Formulations consisting of water-soluble particles of non-curcuminoids and water-soluble particles of curcuminoids

Abstract

Embodiments relate to formulations comprising particles of turmeric pigment, curcumin-free turmeric pigment, turmeric oil, or a combination thereof, wherein the compound is water-soluble and safe, does not contain a pH buffering agent, and further comprises a curcuminoid.

Description

[Technical field]

[0001] Related Applications This application claims priority to Indian Provisional Application No. IN 201841039937, entitled "CURCUMIN COMPOSITIONS AND PROCESS FOR PREPARING SAME," filed on October 23, 2018, which is incorporated by reference in its entirety.

[0002] The invention presented herein relates to the fields of cosmetics, pharmaceuticals, nutraceuticals and food products. The invention also relates to aqueous curcuminoid and non-curcuminoid compositions and formulations thereof. [Background technology]

[0003] Background information on turmeric is clear in many prior art: "Turmeric (Curcuma longa) is a perennial herb widely cultivated in South and Southeast tropical Asia. The rhizome is the part of turmeric most used for food and medicine. "The rhizome is first processed to produce powder, which is then subjected to solvent extraction to produce turmeric pigments (TO)" (Nagarajan et al., 2010). TOs are abundant in curcuminoids and non-curcuminoids (non-curcuminoids are compounds derived from turmeric that lack the biologically active curcuminoids). Curcuminoids are the yellow pigments of turmeric and have been separated from turmeric pigments. Curcuminoids have even been used to study their pharmaceutical properties. Curcumin is the major type of curcuminoid. "Curcumin has been shown to have antioxidant, anti-inflammatory, antibacterial and anti-carcinogenic properties. In addition, it is widely known to be effective in protecting the liver and kidneys, inhibiting thrombosis, reducing the risk of myocardial infarction, as well as in treating hypoglycemia and rheumatism" (Anand P et al., 2007).

[0004] According to Jayaprakasha et al. (2001), “The mother liquor after separation of curcumin from the pigments is known as turmeric decolorized curcumin (CRTO).” CRTO is currently considered an industrial waste and is disposed of in boilers. CRTO is known to have antibacterial properties (Jayaprakasha et al., 2001). CRTO is also a natural antioxidant / preservative and cooling agent in various foods (Nagarajan et al., 2010). It is a non-curcuminoid compound consisting of curcuminoid residues, oils, and resins. “Non-curcuminoids have a broad spectrum of anti-cancer activity against various cell types, including complex tumors and drug-resistant malignancies.” “Clinical studies conducted with non-curcuminoid formulations have shown consistent results and have proven to be a powerful ally in the medical market, especially in fighting numerous diseases, including cancer” (Nair et al., 2019, Evaluation of the Benefits of Non-Curcuminoids).

[0005] The medicinal benefits and therapeutic uses of curcuminoids (or curcumin) and non-curcuminoids are limited due to their poor solubility and bioavailability ( Nair et al., 2019 ; Anand P et al., 2007 ).

[0006] To date, "a number of approaches have been tried to improve the bioavailability of curcuminoids." First, these include the use of adjuvants that prevent glucuronidation, such as piperine; second, liposomal curcumin; third, the use of curcumin nanoparticles; fourth, the use of curcumin-phosphoresin complexes; and fifth, the use of structured analogues of curcumin (eg, EF-24)" (Anand P et al., 2007).

[0007] US 8,568,815 B2 relates to a method for preparing a water-soluble complex of curcumin with an alkyl or ether derivative of gamma-cyclodextrin, comprising: a) placing curcumin and a gamma-cyclodextrin derivative in a molar ratio of about 1:1 to 1:6 in an aqueous phase having a pH of at least 11 to form a solution; and b) lowering the pH of the solution to pH 8 or less, whereby a stable cyclodextrin complex of curcumin is formed in said aqueous phase. Prior art has found the use of pH buffers in formulations. The use of pH in therapeutic formulations may have unknown changes in ion-dependent biochemical reactions in vivo. Ferreira et al., 2015 explains: Buffers such as phosphate, citrate, borate, and succinate have drawbacks when used in vivo and in complex systems.

[0008] US 2016 / 0128939 A9 relates to "curcumin in an amount of not more than 10% by weight, preferably not more than 7.5% by weight, particularly preferably not more than 6% by weight, and at least one emulsifier with an HLB value ranging from 13 to 18, in particular polysorbate 80 or polysorbate 20, or a mixture of polysorbate 20 and polysorbate 80, and in which the average diameter of the micelles loaded with curcumin is between 5 nm and 40 nm, preferably between 6 nm and 20 nm, and more preferably between 7 nm and 10 nm." Small nanoparticles may have nanotoxicity and are therefore potentially unsafe for treatment. Exbrayat et al. (2015) explain that nanoparticles (NPs) are small and therefore "can migrate into cells and reach organelles such as mitochondria, altering the metabolism of cells and inducing cell death." Exbrayat et al. also found that the harmful toxicity of nanoparticles is stronger the smaller the size of the nanoparticles. Summary of the Invention [Problem to be solved by the invention]

[0009] We found that the results of the study showed that it is not possible to manipulate the solubility and biosolubility of non-curcuminoids as defined above. Non-curcuminoids are “equally potent as curcuminoids” (Nair et al., 2019). Both water-soluble formulations containing curcuminoids and non-curcuminoids are safe and stable for therapeutic use, as no water-soluble formulation exists.

[0010] Therefore, there is a long-felt unmet need to develop water-soluble formulations containing curcuminoids and non-curcuminoids, or pharma- ceutically acceptable salts or derivatives thereof, both in the form of water-soluble formulations that are safe and secure for therapeutic use. [Means for solving the problem]

[0011] An embodiment relates to a water-soluble curcuma formulation that is composed of curcuminoids and non-curcuminoids and an emulsifier without a pH buffer.

[0012] Another embodiment relates to a water-soluble curcuma formulation consisting of curcuminoids and non-curcuminoids with improved stability as a self-nanoemulsifying formulation.

[0013] Another embodiment relates to water-soluble curcuma formulations that are comprised of therapeutically safe ultra-fine to fine particle curcuminoids and non-curcuminoids.

[0014] The embodiments relate to pH buffer-free curcumin-depleted turmeric oleoresin-CRTO, and water-soluble curcuma formulations comprised of curcuminoids and emulsifiers.

[0015] Another embodiment relates to a water-soluble curcuma, composed of CRTO and curcuminoids, with improved stability as a self-nanoemulsifying formulation.

[0016] Another embodiment relates to a therapeutically safe, water-soluble curcuma formulation comprising CRTO and ultrafine to fine curcuminoids.

[0017] Another embodiment relates to a pH buffer-free, water-soluble curcuma formulation comprised of turmeric oleoresin-TO, curcuminoids and an emulsifier.

[0018] Another embodiment relates to a water-soluble curcuma formulation composed of TO and curcuminoids with improved biostability as a self-nanoemulsifying formulation.

[0019] Another embodiment relates to a water-soluble curcuma formulation composed of TO and therapeutically safe ultrafine to fine curcuminoids.

[0020] Another embodiment relates to a water-soluble curcuma formulation consisting of turmeric oil-TOIL without pH buffering agents, curcuminoids and emulsifiers.

[0021] Another embodiment relates to a water-soluble curcuma formulation composed of TOIL and curcuminoids with improved biostability as a self-nanoemulsifying formulation.

[0022] Another embodiment relates to an aqueous composition comprising TOIL and therapeutically safe ultrafine to fine curcuminoids.

[0023] Another embodiment relates to a water-soluble curcuma formulation consisting of TO or CRTO or TOIL or a combination thereof and therapeutically safe ultrafine to fine curcuminoids.

[0024] An embodiment relates to a curcuma formulation consisting of particles of turmeric pigment or turmeric pigment-CRTO from which curcumin has been removed, where the compound is water soluble and therapeutically safe.

[0025] Other embodiments relate to curcuma formulations in which: the compound does not contain a pH buffer and therefore the compound comprises a large amount of curcuminoids; the compound comprises about 1% to about 10% by weight of curcuminoids; the compound comprises more than about 10% by weight of curcuminoids; the compound comprises about 40% to 70% by weight of turmeric pigments; the turmeric pigments comprise about 50% to 97% curcuminoids and about 50% to 99% turmerones; the compound comprises about 5% to about 69% by weight of curcumin-removed turmeric pigments; the curcumin-removed turmeric pigments comprise about 1% to 50% curcuminoids and 50% to 99% turmerones; the compound comprises a large amount of non-ionic oil-in-water emulsifiers; the compound comprises an HLB 9-18, preferably 11-16; the compound comprises about 30-45% by weight of a non-ionic oil-in-water emulsifier; the non-ionic oil-in-water emulsifier is selected from polyoxyethylene products of hydrogenated vegetable oils, polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyoxyethylene-sorbitan fatty acid esters, polyoxyethylene castor oil derivatives and / or combinations thereof; N-methyl-2-pyrrolidone or mixtures thereof; the particle size is 1000-40 nm; where preferably the particles are 500 nm or less.

[0026] Another embodiment relates to a curcuma formulation comprised of particles of curcuminoids, non-curcuminoids and lipophilic solvents.

[0027] Other embodiments relate to the lipophilic solvent in the curcuma formulation being about 5% to about 70% by weight of the compound; the lipophilic solvent of the compound being about 50% to about 200% by weight of the curcuminoids; the lipophilic solvent is comprised of triglycerides; the triglycerides are comprised of the following: fractional oils, caprylic triglycerides, oils containing linear fatty acid triglycerides, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate esters of fatty acids, propylene glycol dicaprylate, and the like. an oil comprising propylene glycol, propylene glycol dilaurate, or propylene glycol fatty acid ester; the composition also comprises a non-ionic water-in-oil emulsifier; the non-ionic water-in-oil emulsifier is 30% to 45% by weight; the non-ionic water-in-oil emulsifier comprises a hydrogenated vegetable oil, a polyethoxylated castor oil, a polyethoxylated hydrogenated castor oil, a polyoxyethylene-sorbitan-fatty acid ester, a polyoxyethylene castor oil derivative, or a combination thereof; the composition further comprises a solvent; the solvent is comprised of: ethyl alcohol, isopropyl alcohol, glycofurol, polyethylene glycol, glycerol, polypropylene glycol, propylene glycol, N-methyl-2-pyrrolidone, ethyl alcohol, or mixtures thereof; the particle size is between 1000 and 40 nm; the particle size is preferably 500 nm; the compound is also comprised of a pharma- ceutically acceptable excipient; the compound is also comprised of an absorbent; the absorbent is comprised of: polyethylene glycol, maltodextrin, water-soluble starch, hydrolyzed starch, dietary fiber, water-soluble oligosaccharides, chicory, dextran, cellulose, copolymers of polyvinylpyrrolidone, sugar alcohols, sorbitol, xylitol, mannitol, cellulose derivatives, or combinations thereof; the cellulose derivative is comprised of hydroxypropyl methylcellulose, hydroxypropyl cellulose, cyclodextrin, or combinations thereof; the compound is also comprised of a diluent, filler, or binder;The diluent, filler, or binder may be mannitol, sorbitol, lactose, candy, sugar, or a combination thereof; the compound may also be composed of a water-soluble polymer; the water-soluble polymer may be composed of polyglutamic acid, polyethylene glycol, propylene glycol, glycerol, propylene glycol esters, polyglycerol oleate, polyvinyl alcohol, non-ethoxylated polymers, or a combination thereof; the compound may also be composed of stabilizers, surfactants, plasticizers, lubricants, reducing agents, buffers, sweeteners, bases, adsorbents, flavorings, binders, suspending agents, antioxidants, gloss agents, coating agents, wetting agents, gelling agents, wetting modifiers, fillers, antifoaming agents, refrigerating agents, colorants, flavors, sugar coating agents, isothermal agents, softeners, emulsifiers, foaming agents, pH adjusters, antifoaming agents, flavors, preservatives, diluents, diluents, flavors, isothermal agents. an isotopically active agent, a softener, an emulsifier, a foaming agent, a pH adjusting agent, an antifoaming agent, a flavoring, a preservative, a diluent, an excipient, a dispersing agent, a disintegrating agent, a flavoring, a drying agent, a preservative, a solubilizing agent, a solvent, a superplasticizer, an antistatic agent, an expander, a humectant, or a combination thereof; the form of the compound is solid, semisolid, or liquid; the form is dropwise, powder, tablet, capsule, troche, transdermal patch, cream, or a combination thereof; the tablet dissolves or disintegrates in the human tongue or mouth within 15 to 30 minutes; the curcumin is comprised of a plurality of curcumins; the formulation is also comprised of a pharmaceutically acceptable excipient; where the formulation is comprised of a plurality of curcuminoids and a plurality of non-curcuminoids;

[0028] Another embodiment relates to a water-soluble curcuma formulation comprising curcuminoids and non-curcuminoids, or pharma-ceutically acceptable salts or derivatives thereof, which is therapeutically safe and stable in the form of a water-soluble formulation.

[0029] Yet another embodiment relates to a water-soluble curcuma formulation comprising first particles of curcuminoids and second particles of non-curcuminoid-containing curcumin-depleted turmeric pigments, or pharma-ceutically acceptable salts or derivatives thereof, which is therapeutically safe and stable in the form of a water-soluble formulation.

[0030] Yet another embodiment relates to a water-soluble curcuma formulation comprising a first particle of curcuminoid and a second particle of non-curcuminoid derived from turmeric pigment or curcumin-depleted turmeric pigment or turmeric oil or combinations thereof or pharma-ceutically acceptable salts or derivatives thereof, wherein the water-soluble formulation is therapeutically safe and stable in the form of a water-soluble formulation.

[0031] Yet another embodiment relates to a formulation comprising a compound consisting of curcuminoids and non-curcuminoids, wherein the compound has the following properties: a) solubilization of the curcuminoids in turmeric pigment, curcumin-removed turmeric pigment, turmeric oil, or a combination thereof, resulting in a clear solution with a sediment load of 30% or less; b) solubilization of the turmeric oil, curcumin-removed turmeric pigment, turmeric oil, or a combination of curcuminoids and non-curcuminoids, resulting in particles with an average size of 40-1000 nm; c) formulation that shows no precipitation or separation of particles for a minimum of 24 hours; d) formulation that shows no precipitation or separation of particles when water is added in a ratio of 1 part formulation to 200 parts water for a minimum of 15 minutes.

[0032] Another embodiment relates to: a method for preparing an aqueous curcuma liquid composed of curcuminoids, CRTO, a non-ionic oil-in-water emulsifier, and a solvent to form a uniform mixture; sonicating the mixture of step (a) for 10 seconds at a time and alternately resting for 30 seconds to obtain a clear solution; and diluting the clear solution with an aqueous medium to obtain a desired concentration of curcuma liquid droplets.

[0033] Another embodiment relates to a method for preparing water soluble curcuma powder composed of curcuminoids, CRTO and a non-ionic emulsifier forming a uniform mixture; alternating between sonicating the mixture of step (a) for 10 seconds at a time and resting for 30 seconds to obtain a thick paste; adding an adsorbent while continuing to stir to obtain a mixture; cooling the mixture of step (c) to obtain a dry, brittle mass; grinding the dry, brittle mass to obtain water soluble curcuma powder; and packing the water soluble curcuma powder.

[0034] Another embodiment relates to a method for preparing a transdermal curcuma patch.

[0035] Another embodiment relates to a method for preparing water-soluble curcuma liquid comprising curcuminoids, medium chain triglycerides, non-ionic emulsifiers, adsorbents and a solvent forming a mixture; sonicating the mixture of step (a) for 10 seconds at a time and alternately resting for 30 seconds to obtain a clear solution; and diluting the clear solution with an aqueous medium to obtain a desired concentration of curcuma liquid droplets. [Brief description of the drawings]

[0036] [Figure 1] Figure 1 shows the flow diagram of curcuma formulation. [Diagram 2] Figure 2 shows a schematic diagram of curcuma composite particles. [Figure 3a] FIG. 3a is a graph showing the correlation between particle size of curcumin powder and the time required for transition (transition time or lag time). [Figure 3b] FIG. 3b is a graph showing the correlation between the particle size of CRTO and the time required for transition (transition time or lag time). [Figure 3c] FIG. 3c is a graph showing the correlation between the particle size of TO and the time required for transition (transition time or lag time). [Figure 3d] FIG. 3d is a graph showing the correlation between particle size and the time required for transition (water level time or lag time) in Example 1. [Figure 3e] FIG. 3e is a graph showing the correlation between particle size and time required for transition (level time or lag time) in Example 2. [Figure 3f] FIG. 3f is a graph showing the correlation between particle size and time required for transition (level time or lag time) in Example 3. [Figure 3g] FIG. 3g is a graph showing the correlation between particle size and the time required for transition (water level time or lag time) in Example 4. [Figure 4a] Figure 4a shows the particle size distribution of curcumin powder. [Figure 4b] Figure 4b shows the particle size distribution of CRTO. [Figure 4c] Figure 4c shows the particle size distribution of TO. [Figure 4d] FIG. 4d shows the particle size distribution of Example 1. [Figure 4e] FIG. 4e shows the particle size distribution of Example 2. [Figure 4f] FIG. 4f shows the particle size distribution of Example 3. [Figure 4g] FIG. 4g shows the particle size distribution of Example 4. [Figure 5a] Figure 5a shows the XRD of curcumin powder. [Figure 5b] Figure 5b shows the XRD of CRTO. [Figure 5c] Figure 5c shows the XRD of the PEG-based Curcuma Drops (Curcumin + CRTO) formulation. [Figure 5d] Figure 5d shows the XRD of PG-based Curcuma Drops (Curcumin + CRTO) formulation. [Figure 5e] Figure 5e shows the XRD of the ethanol-based Curcuma Drops (Curcumin + CRTO) formulation. [Figure 5f] Figure 5f shows the XRD of the ethanol-based curcumin droplets (curcumin + CRTO) formulation. [Figure 5g]Figure 5 g shows the XRD of the PEG-based curcumin droplets (curcumin + CRTO) formulation. [Figure 6a(1)] Figure 6a(1) shows the SEM image of curcumin powder. [Figure 6a(2)] Figure 6a(2) shows a magnified SEM image of curcumin powder. [Figure 6b] Figure 6b shows the SEM image of CRTO. [Figure 6c(1)] Figure 6c(1) shows the SEM image of the in-process mixed structure. [Figure 6c(2)] Figure 6c(2) shows the enlarged SEM image of the mixed structure during the process. [Figure 6d(1)] Figure 6d(1) shows the SEM image of the intermediately mixed and solidified mixed structure. [Figure 6d(2)] Figure 6d(2) shows the SEM image of the intermediate mixed solidified mixed structure. [Figure 6d(3)] Figure 6d(3) shows the SEM image of the intermediate mixed solidified mixed structure. [Figure 6d(4)] Figure 6d(4) shows the SEM image of the intermediate mixed solidified mixed structure. [Figure 6e] Figure 6e shows an SEM image of the finished curcuma droplet. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0038] As used herein, the term "including", which is synonymous with "comprises", "including", or "featuring", is defined to be inclusive or open-ended, and does not exclude additional, non-recommended elements or method steps, unless the context clearly requires otherwise.

[0039] All percentages are defined as w / w unless otherwise stated. All measurements are defined according to the International System of Units (SI) unless otherwise stated.

[0040] In order to fully understand the scope of the present invention, the following terms used in this description are here defined.

[0041] "Therapeutically safe" means that the desired therapeutic effect can be achieved by using a formulation that combines the main active ingredients of turmeric, curcuminoids and non-curcuminoids, at a low dose, with the total content of curcuminoids and non-curcuminoids ranging from 1 mg to 500 mg.

[0042] The term "curcuma" is defined as a preparation that combines the biologically active compounds of turmeric, consisting of curcuminoids and non-curcuminoids.

[0043] The term "water soluble" is defined as the ability of a curcuma liquid formulation to remain in the form of a clear solution without precipitation or separation of particles for a minimum of 24 hours, and when added to water in a ratio of 1:200 or greater, to form a clear solution without precipitation or separation of particles for a minimum of 15 minutes.

[0044] The term curcumin is defined as the biologically active curcuminoid found in turmeric.

[0045] The term curcuminoids is defined as linear diarylheptanoids found in turmeric and includes curcumin or derivatives of curcumin.

[0046] The terms "curcumin," "curcuminoid," and "curcuminoids" may be used interchangeably unless otherwise noted. Native curcumin is composed of curcumin, demethoxycurcumin, bisdemethoxycurcumin, and mixtures thereof.

[0047] The term "non-curcuminoid" is defined as bioactive compounds other than curcuminoids, specifically bioactive compounds without the curcumin found in turmeric.

[0048] Turmeric is a rhizomatous herbaceous perennial plant of the genus Curcuma in the family Zingiberaceae, specifically referring to Curcuma Longa.

[0049] The term "pH buffer" is defined as a mixture of a weak acid and its conjugate base, or a weak base and its conjugate acid.

[0050] A "Pharmaceutically acceptable excipient" is defined as a substance, other than an active pharmaceutical ingredient (API), whose safety has been appropriately evaluated, that is intentionally included in a drug delivery system to facilitate processing of the drug formulation during manufacture; and to protect, support, and / or enhance the stability, bioavailability, or patient acceptability; promote the efficacy and / or delivery of the drug formulation, and assist in maintaining the integrity of the drug formulation during storage.

[0051] The term "particle" is defined as a tiny part of a substance, with sizes in the range of 1 to 100 nanometers referred to as ultrafine particles and nanoparticles, and those in the range of 100 to 2500 nanometers referred to as fine particles.

[0052] The term effective diameter is defined as the average size of the particles in a given sample. The effective diameter is equal to the sum of the diameters of the particles in the sample divided by the number of particles in the sample.

[0053] Polydispersity is a measure of the range of particle sizes and is expressed as the polydispersity index (PDI), which describes the distribution of particle size populations within a given sample. PDI values ​​range from 0.0 for a sample that is completely homogeneous in terms of particle size to 1.0 for a highly polydisperse sample with multiple particle size populations.

[0054] The term sediment loading less than 30% is defined as an indistinguishable haze in a clear solution caused by particles in the solution when viewed with the naked eye, and is measured by filtering a clear solution through Whatmann No. 42 filter paper and calculating the residue remaining on the filter paper.

[0055] The term "stable" is defined as a formulation that, when added to water at a ratio of 1:200 or greater, gives a clear, transparent solution when stored under normal environmental conditions (25°C temperature, 60% relative humidity) for up to 6 months and does not show any particle separation or precipitation when the solution prepared by adding the formulation to water is orally ingested within 15 minutes.

[0056] The term "turmeric pigment (TO)" is defined as an extract of turmeric in the form of a viscous oily liquid, a pasty semi-solid, or a hard amorphous solid, containing various concentrations of curcuminoids and essential volatile oils, where the volatile oils consist of a mixture of non-curcuminoids in various concentrations.

[0057] The term "turmeric oil (TOIL)" is defined as an essentially volatile oil composed of a mixture of non-curcuminoids with different concentrations.

[0058] The term "Curcumin-Removed Turmeric Ointment (CRTO)" is defined as the mother liquor obtained after at least one extraction of curcumin from TO, which is used in the extraction process after removal of residual solvents and constitutes essentially a volatile oil containing a mixture of non-curcuminoids. The term may also refer to various concentrations of curcuminoids.

[0059] The hydrophilic-lipophilic balance (HLB) is defined as the relative efficiency of the hydrophilic and lipophilic portions of a surfactant molecule.

[0060] The term "emulsifier" is defined as an emulsifying agent compound or substance that acts as an emulsion stabilizer. An emulsion is a mixture of two or more liquids that are normally immiscible. Emulsifiers prevent the immiscible liquids from separating from each other in a mixture. Emulsifiers are also sometimes defined as a type of surfactant.

[0061] The term "oil-in-water emulsifier" is defined as an emulsifier compound or substance that acts as a stabilizer of an oil-in-water emulsion, where oil is the dispersed phase and water is the continuous phase.

[0062] The term "non-ionic oil-in-water emulsifier" is defined as an emulsifier compound or substance that acts as a stabilizer of an oil-in-water emulsion, where the oil is in the hydrophilic portion of the emulsifying substance and does not contain ionic groups.

[0063] The terms emulsifier and surfactant may be used interchangeably unless otherwise specified.

[0064] A lipophilic solvent is defined as a substance that is capable of dissolving other lipophilic substances.

[0065] The term solvent is defined as a liquid that is capable of dissolving other substances.

[0066] A pharma- ceutically acceptable excipient is defined as a substance, other than an active pharmaceutical ingredient (API), that has been appropriately evaluated for safety and is intentionally included in a drug delivery system to facilitate processing of the drug formulation during manufacturing; and to protect, support, and / or enhance the stability, bioavailability, or patient acceptability; further promote the efficacy and / or delivery of the drug formulation, and assist in maintaining the integrity of the drug formulation during storage.

[0067] The term adsorbent is defined as a solid that has the ability to bind particles in a liquid to its surface.

[0068] The terms diluents, fillers and binders are defined as pharma- ceutically acceptable excipients that impart desirable physical and functional properties to a drug / medical product formulation.

[0069] The term carrier is defined as a pharma- ceutical acceptable excipient. These products are designed to interact with and enhance the properties of the drug substance. Active Pharmaceutical Ingredient = API.

[0070] In one embodiment, the present invention relates to a pH buffer-free, water-soluble curcuma formulation comprising CRTO, a curcuminoid, and an emulsifier or a pharma- ceutically acceptable salt or derivative thereof. In some embodiments, the present invention relates to a pH buffer-free, water-soluble curcuma formulation comprising TO, a curcuminoid, and an emulsifier or a pharma- ceutically acceptable salt or derivative thereof.

[0071] In one embodiment, the curcuma formulation comprises: 1-10% w / w of the compound curcumin and / or its metabolites; 5-70% w / w CRTO; 30~45 % w / w non-ionic emulsifier 0.01% to 90% w / w of one or more other pharma- ceutically acceptable excipients or carriers.

[0072] In one embodiment, the curcuma formulation comprises: 1-10% w / w of the compound curcumin and / or its metabolites; TOIL from 5 to 70% w / w; 30~45 % w / w non-ionic emulsifier 0.01% to 90% w / w of one or more other pharma- ceutically acceptable excipients or carriers.

[0073] In one embodiment, the curcuma formulation comprises: 1-10% w / w of the compound curcumin and / or its metabolites; 5-70% w / w TO; 30-45 % w / w non-ionic emulsifier; 0.01% to 90% w / w of one or more other pharma- ceutically acceptable excipients or carriers.

[0074] In one embodiment, the present invention relates to water-soluble ultrafine and fine particle curcuma formulations with therapeutically safe curcuminoids and non-curcuminoids.

[0075] In some embodiments, the present invention relates to water-soluble curcuma formulations comprising TO and curcuminoids with therapeutically safe ultrafine and fine particles.

[0076] In some embodiments, the present invention relates to water-soluble curcuma formulations composed of CRTO and curcuminoids with therapeutically safe ultrafine and fine particles.

[0077] In one embodiment, the curcuma formulation comprises therapeutically safe ultrafine and microparticles of TOIL and curcuminoids. In one embodiment, the curcuma formulations comprise therapeutically safe ultrafine and microfine particles of TO, CRTO, TOIL and curcuminoids.

[0078] In some embodiments, the average particle size of the curcuma formulation is between about 40 nm and 200 nm. In some embodiments, the average particle size of the curcuma formulation is between about 40 nm and 100 nm. In some embodiments, the average particle size of the curcuma formulation is between about 40 nm and 300 nm. In some embodiments, the average particle size of the curcuma formulation is between about 40 nm and 500 nm. In some embodiments, the average particle size of the curcuma formulation compound is between about 40 nm and 1000 nm. In some embodiments, the average particle size of the curcuma formulation is between 40 nm and 2500 nm. In some embodiments, the average particle size of the curcuma formulation is between about 201 nm and 300 nm. In some embodiments, the average particle size of the curcuma formulation is between about 301 nm and 400 nm. In some embodiments, the average particle size of the curcuma formulation compound is between about 401 nm and 500 nm. In some embodiments, the average particle size of the curcuma formulation is between about 501 nm and 1000 nm. In some embodiments, the average particle size of the curcuma formulation is between about 1001 nm and 2000 nm. In some embodiments, the average particle size of the curcuma formulation is a combination of ultrafine particles in the range of 40 nm to 100 nm and fine particles in the range of 100 nm to 2500 nm.

[0079] In some aspects, blank ultrafine and fine particles devoid of curcuminoids and / or non-curcuminoids can be present in the curcuma formulation.

[0080] In some embodiments, the CRTO comprises a mixture of non-curcuminoids and / or residual amounts of curcuminoids after extraction from TO. In some embodiments, the CRTO is demethoxycurcumin, bisdemethoxycurcumin, aromatic turmerone, β-trans-furanesene, aromatic curcumene, curulone, α-zingiberene, β-bisabolene, caryophyllene oxide, α-pellandrene, β-cymene, 1,8-cineole, trans-ocimene, α-terpineol, dehydrocurcumene, hexadecanoic acid, heptadecanoic acid, and / or mixtures thereof.

[0081] In some embodiments, the TO or CRTO is comprised of sesquiterpenes, diarylheptanoids and / or mixtures thereof, including curcumin-free compounds such as sesquiterpenes, monomeric phenylpropenes, diarylpentanoids, tetrahydrocurcumin, cyclocurcumin, monoterpenes, steroids, alkaloids, diterpenes, triterpenoids, fatty acids, sugars, proteins, carbohydrates, fibers, minerals, resins and / or mixtures thereof. In some embodiments, the non-curcuminoids comprise a mixture of turmerone, turmeronol, turmerone, turmerin, himachalane, bergamotan, aristrene, silinane, carburane, cedrane, dihydrozingerone, sesquisabinane, sesquiphellandrene, curcumene, elemene, and bisacron. Curdione, cyclocurcumin, germacrone, furanodiene, curcumol, calebin A, acrone, santalan, guaiane, curulone, carvacrol, limonene, tetrahydrocurcumin, hexahydrocurcumin, octahydrocurcumin, ferulic acid, in the form of essential oils and / or mixtures thereof.

[0082] In one embodiment, the amount of curcumin and / or its metabolites in CRTO is 1-50% w / w and the amount of non-curcuminoids in CRTO is 49-99% w / w. In some embodiments, the amount of curcumin and / or its metabolites in CRTO is 1-50% w / w and the amount of turmerones in CRTO is 5-40% w / w.

[0083] In one embodiment, the TO comprises curcumin and / or its metabolites and non-curcuminoids, the amount of curcumin and / or its metabolites being 1-95% and the amount of non-curcuminoids being 0.5-99%. In one embodiment, the TO comprises curcumin and / or its metabolites and non-curcuminoids, the amount of curcumin and / or its metabolites being 1-95% and the amount of non-curcuminoids being 0.5-99%.

[0084] In some embodiments, TOIL or EVO comprises curcumin and / or its metabolites and non-curcuminoids, with the amount of curcumin and / or its metabolites being 1-15% and the amount of non-curcuminoids being 5-75%. In some embodiments, TOIL comprises curcumin and / or its metabolites and turmerone, with the amount of curcumin and / or its metabolites being 1-10% and the amount of turmerone being 5-40%.

[0085] In one embodiment, the present invention relates to a water-soluble curcuma compound comprising CRTO and a curcuminoid, or a pharma- ceutically acceptable salt thereof, or a derivative thereof, with improved stability as a self-emulsifying formulation. In one embodiment, the present invention relates to a water-soluble curcuma compound comprising CRTO and a curcuminoid, or a pharma- ceutically acceptable salt thereof, or a derivative thereof, with improved stability as a self-emulsifying formulation. In some embodiments, the present invention relates to a water-soluble curcuma formulation comprising TOIL or EVO and a curcuminoid with improved biological stability as a self-nanoemulsifying formulation. In some embodiments, the present invention relates to a water-soluble curcuma formulation comprising TOIL or EVO, TO, CRTO and a curcuminoid with improved biological stability as a self-nanoemulsifying formulation.

[0086] In certain embodiments, the compound comprises a non-ionic emulsifier. In some embodiments, the compound comprises a non-ionic oil-in-water emulsifier.

[0087] In one embodiment, the amount of emulsifier is 30-45% w / w of the curcuma formulation.

[0088] In some embodiments, the non-ionic oil-in-water emulsion has a high HLB value and is highly soluble in water. The non-ionic emulsion has an HLB value of 9-18, preferably 11-16. In some embodiments, the emulsifiers of the present disclosure can be used alone or in combination to maintain the total HLB of the curcuma formulation at 9-18.

[0089] In one embodiment of the present disclosure, the non-ionic oil-in-water emulsifier is selected from the group consisting of polyoxyethylene products of hydrogenated vegetable oils, including but not limited to commercially available dalda, margarine, polyethoxylated castor oil, polyethoxylated hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, or combinations thereof. Commercially available are: Kolliphor® EL (PEG-35 castor oil), Kolliphor® RH40 (PEG-40 hydrogenated castor oil), Kolliphor® RH60 (PEG-60 hydrogenated castor oil), Labrasol® (PEG-8 caprylic / capric glycerides), Gelucire® (stearoyl polyoxyl glycerides), polysorbates. PLURONIC® L-64 and L-127 (block copolymers based on ethylene oxide and propylene oxide), TRITON® X 100 (polyethylene glycol tert-octylphenyl ether), SIMULSOL® (polyoxyethylated products consisting of polyoxyethylated lauric alcohols. NIKKOL® HCO-50 (polyoxyethylene (50) hydrogenated castor oil), NIKKOL® HCO-35 (polyoxyethylene (35) hydrogenated castor oil), NIKKOL® HCO-40 (polyoxyethylene (40) hydrogenated castor oil), NIKKOL® HCO-60 (polyoxyethylene (60) hydrogenated castor oil), TWEENS® (polysorbates) and mixtures thereof.

[0090] In certain embodiments, the solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol, glycofurol, polyethylene glycol (PEG 200, 400), glycerol, polypropylene glycol, propylene glycol, N-methyl-2-pyrrolidone and ethyl alcohol and / or mixtures thereof.

[0091] In certain embodiments, the lipophilic solvent is selected from, but is not limited to, medium chain triglycerides, caprylic triglycerides, capric triglycerides, and / or oils containing medium chain triglycerides, defined herein as triglycerides having 2 or 3 fatty acids with an aliphatic chain of 8 to 12 carbon atoms, CAPTEX 300, oils containing isopropyl myristate, isopropyl palmitate, ethyl linoleate, fatty acid esters of ethyl oleate, propylene glycol dicaprylate, propylene glycol dilaurate, or propylene glycol difatty acid esters, and / or mixtures thereof.

[0092] In certain embodiments, the lipophilic solvent is 50-200% w / w of the curcumin, hi some embodiments, the lipophilic solvent is 5-70% w / w of the compound.

[0093] In certain embodiments, the compound may contain suitable pharma- ceutically acceptable excipients, including, but not limited to, the following: adsorbents, diluents, fillers, sweeteners, flavorings, polymers, carriers, gelling agents, stabilizers, surfactants, plasticizers, lubricants, reducing agents, buffers, sweeteners, bases, correctives, binders, suspending agents, antioxidants, abrasives, coating agents, wetting agents, gelling agents, wetting regulators, fillers, antifoaming agents, refrigerating agents, colorants, flavors, perfumes, sugar coating agents, isochronic agents, softeners, emulsifiers, foaming agents, pH adjusters, antifoaming agents, flavors, preservatives, diluents, excipients, dispersants, disintegrants, flavors, desiccants, preservatives, solubilizers, solvents, superplasticizers, antistatic agents, expanders, humectants, and the like.

[0094] In certain embodiments, the adsorbent is selected from, but is not limited to, PEG 6000, maltodextrin, starch, hydrolyzed starch, fiber (soluble oligosaccharides from plants such as chicory), dextran, cellulose, copolymers of polyvinylpyrrolidone, sugar alcohols such as isomalt, sorbitol, xylitol, mannitol, cellulose derivatives (such as hydroxypropylmethylcellulose (HPMC) and / or hydroxypropylcellulose (HPC)), cyclodextrin and its derivatives, and combinations thereof. In some embodiments, the adsorbent is PEG 6000 (melting at 60°C) and / or maltodextrin.

[0095] In certain embodiments, the diluent or filler or binder is selected from, but not limited to, mannitol, sorbitol, lactose, hard boiled candy, confectionary sugar, hi some embodiments, the diluent or filler or binder is mannitol or sorbitol.

[0096] In certain embodiments, the carrier is a water soluble polymer, including but not limited to: polyglutamic acid, polyethylene glycol, propylene glycol, glycerol, propylene glycol esters, polyglycerol oleate, polyvinyl alcohol, glyceryl stearate (and) polyglyceryl-6 palmitate / succinate (and) cetearyl alcohol (NatraGem® EW), non-ethoxylated polymers such as N-(2-hydroxypropyl) methacrylamide (PHPMA). The polyethylene glycol may have a number average molecular weight of about 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000.

[0097] In certain embodiments, the gelling agent is selected from, but is not limited to, carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, poloxamer, polyvinyl alcohol, sodium alginate, tragacanth, xanthan gum.

[0098] In some embodiments, the compounds can be taken orally in solid (e.g., tablets or pills), liquid (e.g., solutions, suspensions, or lotions), or semi-solid (e.g., gels, creams, or ointments), or in the form of drops or powders, or capsules. In some embodiments, these compositions are placed in the mouth to provide an ingestible component, making available a therapeutically effective amount of the compound. As such, they can be prepared as water-soluble compositions, provided in liquid form, lyophilized, encapsulated, or provided in a time-release, delayed release, or in a form suitable for intestinal placement, or in any form typically used for oral medicines, dietary supplements, or vitamins. Alternatively, they can be combined with food or other ingestible products. In some embodiments, the oral soluble tablet dissolves in the tongue or buccal cavity within 15 to 30 minutes. In some embodiments, the oral soluble tablet is a troche. In some embodiments, the troche dissolves when placed against the cheek and is sucked to exert its effect around the pharynx (throat). In some embodiments, the troche dissolves in about 5 minutes. In some embodiments, the compounds are applied by nasal sprays, inhalation techniques, transdermal, transmucosal, ophthalmic, suppository, injection, or intravenous infusion. In some embodiments, the compounds can be combined with other dietary supplements, vitamins, amino acids, proteins, dietary fiber, natural products such as honey, and the like, to provide an orally ingestible anti-hangover or health drink.

[0099] In certain embodiments, the compounds may be used to treat a variety of conditions in humans, including, but not limited to, the following inflammatory diseases: cancer, cardiovascular disease, arthritis, uveitis, ulcerative colitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen, gastric inflammation, vitritis, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immune deficiency syndrome, beta-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis.

[0100] In another embodiment of the present disclosure, a process for preparing a compound is disclosed. In an embodiment, the compound can be formulated by techniques including, but not limited to, ultrasonication, emulsification, solvent titration, milling, spray drying, solid dispersion, hot melt extrusion, freeze drying, nano / micro precipitation, which can be performed by methods such as supercritical fluid technology.

[0101] In one embodiment of the present disclosure, the preparation of water soluble curcuma droplets includes the following steps: a. mixing curcumin, TO, or CRTO, or TOIL, or a combination thereof, a non-ionic oil-in-water emulsifier, and a solvent to form a homogenous mixture; b. sonicating the mixture of step (a) for 10 seconds at a time and alternately resting for 30 seconds to obtain a clear solution; and c. Dilute the clear solution with aqueous medium to obtain the desired concentration of curcuma drops.

[0102] In one embodiment of the present disclosure, the preparation of water soluble curcuma powder includes the following steps: a. mixing curcumin, TO, or CRTO, or TOIL, or a combination thereof, and a non-ionic emulsifier to form a homogenous mixture; b. Sonicate the mixture from step (a) for 10 seconds at a time, alternately allowing it to rest for 30 seconds, until a thick paste is obtained; c. Adding the adsorbent to the paste of step (b) with continuous stirring to obtain a mixture; d. Cooling the mixture of step (c) to obtain a dry brittle mass; e. crushing the dried brittle mass to obtain water-soluble curcuma powder; and f. Packing water-soluble curcuma powder.

[0103] In one embodiment of the present disclosure, the preparation of the water soluble curcuma formulation includes the following steps; a. mixing curcumin, TO, CRTO, TOIL, or a combination thereof with a non-ionic emulsifier to form a homogenous mixture; b. The mixture from step (a) is sonicated for 10 seconds at a time, followed by a 30 second rest period, alternately, to obtain a thick paste; c. Adding the adsorbent to the paste of step (b) with continuous stirring to obtain a mixture; d. Cooling the mixture of step (c) to obtain a dry brittle mass; e. Crushing the dry brittle mass to obtain a powder; f. adding pharma- ceutically acceptable diluents, fillers, binders, sweeteners, flavors to the obtained powder, and mixing / fusing to obtain a mixture; g. Compressing the blended mixture to produce conventional and / or water-soluble tablets / lozenges; Packages of water-soluble curcuma tablets / lozenges; h. Dissolve the tablets obtained in step (g) in an appropriate amount of purified water to obtain a water-soluble liquid. i. Package water-soluble curcuma liquid.

[0104] In one embodiment of the present disclosure, the preparation of a transdermal curcuma patch includes the following steps: a. mixing curcumin, TO, CRTO, TOIL, or a combination thereof with a non-ionic emulsifier to form a homogenous mixture; b. Sonicate the mixture of step (a) for 10 seconds and 30 seconds at a time alternately to obtain a thick paste;Add the adsorbent to the thick paste of step (b) with continuous stirring;Mix solvents such as ethanol and methylene chloride to prepare a mixed solvent; c. Mix hydroxypropyl methylcellulose and ethylcellulose in a mortar and pestle to prepare a polymer mixture; d. adding a third portion of the solvent mixture from step (d) to the polymer mixture; e. homogenizing the polymer mixture until a uniform polymer solution is obtained; f. Mix diethyl phthalate into the above polymer solution of step (e); Mix the ultrasonically treated mixture of step b into the obtained mixture until a homogeneous solution or dispersion is obtained; Bring the obtained solution or dispersion to the final volume; Pour the resulting solution into a container such as; a plastic petri dish of 9 cm diameter (with aluminum foil fixed on the bottom of the dish) and disperse the solution evenly around the entire circumference of the dish without introducing air bubbles; Dry the above solution at room temperature for 8-10 hours or keep it in a dryer at 40 °C until a completely dry film is obtained; A peeling film is obtained on one side of the aluminum foil as a support.

[0105] In one embodiment of the present disclosure, the preparation of water soluble curcumad droplets includes the following steps: a. mixing curcumin, TO, CRTO, TOIL, or a combination thereof, medium chain triglyceride, non-ionic emulsifier, adsorbent and solvent to form a mixture; b. Allow the mixture from step (a) to rest for 10 seconds at a time and 30 seconds alternately to obtain a clear solution; c. The clear solution is then diluted with aqueous medium to obtain the desired concentration of curcuma water droplets.

[0106] In one embodiment of the present disclosure, the preparation of water soluble curcuma powder includes the following steps: a. mixing curcumin, TO, CRTO, TOIL, or a combination thereof, a medium chain triglyceride, and a non-ionic emulsifier to form a mixture; b. Ultrasonicate the mixture of step (a) for 10 seconds at a time and alternately for 30 seconds to obtain a thick curcumin paste; c. Mixing the curcumin paste of step (b) with an adsorbent such as PEG-6000 melted at 60°C and cooling to obtain a dry brittle mass; d. The dried brittle mass of step (c) was crushed to obtain water soluble Curcuma powder.

[0107] In one embodiment of the present disclosure, the preparation of water soluble curcuma tablets includes the following steps: a. mixing and dispersing curcumin, TO, CRTO, TOIL, or a combination thereof, medium chain triglyceride, and non-ionic emulsifier in a solvent; b. Ultrasonicate the mixture of step (a) for 10 seconds at a time and alternately for 30 seconds to obtain a thick curcumin paste; c. Mixing the curcumin paste from step (b) with an adsorbent such as molten PEG-6000 at 60°C and cooling to obtain a dry brittle mass; d. Grinding the dried brittle mass of step (c) to obtain water-soluble curcuma powder; e. Pharmaceutically acceptable excipients are added to the curcuma powder of step (d) to obtain tablets.

[0108] The present invention is illustrated in the following examples, in which all parts and amounts are by weight unless otherwise specified, and which are not intended to be construed as limiting the scope of the invention.

[0109] Working example

[0110] Example 1 The mixture of ethanol-based curcuma droplets is shown in Table 1. [Table 1] *"Curcumin (95%)" refers to a mixture containing 95% or more curcuminoids by weight. Sample 1, Curcuma Droplets, was formulated according to the following procedure: Step 1: Take Kolliphor EL and add CRTO while stirring. Heat this mixture with stirring until it reaches the required temperature between 80°C-120°C. Slowly add curcumin powder to this mixture and continue stirring while maintaining the temperature between 80°C-120°C. Continue stirring for 5 minutes until the addition of curcumin is complete. Once a dark brown solution appears, remove from heat and continue stirring until the temperature of the mixture drops to 40°C. Step 2: Dissolve sucralose in a certain amount of ethanol while stirring. Continue stirring for 10 minutes. Step 3: Slowly add step 2 to step 1 and continue stirring for 10 minutes. Step-4: Sonication is carried out using an ultrasonic disintegrator (UP200st Ultrasonic processor, Hielscher, Germany) for the volume of step-3 with the following parameters: Ultrasonic processing – depending on batch size. Energy: 50000 watts Temperature cut-off: 40℃. On-time cycle: 10~20 seconds Off time cycle: 20-30 seconds · Number of cycles: until a certain amount of energy is transferred to the mixture. Step-7: Place the Curcuma droplets in a suitable water droplet storage container.

[0111] Example 2 The composition of propylene glycol (PG) based curcuma droplets is shown in Table 2. [Table 2] Sample 2, curcuma droplets, were formulated according to the following procedure. Step-1: Take Kolliphor EL and add CRTO while stirring. Heat this mixture with stirring until it reaches the required temperature between 80°C-120°C. Slowly add curcumin powder to this mixture and continue stirring while maintaining the temperature between 80°C-120°C. Continue stirring for 5 minutes until the addition of curcumin is complete. Once a dark brown solution appears, remove from heat and continue stirring until the temperature of the mixture drops to 40°C. Step-2: Take HPMC E-5 and disperse it in a certain amount of purified water while stirring. Continue stirring for 5 minutes. Step 3: Slowly add step 2 to step 1 and continue stirring. Continue stirring for 5 minutes. Step-4: Take a specified amount of sucralose and add it to the volume of Step-3 while stirring. Continue stirring for 10 minutes. Step-5: Take a certain amount of propylene glycol and add it to the volume of step-4 while stirring. Continue stirring for 15 minutes. Step-6: Sonication is carried out using an ultrasonic disintegrator (UP200st Ultrasonic processor, Hielscher, Germany) for the volume of step-5 with the following parameters: Ultrasonic processing – depending on batch size. Energy: 50000watts. Temperature cut-off: 40℃. On-time cycle: 10~20 seconds Off time cycle: 20-30 seconds · Number of cycles: until a certain amount of energy is transferred to the mixture. Step-7: Place the Curcuma droplets in a suitable water droplet storage container.

[0112] Example 3 The composition of curcuma droplets formulated with polyethylene glycol (PEG) is shown in Table 3. [Table 3] Sample 3, Curcuma Droplets, was formulated according to the following procedure: Step-1: Take Kolliphor EL, stir and add CRTO. Heat this mixture with stirring until it reaches the required temperature between 80°C-120°C. Slowly add Curcumin powder to this mixture and continue stirring while maintaining the temperature between 80°C-120°C. Continue stirring for 5 minutes until the curcumin addition is complete. Once a dark brown solution appears, remove from heat and continue stirring until the mixture cools to 40°C. Step-2: Take HPMC E-5 and disperse it in a certain amount of purified water while stirring. Continue stirring for 5 minutes. Step 3: Slowly add step 2 to step 1 and continue stirring. Continue stirring for 5 minutes. Step-4: Take a specified amount of sucralose and add it to the volume of Step-3 while stirring. Continue stirring for 10 minutes. Step-5: Take a certain amount of PEG-400 and add it to the volume of Step-4 while stirring. Continue stirring for 15 minutes. Step-6: Sonication is carried out using an ultrasonic disintegrator (UP200st Ultrasonic processor, Hielscher, Germany) for the volume of step-5 with the following parameters: Ultrasonic processing – depending on batch size. Energy: 50000watts. Temperature cut-off: 40℃. On-time cycle: 10~20 seconds Off time cycle: 20-30 seconds · Number of cycles: until a certain amount of energy is transferred to the mixture. Step-7: Place the Curcuma droplets in a suitable water droplet storage container.

[0113] Example 4 Curcuma liquid formulation with increased dose of curcumin using CRTO & PEG 400. The formulation of curcuma droplets with PEG 400 is shown in Table 4. [Table 4] Sample 4, Curcuma Droplets, was formulated according to the following procedure: Step-1: Take Kolliphor EL and add CRTO (Curcumin 10% infused) while stirring. Heat this mixture while stirring until it reaches the required temperature between 100°C-120°C. Slowly add Curcumin powder to this mixture and continue stirring while maintaining the temperature between 100°C-120°C. Continue stirring for 5 minutes until the addition of Curcumin is complete. Step-2: Take HPMC E-5 and disperse it in a certain amount of purified water while stirring. Continue stirring for 5 minutes. Step 3: Slowly add step 2 to step 1 and stir at 100°C to 120°C. Continue stirring for 5 minutes. Step-4: Take PEG-400 and heat with stirring to required temperature between 100°C-120°C. Continue stirring while maintaining the temperature at 100°C-120°C and slowly add the specified curcumin. Continue stirring for 5 minutes. Step 5: Slowly add step 4 to step 1 and continue stirring while maintaining the temperature at 100°C to 120°C. Remove from heat and continue stirring until the temperature of the mixture drops to 70°C. Step 6: Using an ultrasonic disintegrator (UP200st Ultrasonic processor, Hielscher, Germany) for the volume of step 5, perform ultrasonic treatment with the following parameters: Ultrasonic processing – depending on batch size. Energy: 150000watts. Temperature cut-off: 120℃ On-time cycle: 10~20 seconds Off time cycle: 20-30 seconds · Number of cycles: until a certain amount of energy is transferred to the mixture. Step-7: Place the obtained curcumin droplets in a suitable water droplet storage container.

[0114] Example 5 The different batch formulas of Curcuma droplets are shown in Table 5. [Table 5] For all samples of Example 5, the sonication procedure was kept the same during preparation. The sonication was carried out according to the following procedure: TIFF0007671693000006.tif119170TIFF0007671693000007.tif88170TIFF0007671693000008.tif108170The various samples of Example 05 were prepared according to the following procedure: Sample 05 of Example 05 was prepared according to the following procedure: Step-1: Add sucralose and dissolve it manually in ethanol. Step 2: Disperse curcumin in Captex 300 and Kolliphor EL and place in a stainless steel container and heat at 80°C to 130°C while stirring manually. Step-3: Cool step-2 to room temperature. Maintain the temperature at 30°C -35°C and add step-1 to step-2. Add cardamom flavour to step-2. Step 4: Adjust the volume with ethanol. Step 5: Perform ultrasonic treatment under the conditions shown in Table 6. [Table 6] Sample 06 of Example 05 was prepared according to the following procedure: Step-1: Take Kolliphor EL & CRTO in a stainless steel vessel and heat at 80°C-120°C while stirring at 1200-1400 rpm. While continuing to stir at 1200-1400 rpm, slowly add curcumin powder until a deep yellow-brown solution appears. Step 2: Cool Step 1 to room temperature. Step-3: Add sucralose and dissolve it manually in ethanol. Add step-1 to this while stirring at 1200-1400 rpm. Step-4: Perform sonication as in step 1 under the conditions shown in Table 07. [Table 7] Sample 07 of Example 05 was prepared according to the following procedure: Step-1: Take Kolliphor EL in a stainless steel container and heat it at 80°C-120°C while stirring at 1200-1400 rpm. While continuing to stir at 1200-1400 rpm, slowly add curcumin powder until a deep yellow-brown solution appears. Step 2: Cool Step 1 to room temperature. Step-3: While stirring manually, slowly add CRTO. Step 4: Perform sonication as in step 1 under the conditions shown in Table 8. [Table 8] Sample 08 of Example 05 was prepared according to the following procedure: Procedure-1: Take Kolliphor EL and CRTO in a stainless steel vessel and heat at 40°C while stirring at 1200-1400 rpm. While continuing to stir at 1200-1400 rpm, slowly add curcumin powder until a deep yellow-brown solution appears. Step-2: Add sucralose and menthol and dissolve manually in ethanol. Step 3: Cool Step 1 to room temperature. Step-4: Perform sonication as in step 1 under the conditions shown in Table 9. [Table 9] Sample 09 of Example 05 was prepared according to the following procedure: Step-1: Take Kolliphor EL & CRTO in a stainless steel vessel and heat at 80°C-120°C while stirring at 1200-1400 rpm. Slowly add curcumin and black pepper powder while stirring at 1200-1400 rpm until a brown solution is observed. Step 2: Cool Step 1 to room temperature. Step-3: Add sucralose and dissolve it manually in ethanol. Add step-1 to this while stirring at 1200-1400 rpm. Step 4: Perform sonication as in step 1 under the conditions shown in Table 10. [Table 10] Samples 10, 11, 14, and 16 of Example 5 were prepared according to the following procedure: Step-1: Take Kolliphor EL & CRTO in a stainless steel vessel and heat at 80°C-120°C while stirring at 1200-1400 rpm. While continuing to stir at 1200-1400 rpm, slowly add curcumin powder until a deep yellow-brown solution appears. Step 2: While continuing to stir at 1200-1400 rpm, cool Step 1 to room temperature. Step 3: Add sucralose and dissolve it in ethanol while stirring at 800-1000 rpm for 10 minutes. Add this to step 2 while stirring at 1200-1400 rpm. Step-3: Perform sonication as in step 2 under the conditions shown in Table 11. [Table 11] Sample 12 of Example 05 was prepared according to the following procedure: Step-1: Place Kolliphor EL & CRTO in a stainless steel container and heat. Once the temperature reaches 65°C, slowly add the curcumin powder while continuing to stir at 1800 rpm. Maintain the temperature between 80°C-120°C and continue to stir at 1800 rpm for 30 minutes. Step 2: Cool Step 1 to 40°C while stirring at 1900 rpm. Add sucralose and stir. Step 3: Adjust the volume with propylene glycol and stir at 2200 rpm for 30 minutes. Step 4: Perform ultrasonic treatment under the conditions shown in Table 12. [Table 12] Sample 13 of Example 05 was prepared according to the following procedure: Step-1: Place Kolliphor EL, Captex 300 and CRTO oil in a stainless steel container and heat at 80°C-120°C while stirring at 1800 rpm. Slowly add curcumin powder while stirring at 1800 rpm until the solution turns brown. Step 2: While continuing to stir at 1800-1900 rpm, cool Step 1 to 40°C. Add sucralose and stir for 10 minutes. Step 3: Adjust the volume with propylene glycol and stir at 1800-1900 rpm for 15 minutes. Step 4: Perform ultrasonic treatment under the conditions shown in Table 13. [Table 13] Sample 15 of Example 05 was prepared according to the following procedure: Step-1: Take HPMC E-5, disperse it in purified water while stirring at 700-900 rpm, and leave it for 30 minutes to swell. Step-2: Take Kolliphor EL & CRTO in a stainless steel vessel and heat at 80°C-120°C while stirring at 1200-1400 rpm. While continuing to stir at 1200-1400 rpm, slowly add curcumin powder until a deep yellow-brown solution appears. Step 3: Add propylene glycol to step 2 while stirring at 1200-1400 rpm for 10 minutes, then add sucralose while stirring at 1200-1400 rpm. Cool step 2 to room temperature. Step-3: Add step-1 to step-2 while stirring at 1200-1400 rpm. Step 4: Perform sonication as in step 2 under the conditions shown in Table 14. [Table 14] It was observed that the physical properties of the final products of different sample numbers of Example 05 were different. Sample numbers 05, 06, 07, 12, 13 showed precipitation / sediment. Sample numbers 08, 09 showed no precipitation / sediment but were flavored. Sample numbers 10, 11, 14, 16 showed no precipitation / sediment but were flavored and had ethanol present. Sample number 15 showed no precipitation / sediment but were flavored and had propylene glycol and HPMC present.

[0115] Example 6 The composition of Curcuma Droplets of Example 6 is shown in Table 15. [Table 15] **"QS" means sufficient for the desired purpose, such as flavoring in the case of flavorings. The compound of Example 6 was prepared according to the following procedure: Curcumin, CRTO, Coliforme EL, and ethanol were weighed and mixed to form a mixture; the obtained mixture was sonicated for 10 seconds at a time using a Hiescher Ultrasound sonication device, with alternating rest periods of 30 seconds until the total power reached 50,000 watts of energy, to obtain a curcumin solution. This curcumin solution was diluted with water by adding 1-10 ml to 200 ml of water to obtain a clear solution. The clear solution contains 1 mg / ml curcumin. Place 5 drops (equivalent to 5 mg) on ​​the tongue or in the mouth.

[0116] Example 7 The composition of the curcumin powder of Example 7 is shown in Table 16. [Table 16] The compound of Example 7 was prepared according to the following procedure: Curcumin, CRTO, and coliforme EL were weighed and mixed to form a mixture. Using a Hiescher Ultrasound sonication device, the obtained mixture was sonicated for 10 seconds at a time, with alternating rests of 30 seconds, until a total power of 50,000 watts of energy was reached, to obtain a thick paste. To this thick paste, PEG6000 (melted at 60°C) was added with continued stirring to obtain a homogeneous mixture. The mixture was cooled to obtain a dry, brittle mass, which was then crushed to obtain curcuma powder.

[0117] Example 8 The composition of the caliber dissolved curcuma powder is shown in Table 17. [Table 17] The compound of Example 8 was prepared according to Example 7, except that PEG6000 was replaced with maltodextrin.

[0118] Example 9 The composition of the orally dissolving curcumin tablets is shown in Table 18. [Table 18] The compound of Example 9 was prepared according to the following procedure: First, curcumin powder was formed according to Example 7. Then, appropriate excipients were added to the curcuma powder to form tablets.

[0119] Example 10 The composition of the orally dissolving curcumin tablets is shown in Table 19. [Table 19] Example 10 compound was prepared according to Example 09, except PEG6000 was replaced with maltodextrin.

[0120] Example 11 The composition of the orally dissolving Curcuma troches is shown in Table 20. [Table 20] The compound of Example 11 was prepared according to the following procedure: First, curcumin powder was formed according to Example 7. Appropriate excipients were added to the curcuma powder to form lozenges.

[0121] Example 12 The composition of Curcuma troches is shown in Table 21. [Table 21] The compound of Example 12 was prepared according to Example 11, except that PEG6000 was replaced with maltodextrin.

[0122] Example 13 The composition of the transdermal patch loaded with Curcuma is shown in Table 22. [Table 22] The compound of Example 13 was prepared according to the following procedure: The compound of Example 13 was prepared according to the following procedure: Curcumin, CRTO, and Kolliphor EL were mixed to form a curcuma mixture. This mixture in a container was sonicated using a Hiescher Ultrasound ultrasonic device for 10 seconds at a time, 30 seconds alternately, to a total energy of 50,000 watts to obtain a curcuma paste. Ethanol and methylene chloride were mixed to prepare a solvent mixture. HPMC and ethyl cellulose were mixed to form a polymer mixture. The solvent mixture and polymer mixture were mixed to obtain a polymer solution. Diethyl phthalate and curcuma paste were mixed into the polymer solution to form a homogenous mixture. This homogenous mixture was poured into a Petri dish and dried to obtain a film.

[0123] Example 14 The composition of water soluble curcuma powder is shown in Table 23. [Table 23] Note: "^" means that sucralose may be replaced with other sweeteners. The compound of Example 14 was prepared by the following procedure: Captex 300 and Kolliphor EL were mixed to form a mixture; the mixture in the vessel was sonicated using a Hiescher Ultrasound sonicator for 10 seconds at a time, alternately for 30 seconds, to a total energy of 50,000 watts to obtain curcuma paste; the curcuma paste was mixed with PEG-6000 melted at 60°C, poured into a stainless steel tray lined with butter paper, and cooled at room temperature to obtain a dry brittle mass; the dry brittle mass was crushed and sieved through a #40 mesh sieve to obtain a water-soluble curcuma powder. The curcuma powder was added with pharma- ceutically acceptable diluents, fillers, binders, sweeteners, flavors, etc.

[0124] Example 15 The composition of the orally dissolving curcuma tablets is shown in Table 24. [Table 24] Curcuma powder was obtained according to the procedure described in Example 14. Pharmaceutically acceptable excipients were then added to the curcuma powder, mixed and blended to obtain a mixture, which was compressed to produce regular tablets and orally dissolving tablets.

[0125] Example 16 The composition of Curcuma troches is shown in Table 25. [Table 25] Curcuma powder was obtained according to the procedure described in Example 14. Pharmaceutically acceptable excipients were then added to the curcuma powder, mixed and blended to obtain a mixture. The mixture was compressed to produce conventional and oral dissolving lozenges. Sorbitol can be substituted with hard boiled candy / confectioner's sugar / mannitol, etc.

[0126] Example 17 The composition of Curcuma nanodroplets is shown in Table 26. [Table 26] The compound of Example 17 was prepared according to the following procedure: Curcumin, TO, Captex 300, Kolliphor EL, and ethanol were weighed and mixed to form a mixture; the obtained mixture was sonicated using a Hiescher Ultrasound sonication device for 10 seconds at a time, alternately for 30 seconds, until a total energy of 50,000 watts was reached to obtain a curcuma solution.

[0127] Physical, chemical and functional analysis methods of curcuma preparations

[0128] Particle size analysis The particle size of the raw materials (Curcumin Powder, CRTO, TO) and formulations (Examples 1, 2, 3, 4) was measured using the Brookhaven Particle Analyzer (BPA) based on the principle of Zeta potential. BPA is based on the principle that when a light beam (laser) is scattered by a group of particles, the angle of light scattering is inversely proportional to the size of the particle (i.e. the smaller the particle size, the larger the angle of light scattering). Nanoparticle analyzers measure particle size by using backscattering and building a correlation function. Brookhaven Nano Instruments are the solution for characterization of nanoparticles, polymer assemblies and other small molecules / particles. The particle size of the raw material (CRTO / TO / curcumin powder) varies in size. After formulation and nanonization process, the size of the starting material changes from an average range of 2 μm to 40-157 nm. Table 27 shows the physical parameters such as (effective diameter and polydispersity) of the raw material and final product measured by Brookhaven instrumentation. [Table 27] Figure 3 shows the correlation between particle size and time taken for transition (level time or lag time). The smaller the particle, the shorter the time taken for the sample. From the graphical representation in Figures 3a to 3g, it can be inferred that nanoizing the particle size of the raw material will result in a shorter time lag for the nanoized formulation. The particle size distribution of the raw material and the blended sample is graphed in Figures 4a to 4g. Figure 4 shows that as the particle size increases, the strength increases proportionally. Thereafter, the strength decreases consistently without any significant effect on the particle diameter. However, the stability of the particles increases as the size increases further, eventually stabilizing.

[0129] Zeta Potential Test The zeta potentials of the four formulations are shown in Table 28. Zeta potential (also called electrokinetic potential) develops on the surface of a substance when it comes into contact with a liquid medium. The zeta potential of particles reflects the ability of particles to electrostatically repel each other and is therefore an important indicator of the stability of colloidal dispersions. Emulsions with high zeta potential are electrically stable due to ongoing Brownian motion. On the other hand, emulsions with no or very low zeta potential tend to aggregate and are less stable. The high negative zeta potentials of all examples 01-04 indicate that the curcuma formulations are stable as emulsions for extended periods of time. Extended periods are defined as at least 6 months. [Table 28]

[0130] Stability testing Stability study of Curcuma droplets was carried out by storing the Curcuma droplet samples at temperature 25°C ± 2°C, relative humidity 60% ± 5%, and temperature 40°C ± 2°C, relative humidity 75% ± 5%. It was observed that the Curcuma droplet samples showed good stability up to 12 months based on the available stability data as shown in Table 29. Different molar ratios of formulation Example 1 (ethanol formulation) and Example 2 (PG formulation) were tested under different temperatures and relative humidity as mentioned above. [Table 29]

[0131] Structural and terrain testing: Structural evidence of the raw materials and formulated products was determined using X-ray diffraction (XRD) and scanning electron microscopy (SEM). XRD is used to identify the crystalline phases present in the material and reveal the chemical composition information. Each globule constitutes the active ingredient in a very uniformly distributed manner. The graphical representation obtained from XRD is shown in Figure 5. Figure 5a shows the pattern of curcumin powder which is crystalline in nature and Figure 5b shows the amorphous structure of CRTO. XRD of curcuma droplet formulation prepared in polyethylene glycol (PEG) and propylene glycol (PG) with curcumin powder and CRTO as raw material and excipient are described in Figure 5c and 5d. XRD of curcumin droplet formulation prepared in ethanol with curcumin powder and CRTO as raw material and excipient are described in Figure 5d and Figure 5e. Figure 5f also shows curcuma droplet formulation prepared in polyethylene glycol (PEG based) with curcumin powder and CRTO as raw material and excipient. XRD graph proves the amorphous structure of the formulation. This was found after mixing curcumin with appropriate excipients and nanonization process (reducing particle size). XRD investigation of raw material and finished product showed that the crystallized form of raw material gradually changes to amorphous form with blending and homogenization. This amorphous form aids in the solubility of the product and maintains its stability for a long period of time. SEM provides surface topography and compounding information. The SEM photographs of raw curcumin powder are shown in Figure 6a(1) and Figure 6a(2). The figures show the large cubic block structure of curcumin powder. Figure 6a(2) is magnified twice as much as Figure 6a(1). Figure 6b is the SEM image of CRTO. In the formulation process, curcumin powder, CRTO, and excipients are mixed, homogenized, and sonicated to produce the final product. Figure 6c(1) and Figure 6c(2) show the mixed structure during the process. Figure 6c(2) is magnified five times as much as Figure 6c(1). Figure 6d(1), 6d(2), 6d(3), and 6d(4) are the SEM images of the mutant topography region at the intermediate stages of the homogenization procedure. Figure 6e shows the SEM image of the final product. The SEM images of different compounding stages show that the raw material is nanoized and properly coated with excipients. SEM analysis demonstrates the schematic diagram of curcuminoid and non-curcuminoid particles in Figure 2, where curcuminoid or non-curcuminoid particles are coated with excipients along with sonication. As a result, the solubility of the particles in the formulation increases and also when the formulation is diluted in aqueous media.

[0132] Publications as references All publications and references, including patents and publications, and applications cited herein are incorporated by reference in their entirety. Nagarajan, S., Kubra, IR, & Rao, LJM (2010). Isolation of curcuminoid-enriched fraction of spent turmeric pigments and antioxidant capacity. Journal of food science, 75(6), H158-H162. Ravindranath, V., Chandrasekhara, N., 1980. Absorption and tissue distribution of curcumin in rats. Toxicology 16, 259-265. Preetha Anand, Ajaikumar B. Kunnumakkara, Robert A. Newman, and Bharat B. Aggarwal Molecular Pharmacy 2007 4 (6), 807-818 Gera, M., Sharma, N., Ghosh, M., Huynh, DL, Lee, SJ, Min, T., ...& Jeong, DK (2017). Nanostructures of curcumin: an emerging paradigm for improved medical applications. Oncotarget,8(39), 66680. Subramani, PA, Panati, K., Lebaka, VR, Reddy, DD, & Narala, VR (2017). Nanoarchitectural development of curcumin delivery: Potential and challenges. Nano- and microscale drug delivery systems (pp. 393-418). Elsevier. Jayaprakasha, GK, Negi, PS, Anandharamakrishnan, C., & Sakariah, KK (2001). Chemical composition and inhibitory activity against various fungi of turmeric oil-A by-product of turmeric pigment industry. Zeitschrift fur Naturforschung C,56(1-2), 40-44. Ferreira, CM, Pinto, IS, Soares, EV, & Soares, HM (2015). (Un) Suitability of use of pH buffers in biological, biochemical and environmental research and their interactions with metal ions - A review. RSC Advances, 5(39), 30989-31003. Bagchi, A. (2012). Extraction of curcumin. IOSR Journal of Environmental Science, Toxicology and Food Technology, 1(3), 1-16. Anand, P., Kunnumakkara, AB, Newman, RA, & Aggarwal, BB (2007). Curcumin biosolubilization: problems and prospects. Molecular Pharmacology, 4(6), 807-818. Khedekar and Mittal, (2013) Self-emulsifying drug delivery systems: A review, International Journal of Pharmaceutical Sciences and Research; Vol. 4(12): 4494-4507 Wadhwa, J., Nair, A., & Kumria, R. (2012). Emulsion-forming drug delivery systems for lipophilic drugs. Acta Pol Pharm,69(2), 179-91. Exbrayat, JM, Moudilou, EN, & Lapied, E. (2015). Adverse events of nanoparticles in animals. Journal of Nanotechnology, 2015. Nair, A., Amalraj, A., Jacob, J., Kunnumakkara, AB, & Gopi, S. (2019). Turmeric and non-curcuminoids in cancer therapy and anticancer drug delivery formulations. Biomolecules, 9(1), 13

Claims

1. A formulation comprising: a composition comprising nanoparticles comprising a curcuminoid and a curcumin-stripped turmeric pigment, wherein the surface of the nanoparticles is coated with PEG-35 castor oil, wherein the composition is water soluble, pharmaceutical safe and does not contain a pH buffering agent, wherein the nanoparticles comprise 5-10% w / v curcuminoid, about 8-10% w / v curcumin-stripped turmeric pigment, about 40-50% w / v PEG-35 castor oil, and a solvent selected from ethyl alcohol, propylene glycol, polyethylene glycol and mixtures thereof, wherein the surface of the nanoparticles is coated with PEG-35 castor oil, and the nanoparticles have an average size of 40-157 nm.

2. 2. The aqueous formulation of claim 1, comprising a composition comprising nanoparticles comprising a curcuminoid, a non-curcuminoid component in a turmeric pigment, and a lipophilic solvent, wherein the surface of the nanoparticles is coated with PEG-35 castor oil.

3. The formulation of claim 2 , wherein the lipophilic solvent comprises a triglyceride.

4. 4. The formulation of claim 3, wherein the triglyceride comprises the following: caprylic triglyceride, oils containing linear fatty acid triglycerides, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate esters of fatty acids, propylene glycol dicaprylate, propylene glycol dilaurate, or oils containing propylene glycol fatty acid esters.

5. The formulation of claim 2 comprising a pharma- ceutically acceptable excipient.

6. 3. The formulation of claim 2, further comprising an absorbent, wherein the absorbent is one of the following: polyethylene glycol, maltodextrin, water soluble starch, hydrolyzed starch, dietary fiber, water soluble oligosaccharides, chicory, dextran, cellulose, copolymers of polyvinylpyrrolidone, sugar alcohols, sorbitol, xylitol, mannitol, cellulose derivatives, or combinations thereof, wherein the cellulose derivatives include hydroxypropylmethyl cellulose, hydroxypropyl cellulose, cyclodextrin, or combinations thereof.

7. 3. The formulation of claim 2, further comprising a diluent, filler, or binder, wherein the diluent, filler, or binder comprises mannitol, sorbitol, lactose, candy, sugar, or combinations thereof.

8. 3. The formulation of claim 2, further comprising a water soluble polymer, wherein the water soluble polymer comprises: polyglutamic acid, polyethylene glycol, propylene glycol, glycerol, propylene glycol esters, polyglycerol oleate, polyvinyl alcohol, non-ethoxylated polymers, or combinations thereof.

9. The formulation according to claim 1, comprising a composition comprising nanoparticles containing a curcuminoid and a non-curcuminoid component in a turmeric pigment, or a pharma- ceutically acceptable salt thereof, wherein the surface of the nanoparticles is covered with PEG-35 castor oil, and the formulation is pharma- ceutical safe and stable in the form of a water-soluble formulation.

10. 2. The formulation according to claim 1, comprising a composition comprising first nanoparticles containing a curcuminoid or a pharma- ceutically acceptable salt thereof, and nanoparticles containing second nanoparticles containing a curcuminoid-removed turmeric pigment or turmeric oil, the second nanoparticles containing a non-curcuminoid component in a turmeric pigment or a pharma-ceutically acceptable salt thereof, wherein the surface of the nanoparticles is covered with a non-ionic oil-in-water emulsifier, and the formulation is pharma-ceutically safe and stable in the form of a water-soluble formulation.

11. 2. A water-soluble formulation comprising a composition comprising nanoparticles containing curcuminoids and non-curcuminoid components in turmeric pigments, wherein the surface of the nanoparticles is covered with PEG-35 castor oil and has the following properties: a) solubilization of curcuminoids in turmeric pigment, curcumin-removed turmeric pigment, turmeric oil, or a combination thereof, resulting in a clear solution with a sediment load of 30% or less; b) said solubilization of turmeric pigments, curcumin-removed turmeric pigments, turmeric oil, or a combination of curcuminoids and curcumin-removed turmeric pigments resulting from particles having an average particle size in the range of 40-1000 nm; c) the formulation shows no particle settling or separation for a minimum of 24 hours; or d) the formulation, when added to water at a ratio of 1 part formulation to 200 parts water, shows no signs of settling or separation of particles for a minimum of 15 minutes.

12. 12. The formulation of claim 11, comprising multiple curcuminoids and multiple curcumin-depleted turmeric pigments.

13. Methods include: a) mixing curcuminoids, curcuminoid-depleted turmeric pigments, and PEG-35 castor oil to form a mixture; b) alternately sonicating and resting the mixture to obtain a clear solution; c) preparing the formulation of claim 1 comprising a composition comprising nanoparticles coated on their surfaces with a non-ionic water-in-oil emulsifier.

14. 10. The formulation of claim 1 further comprising turmeric oil.

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