Oil-in-water emulsions containing agar and diacetyl tartrate of monoglyceride and diglyceride (DATEM)

Abstract

The present invention relates to compositions for oral administration provided in the form of gelled oil-in-water emulsions, processes for their preparation and their use as pharmaceuticals and nutraceuticals. Specifically, it relates to a gelling oil-in-water emulsion that can be orally administered, the emulsion being a self-supporting viscoelastic solid having a gelling aqueous phase comprising a gelling agent that is agar wherein the emulsion has a water activity in the range of about 0.4 to about 0.9 and is stabilized by a surfactant comprising glyceride, wherein at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with a fatty acid.

Description

Technical Field

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

[0002] More specifically, the present invention relates to oral compositions that are acceptable to patients and consumers who wish to avoid consuming animal by-products, such as those following a vegetarian diet or vegans. The present invention also relates to oral compositions that are acceptable to pescatarians. Background Art

[0003] Soft chewable dosage forms are alternatives to traditional oral administration forms such as tablets, capsules, elixirs and suspensions. They are easier to swallow than tablets and capsules, and are particularly suitable for pediatric and elderly populations and populations with dysphagia. Such dosage forms are common choices for dietary supplements (so-called "nutraceuticals") containing vitamins and / or minerals, and are also suitable for the delivery of active pharmaceutical ingredients (APIs). The active component (nutraceutical or drug) can be present in a gelled oil-in-water emulsion as dispersed particles in the form of lipids, or dissolved in the oil phase or water phase of such emulsions.

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

[0005] A range of gelling agents can 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 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 present in the skin, bones and connective tissues of animals, and is most commonly derived from pigs, cattle and fish. The sol-gel transition temperature of gelatin generally corresponds to the body temperature of the animal from which the gelatin is obtained. Gelatin from mammalian sources therefore has a transition temperature similar to human body temperature, thereby producing a gel that is solid at room temperature but melts in the oral cavity once ingested. Therefore, gelatin-based dosage forms provide a pleasant "melt-in-the-mouth" texture or "mouthfeel". Gelatin also provides rapid and consistent dissolution kinetics of dosage units in the gastrointestinal tract, which can be beneficial to promote the rapid intake of any active ingredient.

[0006] Gelatin has significant surface active properties, which allows 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. Emulsions based on gelatin usually experience an "active filler effect" (wherein oil droplets interact strongly with the surrounding gel network) and are generally referred to as "active fillers". When 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 an oil-free gel (i.e., a separate gel). In contrast, oil droplets distributed throughout the gel and having little or no interaction with the gel network are referred to as "inactive fillers", and cause the modulus of the gelled emulsion to be lower than the modulus of the separate gel. When the oil droplets of the gelled emulsion exist as "inactive fillers", the emulsion may be unstable over time. This can cause the emulsion to lose stability and oil "oozing out".

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

[0008] Gelling agents that are non-animal derived and have been previously proposed for the production of soft chewable dosage forms (such as gelled oil-in-water emulsions) include non-proteinaceous materials such as alginates, carrageenans, and pectins. However, the gelling properties of these materials may be difficult to control due to the need for complexation with metal ions, temperature changes, and / or pH adjustments to produce the desired "gel". This is undesirable in the case of dosage forms to be manufactured on a commercial scale.

[0009] Another widely used gelling agent in food and other non-food applications is agar. Agar is extracted from marine red algae and contains polysaccharides containing galactose subunits. It is a thermosetting polymer that gels at about 30°C-45°C. Agar melts at about 85°C-90°C, and once melted, it remains liquid until cooled to about 40°C. Due to the large hysteresis between the gelling temperature and the melting temperature, it has the potential for large-scale production of dosage units formed by gelled oil-in-water emulsions. However, unlike gelatin, which produces soft, flexible gels that can withstand high compression before rupture, agar-based gels are hard and brittle. For example, gelatin-based gels may withstand up to 70%-90% compression before rupture, whereas agar-based gels typically break at deformations as low as 20%. This severely limits its use in the production of any dosage unit that needs to be soft and chewable and has a pleasant mouthfeel. It also prevents its use in "push-through" blister packaging.

[0010] Different from gelatin-based gels, agar-based gels are also prone to syneresis, i.e., spontaneous release of water from the gel when aging. Gels are 3D networks of polymers that are cross-linked to each other and capture water within the structure. If the polymer network is undisturbed, water remains in place. However, over time, the polymers that form the gel may shrink or change their structure, causing water to be discharged and the gel to shrink. Water seeping out of the gel is referred to as "syneresis", and this must be minimized in any oral dosage unit, because gel is required to have a sufficiently long shelf life, i.e., it should remain stable over a long period of time. Traditionally, one of the methods for solving the syneresis problem of agar gel is by increasing agar concentration. However, this can cause the gel to be harder, firmer and more brittle, which is undesirable when seeking 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 surfactant ("surfactant") to provide a sufficiently stable emulsion. A wide variety of food grade surfactants are known and used in the art, but applicants have recognized that not all of these are suitable for stabilizing gelled agar-based oil-in-water emulsions.

[0012] The type of gelled oil-in-water emulsions disclosed in WO 2007 / 085840, WO 2010 / 041015 and WO 2012 / 140392 represent a special challenge when seeking to replace gelatin with agar as a gelling agent. A prerequisite for stabilizing 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., water). However, in order to reduce the possibility of microbial growth and thus extend the shelf life, the gelled 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, the low water activity is achieved by including a high content of sugar alcohol (filler) in the gelled aqueous phase. Therefore, these gelled emulsions differ from most conventional oil-in-water emulsions in that they have a low water activity (a w The presence of buffer salts (pH adjusters) in the aqueous phase also results in a relatively low pH (usually between 4 and 4.7). Together, these factors cause intense competition for "free" water and the potential for loss of electrostatic charge of any surfactant present (due to the low pH). Applicants have found that many conventional low molecular weight surfactants used in food or pharmaceuticals do not provide stable emulsions under these conditions. Examples of such surfactants include LACTEM (which consists of lactic acid esters of mono- and di-glycerides) and polysorbates (such as Tween 80).

[0013] Therefore, there is a continuing need for alternative soft but chewable compositions for oral delivery of drugs and / or nutraceuticals suitable for vegetarians, pescatarians and vegans. In particular, there is a need for compositions that can provide an acceptable alternative to conventional gelatin-based oil-in-water emulsions in terms of their "chew" and mouthfeel characteristics, while having sufficient stability (i.e., shelf life) for use as a drug and / or nutraceutical. Summary of the invention

[0014] The applicant has now proposed a gelled oil-in-water emulsion which is acceptable to patients and consumers who are vegetarians, pescatarians or vegans, particularly those who follow a vegetarian diet or a vegan diet. These emulsions use agar as a gelling agent and are stabilized using certain low molecular weight surfactants. These surfactants include glycerides, wherein at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with fatty acids. 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 a gelled emulsion with the desired rheological properties for oral delivery of active agents in a soft but chewable dosage form. The applicant has also found that this surfactant can provide an emulsion with a small droplet size and therefore a high initial lipolysis rate after oral delivery. This may be desirable because lipolysis is a prerequisite for intestinal uptake of lipids derived from triglycerides.

[0015] Thus, in one aspect, the present invention provides an orally administrable gelled oil-in-water emulsion which is a self-supporting viscoelastic solid having a gelled aqueous phase comprising a gelling agent (agar), wherein the emulsion has a water activity ranging from about 0.4 to about 0.9 and is stabilized by a surfactant comprising a glyceride, wherein at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with a fatty acid.

[0016] In another aspect, the present invention provides a method for preparing a gelled oil-in-water emulsion as described herein, the method comprising the steps of: forming an oil phase comprising one or more physiologically tolerable lipids; forming an aqueous phase comprising a gelling agent, the gelling agent being agar; mixing the oil phase and the aqueous phase in the presence of a surfactant to form an oil-in-water emulsion, the surfactant comprising a glyceride, wherein at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with a fatty acid; and gelling the emulsion.

[0017] In another aspect, the present invention provides a gelled oil-in-water emulsion as described herein for oral use as a medicament or for oral use in therapy.

[0018] In another aspect, the present invention provides a gelled oil-in-water emulsion as described herein, containing at least one pharmaceutically active ingredient for oral administration for the treatment of a condition responsive to said pharmaceutically active ingredient.

[0019] In another aspect, the present invention provides the use of a pharmaceutically active ingredient in the manufacture of a medicament for oral administration for the treatment of a condition responsive to the pharmaceutically active ingredient, wherein the medicament is provided in the form of a gelled oil-in-water emulsion as described herein.

[0020] In another aspect, the present invention provides a method of treating a human or non-human animal subject (e.g., a patient) against a condition responsive to a pharmaceutically active agent, the method comprising the step of orally administering to the subject a pharmaceutically effective amount of the agent in the form of a gelled oil-in-water emulsion as described herein.

[0021] In another aspect, the present invention provides the use of a gelled oil-in-water emulsion as described herein as a nutraceutical. DETAILED DESCRIPTION

[0022] definition

[0023] The term "gel" refers to a form of matter intermediate between a solid and a liquid. The formation of a "gel" typically involves the association or cross-linking of polymer chains to form a three-dimensional network that entraps or fixes a solvent (e.g., water) therein to form a sufficiently rigid structure that resists flow at ambient temperature, i.e., at temperatures below about 25°C, preferably below about 20°C. In rheological terms, a "gel" can be defined according to its storage modulus (or "elastic modulus") G', which represents the elastic properties of the material (energy storage) and its loss modulus (or "viscous modulus") G" (which represents the viscous properties of the material (energy loss). Their ratio, tan δ (equal to G" / G'), also known as the "loss tangent", is a measure of the degree to which stress and strain are out of phase with each other.

[0024] "Viscoelastic" materials are characterized by rheological properties that are partly similar to the rheological behavior of viscous fluids and partly similar to the rheological behavior of elastic solids.

[0025] The gelled oil-in-water emulsions according to the present invention are "self-supporting viscoelastic solids". This is intended to mean that they exhibit properties intermediate between solids and liquids, but have solid-dominated behavior, i.e., they have rheological properties that are more similar to solids than to liquids. The "solid-dominated behavior" cannot be diluted (i.e., destroyed) by adding more solvent. In contrast, in the case of weak (or entangled) gels lacking stable (i.e., long-lived) intermolecular crosslinks, the entangled network structure of the gel can be removed by adding more solvent and is easily destroyed even at very low shear rates / shear stresses.

[0026] The gelled oil-in-water emulsions of the present invention exhibit mechanical rigidity, but compared to solids, they are deformable. Specifically, when measured at ambient temperature (i.e., a temperature in the range of 18°C ​​to 25°C, for example, at 20°C) and 0.1% strain, the gelled emulsions described herein have a storage modulus G' greater than their loss modulus G" (i.e., G'>G") over a wide frequency range, for example, in the frequency range from 0.001 Hz to 10 Hz. The storage modulus and loss modulus can be measured using known methods, such as using a Kinexus Ultra+ rheometer using a C 4 / 40 measurement geometry. The storage modulus and loss modulus values ​​are not expected to be different when measured using other types of rheometers in the linear viscoelastic range.

[0027] More specifically, the gelled oil-in-water emulsions described herein will have the following properties: G'>G" in the frequency range of 0.001 Hz to 10 Hz at 0.1% strain; and a storage modulus (G') in the range of 10 Pa to 200,000 Pa, preferably 100 Pa to 100,000 Pa, and more preferably 500 Pa to 50,000 Pa at ambient temperature (i.e., at a temperature in the range of 18°C ​​to 25°C, for example at 20°C).

[0028] Weak gels typically have a loss tangent tan δ > 0.1. For strong gels or fully formed gels, G' >> G" and lower tan δ values ​​(< 0.1) are observed. The gelled oil-in-water emulsions described herein are generally considered to be "strong gels" at ambient temperature, i.e., at a temperature in the range of 18°C ​​to 25°C, for example at 20°C.

[0029] As used herein, the term "gelation" refers to the formation of a "gel". The term is used herein in relation to the physical properties of the aqueous phase of an emulsion and to the physical properties of an oil-in-water emulsion. As will be appreciated, the oil droplets behave more or less like a solid when dispersed in the gelled aqueous phase of the oil-in-water emulsion that is the subject of the present invention. The "gelling" nature of the aqueous phase is therefore also a characteristic of an oil-in-water emulsion, i.e. it may also be considered as "gelling" as described herein.

[0030] Unless otherwise defined, the term "liquid" as used herein refers to a substance that flows freely and maintains a constant volume. It includes flowing thickened liquids and viscous liquids. A "liquid" has a loss modulus (G") greater than its storage modulus (G') and a loss tangent (tan δ) greater than 1.

[0031] As used herein, the term "water activity" ("a w ”) refers to the partial pressure of water vapor in a composition at a specific temperature divided by the standard state water vapor pressure at the same temperature. Water activity thus serves as a measure of the amount of free (i.e., unbound) water in a composition. It can be calculated as:

[0032] a w =p / p0

[0033] where p is the partial pressure of water vapor in the composition, and p0 is the vapor pressure of pure water at the same temperature.

[0034] Alternatively, water activity can be calculated as:

[0035] a w = l w x w

[0036] Among them l w is the activity coefficient of water, and x w is the mole fraction of water.

[0037] Water activity can 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, ie 21°C ± 2°C.

[0038] As used herein, the term "pH" is a measure of the concentration of hydrogen ions 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, such as pH measurement using a contact electrode, such as a calibrated Eutech Instruments pHSpear.

[0039] As used herein, the term "surfactant" refers to a surface-active compound or composition that is capable of reducing the interfacial tension between two immiscible liquids (e.g., at the interface between oil and water). It can consist of a single component or it can be a mixture of components. As described herein, the process for producing the surfactant used in the present invention will typically provide a mixture of different components.

[0040] 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, usually represented by the α (alpha) end. The hydrocarbon chain can be saturated or (mono- or poly-) unsaturated. By convention, the numbering of carbon atoms starts from the α end, so the carbon atom of the carboxylic acid group is carbon number 1. The other end, which is usually a methyl (-CH3) group, is usually represented as ω (omega), so that the terminal carbon atom is ω-carbon. Any double bond present can be in cis or trans configuration. The nomenclature "ω-x" is used to indicate that the double bond is located on the xth carbon-carbon bond, counting from the terminal carbon (i.e., ω-carbon) to the carbonyl carbon.

[0041] "Physiologically tolerable" refers to any composition suitable for administration to the human or non-human animal body, particularly any composition suitable for oral administration.

[0042] A "drug" is any product intended for medical purposes, such as for the treatment or prevention of any disease, condition or disorder of the human or non-human animal body, or for preventing its recurrence, or for alleviating or eliminating the symptoms of any such disease, condition or disorder. The use and production of a product that is a "drug" will be strictly regulated by government agencies. It can, but does not have to, be prescribed by a doctor. For example, it can be purchased "over the counter", i.e. without a prescription.

[0043] "Treatment" or "therapy" encompasses any therapeutic application that can benefit humans or non-human animals (e.g., non-human mammals). Both human and veterinary treatments are within the scope of the invention, but the invention is primarily directed to treatment of humans. Veterinary treatments include treatment of livestock and domestic animals (e.g., pets such as cats, dogs, rabbits, etc.). Treatment may be for an existing disorder, or it may be preventative.

[0044] In contrast to drugs, "nutraceuticals" need not be the subject of regulatory authorities. The term "nutraceutical" is used herein to refer to products 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, among others, dietary supplements, such as vitamins and minerals, intended to enhance the health of a subject (e.g., a human subject).

[0045] As will be appreciated, some substances may be considered both a "drug" and a "nutraceutical." Different countries classify substances as one or the other, or both, depending on local regulations related to pharmaceutical products. It may also depend on the recommended daily dose for any given substance. For example, higher daily doses of certain vitamins (e.g., vitamin D) may be regulated as drugs, while lower daily doses may be considered nutraceuticals.

[0046] "Pharmaceutical composition" refers to a composition in any form suitable for pharmaceutical purposes.

[0047] "Nutritional composition" refers to a composition in any form suitable for nutritional purposes.

[0048] "Pharmaceutically effective amount" relates to the amount that will result in the desired pharmacological and / or therapeutic effect, i.e., an amount of a pharmaceutical agent that is effective to achieve its intended pharmaceutical purpose. Although the needs of individual patients may vary, determining the optimal range of the effective amount of any active agent is within the ability of those skilled in the art.

[0049] "Nutritionally effective amount" relates to the amount that will result in the desired nutritional effect, i.e., the amount of an agent effective to achieve its intended nutritional purpose. Although individual needs of a subject may vary, determining the optimal range of effective amounts of any active agent is within the capabilities of those skilled in the art.

[0050] The term "capsule" is used herein to refer to a unitary dosage form having an outer shell or coating (referred to herein as a "capsule shell") which encloses a gelled oil-in-water emulsion as defined herein.

[0051] As used herein, "animal by-product" is intended to refer to any product derived from, separated from, or purified from one or more parts of an animal's body (e.g., bones, skin, tissue, meat, cartilage, hooves, tentacles, etc.). It is also intended to refer to any composition prepared by processing an animal by-product, for example, a derived, functionalized, or otherwise chemically or physically modified animal by-product. As used herein, "animal by-product" is not intended to include milk; eggs; or any compound or composition derived from, separated from, or purified from animal milk or animal eggs. The term "animal by-product" does not include any synthetic material; or any material obtained from any plant, fungal, bacterial, or algal source.

[0052] As used herein, the term "vegetarian diet" generally refers to a diet that does not contain any meat and does not contain any animal by-products as defined herein."Vegetarian diet" may include animal milk and animal eggs and any product derived from, separated from or purified from them. Such a diet may also be generally referred to as a "lacto-ovo vegetarian" diet or a "lacto-ovo vegetarian" diet, which, in addition to food from plants, also includes milk, cheese, other dairy products and eggs. "Pescet diet" refers to a diet in which the only meat source is fish and seafood. "Vegan diet" refers to a completely vegetarian diet, which only includes food (such as fruits, vegetables, cereals, beans, seeds and nuts) from plants. Any "suitable" product, material, composition or preparation mentioned herein for a given diet means that it will be acceptable for those who follow this particular diet. The terms "vegetarian", "pescet" and "vegan" are intended to refer to those who follow a vegetarian, pescet or vegan diet, respectively.

[0053] In a first aspect, the present invention provides an orally administrable gelled oil-in-water emulsion which is a self-supporting viscoelastic solid having a gelled aqueous phase comprising a gelling agent (agar), wherein the emulsion has a water activity ranging from about 0.4 to about 0.9 and is stabilized by a surfactant comprising a glyceride, wherein at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with a fatty acid.

[0054] The aqueous phase of the emulsion according to the 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 it may be a mixture of different types of gelling agents. In the case of using more than one gelling agent, at least one of these gelling agents is agar.

[0055] Agar is well known in the art and is used, 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 hydrocolloidal polysaccharides extracted from red seaweed (i.e., seaweed of the family Rhodophyceae). The hydrocolloidal polysaccharides present in agar contain one or more polymers composed of galactose subunits. Sources of agar include seaweed belonging to the following genera: Gelidium, Gracilaria, Pterocladia, and Gelidiella. Gracilaria is the main source of agar worldwide.

[0056] Although the properties of agar and its characteristics (e.g., its gelling ability) will vary depending on the species from which it is extracted and the extraction method used in its production, it is contemplated that any known agar may be used in the present invention. Agar obtained from Gracilaria species are generally more highly sulfated and therefore have a lower gelling ability. However, their gelling properties may be enhanced by subjecting the seaweed material to alkaline hydrolysis prior to extraction. This converts the L-galactose 6-sulfate units into 3,6-anhydride-L-galactose residues, which are believed to control the gelling properties of the polymer. Alternatively, the agar may be enzymatically treated to remove sulfate groups before and / or after extraction. In one embodiment, the agar used in the present invention may be an agar having a reduced sulfate group content.

[0057] Agar is a linear polysaccharide composed of alternating β(1,3)- and α(1,4)-linked galactopyranose residues. Most of the α-galactose residues can exist 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 by acidic groups (i.e., sulfate, uronide, and pyruvate) and by nonionic methoxy groups have been identified. Early studies showed that agar is composed of two major parts: a neutral part called "agarose" with high gelling ability and a charged part called "agarose" with lower gelling ability. More recent studies have shown that agar is a complex mixture of polysaccharides ranging from essentially neutral to charged galactan molecules. The term "agarose" refers to a neutral polysaccharide with high gelling ability composed of repeating disaccharide units of agarobiose, i.e., 4-O-(β-D-galactopyranosyl)-3,6-anhydride-α-L-galactopyranose. Polysaccharides with repeating disaccharide units of 4-O-(β-D-galactopyranosyl)-α-L-galactopyranose in which anhydride bridges are absent are called "agarans". Alkaline treatment of agar removes sulfates on C6 of 4-linked galactose units and forms the corresponding 3,6-anhydride form. This treatment is widely used to extract industrial agar from Gracilaria species to improve their gelling properties. A more detailed review of agar can be found, for example, in Chapter 24 of Handbook of Hydrocolloids (Sousa et al., 2021), the entire contents of which are incorporated herein by reference.

[0058] Food safety authorities, including the European Food Safety Authority (EFSA) and the Food and Drug Administration (FDA) worldwide allow agar in food products as a food additive (E-406). Agar is provided as a powder with high solubility in water (e.g., a solubility of at least 85% (at 80°C)). Its gel strength can vary but is generally around 700 g / cm 2 About 1100g / cm 2 The gel strength was measured as follows: a solution containing 1.5 wt% agar was prepared. The solution was placed at 20°C for 24 hours. A load was then applied to the obtained gel, and the maximum weight of the load that the gel could withstand for 20 seconds was measured. 2 The maximum weight value is the gel strength of agar. Gel strength can be measured using a Mecmesin Electronic Texture Analyzer. Gel strength is less than 250 g / cm 2Agars with a gel strength of more than 250 g / cm2 are often referred to as "low strength" agars. Due to their lower gel strength, "low strength" agars may be less preferred for use in the present invention. In one embodiment, the agar used in the present invention is not a "low strength" agar as defined herein. Preferred for use in the present invention is an agar having a gel strength of more than 250 g / cm2. 2 For example, the agar may have a density of at least 500 g / cm 2 , at least 600g / cm 2 or at least 700g / cm 2 In one embodiment, agar may have a gel strength of at least 800 g / cm 2 Gel strength.

[0059] The gel point of agar is generally in the range of 30°C to 45°C (measured at 1.5% by weight in water at 20°C). The melting point of agar may, for example, be in the range of 80°C to 95°C (measured at 1.5% by weight in water at 20°C). In one embodiment, agar used in the present invention has a gel point in the range of about 35°C to about 45°C (measured at 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 1.5% by weight in water at 20°C).

[0060] Agar used in the present invention can be obtained from various commercial sources. Non-limiting examples of agar that can be used include Gelagar HDR 800 (from B. & V. srl, Italy) and Qsol TM High Solubility Agar and Qsol Agar (from Hispanagar, Spain).

[0061] The aqueous phase of the gelled oil-in-water emulsion according to the present invention may comprise agar as the sole gelling agent, or it may comprise additional non-agar gelling agents. Where other gelling agents are present, these gelling agents 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 also not be any animal by-product. For example, there is no mammalian gelatin. Preferably, there is no gelatin from any source (including fish gelatin).

[0062] 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 gelling as described herein. This amount will vary to some extent depending on the exact nature of the gelling agent (e.g., the type of agar employed) and / or other components of the aqueous phase, but a suitable amount can be readily determined by one skilled in the art. In the case where a gelling agent other than agar is also employed, a suitable amount can be readily selected by one skilled in the art. The amount of agar can be adjusted accordingly.

[0063] In one set of embodiments, agar can 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, it can 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). Based on the total weight of the composition, the concentration of agar can be in the range of 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, it can be present at a concentration of 0.25%, 0.50%, 0.75%, 1.0%, 1.25%, 1.50%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75% or 3.0% by weight (based on the total weight of the composition).

[0064] The gelled oil-in-water emulsions described herein are stabilized by a surfactant comprising a glyceride wherein at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with a fatty acid.

[0065] In one embodiment, the surfactant used in the present invention is a product containing diacetyl tartaric acid esters of monoglycerides and diglycerides (also known as "DATEM"). DATEM is a synthetic emulsifier made by the esterification reaction of acetic acid, tartaric acid, glycerol and fatty acids from edible sources. It can also be produced by the reaction of diacetyl tartaric anhydride with monoglycerides and diglycerides of fatty acids derived from edible sources. Examples of oils that can be used for its production include sunflower oil, palm oil, rapeseed oil and combinations thereof, such as a combination of sunflower oil and palm oil.

[0066] In one embodiment, the major component of the surfactant will be diacetyl tartaric acid esters of mono- and diglycerides. For example, the surfactant may contain diacetyl tartaric acid esters of mono- and diglycerides in an amount of at least 50 wt%, preferably at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 90 wt%, or at least 95 wt%.

[0067] For use in the present invention, DATEM is preferably made from diacetyl tartaric anhydride. For example, it can be produced by the reaction of diacetyl tartaric anhydride with monoglyceride and / or diglyceride. The reaction of anhydride provides a product having a major portion of carrying free carboxylic acid groups (-CO2H).

[0068] DATEM consists of glycerol mixed with monoacetyltartaric acid and diacetyltartaric acid and fatty acids from edible fats and is approved by the European Food Safety Authority for use as a food additive. It has the E-number E472e and is confirmed as GRAS. It can be provided in the form of a high viscosity liquid (i.e. semi-liquid) or in powder form.

[0069] The main components of DATEM can be represented by the following general formula (I):

[0070]

[0071] wherein each R is independently selected from H and -C(O)(CH2) n CH3, wherein n is an integer from 6 to 21.

[0072] By "major component", it is meant that the compound of formula (I) will be present in the DATEM in an amount of at least 50 wt %. In some embodiments, it may be present in an amount of at least 60 wt %, at least 70 wt %, at least 80 wt %, at least 90 wt % or at least 95 wt %.

[0073] Typically, stearic acid is used as fatty acid to produce DATEM. In the case of using stearic acid, the value of n in the compound of general formula (I) is 16.

[0074] As will be appreciated, due to the nature of the starting materials and the process used to produce DATEM, the product consists of a mixture of components. In addition to esters of glycerol with mono- and diacetyltartaric acids and fatty acids, it may contain any of the following: free glycerol, free glycerides, free fatty acids, free tartaric acid, free acetic acid, tartaric acid esters and acetate esters of fatty acids.

[0075] DATEM is commercially available from a number of suppliers. An example of a DATEM that can be used in the present invention is sold by Danisco under the trade name Products sold under AB 110 / C. AB 110 / C is a diacetyl tartaric acid ester of mono-diglycerides made from edible refined sunflower oil. It also contains the following components: citric acid (E330) (max. 50 ppm), alpha-tocopherol (E307) (max. 200 ppm) and ascorbyl palmitate (E304) (max. 200 ppm), dissolved in propylene glycol (E1520) (max. 50 ppm) and mono-diglycerides (E471) (max. 400 ppm).

[0076] In one group of embodiments, glycerol can be present in the aqueous phase of emulsion as herein described in addition.Advantageously, glycerol can effectively reduce the water activity of composition and therefore reduce the amount of microbial growth and exist.For example, water activity can be reduced to less than about 0.8, for example, in the range of 0.5 to 0.8, or 0.6 to 0.75, or 0.65 to 0.75.A portion of water in the aqueous phase of emulsion can be for example replaced by glycerol.Based on the gross weight of composition, the amount of glycerol can for example be in the range of 0 wt % to 10 wt %, for example, 0 wt % to 7 wt %.Usually, glycerol can exist with the amount in the range of about 6 wt % to 7 wt % (based on the gross weight of composition).In one embodiment, there is no glycerol.

[0077] The oil phase of the emulsion will comprise a physiologically tolerable lipid, or a mixture of different physiologically tolerable lipids. Depending on the property of the lipid (or multiple lipids), the oil phase itself may have nutritional and / or pharmaceutical properties. Therefore, in some embodiments, the lipid constituting the oil phase of the emulsion may be a nutrient or a medicament. The example of such lipids includes, for example, essential fatty acids, such as those described herein. Alternatively, the oil phase may serve as a carrier of a lipophilic medicament or a nutrient. In this case, an activating agent may be dissolved or dispersed in the oil phase.

[0078] A range of different lipids are known to be useful for oral use of nutritional products, and any of these can be used in the oil phase of the emulsions described herein. Lipid sources include vegetable oils, such as but not limited to rapeseed oil, sunflower oil, corn oil, olive oil, sesame oil, palm kernel oil, coconut oil, nut oil (e.g., almond oil or peanut oil) and algae oil. Fish oil and lipids obtained from fish oil are also suitable for use in certain compositions according to the present invention. For example, compositions containing these products are acceptable to fish vegetarians.

[0079] A series of different lipids are known to be used for oral use of drugs, and any of these can be used in the oil phase of the emulsions described herein. Lipid sources include vegetable oils, such as but not limited to 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 obtained from fish oil are also suitable for use in certain compositions according to the present invention. For example, compositions containing these products are acceptable to fish vegetarians.

[0080] The lipid derived from natural products generally comprises a mixture of different lipid components. In one embodiment, the oil phase will therefore comprise a mixture of different lipids. For example, it can comprise a mixture of lipids with different chain lengths and / or different saturations.

[0081] The lipid used in the present invention can 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 can also be used. Solid lipids with a melting point lower than about 100°C, preferably lower than about 70°C, for example, lower than about 50°C can be used in the present invention. Solid lipids that can be used include butter, solid coconut parts, cocoa butter or cocoa butter, etc. If necessary, the total melting point of the lipids constituting the oil phase can be changed by mixing different lipids, for example, by mixing solid lipids (e.g., cocoa butter) with liquid oils. A total melting point in the range of 45°C to 50°C may be desirable.

[0082] Lipids used in the present invention include fatty acids and derivatives thereof. These include naturally occurring fatty acids and derivatives thereof, as well as synthetic analogs. In one embodiment, the oil phase may include a mixture of different fatty acids or fatty acid derivatives.

[0083] The hydrocarbon chain of a fatty acid or fatty acid derivative can be saturated or unsaturated, and it can be unbranched or branched. Preferably, it will be unbranched. Typically, the hydrocarbon chain will contain 4 to 28 carbon atoms, and typically it will have an even number of carbons. The chain lengths of fatty acids vary, and can be classified as "short," "medium," "long," or "very long" chain fatty acids. Those with hydrocarbon chains of 5 or less carbons are referred to as "short-chain fatty acids"; those with hydrocarbon chains of 6 to 12 carbon atoms are referred to as "medium-chain fatty acids"; those with hydrocarbon chains of 13 to 21 carbons are referred to as "long-chain fatty acids"; and those with hydrocarbon chains of 22 or more carbons are referred to as "very long-chain fatty acids." Any of these can be used in the present invention.

[0084] In one embodiment, the oil phase will contain saturated fatty acids or derivatives of saturated fatty acids, including but not limited to any derivatives described herein. Medium-chain saturated fatty acids and their derivatives are particularly suitable for the present invention. Particularly preferred are those having 8 to 12, such as 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, saturated fatty acids or their derivatives can be used as carriers for one or more active components in the oil phase, for example as carriers for medicaments or nutrients.

[0085] Saturated fatty acids and derivatives thereof used for the present invention can be naturally occurring or they can be synthetic production. Most typically, they will be naturally occurring, and therefore can be used in the form of a mixture of different fatty acids and / or different fatty acid derivatives. The source of saturated fatty acids and derivatives thereof includes for example coconut oil and palm kernel oil.

[0086] In another embodiment, the oil phase can include unsaturated fatty acids or derivatives thereof, wherein the carbon chain includes one or more carbon-carbon double bonds. The double bond can be a cis or trans configuration, or any combination thereof, wherein there is more than one double bond. Due to the need to reduce the consumption of so-called "trans fats" as a part of a healthy diet, those in which double bonds exist in a trans configuration are generally less preferred. Therefore, it is preferred to have a fatty acid and a derivative thereof with a cis configuration double bond. Single and polyunsaturated fatty acids and derivatives thereof are well known in the art. This fatty acid generally contains 12 to 26 carbons, more generally 16 to 22 carbons, and will have a single or polyunsaturated hydrocarbon chain. They particularly include polyunsaturated fatty acids (PUFA), such as essential fatty acids.

[0087] The oil containing long-chain unsaturated fatty acids and derivatives thereof is particularly useful in the present invention, for example, in any composition intended to be used as a nutrient. The particularly important essential fatty acids that can be used include ω-3, ω-6 and ω-9 fatty acids. The example of ω-3 fatty acids includes alpha-linolenic acid (ALA), stearic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), tetracospentaenoic acid and tetracoshexaenoic acid. The example of ω-6 fatty acids includes linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenal acid, docosapentaenoic acid and octadecatrienoic acid. The example of ω-9 fatty acids includes oleic acid, eicosenoic acid, eicosatrienoic acid, erucic acid and nervonic acid.

[0088] The source of unsaturated fatty acids and derivatives thereof includes the oil obtained from various fish, plants, algae and microbial sources. Particularly suitable sources are algae oil and vegetable oils, but fish oils may also be suitable for those following a pescatarian diet. These oils are all rich in ω-3, ω-6 and ω-9 fatty acids. For example, fish oils may be obtained from anchovies, sardines and mackerel.

[0089] Any known fatty acid derivative can be used in the present invention. These include carboxylic acid esters, carboxylic anhydrides, glycerides (i.e. monoglycerides, diglycerides or triglycerides) and phospholipids in particular. As used herein, the term "derivative" also includes any pharmaceutically acceptable fatty acid salt in the context of fatty acids. Suitable salts are well known to those skilled in the art and include, but are not limited to, lithium salts, sodium salts, potassium salts, ammonium salts, meglumine salts and diethylamine salts.

[0090] Examples of carboxylic acid esters of fatty acids include compounds having a terminal -CO2R group, wherein R is a straight or branched chain alkyl group, typically a short chain alkyl group, preferably C 1-6The alkyl group is, for example, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and n-hexyl.

[0091] When the fatty acid derivative is a carboxylic anhydride, it may contain a terminal -CO2COR group, wherein R is a straight or branched alkyl group, typically a short chain alkyl group, preferably a C alkyl group selected from, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and n-hexyl. 1-6 Alkyl group.

[0092] Glyceride is an ester derived from glycerol and up to three fatty acids. The fatty acid present can be any fatty acid as described herein, so they can be, for example, saturated or unsaturated. In the case of diglyceride and triglyceride, the fatty acid components can be the same or different. For example, they can have different chain lengths.

[0093] In one embodiment, the lipid carrier used in the present invention may include medium chain triglycerides (MCT). MCT is a triglyceride with two or three medium chain fatty acids, which can be the same or different. For example, sources of MCT include coconut oil and palm kernel oil. The fatty acids present in MCT are generally saturated medium chain fatty acids. For example, MCT from coconut oil contains C 6-12 Fatty acids, mainly C8 and C 10 Fatty acids. A typical fatty acid composition of MCT oil obtained from coconut oil may, for example, comprise: 0.1 wt% caproic acid (C 6:0), 55 wt% caprylic acid (C 8:0), 44.8 wt% capric acid (C 10:0), and 0.1 wt% lauric acid (C 12:0).

[0094] Phospholipids are generally composed of a glycerol molecule connected to two fatty acids (the "tail" group) and a hydrophilic "head" group consisting of a phosphate group. The phosphate group can be modified by attachment to choline, ethanolamine, or serine. In one embodiment, the oil phase may be composed in whole or in part of a phospholipid (e.g., vegetable lecithin).

[0095] 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 drug or nutraceutical that may be present and the desired loading level, and may vary as desired. The oil phase may, for example, constitute 5% to 60% by weight of the gelled oil-in-water emulsion, preferably 5% to 50% by weight, preferably 10% to 45% by weight, for example 15% to 40% by weight, 15% to 30% by weight or 20% to 25% by weight.

[0096] As will be appreciated, in the compositions of the present invention, the oil provides a discontinuous phase in a gelled continuous aqueous phase. The oil is thus 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 coalescence of the oil droplets, for example due to preventing physical collisions between the oil droplets.

[0097] 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 a small oil droplet size. This can be beneficial to increase the initial rate of lipolysis of the gelled emulsion, thereby increasing the intestinal uptake of the lipids constituting the oil phase. For example, an oil droplet having a size based on volume 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 average oil droplet size based on volume can 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 referred to as "D[4,3]" value). This reflects the size of those particles (droplets) that constitute most of the sample volume and is most sensitive to the presence of large droplets in the size distribution.

[0098] A substantially uniform size distribution of the oil droplets may be desirable. 90 The value represents the size value that 90% of the oil droplets in the total oil droplets meet. 90 The value may be in the range of 0.75 μm to 50 μm, preferably 1 μm to 35 μm, in particular 1.5 μm to 25 μm. 50 and D 10 The values ​​represent the size values ​​that 50% and 10% of the oil droplets meet, respectively. 50 The value may range from 0.3 μm to 20 μm, in particular from 0.5 μm to 15 μm, for example from 0.75 μm to 10 μm. 10 The value may range from 0.1 μm to 10 μm, in particular from 0.2 μm to 5 μm, for example from 0.3 μm to 3 μm.

[0099] Lipid droplet size and size distribution can be determined using methods and equipment routine in the art, such as using a Malvern Mastersizer 3000 (Worcestershire, UK) connected to a Hydro MV wet dispersion unit (Malvern, Worcestershire, UK). Data analysis 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 can minimize flocculation during the test). The refractive indices of water and corn oil are set to 1.33 (solvent) and 1.47 (dispersed phase), respectively, and the absorption index of the dispersed droplets is set to 0.01. To avoid multiple scattering or low-intensity scattered light, the dissolved emulsion is added to the dispersion unit (containing about 125 mL of water) until approximately 10% obscuration is obtained.

[0100] The size and size distribution of the oil droplets can vary. If desired, the size reduction of the oil droplets can be achieved in a variety of ways, such as by mechanical processes or by chemical processes involving the selection of smaller lipid molecules, or indeed by a combination of these methods. Chemical methods suitable for achieving oil droplet size reduction can include the selection of a specific type of lipid (or combination of lipids) that can form smaller oil droplets. Certain oils, such as MCTs, for example, have a tendency to produce a finer dispersion of oil droplets. Mechanical reduction involves the use of shear forces to break up larger oil droplets into smaller nanoscale particles. Smaller droplets can therefore be produced by appropriate adjustments to the method used to produce the emulsion, such as by varying the shear forces and / or the duration of mixing of the oil phase and the aqueous phase. Using higher shear forces and / or longer mixing times will produce smaller oil droplets. For example, a conventional homogenizer such as a rotor-stator mixer, such as A homogenizer is used to achieve the appropriate shear. A problem often encountered in mechanical processes for producing oil-in-water emulsions is reaggregation (i.e., coalescence) of the particles, but this problem is addressed in the present invention by using a gelled aqueous phase, which acts to stabilize the emulsion, and by using a surfactant, which reduces the energy required for emulsification (by reducing the interfacial tension) and protects the droplets so that they cannot reaggregate.

[0101] The aqueous phase (i.e., the continuous phase) of the gelled oil-in-water emulsion may constitute 40% to 95% by weight, preferably 50% to 95% by weight, more preferably 55% to 90% by weight, for example 60% to 85%, 70% to 85% or 75% to 80% by weight of the composition.

[0102] In addition to water, gelling agents and surfactants, other physiologically tolerable materials may also be present in the aqueous phase, such as pH regulators (e.g., buffers), viscosity regulators (e.g., thickeners, plasticizers), sweeteners, fillers (i.e., fillers), antioxidants, fragrances, flavorings and coloring agents. The nature and concentration of any such materials can be readily determined by those skilled in the art.

[0103] The presence of fillers (i.e. fillers) in the aqueous phase helps to reduce water activity, thereby reducing 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 can be reduced to less than about 0.8, for example, in the range of 0.5 to 0.8, or 0.6 to 0.75, or 0.65 to 0.75. Those skilled in the art can easily select the amount and type of fillers. Suitable examples include but are not limited to sugar alcohols, sugars and their mixtures. Suitable sugar alcohols include sorbitol, xylitol, glycerol, erythritol, maltitol, mannitol, hydrogenated starch hydrolysate (HSH), isomalt and mixtures thereof. Available sugar includes any non-reducing monosaccharides and oligosaccharides, such as trehalose, sucrose and mixtures thereof. Based on the aqueous phase, fillers can constitute 45% to 70% by weight, preferably 50% to 65% by weight, for example 55% to 60% by weight. In some cases, the selected fillers can also be used as sweeteners, depending on their concentration. For example, the composition according to the invention may comprise, for example, 0.5 to 50 wt%, preferably 1 to 40 wt%, such as 15 to 40 wt% xylitol to improve the taste.

[0104] When the aqueous phase contains a sweetener, it is generally selected from natural sweeteners such as sucrose, fructose, glucose, reduced glucose, maltose, xylitol, maltitol, sorbitol, mannitol, lactitol, isomalt, erythritol, polysaccharide alcohol, polyglucitol, glycerol and stevia, and artificial sweeteners such as aspartame, acesulfame-K, neotame, saccharin and sucralose. It is preferred to use non-cariogenic sweeteners.

[0105] 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 gum, galactomannan (e.g., guar gum and locust bean gum), gum karaya, gum tragacanth, gum arabic, gum ghatti, modified cellulose (e.g., methylcellulose, ethylcellulose, methylethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylethylcellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose) and any combination thereof. As will be appreciated, the viscosity modifier may have some surface active properties and may additionally contribute to the stability of the emulsion. The thickening effect of the viscosity modifier depends on the type of material (hydrocolloid) used and its concentration, other components, and the pH value of the formulation, etc., but a person skilled in the art may easily determine a suitable amount. The typical amount of any viscosity modifier that may be present may be in the range of 0.1% by weight to 5% by weight, preferably 0.2% by weight to 2.5% by weight, for example 0.5% by weight to 2.0% by weight of the total composition. In one embodiment, no viscosity modifier is present.

[0106] Flavoring agents may be present in the composition and may, for example, help mask the taste of certain lipids such as those containing omega-3 fatty acids. Suitable flavoring agents include, but are not limited to, citrus flavorings, such as orange oil, lemon oil, or lime oil.

[0107] 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, for example 4.5 to 5 or 4.5 to 4.7. The pH may be adjusted by selecting a suitable pH adjusting agent. The pH adjusting agent may be easily selected by those skilled in the art and includes food grade acids such as citric acid. Buffers may also be used to adjust the pH value and include organic acid / base buffer systems. Suitable buffers are well known in the art and include, for example, sodium citrate and malic acid.

[0108] Antioxidant can be present in the oil phase and / or the aqueous phase of the composition.When antioxidant is present in the aqueous phase, these antioxidants will be water-soluble and include for example ascorbic acid, citric acid and their salts (such as sodium ascorbate) generally.Depending on the selection of oil, these oils can contain antioxidants such as for example vitamin E in the form of providing.If present, the amount of any antioxidant can be up to 3 weight % of total preparation, for example up to 1 weight %.In some embodiments, antioxidant can be present in the surfactant for the composition of the present invention.For example, commercially available DATEM surfactant, particularly those provided in liquid or semi-liquid form, can contain antioxidant as preservative.The example of this type of antioxidant includes citric acid, alpha-tocopherol and ascorbyl palmitate.

[0109] In addition to lipids, the oily phase of the emulsion may, if desired, contain physiologically tolerable fat-soluble materials, such as pharmaceutically acceptable agents, antioxidants (such as vitamin E), flavoring agents, and coloring agents.

[0110] In some embodiments, additional physiologically active agents may also be present in the gelled emulsions described herein. These may be provided in the aqueous phase and / or the oil phase and may be dissolved and / or dispersed in one or both of these phases. Other active agents that may be present in the oil phase include fat-soluble active agents.

[0111] In one embodiment, the gelled oil-in-water emulsion according to the present invention may comprise, consist essentially of or consist of the following components:

[0112] (a) water;

[0113] (b) a surfactant as defined herein;

[0114] (c) one or more physiologically tolerable lipids;

[0115] (d) agar;

[0116] (e) one or more bulking agents (e.g., sugar alcohols);

[0117] (f) optionally one or more pH adjusting agents;

[0118] (g) optionally one or more viscosity modifiers (e.g., thickeners or plasticizers); and

[0119] (i) optionally one or more additional physiologically active agents.

[0120] "Consisting essentially of means that the emulsion will be substantially free of (eg, free of) other components that materially affect its properties. "Consisting of means that the emulsion will be substantially free of (eg, free of) any other components other than those listed.

[0121] In one set of embodiments, the composition of the present invention can be provided in the form of a dosage unit. "Dosage unit" means that the composition will be taken orally by a subject "as received" (e.g., administered to a patient), i.e., will not be broken or cut before oral delivery. Therefore, the weight of the dosage unit will make the composition suitable for delivery in this manner. For example, its total weight may be 50 mg to 3,000 mg, such as 250 mg to 3,000 mg or 500 mg to 2,500 mg, especially 100 mg to 2,000 mg, such as 750 mg to 2,000 mg, especially 100 mg to 1,500 mg, more especially 400 mg to 1,500 mg, more especially 400 mg to 1,000 mg.

[0122] In one set of embodiments, the dosage unit will typically 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 desired. For example, it can be scaled up or down depending on the properties of the selected active ingredients and their intended dosage.

[0123] Each dosage unit is typically composed of a self-supporting gelled oil-in-water emulsion as described herein. As will be appreciated, in this case, the dosage unit will contain only a defined oil phase and an aqueous phase, i.e. it will not contain any other components. Individual dosage units may be prepared from larger pieces of gelled emulsion that are separated, for example, 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. above the gelling temperature of the gelling agent).

[0124] Alternatively, the core of the gelled oil-in-water emulsion can be provided with a suitable coating of a physiologically tolerable coating material. Such coatings can be of conventional type in the pharmaceutical and nutraceutical industries and can 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 can therefore be provided with a coating. For example, these can be provided in a capsule shell that can be dissolved in the mouth. Therefore, from another aspect, the present invention provides an orally administrable capsule comprising a capsule shell encapsulating a gelled oil-in-water emulsion as described herein.

[0125] In the capsules of the present invention, the shell can be any physiologically tolerable material, but is typically a sugar, a biopolymer, or a synthetic or semisynthetic polymer that is soluble or decomposable in saliva or fluids in the gastrointestinal tract. The shell can be soft, but is preferably substantially rigid. It is particularly desirable that the capsule will have a "jelly bean" consistency. The shell will preferably have a material and thickness that prevents oxidation of the contents. The shell may contain sugar or cellulose, such as sorbitol. The use of sugar and cellulose as capsule shell materials is well known in the pharmaceutical and nutritional fields.

[0126] Thus, the capsule shell material may typically be a sugar or sugar alcohol, such as sucrose, fructose, maltose, xylitol, maltitol or sorbitol, but may additionally contain hydrocolloid materials such as, for example, carrageenan, alginates, pectins, cellulose, modified cellulose, starch, modified starch, gum arabic, etc. The capsule shell may include other ingredients, such as, for example, artificial sweeteners, pigments, fillers, flavorings, antioxidants, etc.

[0127] The capsule shell can be preformed so that the oil-in-water emulsion can be filled into the shell as a liquid or once solidified. Alternatively, the shell precursor (e.g., solution) can be coated onto the solidified emulsion, e.g., using standard coating techniques. If desired, the capsule can be further coated with, e.g., wax.

[0128] The preparation of the gelled oil-in-water emulsion described herein can be carried out by emulsification of the aqueous and oil phase components. It should be understood that the emulsification is carried out under the condition that the aqueous phase is a liquid (e.g., a viscous liquid), i.e., before the formation of a gel. Therefore, the emulsification will be carried out at a temperature above the sol-gel transition temperature of the agar gelling agent (and the sol-gel transition temperature of any other gelling agent that may also be present). The emulsion is then cooled to below its sol-gel temperature to obtain the desired gelled emulsion.

[0129] Before emulsification, any selected activating agent can be added to the oil phase and / or the aqueous phase of the composition. This can be carried out, for example, by dissolving the activating agent in the selected oil phase or aqueous phase before forming the emulsion. Alternatively, the selected activating agent can be added to the mixture of aqueous and oil phase components before emulsification. During the emulsification process, the activating agent will usually migrate to the oil phase or the aqueous phase, depending on their hydrophilic / lipophilic properties.

[0130] The formation of the emulsion can be achieved by conventional techniques and using known equipment, such as a homogenizer based on the rotor-stator principle. The speed and duration of stirring can be adjusted as required, for example, it can be varied to obtain the required shear force to provide the desired droplet size.

[0131] Emulsification is usually carried out under a controlled atmosphere to avoid oxidative degradation of lipids and / or any active agent. For example, emulsification can be carried out in the presence of a non-oxidizing gas such as nitrogen. Degassing can also be carried out during production to remove bubbles, such as before mixing the emulsion components, once a liquid emulsion is formed, before packaging the solidified emulsion, etc. Degassing can be carried out using any conventional method, such as applying a vacuum, or spraying with a non-oxidizing gas (e.g., nitrogen).

[0132] After emulsification and gelling, the emulsion may be dried to reduce the water content. However, if dried, it will still retain a continuous gelled aqueous phase as described herein and a water content within the limits defined herein.

[0133] The gelled oil-in-water emulsion is generally provided in the dosage unit form described herein. A single dosage unit can be formed by methods such as molding, extrusion or cutting. However, typically, the dosage unit can be formed by filling the liquid emulsion into a mold, such as each mold of a blister package that is subsequently sealed. The dosage unit will generally be in tablet or lozenge form.

[0134] The method for preparing the gelled oil-in-water emulsion described herein constitutes another aspect of the invention. Viewed from another aspect, the invention therefore provides a method for preparing an orally administrable gelled oil-in-water emulsion, the method comprising: forming an oil phase comprising one or more physiologically tolerable lipids; forming an aqueous phase comprising a gelling agent, the gelling agent being agar; mixing the oil phase and the aqueous phase in the presence of a surfactant as described herein to form an oil-in-water emulsion; and gelling the emulsion. Optionally, the emulsion may be divided into individual dosage units before or after gelling the emulsion.

[0135] The dosage units are preferably individually packaged in airtight containers such as sealed wrappers or more preferably in blisters of blister packs. On the other hand, the present invention therefore provides a package comprising an airtight and light-tight compartment comprising a dosage unit of the composition according to the invention. By blocking both air (i.e. oxygen) and light with the packaged dosage unit, the long-term stability of the active ingredient is enhanced.

[0136] Package according to the present invention is preferably provided in the form of a blister package containing at least two dosage units (e.g., 2 to 100, preferably 6 to 30 dosage units). Blister packages generally include metal, metal / plastic laminates or plastic sheet substrates with molded indentations, in which dosage forms are placed. Packages are generally sealed with foil (typically metal or metal / plastic laminate foil), such as by applying heat and / or pressure to the region between the indentations. Metal or metal / plastic laminates are used to form blister packages to prevent the contents of air (i.e., oxygen), light and moisture from penetrating the blister packages, thereby enhancing the stability of active ingredients. Package according to the present invention is preferably filled under a non-oxidizing gas atmosphere (e.g., nitrogen) or purged with this gas before sealing.

[0137] The use of agar as a gelling agent in the composition according to the present invention provides additional advantages associated with packaging individual dosage units in blister packages and removing them by the end user. When the emulsion in liquid form is used to fill the indentation of the blister package (i.e. before gelling), it will be in close contact with the inner surface of the indentation. After the dosage unit solidifies and seals the blister package, it is important that the dosage unit can be easily removed from the blister package. In known gelatin-based compositions, the presence of gelatin, which was first developed as a gel, may cause difficulty in removing these gelatins from certain surfaces (such as those made of plastic materials), especially when the liquid emulsion containing gelatin has solidified after contact with the surface. In such cases, once solidified, the dosage unit tends to adhere to the surface and must be torn off, thereby often causing the dosage unit to break in the process, which is unacceptable. When packaging any conventional gelatin-based dosage unit, it is necessary for the inner surface of the blister package to be coated with a suitable stripper such as a neutral oil or fat. Specially developed blister packaging materials in which strippers are bonded to their inner surfaces are available, but increase the cost of the packaging process. The use of release agents also results in surface coating of the medicament on the dosage unit after it is removed from the blister pack, and this can cause an unpleasant mouthfeel or taste to the product.

[0138] In contrast to the use of gelatin, agar-based dosage units do not adhere to conventional blister packaging materials. This means that standard materials can be used, including plastic films to which metal / plastic laminates or plastic / metal foil laminates are heat sealed. Suitable blister trays with preformed cavities can be made, for example, from laminate materials such as VA10600(TekniPlex), (Perlen Packaging), (Amcor) and (ConstantiaFlexibles) are formed. Such materials do not have any surface coating containing a release agent.

[0139] In one embodiment, the dosage units of the invention may thus be packaged in a blister pack having an inner surface which is not coated with any release agent.Such blister packs containing dosage units as described herein constitute a further aspect of the invention.

[0140] The gelled oil-in-water emulsion according to the present invention can be used as a medicine, i.e. for therapeutic purposes, and can be used as a nutraceutical to maintain or enhance the health and / or overall well-being of a human or animal subject. For this purpose, it is expected that they are taken orally, chewed gently in the oral cavity, and then swallowed. It is expected that they should not be retained in the oral cavity for a long time or do not need to be chewed for a long time. Due to their soft texture, chewing gently is enough to break the dosage form into smaller pieces that are easy to swallow. Based on their rheological properties, the gelled oil-in-water emulsion according to the present invention can be expected to have a better mouthfeel than pure aqueous agar gel. While aqueous agar gel is brittle and "breaks" in the oral cavity when chewing, the emulsion described herein has enhanced large-scale deformation properties. Therefore, when chewing, these will have greater resistance to deformation and will be less prone to breakage. Together with the small oil droplet size achieved using the surfactant described herein, this can be expected to provide a more acceptable chewing experience for patients or consumers.

[0141] For example, when used as a nutraceutical, the compositions described herein can be used as a supplement (e.g., as a dietary supplement) to maintain the overall health and / or well-being of a subject. Any agent known for its nutritional effects can be provided in the composition, and suitable agents are well known in the art. Suitable nutrients include, but are not limited to, any of the following nutrients: essential fatty acids (e.g., monounsaturated fatty acids 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., beta-carotene, alpha-carotene, zeaxanthin, astaxanthin, plant lutein, lutein, and lycopene), phytosterols, saponins, probiotics, dietary fiber (e.g., insoluble fiber and beta-glucan), antioxidants (e.g., CoQ10), and plant extracts (e.g., aloe vera, evening primrose oil, garlic, ginger, ginseng, green tea, and caffeine). When magnesium or calcium are present, they are typically used in the form of their phosphates.

[0142] Specifically, the gelled oil-in-water emulsion described herein can be used as a source of one or more essential fatty acids, such as PUFA or its ester, for example ω-3, ω-6 and / or ω-9 fatty acids and their ester derivatives. Examples of ω-3 acids include α-linolenic acid (ALA), linolenic acid (SDA), eicosatrienoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), tetracosopentaenoic acid and tetracoshexaenoic acid. Examples of ω-6 acids include linoleic acid, γ-linolenic acid, eicosadienoic acid, dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosadienoic acid, adrenic acid, docosapentaenoic acid and octadecatrienoic acid. Examples of ω-9 acids include oleic acid, eicosenoic acid, eicosatrienoic acid, erucic acid and nervonic acid. Particularly preferred are ω-3 acids, particularly EPA and DHA.

[0143] The health benefits of essential fatty acids, particularly omega-3 fatty acids, are well known. For example, these fatty acids can reduce triglyceride levels and / or reduce cholesterol levels. Omega-3 fatty acids are essential for daily life and health. EPA and DHA are well known for their beneficial effects on reducing serum triglycerides. They are also known to have other health benefits, such as cardioprotective effects, such as cardioprotective effects in preventing arrhythmias, stabilizing atherosclerotic plaques, reducing platelet aggregation and lowering blood pressure. Therefore, they can be used to treat and / or prevent vascular diseases. Other beneficial effects of omega-3 fatty acids include preventing and / or treating inflammation and neurodegenerative diseases, as well as improving cognitive development and function.

[0144] Essential fatty acids can form part or all of the oil phase in the gelled emulsion, preferably at least 10 weight % of this phase, more particularly at least 50 weight %, particularly at least 80 weight %.They can be used as a single compound or as a compound mixture, such as vegetable oil or marine oil.Free fatty acids, monoacylglycerol and diacylglycerol can be prepared by the complete or partial hydrolysis of triacylglycerol, such as acid, alkali or enzyme-catalyzed hydrolysis, such as using lipase such as pancreatic lipase and / or the enzyme-catalyzed hydrolysis of the lipase produced by bacteria as fermentation product.The alkyl esters of essential fatty acids can be prepared by using the transesterification reaction of suitable alkanol or by the esterification reaction of free fatty acids and this alkanol.When using free fatty acids, it can be acid form or salt form (such as all or part of salt form), and preferably accounts for 5 weight % to 75 weight %, especially 10 weight % to 35 weight % of essential fatty acids in the oil phase.Salt form can be preferred.

[0145] The gelled oil-in-water emulsions described herein can also be used as medicaments in the treatment or prevention of a range of medical conditions that respond to the selected active agent. As will be appreciated, the nature of such conditions will depend on the active agent selected, but can be readily determined by those skilled in the art.

[0146] Any drug substance having the desired therapeutic and / or prophylactic effect may be used. This includes lipophilic, hydrophilic or amphiphilic drug substances.

[0147] Classes of suitable drug substances include, but are not limited to, any of the following: analgesics; anti-inflammatory drugs; anticancer agents; cardiovascular agents; biologics; antiallergic agents (e.g., antihistamines); decongestants; antinausea agents, drugs affecting gastrointestinal function; drugs acting on the blood and hematopoietic organs; drugs affecting renal and cardiovascular function; antifungals; urinary system agents; hormones; antimicrobials, antiepileptics; neuroleptics; antipsychotics; psychostimulants; anticholinesterase agents; and carotenoids.

[0148] Examples of specific drug substances that may be used 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; prochlorperazine; chlorpromazine; hydroxyperchlorpromazine; fluoxetine, buspirone; clemastine; chlorpheniramine; dexchlorpheniramine; astemizole; loratadine; acetaminophen; ketoprofen; naproxen; ibuprofen; acetazolamide sodium, acetylsalicylic acid, aminophylline, amiodarone hydrochloride, ascorbic acid , atenolol, bendroflumethiazide, leucovorin, captopril, cetirizine hydrochloride, chloramphenicol sodium succinate, chlorpheniramine maleate, chlorpromazine hydrochloride, cimetidine hydrochloride, ciprofloxacin hydrochloride, clindamycin hydrochloride, clonidine hydrochloride, codeine phosphate, phencyclidine hydrochloride, cyclophosphamide, dexamethasone sodium phosphate, dicloxacillin sodium, dicyclovir hydrochloride, diltiazem hydrochloride, diphenhydramine hydrochloride, disopyramide phosphate, doxepin hydrochloride, enalapril maleate, erythromycin ethyl succinate, flecainide acetate, fluphenazine hydrochloride, folic acid, granisetron hydrochloride, guaifenesin, haloperidol lactate, hydralazine hydrochloride, hydroxychloroquine sulfur hydrochloride, hydromorphone hydrochloride, hydroxyzine hydrochloride, indomethacin sodium, isoniazid, isoprenaline hydrochloride, ketorolac tromethamine, labetalol hydrochloride, lisinopril, lithium sulfate, mesoridazine besylate, methadone hydrochloride, methylphenidate hydrochloride, methylprednisolone sodium succinate, merrolol tartrate, metronidazole hydrochloride, methyldopa, mexiletine hydrochloride, molindone hydrochloride, morphine sulfate, naltrexone hydrochloride, neomycin sulfate, ondansetron hydrochloride, metaproterenol sulfate, oxacillin sodium, oxybutynin hydrochloride, oxycodone hydrochloride, paracetamol, penicillamine, pentoxifylline, meperidine hydrochloride, barbital sodium, penicillin V potassium, phenylephrine adenosine hydrochloride, phenytoin sodium, potassium iodide, primaquine phosphate, procainamide hydrochloride, procarbazine hydrochloride, prochlorperazine maleate, promazine hydrochloride, promethazine hydrochloride, propranolol hydrochloride, dexephedrine hydrochloride, pyridostigmine bromide, pyridoxine hydrochloride, ranitidine hydrochloride, salbutamol sulfate, ethacrynic acid sodium, sotalol hydrochloride, sumatriptan succinate, terbinafine hydrochloride, terbutaline sulfate, tetracycline hydrochloride, thioridazine hydrochloride, sulfopenthiol hydrochloride, trifluoperazine hydrochloride, triprolidine hydrochloride, sodium valproate, vancomycin hydrochloride, vancomycin hydrochloride, verapamil hydrochloride, warfarin sodium and fenofibrate.

[0149] The amount of drug substance per unit dose of the composition of the present invention is usually in the range of 10% to 100% of the recommended daily dose for adults or children.

[0150] Viewed from another aspect the invention thus provides a gelled oil-in-water emulsion as herein described for use in therapy.

[0151] Viewed from a further aspect the invention provides a gelled oil-in-water emulsion as herein described containing at least one pharmaceutically active ingredient for oral administration for the treatment of a condition responsive to said pharmaceutically active ingredient.

[0152] In another aspect, the present invention provides the use of a pharmaceutically active ingredient in the manufacture of a medicament for oral administration for the treatment of a condition responsive to the pharmaceutically active ingredient, wherein the medicament is provided in the form of a gelled oil-in-water emulsion as described herein.

[0153] Corresponding medical methods form another aspect of the invention. Viewed from a further aspect, the invention therefore provides a method of treating a human or non-human animal subject (e.g. a patient) against a condition responsive to a pharmaceutically active agent, the method comprising the step of orally administering to the subject a pharmaceutically effective amount of the agent in the form of a gelled oil-in-water emulsion as described herein.

[0154] In another aspect, the present invention provides the use of the gelled oil-in-water emulsion as described herein as a nutraceutical. Corresponding methods of administering the gelled oil-in-water emulsion to achieve a nutritional health benefit also form part of the present invention.

[0155] Thus, viewed from another aspect, the invention 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 the step of orally administering to the subject a nutritionally effective amount of the active agent in the form of a gelled oil-in-water emulsion as described herein.

[0156] In another aspect, the present invention provides the use of a gelled oil-in-water emulsion as described herein as a nutraceutical.

[0157] When used in any of the above-described treatments or methods, or as a nutritional supplement or pharmaceutical formulation, the effective amount of the active agent can be readily determined.

[0158] The effective dosage level for any particular subject will depend on a variety of factors, including the disorder and its severity; the ingredients and activities of the particular composition; the age, weight, general health of the subject (e.g., patient); the time of administration; the duration of the treatment; other drugs used in combination with the treatment, etc. The selection of the desired dosage to achieve the desired therapeutic effect is well within the skill of the art.

[0159] The present invention will now be further described with reference to the following non-limiting examples and accompanying drawings, in which:

[0160] Figure 1It shows that it contains 0.69 wt% Oil droplet size distribution of agar (measured initially and after 20 h under gentle magnetic stirring in a 55°C water bath).

[0161] Figure 2 The hardness (force) of agar-based gelled oil-in-water emulsions according to the invention when subjected to large-scale deformation is shown.

[0162] Figure 3 It is shown that in a 55°C water bath, under mild magnetic stirring, 0.69 wt%, 0.46 wt% and 0.23 wt% Initial oil droplet size distribution of agar.

[0163] Figure 4 It shows that after adding different amounts of HCl, the Changes in the size of the agar oil droplets.

[0164] Figure 5 The initial lipolysis rate of an agar-based gelled oil-in-water emulsion according to the invention is shown.

[0165] Figure 6 Shown are the 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.

[0166] Example

[0167] Test method:

[0168] 1. Rheological Characterization of Agar Emulsion Gels

[0169] 1a—Small-scale deformation

[0170] The gel was subjected to rheological analysis with a rheometer (Malvern Kinexus ultra+, Westborough, United States). The lower plate was a curved sandblasted lower plate of KNX0127 50 mm diameter. The upper geometry was a CP4 / 40 40 mm diameter 4 ° cone for gelatin emulsion gels and a serrated PP40X SW1648 SS for agar gels and agar emulsion gels. Instrument calibration (zero gap) was performed before analysis. For gelatin-based gels, after gel preparation, approximately 2 grams of gel were placed on the lower plate and heated to 60 ° C. In the case of agar-based gels, a liquid solution (i.e., before gelation) was placed on the plate and gelled. The rheometer was operated in 0.1% shear strain control mode, and the frequency was set to 1 Hz. Confirm that the selected strain was within the linear viscoelastic region of all samples. In order to avoid evaporation, the gelatin emulsion gel sample was covered with silicone oil (10 cS fluid, DowCorning, UK) before measurement. For gelatin emulsion gels, the viscoelastic properties of the samples were obtained by using a temperature gradient of 2°C / min, with a starting and ending temperature of 60°C and a holding time of 15 min at 20°C. For agar emulsion gels, the ending temperature was 90°C and oscillation was continued at 90°C for 10 minutes. The results were analyzed using Kinexus rSpace software. The gelling temperature and melting temperature of the samples were estimated as the temperature at which the phase angle corresponded to 45° during cooling and heating, respectively. The maximum storage modulus (G') (Pa) was determined as the highest measurement point during solidification at 20°C.

[0171] 1b—Large-Scale Deformation

[0172] The texture properties of the gel were analyzed using a TA.XT plusC texture analyzer (Stable Micro Systems Ltd., UK). During preparation, a cylindrical mold of standard size (19.6 mm height, 8 mm diameter) was used to cast the gel. The gel was cured at ambient temperature for 18 hours before analysis. Single-stage compression analysis and standard texture analysis (TPA) were performed using a 5 kg load cell. A P / 35 35 mm diameter cylindrical aluminum probe provided by Stable Micro Systems Ltd. was used. For single-stage compression of 75% large and strained, the speed before and after the test was 2 mm / sec, while the test speed was 0.5 mm / sec and the trigger force was 5 grams. The strain height was automatically measured during the compression process. Maximum stress (g) and failure strain (%) data were obtained from the fractional moment of the gel. The gradient (N / m) was calculated by the ratio of the forces at 2% and 3% strain. Young's modulus (N / m2) was calculated by the gradient using the following equation:

[0173]

[0174] The area of ​​the gel is the contact area between the gel and the probe.

[0175] 2. Syneresis Measurement

[0176] Syneresis measurements were based on the weight loss of the gel. The gel was weighed and sealed with airtight and moisture-proof aluminum foil. After freezing at -20°C and thawing at ambient temperature, and after removing excess liquid, the gel was weighed again and the difference in gel weight was normalized to the percentage loss.

[0177] 3. Water activity measurement

[0178] Water activity was measured at ambient temperature using a HygroPalm HC2-AW (Rotronic, Switzerland). The sample was placed in the measuring chamber and the water activity was recorded after 45 minutes.

[0179] Example 1 - Gelled Oil-in-Water Composition and Preparation Method

[0180] Composition:

[0181] Typical gelled oil-in-water compositions according to the present invention are listed in the table below. It should be understood that any component that may be present in an amount of 0 wt% is optional.

[0182]

[0183]

[0184] Preparation method:

[0185] In the following method, the pH adjuster is an organic acid / base buffer system consisting of trisodium citrate and malic acid, and the plasticizer, if present, is glycerol.

[0186] 1. Mix agar, sugar alcohol and any sweeteners into a homogeneous powder mixture.

[0187] 2. Weigh sterile water into the bottle and add the powder mixture to the water.

[0188] 3. Place the bottle in a 90°C water bath and mix for 30 minutes with magnetic stirring at 100 rpm. If using glycerol, heat the glycerol alone at 60°C for 30 minutes.

[0189] 4. Reduce the temperature to 60°C and mix the aqueous phase for an additional 30 minutes under magnetic stirring (approximately 60 minutes total). If using glycerol, add the heated glycerol to the mixture using a syringe.

[0190] 5. In a beaker, mix the oil with any flavoring and / or coloring and preheat to 50°C for 30 minutes.

[0191] 6. When the ingredients are completely dissolved, slowly add the surfactant and trisodium citrate to the water phase. Mix for 10 minutes and slowly add the malic acid (carefully and gradually). Mix the mass for another 10 minutes.

[0192] 7. If using a defoaming agent, add half of the agent and let sit for 1 minute without stirring.

[0193] 8. Weigh the bottle containing the water phase and vacuum the mass. Add the lost water (heated) and mix for 1 minute.

[0194] 9. Add the oil phase to the agar mass (aqueous phase) and homogenize the two phases using a high-speed blender / homogenizer (such as Ultra-Turrax T 18) at 10000 rpm for approximately 10 minutes.

[0195] 10. If appropriate, add the other half of the (heated) antifoam and let sit without stirring for 1 minute.

[0196] 11. Weigh the bottle and vacuum the mass. Add lost water (heated) and mix for 1 minute.

[0197] 12. If necessary, fill the resulting emulsion into blisters of a blister pack and seal.

[0198] Example 2 - Gelled Oil-in-Water Emulsion: Typical Formulation

[0199]

[0200]

[0201] The emulsion can be prepared according to the general method in Example 1.

[0202] Example 3 - Gelled oil-in-water emulsion containing sunflower oil

[0203] Element weight% <![CDATA[Agar HDR 1 > 1.60 <![CDATA[Surfactant 2 > 0.69 Sorbitol 14.41 Xylitol 26.85 ascorbic acid 0.33 Malic Acid 0.61 Trisodium Citrate 1.87 Sunflower Oil 30.00 Lemon Flavor 1.10 water 22.53

[0204] 1 Gelagar HDR 800 (BVsrl, Italy)

[0205] 2 AB 110 / C (Danisco) - diacetyl tartaric acid esters of mono- and diglycerides (DATEM) made from edible refined sunflower oil.

[0206] The emulsion was prepared according to the general method in Example 1. The final pH of the emulsion was 4.6-4.7. The pH inside the gel was measured at ambient temperature (20°C ± 2°C) using a calibrated Eutech Instruments pHSpear.

[0207] Example 4 - Multivitamin Supplement

[0208]

[0209] 1 Contains 10mcg of Vitamin D and 45mcg of Vitamin K in a neutral carrier oil

[0210] 2 Aqueous phase containing 2mcg of vitamin B12

[0211] The emulsion was prepared according to the general method in Example 1. Vitamin D and vitamin K were added to the oil in step 5, and vitamin B12 was added to the aqueous phase in step 6.

[0212] Example 5 - Multi-Mineral Supplement

[0213]

[0214] 1 Aqueous phase containing 150mcg iodine, 40mcg selenium, 20mg iron and 2.5mg zinc

[0215] The emulsion was prepared according to the general method in Example 1. In step 6 the minerals were added to the water phase.

[0216] Example 6 - Calcium Supplement

[0217]

[0218]

[0219] 1 Vegetable oil containing 400 IU of vitamin D3

[0220] The emulsion was prepared according to the general method in Example 1. Calcium phosphate was mixed with AB 110 / C and trisodium citrate were added to the aqueous phase.

[0221] Example 7 - Multivitamin Supplement

[0222]

[0223] Emulsions were prepared according to the general method in Example 1. Fat soluble vitamins (E, A, D3) were mixed into the oil as in Example 4, and water soluble vitamins (C, B3, B6, B12, folic acid, D-biotin) and iodine were mixed as CaHPO4 was mixed in Example 6.

[0224] Example 8 - Packaging

[0225] Blister Packaging :

[0226] Prior to solidification, the emulsion produced in any of Examples 1 to 7 may be filled into a blister tray made of a metal / plastic laminate or plastic film to which a plastic / metal foil laminate is heat sealed. The blister tray with preformed cavities may be made of a laminate such as VA10600(TekniPlex), (PerlenPackaging), (Amcor) and (Constantia Flexibles) are formed.

[0227] Use syringe to fill the liquid emulsion produced in any example in embodiment 1 to 7 into blister tray, and ensure that the cavity is filled evenly and completely.Then blister tray is purged with nitrogen for 5 seconds to 10 seconds, and by applying a flat iron set at 160°C, keep 2 seconds to 4 seconds, cover the foil with metal / plastic or metal / heat seal paint to seal.The sample is cured at room temperature for 24 hours, and it is transferred to a controlled holding room of 40°C, 65% RH and kept for 30 days.On the 5th day, 10th day, 15th day, 20th day, 25th day and 30th day, take out the sample from the control room.After 24 hours at room temperature, open the blister package.Record the amount of residue adhered to the tray and the force required for taking out the unit dose from the package on a scale of 1-9, wherein 1 represents that there is no adhesion and the force required for taking out the unit dose is very small ("pop-up"), and 9 represents that it is fully adhered to the foil and the unit dose needs to be torn off from the foil. Each of the laminates listed above gave a score of 1, 2 or 3 (mostly 1 or 2) in each test.

[0228] Strip :

[0229] Prior to solidification, the emulsion produced in any of Examples 1 to 7 may be extruded into individual strips which, once solidified, are then sealed into individual plastic / metal foil laminated pouches. Alternatively, the single extruded strip, once solidified, may be cut into individual strips as desired prior to packaging.

[0230] Example 9 - Coated Gelled Emulsion

[0231] The coagulated emulsion produced in any of Examples 1 to 7 can be coated with a sorbitol solution comprising sorbitol (80 wt %), lemon flavor (0.15 wt %), yellow pigment (0.5 wt %) and water (ad 100 wt %). The coating solution can be cured at 99° C. to 95° C. for 4 to 5 hours before coating. Coating is performed by dipping or rolling at 20° C. to 45° C. Several layers of coating material can be added, drying between each layer until the final composite layer is hardened.

[0232] Alternatively, before solidification, the liquid emulsion prepared in any one of Examples 1 to 7 can be filled into a soft capsule shell. The capsule shell material can generally be a sugar, such as sucrose, fructose, maltose, xylitol, maltitol or sorbitol, but can additionally contain a hydrolyzed colloid material such as carrageenan, alginate, pectin, cellulose, modified cellulose, starch, modified starch or gum arabic. The capsule shell can contain other ingredients, such as artificial sweeteners, colorants, flavorings and antioxidants.

[0233] Example 10 - Droplet Size and Size Distribution

[0234] An oil-in-water emulsion was prepared according to Example 3 and then placed in a water bath at 55°C with gentle magnetic stirring. The average droplet size was measured initially (t=0) and 1, 2 and 20 hours after preparation.

[0235] Droplet size and size distribution were measured using a Malvern Mastersizer 3000 (Worcestershire, UK) connected to a Hydro MV wet dispersion device (Malvern, Worcestershire, UK). Data analysis can be performed using the manufacturer's software (Mastersizer 3000, v1.0.1). The test was performed by diluting the emulsion (1:100) in 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 absorption index of the dispersed droplets was set to 0.01. To avoid multiple scattering or low-intensity scattered light, each dissolved emulsion was added to a dispersion unit (containing approximately 125 mL of water) until approximately 10% obscuration was obtained.

[0236] The droplet size distribution is Figure 1 The small increase in droplet size and tail shown at T20 occurred between T0 and T1 and was probably not due to coalescence but rather to stirring of some of the solidified agar on the side of the bottle (particles observed under the 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.

[0237] Table 1

[0238] Time (hours) D[4;3](μm) D[3;2](μm) 0 1.07 0.865 1 1.35 0.943 2 1.34 0.94 20 1.37 0.947

[0239] Example 11 - Textural Properties

[0240] Experiments were conducted to compare the large-scale deformation of an agar-based gelling emulsion prepared according to Example 3, a gelatin-based gelling emulsion, and a pure aqueous agar gel. The pure aqueous agar gel was prepared by mixing agar (2 wt %) and 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:

[0241] Composition :

[0242]

[0243] Preparation method :

[0244] The gelatin emulsion gel was prepared by mixing Type B 160 Bloom bovine gelatin ( Germany) was mixed with water for 30 minutes. Sorbitol and xylitol were then added and mixed for 10 minutes after each addition. Trisodium citrate and malic acid were added and mixed for 10 minutes after each addition. Witafrole (0.06 wt %) was added to the gel and degassed using a diaphragm vacuum pump (Vacuubrand, MZ 2C) until no bubbles were visible. The loss of water was compensated after degassing. Corn oil preheated at 60°C was added to the aqueous phase and homogenized at 9.8k rpm for 5 minutes at ambient temperature. The mixture was degassed again.

[0245] The tests were performed according to the large-scale deformation method described in this paper. Figure 2 The results are shown in Table 2.

[0246] Table 2

[0247]

[0248] Compared with aqueous agar gel, the Agar-based gelling emulsions as surfactants provide stronger and more flexible gels. The texture of the agar-based emulsion gel is improved (longer) and approaches the texture of the gelatin-based emulsion gel. This will result in a more pleasant mouthfeel compared to pure agar gel, as it will not break significantly when chewing.

[0249] Example 12 - Droplet size and size distribution - Effect of different amounts of surfactant

[0250] According to Example 3, different amounts of The emulsions contained 0.69 wt %, 0.46 wt % (2 / 3) and 0.23 wt % (1 / 3) of surfactant, respectively. % and 0.23 wt. %, but the corresponding increase in xylitol in the composition of Example 3 compensates for this decrease.

[0251] The average droplet size was measured initially (t=0) and after 20 hours (T20) in a 55°C water bath with magnetic stirring as described in Example 10. Figure 3 The results are shown in Table 3.

[0252] Table 3

[0253]

[0254] Lower amount A more dispersed droplet size distribution and larger droplets were given. However, the droplets were still relatively stable and no significant phase separation was observed.

[0255] Example 13 - Droplet Size and Size Distribution - Effect of Different Amounts of Oil

[0256] Oil-in-water emulsions containing different amounts of oil were prepared and tested to determine their average droplet size and size distribution. The amount relative to the aqueous phase was kept constant (corresponding to 0.69 wt % in a 30 wt % oil system). ). 30 wt% of oil was initially added, then the amount of oil was gradually increased by 5 wt% and then by another 5 wt% with emulsification (using a large Turrax 9.8k for 2 minutes) after each oil addition. After each emulsification, a sample was taken for droplet size measurement. The average droplet size was measured as described in Example 10. The results are shown in Table 4.

[0257] Table 4

[0258]

[0259] *Measured in a 55°C water bath with magnetic stirring

[0260] The viscosity increased significantly from 40-45 wt% oil, and the Turrax could barely absorb and mix the 45 wt% oil lumps. At 50 wt%, the Turrax did not work, and the mixture had to be emulsified by manual shaking.

[0261] It can be seen that the 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 over time, although the increase from t=0 to t=1 hour is significantly greater than the increase from t=1 hour to t=4 hours. The apparent increase when homogenized by manual shaking is likely due to an inhomogeneous emulsification that settles when placed under more static conditions in a water bath.

[0262] Example 14 - Droplet Size and Size Distribution - Effect of pH

[0263] To determine the effect of pH on droplet size, an emulsion according to Example 3 was prepared containing 0.69 wt % of But without agar. The removal of agar was compensated by increasing the content of xylitol. The temperature of the emulsion was set to 60°C and 4M HCl was gradually added dropwise. After each addition, a small amount of the emulsion was taken out for pH and droplet size measurement. The pH was measured at ambient temperature (20°C ± 2°C) using a calibrated Eutech Instruments pHSpear.

[0264] Figure 4 , and Table 5 show the change in droplet size based on the pH of the emulsion.

[0265] Table 5

[0266]

[0267] Due to the absence of agar, the initial droplet size (at pH 4.65) is slightly larger than the droplet size in the gelled agar emulsion described herein (lower viscosity and therefore lower energy input). It can be seen that the droplet size increases with decreasing pH, particularly from 4.30-3.97, where there is a relatively significant increase. While not wishing to be bound by theory, this may be due to the DATEM Partially protonated and therefore progressively less effective in gelling oil-in-water emulsions at low water activities. Droplets appear relatively stable even at pH 3.32, despite a significant increase in droplet size. Significant phase separation becomes prominent at pH 3.20.

[0268] Example 15 - Lipolysis

[0269] In vitro lipolysis according to the emulsion gel of Example 3 was carried out at 37°C. By mixing 450mg porcine bile extract (Sigma, USA, lot#SLCC9272) with 34ml deionized water (dH2O) in a beaker for 30 minutes under magnetic stirring, simulated intestinal fluid (SIF) was formed. Then, 12.5ml salt mixture (40mM CaCl2 / 600mM NaCl / dH2O) was added to the beaker and mixed for 10 minutes. 69.6mg pancreatin preparation (Sigma, USA, lot#SLBZ5739) from porcine pancreas and lipase (Sigma, USA, lot#SLBZ7254) from porcine pancreas were dissolved in 1160μl water in separate Eppendorf tubes by vortex mixing for 3 minutes. The gelled emulsion was pushed through a metal mesh with a pore size of 1.7 mm (Endecotts Ltd, UK), and 1.5 g of gel was added to SIF while continuously mixing under magnetic stirring. A pH combination electrode (A 1622M DI, SI Analytics, Germany) was placed in a beaker. The electrode was coupled to a titrator 7000-M1 / 20, TitroLine (SI Analytics, Germany). The pH was adjusted to 7 by manually adding droplets of 1 mM and 0.1 mM NaOH. The pH-stat method was started, and 1 ml of pancreatic enzyme preparation and lipase solution were added to SIF to induce lipolysis. The pH-stat method was set to maintain pH at 7 by adding 0.1 mM NaOH droplets. The total lipolysis time was 1 hour. The final concentrations of the SIF components were 9 mg / ml porcine bile extract, 10 mM CaCl2, 150 mM NaCl, 1.2 mg / ml pancreatic enzyme preparation and 1.2 mg / ml lipase. The final volume of SIF was 50 ml.

[0270] Figure 5 The results are shown in Table 6.

[0271] Table 6

[0272]

[0273] Example 16 - Gelled Oil-in-Water Emulsion Containing Corn Oil and Characterization

[0274]

[0275] 1 Gelagar HDR 800 (BVsrl, Italy)

[0276] Following the general method in Example 1, an emulsion was prepared according to the following scheme:

[0277]

[0278] The pH inside the gel was measured using a calibrated Eutech Instruments pHSpear at ambient temperature (20° C.±2° C.). The measured pH was 4.5.

[0279] The average droplet size was measured as described in Example 10:

[0280] At T = 0 hours: D[4;3] = 0.48 μm; D[3;2] = 0.44 μm

[0281] Water activity was measured as described herein. a w =0.747

[0282] The average weight loss was measured as described in the Syneresis Test described herein.Average Weight Loss: 6.96%.

[0283] Prior to the SAOS (Small Amplitude Oscillatory Shear) rheological measurements described herein, viscosity measurements were performed at 50°C by applying a serrated PU40 SW1556 SS and sandblasting the lower plate. The results are as follows:

[0284] Table 7

[0285]

[0286] Rheological analysis was performed according to the small-scale deformation test described herein.

[0287] T = 0 hours: G'max = 14490 kPa.

[0288] Example 17 - Gelled Oil-in-Water Emulsion Containing Sunflower Oil

[0289] Element weight% <![CDATA[Agar HDR 1 > 1.60 <![CDATA[Surfactant 2 > 0.69 Sorbitol 14.41 Xylitol 27.05 Malic Acid 0.75 Trisodium Citrate 1.87 Sunflower Oil 30.00 Lemon Flavor 1.10 water 22.53

[0290] 1 Gelagar HDR 800 (BVsrl, Italy)

[0291] 2 AB 100VEG-FS MB (Danisco) - diacetyl tartaric acid esters of mono- and diglycerides (DATEM) made from edible refined sunflower and palm oils.

[0292] The emulsion was prepared according to the general method in Example 1. The average droplet size of the emulsion at t=0 hours was measured as described in Example 10 and the results are shown in Table 8:

[0293] Table 8

[0294]

[0295] Testing was also performed on gelled emulsions according to the large scale deformation method described herein. The results are listed in Table 9 and compared with the results of the agar based gelled emulsion of Example 3.

[0296] Table 9

[0297]

[0298] The results demonstrate that DATEM obtained from different sources can be used to produce gelled oil-in-water emulsions.

[0299] Example 18 - Effect of Different Surfactants

[0300] Experiments were conducted to compare the effects of different surfactants on emulsion stability. Polyoxyethylene (80) sorbitan monooleate (polysorbate 80 or "PS80") and LACTEM (lactic acid esters of mono- and diglycerides) were selected as examples of other food-grade surfactants. Unlike DATEM, both polysorbate 80 and LACTEM are nonionic surfactants. They are both completely neutral, i.e., they do not have a static charge.

[0301] 1. Agar emulsion-PS80

[0302] An attempt was made to prepare an oil-in-water emulsion with different amounts of sugar alcohols to determine at what point PS80 no longer acts as an emulsifier in the system. A "standard" oil-in-water formulation (40 g) was prepared using PS80 instead of DATEM and compared with formulations in which 1 / 2 and 3 / 4 of the sugar alcohol content was replaced by water. The formulations were prepared according to the general method in Example 1. PS80 was preheated before being added to the remaining components of the emulsion. Each formulation contained 25% by weight corn oil. The details of the formulations are set forth in Table 10:

[0303] Table 10

[0304]

[0305]

[0306] 1 Gelagar HDR 800 (BVsrl, Italy)

[0307] 2 Polysorbate 80 (Sigma Aldrich)

[0308] The water activity of the formulation was measured as described herein:

[0309] "1 / 2s.alk": aw = 0.926

[0310] "3 / 4s.alk": aw = 0.855

[0311] When PS80 was used as the surfactant, no stable emulsion was produced for the "Standard" formulation. The emulsion droplet size and stability for the "1 / 2s.alk" and "3 / 4s.alk" formulations were determined as described herein. The emulsion droplet size and stability are shown in Table 11. Figure 6 The droplet size volume distribution of the emulsion is shown.

[0312] Table 11: Emulsion droplet size and stability

[0313]

[0314] Observations :

[0315] After addition, 1 / 2 sugar alcohol:PS80 did not seem to be completely dissolved (mixture became turbid). It easily formed an emulsion with very low droplet size (about 1 μm) and narrow unimodal distribution (slightly bimodal at T=20 hours). The emulsion was nearly completely stable at 55°C overnight.

[0316] 3 / 4 Sugar alcohol: The mixture became cloudy after adding PS80. An emulsion appeared to form after homogenization, but it looked yellow / translucent (indicating the presence of large droplets). The initial droplet size was large with a broad multimodal distribution. The emulsion was highly unstable and nearly completely phase separated after about 30 minutes at 55°C.

[0317] 2. Agar emulsion-LACTEM

[0318] An attempt was made to prepare an oil-in-water emulsion using LACTEM as an emulsifier. The components listed below were mixed according to the general method in Example 1:

[0319] Element weight% <![CDATA[Agar HDR 1 > 1.63 <![CDATA[LACTEM 2 ]]> 1.22 Sorbitol 11.61 Xylitol 23.43 Malic Acid 0.81 Trisodium Citrate 1.63 Corn Oil 40.00 water 19.66

[0320] 1 Gelagar HDR 800 (BVsrl, Italy)

[0321] 2 Grinsted Lactem B 30Veg MB(Danisco)

[0322] Observations :

[0323] These components are completely incompatible. Phase separation is observed immediately.

[0324] The results show that fully esterified surfactants (i.e., without free acid functional groups such as carboxylic acid groups) and surfactants without static charge cannot effectively stabilize oil-in-water emulsions based on agar with low water activity due to their low solubility in the continuous aqueous phase. DATEM (diacetyl tartaric acid esters with mono- and diglycerides from sunflower oil) always carries a charge. The results presented herein confirm that DATEM provides stable emulsions far below pH 3.5, and these emulsions contain small oil droplets.

Claims

1. An orally administrable gelled oil-in-water emulsion, the emulsion being a self-supporting viscoelastic solid having a gelled aqueous phase comprising a gelling agent which is agar, wherein The emulsion has a water activity ranging from about 0.4 to about 0.9 and is stabilized by a surfactant comprising a glyceride wherein at least one hydroxyl group is esterified with diacetyl tartaric acid and at least one hydroxyl group is esterified with a fatty acid.

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

3. The orally administrable gelled oil-in-water emulsion according to claim 1 or claim 2, wherein The surfactants include diacetyl tartaric acid esters of mono- and diglycerides (DATEM).

4. The orally administrable gelled oil-in-water emulsion according to claim 3, wherein The surfactant is obtained by the reaction of diacetyl tartaric anhydride with mono- and diglycerides of fatty acids obtained from edible oils.

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

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

7. The orally administrable gelled oil-in-water emulsion according to claim 1, in, The surfactant comprises a compound having the following general formula: wherein each R is independently selected from H and -C(O)(CH2) n CH3, wherein n is an integer from 6 to 21, preferably wherein n is 16.

8. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, wherein The emulsion has a water activity ranging from 0.5 to 0.

8.

9. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, wherein The emulsion has a gelled aqueous phase with a pH of 4.2 to 7.

10. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, comprising agar in a concentration of about 0.1 wt% to about 5 wt% based on the total weight of the emulsion.

11. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, wherein The aqueous phase comprises 40 to 95 wt %, preferably 50 to 95 wt %, more preferably 55 to 90 wt %, for example 60 to 85 wt %, 70 to 85 wt % or 75 to 80 wt % of the emulsion.

12. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, wherein The aqueous phase also includes one or more bulking agents, such as sugar alcohols and / or sugars.

13. The orally administrable gelled oil-in-water emulsion according to claim 12, wherein The filler 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. An orally administrable gelled oil-in-water emulsion according to any one of the preceding claims, having an oil phase comprising one or more physiologically tolerable lipids derived from rapeseed oil, sunflower oil, corn oil, olive oil, sesame oil, palm kernel oil, coconut oil, nut oil or algae oil.

15. An orally administrable gelled oil-in-water emulsion according to any preceding claim, which has an oil phase which comprises 5 to 60 wt %, preferably 5 to 50 wt %, more preferably 10 to 45 wt %, for example 15 to 40 wt %, 15 to 30 wt % or 20 to 25 wt % of the emulsion.

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

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

18. The orally administrable gelled oil-in-water emulsion according to claim 17, wherein The nutritionally active agent is a vitamin or a mineral.

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

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

21. A package comprising an airtight and light-tight compartment containing one dosage unit of the gelled oil-in-water emulsion according to claim 19 or claim 20.

22. A method for preparing an orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 20, comprising the steps of: forming an oil phase comprising one or more physiologically tolerable lipids; forming an aqueous phase comprising a gelling agent, the gelling agent being agar; mixing the oil phase and the aqueous phase in the presence of a surfactant to form an oil-in-water emulsion, the surfactant comprising a glyceride 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; and gelling the emulsion.

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

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

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

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