Oil-in-water emulsions with agar and diacetyl tartaric acid esters of mono- and di-glycerides (DATEM)

Abstract

The present invention relates to compositions for oral administration provided in the form of gelled oil-in-water emulsions, methods for their preparation, and their use as pharmaceutical and nutraceutical products. In particular, the present invention relates to orally administrable gelled oil-in-water emulsions that are self-supporting viscoelastic solids having a gelled aqueous phase that comprises a gelling agent that is agar, the gelling agent having a water activity in the range of about 0.4 to about 0.9, and that are stabilized by a surfactant that comprises an ester of glycerol having at least one hydroxyl group esterified with diacetyltartaric acid and at least one hydroxyl group esterified with a fatty acid.

Description

[Technical field]

[0001] The present invention relates generally to compositions for oral administration provided in the form of gelled oil-in-water emulsions, their methods of preparation, and their use as delivery vehicles for pharmaceutical and nutraceutical products. The compositions can be provided in soft, yet chewable, easy-to-swallow unit dosage forms.

[0002] More specifically, the present invention relates to oral compositions acceptable to patients and consumers who wish to abstain from consuming animal by-products, such as those who follow a vegetarian diet or who are vegans. The present invention also relates to oral compositions acceptable to pescetarians. [Background technology]

[0003] Soft, chewable dosage forms are alternatives to traditional oral dosage forms such as tablets, capsules, elixirs, and suspensions. They are easier to swallow than tablets and capsules, and are particularly suitable for children and the elderly, as well as those suffering from swallowing disorders. Such dosage forms are a popular choice for nutritional supplements containing vitamins and / or minerals (so-called "nutraceutical products"), and are also suitable for the delivery of active pharmaceutical ingredients (Active Pharmaceutical Ingredients, APIs). The active ingredient (nutraceutical product or pharmaceutical) may be present in the form of lipids in a gelled oil-in-water emulsion, as dispersed particles, or dissolved in the oil or water phase of such an emulsion.

[0004] Chewable compositions in unit dosage form, comprising an oil-in-water emulsion in which the aqueous phase is gelled and the oil phase comprises physiologically acceptable unsaturated fatty acid ester, are disclosed, for example, in WO 2007 / 085840. These compositions are suitable for oral delivery of fish oil without any bad smell or taste. In WO 2010 / 041015 and WO 2012 / 140392, drug substances are dissolved or dispersed in the oil or aqueous phase of the gelled oil-in-water emulsion to mask the taste of the drug substances.

[0005] A range of gelling agents may be used in the preparation of soft, chewable dosage forms, such as the gelled oil-in-water emulsions described in WO 2007 / 085840, WO 2010 / 041015 and WO 2012 / 140392, but gelatin is by far the most widely used due to its availability, ease of use and its sol-gel transition temperature. Gelatin is produced by partial hydrolysis of collagen found in the skin, bones and connective tissues of animals, most commonly derived from pork, beef and fish sources. The sol-gel transition temperature of gelatin generally corresponds to the body temperature of the animal from which it is obtained. Thus, gelatin from mammalian sources has a transition temperature similar to human body temperature, resulting in a gel that is solid at room temperature but dissolves in the mouth when ingested. Thus, gelatin-based dosage forms provide a pleasant "melt in the mouth" texture or "mouthfeel". Gelatin also provides rapid and consistent dissolution kinetics of the dosage unit in the gastrointestinal tract, which can be beneficial in facilitating rapid uptake of any active ingredient.

[0006] Gelatin has significant surface active properties that allow it to act as an emulsifier as well as a gelling agent. This makes it a particularly good choice for use as a gelling agent to produce chewable oil-in-water emulsions. Gelatin-based emulsions typically experience an "active filler effect" in which the oil droplets strongly interact with the surrounding gel network, and are commonly referred to as "active fillers." If the oil droplets are small enough, this interaction between the gel network and the oil droplets increases the storage modulus of the gelled emulsion compared to a gel without oil, i.e., the gel alone. In contrast, oil droplets that are distributed throughout the gel with little or no interaction with the gel network are known as "inert fillers" and result in a lower modulus of the gelled emulsion than that of the gel alone. If the oil droplets of a gelled emulsion are present as "inert fillers," the emulsion may not be stable over time. This can result in destabilization of the emulsion and "leaching out" of the oil.

[0007] Despite the many advantageous properties of gelatin for use in the manufacture of soft, chewable dosage forms, its animal origin makes it unacceptable to many patients and consumers due to religious beliefs or dietary choices. As an animal by-product, gelatin is, for example, unacceptable to vegans.

[0008] Gelling agents previously proposed for use in the manufacture of soft, chewable dosage forms, such as gelled oil-in-water emulsions, that are not of animal origin, include non-proteinaceous substances such as alginates, carrageenans, and pectins. However, the gelling properties of these materials can be difficult to control due to their need for complexation with metal ions, temperature changes, and / or pH adjustments to produce the desired "gel". This is not ideal for dosage forms manufactured on a commercial scale.

[0009] Another gelling agent that is widely used in food and other non-food applications is agar. Agar is extracted from marine red algae and contains a polysaccharide that contains galactose subunits. It is a thermosetting polymer that gels at about 30°C to 45°C. Agar melts at about 85°C to 90°C and once dissolved, it retains its liquid state until cooled to about 40°C. Due to its large hysteresis between gelling and dissolution temperatures, it has the potential for use in large-scale production of dosage units formed from gelled oil-in-water emulsions. However, unlike gelatin, which produces soft, flexible gels that can withstand a high degree of compression before breaking, agar-based gels are hard and brittle. While gelatin-based gels can withstand up to 70% to 90% compression before breaking, for example, agar-based gels will typically fragment under deformations on the order of 20%. This severely limits its use in the manufacture of any dosage unit that needs to be soft, chewable, and have a pleasant mouthfeel. It also precludes its use in "push-through" blister packs.

[0010] Unlike gelatin-based gels, agar-based gels are also prone to syneresis, i.e., the spontaneous release of water from the gel upon aging. Gels are 3D networks of polymers that crosslink with each other and trap water within their structure. If the polymer network is not disturbed, the water remains in place. However, over time, the polymers that form the gel may shrink or change their conformation, allowing the water to escape and shrinking the gel. The seepage of water from the gel is known as "syneresis", which must be minimized in any oral dosage unit due to the need for it to have a suitable shelf life, i.e., it should remain stable over an extended period of time. One of the ways in which the problem of syneresis in agar gels was originally addressed is by increasing the agar concentration. However, this can result in a harder, more solid, and more brittle gel, which is undesirable when trying to provide a soft, chewable dosage form.

[0011] The use of agar as a gelling agent to produce gelled oil-in-water emulsions presents additional challenges. Unlike gelatin, which has significant surface active properties, agar must be used with a surface active agent ("surfactant") to provide a sufficiently stable emulsion. Although a wide range of food grade surfactants are known and used in the art, the applicants recognize that not all of these are suitable for use in stabilizing gelled agar-based oil-in-water emulsions.

[0012] The types of gelling oil-in-water emulsions disclosed in WO 2007 / 085840, WO 2010 / 041015 and WO 2012 / 140392 present particular challenges when trying to replace gelatin with agar as the gelling agent. A prerequisite for the stabilization of any oil-in-water emulsion is that the selected surfactant has the ability to at least partially dissolve or disperse in the continuous aqueous phase (i.e. in water). However, to reduce the possibility of microbial growth and thus extend the shelf life, the gelling oil-in-water emulsion should have a low water activity, i.e. a low content of "free" water. In the gelatin-based emulsions disclosed in WO 2007 / 085840, WO 2010 / 041015 and WO 2012 / 140392, low water activity is achieved by including a high content of sugar alcohol (bulking agent) in the gelling aqueous phase. As a result, these gelling emulsions have the advantage that they have a low water activity (less than 0.8, e.g., typically about 0.75 a w), which differs from most conventional oil-in-water emulsions. The presence of buffer salts (pH adjusters) in the aqueous phase also results in a relatively low pH (typically 4-4.7). Together, these factors cause intense competition for "free" water and possible loss of electrostatic charge of any surfactant present (due to the low pH). Applicant has found that many conventional low molecular weight surfactants used in food or pharmaceutical products are unable to provide stable emulsions under these conditions. Examples of such surfactants include LACTEM (consisting of lactic acid esters of mono- and di-glycerides) and polysorbates such as Tween 80. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2007 / 085840 [Patent Document 2] International Publication No. 2010 / 041015 [Patent Document 3] International Publication No. 2012 / 140392 Summary of the Invention [Problem to be solved by the invention]

[0014] Thus, there continues to be a need for alternative soft but chewable compositions for oral delivery of pharmaceutical and / or nutraceutical products suitable for vegetarians, piscine vegetarians and vegans. In particular, there is a need for such compositions that can provide an acceptable alternative to conventional gelatin-based oil-in-water emulsions in terms of their "chew" and mouthfeel properties, while having adequate stability (i.e., shelf life) for use as pharmaceutical and / or nutraceuticals. [Means for solving the problem]

[0015] [Summary of the Invention] The applicant now proposes a gelled oil-in-water emulsion that is acceptable to vegetarian, piscineo-vegetarian or vegan patients and consumers, especially those following a vegetarian or vegan diet. The emulsion utilizes agar as a gelling agent and is stabilized using specific low molecular weight surfactants. These surfactants include esters of glycerol in which at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with a fatty acid. The applicant has found that these specific surfactants are effective in stabilizing agar-based gelled oil-in-water emulsions with low water activity while also providing gelled emulsions with desirable rheological properties for oral delivery of active agents in soft but chewable dosage forms. The applicant has also found that such surfactants can provide emulsions with small droplet sizes and therefore high initial lipolysis rates after oral delivery. This may be desirable since lipolysis is a prerequisite for intestinal uptake of lipids derived from triglycerides.

[0016] Thus, in one aspect, the invention provides an orally administrable gelled oil-in-water emulsion that is a self-supporting viscoelastic solid having a gelled aqueous phase that comprises a gelling agent that is agar, the orally administrable gelled oil-in-water emulsion having a water activity in the range of about 0.4 to about 0.9, and stabilized by a surfactant that comprises an ester of glycerol having at least one hydroxyl group esterified with diacetyltartaric acid and at least one hydroxyl group esterified with a fatty acid.

[0017] In another aspect, the invention provides a method of preparing a gelled oil-in-water emulsion as described herein, comprising forming an oil phase comprising one or more physiologically acceptable lipids, forming an aqueous phase comprising a gelling agent that is agar, combining the oil phase and the aqueous phase in the presence of a surfactant comprising an ester of glycerol having at least one hydroxyl group esterified with diacetyltartaric acid and at least one hydroxyl group esterified with a fatty acid to form an oil-in-water emulsion, and gelling the emulsion.

[0018] In a further aspect, the invention provides a gelled oil-in-water emulsion as described herein for oral use as a medicament or in therapy.

[0019] In another aspect, the present invention provides a gelled oil-in-water emulsion as described herein containing at least one pharma- ceutical active ingredient, for oral use in the treatment of a condition responsive to said pharma-ceutical active ingredient.

[0020] In another aspect, the invention provides the use of a pharma- ceutical active ingredient in the manufacture of a medicament for oral use in the treatment of a condition responsive to the pharma- ceutical active ingredient, wherein the medicament is provided in the form of a gelled oil-in-water emulsion as described herein.

[0021] In another aspect, the invention provides a method of treating a human or non-human animal subject (e.g., a patient) for a condition responsive to a pharma- ceutical active agent, comprising orally administering to the subject a pharma- ceutical effective amount of the agent in the form of a gelled oil-in-water emulsion as described herein.

[0022] In another aspect, the present invention provides the use of a gelled oil-in-water emulsion as described herein as a dietary supplement product. [Brief description of the drawings]

[0023] [Figure 1] 1 shows the oil droplet size distribution for agar with 0.69% by weight PANODAN®, measured initially and after 20 hours in a 55° C. water bath with gentle magnetic stirring. [Diagram 2] FIG. 1 shows the hardness (force) of an agar-based gelling oil-in-water emulsion according to the present invention when subjected to large scale deformation. [Diagram 3] 1 shows the initial oil droplet size distribution for agar with 0.69%, 0.46% and 0.23% by weight PANODAN® in a 55° C. water bath with gentle magnetic stirring. [Figure 4] 1 shows the variation in oil droplet size for agar with 0.69 wt % PANODAN® after the addition of various amounts of HCl. [Diagram 5] FIG. 1 shows the initial lipolysis rate of an agar-based gelling oil-in-water emulsion according to the present invention. [Figure 6] Figure 2 shows droplet size volume distributions for "1 / 2 s.alk" and "3 / 4 s.alk" oil-in-water formulations with PS80 as surfactant and 25 wt% oil. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] definition The term "gel" refers to a form of matter intermediate between a solid and a liquid. The formation of a "gel" typically involves linking or crosslinking polymer chains to form a three-dimensional network in which a solvent (e.g., water) is trapped or immobilized to form a sufficiently rigid structure that resists flow at ambient temperatures, i.e., temperatures below about 25° C., preferably below about 20° C. In rheological terms, a "gel" may be defined according to its storage modulus (or "elastic modulus") G', which describes the elasticity (energy storage) of the material, and its loss modulus (or "viscous modulus") G'', which describes the viscosity (energy loss) of the material. The ratio of the storage modulus to the loss modulus, tan δ (equal to G'' / G'), also referred to as the "loss tangent", provides a measure of how much the stress and strain are out of phase with each other.

[0025] A material that is "viscoelastic" is characterized by rheological properties that resemble in part the rheological behavior of a viscous fluid and in part the rheological behavior of an elastic solid.

[0026] The gelled oil-in-water emulsions according to the present invention are "self-supporting viscoelastic solids". This is intended to mean that they exhibit intermediate properties between solids and liquids, but have predominantly solid behavior, i.e., they have rheological properties more similar to those of solids than to those of liquids. The "predominant behavior of solids" cannot be diluted (i.e., destroyed) by adding more solvent. In contrast, in the case of weak (or entangled) gels that lack stable (i.e., long-lived) intermolecular crosslinks, the entangled network structure of the gel can be removed by adding solvent and can be easily destroyed even at very low shear rates / shear stresses.

[0027] The gelled oil-in-water emulsions of the present invention exhibit mechanical rigidity, but in contrast to solids, they are deformable. Specifically, the gelled emulsions described herein have a storage modulus G' that is greater than their loss modulus G'' (i.e., G'>G'') over a wide frequency range, e.g., 0.001 Hz to 10 Hz, when measured at ambient temperature (i.e., temperatures in the range of 18°C ​​to 25°C, e.g., 20°C) and 0.1% strain. The storage and loss moduli may be measured using known methods, e.g., using a Kinexus Ultra+Rheometer applying a C4 / 40 measurement geometry. There is expected to be no difference between the storage and loss modulus values ​​when measured using other types of rheometers within the linear viscoelastic range.

[0028] More specifically, the gelled oil-in-water emulsions described herein will have the following properties: G'>G'' over the frequency range of 0.001 Hz to 10 Hz at 0.1% strain, and a storage modulus (G') at ambient temperature (i.e., at temperatures in the range of 18°C ​​to 25°C, e.g., 20°C) in the range of 10 Pa to 200,000 Pa, preferably 100 Pa to 100,000 Pa, more preferably 500 Pa to 50,000 Pa.

[0029] Weak gels will typically have a loss tangent of tan δ>0.1. For strong, or fully developed, gels, G'>>G'' and lower tan δ values ​​(<0.1) are observed. The gelled oil-in-water emulsions described herein would generally be considered "strong gels" at ambient temperatures, i.e., temperatures in the range of 18°C ​​to 25°C, e.g., 20°C.

[0030] As used herein, the term "gelation" refers to the formation of a "gel." The term is used herein in reference to both the physical properties of the aqueous phase of an emulsion and the physical properties of an oil-in-water emulsion. As will be understood, the oil droplets behave more or less like a solid when dispersed throughout the gelled aqueous phase of the oil-in-water emulsions that are the subject of the present invention. Thus, the "gelation" property of the aqueous phase is also characteristic of the oil-in-water emulsion, i.e., it may also be considered "gelation" as described herein.

[0031] Unless otherwise defined, the term "liquid" as used herein refers to a substance that is free to flow and maintains a constant volume. This includes thick and viscous liquids that flow. A "liquid" has a loss modulus (G'') greater than its storage modulus (G') and a loss tangent (tan δ) greater than 1.

[0032] As used herein, the term "water activity ("a w "Water activity" refers to the partial vapor pressure of water in a composition at a particular temperature divided by the standard partial vapor pressure of water at the same temperature. Thus, water activity serves as a measure of the amount of free (i.e., unbound) water in a composition. It is a w =p / p0 (where p is the partial vapor pressure of water in the composition and p0 is the vapor pressure of pure water at the same temperature). It can be calculated as follows:

[0033] Alternatively, the water activity is a w =l w x w (In the formula, l w is the activity coefficient of water, and x w is the mole fraction of water.) It can be calculated as follows:

[0034] Water activity may be measured by methods known to those skilled in the art, for example by using a Rotronic Hygrolab instrument. Unless otherwise stated, water activity is measured at ambient temperature, i.e., 21° C.±2° C.

[0035] As used herein, the term "pH" is a measure of hydrogen ion concentration in an aqueous medium at ambient temperature, i.e., 21° C.±2° C. pH can be measured by methods known to those skilled in the art, for example, using a pH measuring contact electrode such as a calibrated Eutech Instruments pHSpear.

[0036] As used herein, the term "surfactant" refers to a surface-active compound or composition capable of reducing the interfacial tension between two immiscible liquids (e.g., the interface between oil and water). It may consist of a single component or may be a mixture of components. As described herein, the method of producing surfactants for use in the present invention will typically provide a mixture of different components.

[0037] As used herein, the term "fatty acid" refers to an unbranched or branched, preferably unbranched, hydrocarbon chain having a carboxylic acid (-COOH) group at one end, conventionally referred to as the α (alpha) end. The hydrocarbon chain may be saturated or (mono- or poly-) unsaturated. By convention, the numbering of the carbon atoms begins at the α end, such that the carbon atom of the carboxylic acid group is carbon atom number 1. The other end is usually a methyl (-CH3) group, conventionally referred to as ω (omega), such that the terminal carbon atom is the ω-carbon. Any double bonds present may be in a cis- or trans-configuration. The nomenclature "ω-x" is used to indicate that the double bond is on the xth carbon-carbon bond, counting from the terminal carbon (i.e., the ω-carbon) toward the carbonyl carbon.

[0038] By "physiologically acceptable" is meant any component that is suitable for administration to the human or non-human animal body, particularly suitable for oral administration.

[0039] By "drug product" is meant any product intended for medical purposes, e.g., for the treatment or prevention of a disease, condition, or disorder of the human or non-human animal body, or for preventing the recurrence thereof, or for the reduction or elimination of any of the symptoms of such disease, condition, or disorder. The use and manufacture of products as "drug products" will be heavily regulated by government agencies. Products may, but need not, be prescribed by a physician. For example, products may be available "over the counter," i.e., without a prescription.

[0040] "Treatment" or "treating" includes any therapeutic application that can benefit a human or a non-human animal (e.g., a non-human mammal). While both human and animal treatments are within the scope of the invention, the invention is primarily directed to human treatment. Veterinary treatment includes the treatment of livestock and domestic animals (e.g., pets such as cats, dogs, rabbits, etc.). Treatment may be in respect of an existing disorder or may be prophylactic.

[0041] In contrast to pharmaceuticals, "nutraceutical products" are not required to be subject to regulatory approval. The term "nutraceutical product" is used herein to refer to products that are generally considered to be beneficial for maintaining or enhancing the health and / or general well-being of a human or non-human animal subject. Such substances include, in particular, nutritional supplements such as vitamins and minerals that are intended to enhance the health of a subject (e.g., a human subject).

[0042] As will be appreciated, some substances may be considered both "drugs" and "dietary supplements." The classification of a substance as either, or indeed both, may vary from country to country depending on local regulations related to drugs. It may also depend on the recommended daily dosage of any given substance. For example, a higher daily dosage of a particular vitamin, such as vitamin D, may be regulated as a drug, while a lower daily dosage may be considered a dietary supplement.

[0043] By "pharmaceutical composition" is meant a composition in any form suitable for use for pharmaceutical purposes.

[0044] By "nutraceutical composition" is meant a composition in any form suitable for use for nutritional purposes.

[0045] A "pharmaceutical effective amount" refers to an amount that will produce a desired pharmacological and / or therapeutic effect, i.e., an amount of an agent effective to achieve its intended medical purpose. While the needs of individual patients may vary, determination of optimal ranges of effective amounts of any active agent is within the ability of one of ordinary skill in the art.

[0046] A "nutraceutical effective amount" refers to an amount that will produce a desired nutraceutical effect, i.e., an amount of an agent that is effective to achieve its intended nutraceutical purpose. While the individual needs of a subject may vary, determining the optimal range of effective amounts of any active agent is within the ability of one of ordinary skill in the art.

[0047] The term "capsule" is used herein to refer to a unitary dosage form having a casing or coating (referred to herein as a "capsule shell") that encloses a gelled oil-in-water emulsion as defined herein.

[0048] As used herein, "animal by-product" is intended to refer to any product derived from, isolated from, or purified from one or more parts of an animal's body (e.g., bone, skin, tissue, meat, cartilage, hoof, horn, etc.). It is also intended to refer to any composition prepared by processing an animal by-product, such as a derivatized, functionalized, or otherwise chemically or physically modified animal by-product. As used herein, "animal by-product" is not intended to include any compound or composition derived from, isolated from, or purified from milk, eggs, or animal milk or eggs. The term "animal by-product" does not include any synthetic materials or any materials obtained from any plant, fungal, bacterial, or algal source.

[0049] As used herein, the term "vegetarian diet" generally refers to a diet that lacks any meat and also lacks any animal by-products as defined herein. A "vegetarian diet" may include animal milk and animal eggs, and any products derived, isolated, or purified therefrom. Such diets are also commonly known as "ovo-lactovegetarian" or "lacto-ovovegetarian" diets, and include milk, cheese, other dairy products, and eggs, in addition to foods from plants. A "piscine vegetarian diet" refers to a diet in which the only source of meat is fish and seafood. A "vegan diet" refers to a diet that is entirely vegetarian and includes only foods from plants (e.g., fruits, vegetables, grains, legumes, seeds, and nuts). Any reference herein to a product, substance, composition, or formulation that is "suitable" for a given diet means that it would be considered acceptable to those following that particular diet. The terms "vegetarian," "piscine vegetarian," and "vegan" are intended to refer to those who follow a vegetarian, piscine vegetarian, or vegan diet, respectively.

[0050] In a first aspect, the present invention provides an orally administrable gelled oil-in-water emulsion that is a self-supporting viscoelastic solid having a gelled aqueous phase that comprises a gelling agent that is agar, the orally administrable gelled oil-in-water emulsion having a water activity in the range of about 0.4 to about 0.9, and stabilized by a surfactant that comprises an ester of glycerol having at least one hydroxyl group esterified with diacetyltartaric acid and at least one hydroxyl group esterified with a fatty acid.

[0051] The aqueous phase of the emulsion according to the present invention comprises water and is gelled using agar as a gelling agent. The aqueous phase is also referred to herein as the "continuous phase" of the emulsion. The gelling agent may be a single type of gelling agent or a mixture of different types of gelling agents. When more than one gelling agent is used, at least one of the gelling agents is agar.

[0052] Agar is well known and used in the art, for example, in food and other non-food applications. It is contemplated that any known type of agar may be used in the present invention. As used herein, the term "agar" is intended to broadly define any product containing hydrocolloid polysaccharides extracted from red algae (i.e., seaweeds of the Rhodophyta family). The hydrocolloid polysaccharides present in agar contain one or more polymers composed of galactose subunits. Sources of agar include seaweeds belonging to the following genera: Gelidium, Gracilaria, Pterocladia, and Gelidiella. Gracilaria is the major source of agar worldwide.

[0053] Although the nature of the agar and its properties (e.g., its gelling ability) will vary depending on the species from which the agar is extracted and the extraction method used to make it, it is envisioned that any known agar may find use in the present invention. Agar obtained from Gracilaria species are typically more sulfated and therefore have a lower gelling ability. However, their gelling properties may be enhanced by alkaline hydrolysis of the seaweed material prior to extraction. This converts L-galactose 6-sulfate units to 3,6-anhydro-L-galactose residues, which are believed to be responsible for the gelling properties of the polymer. Alternatively, the agar before and / or after extraction may be subjected to an enzymatic treatment to remove sulfate groups. In one embodiment, the agar for use in the present invention may have a reduced content of sulfate groups.

[0054] Agar is a linear polysaccharide composed of alternating β(1,3)- and α(1,4)-linked galactopyranose residues. A substantial portion of the α-galactose residues may be present as 3,6-anhydride derivatives. The (1,3)-linked residues are D-enantiomers, while the (1,4)-linked residues are L-enantiomers. Natural chemical modifications of these structures with acidic groups (i.e., sulfate, uronic acid, and pyruvic acid) as well as non-ionic methoxy groups have been identified. Early studies suggested that agar consists of two major fractions: a neutral fraction, called "agarose," with high gelling capacity, and a charged fraction, called "agaropectin," with lower gelling capacity. More recent studies have shown that agar is essentially a complex mixture of polysaccharides ranging from neutral to charged galactan molecules. The term "agarose" refers to agarobiose, a neutral polysaccharide with high gelling ability composed of repeating disaccharide units of 4-O-(β-D-galactopyranosyl)-3,6-anhydro-α-L-galactopyranose. Polysaccharides with repeating disaccharide units of 4-O-(β-D-galactopyranosyl)-α-L-galactopyranose, in the absence of anhydride bridges, are called "agarans". Alkaline treatment of agar removes the sulfate esters on C6 of the 4-linked galactose units, forming the corresponding 3,6-anhydride forms. This treatment is widely used in industrial agar extraction from Gracilaria species to improve its gelling properties. A more detailed overview of agar can be found, for example, in Chapter 24 of the Handbook of Hydrocolloids (Sousa et al., 2021), which is incorporated herein by reference in its entirety.

[0055] Agar is approved worldwide in food products by food safety authorities including the European Food Safety Authority (EFSA) and the Food and Drug Administration (FDA) as a food additive (E-406). Agar is supplied as a powder with high solubility in water, e.g., at least 85% solubility (at 80°C). Its gel strength can vary, but is typically around 700 g / cm. 2~Approx. 1100g / cm 2 (measured for a concentration of 1.5% by weight in water at 20°C). Gel strength is measured as follows: A solution containing 1.5% by weight of agar is prepared. The solution is left at 20°C for 24 hours. A load is then applied to the resulting gel and the maximum weight of the load that the gel can withstand for 20 seconds is measured. 2 The maximum weight value per unit weight is the gel strength of the agar. Gel strength can be measured using a Mecmesin Electronic Texture Analyzer. 2 Agar having a gel strength of less than 250 g / cm is commonly referred to as "low strength" agar. Due to its lower gelling strength, "low strength" agar may be less preferred for use in the present invention. In one embodiment, the agar for use in the present invention is not a "low strength" agar as defined herein. Preferred for use in the present invention is agar having a gel strength of less than 250 g / cm 2 Agar having a higher gel strength. For example, the agar has a gel strength of at least 500 g / cm 2 , at least 600g / cm 2 , or at least 700 g / cm 2 In one embodiment, the agar may have a gel strength of at least 800 g / cm 2 The gel strength may be

[0056] The gelling point of agar is typically in the range of 30° C. to 45° C. (measured at a concentration of 1.5% by weight in water at 20° C.). The melting point of agar may be, for example, in the range of 80° C. to 95° C. (measured at a concentration of 1.5% by weight in water at 20° C.). In one embodiment, agar for use in the present invention has a gelling point in the range of about 35° C. to about 45° C. (measured at a concentration of 1.5% by weight in water at 20° C.) and / or a melting point of about 80° C. to 95° C., e.g., about 85° C. to 92° C. (measured at a concentration of 1.5% by weight in water at 20° C.).

[0057] Agar for use in the present invention can be obtained from a variety of commercial sources. Non-limiting examples of agar that can be used include Gelagar HDR 800 (from B. & V. srl, Italy), and Qsol™ High Solubility Agar, and Qsol Agar (from Hispanagar, Spain).

[0058] The aqueous phase of the gelled oil-in-water emulsion according to the present invention may contain agar as the only gelling agent, or may contain additional non-agar gelling agents. If other gelling agents are present, they may be selected from other gelling agents known in the art. Consistent with the intended "vegetarian" or "vegan" nature of any of the products defined herein, any additional gelling agent should not be any animal by-product. For example, there will be no mammalian gelatin. Preferably, there will be no gelatin from any source, including fish gelatin.

[0059] The gelling agent, or combination of gelling agents, will be present in the aqueous phase in an amount suitable to provide the desired degree of gelation as described herein. This amount will vary to some extent depending on the exact nature of the gelling agent(s) (e.g., the type of agar used) and / or other components of the aqueous phase, and the suitable amount can be readily determined by one of skill in the art. If a gelling agent other than agar is also used, the appropriate amount can be readily selected by one of skill in the art. The amount of agar may be adjusted accordingly.

[0060] In one set of embodiments, the agar may be present in the aqueous phase at a concentration of about 0.1% to about 7.5% by weight, preferably about 0.25% to about 5% by weight, particularly about 0.3% to about 3.5% by weight, for example about 0.5% to about 3% by weight (i.e., based on the weight of the aqueous phase). For example, the agar may be present at a concentration of 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, or 3.0% by weight (based on the weight of the aqueous phase). The concentration of agar based on the total weight of the composition may range from about 0.1% to about 5% by weight, preferably about 0.15% to about 4.5% by weight, more preferably about 0.2% to about 4% by weight, for example about 0.25% to about 3.5% by weight, or about 0.25% to about 3% by weight. For example, agar may be present in a concentration of 0.25%, 0.50%, 0.75%, 1.0%, 1.25%, 1.50%, 1.60%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, or 3.0% by weight (based on the total weight of the composition).

[0061] The gelled oil-in-water emulsions described herein are stabilized by a surfactant comprising an ester of glycerol having at least one hydroxyl group esterified with diacetyltartaric acid and at least one hydroxyl group esterified with a fatty acid.

[0062] In one embodiment, the surfactant for use in the present invention is a product containing diacetyl tartaric acid esters of mono- and di-glycerides, also known as "DATEM". DATEM is a synthetic emulsifier produced from the esterification reaction of acetic acid, tartaric acid, glycerol and fatty acids derived from edible sources. DATEM can also be produced from the reaction of mono- and di-glycerides of fatty acids derived from edible sources with diacetyl tartaric anhydride. Examples of oils that can be used in its production include sunflower oil, palm oil, rapeseed oil, and combinations thereof, such as a combination of sunflower oil and palm oil.

[0063] In one embodiment, the major component of the surfactant will be diacetyl tartaric acid esters of mono- and di-glycerides. For example, the surfactant may contain diacetyl tartaric acid esters of mono- and di-glycerides in an amount of at least 50% by weight, preferably at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, or at least 95% by weight.

[0064] For use in the present invention, DATEM is preferably made from diacetyltartaric anhydride. For example, DATEM can be produced by the reaction of diacetyltartaric anhydride with mono-glycerides and / or di-glycerides. The reaction of the anhydrides provides a product with a major fraction carrying a free carboxylic acid group (-CO2H).

[0065] DATEM consists of mixed esters of glycerol, mono- and diacetyl tartaric acid, and fatty acids derived from edible fats and has been approved for use as a food additive by the European Food Safety Authority. It has the E number E472e and is confirmed as GRAS. GRAS may be supplied in a thick liquid (i.e. semi-liquid) form or in a powder form.

[0066] The main component of DATEM is represented by the following general formula (I):

[0067] [ka]

[0068] wherein each R is independently H or -C(O)(CH) n CH3 (wherein n is an integer from 6 to 21) It can be expressed as:

[0069] By "major component" it is meant that the compound of formula (I) is present in the DATEM in an amount of at least 50% by weight. In some embodiments, it may be present in an amount of at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, or at least 95% by weight.

[0070] Typically, stearic acid can be used as the fatty acid to prepare DATEM. When stearic acid is used, the value of n will be 16 in the compound of general formula (I).

[0071] As will be appreciated, due to the nature of the starting materials and the process used to produce DATEM, the product will consist of a mixture of components that, in addition to esters of glycerol with mono- and diacetyltartaric acid and fatty acids, may contain any of the following: free glycerol, free glycerides, free fatty acids, free tartaric acid, free acetic acid, tartaric and acetate esters of fatty acids.

[0072] DATEM is commercially available from various suppliers. One example of DATEM that may be used in the present invention is the product sold by Danisco under the trade name Panodan® AB 110 / C. Panodan® AB 110 / C is a diacetyl tartaric acid ester of mono-diglycerides produced from edible refined sunflower oil. It also contains the following components: citric acid (E330) up to 50 ppm, α-tocopherol (E307) up to 200 ppm, and ascorbyl palmitate (E304) up to 200 ppm, dissolved in propylene glycol (E1520) up to 50 ppm and mono-diglycerides (E471) up to 400 ppm.

[0073] In one set of embodiments, glycerol may further be present in the aqueous phase of the emulsion described herein. Advantageously, glycerol may be present in an amount effective to reduce the water activity of the composition and thus reduce microbial growth. The water activity may be reduced, for example, to less than about 0.8, for example in the range of 0.5 to 0.8, or in the range of 0.6 to 0.75, or in the range of 0.65 to 0.75. The proportion of water in the aqueous phase of the emulsion may be replaced, for example, by glycerol. The amount of glycerol may, for example, range from 0% to 10% by weight, for example from 0% to 7% by weight, based on the total weight of the composition. Typically, glycerol may be present in an amount in the range of about 6% to 7% by weight (based on the total weight of the composition). In one embodiment, glycerol is not present.

[0074] The oil phase of the emulsion will contain a physiologically acceptable lipid or a mixture of different physiologically acceptable lipids. Depending on the nature of the lipid (or lipids), the oil phase itself may have nutraceutical and / or pharmaceutical properties. Thus, in some embodiments, the lipid constituting the oil phase of the emulsion may be a nutraceutical product or a pharmaceutical product. Examples of such lipids include, for example, essential fatty acids, such as those described herein. Alternatively, the oil phase may act as a carrier for lipophilic pharmaceuticals or a carrier for lipophilic nutraceuticals. In this case, the active agent may be dissolved or dispersed in the oil phase.

[0075] A wide variety of different lipids are known for oral use in pharmaceuticals and / or dietary supplements, and any of these may be used in the oil phase of the emulsion described herein.Lipid sources include, but are not limited to, vegetable oils such as rapeseed oil, sunflower oil, corn oil, olive oil, sesame oil, palm kernel oil, coconut oil, nut oil (e.g., almond oil or peanut oil), algae oil and hemp oil.Fish oil and lipids derived from fish oil are also suitable for use in certain compositions according to the present invention.Compositions containing these products are acceptable, for example, to fish vegetarians.

[0076] Lipids derived from natural sources typically contain a mixture of different lipid components. Thus, in one embodiment, the oil phase will contain a mixture of different lipids. For example, the oil phase may contain a mixture of lipids with different chain lengths and / or different degrees of saturation.

[0077] Lipids for use in the present invention may be liquid, solid, or semi-solid at ambient temperature (i.e., at a temperature of about 18°C ​​to about 25°C). Those that are liquid at such temperatures are generally preferred. Any combination of liquid, solid, and semi-solid lipids may also be used. Solid lipids having a melting point below about 100°C, preferably below about 70°C, for example below about 50°C, may be used in the present invention. Solid lipids that may be used include butter, solid coconut splits, cocoa butter or cocoa fat, etc. If desired, the overall melting point of the lipids constituting the oil phase may be adjusted by mixing different lipids, for example by mixing solid lipids (e.g., cocoa butter) with liquid oils. An overall melting point in the range of 45°C to 50°C may be desirable.

[0078] Lipids for use in the present invention include, in particular, fatty acids and their derivatives. These include both naturally occurring fatty acids and their derivatives, as well as synthetic analogues. In one embodiment, the oil phase may comprise a mixture of different fatty acids, or fatty acid derivatives.

[0079] The hydrocarbon chain of the fatty acid or fatty acid derivative may be saturated or unsaturated, and it may be unbranched or branched. Preferably, it will be unbranched. Typically, the hydrocarbon chain will contain 4 to 28 carbon atoms, and generally the hydrocarbon chain will have an even number of carbons. Fatty acids vary in their chain length and may be classified as "short", "medium", "long", or "very long" chain fatty acids. Those with a hydrocarbon chain of 5 carbons or less are referred to as "short chain fatty acids", those with a hydrocarbon chain of 6 to 12 carbons are referred to as "medium chain fatty acids", those with a hydrocarbon chain of 13 to 21 carbons are referred to as "long chain fatty acids", and those with a hydrocarbon chain of 22 carbons or more are referred to as "very long chain fatty acids". Any of these may be used in the present invention.

[0080] In one embodiment, the oil phase will comprise a saturated fatty acid or a derivative of a saturated fatty acid, including but not limited to any of the derivatives described herein. Medium chain saturated fatty acids and their derivatives find particular use in the present invention. Particularly preferred are those having 8 to 12, e.g., 8, 10 or 12 carbon atoms in the hydrocarbon chain, i.e., caprylic acid (C8), capric acid (C10), or lauric acid (C12), and any derivatives thereof. Typically, the saturated fatty acid or its derivative may be used as a carrier for one or more active ingredients in the oil phase, e.g., as a carrier for a pharmaceutical or nutritional supplement.

[0081] The saturated fatty acids and their derivatives for use in the present invention may be naturally occurring or they may be synthetically produced. Most typically, they will be naturally occurring and therefore may be used in the form of a mixture of different fatty acids and / or different fatty acid derivatives. Sources of saturated fatty acids and their derivatives include, for example, coconut oil and palm kernel oil.

[0082] In another embodiment, the oil phase may comprise unsaturated fatty acids or derivatives thereof, whose carbon chains contain one or more carbon-carbon double bonds. The double bonds may be in the cis or trans configuration, or any combination thereof in which one or more double bonds are present. Those in which the double bonds are in the trans configuration are generally less preferred, due to the need to reduce the consumption of so-called "trans fats" as part of a healthy diet. Thus, fatty acids and their derivatives having cis-configured double bonds are preferred. Mono- and polyunsaturated fatty acids and their derivatives are well known in the art. Such fatty acids will typically contain 12 to 26 carbons, more typically 16 to 22 carbons, and will have mono- or polyunsaturated hydrocarbon chains. They include, in particular, polyunsaturated fatty acids (PUFAs), such as essential fatty acids.

[0083] Oils containing long-chain unsaturated fatty acids and their derivatives find particular use in the present invention, for example in any composition intended for use as a dietary supplement.Particularly important essential fatty acids that can be used include omega-3 fatty acids, omega-6 fatty acids, and omega-9 fatty acids.Examples of omega-3 fatty acids include alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), tetracosapentaenoic acid, and tetracosahexaenoic acid. Examples of omega-6 fatty acids include linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), docosatetraenoic acid, adrenic acid, docosapentaenoic acid, and calendic acid. Examples of omega-9 fatty acids include oleic acid, eicosenoic acid, mead acid, erucic acid, and nervonic acid.

[0084] Sources of unsaturated fatty acids and their derivatives include oils obtained from various fish, plants, algae and microbial sources.Particularly suitable sources are algae oils and vegetable oils, but fish oils may also be suitable for those who follow a fish vegetarian diet.All of these oils are rich in omega-3, omega-6 and omega-9 fatty acids.Fish oils may be obtained, for example, from anchovies, sardines and mackerel.

[0085] Any known derivative of fatty acid may be used in the present invention. These include, in particular, carboxylic acid esters, carboxylic acid anhydrides, glycerides (i.e., mono-, di-, or triglycerides) and phospholipids. As used herein, the term "derivative" in the context of fatty acids also encompasses any pharma- ceutically acceptable salt of fatty acid. Suitable salts are well known to those skilled in the art and include, but are not limited to, lithium, sodium, potassium, ammonium, meglumine, and diethylamine salts.

[0086] Examples of carboxylate esters of fatty acids include compounds having a terminal -COR group, where R is a straight or branched chain alkyl group, typically a short chain alkyl, preferably a C1-6 alkyl group selected from, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and n-hexyl.

[0087] When the fatty acid derivative is a carboxylic acid anhydride, it may contain a terminal -CO2COR group, where R is a straight or branched chain alkyl group, typically a short chain alkyl, preferably a C1-6 alkyl group selected from, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and n-hexyl.

[0088] Glycerides are esters derived from glycerol and up to three fatty acids. The fatty acids present may be any of those described herein, and therefore may be, for example, saturated or unsaturated. In the case of di- and tri-glycerides, the fatty acid components may be the same or different. For example, they may be of different chain length.

[0089] In one embodiment, the lipid carrier for use in the present invention may comprise a medium chain triglyceride (MCT). MCTs are triglycerides with two or three medium chain fatty acids, which may be the same or different. Sources of MCTs include, for example, coconut oil and palm kernel oil. The fatty acids present in MCTs are typically saturated medium chain fatty acids. MCTs from coconut oil include, for example, C6 to C8. 12 Fatty acids, mainly C8 and C 10 A typical fatty acid composition of MCT oil obtained from coconut oil may include, for example, 0.1% by weight caproic acid (C6:0), 55% by weight caprylic acid (C8:0), 44.8% by weight capric acid (C10:0), and 0.1% by weight lauric acid (C12:0).

[0090] Phospholipids generally consist of a glycerol molecule attached to a hydrophilic "head" group consisting of two fatty acids (the "tail" group) and a phosphate group. The phosphate group may be modified by linkage to choline, ethanolamine, or serine. In one embodiment, the oil phase may be composed in whole or in part of a phospholipid, such as vegetable lecithin.

[0091] The amount of oil present in the compositions of the invention will depend on factors such as the nature of the oil, the nature of any pharmaceutical or nutraceutical products that may be present and the desired loading, and may vary as required. The oil phase may, for example, constitute from 5% to 60% by weight of the gelled oil-in-water emulsion, preferably from 5% to 50% by weight, preferably from 10% to 45% by weight, for example from 15% to 40% by weight, 15% to 30% by weight or 20% to 25% by weight.

[0092] As will be understood, in the compositions of the present invention, the oil provides a discontinuous phase within the continuous aqueous phase that is gelled. Thus, the oil is dispersed throughout the gelled aqueous phase in the form of oil droplets (also referred to herein as oil "particles"). The gelling of the aqueous phase provides a stable emulsion that prevents the oil droplets from gathering together, for example, due to the prevention of physical collisions between the droplets.

[0093] The size of the oil droplets in the gelled oil-in-water emulsion is not particularly limited. However, the applicant has found that the gelled emulsion can be provided with small oil droplet sizes. This can be advantageous for increasing the initial rate of lipolysis of the gelled emulsion and thus enhancing the intestinal uptake of the lipids constituting the oil phase. For example, oil droplets having a volume-based size in the range of about 100 nm to about 50 μm, preferably about 0.25 μm to 20 μm, for example, about 0.3 μm to 10 μm, can be provided. The volume-based average particle size may be in the range of about 0.2 μm to 10 μm, preferably about 0.4 μm to 5 μm, for example, about 0.5 μm to 2.5 μm. As used herein, "volume-based average" refers to the volume moment average or De Brouckere Mean Diameter (also known as the "D[4,3]" value). It reflects the size of the particles (droplets) that make up the majority of the sample volume and is most sensitive to the presence of large droplets in the size distribution.

[0094] An essentially uniform size distribution of the oil droplets may be desirable. 90 The value indicates the size that 90% of all oil droplets meet. D 90 The value may be in the range of 0.75 μm to 50 μm, preferably 1 μm to 35 μm, and in particular 1.5 μm to 25 μm. 50 Value and D 10 The values ​​indicate the size values ​​that 50% and 10% of the oil droplets meet among the total of all oil droplets. D 50 The value may be in the range of 0.3 μm to 20 μm, in particular 0.5 μm to 15 μm, for example 0.75 μm to 10 μm. 10 The value may be in the range of 0.1 μm to 10 μm, in particular 0.2 μm to 5 μm, for example 0.3 μm to 3 μm.

[0095] The size and size distribution of the lipid droplets can be determined using methods and equipment conventional in the art, for example, a Malvern Mastersizer 3000 (Worcestershire, UK) connected to a Hydro MV, wet dispersion unit (Malvern, Worcestershire, UK). Analysis of the data can be performed using the manufacturer's software (Mastersizer 3000, v1.0.1). The test can be performed by dissolving and diluting the gelled emulsion in a suitable solvent (1:100) at 50°C. Suitable solvents include Milli-Q water and 10% (v / v) HCl solution (the latter may minimize aggregation during the test). The refractive index of water and corn oil are set to 1.33 (solvent) and 1.47 (dispersed phase), respectively, and the absorptivity of the dispersed droplets is set to 0.01. To avoid multiple scattering or low intensity of scattered light, the dissolved emulsion is added to the dispersion unit (containing about 125 mL of water) until approximately 10% obscuration is obtained.

[0096] The size and size distribution of the oil droplets may vary. If desired, size reduction of the oil droplets may be achieved by a variety of different means, for example, by mechanical processes, or by chemical processes including the selection of smaller lipid molecules, or indeed by a combination of these approaches. Suitable chemical methods for achieving size reduction of the oil droplets may include the selection of a particular type of lipid (or combination of lipids) that can form smaller oil droplets. For example, certain oils, such as MCT, tend to generate finer dispersions of oil droplets. Mechanical reduction involves breaking down larger oil droplets into smaller nanoscale particles using shear forces. Thus, smaller particles may be generated by suitable adjustments to the method used to generate the emulsion, for example, by varying the shear forces and / or duration of mixing of the oil and water phases. Using higher shear forces and / or longer mixing times will generate smaller oil droplets. Suitable shear may be achieved, for example, using a conventional homogenizer such as a rotor stator mixer, for example, an Ultra-turrax® homogenizer. A problem often encountered in mechanical processes for the production of oil-in-water emulsions is particle reagglomeration (i.e., coalescence), which is addressed in the present invention by the use of a gelled aqueous phase which helps to stabilize the emulsion, and by the use of surfactants which reduce the energy required for emulsification (by reducing interfacial tension) and protect the droplets from reagglomeration.

[0097] The aqueous phase (i.e., the continuous phase) of the gelled oil-in-water emulsion may constitute 40% to 95% by weight of the composition, preferably 50% to 95% by weight, more preferably 55% to 90% by weight, for example 60% to 85% by weight, 70% to 85% by weight, or 75% to 80% by weight.

[0098] In addition to water, gelling agent(s), and surfactant(s), other physiologically acceptable substances may also be present in the aqueous phase, such as pH adjusting agents (e.g., buffering agents), viscosity adjusting agents (e.g., thickeners, plasticizers), sweeteners, bulking agents (i.e., fillers), antioxidants, flavoring agents, flavoring agents, and coloring agents. The nature and concentration of any such materials may be readily determined by one of ordinary skill in the art.

[0099] The presence of a bulking agent (i.e., a filler) in the aqueous phase helps to reduce the water activity and therefore the growth of microorganisms. The water activity of the emulsion will be in the range of about 0.4 to about 0.9. In certain embodiments, the water activity may be reduced to less than about 0.8, for example, in the range of 0.5 to 0.8, or in the range of 0.6 to 0.75, or in the range of 0.65 to 0.75. The amount and type of bulking agent can be readily selected by one of ordinary skill in the art. Suitable examples include, but are not limited to, sugar alcohols, sugars, and mixtures thereof. Suitable sugar alcohols include sorbitol, xylitol, glycerol, erythritol, maltitol, mannitol, hydrogenated starch hydrolysates (HSH), isomalt, and mixtures thereof. Sugars that may be used include any non-reducing monosaccharides and oligosaccharides, such as trehalose, sucrose, and mixtures thereof. The bulking agent may constitute 45% to 70% by weight, preferably 50% to 65% by weight, for example 55% to 60% by weight, based on the aqueous phase. In some cases, the selected bulking agent(s) may also function as a sweetener depending on their concentration. For example, the composition according to the invention may contain xylitol, for example 0.5% to 50% by weight, preferably 1% to 40% by weight, for example 15% to 40% by weight, to improve the taste.

[0100] If a sweetener is included in the aqueous phase, it will typically be selected from natural sweeteners such as sucrose, fructose, glucose, reduced glucose, maltose, xylitol, maltitol, sorbitol, mannitol, lactitol, isomalt, erythritol, polyglycitol, polyglucitol, glycerol, and stevia, and artificial sweeteners such as aspartame, acesulfame-kappa, neotame, saccharin, and sucralose. The use of non-cariogenic sweeteners is preferred.

[0101] In one embodiment, a viscosity modifier may also be provided in the aqueous phase. Suitable viscosity modifiers include other hydrocolloids, such as starch, modified starch (e.g., hydroxyethyl starch, hydroxypropyl starch), xanthan, galactomannan (e.g., guar gum and locust bean gum), karaya gum, tragacanth gum, arabic gum, ghatti gum, modified cellulose (e.g., methyl cellulose, ethyl cellulose, methyl ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose), and any combination thereof. As will be understood, the viscosity modifier may have some surfactant properties and may also assist in stabilizing the emulsion. The thickening effect of the viscosity modifier depends on the type of material (e.g., hydrocolloid) used and its concentration, other components, and the pH of the formulation, but the suitable amount can be easily determined by those skilled in the art. Typical amounts of optional viscosity modifiers that may be present may range from 0.1% to 5%, preferably from 0.2% to 2.5%, for example from 0.5% to 2.0% by weight of the total composition. In one embodiment, no viscosity modifiers are present.

[0102] Flavoring agents may be present in the composition and may aid in taste-masking certain lipids, such as those containing omega-3 fatty acids.Suitable flavoring agents include, but are not limited to, citrus flavoring agents, such as orange oil, lemon oil, or lime oil.

[0103] In one embodiment, the aqueous phase of the gelled emulsion will have a low pH. For example, the pH of the aqueous phase may be less than about 7. In one set of embodiments, it may be in the range of 4 to 7, particularly 4.2 to 7, preferably 4.5 to 6, such as 4.5 to 5 or 4.5 to 4.7. The pH can be adjusted by selection of a suitable pH adjuster. pH adjusters may be readily selected by one of skill in the art and include food grade acids such as citric acid. Buffers may also be used to adjust the pH and include organic acid / base buffer systems. Suitable buffers are well known in the art and include, for example, sodium citrate and malic acid.

[0104] Antioxidants may be present in the oil and / or water phase of the composition. When antioxidants are present in the water phase, they are generally water-soluble and will include, for example, ascorbic acid, citric acid, and their salts, such as sodium ascorbate. Depending on the choice of oil, they may be provided in a form that contains an antioxidant, such as, for example, vitamin E. If present, the amount of any antioxidant(s) may be up to 3% by weight, such as up to 1% by weight, of the total formulation. In some embodiments, antioxidants may be present in surfactants used in the compositions of the present invention. For example, commercially available DATEM surfactants, especially those provided in liquid or semi-liquid form, may contain antioxidants as preservatives. Examples of such antioxidants include citric acid, alpha-tocopherol, and ascorbyl palmitate.

[0105] In addition to the lipid(s), the oil phase of the emulsion may also contain physiologically acceptable lipid-soluble materials, if desired, such as pharma- ceutically acceptable drugs, antioxidants (e.g., vitamin E), flavoring agents, and colorants.

[0106] In some embodiments, additional physiologically active agents may also be present in the gelled emulsions described herein. These may be provided in the aqueous and / or oily phases, and may be dissolved and / or dispersed in one or both of these phases. Other active agents that may be present in the oily phase include lipophilic active agents.

[0107] In one embodiment, a gelled oil-in-water emulsion according to the present invention may comprise, consist essentially of, or consist of the following components: (a) water, (b) a surfactant, as defined herein; (c) one or more physiologically acceptable lipids; (d) agar; (e) one or more bulking agents (e.g., sugar alcohols); (f) optionally, one or more pH adjusters; (g) optionally, one or more viscosity modifiers (e.g., thickeners or plasticizers); and (i) Optionally, one or more additional physiologically active agents.

[0108] By "consisting essentially of" it is intended that the emulsions are substantially free (e.g., free of) other components that would materially affect their properties. By "consists of" it is intended that the emulsions are substantially free (e.g., free of) components other than those listed.

[0109] In one set of embodiments, the compositions of the invention may be provided in the form of a dosage unit. By "dose unit" is intended that the composition is intended to be taken orally by a subject (e.g., administered to a patient) "as received", i.e., not broken or cut prior to oral delivery. The weight of the dosage unit will therefore be such that the composition is suitable for delivery in this manner. For example, the dosage unit may have a total weight in the range of 50 mg to 3,000 mg, e.g., 250 mg to 3,000 mg or 500 mg to 2,500 mg, particularly 100 mg to 2,000 mg, e.g., 750 mg to 2,000 mg, particularly 100 mg to 1,500 mg, more particularly 400 mg to 1,500 mg, more particularly 400 mg to 1,000 mg.

[0110] In one set of embodiments, the dosage units will generally be quite large, for example having a mass of 400 mg to 3,000 mg, for example 600 mg to 1,500 mg. The total dosage unit weight can be selected as needed. For example, it can be scaled up or down depending on the nature of the selected active ingredients and their intended dose.

[0111] Each dosage unit will typically consist of a self-supporting gelled oil-in-water emulsion as described herein. As will be understood, in this case, the dosage unit will contain only the defined oil and water phases, i.e., will not include any other components. Individual dosage units may be prepared from larger pieces of gelled emulsion, for example, divided by cutting. However, more typically, each dosage unit will be formed by extrusion or molding from a liquid emulsion, or an incompletely gelled emulsion, prior to gelling (i.e., at a temperature above the gelling temperature of the gelling agent).

[0112] Alternatively, the gelled oil-in-water emulsion core may be provided with a suitable coating of a physiologically acceptable coating material. Such coatings may be conventional in the pharmaceutical and nutraceutical industries and may be applied by any conventional means, for example by dipping or spraying. In one set of embodiments, the gelled oil-in-water emulsions described herein may thus be provided with a coating. For example, they may be provided within a capsule shell that dissolves in the mouth. Viewed from another aspect, therefore, the invention provides an orally administrable capsule comprising a capsule shell encapsulating a gelled oil-in-water emulsion as described herein.

[0113] In the capsules of the present invention, the shell may be any physiologically acceptable material, but will typically be a sugar, a biopolymer, or a synthetic or semi-synthetic polymer that is soluble or degradable in saliva or fluids in the gastrointestinal tract. The shell may be soft, but is preferably substantially rigid. Particularly desirably, the capsule will have a "jelly bean" consistency. The shell will preferably be of a material and thickness to prevent oxidation of the contents. The shell may comprise a sugar or cellulose, e.g., sorbitol. The use of sugar and cellulose as capsule shell materials is well known in the pharmaceutical and nutraceutical fields.

[0114] Thus, the capsule shell material may typically be a sugar or sugar alcohol, such as sucrose, fructose, maltose, xylitol, maltitol, or sorbitol, but may also include hydrocolloid materials, such as, for example, carrageenan, alginates, pectin, cellulose, modified cellulose, starch, modified starch, gum arabic, etc. The capsule shell may also contain other ingredients, such as, for example, artificial sweeteners, colors, fillers, flavoring agents, antioxidants, etc.

[0115] The capsule shell may be preformed so that the oil-in-water emulsion can be filled into the shell as a liquid or once solidified. Alternatively, a shell precursor (e.g., a solution) may be coated onto the hardened emulsion, for example, using standard coating techniques. If desired, the capsule may be further coated, for example, with a wax.

[0116] The preparation of the gelled oil-in-water emulsion described herein may be carried out by emulsification of the aqueous phase components and the oil phase components. It will be understood that the emulsification is carried out under conditions where the aqueous phase is liquid (e.g., viscous liquid), i.e., prior to the formation of a gel. Thus, the emulsification will be carried out at a temperature higher than the sol-gel transition temperature of the agar gelling agent (and the sol-gel transition temperature of any other gelling agents that may be present). Subsequent cooling of the emulsion below the sol-gel temperature will result in the desired gelled emulsion.

[0117] Prior to emulsification, any selected active agent may be added to the oil phase and / or water phase of the composition.This may be carried out, for example, by dissolving the active agent in the selected oil phase or water phase prior to forming the emulsion.Alternatively, prior to emulsification, the selected active agent(s) may be added to the mixture of water phase components and oil phase components.During the emulsification process, active agents will typically migrate to the oil phase or water phase depending on their hydrophilic / lipophilic properties.

[0118] The formation of the emulsion may be achieved by conventional techniques and by using known equipment, for example homogenizers based on the rotor-stator principle. The speed and duration of stirring may be adjusted as needed, for example varied to achieve the desired shear forces and provide the desired droplet size.

[0119] Emulsification will generally be carried out under controlled atmosphere to avoid oxidative degradation of lipids and / or any active agents.For example, emulsification may be carried out in the presence of a non-oxidizing gas such as nitrogen.Degassing to remove air bubbles may also be carried out during the manufacturing process, for example, before mixing the components of the emulsion, once the liquid emulsion is formed, before packaging the hardened emulsion, etc.Degassing may be carried out using any conventional means, such as applying vacuum or sparging with a non-oxidizing gas (e.g., nitrogen).

[0120] After emulsification and gelation, the emulsion may be dried to reduce the water content, however, when dried it will still retain a continuous gelled water phase as described herein and a water content within the ranges defined herein.

[0121] The gelled oil-in-water emulsion will typically be provided in the form of a dosage unit as described herein. The individual dosage units may be formed by methods such as molding, extrusion, or cutting. Typically, however, the dosage units will be formed by filling the liquid emulsion into molds, such as individual molds of a blister pack, which are then sealed. The dosage units will typically be in the form of a tablet or lozenge.

[0122] The method for preparing a gelled oil-in-water emulsion as described herein forms a further aspect of the present invention. Viewed from a further aspect, the present invention therefore provides a method for preparing an orally administrable gelled oil-in-water emulsion, comprising forming an oil phase containing one or more physiologically acceptable lipids, forming an aqueous phase containing a gelling agent that is agar, combining the oil phase and the aqueous phase to form an oil-in-water emulsion in the presence of a surfactant as described herein, and gelling the emulsion. Optionally, before or after gelling the emulsion, the emulsion may be divided into individual dosage units.

[0123] The dosage unit is preferably individually packaged in an airtight container, for example, a sealed wrapper, or more preferably, a blister of a blister pack.Accordingly, in another aspect, the present invention provides a package that includes an airtight compartment and a lighttight compartment that contains a dosage unit of the composition according to the present invention.By excluding both air (i.e. oxygen) and light from the packaged dosage unit, the long-term stability of the active ingredient is enhanced.

[0124] The packaging according to the invention is preferably provided in the form of a blister pack containing at least 2 dosage units, for example 2 to 100, preferably 6 to 30 dosage units. The blister pack will generally comprise a metal, metal / plastic laminate, or plastic sheet substrate with molded recesses into which the dosage forms are placed. The pack is usually sealed with a foil, typically a metal or metal / plastic laminate foil, for example by applying heat and / or pressure to the area between the recesses. The use of metal or metal / plastic laminate to form the blister pack helps to prevent air (i.e. oxygen), light, and moisture from penetrating the contents of the blister pack, thus enhancing the stability of the active ingredient(s). The packaging according to the invention is preferably filled under a non-oxidizing gas atmosphere (e.g. nitrogen) or flushed with such a gas before sealing.

[0125] The use of agar as a gelling agent in the composition according to the invention provides further advantages with regard to the packaging of individual dosage units in blister packs and their removal by end users. When a liquid form of the emulsion is used to fill the cavities of the blister pack (i.e. before gelling), the emulsion will be in intimate contact with the inner surface of the cavities. After the dosage units are set and the blister pack is sealed, it is important that the dosage units can be easily removed from the blister pack. The presence of gelatin, which was initially developed as an adhesive, in known gelatin-based compositions can make them difficult to remove from certain surfaces, such as surfaces made from plastic materials, especially when liquid emulsions containing gelatin are brought into contact with the surface and allowed to harden. In such cases, once hardened, the dosage units tend to adhere to the surface and must be peeled off, often resulting in fragmentation of the dosage units during the process, which is not acceptable. When packaging any conventional gelatin-based dosage units, the inner surface of the blister pack needs to be coated with a suitable release agent, such as a neutral oil or a neutral fat. Specially developed blister pack materials are available that incorporate release agents on the inside surface, but add cost to the packaging process. The use of a release agent also results in a surface coating of the release agent on the dosage unit once removed from the blister pack, which can result in an unpleasant feel or taste of the product.

[0126] In contrast to the use of gelatin, agar-based dosage units do not adhere to conventional blister pack materials. This means that standard materials can be used, including metal / plastic laminates, or plastic films to which plastic / metal foil laminates are heat sealed. Suitable blister trays with preformed cavities may be formed from laminated materials, such as, for example, Tekniflex® Aclar® VA10600 (TekniPlex), Perlalux® (Perlen Packaging), Formpack® (Amcor), and Regula® (Constantia Flexible). Such materials do not have any surface coatings that contain release agents.

[0127] Thus, in one embodiment, the dosage units of the invention may be packaged in a blister pack having an inner surface that is not coated with a release agent. Such blister packs containing the dosage units described herein form a further aspect of the invention.

[0128] The gelled oil-in-water emulsions according to the invention find use both as pharmaceuticals, i.e. for therapeutic purposes, and as dietary supplement products to maintain or enhance the health and / or general well-being of human or animal subjects. For this purpose, they are intended to be taken orally, chewed lightly in the mouth, and then swallowed. It is not intended that they should remain in the mouth or need to be chewed for extended periods of time. Due to their soft texture, light chewing is sufficient to fragment the dosage form into smaller pieces that are easily swallowed. Based on their rheological properties, the gelled oil-in-water emulsions according to the invention can be expected to have a much better mouthfeel than pure aqueous agar gels. While aqueous agar gels are brittle and "fracture" in the mouth when chewed, the emulsions described herein have improved large-scale deformation properties. As such, they will have a greater resistance to deformation and will be less likely to break when chewed. Together with the small oil droplet size achieved using the surfactants described herein, this can be expected to provide a much more acceptable chewing experience for the patient or consumer.

[0129] For example, when used as a dietary supplement, the compositions described herein may be used as a supplement (e.g., a nutritional supplement) to maintain the general health and / or well-being of a subject. Any agent known for its dietary supplement effect may be provided in the composition, and suitable agents are well known in the art. Suitable nutritional supplements include, but are not limited to, any of the following: essential fatty acids (e.g., monounsaturated and polyunsaturated fatty acids), essential amino acids (e.g., taurine, tryptophan, tyrosine, cysteine, and homocysteine), vitamins (e.g., vitamins A, B1-B12, C, D, E, K, and folic acid), minerals (e.g., iodine, selenium, iron, zinc, calcium, and magnesium), flavonoids, carotenoids (e.g., β-carotene, α-carotene, zeaxanthin, astaxanthin, lutein, xanthophyllis, and lycopene), phytosterols, saponins, probiotics, dietary fiber (e.g., insoluble fiber and β-glucan), antioxidants (e.g., CoQ10), and botanical extracts (e.g., aloe vera, evening primrose oil, garlic, ginger, ginseng, green tea, caffeine, and cannabinoids). When magnesium or calcium are present, they will generally be used in the form of their phosphates.

[0130] In particular, the gelled oil-in-water emulsions described herein may be used as a source of one or more essential fatty acids, such as PUFAs (Poly Unsaturated Fatty Acids) or their esters, such as omega-3 fatty acids, omega-6 fatty acids, and / or omega-9 fatty acids, and their ester derivatives. Examples of omega-3 acids include alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), tetracosapentaenoic acid, and tetracosahexaenoic acid. Examples of omega-6 acids include linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), docosatetraenoic acid, adrenic acid, docosapentaenoic acid, and calendic acid. Examples of omega-9 acids include oleic acid, eicosenoic acid, mead acid, erucic acid, and nervonic acid. Omega-3 acids, particularly EPA and DHA, are highly preferred.

[0131] The health benefits of essential fatty acids, especially omega-3 fatty acids, are well known. For example, they can lower the amount of triglycerides and / or lower the amount of cholesterol. Omega-3 fatty acids are essential for daily life and health. The beneficial effects of EPA and DHA on lowering serum triglycerides are well known. They are also known for other health benefits, such as the cardioprotective effect in preventing cardiac arrhythmias, stabilizing atherosclerotic plaques, reducing platelet aggregation, and lowering blood pressure. Thus, they find use in treating and / or preventing vascular diseases. Other benefits of omega-3 fatty acids include the prevention and / or treatment of inflammation and neurodegenerative diseases, and improving cognitive development and cognitive function.

[0132] The essential fatty acids may form part or all of the oil phase in the gelling emulsion, preferably at least 10% by weight, more particularly at least 50% by weight, especially at least 80% by weight of that phase. They may be used as single compounds or as a mixture of compounds, for example vegetable oils or fish oils. Free fatty acids, monoacylglycerides and diacylglycerides may be prepared by complete or partial hydrolysis of triacylglycerides, for example acid, base or enzyme-catalyzed hydrolysis, using lipases, for example pancreatic lipase and / or lipases that may be produced from bacteria as fermentation products. Alkyl esters of essential fatty acids may be prepared by transesterification using a suitable alkanol or by esterifying the free fatty acid with the alkanol. When free fatty acids are used, they may be in acid form or salt form (for example fully or partially in salt form) and preferably constitute 5% to 75% by weight, especially 10% to 35% by weight, of the essential fatty acids in the oil phase. The salt form may be preferred.

[0133] The gelled oil-in-water emulsions described herein also find use as pharmaceuticals in the treatment or prevention of a range of medical conditions responsive to a selected active agent(s). As will be appreciated, the nature of such conditions will depend on the active agent(s) selected, but can be readily determined by one of skill in the art.

[0134] Any drug substance having the desired therapeutic and / or prophylactic effect may be used, including lipophilic, hydrophilic, or amphiphilic drug substances.

[0135] Suitable drug substance classes include, but are not limited to, any of the following: analgesics, anti-inflammatory agents, anti-cancer agents, cardiovascular agents, biological agents, anti-allergy agents (e.g., antihistamines), decongestants, antiemetics, agents affecting gastrointestinal function, agents acting on blood and blood-forming organs, agents affecting renal and cardiovascular function, antifungals, urological agents, hormones, antibacterial agents, antiepileptic agents, tranquilizers, antipsychotics, psychostimulants, anticholinesterase agents, and carotenoids.

[0136] Examples of particular drug substances that may find use in the compositions of the present invention include: temazepam, diphenhydramine, zolpidem, triazolam, nitrazepam, testosterone, estradiol, progesterone, benzodiazepines, barbiturates, cyclosporine, insulin, calcitonin, dextromethorphan, pseudoephedrine, phenylpropanolamine, bromocriptine, apomorphine, selegiline, amitriptyline, dextroamphetamine, phentermine, mazindol, compazine, chlorpromazine, Perphenazine, fluoxetine, buspirone, clemastine, chlorpheniramine, dexochlorphenylamine, astemizole, loratadine, paracetamol, ketoprofen, naproxen, ibuprofen, acetazolamide sodium, acetylsalicylic acid, aminophylline, amiodarone hydrochloride, ascorbic acid, atenolol, bendroflumethadiazide, calcium folinate, captopril, cetrizine hydrochloride, chloramphenicol sodium succinate, chlorpheniramine maleate, chlorpromazine hydrochloride, cimetidine hydrochloride, Ciprofloxacin hydrochloride, clindamycin hydrochloride, clonidine hydrochloride, codeine phosphate, cyclizine hydrochloride, cyclophosphamide, dexamethasone sodium phosphate, dicloxacillin sodium, dicyclomine hydrochloride, diltiazem hydrochloride, diphenhydramine hydrochloride, disopyramide phosphate, doxepin hydrochloride, enalapril maleate, erythromycin ethylsuccinate, flecanide acetate, fluphenazine hydrochloride, folic acid, granisterone hydrochloride, guaifenesin, haloperidol lactate, hydralazine hydrochloride, hydrochloroquine sulfate, hydromorphone methadone hydrochloride, hydroxyzine hydrochloride, indomethacin sodium, isoniazid, isoprenaline hydrochloride, ketorolac trometamol, labetalol hydrochloride, lisinopril, lithium sulfate, mesoridazine benzilate, methadone hydrochloride, methylphenidate hydrochloride, methylprednisolone sodium succinate, metholprolol tartrate, metronidazole hydrochloride, methyldopa, mexiletine hydrochloride, molidone hydrochloride, morphine sulfate, naltrexone hydrochloride, neomycin sulfate, ondansetone hydrochloride, orciprenaline sulfate, oxacillin sodium,Oxybutynin chloride, oxycodone hydrochloride, paracetamol, penicillamine, pentoxifylline, pethidine hydrochloride, phenobarbital sodium, phenoxymethylpenicillin potassium, phenylephrine hydrochloride, phenytoin sodium, potassium iodide, primaquine phosphate, procainamide hydrochloride, procarbazine hydrochloride, prochlorperazine maleate, promazine hydrochloride, promethazine hydrochloride, propranolol hydrochloride, pseudoephedrine hydrochloride, bromide Pyridostigmine, pyridoxine hydrochloride, ranitidine hydrochloride, salbutamol sulfate, sodium ethacrynate, sotalol hydrochloride, sumatripan succinate, terbinafine hydrochloride, terbutaline sulfate, tetracycline hydrochloride, thioridazine hydrochloride, thiothixene hydrochloride, trifluoperazine hydrochloride, triprolidine hydrochloride, sodium valproate, vancomycin hydrochloride, vancomycin hydrochloride, verapamil hydrochloride, warfarin sodium, and fenofibrate.

[0137] The amount of drug substance per unit dose of the composition of the invention will conveniently be in the range of 10% to 100% of the recommended daily dose for an adult or child.

[0138] Viewed from another aspect therefore, the present invention provides a gelled oil-in-water emulsion as described herein for use in therapy.

[0139] Viewed from yet another aspect, the present invention provides a gelled oil-in-water emulsion as described herein containing at least one pharma- ceutical active ingredient, for oral use in the treatment of a condition responsive to said pharma- ceutical active ingredient.

[0140] In another aspect, the invention provides the use of a pharma- ceutical active ingredient in the manufacture of a medicament for oral use in the treatment of a condition responsive to the pharma- ceutical active ingredient, wherein the medicament is provided in the form of a gelled oil-in-water emulsion as described herein.

[0141] Corresponding medical methods of treatment form a further aspect of the invention. Viewed from yet another aspect, the present invention therefore provides a method of treating a human or non-human animal subject (e.g. a patient) for a condition responsive to a pharma- ceutical active agent, the method comprising orally administering to the subject a pharma- ceutical effective amount of the agent in the form of a gelled oil-in-water emulsion as described herein.

[0142] In another aspect, the present invention provides the use of a gelled oil-in-water emulsion as described herein as a nutritional supplement product. Corresponding methods of administering the gelled oil-in-water emulsion to achieve a nutritional supplement effect also form part of the present invention.

[0143] Viewed from another aspect, the invention therefore provides a method of administering an active agent to a human or non-human animal subject to enhance and / or maintain the health or well-being of the subject, the method comprising orally administering to the subject a nutraceutical effective amount of the active agent in the form of a gelled oil-in-water emulsion as described herein.

[0144] In another aspect, the present invention provides the use of a gelled oil-in-water emulsion as described herein as a dietary supplement product.

[0145] When used in any of the above treatments or methods, or as a dietary supplement or pharmaceutical formulation, the effective amount of the active agent can be readily determined.

[0146] The amount of an effective dose for any particular subject will depend on a variety of factors, including the disorder and its severity, the identity and activity of the particular composition, the subject's (e.g., patient's) age, weight, general health, timing of administration, duration of treatment, other drugs used in combination with the treatment, etc. It is well within the skill of one of ordinary skill in the art to select the desired dose to achieve the desired therapeutic effect.

[0147] The present invention will now be further described with reference to the following non-limiting examples and the accompanying figures.

[0148] [Brief description of the drawings] [Figure 1] Oil droplet size distribution for agar with 0.69 wt% PANODAN®, measured initially and after 20 hours in a 55°C water bath with gentle magnetic stirring. [Figure 2] Hardness (force) of an agar-based gelling oil-in-water emulsion according to the present invention when subjected to large scale deformation. [Figure 3] Initial oil droplet size distribution for agar with 0.69 wt%, 0.46 wt%, and 0.23 wt% PANODAN® in a 55°C water bath with gentle magnetic stirring. [Figure 4] Figure 4 shows the variation in oil droplet size for agar with 0.69 wt% PANODAN® after the addition of various amounts of HCl.

[0023] FIG. 5 shows the initial lipolysis rate of an agar-based gelling oil-in-water emulsion according to the present invention. [Figure 6] Droplet size volume distribution for "1 / 2 s.alk" and "3 / 4 s.alk" oil-in-water formulations with PS80 as surfactant and 25 wt% oil.

[0149] [Example] Test Method: 1. Rheological characterization of agar emulsion gels 1a- Small scale deformation Rheological analysis of the gels was carried out using a rheometer (Malvern Kinexus ultra+, Westborough, USA). The lower plate was a KNX0127, curved sandblasted lower plate with a diameter of 50 mm. The upper geometry was a CP4 / 40, 4° angle cone with a diameter of 40 mm for gelatin emulsion gels, and a serrated PP40X SW1648 SS for agar and agar emulsion gels. Instrument calibration (0 gap) was performed prior to analysis. For gelatin-based gels, after gel preparation, approximately 2 grams of gel was placed on the lower plate, which was heated to 60°C. For agar-based gels, a liquid solution (i.e., pre-gelled) was placed on the plate and allowed to gel. The rheometer was operated in 0.1% shear strain control mode and the frequency was set at 1 Hz. It was confirmed that the selected strain was within the linear viscoelastic region for all samples. To avoid evaporation, gelatin emulsion gel samples were covered with silicone oil (10 cS fluid, Dow Corning, UK) prior to measurements. Viscoelastic properties of the samples were obtained with a starting and ending temperature of 60°C for gelatin emulsion gels and a holding time of 15 min at 20°C using a temperature gradient of 2°C / min. For agar emulsion gels, the final temperature was 90°C and the oscillation lasted for 10 min at 90°C. The results were analyzed using rSpace of Kinexus software. The gelling and melting temperatures of the samples were estimated as the temperatures corresponding to a phase angle of 45° in the cooling and heating processes, respectively. The maximum storage modulus (G') (Pa) was determined as the highest measured point during hardening at 20°C.

[0150] 1b-Large-scale deformation The texture properties of the gels were analyzed with a TA.XT plusC Texture Analyser (Stable Micro Systems Ltd., UK). Upon preparation, the gels were cast using a cylindrical mould of standard dimensions (height 19.6 mm, diameter 8 mm). The gels were allowed to cure for 18 hours at ambient temperature before analysis. Single compression analysis and standard texture profile analysis (TPA) were performed using a 5 kg load cell. A 35 mm diameter cylinder aluminium probe P / 35, supplied by Stable Micro Systems Ltd., was used. For the 75% large strain single compression, the pre- and post-test speeds were 2 mm / s, while the test speed was 0.5 mm / s and the trigger force was 5 grams. The strain height was measured automatically during compression. Maximum stress (g) and strain (%) data at break were obtained from the splitting moment of the gels. The slope (N / m) was calculated by the ratio of the force at 2% strain to the force at 3% strain. Young's modulus (N / m 2 ) was calculated from the slope by the following formula:

[0151]

number

[0152] 2. Syneresis Measurement Syneresis measurements were based on the weight loss of the gel. The gels were weighed and sealed in airtight, moisture-proof aluminum foil. After freezing at -20°C, thawing at ambient temperature and removing excess liquid, the gels were weighed again and the difference in gel weight was normalized to the percent loss.

[0153] 3. Water Activity Measurement Water activity was measured at ambient temperature using a HygroPalm HC2-AW (Rotronic, Switzerland). Samples were placed in the measurement chamber and the water activity was recorded after 45 min.

[0154] Example 1 - Gelled oil-in-water compositions and methods of preparation Composition: Exemplary gelled oil-in-water compositions according to the present invention are listed in the table below. It will be understood that any component that may be present in an amount of 0% by weight is optional.

[0155] [Table 1]

[0156] Preparation method: In the following methods, the pH adjuster is an organic acid / base buffer system consisting of trisodium citrate and malic acid, and the plasticizer, if present, is glycerol. 1. Mix agar, sugar alcohol, and optional sweetener(s) into a homogenous powder mixture. 2. Weigh out sterile water into a bottle and add the powder mixture to the water. 3. Place the bottle in a 90°C water bath and mix with magnetic stirring at 100 rpm for 30 minutes. If glycerol is used, heat it separately at 60°C for 30 minutes. 4. Reduce the temperature to 60° C. and mix the aqueous phase with magnetic stirring for an additional 30 minutes (approximately 60 minutes total). If glycerol is used, add the heated glycerol to the mixture via syringe. 5. Mix the oil along with any flavoring and / or colorant(s) in a beaker and preheat to 50° C. for 30 minutes. 6. When the ingredients are completely dissolved, slowly add the surfactant and trisodium citrate to the water phase. Mix for 10 minutes and slowly (carefully and gradually) add the malic acid. Mix the mass for an additional 10 minutes. 7. If using an antifoaming agent, add half of this agent and leave without stirring for 1 minute. 8. Weigh the bottle containing the water phase and vacuum the mass. Add the (heated) water loss and mix for 1 minute. 9. Add the oil phase to the agar mass (water phase) and homogenize the two phases for approximately 10 minutes using a high speed blender / homogenizer such as an Ultra-Turrax T 18 at 10,000 rpm. 10. If appropriate, add the second half of the (heated) antifoam agent and leave without stirring for 1 minute. 11. Weigh the bottle and vacuum the mass. Add the (heated) water loss and mix for 1 minute. 12. If desired, fill the resulting emulsion into blisters of a blister pack and seal.

[0157] Example 2 - Gelled Oil-in-Water Emulsion - Typical Formulation

[0158] [Table 2]

[0159] The emulsion can be prepared according to the general method of Example 1.

[0160] Example 3 - Gelled Oil-in-Water Emulsion Containing Sunflower Oil

[0161] [Table 3]

[0162] Prepare the emulsion according to the general method of Example 1. The final pH of the emulsion is 4.6-4.7. Measure the pH inside the gel at ambient temperature (20°C ± 2°C) using a calibrated Eutech Instruments pHSpear.

[0163] Example 4 - Multivitamin supplement

[0164] [Table 4]

[0165] The emulsion is prepared according to the general method of Example 1. Vitamin D and Vitamin K are added to the oil in step 5 and Vitamin B12 is added to the water phase in step 6.

[0166] Example 5 - Multimineral Supplement

[0167] [Table 5]

[0168] The emulsion is prepared according to the general method of Example 1. Minerals are added to the water phase in step 6.

[0169] Example 6 - Calcium Supplements

[0170] [Table 6]

[0171] The emulsion is prepared according to the general method of Example 1. Calcium phosphate is added to the water phase along with Panodan® AB 110 / C and sodium tricitrate.

[0172] Example 7 - Multivitamin supplement

[0173] [Table 7]

[0174] Emulsions are prepared according to the general method of Example 1. Fat soluble vitamins (E, A, D3) are mixed into the oil as in Example 4, and water soluble vitamins (C, B3, B6, B12, folic acid, D-biotin) as well as iodine are mixed as in Example 6 with CaHPO4.

[0175] Example 8 - Packaging Blister Pack: Prior to curing, the emulsions produced in any of Examples 1-7 may be filled into blister trays made from metal / plastic laminates or plastic films to which plastic / metal foil laminates are heat sealed. Blister trays with preformed cavities may be made from laminate materials such as Tekniflex® Aclar® VA10600 (TekniPlex), Perlalux® (Perlen Packaging), Formpack® (Amcor), and Regula® (Constantia Flexible).

[0176] The liquid emulsion produced in any of Examples 1-7 is filled into the blister tray using a syringe, ensuring that the cavity is filled evenly and completely. The blister tray is then flushed with nitrogen for 5-10 seconds and sealed with metal / plastic or metal / heat seal lacquer coated foil by applying a flat iron set at 160°C for 2-4 seconds. The samples are left to cure at room temperature for 24 hours and subjected to a controlled holding chamber at 40°C, 65% RH for 30 days. Samples were removed from the controlled chamber on days 5, 10, 15, 20, 25, and 30. After 24 hours at room temperature, the blister pack is opened. The amount of residue adhering to the tray and the force required to remove the unit dose from the pack are recorded on a scale of 1-9, with 1 indicating no adhesion and very little force required to remove the unit dose ("pop out") and 9 indicating complete adhesion to the foil and the unit dose having to be peeled from the foil. Each of the laminate materials listed above received a score of 1, 2, or 3 (predominantly 1 or 2) in each test.

[0177] Small piece: Prior to curing, the emulsions produced in any of Examples 1-7 may be extruded into individual pieces which, once cured, are then sealed into individual plastic / foil laminate pouches. Alternatively, the single extruded piece, once cured, may be cut into individual pieces as desired prior to packaging.

[0178] Example 9 - Coated gelled emulsion The hardened emulsion produced in any of Examples 1-7 may be coated with a sorbitol solution containing sorbitol (80% by weight), lemon flavoring (0.15% by weight), yellow color (0.5% by weight) and water (ad 100% by weight). The coating solution may be cured at 99°C-95°C for 4-5 hours before application. Coating is carried out by dipping or panning at 20°C-45°C. Several layers of coating material may be added with drying between each layer until the final composite layer is hard.

[0179] Alternatively, the liquid emulsion prepared in any of Examples 1-7 may be filled into a soft capsule shell prior to hardening. The capsule shell material may typically be a sugar, such as sucrose, fructose, maltose, xylitol, maltitol, or sorbitol, but may also contain hydrocolloid materials such as carrageenan, alginates, pectins, cellulose, modified cellulose, starch, modified starch, or gum arabic. The capsule shell may contain additional ingredients such as artificial sweeteners, colors, flavoring agents, and antioxidants.

[0180] Example 10 - Droplet size and size distribution An oil-in-water emulsion was prepared according to Example 3 and then placed in a water bath with gentle magnetic stirring at 55° C. The average droplet size was measured initially (t=0) and 1, 2 and 20 hours after preparation.

[0181] Droplet size and size distribution were measured using a Malvern Mastersizer 3000 (Worcestershire, UK) connected to a Hydro MV, wet dispersion unit (Malvern, Worcestershire, UK). Analysis of the data was performed using the manufacturer's software (Mastersizer 3000, v1.0.1). Tests were performed by diluting the emulsions (1:100) with distilled water at 70°C. The refractive indices of water and oil were set to 1.33 (solvent) and 1.47 (dispersed phase), respectively, and the absorptivity of the dispersed droplets was set to 0.01. To avoid multiple scattering or low intensity of scattered light, each dissolved emulsion was added to the dispersion unit (containing about 125 mL of water) until approximately 10% obscuration was obtained.

[0182] The droplet size distribution is shown in Figure 1. A slight increase in droplet size and tail shown at T20 occurs between T0 and T1 and is likely not due to coalescence but rather to some solidified agar being stirred up from the side of the bottle (particles were observed under a microscope). The lack of change in droplet size from T1 to T20 also supports that this is an artifact and not due to emulsion instability. The average droplet sizes are shown in Table 1.

[0183] [Table 8]

[0184] Example 11 -Texture properties Experiments were conducted to compare the gelling agar-based emulsion prepared according to Example 3, the large scale modification of the gelling gelatin-based emulsion, and the large scale modification of a pure aqueous agar gel. A pure aqueous agar gel was prepared by mixing agar (2 wt%) with Milli-Q-water (MQ-H2O) at 90°C. The mixture was cooled to ambient temperature for further characterization of the gel. The composition of the gelatin-based emulsion gel and its preparation method are as follows:

[0185] composition:

[0186] [Table 9]

[0187] Preparation method: Gelatin emulsion gels were prepared by mixing type B 160 Bloom bovine gelatin (Gelita®, Germany) with water for 30 minutes at 60°C under magnetic stirring. Sorbitol and xylitol were then added, mixing for 10 minutes after each addition. Trisodium citrate and malic acid were added, mixing for 10 minutes after each addition. Witafrol (0.06% by weight) was added to the gel and degassed using a Diaphragm Vacuum Pump (Vacuubrand, MZ 2C) until no air bubbles were visible. Water loss was compensated after degassing. Corn oil preheated to 60°C was added to the water phase and homogenized for 5 minutes at ambient temperature at a speed of 9.8k rpm. The mixture was degassed again.

[0188] Testing was performed according to the large scale deformation method described herein, and the results are shown in Figure 2 and Table 2.

[0189] [Table 10]

[0190] The gelling agar-based emulsion according to Example 3 containing Panodan® as a surfactant provides a stronger and more flexible gel compared to aqueous agar gels. The agar-based emulsion gel containing Panodan® has an improved (longer) texture compared to pure agar gels and is closer to the texture of gelatin-based emulsion gels. This results in a more pleasant mouthfeel compared to pure agar gels, as they will not crumble dramatically when chewed.

[0191] Example 12 - Droplet size and size distribution - effect of different amounts of surfactant Gelled oil-in-water emulsions containing different amounts of Panodan® surfactant were prepared according to Example 3 and tested to determine their average droplet size and size distribution. The emulsions contained 0.69%, 0.46% (2 / 3), and 0.23% (1 / 3) by weight of Panodan®, respectively. The reduction of Panodan® to 0.46% and 0.23% by weight was compensated by a corresponding increase in xylitol in the composition of Example 3.

[0192] The average droplet size was measured initially (t=0) and after 20 hours (T20) in a water bath at 55° C. with magnetic stirring as described in Example 10. The results are presented in FIG.

[0193] [Table 11]

[0194] Lower amounts of Panodan® gave a more dispersed droplet size distribution with larger droplets, however the droplets were still relatively stable and no significant phase separation was observed.

[0195] Example 13 - Droplet size and size distribution - effect of different amounts of oil Oil-in-water emulsions containing different amounts of oil were prepared and tested to determine their average droplet size and size distribution. The amount of surfactant (Panodan®) relative to the water phase was kept constant (corresponding to 0.69 wt% Panodan® in a 30 wt% oil system). 30 wt% oil was added initially, then the amount of oil was gradually increased by 5 wt%, then increased by another 5 wt% with emulsification (using a large Turrax 9.8k for 2 minutes) after each addition of oil. After each emulsification, samples were taken for droplet size measurement. The average droplet size was measured as described in Example 10. The results are presented in Table 4.

[0196] [Table 12]

[0197] Viscosity increased significantly from 40% to 45% oil by weight, and the Turrax was barely able to absorb and mix the mass at 45% oil by weight. At 50% by weight, the Turrax did not work and the mixture had to be shaken by hand to emulsify.

[0198] It can be seen that droplet size generally increases with increasing oil content, but even at 50 wt% oil, the droplet size is acceptable (at least initially). At 50 wt% oil, the droplet size increases with time, but the increase from t=0 to t=1 hr is significantly greater than the increase from t=1 hr to t=4 hr. This was homogenized by shaking by hand, so the apparent increase can be attributed to a non-uniform emulsion that would settle if placed under more stationary conditions in a water bath.

[0199] Example 14 - Droplet size and size distribution - effect of pH To determine the effect of pH on droplet size, an emulsion according to Example 3 was prepared containing 0.69 wt% Panodan® but no agar. Removal of the agar was compensated for by increasing the xylitol content. The emulsion was set at a temperature of 60° C. and 4M HCl was slowly added dropwise. After each addition, a small amount of emulsion was removed for pH and droplet size measurement. pH was measured at ambient temperature (20° C.±2° C.) using a calibrated Eutech Instruments pHSpear.

[0200] The variation in droplet size based on emulsion pH is shown in FIG.

[0201] [Table 13]

[0202] Due to the absence of agar, the initial droplet size (at pH 4.65) is somewhat larger than that in the gelling agar emulsions described herein (lower viscosity, therefore lower energy input). The droplet size is seen to increase as the pH decreases, particularly from 4.30 to 3.97 where there is a relatively large increase. Without wishing to be bound by theory, this is likely because DATEM (Panodan®) becomes partially protonated and therefore gradually less effective in low water activity gelling oil-in-water emulsions. Although the droplet size increased significantly, the droplets appeared to be relatively stable even at pH 3.32. Significant phase separation became evident at pH 3.20.

[0203] Example 15 - Lipolysis In vitro lipolysis of emulsion gel according to Example 3 was carried out at 37°C. Simulated intestinal fluid (SIF) was formed by mixing 450 mg of porcine bile extract (Sigma, USA, lot#SLCC9272) with 34 ml of deionized water (dH2O) in a beaker with magnetic stirring for 30 minutes. Then, 12.5 ml of salt mixture (40 mM CaCl2 / 600 mM NaCl / dH2O) was added to the beaker and mixed for 10 minutes. 69.6 mg of porcine pancreatin (Sigma, USA, lot#SLBZ5739) and porcine pancreatic lipase (Sigma, USA, lot#SLBZ7254) were dissolved in 1160 μl of water in separate Eppendorf tubes by vortex mixing for 3 minutes. The gelled emulsion was forced through a metal mesh with pore size 1.7 mm (Endecotts Ltd, UK) and 1.5 g of gel was added to the SIF while constantly mixing with magnetic stirring. A pH combination electrode (A 1622M DI, SI Analytics, Germany) was placed in the beaker. The electrode was connected to a titrator 7000-M1 / 20, TitroLine (SI Analytics, Germany). The pH was adjusted to 7 by manually adding drops of 1 mM and 0.1 mM NaOH. The pH-stat was started and 1 ml of pancreatin and lipase solutions were added simultaneously to the SIF to start the lipolysis reaction. The pH-stat was set to maintain the pH at 7 by adding drops of 0.1 mM NaOH. The total lipolysis time was 1 h. The final concentrations of the SIF components were 9 mg / ml porcine bile extract, 10 mM CaCl2, 150 mM NaCl, 1.2 mg / ml pancreatin, and 1.2 mg / ml lipase. The final volume of the SIF was 50 ml.

[0204] The results are presented in FIG.

[0205] [Table 14]

[0206] Example 16 - Gelled Oil-in-Water Emulsions Containing Corn Oil and Characterization

[0207] [Table 15]

[0208] Following the general method of Example 1, emulsions were prepared according to the following protocol.

[0209] [Table 16]

[0210] The pH inside the gel was measured at ambient temperature (20° C.±2° C.) using a calibrated Eutech Instruments pHSpear and was measured to be 4.5.

[0211] The average droplet size was measured as described in Example 10. At T=0 time: D[4;3]=0.48 μm; D[3;2]=0.44 μm Water activity was measured as described herein. w =0.747

[0212] The average weight loss was measured as described in the Syneresis Test described herein. Average weight loss: 6.96%

[0213] Viscosity measurements were carried out at 50° C. by applying a serrated PU40 SW1556 SS and a sandblasted bottom plate prior to the SAOS (small amplitude oscillatory shear) rheology measurements described herein. The results are as follows:

[0214] [Table 17]

[0215] Rheological analysis was carried out according to the small scale deformation test described herein. T=0 time: G'max=14490kPa.

[0216] Example 17 - Gelled oil-in-water emulsion containing sunflower oil

[0217] [Table 18]

[0218] Emulsions were prepared according to the general method of Example 1. The average droplet size of the emulsions at t=0 time was measured as described in Example 10 and the results are shown in Table 8.

[0219] [Table 19]

[0220] Tests were also performed on gelling emulsions according to the large scale variation method described herein, and the results are shown in Table 9 in comparison with the results for the gelling agar-based emulsion of Example 3.

[0221] [Table 20]

[0222] The results confirm that DATEM obtained from different sources can be used to generate gelling oil-in-water emulsions.

[0223] Example 18 - Effect of different surfactants Experiments were conducted to compare the effect of different surfactants on emulsion stability. Polyoxyethylene (80) sorbitan monooleate (Polysorbate 80 or "PS80") and LACTEM (lactic acid esters of mono- and di-glycerides) were chosen as examples of other food-grade surfactants. Unlike DATEM, both Polysorbate 80 and LACTEM are non-ionic surfactants. They are both completely neutral, i.e., they do not carry a static charge.

[0224] 1. Agar emulsion - PS80 Attempts were made to prepare oil-in-water emulsions with different amounts of sugar alcohol to determine at what point PS80 no longer functions as an emulsifier in this system. A "standard" oil-in-water formulation (40 g) was prepared using PS80 instead of DATEM and compared to formulations in which ½ and ¾ of the sugar alcohol content was replaced with water. The formulations were prepared according to the general method of Example 1. The PS80 was preheated before being added to the remaining components of the emulsion. The formulations each contained 25% corn oil by weight. Details of the formulations are shown in Table 10.

[0225] [Table 21]

[0226] The water activity of the formulations was measured as described herein. "1 / 2 s.alk":aw=0.926 "3 / 4 s.alk":aw=0.855

[0227] When PS80 was used as the surfactant, a stable emulsion could not be produced for the "standard" formulation. The emulsion droplet size and stability for the "1 / 2 s.alk" and "3 / 4 s.alk" formulations were determined as described herein. The emulsion droplet size and stability are shown in Table 11. Figure 6 shows the emulsion droplet size volume distribution.

[0228] [Table 22]

[0229] Observations: The 1 / 2 sugar alcohol: PS80 did not appear to completely dissolve upon addition (the mixture became cloudy). It readily formed an emulsion with very small droplet size (~1 μm) and a narrow unimodal distribution (slightly bimodal at T=20 hours). The emulsion was nearly completely stable overnight at 55°C.

[0230] 3 / 4 Sugar Alcohol: The mixture became cloudy upon addition of PS80. Upon homogenization an emulsion appeared to form but appeared yellow / translucent (indicating the presence of large droplets). The initial droplet size was large with a broad multimodal distribution. The emulsion was very unstable and was close to complete phase separation after approximately 30 minutes at 55°C.

[0231] 2. Agar Emulsion - LACTEM An attempt was made to prepare an oil-in-water emulsion using LACTEM as the emulsifier. The components shown below were combined according to the general method of Example 1.

[0232] [Table 23]

[0233] Observations: These components were completely incompatible. Phase separation was observed immediately.

[0234] The results show that fully esterified (i.e., no free acid functional groups such as carboxylic acid groups) surfactants and surfactants that do not carry electrostatic charges do not function to effectively stabilize agar-based oil-in-water emulsions with low water activity due to their low solubility in the continuous aqueous phase. DATEM (diacetyl tartaric acid esters with mono- and di-glycerides derived from sunflower oil) always carries one charge. The results presented herein confirm that DATEM provides stable emulsions well below pH 3.5 and that these emulsions contain small oil droplets.

Claims

1. 1. An orally administrable gelled oil-in-water emulsion that is a self-supporting viscoelastic solid having a gelled aqueous phase that comprises a gelling agent that is agar, the orally administrable gelled oil-in-water emulsion having a water activity in the range of about 0.4 to about 0.9 and stabilized by a surfactant comprising an ester of glycerol having at least one hydroxyl group esterified with diacetyltartaric acid and at least one hydroxyl group esterified with a fatty acid.

2. 2. The orally administrable gelled oil-in-water emulsion of claim 1 , wherein the gelled aqueous phase of the emulsion has a pH of less than 7.

3. 3. The orally administrable gelled oil-in-water emulsion of claim 1 or 2, wherein the surfactant comprises diacetyl tartaric acid esters of mono- and di-glycerides (DATEM).

4. 4. The orally administrable gelled oil-in-water emulsion of claim 3, wherein said surfactant is obtained by reaction of mono- and di-glycerides of fatty acids obtained from edible oils with diacetyltartaric anhydride.

5. 5. The orally administrable gelled oil-in-water emulsion of claim 4, wherein the edible oil is sunflower oil or palm oil, or a combination thereof.

6. 2. The orally administrable gelled oil-in-water emulsion of claim 1, wherein said surfactant has the E number E472e.

7. The surfactant has the general formula: 【Chemistry 2】 wherein each R is independently H, or -C(O)(CH 2 ) n CH 3 wherein n is an integer from 6 to 21, preferably wherein n is 16. Compounds having the formula:

2. The orally administrable gelled oil-in-water emulsion of claim 1.

8. 8. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 7, having a water activity in the range of 0.5 to 0.

8.

9. 9. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 8, having a gelled aqueous phase with a pH of 4.2 to 7.

10. 10. The orally administrable gelled oil-in-water emulsion of any one of claims 1 to 9, comprising agar at a concentration of about 0.1 to about 5% by weight, based on the total weight of the emulsion.

11. 11. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, wherein the aqueous phase constitutes 40% to 95% by weight of the emulsion, preferably 50% to 95% by weight, more preferably 55% to 90% by weight, such as 60% to 85% by weight, 70% to 85% by weight, or 75% to 80% by weight.

12. 12. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 11, wherein the aqueous phase further comprises one or more bulking agents, such as a sugar alcohol and / or a sugar.

13. 13. An orally administrable gelled oil-in-water emulsion according to claim 12, wherein the bulking agent is present in a concentration of 45% to 70% by weight, preferably 50% to 65% by weight, for example 55% to 60% by weight, based on the aqueous phase.

14. 14. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 13, having an oil phase comprising one or more physiologically acceptable lipids derived from rapeseed oil, sunflower oil, corn oil, olive oil, sesame oil, palm kernel oil, coconut oil, nut oil, algae oil or hemp oil.

15. 15. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, comprising an oil phase which constitutes from 5% to 60% by weight of the emulsion, preferably from 5% to 50%, more preferably from 10% to 45%, such as from 15% to 40%, 15% to 30%, or 20% to 25%.

16. 16. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 15, further comprising at least one pharma- ceutical active agent.

17. 17. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 16, further comprising at least one nutraceutical active agent.

18. 20. The orally administrable gelled oil-in-water emulsion of claim 17, wherein said nutritional active is a vitamin or mineral.

19. 19. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 18 provided in unit dosage form.

20. 20. The orally administrable gelled oil-in-water emulsion of claim 19, wherein said unit dosage form is uncoated.

21. 21. A package with airtight and lighttight compartments containing a dosage unit of a gelled oil-in-water emulsion according to claim 19 or 20.

22. A method for preparing an orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 20, said method comprising: forming an oil phase comprising one or more physiologically acceptable lipids; forming an aqueous phase containing a gelling agent that is agar; combining the oil phase and the aqueous phase in the presence of a surfactant comprising an ester of glycerol having at least one hydroxyl group esterified with diacetyl tartaric acid and at least one hydroxyl group esterified with a fatty acid to form an oil-in-water emulsion; gelling the emulsion; A method comprising:

23. 21. A gelled oil-in-water emulsion according to any one of claims 1 to 20 for oral use as a medicament or in therapy.

24. 21. A gelled oil-in-water emulsion according to any one of claims 1 to 20, containing at least one pharma- ceutical active ingredient, for oral use in the treatment of a condition responsive to said pharma- ceutical active ingredient.

25. 21. Use of a gelled oil-in-water emulsion according to any one of claims 1 to 20 as a nutritional supplement product.

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