[0069] In some embodiments, the dispersion optionally comprises one or more viscosity modifying agents, particularly a wax or waxes, in an amount of at least 0.1 % up to about 15% of the dispersion, by weight. Thus, in certain embodiments, the dispersion can optionally comprise one or more waxes in an amount of at least 1 %, at least 3%, at least 5%, at least 7%, or at least 9%, of the dispersion, by weight. Preferably, when used, the dispersion comprises waxes in an amount of between 0.1 % to 15% by weight of the dispersion, further preferably 1 % to 10%, and even more preferably 2% to 7% by weight of the dispersion

[0070] In some embodiments, the dispersion optionally comprises additional additives. Such additives may include, but are not limited to hydrocolloids (such as gums, proteins, modified starches), binders, encapsulating agents/materials, matrix compounds, emulsifiers, surfactants, solubilising agents (such as emulsifiers and surfactants), polyunsaturated fatty acids, adsorbents, carriers or excipients, fillers, co-compounds, dispersing agents, wetting agents, plasticisers, processing aids (solvents), sweeteners, flavouring agents, flowing agents, taste masking agents, weighting agents, opacifying agents, gel forming agents, antioxidants, antimicrobials, pharmaceuticals, nutraceuticals, cofactors (such as coenzyme Q10, NADH, NADPH and coenzyme R), amino acids (such as glucosamine), colourants, herbal extracts, vitamins and trace elements. The amount and type of additional additives, if used, will depend on the purpose of the dispersion and the amount of other constituents present in the dispersion, provided that the requirements flowability and stability are met. Ultimately, the person skilled in the art would easily be able to determine the amount and type of additional ingredients required.

[0071 ] The term "emulsifier" refers to a substance having molecules with a "hydrophilic" or "water soluble" part, and a "lipophilic" or "fat-like" part. Emulsifiers suitable for the dispersion of the invention may include, but are not limited to: lecithins, hydroxylated lecithins, acetylated lecithins, single pure components of lecithins (such as phosphatidylcholine, phosphatidylinisitol, phosphatidic acid, and phosphate monoglycerides), monoglycerides, diacetyl tartaric esters of mono- and diglycerides, ethoxylated monoglycerides, acetylated monoglycerides, succinylated monoglycerides, fatty acid esters of polyglycerol, polyethylene glycol fatty acid esters, fatty acid esters of sugar compounds such as sucrose, fatty acid esters of sorbitan, citric acid esters of mono- and diglycerides, lactylic esters of fatty acids and their salts (sodium and calcium), succistearin, and mixtures thereof. [0072] In some embodiments, the dispersion optionally comprises emulsifier in an amount of at least 1 % up to about 5% by weight of the dispersion. Thus, in certain embodiments, the dispersion can optionally comprise emulsifier in an amount of at least 1 %, at least 2%, at least 3%, at least 4%, or up to about 5% by weight, of the dispersion. Preferably, when used, the dispersion of the invention comprises emulsifier in an amount of between 1 % to 5% by weight of the dispersion, more preferably 1 % to 4%, and even more preferably 1 % to 3%. Even more preferably, still, the emulsifier is a lecithin or combination of lecithins.

[0073] Suitable vitamins include, but are not limited to, vitamin A, B1 , B2, B6, B12, C, D, E, K, niacin, folic acid, thiamine, biotin and riboflavin. Trace elements may include, but are not limited to, bromine, chromium, cobalt, copper, fluorine, iodine, iron, manganese, molybdenum, selenium, silicon and zinc.

[0074] Suitable herbal extracts include, but are not limited to, American ginseng, avena sativa, chamomile, echinacea, fenugreek, grapeseed, hawthorn, hops, horesradish, Korean ginseng, lemon balm, marshmallow, milk thistle, rosehip, withania, Siberian ginseng, slippery elm, St John's wort, willow bark, and zizyphus.

[0075] In some preferred embodiments of the invention, the dispersion may comprise: algae-derived DHA from at least 250 mg up to 1000 mg per gram of the dispersion, preferably 300 mg to 650 mg, more preferably 350 mg to 600 mg, even more preferably, 400 mg to 500 mg, a natural mineral extract, preferably Aquamin® F, from at least 10 mg, preferably 25 mg to 200 mg, more preferably 30 mg to 150 mg, 40 mg to 100 mg, even more preferably 50 to 100 mg. an emulsifier, preferably lecithin, from at least 15 mg to 40 mg per gram of the dispersion, preferably 20 to 35 mg, and more preferably 25 to 30 mg, a wax, preferably beeswax from at least 20 mg up to 70 mg per gram of the dispersion, preferably 30 mg to 60 mg, more preferably 40 mg to 55 mg, even more preferably, 45 mg to 50 mg, a first edible oil, preferably hydrogenated vegetable oil, from at least 100 mg up to 250 mg per gram of the dispersion, preferably 130 mg to 230 mg, further preferably 150 mg to 200 mg, even further preferably, 170 mg to 190 mg, a second edible oil, preferably soyabean oil, from at least 50 mg up to 200 mg per gram of the dispersion, preferably 70 mg to 160 mg, more preferably 80 mg to 140 mg, even more preferably, 90 mg to 120 mg, optionally fish oil, from at least 100 mg up to 400 mg per gram of the dispersion, preferably 150 mg to 350 mg, more preferably 200 mg to 300 mg, even more preferably, 250 mg to 300 mg, and optionally krill oil, from at least 100 mg up to 400 mg per gram of the dispersion, preferably 150 mg to 350 mg, more preferably 200 mg to 300 mg, even more preferably, 250 mg to 300 mg.

[0076] Ingredients suitable for manufacturing the dispersion may be mixed by conventional mixing apparatus including, but not limited to, a high-speed mixer, a homogenizer, a high-speed impact mill, a Banbury mixer, a homomixer, a kneader, a ball mill, a vibration ball mill, an epicyclic ball mill, an attritor, a sand mill, a bead mill, a colloidmill, a jet mill, a roller mill, a trommel and a high-speed stone mill, and combinations thereof. [0077] One of the main considerations in developing the dispersion of the invention is to have the bioactive component or components optimally delivered, absorbed and metabolised in vivo. Other considerations include, but are not limited to, the odour, taste, colour, dosage size, and dosage frequency. In this regard, in some embodiments, the dispersion of the invention may optionally be further processed into the form of a pill, capsule, gelcap, caplet, softgel, softgel capsule liquid or tablet. Flowability characteristics of the dispersion maybe adjusted by use of a viscosity modifier such as previously described so as to enable smooth handling in for example, encapsulation processes.

[0078] Variations in formulations can provide hard- or soft-shelled capsules/tablets/pills. The formulations in capsule/tablet/pill form may comprise the dispersion containing a bioactive component/components and other additives.

[0079] One suitable dosage form is an encapsulated dispersion. Processes for encapsulation and the formation of the capsule will be well understood by those skilled in the art.

[0080] Another suitable dosage form is a softgel or softgel capsule. The general method of formation of a softgel will be understood by those skilled in the art. Commonly, softgels are a gelatin based shell surrounding a liquid fill. Softgel shells may be a combination of gelatin, water, opacifier and a plasticiser such as glycerin and/or sorbitol(s). One method of formation is in an encapsulation process using a rotary die. One standard base mix for a softgel formulation may include soyabean oil, wax mixture (hydrogenated vegetable oil and beeswax) and lecithin. In such a softgel formulation, the solids content may range from 0-60%, the wax mixture is typically about 10% of the total oils present but may be adjusted dependent on the required viscosity. Lecithin may be present in an amount of about 3% of the total oils present.

[0081 ] Solid-state components, such as vitamins, minerals or other additives, preferably have a particle size which is optimised for formulation into a stable slurry or dispersion for both processing and stability purposes. Preferably, 100% of solid state components pass though a No. 80 sieve, that is are smaller than 180 micron.

[0082] Further examples of the invention are described below. However, it should be noted that the invention should not be limited to these examples, and that the invention is susceptible to variations, modifications and/or additions other than those specifically described, and it is to be understood that the invention includes all such variations, modifications and/or additions which fall within the scope of the claims.

EXAMPLES

Example 1

[0083] A dispersion was made having the following ingredient profile (showing percentage weight of total weight of the dispersion):

Ingredient %

Algal DHA 53.3

Mineral Extract 10.6

Lecithin 2.7

Beeswax 5.4

Hydrogenated vegetable oil 16.1

Soyabean oil 1 1 .9 The dispersion showed good short term stability and suitability for delivery of the mineral and DHA content as a nutritional supplement.

Examples 2A-E

[0084] Further examples of dispersions prepared according to the process of the invention are as follows:

Ingredient

/ A B C D weight mg/g

Algal DHA 322 322 606 500

Mineral Extract 65 65 121 50

Fish oil 322

Krill oil 322

Lecithin 29 29 27 25

Beeswax 46 46 44 50.5

Hydrogenated vegetable 141 141 134 151 .5 oil Soyabean oil 73 73 73 1 12

Example 3

[0085] It is expected that dispersions having the following ingredient profile could be prepared according to the process of the invention. In these formulations, the quantity of mineral is reduced so as to enable ease of ingestion of the dosage form, or so as to be able to include further additives such as additional omega-3 fatty acid, vitamins or herbs in a suitable dosage form:

Ingredient mg/g

Algal DHA 400-1000

Mineral extract 50-100

Lecithin 1 -40

Beeswax 10-55

Hydrogenated vegetable oil 50-150 edible oil (eg soyabean or marine-derived oil) 10-150

Example 4

[0086] A dispersion of each of the compositions Examples 1 and 2 was made using the following steps: • Beeswax, hydrogenated vegetable oil and soyabean oil were heated with stirring to 65-75°C.

• The mixture was allowed to cool to 55-60 °C, and lecithin was added with stirring.

• The mixture was further cooled to 35-40°C and mineral extract was added portion-wise with stirring.

• Algal DHA, cooled to 1 -10 °C, was added to the mixture with stirring to give a uniform dispersion.

Dispersion made in accordance with this process showed excellent short term stability and suitability for delivery of the mineral and DHA content as a nutritional supplement.

Example 5

[0087] Stability studies were carried out on samples prepared according to Examples 1 to 3 as follows:

• under accelerated conditions at 40^°C, 75% relative humidity (RH),

• under standard conditions at ambient room temperature 20-25^°C, ambient RH varying from 30% to about 70%,

• at 30^°C, 65% RH, and

• at 5^°C, less than 10% RH.

[0088] The length of the study in relation to the 30^°C and 40^°C conditions was 7 days. The length of the study in relation to the 20-25^°C and 5^°C conditions was greater than 24 days. [0089] As shown in Table 1 , the samples had the appearance of a light green liquid slurry. In all stability studies phase separation of the sample was not significant and the phases remained dispersed for the length of the study.

Example 6

[0090] In order to establish the stability of the formulations prepared in accordance with the invention, batches of commercial softgel capsules were prepared in a manner that would be well understood by those skilled in the art containing a dispersion prepared according the process of the invention. Two different formulations were tested:

Ingredient Formulation (i) Formulation (ii) mg/capsule Mg/capsule

Life's DHA® 500 500

Calcified 50 50

Lithothamnion

tophiforme

Krill oil 500 nil

Concentrated omega- nil 750

3 fatty acids from fish lecithin 30 30 beeswax 45 45 hydrogenated 145 145 vegetable oil

Soyabean oil 39 38.75 gelatin 335 370 glycerol 104 1 15

Water - purified 42.89 50 cochineal 2.1 2.77

Alpha-tocopherol 1 1 .25

Opaque red Yellow/orange

Visual characteristics complete phase complete phase of dispersion within continuity - no continuity - no

capsule upon separation separation manufacture

paste thick emulsion

[0091 ] These batches were visually tested for shelf stability by cutting the softgel capsule open and examining the contents for inconsistencies and changes in colouration, viscosity (consistency) and phase continuity of the dispersion contained within the capsule. Comparison was made with a freshly made sample. The results are shown in table 2. [0092] Results showed that the softgel capsules tested having an age of 6-7 months having been stored at room temperature had no disintegration in shelf stability when compared to freshly prepared softgel capsules.

Table 1 . Stability Comparison of Dispersions

Table 2. shelf - stability of softgel capsules containing dispersions measured according to examples 6

Example Manufacture FormulConsistency/ Colour No Date tested Date ation capsules Number type Separation tested

A Sept 2014 (i) Paste, no separation Red 3 March 2015 B Sept 2014 (i) Paste, no separation Red 4 March 2015 C Aug 2014 (ϋ) Thick emulsion, no Yellow/ 4 March 2015 separation orange

D Aug 2014 (i) Paste, no separation Red 6 March 2015 E Aug 2014 (i) Paste, no separation Red 6 March 2015 F Aug 2014 (i) Paste, no separation Red 6 March 2015 G Oct (ϋ) Thick emulsion, no Yellow/ 4 March 2015

2014 separation orange

H Nov 2014 (i) Paste, no separation Red 6 March 2015 J Aug 2014 (ϋ) Thick emulsion, no Yellow/ 6 March 2015 separation orange

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1 . A process of preparing a shelf-stable dispersion comprising the step of combining: a first phase comprising one or more edible oils, one or more minerals, and optionally, one or more viscosity modifying agents, and a second phase comprising one or more omega-3 fatty acids, wherein, when combining said phases, there exists a temperature differential of at least 15°C between said first phase and said second phase which promotes the formation of the stable dispersion.

2. The process according to claim 1 , wherein said second phase is in a chilled state relative to ambient temperature at the time of its combination with said first phase.

3. The process according to claim 1 or 2, wherein said second phase consists of omega-3 fatty acid.

4. The process according to any one of claims 1 -3 wherein the omega-3 fatty acid is an extract of, or from a marine source.

5. The process according to any one of claims 1 -4 wherein said omega-3 fatty acid is chilled to a temperature of about 0°C to 20°C.

6. The process according to any one of claims 1 -5, wherein said one or more minerals is a calcareous mineral extract.

7. The process according to any one of claims 1 -6 in which the first phase further includes krill oil or concentrated fish oil.

8. The process according to any one of claims 1 -7 wherein the process produces a dispersion with a shelf stability of at least 3 months, preferably of at least 6 months, more preferably of at least 12 months, more preferably still of at least 18 months and even more preferably still of at least 24 months.

9. A shelf stable dispersion of a bioactive agent prepared by a process comprising combining: a first phase comprising one or more edible oils, one or more minerals, and optionally, one or more viscosity modifying agents, and a second phase comprising one or more omega-3 fatty acids, wherein, when combining said phases, there exists a temperature difference of at least 15°C between said first phase and said second phase, which promotes the formation of the stable dispersion.

10. The process according any one of claims 1 -8 or the shelf stable dispersion according to claim 9, wherein the shelf-stable dispersion comprises beeswax, soyabean oil, hydrogenated vegetable oil, lecithin, a calcareous mineral extract and one or more omega-3 fatty acids, and optionally, one or more additional additives.

1 1 . The process or the shelf stable dispersion according to claim 10 or 1 1 wherein the process of preparing the shelf-stable dispersion comprises the steps of:

(i) heating the soyabean oil, hydrogenated vegetable oil and beeswax to a temperature of between 60°C to 80°C to form a liquid wax mixture,

(ii) cooling the liquid wax mixture to a temperature between 45°C to 60°C, (iii) mixing lecithin with the cooled mixture of step (ii),

(v) mixing the calcareous mineral extract with the further cooled mixture of step (iv),

12. The shelf- stable dispersion of any one of claims claim 9-1 1 comprising: omega-3 fatty acid 30 to 70% by weight calcareous mineral extract 5 to 20% by weight lecithin 1 to 5% by weight beeswax 0.1 to 15% by weight hydrogenated vegetable oil 5 to 50% by weight soyabean oil 5 to 50% by weight and optionally comprising one or more further additives.

13. The shelf-stable dispersion of anyone of claims 9-12 wherein the dispersion has a shelf stability of at least 3 months, preferably of at least 6 months, more preferably of at least 12 months, more preferably still of at least 18 months and even more preferably still of at least 24 months

14. A shelf stable dispersion of a bioactive agent comprising one or more edible oils, one or more minerals, one or more omega-3 fatty acids and optionally one or more viscosity modifying agents in conjunction with pharmaceutically acceptable excipients wherein said dispersion has a shelf stability of at least 3 months, preferably of at least 6 months, more preferably of at least 12 months, more preferably still of at least 18 months and even more preferably still of at least 24 months.

15. The shelf- stable dispersion of claim 14 comprising: omega-3 fatty acid 30 to 70% by weight calcareous mineral extract 5 to 20% by weight lecithin 1 to 5% by weight beeswax 0.1 to 15% by weight hydrogenated vegetable oil 5 to 50% by weight soyabean oil 5 to 50% by weight and optionally comprising one or more further additives wherein said dispersion has a shelf stability of at least 3 months, preferably of at least 6 months, more preferably of at least 12 months, more preferably still of at least 18 months and even more preferably still of at least 24 months.

SANOFI AVENTIS HEALTHCARE PTY LIMITED

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