Microcapsules with enhanced aqueous stability

Abstract

Particles comprising a polysaccharide shell and encapsulating hydrophobic compounds are provided. Further provided is a composition and a kit comprising the particle and methods of preparation thereof. Methods of use, such as for enhancing the bioavailability of the hydrophobic compound, are also provided.

Description

MICROCAPSULES WITH ENHANCED AQUEOUS STABILITYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 575,897, titled “MICROCAPSULES WITH ENHANCED AQUEOUS STABILITY", filed April 08, 2024. The contents of which are incorporated herein by reference in their entirety.FIELD OF INVENTION

[0002] The present invention provides microparticles encapsulating an active agent and liquid compositions comprising same.BACKGROUND OF THE INVENTION

[0003] Incorporation of high concentrations of the active compounds such as nutraceuticals and pharmaceutically active agents into liquid food products including inter alia dairy products, juices, shakes, etc., is a long-felt need. Many natural and / or synthetic active compounds are usually unstable, and are prone to oxidation / decompo sition, and in addition usually are characterized by an unpleasant taste and / or odor.

[0004] Taken together, the chemical lability and unfavorable organoleptic properties of the active compounds negatively affect the organoleptic properties of the food product, especially upon prolonged storage thereof.

[0005] Accordingly, there is a need for compositions and methods for improving stability and for reducing or eliminating the unpleasant taste of the food supplements incorporated into a food product. Furthermore, it is highly desirable to obtain a food product comprising an effective amount of the active agent, which substantially retains the initial organoleptic properties of the pristine (non-supplemented) food product.SUMMARY OF THE INVENTION

[0006] The invention in one aspect thereof, relates to a composition comprising a plurality of particles, each of the particles comprises an active agent core encapsulated by a shell; wherein the plurality of particles is characterized by an average particle size between 10 and 1000 um; the shell comprises a hydrophobic compound comprising a fatty acid, an ester thereof, a wax,plant fat, hydrogenated plant oil, including any salt or any combination thereof; a weight ratio between the shell and the core within the particle is between 1:3 and 3:1; the active agent is selected from a food supplement and a pharmaceutically active agent, or both; and wherein plurality of particles stably encapsulates the active agent in an aqueous solution for a time period of at least 90 days.

[0007] In one embodiment, the hydrophobic compound is a solid at a temperature below 30°C and is characterized by a melting temperature between 40 and 100°C.

[0008] In one embodiment, the plurality of particles is characterized by an average particle size between 100 and 700 um, and wherein a weight ratio between the shell and the core within the particle is between 1:2 and 2:1.

[0009] In one embodiment, the shell is characterized by a pore size in a range between lOnm and lOum.

[0010] In one embodiment, the core is a multi-layered core comprising a first inner layer in contact with a second layer facing the shell, wherein the second layer comprises the active agent.[Oi l] In one embodiment, a weight portion of the active agent within the particle is between 5 and 50%.

[0012] In one embodiment, a w / w ratio between the first inner layer and the second layer is between 5:1 and 1:1, and wherein a weight portion of the active agent within the particle is between 5 and 50%.

[0013] In one embodiment, the first inner layer comprises a particle comprising a monosaccharide, a di- saccharide, or a polysaccharide including any mixture, or any derivative thereof.

[0014] In one embodiment, the shell further comprises an additional outer layer comprising a film forming agent.

[0015] In one embodiment, the plurality of particles are composed essentially of food grade compounds.

[0016] In another aspect, there is provided a food product comprising the composition of the invention.

[0017] In one embodiment, a w / w concentration of the composition within the liquid food product is between 0.1 and 10%.

[0018] In one embodiment, the food product is a liquid food product being in a form of a beverage, a dairy food product, a gel, or any combination thereof.

[0019] In one embodiment, the liquid food product retains at least 90% of the initial amount of the active agent encapsulated within the plurality of particles, for a time period of up to 200 days under appropriate storage conditions.

[0020] In one embodiment, the food product is substantially devoid of off-taste associated with the active agents.

[0021] In another aspect, there is provided a method of supplementing a subject with an active agent, the method comprising administering to the subject the plurality of particles of the invention, or the food product of the invention.

[0022] In another aspect, there is provided a composition comprising a plurality of particles, each particle comprising a core and a shell, wherein the core comprises an active agent and is encapsulated by the shell; wherein the plurality of particles is characterized by an average particle size between 10 and 1000 um; said shell comprises a hydrophobic compound comprising a fatty acid, a fatty acid ester, a wax, plant fat, hydrogenated plant oil, including any salt or any combination thereof; a weight ratio between the shell and the core within the particle is at least about 0.8:1; and the active agent is selected from a food supplement and a pharmaceutically active agent, or both.

[0023] In one embodiment, the hydrophobic compound is a solid at a temperature below 30°C and is characterized by a melting temperature between 40 and 100°C.

[0024] In one embodiment, the hydrophobic compound is or comprises any one of: the fatty acid and the wax, wherein the wax is a plant wax.

[0025] In one embodiment, the fatty acid is a saturated fatty acid being between 16 and 20 carbon long.

[0026] In one embodiment, at least 90% by weight of the shell consists of the saturated fatty acid and wherein a w / w ratio between the saturated fatty acid and the core is between about 0.8:1 and about 3:1.

[0027] In one embodiment, a w / w ratio between the saturated fatty acid and the core is between about 1 : 1 and about 3: 1.

[0028] In one embodiment, saturated fatty acid is or comprises stearic acid

[0029] In one embodiment, a w / w ratio between the stearic acid and the core is between about 1:1 and about 3:1.

[0030] In one embodiment, the plant wax is selected from sunflower wax, carnauba wax, candelilla wax, soy wax and palm wax, including any combinations thereof.

[0031] In one embodiment, the active agent is a solid at a temperature of between 2 and 30C.

[0032] In one embodiment, the active agent is a natural compound.

[0033] In one embodiment, the natural compound is a nutraceutical.

[0034] In one embodiment, the active agent is a drug.

[0035] In one embodiment, the plurality of particles is characterized by an average particle size between 100 and 700 um, and wherein a weight ratio between the shell and the core within the particle is between about 1:1 and about 3:1 wherein each of the plurality of particles is a solid particle at a temperature of at least 25C; and wherein each of the core and the shell of the solid particle is a solid at a temperature of at least 25C.

[0036] In one embodiment, the shell is characterized by an average pore size in a range between lOnm and lOum.

[0037] In one embodiment, a weight portion of the active agent within each of the plurality of particles is between 5 and 50%.

[0038] In one embodiment, the core is a multi-layered core comprising a first inner layer in contact with a second layer facing and / or in contact with the shell, wherein the second layer comprises the active agent; and wherein the first inner layer consists essentially of a water soluble material.

[0039] In one embodiment, a w / w ratio between the first inner layer and the second layer is between 5:1 and 1:1, and wherein a weight portion of the active agent within the particle is between 5 and 50%.

[0040] In one embodiment, the water soluble material is a natural compound and wherein the first inner layer consists of the water soluble material.

[0041] In one embodiment, the water soluble material comprises any one of: a monosaccharide, a di-saccharide, and a polysaccharide including any mixture thereof; and wherein each of the first inner layer and the second layer is a solid at a temperature of at least 25C.

[0042] In one embodiment, the shell further comprises an additional outer layer comprising a film forming agent.

[0043] In one embodiment, the plurality of particles are composed essentially of food grade or pharmaceutical grade constituents.

[0044] In one embodiment, the natural compound is or comprises any one of: a carotenoid, a natural phenol, a vitamin, an alkaloid, a terpene, a cannabinoid, a polyunsaturated fatty acid salt, a phytosterol, an isoflavone, a polysaccharide, an anthocyanin and taurine, including any salt or any combination thereof.

[0045] In one embodiment, at least 90% by weight of the shell consists of the plant wax and wherein a w / w ratio between the plant wax and the core is between 1.2:1 and 3:1.

[0046] In one embodiment, the plurality of particles stably encapsulates the active agent in an aqueous solution for a time period of at least 90 days; and wherein the stably encapsulate comprises release of the active agent into the aqueous solution below 10% at a temperature between 20 and 25C.

[0047] In one embodiment, the aqueous solution is an acidic solution having a pH value of at least 3.

[0048] In one embodiment, the active agent is characterized by unpleasant taste, and wherein the composition is for masking the unpleasant taste of the active agent.

[0049] In another aspect, there is provided a method of supplementing a subject with an active agent, the method comprising administering to the subject the composition or the plurality of particles of the invention, or the food product of the invention.

[0050] In one embodiment, the method is for a targeted delivery of the active agent to the gastrointestinal tract of the subject.

[0051] In one embodiment, at least 70%, or at least 80% or between 70 and 99% w / w of the initial loading of the active agent is released within the gastrointestinal tract.

[0052] In one embodiment, released comprises a residence time period of between 10 min and 500 min within the gastrointestinal tract.

[0053] In one embodiment, the method is for a targeted delivery of the active agent to the gastrointestinal tract of the subject.

[0054] In one embodiment, the method comprises administering to the subject a nutritionally or a therapeutically effective amount of the particles, or of the food product.

[0055] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0056] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figures 1A-1F are SEM micrographs at various magnitudes showing exemplary particles of the invention encapsulating Salix (Figures 1A-1B) and caffeine (Figures 1C-1D), and the control particles (Figures IE- IF).

[0058] Figures 2A-2C are graphs demonstrating aqueous stability (at pH 4) of the of the exemplary particles of the invention encapsulating Salix (Figure 2A) and caffeine (Figure 2B, 2C), as determined by HPLC.

[0059] Figure 3 is a graph demonstrating caffeine leakage from exemplary particles of the invention in an aqueous environment (water, pH 3 at 25C) as a function of coating weight gain. Coating material: stearic acid.

[0060] Figure 4 is a graph demonstrating dissolution profile of coated caffeine exemplary particles of the invention in a simulated gastric fluid as a function of coating weight gain. Coating material: Stearic acid.DETAILED DESCRIPTION OF THE INVENTION

[0061] The invention relates to a food product (e.g. a beverage) comprising a plurality of particles (e.g. microparticles), each particle comprising a hydrophobic shell encapsulating a core, wherein the core comprises an active agent, and wherein the active agent is stable encapsulated within the particle to prevent leakage of the active agent during the shelf-life of the food product.

[0062] The invention further relates to methods of preparation of the particles (e.g. by fluid bed hot melt coating of the core by the hydrophobic shell), and methods for using the compositions of the invention, such as for supplementing a subject with a nutraceutical or a pharmaceutically active compound.

[0063] The present invention is directed, in one embodiment thereof, to solid particles (e.g. a particle substantially in a solid state at a temperature below 40°C, or below 30°C) comprising a hydrophobic compound composing the shell of the particle and an active agent (composing the core of the particle) selected from a food supplement (nutraceutical) and a pharmaceutically active agent, or a combination thereof; wherein the solid particles are characterized by an average particle size between 10 and 1000 um; and wherein a weight ratio (i) between the hydrophobic compound and the core, or (ii) between the shell and the core within the particle is at least about 0.8:1. In one embodiment, the particle is a solid particle and consists of a shell and a core, wherein the core comprises the active agent and the shell comprises the hydrophobic compound.

[0064] In another embodiment, provided herein a food product (e.g. a liquid, semi-liquid or semi-solid food product) composition comprising a plurality of particles as described herein. In one embodiment, the particles are water-dispersible particles.

[0065] In another embodiment, there is provided herein a liquid or a semi-solid composition (e.g. a liquid / semi-solid food product, such as a beverage, a hydrogel, etc.), comprising the plurality of particles of the invention, wherein an average particle size of the plurality of particles within the liquid composition is between 10 and 1000 pm, and wherein the plurality of particles stably encapsulates the active agent within the liquid composition for a time period of at least 60 days, at least 90 days, at least 200 days, at least 150 days, at least 300 days, at least 1 year, including any range between. In some embodiments, the composition is a food product (e.g. in a form of a beverage, a dairy food product, a semi-solid or gel, or any combination thereof), and wherein a w / w concentration of the particles within the food product is between 0.1 and 10%.

[0066] In some embodiments, the present invention provides a method for supplementing a subject with the active agent, by administering the particles or the food product as described herein to the subject.Particle

[0067] In one aspect, there is provided herein a composition (e.g. a powderous composition) comprising a plurality of particles (e.g. micro-particles), each particle comprises a core and a shell, wherein the shell consists of, consists essentially of or comprises the hydrophobic compound and encapsulates and / or encloses the core, wherein the core consists of, consists essentially of or comprises the active agent, and wherein a weight / weight (w / w) ratio between the shell and the core within the particle is at least about 0.8:1, at least about 0.9:1, at least about 1:1, at least about 1.1:1, at least about 1.2:1, at least about 1.3:1, at least about 1.4:1, at least about 1.5:1, including any range between.

[0068] In some embodiments, a w / w ratio between (i) the hydrophobic compound and the core or (ii) the shell and the core within the particle and / or within the composition is between 0.8:1 and 10:1, between 0.8:1 and 8:1, between 0.8:1 and 6:1, between 0.8:1 and 5:1, between 0.8:1 and 4:1, between 0.8:1 and 3:1, between 0.8:1 and 2.5:1, between 0.8:1 and 2.3:1, between 0.8:1 and 2:1, between 0.8:1 and 1.8:1, between 0.8:1 and 1.6:1, between 0.9:1 and 10:1, between 0.9:1 and 5:1, between 0.9:1 and 4:1, between 0.9:1 and 3:1, between 0.9:1 and 2.5:1, between 0.9:1 and 1.8:1, between 0.9:1 and 1.5:1, between 1:1 and 10:1, between 1:1 and 6:1, between 1:1 and 4:1, between 1:1 and 1.8:1, between 1.8:1 and 4:1, between 1.8:1 and 2:1, between 2:1 and 3:1, between 3:1 and 4:1, between 4:1 and 5:1, between 5:1 and 8:1, between 1:1 and 2:1, between 1:1 and 1.2:1, between 1:1 and 1.3:1, between 1:1 and 1.4:1, between 1:1 and 1.5:1, between 1.5:1 and 2:1, between 1.5:1 and 1.8:1, between 1.8:1 and 2:1, between 1.4:1 and 3:1, between 1.4:1 and 5:1, between 1.4:1 and 2:1, between 1.4:1 and 2.5:1, between 1.5:1 and 3:1, between 1.5:1 and 5:1, between 1.5:1 and 10: 1, including any range between. In some embodiments, a w / w ratio between the hydrophobic compound and the core within the particle and / or within the composition is between .8:1 and 10:1, between 0.8:1 and 8:1, between 0.8:1 and 6:1, between 0.8:1 and 5:1, between 0.8:1 and 4:1, between 0.8:1 and 3:1, between 0.8:1 and 2.5:1, between 0.8:1 and 2.3:1, between 0.8:1 and 2:1, between 0.8:1 and 1.8:1, between 0.8:1 and 1.6:1, between 0.9:1 and 10:1, between 0.9:1 and 5:1, between 0.9:1 and 4:1, between 0.9:1 and 3:1, between 0.9:1 and 2.5:1, between 0.9:1 and 1.8:1, between 0.9:1 and 1.5:1, between 1:1 and 10:1, between 1:1 and 6:1, between 1:1 and 4:1, between 1:1 and 1.8:1, between 1.8:1 and 4:1, between 1.8:1 and 2:1, between 2:1 and 3:1, between 3:1 and 4:1,between 4:1 and 5:1, between 5:1 and 8:1, between 1:1 and 2:1, between 1:1 and 1.2:1, between 1:1 and 1.3:1, between 1:1 and 1.4:1, between 1:1 and 1.5:1, between 1.5:1 and 2:1, between 1.5:1 and 1.8:1, between 1.8:1 and 2:1, between 1.4:1 and 3:1, between 1.4:1 and 5:1, between 1.4:1 and 2:1, between 1.4:1 and 2.5:1, between 1.5:1 and 3:1, between 1.5:1 and 5:1, between 1.5:1 and 10:1, including any range between.

[0069] In some embodiments, a w / w ratio between the hydrophobic compound and the core within the particle and / or within the composition is between 0.8:1 and 3:1, between 0.8:1 and 2.8:1, between 0.8:1 and 2.6:1, between 0.8:1 and 2.5:1, between 0.8:1 and 2.2:1, between 0.8:1 and 2:1, between 0.8:1 and 1.8:1, between 1:1 and 3:1, between 1:1 and 1.8:1, between 1.8:1 and 3:1, between 1.8:1 and 2:1, between 2:1 and 3:1, between 1:1 and 2:1, between 1:1 and 1.2:1, between 1:1 and 1.3:1, between 1:1 and 1.4:1, between 1:1 and 1.5:1, between 1.5:1 and 2:1, between 1.5:1 and 1.8:1, between 1.8:1 and 2:1, between 1.4:1 and 3:1, between 1.4:1 and 5:l, between 1.4:1 and 2:1, between 1.4:1 and 2.5:1, between 1.5:1 and 3:1, including any range between.

[0070] In some embodiments, the particle is a micro-particle. In some embodiments, the particle is a solid particle, a solid granule or a solid capsule, wherein the shell is a solid shell (or coating) and wherein the core is a solid core, wherein solid is at a temperature below 40, below 30 or between 2 and 30°C, under atmospheric pressure of Ibar.

[0071] In some embodiments, the particles are characterized by an average particle size of between 10 and 1000 pm, between 20 and 1000 pm, between 50 and 1000 pm, between 70 and 1000 pm, between 100 and 1000 pm, between 150 and 1000 pm, between 200 and 1000 pm, between 300 and 1000 pm, between 100 and 800 pm, between 100 and 700 pm, between 100 and 500 pm, including any range between.

[0072] In some embodiments, the average particle size refers to the dry size of the particles within the composition (as determined by PSD test, based on sieving or based on microscopy images, such as SEM or TEM images). In some embodiments, the particle size refers to the average size of the particles in a liquid (e.g. an aqueous composition, such as a beverage), as determined by DLS.

[0073] In some embodiments, the particles have a spherical or elliptical geometry or shape. In some embodiments, the particles have an inflated or a deflated shape. In some embodiments, a plurality of the particles is devoid of any characteristic geometry or shape. In some embodiments, the particles have a spherical or elliptical shape, a quasi- spherical shape, a quasi-elliptical sphere, a deflated shape, a concave shape, an irregular shape, or any combination thereof.

[0074] In some embodiments, the particles are substantially spherically or elliptically shaped, wherein substantially is as described herein. One skilled in the art will appreciate that the exact shape of each of the plurality of core- shell particles may differ from one particle to another. Moreover, the exact shape of the particle(s) may be derived from any of the geometric forms listed above, so that the shape of the particle does not perfectly fits to a specific geometrical form. One skilled in the art will appreciate that the exact shape of the particle may have substantial deviations (such as at least 5%, at least 10%, at least 20% deviation) from a specific geometrical shape (e.g., a sphere or an ellipse).

[0075] In some embodiments, the core and / or the shell of the particle is in a solid state at a room temperature (e.g. between 15 and 35C, as between 2 and 40C, between 2 and 35C, or below the room temperature). In some embodiments, the shell comprises a hydrophobic compound, characterized by a melting temperature between 40 and 100°C, between 40 and 80°C, between 40 and 70°C, between 40 and 60°C, between 40 and 50°C, including any range between.

[0076] In some embodiments, the core is substantially enclosed by the shell, e.g. between 80 and 100%, between 80 and 99.9%, between 90 and 100%, between 95 and 100%, between 95 and 99.9%, between 97 and 99.9% of the core’s surface is incorporated within or enclosed by the shell, including any range between.

[0077] In some embodiments, the shell is in a form of a unform layer, characterized by substantially uniform thickness and nanosized surface roughness. In some embodiments, the shell is in a form of a distinct layer (e.g. having a different chemical composition and physical structure than the core). In some embodiments, the shell is in a form of a consecutive layer bound to and / or on top of the core. In some embodiments, the shell is substantially devoid of opening. In some embodiments, the shell is substantially non-porous shell. In some embodiments, the shell is substantially devoid of pores or openings characterized by an average size of at least 3um, at least 5um, at least 7um, at least lOum, at least 15um, at least 20um, including any range between.

[0078] In some embodiments, the shell comprises a plurality of pores or craters characterized by an average pore size (e.g. cross-section, diameter, or longitudinal / transverse cross-section) between Inm and lOum, between lOnm and lOum, between lOnm and lum, between Inm and lum, between lOnm and 500nm, between Inm and 500nm, between lOOnm and lOum, betweenlOOnm and 3um, between lOnm and 2um, between 500nm and 3um, including any range between. The average pore size (e.g. arithmetic mean value) is determined microscopically (SEM, TEM).

[0079] In some embodiments, the shell and / or the plurality of particles is characterized by a porosity below 50%, below 40%, below 30%, below 20%, below 10%, including any range between. In some embodiments, the plurality of particles are substantially non-porous, characterized by a porosity of less than 20%, less than 10%, less than 5%, including any range between. Particles porosity can be determined by nay of the methods disclosed below:- Mercury Intrusion Porosimetry: This method involves forcing mercury into the pores under controlled pressure to measure pore size distribution and total porosity.- Gas Adsorption (BET Method): Utilizes gas molecules to adsorb onto the surface of the material, providing data on surface area and pore size.- Optical Microscopy: Directly visualizes and measures pores using high-resolution imaging techniques.- Gravimetric Method: Measures the bulk volume of a sample by immersing it in a fluid and calculating the volume of fluid displaced.

[0080] In some embodiments, the shell is substantially devoid of one or more core constituents (e.g. the active agent). In some embodiments, the shell consists essentially of the hydrophobic compound. In some embodiments, the shell consists essentially the hydrophobic compound (and optionally a film forming agent coating or outer layer) and less than 20%, less than 10%, less than 5%, 1% or 0.1%w / w of other ingredients (impurities or inert materials such as coloring agents, flavoring, additives, etc.).

[0081] In some embodiments, at least 80%, at least 85%, at least 90%, or between 80 and 99.5%, between 85 and 99.5%, between 83 and 99.5%, between 87 and 99.5%, between 90 and 99.5%, between 80 and 95%, between 85 and 95%, between 90 and 95%, between 90 and 97%, between 90 and 99%, between 95 and 99.5%, between 95 and 99%, between 95 and 97%, between 95 and 98%, between 90 and 98%w / w of the shell consists of the hydrophobic compound (and optionally of the film forming agent) including any range between.

[0082] In some embodiments, the shell is a single layer shell. In some embodiments, the shell is a multi-layer shell. In some embodiments, the shell comprises a first inner portion facing the core and a second outer portion facing the ambient. In some embodiments, the second outerportion of the shell is further in contact or bound to an additional chemically distinct layer (e.g. as gas barrier or moisture barrier). In some embodiments, the additional layer comprises a film forming agent (e.g. acrylate and derivatives, albumin, chitosan, alginate, pectin, carbomers, carrageenan, cellulose and derivatives such as alkyl cellulose, dextran, dextrin, gelatine, polyvinylpyrrolidone, and starch, including any salt or any copolymer thereof).

[0083] In some embodiments, the shell has a gas barrier properties. In some embodiments, the shell is substantially gas impermeable.

[0084] In some embodiments, the critical surface tension of the particles and / or of the shell is between 15 and 60 dyn / cm, between 20 and 45 dyn / cm, between 28 and 32 dyn / cm, about 30 dyn / cm, or about 35 dyn / cm including any range between.

[0085] In some embodiments, the shell and / or the hydrophobic compound is characterized by (i) a melting point between 40 and 100°C, about 50 and about 75°C, about 50 and about 60°C, or about 50 and about 70°C; (ii) Hydrophilic-lipophilic balance (HLB) value below 6, below 5 or between 3 and 5.5, or both (i) and (ii).

[0086] In some embodiments, the hydrophobic compound is water insoluble, having solubility in DDW of at most 0.5g / l, at most 0.3g / l, at most O.lg / 1 at a temperature of 25C, including any range between.

[0087] In some embodiments, a density of the shell and / or the hydrophobic compound is below lg / cm3, between 0.2 and 0.95 g / cm3, between 0.5 and 0.95 g / cm3, between 0.6 and 0.95 g / cm3, between 0.8 and 0.95 g / cm3, between 0.6 and 0.9 g / cm3, between 0.7 and 0.9 g / cm3, including any range between. In some embodiments, the hydrophobic compound is characterized by melting point, HLB and density as described above, and is further characterized by critical surface tension between 15 and 60 dyn / cm.

[0088] In some embodiments, the hydrophobic compound and / or the shell is characterized by acid value between 0.5 and 8, between 1 and 8, between 2 and 8, between 3 and 8, between 4 and 8, between 3 and 6, including any range between. As used herein, the term “acid value” refers to mass of KOH in mg that is required to neutralize 1 g of the hydrophobic compound and / or the shell.

[0089] In some embodiments, the shell comprises or consists essentially of one or more hydrophobic compounds. In some embodiments, the shell comprises a food grade hydrophobic compound selected inter alia from solid fat (e.g. comprising natural esters of glycerol and various fatty acids, which are solid at room temperature and are the main constituents of animaland vegetable fat), wax (e.g. natural wax including beeswax, candelilla wax, carnauba wax, berry wax, sunflower wax, Myrica fruit wax, rice bran wax, lanolin and jojoba oil), phospholipid and fatty acid, or any combination thereof. In some embodiments, the wax is a plant wax.

[0090] Non-limiting examples of phospholipids include but are not limited to: lecithin (e.g. a plant based lecithin), sunflower lecithin, phosphatidylcholine (e.g., plant-based phosphatidylcholine), sunflower phosphatidylcholine, egg lecithin, egg phosphatidylglycerol, phosphatidic acid, lysolecithin, soy lecithin, hydrogenated soy lecithin, and sphingomyelin or any combination thereof. In some embodiments, the phospholipid comprises sunflower lecithin, soybean lecithin, or a combination thereof.

[0091] In some embodiments, the plant wax is selected from sunflower wax, carnauba wax, candelilla wax, soy wax and palm wax, including any combinations thereof. In some embodiments, the plant wax is sunflower wax.

[0092] In some embodiments, the hydrophobic compound is suitable for hot melt processing. In some embodiments, the hydrophobic compound include fatty acids, fatty acid ester, fatty acid triesters, salts of fatty acid such as aluminum, sodium, potassium and magnesium, fatty alcohol, phospholipid, solid lipid, wax, and a combination thereof.

[0093] Non-limiting examples of fatty acid include inter alia: lauric acid, myristic acid, palmitic acid, palmitate, palmitoleate, hydroxypalmitate, arachidic acid, oleic acid, stearic acid, sodium stearat, calcium stearate, magnesium stearate, hydroxyoctacosanyl hydroxystearate, oleate esters of long-chain, esters of fatty acids, fatty alcohols, esterified fatty diols, hydroxylated fatty acid, hydrogenated fatty acid (saturated or partially saturated fatty acids), partially hydrogenated soybean, partially hydrogenated cottonseed oil, aliphatic alcohols, phospholipids, lecithin, phosphathydil cholin, triesters of fatty acids, coconut oil, hydrogenated coconut oil, cacao butter; palm oil; fatty acid eutectics; mono and diglycerides, poloxamers, block-copolymers of polyethylene glycol and polyesters or a combination thereof. In some embodiments, the fatty acid is or comprises Stearic acid, Caprylic acid, Capric acid, Lauric acid, Myristic acid, Palmitic acid, Arachidic acid, Behenic acid, Lignoceric acid and Cerotic acid, including any salt and any combination thereof. In some embodiments, the fatty acid is or comprises Stearic acid.

[0094] In some embodiments, the hydrophobic compound is selected from a fatty acid and a plant wax. In some embodiments, the fatty acid chain is a saturated fatty acid being between 10and 30, between 10 and 25, between 12 and 20, between 16 and 22, between 16 and 20 carbon atoms long (e.g. the fatty acid is C16-C22, C16-C19 or C16-C18 saturated fatty acid).

[0095] In some embodiments, at least 80%, at least 90%, at least 95% or between 80 and 100%, between 85 and 99.5%, between 90 and 99.5% or between 90 and 100% by weight of the shell consists of the C10-C30 saturated fatty acid (e.g. C16-18 fatty acid) and wherein a w / w ratio between the saturated fatty acid (or between the shell) and the core is between about 0.8:1 and about 3:1, between about 0.9:1 and about 3:1 between about 1:1 and about 2:1 between about 0.8:1 and about 5:1 between about 1:1 and about 3:1, between about 1:1 and about 5:1, including any range between. In some embodiments, at least 80%, at least 90%, at least 95% or between 80 and 100%, between 85 and 99.5%, between 90 and 99.5% or between 90 and 100% by weight of the shell consists of stearic acid, and wherein a w / w ratio between the stearic acid and the core is between about 0.8:1 and about 3:1, between about 0.9: 1 and about 3:1 between about 1:1 and about 2:1 between about 0.8:1 and about 5:1 between about 1:1 and about 3:1, between about 1:1 and about 5:1, including any range between.

[0096] In some embodiments, the shell and / or the particle substantially retains its shape of within a liquid (e.g. an aqueous solution). In some embodiments, the shell is water impermeable. In some embodiments, the shell stabilizes the particle within a liquid (e.g. an aqueous solution), by providing water barrier properties thereto. In some embodiments, the shell substantially prevents from dissociation or degradation of the particle, and / or substantial release of the active agent therefrom within an aqueous solution. In some embodiments, the shell provides aqueous dispersibility to the particle. In some embodiments, the shell enhances stability (e.g. storage stability) of an aqueous dispersion comprising the particles of the invention.

[0097] In some embodiments, the hydrophobic compound is a chemically pure single compound. In some embodiments, the hydrophobic compound is or comprises a mixture of chemically distinct compounds.

[0098] In some embodiments, the hydrophobic compound and / or the entire shell constituents is characterized by chemical purity of at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, at least 92%, including any range between.

[0099] In some embodiments, the core comprises the active agent as described hereinbelow. In some embodiments, the active agent is a nutraceutical and / or a pharmaceutically active agent. In some embodiments, the active agent is characterized by an off-taste and / or unpleasant odor (e.g. bitter taste). In some embodiments, the active agent is characterized by water solubility inDDW of at least 0.01g / l, at least 0.05g / l, at least 0.1g / l, at least 0.5g / l, at least lg / 1, at least 5g / l or at least 10g / l at a temperature of 25C.

[0100] In some embodiments, the active agent is a solid (i.e. non-fluid) at a temperature of between 2 and 30C, below 75, below 70, below 60, below 65, below 50°C, or between 20 and 30, between 20 and 40°C, between 20 and 65°C, between 20 and 68°C, between 20 and 69°C, between 20 and 60°C, between 20 and 50, between 20 and 55°C, between 20 and 45°C at normal conditions (i.e. at ambient atmosphere and a pressure of 105pascal (1 bar).

[0101] In some embodiments, the active agent is a natural compound. In some embodiments, the natural compound is a nutraceutical or a food supplement.

[0102] In some embodiments, the active agent is selected from the group consisting of: a carotenoid (e.g., astaxanthin (AX), astaxanthin oleoresin (AX oleoresin), beta-carotene, alphacarotene, canthaxanthin, lutein, zeaxanthin, beta-zeacarotene, lycopene, apo carotenal, bixin, paprika oleoresin, capsanthin, vitamin A (retinol), capsorubin or any combination thereof), a natural phenol (e.g. resveratrol), a vitamin (e.g. A, B, C, D, E, K), an alkaloid (e.g. methylxanthine such as caffeine, theobromine, theophylline; morphine, strychnine, quinine, ephedrine, nicotine, atropine, cocaine, berberine, psilocin, vincristine, codeine, reserpine, and scopolamine), a cannabinoid, a terpene, a prebiotic nutritional agent, a polyunsaturated fatty acid salt (e.g., an omega-3 fatty acid), a phytosterol, a nutraceutical (e.g. co-QlO, genistein, daidzein, curcumin), an antioxidant, an isoflavone (e.g., genistein, daidzein, glycitein), a phytoestrogen, a polyphenol or a natural phenol (e.g., phenolic acids, flavonoids (e.g. quercetin, kaempferol, catechin, anthocyanin, hesperidin), tannins, stilbenes (e.g. resveratrol), curcuminoids (e.g. curcumin tetrahydrocurcumin, hexahydrocurcumin, curcumin sulfate, dihydrocurcumin, curcumin glucuronide or any combination thereof), coumarins, lignans, quinones or any combination thereof), a polysaccharide, an anthocyanin, taurine including any salt or any combination thereof.

[0103] In some embodiments, the active agent is a small molecule, having a molecular weight below 1000, below 900, below 800, below 700 or below 500Da, including any range between.

[0104] In some embodiments, the active agent (i.e., a therapeutically active agent) is or comprises a hydrophobic or a hydrophilic drug , such as a peptide or a protein, a polynucleic acid, an anti-inflammatory agent, an antibiotic agent, an anti-cancer drug, analgesic, a steroid or any combination thereof.

[0105] Non-limiting examples of active agents that can be beneficially used in embodiments of the present invention include, without limitation, one or more of an agonist agent, an amino acid agent, an analgesic agent, an antagonist agent, an antibiotic agent, an antibody agent, disinfectant, an antidepressant agent, an antigen agent, an antihistamine agent, an antihypertensive agent, an anti-metabolic agent, an antimicrobial agent, an antioxidant agent, an anti-proliferative drug, an antisense agent, a chemotherapeutic drug (e.g. Cisplatin, Carboplatin, 5 -fluorouracil (5-FU), Paclitaxel, Docetaxel, Methotrexate, Ifosfamide, and Bleomycin), a cofactor, a cytokine, a drug, an enzyme, a growth factor, a heparin, a hormone, an immunoglobulin, an inhibitor, a ligand, a nucleic acid, an oligonucleotide, a peptide, a phospholipid, a prostaglandin, a protein, a toxin, anti-inflammatory agents (e.g. indometacin, ibuprofen), coronary vasodilators (e.g. nitroglycerin, isosorbide dinitrate, nifedipine), antiasthmatics (e.g. disodium cromoglycate), antibiotics (e.g. penicillins, erythromycin), chemothera- peutics (e.g. sulfathiazole, nitrofurazone), local anesthetics (e.g. benzocaine), cardiotonics (e.g. digitalis, digoxin), antitussives and expectorants (e.g. codeine phosphate, isoproterenol hydrochloride), agents affecting digestive organs (e.g. water-soluble azulene (sodium azulene sulfonate), vitamin U), antihistamins (e.g. diphenhydramine hydrochloride, chlorpheniramine maleate), antiinflammatory steroids (e.g. prednisolone, triamci- nolone), antifungal agents (e.g., miconazoel, nystatin and amphotericin), hemostatics, sexual hormones, sedatives, and any combination thereof.

[0106] In some embodiments, the core comprises the active agent in a solid state. In some embodiments, the core comprises the active agent in a crystalline form. In some embodiments, the core of the particle of the invention consists essentially of the active agent.

[0107] In some embodiments, a w / w concentration of the active agent within the particle ranges from 5 to 50%, from 5 to 10%, from 10 to 15%, from 15 to 20%, from 20 to 40%, from 10 to 40%, from 30 to 40%, from 15 to 30%, from 15 to 50%, from 10 to 40%, from 10 to 30%, including any range between.

[0108] In some embodiments, the core (and / or the shell) further comprises between 1 and 20% of an additive. In some embodiments, the additive comprises a surfactant, a lipid, an oil, a fat, a taste masking agent, a coloring agent, a stabilizer, an antioxidant, or any combination thereof.

[0109] In some embodiments, a w / w concentration of the active agent within the core of the particle ranges from 20 to 100%, from 20 to 90%, from 20 to 50%, from 20 to 70%, from 20 to80%, from 50 to 100%, from 40 to 100%, from 30 to 100%, from 60 to 100%, from 30 to 100%, from 40 to 90%, including any range between.

[0110] In some embodiments, a weight content of the core within the particle is between 30 and 60%, between 33 and 57%, between 35 and 50%, between 30 and 55%, between 30 and 50%, including any range between.

[0111] In some embodiments, the core has an average size between 10 and 500um, between 10 and 400um, between 10 and 300um, between 50 and 500um, between 50 and 400um, between 50 and 300um, between 50 and 200um, including any range between.

[0112] In some embodiments, the core is a multi-layered core comprising a first inner layer in contact with a second layer facing the shell, wherein the second layer comprises the active agent. In some embodiments, the active agent is adsorbed to or embedded within the first inner layer. In some embodiments, the second layer comprises one or more distinct layers. In some embodiments, the second layer comprises a plurality of layers, wherein each of the plurality of layers comprises the same or different active agent.

[0113] In some embodiments, the first inner layer is substantially devoid of the active agent. In some embodiments, the first inner layer is a water-soluble material or consists essentially of a water soluble material (i.e. having solubility in DDW of at least 0.1g / l, at least 0.5g / l, at least lg / 1, at least 5g / l or at least 10g / l at a temperature of 25C).

[0114] In some embodiments, the water-soluble material is or consists essentially of a natural compound(s). In some embodiments, at least 80%, at least 90%, at least 95% or between 80 and 100%, between 85 and 99.5%, between 90 and 99.5% or between 90 and 100% by weight of the first inner layer consists of the water-soluble natural compound.

[0115] In some embodiments, the natural compound comprises a mono- saccharide (e.g. glucose, fructose, mannose, allulose), a di-saccharide (e.g. sucrose, trehalose, lactose, maltose), or a polysaccharide (e.g. starch, cellulose, gum, ulvan, levan, hyaluronic acid, pectin, alginate) including any mixture, or any salt / derivative thereof.

[0116] In some embodiments, the first inner layer comprises a mono-saccharide, a disaccharide, or a polysaccharide including any mixture, or any derivative thereof. In some embodiments, the first inner layer is in a form of a particulate matter (e.g. granules, spheres). In some embodiments, the first inner layer comprises a mono -saccharide and / or a di- saccharide- based particle (e.g. having a spherical or elliptical shape, such as a sugar sphere).

[0117] In some embodiments, the particulate matter is characterized by an average particle size between 1 and lOOum, between 10 and lOOum, between 10 and 50um, between 50 and lOOum, between 50 and 200um, between 1 and lOum, between 1 and 50um, including any range between.

[0118] In some embodiments, the first inner layer comprises a mono -saccharide and / or a di- saccharide-based particle coated by a coating comprising a film forming agent. In some embodiments, the film forming agent comprises a polysaccharide (e.g. a cellulose or a derivative thereof, such as HPMC, CMC, etc.). In some embodiments, the film forming agent comprises an alkyl cellulose (e.g. methyl cellulose, ethyl cellulose, or both).

[0119] In some embodiments, the coating further comprises an oil (e.g. a plant oil), and / or a fat.

[0120] In some embodiments, a w / w portion of the coating relative to the first inner layer is between 1 and 20%, between 1 and 10, 3 and 20%, 5 and 20%, including any range between.

[0121] In some embodiments, a w / w concentration of the polysaccharide within the particle ranges from 5 to 40%, from 5 to 10%, from 10 to 15%, from 15 to 20%, from 20 to 40%, from 10 to 40%, from 30 to 40%, from 15 to 30%, including any range between.

[0122] In some embodiments, a w / w ratio between the first inner layer and the second layer within the core is between 5:1 and 1:1, between 5:1 and 2:1, between 5:1 and 3:1, between 3:1 and 1:1, between 4:1 and 1:1, between 4:1 and 2: 1, including any range between.

[0123] In some embodiments, the particle of the invention consists essentially of the hydrophobic compound, the active agent and optionally a mono- saccharide, di- saccharide, and / or poly-saccharide. In some embodiments, the particle of the invention consists essentially of the hydrophobic compound, and the active agent (also referred to herein as “essential components”), wherein a w / w concentration and / or ratio of the essential components within the particle are as described herein. In some embodiments, each of the constituents of the particle is of food, nutraceutical and / or pharmaceutical grade.

[0124] In some embodiments, the particles of the invention significantly improve bioavailability and / or bio-accessibility of the active agent. In some embodiments, the particles of the invention are configured to substantially release the active agent in the gastrointestinal tract of a subject.

[0125] In some embodiments, the particles are hot melt coated particles. In some embodiments, hot-melt coating is performed using a fluidized bed process. In some embodiments, the core of the particle is hot melt coated by the shell material (e.g. the hydrophobic compound) to obtain a weight gain of the coated particle of at least 80%, or between about 80 and about 300%, between 80 and 200%, between 100 and 300%, including any range between.Composition

[0126] In some embodiments, there is provided herein a composition comprising a plurality of particles of the invention. In some embodiments, the composition is a pharmaceutical composition comprising a therapeutically effective amount of the particles of the invention. In some embodiments, the composition is a pharmaceutical composition comprising a therapeutically effective amount of the active agent. In some embodiments, the composition is a nutraceutical composition comprising a nutraceutical effective amount of the particles of the invention. In some embodiments, the composition is a nutraceutical composition comprising a nutraceutical effective amount of the active agent.

[0127] In some embodiments, the composition is a dry composition. In some embodiments, the composition is a powderous composition. In some embodiments, the plurality of particles of the invention are in a form of an agglomerate within the composition (e.g., powderous composition). In some embodiments, the plurality of particles of the invention are in a form of a particle cluster or agglomerate, also referred to herein, as a secondary particle.

[0128] In some embodiments, the particle as described herein is within a composition of the present invention. In some embodiments, the composition of the present invention comprises a solid particle. In some embodiments, the composition of the present invention comprises a stable particle. In some embodiments, the composition comprises an aqueous solution and a particle as described herein. In some embodiments, the composition comprises an aqueous solution and the particle of the invention dispersed therewithin. In some embodiments, the particle and / or the composition of the invention consists essentially of plant-based ingredients. In some embodiments, the particle and / or the composition of the invention consists essentially of food grade ingredients.

[0129] In some embodiments, the composition (e.g. a dry composition) is characterized by an average particle size (e.g. of the primary particles) ranging from 1 to 200 pm, from 1 to 5 pm, from 1 to 10 pm, from 1 to 100 pm, from 10 to 20 pm, from 20 to 50 pm, from 50 to 70 pm, from 70 to 100 pm, from 100 to 200 pm, from 200 to 300 pm, from 300 to 500 pm, includingany range between. In some embodiments, the particle size refers to the dry size of the particles within the composition. In some embodiments, the powderous composition comprises a plurality of secondary particles.

[0130] In some embodiments, the powderous composition further comprises an additive (e.g. a non-bioactive or a non-therapeutic or nutritional additive) or excipient such as anti-caking agent, a desiccant, an antioxidant, a preservative, a cryoprotectant, a bioavailability enhancer, or any combination thereof. In some embodiments, the additive is or comprises a filler (e.g. an organic or an inorganic filler in a form of a particulate matter). In some embodiments, the filler comprises a mono-, a di-, and / or a poly -saccharide.

[0131] In some embodiments, the powderous composition is pressed into tablets for administration. In some embodiments, the powderous composition is formulated in a suspension, a liquid or semiliquid for various administration including internal and topical uses.

[0132] In some embodiments, a w / w concentration of the additive within the composition is between 0.01 and 95% including any range between.

[0133] In some embodiments, the water content of the powderous composition is less than 1, 2, 5 or 10 %w / w.

[0134] In some embodiments, the composition (e.g. a dry composition) is stable (in a form of a powder) for at least 50 d, at least 100 d, at least 200 d, at least 300 d, at least 1 year (y), at least 2 y, at least 3y, including any range or value therebetween.

[0135] In some embodiments, the particles of the invention refers to as “stable” indicates that the particle retains at least about 80%, at least about 90%, at least about 95%, at least about 97% of the initial content of the active agent upon storage thereof at a temperature less than 40°C, or less than 35°C, less than 30°C or at an ambient temperature (between about 20 and about 25°C), and at a relative humidity below 60%, below 50% or below 40% for a time period indicated hereinabove.

[0136] Specifically, the term "stable" (or the term stable particle), including any grammatical form thereof, as used herein indicates that at least 80%, or at least 95% of the initial weight of the active agent remains intact upon storage of the composition under appropriate conditions for at least 1 month, at least 100 d, at least 200 d, at least 300 d, at least 1 year (y), at least 2 y, at least 3y, including any range or value therebetween.

[0137] In some embodiments, a stable particle is substantially devoid of disintegration, agglomeration, and / or release of the active agent. In some embodiments, a stable particle substantially retains its physical and / or chemical properties. In some embodiments, a stable particle substantially retains its structure and / or geometrical shape. In some embodiments, a stable particle substantially retains its size or any other physical parameter. In some embodiments, a stable particle refers to chemical stability of the active agent encapsulated therewithin (e.g., being devoid of oxidation).

[0138] In some embodiments, the particle is stable upon storage under appropriate conditions, for a time period as described herein. In some embodiments, appropriate conditions comprise a temperature of at most 40 °C at most 30 °C at most 10 °C at most 0 °C, at most -10 °C including any range or value therebetween. In some embodiments, appropriate conditions comprise a temperature of between -80 °C and 50 °C, and relative humidity as disclosed herein, including any range or value therebetween.

[0139] In some embodiments, the appropriate conditions comprise storage conditions. In some embodiments, the appropriate conditions comprise on the shelf conditions. In some embodiments, the appropriate conditions comprise the conditions wherein the end user stores or preserves the herein disclosed composition.

[0140] In some embodiments, appropriate conditions comprise conditions wherein at the activity of the herein disclosed composition is preserved or maintained. In some embodiments, appropriate conditions comprise conditions wherein the particle is kept in close and dry conditions (e.g., humidity content below 30%, below 20%, or below 10%, etc.), maintained by the use of vacuum, a separated container of a water scavenger, e.g., silica gel, molecular sieves, or aerosol.

[0141] In some embodiments, appropriate conditions comprise a relative humidity ranging from 10 to 60% including any range or value therebetween.

[0142] In some embodiments, at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% of the particles are stable, wherein stable is as described hereinabove.

[0143] In some embodiments, the composition of the invention comprises a plurality of particles of the invention, and an acceptable carrier. In some embodiments, the acceptable carrier is a pharmaceutically acceptable carrier. In some embodiments, the acceptable carrier is a nutraceutical acceptable carrier. In some embodiments, the acceptable carrier is apharmaceutically acceptable and / or nutraceutical acceptable carrier. In some embodiments, the acceptable carrier is a pharmaceutically acceptable and / or nutraceutical acceptable liquid. In some embodiments, the acceptable carrier is a pharmaceutically acceptable and / or nutraceutical acceptable aqueous solution.

[0144] In some embodiments, the w / w concentration of the carrier within the composition is between 1 and 99% including any range between.

[0145] In some embodiments, the carrier is a physiologically acceptable carrier. In one embodiment, the phrases "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" which be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. An adjuvant is included under these phrases. In one embodiment, "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active agent. In one embodiment, excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0146] In some embodiments, the composition is a liquid composition. In some embodiments, the composition is a semi-liquid or a semi-solid. In some embodiments, the composition is a liquid formulation. In some embodiments, the composition is a suspension. The words “suspension” and “dispersion” are hereby interchangeable. In some embodiments, the particle (e.g., the primary particle and / or the secondary particle) is suspended in an aqueous solution. In some embodiments, the composition is a stable suspension. In some embodiments, the composition is a homogenous suspension or homogenous dispersion. Dispersion / suspension homogeneity can be determined by measuring the concentration of the active agent in a plurality of dispersion / suspension samples. Determining dispersion homogeneity can be done using several methods:Levene's Test: This statistical test assesses the equality of variances for a variable calculated for two or more groups. It is robust against non-normal data.Bartlett's Test: Another statistical test used to examine if multiple samples have equal variances. It is sensitive to departures from normalityPERMDISP (Permutational Analysis of Multivariate Dispersions): This method tests the homogeneity of multivariate dispersions based on any resemblance measure. It is a multivariate extension of Levene's test.ANOVA (Analysis of Variance): Can be used to compare the means of different groups and assess the homogeneity of variances.

[0147] In some embodiments, the particle forms a stable dispersion in an aqueous solvent. In some embodiments, the stable liquid formulation is substantially devoid of a substantial agglomeration of the particles. In some embodiments, the stable dispersion is substantially devoid of precipitation of the particles for at least 10 min, at least Ih, at least 1 week, at least 1 month, at least 1 year or more, including any range between. In some embodiments, the stable dispersion is substantially devoid of precipitation within a time range described herein, when stored under appropriate conditions (comprising inter alia a temperature range of between 10 and 40°C, or less; ambient pressure, and ambient atmosphere).

[0148] In some embodiments, the liquid composition comprises the particles dispersed or distributed in an aqueous solution.

[0149] In some embodiments, the liquid composition comprises an aqueous buffered solution. In some embodiments, the pH value of the liquid composition is at least 3 or ranges from 2 to 8, from 3 to 8, from 3 to 7, from 6.5 to 7, from 6.8 to 7.5, from 3 to 4, from 2.5 to 7.5 or up to 8, or more.

[0150] In another aspect, there is provided a food product comprising the composition (e.g. the plurality of particles of the invention). In some embodiments, the food product is selected from a liquid, a semi-liquid, or a semi-solid. In some embodiments, the food product is in a form of a beverage, a dairy food product, a gel, or any combination thereof. In some embodiments, the composition disclosed herein is a food product.

[0151] In some embodiments, the pH value of the food product ranges from 6.5 to 7, from 6.8 to 7.5, from 2 to 3, from 3 to 4, from 3 to 8, from 2.5 to 7.5 or up to 8, or more, including any range between.

[0152] In some embodiments, pH value of the food product ranges from 6.5 to 7, from 6.8 to 7.5, from 2 to 3, from 3 to 4, from 3 to 8, from 2.5 to 7.5 or up to 8, or more, including any range between, and wherein the particles are substantially stable within the food product for a time period ranging up to 90 days, up to 150 days, up to 200 days, up to 250 days, up to 300 days, up to 350 days, up to 2 years, including any range between; wherein “stable” is as described herein.

[0153] In some embodiments, the particles are stably encapsulating the active agent within the food product for a time period ranging for at least 60d, at least 70d, at least 80d, at least 90d, atleast lOOd, at least 200d, up to 90 days, up to 150 days, up to 200 days, up to 250 days, up to 300 days, up to 350 days, up to 2 years, including any range between; wherein “stable” is as described herein.

[0154] In some embodiments, the food product is a liquid or semi-liquid / semi-solid food product and has a pH value from 6.5 to 7, from 6.8 to 7.5, from 2 to 3, from 3 to 4, from 3 to 8, from 2.5 to 7.5 or up to 8, or more, including any range between, and wherein the food product retains at least 90%, at least 95%, at least 97%, at least 99%, or between 90 and 99%, between 90 and 97%, between 90 and 95% by weight of the initial amount of the active agent encapsulated within the plurality of particles, for a time period of up to 90 days, up to 150 days, up to 200 days, up to 250 days, up to 300 days, up to 350 days, up to 2 years, under appropriate storage conditions (e.g. temperature of the food product below 40C, below 35C, below 30C or between 5 and 25C, between 5 and 30C), including any range between.

[0155] In some embodiments, a w / w concentration of the particles and / or of the composition of the invention within the food product is between 0.1 and 10%, between 1 and 10%, between 0.1 and 1%, between 0.1 and 5%, between 5 and 10%, including any range between.

[0156] In some embodiments, the particles of the invention encapsulating the active agent are configured to mask the undesirable flavor or taste associated with the active agent. In some embodiments, the particles of the invention mask and / or improve the natural taste and / or flavor of the active agent.

[0157] In some embodiments, the food product is substantially devoid of off-taste associated with the active agent. In some embodiments, the food product is substantially devoid of the off- taste for a time period of up to 90 days, up to 150 days, up to 200 days, up to 250 days, up to 300 days, up to 350 days, up to 2 years upon manufacture date of the food product. In some embodiments, the off-taste refers to unpleasant taste and / or flavor associated with the active agent. In some embodiments, the off-taste refers to organoleptic property (e.g. taste, smell, appearance etc.) of the active agent. The taste of the food product can be evaluated using well- known methods, such as a taste test.

[0158] In some embodiments, the composition and / or the food product is for supplementing a subject with a nutraceutical. In some embodiments, the composition and / or the food product is for use in the administration of a therapeutically active agent to a subject in need thereof.

[0159] In some embodiments, the food product is configured to release at least 70%, at least 75%, at least 80%, at least 85%, at least 90% of the initial active agent loading within a timeperiod of at least 5min, at least lOmin, at least 20 min, at least 30 min, between 5 and 500min, between 10 and 400min, between 10 and 300min, including any range between; and wherein the release is determined by simulated digestion method.Methods of use

[0160] In another aspect, the present invention is directed to a method for enhancing bioaccessibility of an active agent. In some embodiments, the method for enhancing bioaccessibility of an active agent comprises administering the particles or the composition (e.g. the food article) of the invention to a subject in need thereof, thereby increasing bioaccessibility of the active agent within the subject. In some embodiments, the method for enhancing bioavailability of an active agent comprises administering the composition of the invention to a subject in need thereof, thereby increasing bioavailability of the active agent within the subject. In some embodiments, the method for enhancing bioavailability of an active agent comprises administering the food article of the invention to a subject in need thereof, thereby increasing bioavailability of the active agent within the subject. In some embodiments, the composition and / or the food article comprises any of the particles of the invention. In some embodiments, the active agent is as described herein.

[0161] The term “bioaccessibility” as used herein, is directed to ability to release an active agent in-vitro by any one of the particles of the present invention and / or by a food article comprising same. The in-vitro release can be evaluated by using a protocol of simulated digestion.

[0162] In some embodiments, the composition of the present invention enhances the bioaccessibility of an active agent.

[0163] In some embodiments, increasing or enhancing is by at least 50%, at least 70%, at least 100%, at least 150%, at least 200%, at least 300%, at least 500%, at least 400%, at least 450%, at least 500%, at least 550%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1000% as compared to the bioaccessibility of the non-encapsulated active agent .

[0164] In some embodiments, there is a method of supplementing a subject with an active agent , comprising the step of administering to a subject the food product of the present invention. In some embodiments, the method comprises administering to a subject the composition of the present invention.

[0165] In some embodiments, a subject is a human. In some embodiments, a subject is a pet. In some embodiments, a subject is a farm animal. In some embodiments, a subject is a rodent. In some embodiments, a subject is an infant. In some embodiments, a subject is a toddler.

[0166] In some embodiments, the present invention further provides a method of supplementing a subject with a nutraceutical as an active agent, comprising the step of administering to a subject a food product comprising the particles of the present invention. In some embodiments, the food product is administered orally.

[0167] In some embodiments, a nutraceutical is any non-toxic food component which has demonstrated health benefits. In some embodiments, a nutraceutical is any sparingly water soluble, non-toxic food component, which has demonstrated health benefits. In some embodiments, a nutraceutical is any fat soluble, non-toxic food component, which has demonstrated health benefits.General

[0168] As used herein, the terms “treatment” or “treating” of a disease, disorder, or condition encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured. To be an effective treatment, a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life.

[0169] As used herein, the term “prevention” of a disease, disorder, or condition encompasses the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter, the term "prevention" relates to a process of prophylaxis in which a subject is exposed to the presently described active agents prior to the induction or onset of the disease / disorder process. This could be done where an individual has a genetic pedigree indicating a predisposition toward occurrence of the disease / disorder to be prevented. For example, this might be true of an individual whose ancestors show a predisposition toward certain types of inflammatory disorders.

[0170] The term "suppression" is used to describe a condition wherein the disease / disorder process has already begun but obvious symptoms of the condition have yet to be realized. Thus, the cells of an individual may have the disease / disorder, but no outside signs of the disease / disorder have yet been clinically recognized. In either case, the term prophylaxis can be applied to encompass both prevention and suppression.

[0171] In some embodiments, the term “reducing”, or “enhancing” including any grammatical from thereof relates to at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% reduction / enhancement (e.g. of enzymatic activity), compared to a control or a baseline, including any range between.

[0172] Conversely, the term "treatment" refers to the clinical application of active agents to combat an already existing condition whose clinical presentation has already been realized in a patient.

[0173] In the discussion unless otherwise stated, adjectives such as “substantially” and “about” modifying a condition or relationship characteristic of a feature or features of an embodiment of the invention, are understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of, or any combination of items it conjoins.

[0174] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a”, “an” and “at least one” are used interchangeably in this application.

[0175] As used herein the term “about” refers to ± 10 %.

[0176] The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.

[0177] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0178] In the description and claims of the present application, each of the verbs, “comprise”, “include”, and “have” and conjugates thereof, are used to indicate that the object or objects ofthe verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.

[0179] Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0180] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive.

[0181] Throughout this specification and claims, the word “comprise” or variations such as “comprises” or “comprising” indicate the inclusion of any recited integer or group of integers but not the exclusion of any other integer or group of integers.

[0182] As used herein, the term “consists essentially of’ or variations such as “consist essentially of’ or “consisting essentially of’ as used throughout the specification and claims, indicate the inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers that do not materially change the basic or novel properties of the specified method, structure, or composition.

[0183] As used herein, the terms "comprises", "comprising", "containing", "having" and the like can mean "includes", "including", and the like; "consisting essentially of or "consists essentially" likewise has the meaning ascribed in U.S. patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0184] In one embodiment, the terms "comprises" "comprising", and "having" are / is interchangeable with "consisting".

[0185] Unless otherwise indicated, the word “or” in the specification and claims is considered to be the inclusive “or” rather than the exclusive or, and indicates at least one of, or any combination of items it conjoins.

[0186] It should be understood that the terms “a” and “an” as used above and elsewhere herein refer to “one or more” of the enumerated components. It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated otherwise. Therefore, the terms “a”, “an” and “at least one” are used interchangeably in this application.

[0187] For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0188] Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0189] In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the nature of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses can be extrapolated from dose-response curves derived from in-vitro or in-vivo animal model test bioassays or systems.

[0190] As used herein, the terms “administering”, “administration”, and like terms refer to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect.

[0191] For oral applications, the pharmaceutical composition may be in the form of tablets or capsules, which can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide. When the dosage unit form is a capsule, it can contain an excipient, in addition to materials listed above. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The tablets of the invention can further be film coated. In some embodiment, oral application of the pharmaceutical composition may be in the form of drinkable liquid. In some embodiment, oral application of the pharmaceutical composition may be in the form of an edible product.

[0192] In some embodiments, the present invention provides combined preparations. In some embodiments, “a combined preparation” defines especially a “kit of parts” in the sense that thecombination partners as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners i.e., simultaneously, concurrently, separately or sequentially. In some embodiments, the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. The ratio of the total amounts of the combination partners, in some embodiments, can be administered in the combined preparation. In some embodiments, the combined preparation can be varied, e.g., in order to cope with the needs of a patient subpopulation to be treated or the needs of the single patient which different needs can be due to a particular disease, severity of a disease, age, sex, or body weight as can be readily made by a person skilled in the art.

[0193] In some embodiments, depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is affected or diminution of the disease state is achieved.

[0194] In some embodiments, the composition of the preset invention is administered in a therapeutically safe and effective amount. As used herein, the term “safe and effective amount” refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects, including but not limited to toxicity, such as calcemic toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio when used in the presently described manner.

[0195] In some embodiments, toxicity and therapeutic efficacy of the active agents described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. In some embodiments, the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. In some embodiments, the dosages vary depending upon the dosage form employed and the route of administration utilized. In some embodiments, the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13thEd., McGraw-Hill / Education, New York, NY (2017)].

[0196] In some embodiments, compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0197] In some embodiments, compositions of the present invention are presented in a pack or dispenser device, such as an FDA approved kit, which contains, one or more unit dosages forms containing the active agent. In some embodiments, the pack, for example, comprises metal or plastic foil, such as a blister pack. In some embodiments, the pack or dispenser device is accompanied by instructions for administration. In some embodiments, the pack or dispenser is accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, in some embodiments, is labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

[0198] Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0199] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0200] In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the nature of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses can be extrapolated from dose-response curves derived from in-vitro or in-vivo animal model test bioassays or systems.

[0201] As used herein, the terms “administering”, “administration”, and like terms refer to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect.

[0202] For oral applications, the pharmaceutical composition may be in the form of tablets or capsules, which can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide. When the dosage unit form is a capsule, it can contain an excipient, in addition to materials listed above. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The tablets of the invention can further be film coated. In some embodiment, oral application of the pharmaceutical composition may be in the form of drinkable liquid. In some embodiment, oral application of the pharmaceutical composition may be in the form of an edible product.

[0203] In some embodiments, the present invention provides combined preparations. In some embodiments, “a combined preparation” defines especially a “kit of parts” in the sense that the combination partners as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners i.e., simultaneously, concurrently, separately or sequentially. In some embodiments, the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts. The ratio of the total amounts of the combination partners, in some embodiments, can be administered in the combined preparation. In some embodiments, the combined preparation can be varied, e.g., in order to cope with the needs of a patient subpopulation to be treated or the needs of the single patient which different needs can be due to a particular disease, severity of a disease, age, sex, or body weight as can be readily made by a person skilled in the art.

[0204] In some embodiments, depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is affected or diminution of the disease state is achieved.

[0205] In some embodiments, the composition of the preset invention is administered in a therapeutically safe and effective amount. As used herein, the term “safe and effective amount” refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects, including but not limited to toxicity, such as calcemic toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio when used in the presently described manner.

[0206] In some embodiments, toxicity and therapeutic efficacy of the active agents described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. In some embodiments, the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. In some embodiments, the dosages vary depending upon the dosage form employed and the route of administration utilized. In some embodiments, the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. [See e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13thEd., McGraw-Hill / Education, New York, NY (2017)].

[0207] In some embodiments, compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0208] In some embodiments, compositions of the present invention are presented in a pack or dispenser device, such as an FDA approved kit, which contains, one or more unit dosages forms containing the active agent. In some embodiments, the pack, for example, comprises metal or plastic foil, such as a blister pack. In some embodiments, the pack or dispenser device is accompanied by instructions for administration. In some embodiments, the pack or dispenser is accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, in some embodiments, is labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.EXAMPLES

[0209] The inventors successfully manufactured micron-sized core-shell particles disclosed herein by coating the active agent (e.g. salix or caffeine) core with a water barrier shell comprising a hydrophobic agent (e.g. stearic acid). An exemplary manufacturing process is described in Example 1.EXAMPLE 1

[0210] The inventors successfully manufactured micron-sized core-shell particles disclosed herein by coating the active agent (e.g. salix or caffeine) core with a water barrier shell comprising a hydrophobic agent (e.g. stearic acid). An exemplary manufacturing process is described hereinbelow.General Procedure A1. Preparation of the core:Sugar spheres, 100-200 pm in size, were coated in a fluid bed coater using the coating solution above.Preparation of the drug layer2.1. Preparation of the coating dispersion: 200-300 g of modified starch were dissolved in about 2000 g of hot water. About 1000 g of Salix (50% Salicin) were added and stirred until completely dissolved. Subsequently, 30-40 g g of mono-glycerol stearate and 10- 20 g of Tween surfactant were added, mixed and the solution was emulsified with a homogenizer. 2000 g of cold water were added, and the solution was cooled to 50 °C.2.2. The spheres from step 1.2 were coated in a fluid bed coater using the coating dispersion from 2.1. so as to result in Salix content of about 30% within the sphere.2. Preparation of the hydrophobic (waterproof) coating layer.

[0211] The Salix spheres from step 2.2 were hot melt coated with stearic acid, as follows. End weight gain was about 100% - 200%. Hot melt coating was performed using a Huttlin Solidlab fluid bed coater equipped with an additional system for working with melting coating materials. The main parameters were as follows:General Procedure B

[0212] Granular Caffeine crystals (200-500microns) were hot melt coated with melted stearic acid in a fluid bed coater. End weight gain was 100- 200%. Hot melt coating was performed using a Huttlin Solidlab fluid bed coater equipped with an additional system for working with melting coating materials. The main parameters were as follows:

[0213] Alternatively, the inventors successfully performed encapsulation by sunflower wax, to result in water-stable particles. The main parameters were as follows:

[0214] The particles encapsulating Salix or Caffeine have been further analyzed by SEM, in order to evaluated it’s structure and morphology. Exemplary SEM images of the tested particles are presented in Figures 1A-F.

[0215] As demonstrated by the SEM micrographs (Figures 1A-D), the particles of the invention are characterized by a smooth outer surface, substantially devoid of pores and / or mesh-like shell. In contrast, particles obtained by a similar method without subsequent atomization (also used herein as “control particles) have been characterized by enhanced porosity and by a meshlike structure of the particle’s surface (see Figures 1E-F).

[0216] Additionally, as presented by Figure IF, control particles have been characterized by a plurality of pores with a pore size ranging between 3-10 um, whereas the exemplary particles of the invention exhibited surface defects (or craters) with sub-micron cross-section ranging from several nanometers up to about 1 um.EXAMPLE 2

[0217] Subsequently, the aqueous stability of the exemplary particles of the invention has been tested and compared to control particles, as described herein below. It was surprisingly found that the particles of the invention exhibit very high aqueous stability of at least 200 days. In contrast, the control particles underwent fast decomposition under similar conditions.

[0218] Exemplary particles prepared according to the General Procedure B and encapsulating Salix or caffeine respectively, were placed in a phosphate buffer (pH 4) and stored at room temperature (RT) and at 2-8°C. Samples from the water solution were taken by filtration. The concentration of the released active agent (Salix or caffeine) into the water was analyzed periodically by HPLC. Test results are presented in the Figures 2A-B.

[0219] As can be seen from the release tests (Figure 2A-B), the particles remained stable in the aqueous solution within the tested time period. Further tests confirmed even longer aqueous stability of the tested particles at 2-8°C and at RT (for at least 200 days). Based on the experimental results, the particles stably encapsulate the active agent (showing a negligible release of the active agent below about 5%w / w).

[0220] Furthermore, the inventors tested the effect of the weight gain on the aqueous stability of the particles of the invention. As shown in Figure 3, a weight gain of 80% (corresponding toa weight ratio between the core and the shell of 0.8:1) resulted in particles with sufficient aqueous stability (equal or greater than 90 days) at pH 3.

[0221] Similar results were obtained using sunflower wax as the shell material. Here, in order to obtain particles with extremely high aqueous stability, a somewhat higher weight gain was required (higher than 120%). Although, if the stability requirement is lowered to about 30 days, particles with a weight gain of 80% can also be used.

[0222] Furthermore, the release profile of the active agent form the exemplary particles of the invention has been tested using a simulated digestion test (based on M. Minekus M. and Alminger et al. A standardized static in-vitro digestion method suitable for food - an international consensus, Food Funct., 2014, DOI: 10.1039 / C3F060702J). In brief, particles were incubated in a solution simulating gastric fluid (aqueous solution including Pepsin (2000U / ml), Pancreatin 4xUSP (Protease 100U / ml)).

[0223] In-vitro simulation of the release of an encapsulated active ingredient during passage through the gastrointestinal tract is carried out in a standard dissolution apparatus. During the test, pH and fermentation conditions are adjusted, and a surfactant (0.25%) SDS is added according to the table below.

[0224] At each timepoint the concentration of the active agent (caffeine) in the simulated gastric solution was determined by HPLC.

[0225] The results of the dissolution experiment are summarized in Figure 4. As shown in Figure 4, even the particles with the greatest tested weight gain of 120% substantially released the active agent (80% release) under the tested conditions within a time period of 150 min. accordingly the particles of the invention have prolonged stability in an aqueous medium (especially acidic medium) and can be implemented for supplementing a subject with an active agent (a nutraceutical or a drug).

[0226] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0227] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

CLAIMS1. A composition comprising a plurality of particles, each particle comprising a core and a shell, wherein the core comprises an active agent and is encapsulated by the shell; wherein: the plurality of particles is characterized by an average particle size between 10 and 1000 um; said shell comprises a hydrophobic compound comprising a fatty acid, a fatty acid ester, a wax, plant fat, hydrogenated plant oil, including any salt or any combination thereof; a weight ratio between the shell and the core within said particle is at least about 0.8:1 ; and said active agent is selected from a food supplement and a pharmaceutically active agent, or both.

2. The composition of claim 1, wherein said hydrophobic compound is a solid at a temperature below 30°C and is characterized by a melting temperature between 40 and 100°C.

3. The composition of claim 1 or 2, wherein said hydrophobic compound is or comprises any one of: the fatty acid and the wax, wherein the wax is a plant wax.

4. The composition of any one of claims 1 to 3, wherein said fatty acid is a saturated fatty acid being between 16 and 20 carbon long.

5. The composition of claim 4, wherein at least 90% by weight of said shell consists of the saturated fatty acid and wherein a w / w ratio between the saturated fatty acid and the core is between about 0.8: 1 and about 3:1.

6. The composition of claim 5, wherein a w / w ratio between the saturated fatty acid and the core is between about 1: 1 and about 3:1.

7. The composition of claim 5 or 6, wherein said saturated fatty acid is or comprises stearic acid.

8. The composition of claim 7, wherein a w / w ratio between the stearic acid and the core is between about 1: 1 and about 3: 1.

9. The composition of claim 3, wherein the plant wax is selected from sunflower wax, carnauba wax, candelilla wax, soy wax and palm wax, including any combinations thereof.

10. The composition any one of claims 1 to 9, wherein said active agent is a solid at a temperature of between 2 and 30C.

11. The composition any one of claims 1 to 10, wherein said active agent is a natural compound.

12. The composition of claim 11, wherein the natural compound is a nutraceutical.

13. The composition any one of claims 1 to 10, wherein said active agent is a drug.

14. The composition of any one of claims 1 to 13, wherein said plurality of particles is characterized by an average particle size between 100 and 700 um, and wherein a weight ratio between the shell and the core within said particle is between about 1: 1 and about 3: 1 wherein each of said plurality of particles is a solid particle at a temperature of at least 25C; and wherein each of the core and the shell of said solid particle is a solid at a temperature of at least 25C.

15. The composition of any one of claims 1 to 14, wherein said shell is characterized by an average pore size in a range between lOnm and lOum.

16. The composition of any one of claims 1 to 15, wherein a weight portion of the active agent within each of the plurality of particles is between 5 and 50%.

17. The composition of any one of claims 1 to 16, wherein said core is a multi-layered core comprising a first inner layer in contact with a second layer facing and / or in contact with the shell, wherein the second layer comprises the active agent; and wherein the first inner layer consists essentially of a water soluble material.

18. The composition of claim 17, wherein a w / w ratio between the first inner layer andthe second layer is between 5 : 1 and 1:1, and wherein a weight portion of the active agent within the particle is between 5 and 50%.

19. The composition of claim 17 or 18, wherein said water soluble material is a natural compound and wherein the first inner layer consists of the water soluble material.

20. The composition of any one of claims 17 to 19, wherein the water soluble material comprises any one of: a mono-saccharide, a di-saccharide, and a polysaccharide including any mixture thereof; and wherein each of the first inner layer and the second layer is a solid at a temperature of at least 25C.

21. The composition of any one of claims 1 to 20, wherein said shell further comprises an additional outer layer comprising a film forming agent.

22. The composition of any one of claims 1 to 21, wherein said plurality of particles are composed essentially of food grade or pharmaceutical grade constituents.

23. The composition of any one of claims 11 to 22, wherein the natural compound is or comprises any one of: a carotenoid, a natural phenol, a vitamin, an alkaloid, a terpene, a cannabinoid, a polyunsaturated fatty acid salt, a phytosterol, an isoflavone, a polysaccharide, an anthocyanin and taurine, including any salt or any combination thereof.

24. The composition of any one of claims 9 to 23, wherein at least 90% by weight of said shell consists of the plant wax and wherein a w / w ratio between the plant wax and the core is between 1.2:1 and 3:1.

25. The composition of any one of claims 1 to 24, wherein the plurality of particles stably encapsulates the active agent in an aqueous solution for a time period of at least 90 days; and wherein said stably encapsulate comprises release of the active agent into said aqueous solution below 10% at a temperature between 20 and 25C.

26. The composition of claim 25, wherein the aqueous solution is an acidic solution having a pH value of at least 3.

27. The composition of any one of claims 1 to 26, wherein said active agent is characterized by unpleasant taste, and wherein the composition is for masking the unpleasant taste of the active agent.

28. A food product comprising the composition or the plurality of particles of any one of claims 1 to 27.

29. The food product of claim 28, wherein a w / w concentration of the composition within the liquid food product is between 0.1 and 10%, wherein the food product is selected from a beverage, a dairy food product, a gel, or any combination thereof.

30. The food product of claim 28 or 29, wherein the food product retains at least 90% of the initial amount of the active agent encapsulated within the plurality of particles, for a time period of at least 200 days at a temperature below 30C, optionally wherein the food product has a pH value of at least 3.

31. The food product of any one of claims 28 to 30, wherein said food product is substantially devoid of off-taste associated with the active agent.

32. The food product of any one of claims 28 to 31, wherein said plurality of particles are homogenously dispersed within said food product.

33. A method of supplementing a subject with an active agent, the method comprising administering to said subject the composition or the plurality of particles of any one of claims 1 to 27, or the food product of any one of claims 28 to 32.

34. The method of claim 33, wherein said method is for a targeted delivery of the active agent to the gastrointestinal tract of said subject.

35. The method of claim 34, wherein at least 70%w / w of the initial loading of said active agent is released within the gastrointestinal tract.

36. The method of claim 35, wherein said released comprises a residence time period ofbetween 10 min and 500 min within said gastrointestinal tract.

37. The method of any one of claims 33 to 36, wherein said method comprising administering to said subject a nutritionally or a therapeutically effective amount of the particles, or of the food product.

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