Formulations for encapsulation of bioactive compounds

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

FORMULATIONS FOR ENCAPSULATION OF BIOACTIVE COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 575,891, titled "FORMULATIONS FOR ENCAPSULATION OF BIO ACTIVE COMPOUNDS", filed April 08, 2024. The contents of which are incorporated herein by reference in their entirety.FIELD OF INVENTION

[0002] The present invention provides a formulation for improving solubilization of hydrophobic and lipophilic compounds.BACKGROUND OF THE INVENTION

[0003] Numerous bioactive compounds, including nutraceuticals and drugs, are poorly bioavailable, due to their poor solubility, and often also due to the action of either efflux transporters, like P-gp, or of detoxification enzymes, like Cytochrome P 450 enzyme family, or both.

[0004] Curcumin, for example, is a natural polyphenol compound, found in the turmeric plant. Curcumin aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia. Most of these benefits can be attributed to its antioxidant and anti-inflammatory effects. A major limitation of curcumin is a low bioaccessibility and bioavailability, which stems from the fact that the compound is almost insoluble in an aqueous solution.

[0005] Encapsulation is an expanding technology, with great potential in several areas, including the pharmaceutical and food industries. The delivery of bioactive compounds into the human body is highly affected by particle size, thus nanoencapsulation is an option to enhance bioavailability of such compounds. Encapsulation of bioactive components, with poor solubility in aqueous solutions, can improve their dispersibility in water, and therefore also their bioavailability and bioactivity.

[0006] Lecithin (LEC) is a mixture of several phospholipids containing mainly phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. LEC is absorbed in the human body as a lipid, assisted by bile salts. The presence of fat, fatty acids and lipidsin the formulation increases the excretion of bile salts, thus it may enhance the bioavailability of curcumin and other water-insoluble compounds.

[0007] Various encapsulation technologies have been found to be effective in protecting the encapsulated bioactive during thermal treatment, exposure to UV or visible light, low pH, and during prolonged storage. However, there is still lack of non-alcohol based formulations characterized by improved dispersibility, and are suitable for the food or pharmaceutical industry.

[0008] To improve the bioavailability of curcumin and additional water-insoluble compounds, several approaches were evaluated in order to find appropriate biomaterials, which would solubilize or disperse hydrophobic compounds in water, and facilitate its intestinal absorption. To end, most of these approaches are based on the utilization of an organic solvent, such as ethanol, within the liquid formulation. There is a need for development of non-organic solvent based formulation for solubilization of water insoluble compounds.SUMMARY OF THE INVENTION

[0009] The invention in one aspect thereof, relates to a composition comprising a plurality of particles, each of the particles comprises an inner portion in contact with an outer portion, wherein: the outer portion comprises a polysaccharide a derivative thereof, or both; the inner portion comprises a hydrophobic compound, a phospholipid and a surfactant; a w / w concentration of the phospholipid within the particle ranges from 5 to 60%; a w / w concentration of the surfactant within the particle ranges from 1 to 10%; a w / w concentration of the polysaccharide within the particle ranges from 5 to 40%, and wherein the composition is characterized by an average particle size of between 50 and 800 nm.

[0010] In one embodiment, the hydrophobic compound has a low solubility in an aqueous solution and is optionally selected from the group consisting of: a phenolic compound, a tannin, a stilbene, a curcuminoid, a coumarin, a lignan, a quinone, or any combination thereof.[Oi l] In one embodiment, the outer portion is in a form of a shell encapsulating the inner portion.

[0012] In one embodiment, a w / w ratio of the phospholipid to the hydrophobic compound ranges from 4: 1 to 2: 1; and wherein the phospholipid is or comprises a plant-based phospholipid.

[0013] In one embodiment, a w / w ratio of the polysaccharide to the hydrophobic compound ranges from 3: 1 to 1:3.

[0014] In one embodiment, the phospholipid comprises a phosphatidylcholine, a lecithin, or both.

[0015] In one embodiment, the lecithin comprises sunflower lecithin, soybean lecithin, or a combination thereof; and wherein the phosphatidylcholine is or comprises a sunflower phosphatidylcholine.

[0016] In one embodiment, the polysaccharide comprises a starch, a modified starch, dextrin, Xanthan gum, Gum Arabic, chitosan, cellulose, carboxymethyl cellulose, alkylated cellulose (e.g. methyl cellulose, hydroxypropyl methyl cellulose (HPMC)), nitrocellulose, alginate, pectin, including any salt, any combination, or any copolymer thereof.

[0017] In one embodiment, the hydrophobic compound comprises the curcuminoid, and the polysaccharide comprises the HPMC.

[0018] In one embodiment, the surfactant comprises a cationic surfactant, an anionic surfactant, a non-ionic surfactant, or any combination thereof.

[0019] In one embodiment, the particle is configured to form a stable dispersion in an aqueous solution.

[0020] In one embodiment, the composition further comprising an aqueous solution, wherein the hydrophobic compound is at a concentration of 0.001 to 10%w / v in the composition.

[0021] In one embodiment, the particles are configured to release the hydrophobic compound in the gastrointestinal tract of a subject.

[0022] In another aspect, there is provided a method of supplementing a subject with a hydrophobic compound, comprising the step of administering to the subject a composition of the invention, thereby supplementing the subject with the hydrophobic compound.

[0023] In one embodiment, supplementing further comprises enhancing bioavailability of the hydrophobic compound.

[0024] In one embodiment, the subject is selected from a human subject and an animal subject.

[0025] In one embodiment, administering comprises oral administration.

[0026] In one embodiment, supplementing comprises releasing at least a portion of the hydrophobic compound within the gastrointestinal tract of the subject.

[0027] 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.

[0028] 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

[0001] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0002] Fig. 1. is a graph representing water solubility of curcumin-based particles at different curcumin to lecithin ratios. The particles further contained Tween 80 and modified starch.

[0003] Fig. 2. is a graph representing water solubility of curcumin-based particles including Tween 80 or SDS as the surfactant. Curcumin: lecithin ratio is 1:2.

[0004] Fig. 3. is a graph representing water solubility of curcumin-based particles including HPMC (Hypromellose) or modified starch as the polysaccharide. Curcumin decithin ratio is 1 :2.

[0005] Fig. 4. is a graph representing water solubility of quercetin-based particles including modified starch as the polysaccharide and Tween 80. Quercetin: lecithin ratio is 1:2.

[0006] Fig. 5. is a graph representing water solubility of resveratrol-based particles including modified starch as the polysaccharide and Tween 80. Resveratrol: lecithin ratio is 1:2.DETAILED DESCRIPTION OF THE INVENTION

[0029] The invention relates to a particle comprising a polysaccharide shell and encapsulating water-insoluble compound(s), and a composition comprising same. The invention further relates to methods of preparation thereof, and methods for using same, such as for supplementing a subject with a water-insoluble compound.

[0030] The present invention is directed, in one embodiment thereof, to a particle (e.g. a particle in a solid state) comprising a polysaccharide a derivative thereof, or both; a hydrophobic compound; a phospholipid; and a surfactant. In another embodiment, provided herein a composition or a kit comprising a particle as described herein. In one embodiment, the particle is a water-dispersible particle. In one embodiment, the particle is a solid particle and consists of a shell and a core.

[0031] In one aspect, there is provided herein a particle (e.g. a nano-particle), comprising a hydrophobic core and a shell, wherein the hydrophobic core comprises a hydrophobic compound, and a phospholipid, wherein the shell comprises polysaccharide and / or a derivative thereof, wherein the shell, and / or the core comprises a surfactant; and wherein a weight / weight (w / w) concentration of the phospholipid within the particle ranges from 5 to 40%. In some embodiments, the shell is amphiphilic. In some embodiments, a w / w concentration of the surfactant within the particle ranges from 1 to 10%. In some embodiments, a w / w concentration of the polysaccharide within the particle ranges from 5 to 40%. In some embodiments, the particle is a nano-particle. In some embodiments, the hydrophobic core of the particle is in a form of a micelle.

[0032] In another embodiment, there is provided herein a composition comprising a plurality of particles of the invention, wherein an average particle size (e.g. particle size of the dry powder) of the composition is between 50 and 800 nm.

[0033] In another embodiment, provided herein is a method for solubilizing a hydrophobic compound encapsulated within a particle in an aqueous solution, comprising contacting an aqueous solution with the particles as described herein.

[0034] In some embodiments, the present invention provides a method for enhancing the bioavailability of a hydrophobic compound in a subject, by administering a composition as described herein to the subject.Particle

[0035] 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.

[0036] In some embodiments, the hydrophobic core is in a solid state at a room temperature (e.g. between 15 and 35C). In some embodiments, the hydrophobic core comprises a hydrophobic compound, a phospholipid, and optionally a surfactant. In some embodiments, the hydrophobic compound is in contact with the phospholipid. In some embodiments, the hydrophobic compound is bound to the phospholipid. In some embodiments, the hydrophobic compound and the phospholipid are stably bound to each other within the particle. In some embodiments, the hydrophobic compound and the phospholipid are bound via non-covalent interactions.

[0037] In some embodiments, the hydrophobic core is in a form of a micelle. In some embodiments, the micelle comprises an inner portion comprising the hydrophobic compound and the phospholipid; and an outer portion. In some embodiments, the outer portion comprises the surfactant and optionally further comprises the phospholipid.

[0038] In some embodiments, the particle and / or the composition of the invention is substantially devoid of ethanol.

[0039] In some embodiments, the shell is a single layer shell. In some embodiments, the amphiphilic shell is a multi-layer shell. In some embodiments, the amphiphilic shell comprises a first inner portion facing the core and a second outer portion facing the ambient.

[0040] In some embodiments, the shell comprises a polymer (e.g., a hydrophilic polymer). In some embodiments, the shell comprises a polysaccharide. In some embodiments, the shellof the particle comprises a single polysaccharide specie, or a plurality of chemically distinct a polysaccharide species. In some embodiments, the shell further comprises a surfactant.

[0041] In some embodiments, the shell substantially retains the shape of the particle within a liquid (e.g. an aqueous solution). In some embodiments, the polysaccharide stabilizes the core. In some embodiments, the polysaccharide is amphiphilic. In some embodiments, the shell substantially preserves the hydrophobic compound. In some embodiments, the shell enhances solubilization of the particle within a liquid (e.g. an aqueous solution). In some embodiments, the shell stabilizes the particle within a liquid (e.g. an aqueous solution). In some embodiments, the polysaccharide enhances mechanical stability (e.g. strength or rigidity) of the particle. In some embodiments, the polysaccharide enhances stability of the particle within a liquid (e.g. an aqueous solution). In some embodiments, the shell substantially prevents from dissociation or degradation of the particle within an aqueous solution. In some embodiments, the shell enhances dispersibility of the particle. In some embodiments, the shell enhances stability (e.g. storage stability) of an aqueous dispersion comprising the particles of the invention.

[0042] In some embodiments, the shell comprises a single layer, comprising the surfactant and the polysaccharide. In some embodiments, the polysaccharide and the surfactant and mixed (e.g. homogenously distributed) within the shell.

[0043] In some embodiments, the shell comprises a first layer or an inner portion (i.e., surrounding the core) in contact with or facing the core. In some embodiments, the shell comprises a second layer or an outer portion in contact with or facing the ambient. In some embodiments, the outer portion is bound to the inner portion. In some embodiments, the outer portion is on top of the inner portion. In some embodiments, the inner portion comprises the surfactant, and the outer portion comprises the polysaccharide.

[0044] In some embodiments, the hydrophobic segment of the inner layer is in contact with the hydrophobic core of the particle. In some embodiments, the hydrophilic segment of the outer layer faces an aqueous solution, thus stabilizing the particle in the solution.

[0045] In some embodiments, the phospholipid is or comprises a single phospholipid specie. In some embodiments, the phospholipid is or comprises a mixture of distinct phospholipid species.

[0046] In some embodiments, the phospholipid is or comprises a lecithin, a phosphatidylcholine, or a mixture thereof. In some embodiments the phospholipid is isolatedform a plant or a plant part. In some embodiments the phospholipid is derived form a plant or a plant part (e.g., isolated and further processed, such as by hydrogenation or hydrolysis, to obtain a chemically modified phospholipid). In some embodiments, the phospholipid isolated and / or derived from a plant source is also referred to herein as a plant-based phospholipid. In some embodiments, the plant -based phospholipid (or any plant-based or food grade ingredient disclosed herein) is a 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.

[0047] 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.

[0048] In some embodiments, the phospholipid surfactant is water soluble or water dispersible. In some embodiments, the surfactant is a de-oiled lecithin. In some embodiments, the surfactant is or comprises sunflower lecithin, sunflower phosphatidylcholine, or both. In some embodiments, the surfactant is de-oiled sunflower lecithin. Further non-limiting examples of lecithin include but are not limited to: Sunflower lecithin, phosphatidylcholine content > 90 % , Sunflower lecithin, phosphatidylcholine content > 60 %, Soybean lecithin, phosphatidylcholine content > 45 %, Soybean lecithin, phosphatidylcholine content > 90%.

[0049] In some embodiments, the polysaccharide comprises a starch, dextrin, Xanthan gum, Gum Arabic, chitosan, cellulose, alginate, pectin, including any salt, any combination, or any copolymer thereof.

[0050] In some embodiments, a derivative of the polysaccharide refers to a chemically or enzymatically modified polysaccharide, and / or to a hydrolysate thereof. In some embodiments, a derivative of the polysaccharide refers to a polysaccharide which underwent a physical, chemical, or biological treatment.

[0051] Non-limiting examples of polysaccharide derivatives include but are not limited to: modified starch, alkylated starch, esterified starch, acetylated starch, cationic starch, starch acetate, carboxymethyl cellulose, alkylated cellulose, nitrocellulose, or any combination thereof.

[0052] Modified starch is a type of starch that has been physically, enzymatically, or chemically treated to change its properties. These modifications enhance the starch's performance in various applications, such as increasing its stability against heat, acid, and shear, or altering its texture and viscosity. Non-limiting examples of Modified Starch include Acid-treated starch (INS 1401): Treated with inorganic acids to reduce viscosity; Oxidized starch (INS 1404): Treated with oxidizing agents like sodium hypochlorite to break down viscosity.

[0053] In some embodiments, a polysaccharide is or comprises a hydrophobic starch. In some embodiments, a polysaccharide is or comprises a hydrophobic maize starch. In some embodiments, a polysaccharide is or comprises a starch modified with 2-Octen-l-ylsuccinic anhydride. In some embodiments, the polysaccharide is water soluble or water dispersible polysaccharide.

[0054] In some embodiments, the polysaccharide is characterized by a molecular weight between 104and 107g / mol, between 104and 105g / mol, between 105and 106g / mol, between 106and 107g / mol, including any range between.

[0055] In some embodiments, the core comprises the hydrophobic compound as described hereinbelow. In some embodiments, the core comprises the hydrophobic compound and the phospholipid, and optionally comprises the surfactant. In some embodiments, the surfactant is at least partially located at the interface between the core and the shell.

[0056] In some embodiments, the surfactant (e.g. a hydrophobic portion thereof) is in contact with the hydrophobic core (e.g. the hydrophobic compound and the phospholipid). In some embodiments, the surfactant (e.g. a hydrophilic portion thereof) is in contact with the shell.

[0057] In some embodiments, the surfactant is food-grade surfactant. In some embodiments, a surfactant comprises a non-ionic surfactant, a cationic surfactant, an anionic surfactant or any combination thereof.

[0058] In some embodiments, the term "anionic surfactant" refers to any surfactant containing a lipophilic tail (e.g. a carbohydrate, for example C10-C30 alkyl) and an anionic functional group including sulfate, sulfonate, phosphate, and carboxylate. In some embodiments, the anionic surfactant is or comprises a C10-C30 alkyl-sulfate (e.g. sodium dodecyl sulfate SDS). Non-limiting examples of anionic surfactants include, but are not limited to Sodium lauryl sulfate (SLS), Sodium laureth sulfate (SLES), Ammonium lauryl sulfate (ALS), Ammonium laureth sulfate (ALES), Sodium stearate, Potassium cocoate.

[0059] In some embodiments, the term "non-ionic surfactant" refers to any surfactant having covalently linked oxygen-containing hydrophilic groups, which are bonded to hydrophobic parent structures.

[0060] In some embodiments, the term "cationic surfactant" refers to any surfactant having a cationic functional group, such as quaternary ammonia compounds with positively charged surface-active moieties. Non-limiting examples of cationic surfactants include, but are not limited to benzalkonium, benzethonium, methylbenzethonium, cetylpyridinium, alkyldimethyl dichlorobenzene ammonium, dequalinium and phenamylinium chlorides, cetrimonium and cethexonium salts (e.g. halide salts).

[0061] Non-limiting examples of nonionic surfactants include, but are not limited to, polysorbate (e.g., polysorbate or Tween 20, 40, 60, and 80), ethoxylated castor oil, narrowrange ethoxylate, octa ethylene glycol mono dodecyl ether, penta ethylene glycol monododecyl ether, nonoxynols, triton X-100, polyethoxylated tallow amine, cocamide monoethanolamine, cocamide diethanolamine, poloxamers, glycerol monostearate, glycerol monolaurate, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, decyl glucoside, lauryl glucoside, octyl glucoside, lauryl dimethylamine oxide, dimethyl sulfoxide, phosphine oxide, and others.

[0062] In some embodiments, the surfactant of the invention comprises a polyether. In some embodiments, the polyether comprises an aliphatic polyglycol, also used herein as polyalkoxylate. In some embodiments, the polyether comprises polyethylene glycol (PEG), alkylated PEG, polypropylene glycol (PPG), alkylated PPG, branched PEG, branched PPG, polytetramethylene ether glycol, amino-modified polypropylene glycol, and ester-modified polypropylene glycol, or any copolymer comprising PPG and PEG blocks. Other poly ethers include inter alia modified C5-C18 fatty alcohol ethoxylates, C10-C18 oxo alcohol ethoxylates, Cl 6- 18 unsaturated fatty alcohol ethoxylates, Sorbitan ester ethoxylates, castor oil ethoxylates or any combination thereof.

[0063] In some embodiments, the surfactant is or comprises polysorbate 80.

[0064] In some embodiments, a w / w concentration of the phospholipid within the particle ranges from 5 to 40%, from 5 to 10%, from 5 to 30%, from 15 to 30%, from 20 to 30%, from 10 to 20%, from 20 to 40%, from 15 to 40%, including any range between.

[0065] In some embodiments, a w / w concentration of the surfactant within the particle ranges from 1 to 10%, from 1 to 3%, from 1 to 5%, from 3 to 10%, from 5 to 10%, from 3 to 7%, from 7 to 10%, including any range between.

[0066] 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.

[0067] In some embodiments, a w / w ratio of the phospholipid to the hydrophobic compound within the particle ranges from 4: 1 to 1: 1, from 4:1 to 3: 1, from 3: 1 to 2: 1, from 4: 1 to 2: 1, from 2: 1 to 1: 1, including any range between.

[0068] In some embodiments, a w / w ratio of the polysaccharide to the hydrophobic compound within the particle ranges from 3:1 to 1:3, from 3: 1 to 2: 1, from 2: 1 to 1: 1, from 1: 1 to 1:2, from 1:2 to 1:3, including any range between.

[0069] In some embodiments, a w / w ratio of the surfactant to the polysaccharide within the particle ranges from 1:2 to 1: 10, from 1:2 to 1:8, from 1:2 to 1:5, from 1:2 to 1:4, from 1:3 to 1:5, from 1:3 to 1:8, from 1:3 to 1: 10, from 1:2 to 1:4, including any range between.

[0070] In some embodiments, a w / w ratio of the surfactant to the hydrophobic compound within the particle ranges from 1:2 to 1: 10, from 1:2 to 1:8, from 1:2 to 1:5, from 1:2 to 1:4, from 1:3 to 1:5, from 1:3 to 1:8, from 1:3 to 1: 10, from 1:2 to 1:4, including any range between.Hydrophobic compound

[0071] In some embodiments, the composition of the present invention comprises a hydrophobic compound. In some embodiments, the hydrophobic compound is an active ingredient of the composition. In some embodiments, the hydrophobic compound is a bioactive compound.

[0072] In some embodiments, the hydrophobic compound is a lipophilic compound. In some embodiments, the hydrophobic compound is oil soluble. In some embodiments, the hydrophobic compound is soluble in a plant oil. In some embodiments, the hydrophobic compound is soluble in a non-polar organic solvent. In some embodiments, the hydrophobic compound is non-soluble in an aqueous solution. In some embodiments, the hydrophobic compound has a low solubility in an aqueous solution. In some embodiments, thehydrophobic compound is oil insoluble. In some embodiments, the hydrophobic compound is substantially oil insoluble. In some embodiments, the hydrophobic compound is soluble in a polar organic solvent. In some embodiments, the hydrophobic compound is soluble in ethanol. In some embodiments, the organic solvent is a terpenoid oil.

[0073] In some embodiments, the hydrophobic compound has maximal aqueous solubility (i.e. water solubility at 25C) below 1 g / 1. In some embodiments, the hydrophobic compound has maximal aqueous solubility below 0.5 g / 1. In some embodiments, the hydrophobic compound has maximal aqueous solubility below 0.1 g / 1. In some embodiments, the hydrophobic compound has maximal aqueous solubility below 0.01 g / 1, below 100mg / l, below 50 mg / 1, below 20 mg / 1, below 10mg / l, below 5 mg / 1, including any range between.

[0074] In some embodiments, the hydrophobic compound is an oil-soluble hydrophobic compound having oil solubility of at least 1 g / 1, at least 0.7 g / 1, at least 0.5 g / 1, at least 0.3 g / 1, at least 0.2 g / 1, including any range or value therebetween.

[0075] In some embodiments, a solubility of the hydrophobic compound within a plant-oil is at most 100 g / 1, at most 70 g / 1, at most 50 g / 1, at most 30 g / 1, at most 20 g / 1, at most 10 g / 1, at most 5 g / 1, at most 3 g / 1, at most 1 g / 1, at most 0.7 g / 1, at most 0.5 g / 1, at most 0.3 g / 1, including any range or value therebetween.

[0076] In some embodiments, the hydrophobic compound is a natural nutraceutical. In some embodiments, the hydrophobic compound is a nutraceutical selected from the group consisting of: a carotenoid, a natural phenol (e.g. resveratrol), a vitamin, a hydrophobic vitamin (e.g. A, D, E, K), a cannabinoid, a polyunsaturated fatty acid (e.g. an omega-3 fatty acid), a phytosterol, a nutraceutical (e.g. co-QlO, genistein, daidzein, curcumin), an antioxidant, a phytoestrogen, a polyphenol, an anthocyanin, taurine or any combination thereof. In some embodiments, the hydrophobic compound is or comprises a hydrophobic drug. Cannabinoids (including but not limited to THC and CBD and / or derivatives thereof) and hydrophobic drugs are well-known in the art.

[0077] In some embodiments, the hydrophobic compound is a small molecule, having a molecular weight below 1000, below 900, below 800, below 700 or below 500Da, including any range between.

[0078] In some embodiments, the hydrophobic compound is a carotenoid. Non- limiting examples of carotenoids include but are not limited to: astaxanthin (AX), astaxanthin oleoresin (AX oleoresin), beta-carotene, alpha-carotene, canthaxanthin, lutein, zeaxanthin,beta-zeacarotene, lycopene, apo carotenal, bixin, paprika oleoresin, capsanthin, vitamin A (retinol), capsorubin or any combination thereof.

[0079] In some embodiments, the hydrophobic compound is a natural phenol. Natural phenols (e.g. oil-insoluble phenols) are well-known in the art. Non-limiting examples of natural phenols include but are not limited to: phenolic acids, flavonoids (e.g. quercetin, kaempferol, catechin, anthocyanin, hesperidin), tannins, stilbenes (e.g. resveratrol), curcuminoids (e.g. curcumin), coumarins, lignans, quinones or any combination thereof. In some embodiments, the hydrophobic compound comprises a nutraceutical and / or a hydrophobic drug.

[0080] In some embodiments, the hydrophobic compound is a curcuminoid. Non-limiting examples of curcuminoids include but are not limited to curcumin, a derivative of curcumin (e.g. tetrahydrocurcumin, hexahydrocurcumin, curcumin sulfate, dihydrocurcumin, curcumin glucuronide or any combination thereof).

[0081] In some embodiments, the particle of the invention consists essentially of the hydrophobic compound, the phospholipid, the surfactant and the polysaccharide. In some embodiments, the particle of the invention consists essentially of the hydrophobic compound, the phospholipid, the surfactant and the polysaccharide (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 hydrophobic compound, the phospholipid, the surfactant and the polysaccharide is of food, nutraceutical or pharmaceutical grade.Composition

[0082] 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 hydrophobic compound. 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 hydrophobic compound.

[0083] In some embodiments, the composition is a dry composition. In some embodiments, the composition is a powderous composition. In some embodiments, the plurality of particlesof 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.

[0084] 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 10 to 800 nm, from 50 to 500 nm, from 50 to 300 nm, from 50 to 800 nm, from 100 to 500 nm, from 100 to 300 nm, from 150 to 250 nm, from 150 to 200 nm, from 200 to 500 nm, from 150 to 300 pm, from 150 to 500 nm, including any range between.

[0085] In some embodiments, the composition is characterized by an average particle size below lum, below 900nm, below 800 nm, below 600nm, below 500 nm, including any range between. In some embodiments, the particle size refers to the dry size of the particles within the composition (as determined by PSD test, based on sieving). In some embodiments, the powderous composition comprises a plurality of secondary particles. In some embodiments, the particle size refers to the average size of the particles in a liquid (e.g. an aqueous dispersion), as determined by DLS.

[0086] In some embodiments, the composition is characterized by PDI (polydispersity index) of the plurality of particles ranging between 0.05 and 0.4, between 0.05 and 0.3, between 0.05 and 0.2, between 0.1 and 0.4, between 0.1 and 0.3, below 0.4, below 0.3, or below 0.25, including any range between, as determined by DLS.

[0087] 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.

[0088] Non-limiting examples of bioavailability enhancers include but are not limited to: quercetin (QUE), rutin, hesperidin, curcumin, piperine, or any combination thereof.

[0089] In some embodiments, the powderous composition is a dry formulation. In some embodiments, the powderous composition is encapsulated (e.g., inside a capsule or a gel) for administration. In some embodiments, the powderous composition is pressed into tablets for administration.

[0090] In some embodiments, a w / w concentration of the additive within the composition is between 0.01 and 95% including any range between.

[0091] In some embodiments, the water content of the powderous composition is less than 30, 20 or 10 %w / w. In some embodiments, the water content of the powderous composition is less than 5 %w / w. In some embodiments, the water content of the powderous composition is less than 2 %w / w. In some embodiments, the water content of the powderous composition is less than 1 %w / w.

[0092] In some embodiments, the composition is characterized by a water content of less than 30, 20 or 10 %w / w. In some embodiments, the water content of the powderous composition is less than 5 %w / w. In some embodiments, the water content of the powderous composition is less than 2 %w / w. In some embodiments, the water content of the powderous composition is less than 1 %w / w.

[0093] In some embodiments, at least 90%, at least 92%, at least 93%, at least 95%, at least 97%, or between 90% and 100%, between 95% and 100%, between 92% and 100%, between 90% and 99%, between 90% and 97%, between 90% and 95% by dry weight of the composition consist of the plurality of particles.

[0094] 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.

[0095] In some embodiments, the particle of the invention refers to as “stable” in an aqueous formulation indicates that at least about 80% by total weight of the divalent metal carbonate remains amorphous upon storage of the aqueous formulation 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), for a time period of at least 24 h, at least 2 days (d), at least 7 d, , including any range or value therebetween.

[0096] The term "stable" (or the term stable particle), including any grammatical form thereof, as used herein indicates that the calcium carbonate is maintained in the amorphous form for a long period of time (under appropriate conditions, as described herein) in the solid form having less than or about 30%, about 20%, about 15%, about 10%, about 5% of crystalline divalent metal carbonate by total weight of the particle and / or of the composition comprising thereof. 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% by totalweight of the divalent metal carbonate remains amorphous 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.

[0097] In some embodiments, a stable particle is substantially devoid of disintegration, agglomeration, and / or crystallization of the divalent metal carbonate specie. 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 particle (e.g., being devoid of oxidation). In some embodiments, a stable particle is a chemically inert particle.

[0098] 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, including any range or value therebetween.

[0099] 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.

[0100] 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.

[0101] In some embodiments, appropriate conditions comprise a relative humidity ranging from 10 to 60% including any range or value therebetween.

[0102] 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.

[0103] 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 a pharmaceutically 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.

[0104] In some embodiments, the w / w concentration of the carrier within the composition is between 1 and 99% including any range between. In some embodiments, the composition (i.e. the powderous composition and the carrier) is formulated in a form of a suspension, a liquid or semiliquid composition for various administration including internal and topical uses.

[0105] 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 ingredient. In one embodiment, excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0106] As used herein, the term “carrier,” “excipient,” or “adjuvant” refers to any component of a pharmaceutical composition that is not the active agent. As used herein, the term “pharmaceutically acceptable carrier” refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline. Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such asethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Some non-limiting examples of substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants, and preservatives may also be present. Any non- toxic, inert, and effective carrier may be used to formulate the compositions contemplated herein. Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001); the CTFA (Cosmetic, Toiletry, and Fragrance Association) International Cosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); and the “Inactive Ingredient Guide,” U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Management, the contents of all of which are hereby incorporated by reference in their entirety. Examples of pharmaceutically acceptable excipients, carriers and diluents useful in the present compositions include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO. These additional inactive components, as well as effective formulations and administration procedures, are well known in the art and are described in standard textbooks, such as Goodman and Gillman’s: The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds. Pergamon Press (1990); Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990); and Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., (2005), each of which is incorporated by reference herein in its entirety. The presently described composition may also be contained in artificially created structures such as liposomes, ISCOMS, slow-releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides in serum. Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. Liposomes for use with the presently described peptides are formed from standard vesicle-forming lipids which generally include neutral and negatively chargedphospholipids and a sterol, such as cholesterol. The selection of lipids is generally determined by considerations such as liposome size and stability in the blood. A variety of methods are available for preparing liposomes as reviewed, for example, by Coligan, J. E. et al, Current Protocols in Protein Science, 1999, John Wiley & Sons, Inc., New York, and see also U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0107] In some embodiments, the composition is a liquid composition. 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 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).

[0108] In some embodiments, the liquid composition comprises the particles dispersed in an aqueous solution. In some embodiments, the hydrophilic outer portion of the particle shell forms bonding interaction with water molecules, thereby stabilizing the particle in the formulation.

[0109] In some embodiments, the liquid composition is substantially devoid of a solvent. In some embodiments, the liquid composition is substantially devoid of ethanol.

[0110] In some embodiments, the dry formulation forms a stable aqueous formulation upon reconstitution with water. In some embodiments, the dry formulation forms a stable emulsion upon reconstitution with water. In some embodiments, the dry formulation forms a stable dispersion or emulsion upon reconstitution. In some embodiments, the w / w concentration of the hydrophobic compound in the liquid composition ranges from 0.001 to l%w / v, from 0.001 to 0.01%w / v, from 0.01 to 0.05%w / v, from 0.05 to 0.1%w / v, from 0.1 to 0.5%w / v, from 0.5 to l%w / v, or more including any range between.

[0111] In some embodiments, wherein a w / w concentration of the plurality of particles within the liquid composition is between 0.01 and 40%, between 0.1 and 40%, between 0.01 and 35%, between 0.1 and 35%, between 0.01 and 33%, between 0.01 and 38%, between 0.01 to and 30%, including any range between.

[0112] In some embodiments, the liquid composition is an aqueous formulation. In some embodiments, the liquid composition comprises an aqueous buffered solution. In some embodiments, the pH value of the liquid composition ranges from 2 to 8. In some embodiments, the pH value of the liquid composition ranges from 6.5 to 7. In some embodiments, the pH value of the liquid composition ranges from 6.8 to 7.5. In some embodiments, the pH value of the liquid composition ranges from 2 to 3. In some embodiments, the pH value of the liquid composition ranges from 3 to 4. In some embodiments, the pH value of the liquid composition ranges from 2.5 to 7.5 or up to 8, or more.

[0113] In some embodiments, the composition comprising the particles of the invention significantly improves bioavailability and / or bio-accessibility of the hydrophobic compound. In some embodiments, the composition comprising the particles of the invention configured to release the hydrophobic compound in the gastrointestinal tract of a subject. In some embodiments, the composition is for supplementing a subject with a nutraceutical. In some embodiments, the composition is for use in the administration of a therapeutically active agent to a subject in need thereof.Method of preparation (dispersion / dry composition)

[0114] In some embodiments, the present invention comprises a method for solubilizing the hydrophobic compound in an aqueous solution. In some embodiments, the present invention comprises a method for solubilizing the hydrophobic compound in an aqueous formulation.

[0115] In some embodiments, an exemplary method for manufacturing an aqueous composition of the invention comprises the following steps: (i) preparing an aqueous dispersion comprising the active agents disclosed herein, such as the hydrophobic compound, the phospholipid (e.g., lecithin), the surfactant, and the polysaccharide and / or a derivative thereof (e.g. a water-soluble polysaccharide); (ii) homogenizing the aqueous dispersion under operable conditions (e.g. in a high shear homogenizer), thereby obtaining the aqueous composition of the invention.

[0116] In some embodiments, an exemplary method for manufacturing a powderous composition of the invention comprises substantially removing water from the aqueous composition of the invention, thereby obtaining a dry powder. In some embodiments, removing water is by a process selected from spray drying, and fluidized bed or both. In some embodiments, the powderous composition of the invention is obtained by applying a fluidized bed process to the aqueous composition of the invention in contact with a particulate solid matter (e.g., microcrystalline cellulose).Methods of use

[0117] In another aspect, the present invention is directed to a method for enhancing bioaccessibility of a hydrophobic compound. In some embodiments, the method for enhancing bioaccessibility of a hydrophobic compound comprises administering the composition (e.g. the particle, the liquid formulation) of the invention to a subject in need thereof, thereby increasing bioaccessibility of the hydrophobic compound within the subject. In some embodiments, the method for enhancing bioavailability of a hydrophobic compound comprises administering the composition of the invention to a subject in need thereof, thereby increasing bioavailability of the hydrophobic compound within the subject. In some embodiments, the composition comprises any of the particles of the invention. In some embodiments, the hydrophobic compound is as described herein. The term “bioaccessibility” as used herein, is directed to ability to release a hydrophobic compound in-vitro by any one of the formulations of the present invention. The in-vitro release can be evaluated by using a protocol of simulated digestion. The protocol is provided in the experimental section. The bioaccessible fraction is the fraction of the active hydrophobic compound found in the supernatant following simulated gastrointestinal digestion.

[0118] In some embodiments, the composition of the present invention enhances the bioaccessibility of a hydrophobic compound (such as a carotenoid).

[0119] 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 hydrophobic compound.

[0120] In some embodiments, the present invention is directed to a method for enhancing bioavailability of a hydrophobic compound. In some embodiments, the method comprisesadministering a capsule, comprising the hydrophobic compound to a subject in need thereof. In some embodiments, the method comprises administering the composition of the present invention to a subject in need thereof. In some embodiments, the method comprises administering the reconstituted composition of the present invention to a subject in need thereof. In some embodiments, the composition is o / w emulsion. In some embodiments, the composition is a powderous composition.

[0121] In some embodiments, the present invention is directed to a method for enhancing the concentration of a hydrophobic compound in the blood of a subject in need thereof. In some embodiments, the method comprises administering the composition of the present invention to a subject. In some embodiments, the method comprises administering the capsule, comprising the hydrophobic compound to a subject.

[0122] In some embodiments, there is a method of supplementing a subject with a hydrophobic compound, comprising the step of administering to a subject the composition of the present invention. In some embodiments, the method comprises administering to a subject the reconstituted composition of the present invention. In some embodiments, the composition further comprises an aqueous liquid. In some embodiments, an aqueous liquid comprises the hydrophobic compound formulated within the composition. In some embodiments, an aqueous liquid comprises oil-in-water emulsion comprising the hydrophobic compound. In some embodiments, the method of supplementing a subject with the hydrophobic compound comprises administering to a subject the capsule comprising the hydrophobic compound.

[0123] 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.

[0124] In some embodiments, the present invention further provides a method of supplementing a subject with a nutraceutical as a hydrophobic compound, comprising the step of administering to a subject a capsule comprising the composition of the present invention. In some embodiments, the capsule is administered orally.

[0125] In some embodiments, administering comprises 1, 2, 3, 4 or more times per day. In some embodiments, administering comprises administering to the subject an amount of the composition corresponding to the recommended daily dose of the hydrophobic compound.

[0126] In some embodiments, the recommended daily dose is between 10 and 5000 mg, between 100 and 5000 mg, between 100 and 3000 mg, between 100 and 2000 mg, between 200 and 2000 mg, between 100 and 500 mg, between 500 and 5000 mg, between 500 and 1000 mg, between 1000 and 5000 mg, between 1000 and 2000 mg, between 2000 and 5000 mg, including any range between.

[0127] 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

[0128] 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.

[0129] 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 ingredients 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] As used herein the term “about” refers to ± 10 %.

[0136] The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.

[0137] 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 shouldat least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0138] 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 of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.

[0139] Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0140] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] In one embodiment, the terms "comprises" "comprising", and "having" are / is interchangeable with "consisting".

[0145] 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.

[0146] 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.

[0147] 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.

[0148] Other terms as used herein are meant to be defined by their well-known meanings in the art.

[0149] 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.

[0150] 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.

[0151] 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. Effectivedoses can be extrapolated from dose-response curves derived from in-vitro or in-vivo animal model test bioassays or systems.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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 oftreatment lasting from several days to several weeks or until cure is affected or diminution of the disease state is achieved.

[0156] 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.

[0157] In some embodiments, toxicity and therapeutic efficacy of the active ingredients 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)].

[0158] 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.

[0159] 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 ingredient. 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

[0160] The inventors successfully solubilized an exemplary hydrophobic compound (curcumin, quercetin and resveratrol) in an aqueous solution by manufacturing an aqueous formulation comprising curcumin / lecithin complex encapsulated by a water soluble modified starch (e.g., Hi Cap 100, or Crystal Tex 626). Alternatively, lecithin has been replaced by phosphatidylcholine (e.g., sunflower phosphatidylcholine, Lipoid H90), to obtain a stable aqueous formulation. Further, modified starch was successfully replaced by HPMC.

[0161] Optionally, the aqueous formulation is manufactured by mixing the ingredients of the composition as disclosed herein, with an aqueous solution. In some embodiments, mixing is performed at a temperature ranging between 20 and 70°C, including any range between. In some embodiments, mixing is performed until a homogenous solution is formed (e.g. indicating the formation of the aqueous formulation comprising particles of the invention dispersed in an aqueous solution).

[0162] Various mixing techniques suitable for manufacturing of aqueous formulation (suitable for encapsulation or solubilization of water-insoluble compounds) are well known in the art.

[0163] The encapsulated curcumin has been subsequently dried in a spray dryer, to obtain an exemplary dry powderous composition of the invention. The dry composition has been further resuspended in an aqueous solution (at various pH values, such as 2.5 and 7.5) so as to obtain curcumin solubilized in an aqueous solution at a w / v concertation of curcumin up to about 0.4g / L.

[0164] Exemplary composition of water dispersible powders successfully prepared by the inventors is as disclosed in Table 1.

[0165] Table 1:

[0166] In an exemplary embodiment, the powderous compositions exemplified herein have been successfully resuspended in an aqueous solution (at different pH ranges) up to a concertation of about 30% w / v.

[0167] The inventors performed particle size measurement of an exemplary powderous composition disclosed above by DLS (dynamic light scattering), using Malvern Zetasizer instrument. The measured average particle size of the tested sample was about 206nm (intensity based), and PDI of 0.2.

[0168] The inventors further tested curcumin-based compositions containing various curcumin : lecithin ratio. The results are presented in Figure 1. As shown in Figure 1, at the tested range (curcumin : lecithin = between 1: 1 and 1:4) a dramatic solubility increase was observed, as compared to pristine curcumin solubility (having a theoretic water solubility of below 5mg / L).

[0169] Further, the inventors showed that replacing Tween 80 by an anionic surfactant (SDS), as well as replacing modified starch by HPMC within the particle / composition of the invention doesn’t significantly change curcumin solubility (see Figures 2 and 3).

[0170] Similarly, quercetin and resveratrol were successfully solubilized in water using the particles of the invention (see Figures 4 and 5).

[0171] 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.

[0172] 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 of said particles comprises an inner portion in contact with an outer portion, wherein: said outer portion comprises a polysaccharide a derivative thereof, or both; said inner portion comprises a hydrophobic compound, a phospholipid and a surfactant; a w / w concentration of said phospholipid within said particle ranges from 5 to 60%; a w / w concentration of said surfactant within said particle ranges from 1 to 10%; a w / w concentration of said polysaccharide within said particle ranges from 5 to 40%, and wherein said composition is characterized by an average particle size of between 50 and 800 nm.

2. The composition of claim 1 , wherein said hydrophobic compound has a low solubility in an aqueous solution and is small molecule; and wherein the small molecule is a natural compound or a natural nutraceutical.

3. The composition of claim 2, wherein the natural compound is selected from a phenolic compound.

4. The composition of claim 3, wherein the phenolic compound is or comprises any of: phenolic acid, flavonoid, tannin, stilbene, curcuminoid, coumarin, lignan, quinone or any combination thereof.

5. The composition of claim 4, wherein said phenolic compound is selected from curcuminoid, flavonoid and stilbene.

6. The composition of claim 4 or 5, wherein the hydrophobic compound comprises at least one of: curcumin, resveratrol and quercetin.

7. The composition of any one of claims 1 to 6, wherein said outer portion is in a form of a shell encapsulating said inner portion.

8. The composition of any one of claims 1 to 7, wherein a w / w ratio of said phospholipid to said hydrophobic compound ranges from about 4: 1 to about 1: 1; and wherein the phospholipid is or comprises a plant-based phospholipid.

9. The composition of any one of claims 1 to 8, wherein a w / w ratio of said surfactant to said hydrophobic compound ranges from 1:2 to 1: 10.

10. The composition of any one of claims 1 to 9, wherein a w / w ratio of said polysaccharide to said hydrophobic compound ranges from 3: 1 to 1:3.

11. The composition of any one of claims 1 to 10, wherein said phospholipid is or comprises a phosphatidylcholine.

12. The composition of any one of claims 1 to 10, wherein said phospholipid comprises a lecithin.

13. The composition of claim 12, wherein said lecithin comprises sunflower lecithin, soybean lecithin, or a combination thereof; and wherein said phosphatidylcholine is or comprises a sunflower phosphatidylcholine.

14. The composition of any one of claims 1 to 13, wherein w / w ratio of said phospholipid to said hydrophobic compound ranges from 4: 1 to 1:

115. The composition of claim 14, wherein w / w ratio of said phospholipid to said hydrophobic compound ranges from about 4: 1 to about 2:

116. The composition of any one of claims 1 to 15, wherein said polysaccharide comprises a starch, a modified starch, dextrin, Xanthan gum, Gum Arabic, chitosan, cellulose, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose, alkylated cellulose, nitrocellulose, alginate, pectin, including any salt, any combination, or any copolymer thereof.

17. The composition of claim 16, wherein said polysaccharide is or comprises said modified starch or HPMC.

18. The composition of any one of claims 1 to 17, wherein said hydrophobic compound comprises said phenolic compound, and said polysaccharide is or comprises said modified starch.

19. The composition of any one of claims 1 to 18, wherein said surfactant comprises a cationic surfactant, an anionic surfactant, a non-ionic surfactant, or any combination thereof.

20. The composition of any one of claims 1 to 19, wherein said surfactant is a small molecule surfactant.

21. The composition of any one of claims 1 to 20, wherein at least 90% by weight of said composition consist of said plurality of particles.

22. The composition of any one of claims 1 to 21, wherein between 95% and 100% by weight of said composition consist of said plurality of particles.

23. The composition of any one of claims 1 to 22, further comprising an aqueous solution, wherein said hydrophobic compound is at a concentration of 0.001 to 10%w / v in said composition.

24. The composition of claim 23, wherein said composition is an aqueous dispersion.

25. The composition of claim 24, wherein a w / w concentration of said plurality of particles within said aqueous dispersion is up to about 40%.

26. The composition of claim 24 or 25, wherein a w / w concentration of said plurality of particles within said aqueous dispersion is between 0.1 and 35%.

27. The composition of any one of claims 1 to 26, wherein said particles are configured to release said hydrophobic compound in the gastrointestinal tract of a subject.

28. A method of supplementing a subject with a hydrophobic compound, comprising the step of administering to said subject a composition of any one of claims 1 to 27, thereby supplementing said subject with said hydrophobic compound.

29. The method of claim 28, wherein said supplementing further comprises enhancing bioavailability of said hydrophobic compound.

30. The method of any one of claims 28 or 29, wherein said subject is selected from a human subject and an animal subject.

31. The method of any one of claims 28 to 30, wherein said administering comprises oral administration.

32. The method of any one of claims 28 to 31, wherein said supplementing comprises inducing a release of at least a portion of the hydrophobic compound within the gastrointestinal tract of the subject.

33. The method of any one of claims 28 to 32, wherein said administering comprises an amount of said composition corresponding to the recommended daily dose of the hydrophobic compound.

34. The method of claim 33, wherein the recommended daily dose is between 10 and 5000 mg.

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