Soluble curcumin and derivatives thereof

Abstract

Disclosed is a composition comprising ammonia and a curcumin or curcuminoid, such as an ammonium phenolate salt of curcumin. Also disclosed is a method for forming an ammonium phenolate salt of curcumin or curcuminoid, the method comprising dissolving curcumin or curcuminoid in an ammonia solution. Further disclosed is a method of treating a condition in which curcumin can ameliorate, the method comprising administering to a subject an ammonium phenolate salt of curcumin or curcuminoid.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 470,712, filed June 2, 2023, and U.S. Provisional Patent Application No. 63 / 508,470, filed June 15, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to a process for preparing curcumin and curcuminoid formulations with improved solubility and bioavailability. Background Technology

[0004] Curcumin is a bright yellow chemical substance produced by plants in the genus *Curcuma*. It is the main curcuminoid in turmeric (*Curcuma longa*), a member of the family Zingiberaceae. Chemically, curcumin is a diarylheptane compound belonging to the curcuminoid group, which are phenolic pigments that give turmeric its yellow color. Figure 1 The chemical structure of curcumin was described. Figure 2 The chemical structures of curcumin metabolites were described. Figure 3 The chemical structures of some exemplary curcuminoids are described.

[0005] Curcumin is sold as an herbal supplement, cosmetic ingredient, food flavoring, and food coloring. Although turmeric has a long history as a medicinal ingredient in traditional Chinese and Indian medicine, no laboratory or clinical studies have confirmed any medicinal use for curcumin. This is because it is difficult to study the effects of curcumin in humans or even animal models. The compound is unstable and has poor bioavailability. The main reason for its poor bioavailability is its poor solubility in water. In fact, curcumin is almost insoluble in pure water under standard conditions (0.6 μg / mL), but its solubility is improved under standard conditions in organic solvents such as ethanol (1 mg / mL).

[0006] To date, numerous methods have been employed to improve the bioavailability of curcumin. One approach involves using adjuvants that interfere with glucuronidation, such as piperine. Other methods utilize liposome delivery strategies, nanoparticles, or curcumin phospholipid complexes. The use of structural analogs of curcumin (e.g., EF-24) is another widely used method. Finally, boiling curcumin in water is another approach to improve its water solubility. Figure 4 (Retrieved from Tabanelli et al., Pharmaceutics. 2021, 13(10): 1715) describes an exemplary approach to attempting to improve the bioavailability of curcumin.

[0007] All current methods have drawbacks. Figure 4 Many of the delivery formulations shown have been discontinued because they are not suitable for commercial use. Some of the problems with these formulations are that they are too expensive and too difficult to produce, unstable under environmental conditions, and contain ingredients unsuitable for food applications.

[0008] Therefore, new strategies are needed to provide an economical and simple production method that uses FDA-approved excipients and ingredients to improve the bioavailability of curcumin. Summary of the Invention

[0009] In attempting to develop new curcumin formulations, numerous experiments were conducted using various organic bases. These organic bases included creatine, creatine anhydride, arginine, lysine, histidine, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptanamine, diethylamine, spermidine, putrescine, trimethylamine, isobutylamine, isoamylamine, pyrrolidine, cadaverine, guanidine, phenethylamine, barley alkaloids, trigonelline, carnitine, choline, guanidinoacetic acid, guanidine, methylguanidine, and dimethylguanidine. After all these numerous unnecessary experiments, only acetaminophen salts were found to yield stable complexes with curcumin that exhibited improved solubility. Therefore, a method for producing acetaminophen salts of curcumin or curcuminoids (and related substances) using ammonia and formulations with improved solubility and dissolving properties are described.

[0010] The success of the disclosed method is surprising because stable solid complexes would theoretically be impossible due to the weak acidity of phenols and the weak base of ammonia. It would be even more impossible if the powder were subjected to a vacuum, as ammonia is a gas. When predicting the equilibrium of phenol and ammonia relative to phenolate and ammonium in aqueous solution, the pKa of ammonium is lower than that of phenol (ammonium 9.25 vs. phenol 9.95), making ammonium a relatively stronger acid. Therefore, the reaction to form phenolate and ammonium is theoretically energy-disadvantaged, and ammonia cannot deprotonate phenols.

[0011] A method for producing phenolic salts of curcumin or curcuminoids (and related substances) comprises dissolving curcumin or curcuminoids in an aqueous ammonia solution (or other suitable solvent) at a molar ratio of at least 1:1 or preferably 1:2; drying the solution preferably at 60°C or lower, preferably under vacuum, until an orange-yellow dried product is obtained; and grinding the resulting complex into a powder. In some implementations, the method further comprises mixing the powder with a solubility enhancer such as sodium carbonate.

[0012] In some implementations of the method, the ammonia solution contains about 5% to about 40% by weight of ammonia.

[0013] In some respects, ammonium phenolates of curcumin or curcuminoids have been described. The expected molecular formula of the ammonium phenolate of curcumin is as follows:

[0014] .

[0015] The calculated molar mass is 402.442 g / mol, which has been experimentally verified by weighing the finished product.

[0016] If a curcumin to ammonia ratio less than 1:2 is used, such as a 1:1 ratio, then monophenol salts are formed:

[0017] .

[0018] The expected ammonium phenolate salts of curcumin metabolites are as follows:

[0019] ,

[0020] ,

[0021] ,

[0022] , and

[0023] .

[0024] The expected ammonium phenolate salts of some curcumin derivatives are as follows:

[0025] ,

[0026] , and

[0027] .

[0028] Compositions comprising ammonia and curcumin or curcuminoids (e.g., tetrahydrocurcumin) are also disclosed. In some aspects of the composition, ammonia and curcumin or curcuminoids form an ammonium phenolate of curcumin or an ammonium phenolate of curcuminoids.

[0029] A method for treating curcumin-ammoniazide-mediated conditions is further described. The method includes administering curcumin or an ammonium phenolate of curcumin or curcumin metabolites to a subject. In some implementations, the curcumin ammonium phenolate or an ammonium phenolate of curcumin metabolites is administered to the subject at a dose of 1-30,000 mg daily. Multiple doses of the curcumin ammonium phenolate or an ammonium phenolate of curcumin metabolites may be administered daily. The administration route may be topical, transdermal, oral, rectal, ocular, nasal, vaginal, and / or parenteral. In some implementations, the curcumin ammonium phenolate or an ammonium phenolate of curcumin metabolites is administered orally to the subject to treat curcumin-ammoniazide-mediated conditions. Brief description of the attached diagram

[0030] The implementation will be described below in conjunction with the accompanying and / or included drawings, wherein the same reference numerals denote the same elements.

[0031] The patent or application document contains at least one color drawing. A copy of the patent or patent application disclosure with the color drawing will be provided by the patent office upon request and payment of the necessary fees.

[0032] Figure 1 The chemical structure of curcumin was described.

[0033] Figure 2 The chemical structures of curcumin metabolites were described.

[0034] Figure 3 The chemical structures of some exemplary curcuminoids are described.

[0035] Figure 4 An exemplary approach to attempting to improve the bioavailability of curcumin is described, which is reproduced from Tabanelli et al., Pharmaceutics. 2021, 13(10): 1715.

[0036] Figure 5 These are photos of the ammonium phenolate of curcumin (top) and curcumin (bottom).

[0037] Figure 6 It is a photo of a beaker containing 50 ml of water and 0.5 g of curcumin.

[0038] Figure 7 These are photos of two beakers taken approximately one minute after 1 g of 95% curcumin powder (right) or 1 g of curcumin ammonium phenolate (left) was added to 100 ml of water. The mixture was not stirred.

[0039] Figure 8 These are photos of two beakers taken approximately ten minutes after 1 g of 95% curcumin powder (right) or 1 g of curcumin ammonium phenolate (left) was added to 100 ml of water. The mixture was not stirred.

[0040] Figure 9 These are photos of two beakers taken approximately 10 seconds after 1 g of 95% curcumin powder (left) or 1 g of curcumin ammonium phenolate (right) has been added to 100 ml of water while stirring (1200 rpm, with a magnetic stirrer).

[0041] Figure 10 It comes from Figure 9 A photograph of the filtrate after centrifuging this solution at 1000 rpm for 10 seconds, containing 1 g of 95% curcumin in 100 ml of water.

[0042] Figure 11 It comes from Figure 9 A photograph of the filtrate after centrifuging this solution at 1000 rpm for 10 seconds, showing a solution of 1 g curcumin ammonium phenolate in 100 ml of water.

[0043] Figure 12 This is a photograph of the filtrate of a solution containing 2 g of curcumin ammonium phenolate in 200 ml of saturated citric acid solution (pH=3).

[0044] Figure 13 This is a photograph of the filtrate of a solution containing 2 g of 95% curcumin in 200 ml of saturated citric acid solution (pH=3).

[0045] Figure 14 This is the spectrum of curcumin powder obtained using Fourier transform infrared spectroscopy (FTIR).

[0046] Figure 15 This is the spectrum of curcumin ammonium phenolate using FTIR.

[0047] Figure 16 Depicting from Figure 14 The curcumin spectrum relative to that from Figure 15 The curve of the spectrum of curcumin ammonium phenolate.

[0048] Figure 17 This is the spectrum of tetrahydrocurcumin powder obtained using FTIR.

[0049] Figure 18 This is the spectrum of the ammonium phenolate of tetrahydrocurcumin obtained using FTIR.

[0050] Figure 19 Depicting from Figure 19 The tetrahydrocurcumin spectrum relative to that from Figure 18 The curve of the spectrum of tetrahydrocurcumin ammonium phenolate.

[0051] Figure 20 The absorbance of a 1:10 dilution of the filtrate obtained by mixing 100 mg curcumin in 100 ml distilled water, emulsifying by sonication, and then filtering was depicted.

[0052] Figure 21 The absorbance of a 1:10 dilution of the filtrate obtained by mixing 100 mg of curcumin ammonium phenolate in 100 ml of distilled water, emulsifying by sonication, and then filtering was depicted.

[0053] Figure 22 The absorbance of a 1:10 dilution of the filtrate obtained by mixing 100 mg of tetrahydrocurcumin in 100 ml of distilled water, emulsifying by sonication, and then filtering was depicted.

[0054] Figure 23The absorbance of a 1:10 dilution of the filtrate obtained by mixing 100 mg of tetrahydrocurcumin ammonium phenolate in 100 ml of distilled water, emulsifying by sonication, and then filtering is depicted. Detailed Implementation

[0055] Detailed aspects and applications of this disclosure are described in the accompanying drawings and embodiments. Unless otherwise specified, the words and phrases in this specification and claims are intended to be given their simple, common, and customary meaning to those skilled in the art.

[0056] In the following description, and for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of various aspects of this disclosure. However, those skilled in the art will understand that this disclosure can be practiced without these specific details. It should be noted that many different and alternative configurations, devices, and techniques exist to which the disclosed content can be applied. The full scope of this disclosure is not limited to the examples described below.

[0057] Unless the context clearly specifies otherwise, the singular forms “a / an” and “the” include plural indicators. Thus, for example, referring to “a step” includes referring to one or more such steps.

[0058] It will be understood that the term "curcumin" refers to the molecule of curcumin itself (also known as diferuloylmethane) which can be isolated from or synthesized from plants, as well as its metabolites or derivatives. By way of non-limiting example, "curcumin" as used herein includes curcumin glucoside, curcumin sulfate, tetrahydrocurcumin, hexahydrocurcumin, hexahydrocurcuminol, demethoxycurcumin, didemethoxycurcumin, dimethylcurcumin, hydrazylcurcumin, and curcumin metal complexes, such as complexes with copper and magnesium.

[0059] As used herein, the term "curcuminoid" refers to curcuminoids other than curcumin that can be isolated or synthesized in plants, as well as their metabolites or derivatives. As a non-limiting example, references to "curcuminoid" herein include demethoxycurcumin, bisdemethoxycurcumin, cyclocurcumin, and curcuminoid metal complexes, such as those with copper and magnesium.

[0060] As used herein, “pharmaceuticalally acceptable additive” or “additive” is the term used in its broadest sense. Specific implementations of the compositions described in this document may also include additives (e.g., solubilizers, enzyme inhibitors, anticoagulants, antifoamers, antioxidants, colorants, coolants, cryoprotectants, diluents, hydrogen-bonding agents, flavoring agents, flow agents, plasticizers, preservatives, sweeteners, thickeners, and combinations thereof) and / or carriers (e.g., excipients, lubricants, binders, disintegrants, diluents, extenders, solvents, suspending agents, solubilizers, isotonic agents, buffers, soothing agents, amphiphilic lipid delivery systems, and combinations thereof). These additives may be solid or liquid, and the type of additive is generally selected based on the type of application used. Those skilled in the art will be able to readily select suitable pharmaceutically effective additives from the disclosures in this document. In specific implementations, pharmaceutically acceptable additives may include, but are not limited to, calcium phosphate, cellulose, stearic acid, croscarmellose cellulose, magnesium stearate, and silica.

[0061] As used in this document, "pharmaceutical effective" is the phrase used in its broadest sense, including but not limited to being effective in clinical trials or in a particular patient. When used in a method claim, pharmaceutically effective means a dose sufficient to achieve the preamble of the claim.

[0062] As used in this document, "pharmaceuticalally acceptable" is the phrase used in its broadest sense and can describe ingredients in a pharmaceutical composition that meet the standards of the Food and Drug Administration (FDA), the United States Pharmacopeia (USP), the United States Department of Agriculture (USDA) food-grade material standards, generally accepted standards of the nutritional supplement industry, industry standards, botanical standards, or standards established by any individual. These standards can define the acceptable range of aspects of the ingredients in a pharmaceutical composition, such as the chemical substances used in the realization of the pharmaceutical composition, the edibility, toxicity, pharmacological effects, or any other aspect of the composition or formulation.

[0063] As used herein, the term "human saliva" will be understood in its common physiological sense as a viscous, usually colorless (except in cases of certain diseases) milky-white fluid that is persistently present in the human oral cavity. Human saliva contains water, mucus, proteins, mineral salts, and amylase. As saliva circulates in the oral cavity, it picks up food debris, bacterial cells, and leukocytes, as well as dissolves compounds that are soluble in water, such as those described in this application. It can be present in the air through speaking or coughing and can be a contaminant in food supplements and medications.

[0064] As used herein, the term "human gastric juice" will be understood through its common physiological meaning: a watery, acidic fluid that aids digestion and is secreted by glands in the stomach wall. Almost all enteric-coated compounds, except for those that are enteric-coated, come into contact with gastric juice, and most of them dissolve at least partially.

[0065] As used in this article, the term "human enteric fluid" (also known as "human enteric juice") will be understood through its common physiological meaning, which is a fluid present in the human intestine that typically contains processing products of gastric juice as well as various other enzymes, bile, and electrolytes that aid in nutrient absorption.

[0066] This disclosure relates to the preparation of curcumin and curcuminoid formulations with improved solubility and dissolution. The preparation method comprises dissolving curcumin or curcuminoid in an aqueous ammonia solution (or other suitable solvent) at a molar ratio of at least 1:1, such as 1:2; drying the solution at 60°C or lower, possibly under vacuum, until an orange-yellow dried product is obtained; and grinding the resulting complex into a powder. In some implementations, the method further comprises mixing the powder with a solubility enhancer such as sodium carbonate. In some implementations of the method, the ammonia solution contains about 5% to about 40% ammonia.

[0067] This disclosure also relates to compositions comprising an ammonium phenolate salt of curcumin or curcuminoids (e.g., tetrahydrocurcumin). In some implementations, the composition further comprises, for example, a solubility enhancer, such as sodium carbonate. In some other implementations, the ammonium phenolate salt of curcumin or curcuminoids is combined with dietary ingredients, food additives, and / or pharmaceutically acceptable additives.

[0068] Supplements and ingredients that can be used in ammonium phenolate salts of curcumin or curcuminoid compositions to enhance efficacy include, but are not limited to: 1,3-DMAA, 1,3-DMBA, 1,4-butanediol, 1,4-DMAA, 1-androgenes, 1-epidosterone, 19-nor-DHEA, 4-androgenes, 5-decazole, 5-HTP, 5aOHP, 6-bromo, 7,8-benzoflavones, 7-α-hydroxy-DHEA, 7-β-hydroxy-DHEA, 7-keto-DHEA, 7-methoxyflavones, creeping sedge root, American sage, hard acacia, acai berry, acerola cherry, acetyl-L-carnitine, West African litchi fruit, aconite, activated charcoal, active hexose-related compounds (AHCC), adenosine, adrifenib, adrenal extract. Plants, Cyperus rotundus, Acinium arvense, African wild potato, Agar, Agave, Guanidine, Agrimonia pilosa, Alanine, Albizia julibrissin, Mantle grass, Rhamnus shrubs, Lunggrass, Alfalfa, Algae oil, Alginic acid, Purple cinnabar grass, Allspice, Aloe vera, α-GPC, α-ketoglutarate (AKG), α-linolenic acid (ALA), α-lipoic acid, Senecio scandens, Alpinia galanga, Amaranth, Ambergris, American viper tongue, American chestnut, American cornelian cherry, American elderberry, American ginseng, American sedge, American ivy, American mistletoe, American papaya, American nard, American white water lily, Andalus, Andrographis paniculata, Androstenediol, Androstenedione, Androstenedione, Androstenedione, Angelica dahurica, Angelica sinensis, Angustrum lucidum, Anhydrous Crystallized maltose, fennel, redwood, antitumor ketones, antioxidants, apo-co-dependent jellyfish luminescent protein, apple, apple cider vinegar, apple polyphenols, apricot, almond, arabinoxylan, red spinach, alistair, aristolochic acid, arnica, aragonite, arsenic, Mediterranean artemisia, artichoke, taro, asafoetida, asarum, ascorbic acid, ash, ashwagandha, Asian water hyacinth, asparagus, racemose asparagus, aspartic acid, poplar, astaxanthin, astragalus, Atlantic cedar, atractylodes macrocephala, autumn saffron, myrica, avocado, avocado soybean unsaponifiables (ASU), avocado sugar extract, South American kapok, Brazilian palm, Bach flower essence, Bacillus coagulans, false purslane, betel nut, scutellaria baicalensis, morinda officinalis, bamboo, crape myrtle, banana Baobab tree, barley, basil, bay leaf, bayberry, bear garlic, bee pollen, bee venom, beer, beeswax, beetroot, belladonna, benzoin, berberine, bergamot, β-alanine, β-carotene, β-cryptoxanthin, β-glucan, β-hydroxybutyrate (BHB), β-methylphenethylamine (BMPEA), β-sitosterol, anhydrous betaine, betaine hydrochloride, areca nut, besylvianella root, Stachys spp., Bifidobacterium animalis subsp., lactobacillus, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, blueberry, biotin, birch, bipinnatifida, bismuth, bismuth nitrate, bistorta, bitter almond, bitter melon, Polygala tenuifolia, bitter orange, bitter yam, bitter solanum, black alder, black moss, black cohosh, blackcurrant, black hawthorn, black sedge, black hoof mushroom.Black summer solstice grass, black mulberry, black mustard, black nightshade, black pepper, black plantain, black raspberry, black rice, black root, black seeds, black tea, black walnut, blackberry, blackthorn plum, blessing thistle, psyllium husk, blood root, blue cohosh, blue flag, blue-green algae, blueberry, swamp blueberry, swamp Labrador tea, swamp bean, rose oil, Bordeaux leaf, orchid, borage, bovine cartilage, bovine colostrum, boxwood, branched-chain amino acids (BCAA), breadfruit, brewer's yeast, brickleaf chrysanthemum, ground honey tree, broccoli, broccoli sprouts, bromelain, brown rice, Brussels sprouts, sedge, broomcorn, buck's-horn plantain, buckhorn plantain Plantain), buckwheat, morning glory, selfheal, bulb, bulbous ranunculus, bupleurum, burdock, burning shrub, hairy marigold, butcher's broom, bright purple butcher's broom, coltsfoot, ranunculus, walnut, butylated hydroxytoluene (BHT), cabbage, pointed-leaved juniper, caffeic acid, caffeine, jade tree oil, kalabar bean, gourd chalk, windmill, calamus, calamus oil, calcium, D-calcium gluconate, black-eyed flower, calendula, California poppy, horn gourd, African stephania root, camphor, camu camu, Canadian balsam, Canadian senna, Canadian hemp, membranous sorrel, ylang-ylang essential oil, cannabinoids (CBC), cannabidiol (CBD), cannabidiol (CBDV), cannabinol (CBG), cannabinol (CBN), cannabis, rapeseed oil, canthaxanthin, capers, caprylic acid, capsicum, buffalo horn, caraway, C60 (C60), cardamom, cashew alkaloid, scabra, carnosine, carob, chamomile, carrageenan, carrot, saffron oil, acerola, casein peptide, casein, cashew, cassia, cassia bark, acacia essential oil, castor oil, castor oil, cat's claw, centella asiatica, catechu, catnip, cattuba, flowers Cabbage, Celery, Caesalpinia, Cesium, Esterified Fatty Acids (CFA), Ceylon Cinnamon, Plumeria, Willow-leaved Wood, Birch Polygonum, Gravel Grass, Shrubs, Hydrangea macrophylla, South American Clove, Chelating Therapy Products, Catnip Oil, Celery, Salvia Miltiorrhiza, Chickweed, Chicory, Trichosanthes kirilowii, Chinese Mallow, Sichuan Pepper, Swertia japonica, Chitosan, Leek, Chlorella, Chlorine Dioxide, Chlorophyll, Chlorophyll Acid, Rowan Fruit, Choline, Chondroitin Sulfate, Chromium, Chlorophyll, Aspergillus, Chuchuhuasi, Chymotrypsin, Coriander Leaves, Cinchona, Square Stem White powder vine, Cistanche deserticola, Citicoline, Citric acid, Lemongrass oil, Sage, Clay, Upright Clematis, Galium aparine, Clove, Twisted Flower, Rock Maple, Cnidium monnieri, Golden Flower, Coca, South American expectorant bark, Coconut, Coconut oil, Coconut water, Cod liver oil, Codonopsis pilosula, Coenzyme Q10, Coffee, Activated charcoal coffee, Kola nut, Corydalis yanhusuo, Collagen peptides, Type I collagen (natural), Type II collagen (natural), Kale, Colloidal minerals, Colloidal silver, Medicinal watermelon, Coltsfoot, Columbine, Small-flowered windmill, Comfrey, Sedum, South American milkweed, Conjugated linoleic acid (CLA)Copaiba balsam, copper, coral, cordyceps, coriander, from cork tree, poppy, corn silk, cornflower, corydalis, ginger stalks, cotton, sofa grass, boletus, yellow clover, bark of the cranberry tree, cranberry, creatine, croton seed, copaiba balsam, cucumber, cudweed, dill seed, ranunculus, cyanane, cyclamen, cypress, D-mannose, daffodil, damia, dandelion, salvia, dates, datura, tannin, deer antler, δ-8-tetrahydrocannabinol (δ-8-THC), δ-9-tetrahydrocannabinol (THC), dendrobium, desert parsley, devil's claw, devil's thorn, DHEA, diacylglycerol, diatomaceous earth, diindolemethane, diiodothyronine, dill, dimethylglycine (DMG), dimethylhexylamine (DMHA) Dimethyl sulfoxide (DMSO), geraniol, *Gnaphalium affine*, docosahexaenoic acid (DHA), dodder seed, dolomite, angelica, Douglas fir, dragon fruit, dragon's blood, duckweed, palmate red algae, nandrolone phenylpropionate, durian, silverleaf chrysanthemum, dwarf elderberry, dwarf pine needle oil, genus *Dalbergia*, mebozin, Canada hemlock, Oriental red cedar, ecdysone, echinacea, brown algae *Eriocaulon ergère*, eicosapentaenoic acid (EPA), elderberry fruit, elderberry flower, *Saussurea costus*, *Ligustrum lucidum*, eleutherococcus senticosus, ellagic acid, slippery elm bark, emu oil, viper's tongue fern, peppermint, ivy, English walnut, ephedra, epiandrolone, methylcyclothiosterol, estrol, ergot, ergothioneine, *Eryngium*, eucalyptus, European cypress euphorbia, *Euphorbia humifusa*, European barberry, *Rhamnus spp.*, European chestnut, creeping cinquefoil, European Mandrake, European mistletoe, Lespedeza bicolor, Evening primrose, Evodia rutaecarpa, Eyebright, Eriocaulon buergerianum, Lilium globosum, Fennel, Fenugreek, Fermented milk, Fermented wheat germ extract, Fever bark, Chrysanthemum morifolium, Fig protease, Wild widow's grass, Fig, Scrophularia ningpoensis, Fir, Fireweed, Fish oil, Flaxseed, Flaxseed oil, Fluoride, Amanita muscaria, Polygonum multiflorum, Folic acid, Parsley, Forget-me-not, Forsythia suspensa, Foxglove, Frankincense, Fritillaria cirrhosa, Frost grass, Fructooligosaccharides (FOS), Fucus vesiculosus, Fulvic acid, Corydalis yanhusuo, G, Galactooligosaccharides (GOS), White rosin, Goldenrod, Orpiment, Gamma-butyrolactone (GBL), GABA, GHB, GLA, Gamma-oryzanol, Garcinia cambogia, Garden watercress Gardenia, garlic, gelatin, gelsemium, genistein-bound polysaccharide, gentian, German chamomile, German ipecac, wild smilax, caddisfly, germanium, ginger, ginkgo, earth flower, globular sunflower, privet, glucomannan, glucosamine, glucuronide, glutamine, glutamine, glutathione, glycerol, glycine, glycolic acid, glycomacropeptide, glyconutrients, goat's milk powder, American gray leaf, wolfberry, golden senecio, goldenrod, white buttercup, coptis, gossypol, centella asiatica, celery, Moroccan cardamom, grape, grapefruit, gravelly root, custard apple, plantain, sanguisorba officinalis, celandine, Greek sage, green coffee, green tea, sage, gynostemma pentaphyllum, ground pine, *Lysimachia christinae*, *Senecio scandens*, guaiac wood, guar gum, guarana, guarumaGuava, Indian gum tree, gum arabic, gum grass, gymnospermum, halool-50, *Gnaphalium affine*, *Fernonia aurea*, Hawaiian rose, hawthorn, hazelnut, pansy, heather, linear garlic mustard, hedge - hyssop, hemlock, hemlock water lily, cannabis, cannabis leaf *Eupatorium fortunei*, weasel petal flower, henbane, henna, four-leaf Paris, *Houttuynia cordata*, southern pepper, hesperidin, pentanone, hexylamine, hibiscus, sea mint, histidine, holly, hollyhock, holy basil, high taurine, honey, honeysuckle, *Opuntia ficus-indica*, hops, malt alkaloid, *Aegilops hornya*, horse chestnut, lemon balm, horseradish, horsetail, large borage, stone lotus, Japanese knotweed, humic acid, huperzine A, hyacinth bean, hyaluronic acid, hydrangea, hydrazine sulfate, hydroxymethylbutyric acid (HMB) ), Superimmune egg, Hyssop, Eboga, Icelandic moss, Idebenone, Ignatius bean, Helichrysum, Indian cassia seed, Indian gooseberry, Indian long pepper, Indian snake root, Indigofera, Indium, Indole-3-carbinol, Inosine, Inositol, Inositol nicotinate, Inulin, Iodine, IP-6, Ipecain, Peruvian herb, Eupatorium flavonoids, Iron, Gaboon false mango, Isatis root, Isopropyl nor synephrine, Ivy, Hairy rue, Jackfruit, Galapagos, Jamaican purslane, Syzygium aromaticum, Prunus cerasifera, Japanese mint, Japanese persimmon, Jasmine, Java tea, Java turmeric, Jenny Craig diet, Red bean, Gemwort, Gynostemma pentaphyllum, King purslane, Job's tears, Jojoba, Juniper, Cashew, K2 / spice, Kale, Kamala, Kaolin, Kalaya gum, Kava, Kefir Ketogenic diet, arabinoche, fennel, kinetin, kiwifruit, Asteraceae plants, turnip, kombucha, red pine, bitter sage, kaempferia leaf, krill oil, kudzu root, L-arginine, L-carnitine, L-citrulline, L-cysteine, L-ornithine, L-aspartic acid, L-tryptophan, rock sugar, golden chain flower, lactase, lactic acid, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus curvatureii, Lactobacillus delbrueckii, Lactobacillus gasseri, Lactobacillus jansensis, Lactobacillus Johannesburgus, lactoferrin, kelp, larch arabinogalactan, larch turpentine, cornelian cherry, Lactobacillus brewing, laurel, lauric acid, lavender, lavender cotton, lasho saponin. Lecithin, lemon, lemon balm, lemon eucalyptus, lemon verbena, lemongrass, lentinan, celandine, Levantine berries, Lactobacillus brevis, licorice, glycyrrhizin, Lactobacillus salivarius, lily of the valley, lime, limonene, fermented Lactobacillus limosinophila, Lactobacillus reuteri, linden, blueberry, lion's mane mushroom, lipase, lithium, liver extract, liverwort, lobelia, log, Lorenzo oil, lotus, milkweed, angelica, loofah, laurel, lung grass, lungwort, lupin, lutein, lychee, lycopene, lysine, M1-4ADD, maca, macadamia nut, dried nutmeg bark, Madagascar periwinkle, madder, magnesium, magnolia, maidenhair fern, maitake mushroom, Malabar nut, male fern, malic acid, mallow, mannaca, Manchurian thorn, manganese, mangosteen.Mangosteen, Marquis, Maralgen, Ocean Pine, Marjoram, Liatris, Swamp Labrador Tea, Swamp Marigold, Cotton Candy, Motherwort, Frankincense, Spiraea, Medium Chain Triglycerides (MCT), Melanotan, Melatonin, Mentaboran, Mercury, Methacin, Methadone, Methoxydienone, Methoxyflavonoid, Methyldiazine, Methylstanbolone, Methylsulfomethyl (MSM), Methylsynephrine, Clove, Milk Thistle, Miracle Fruit, Molybdenum, Lysimachia, Lauric Acid, Radiata Pine, Moringa, Mormon Tea, Motherwort, Mountain Ash, Mountain Sesame, Mountain Laurel, Mouse Ear Hawksbill, Artemisia, Brazilian Ephedra, Mullein, Musk, Laurel Leaf, Myrrh, Myrtle, N,N-DMPEA, N-acetylcysteine ​​(NAC), N-methyl Tyramine, NADH, Nasturtium, Nattokinase, Neem, Nerve Root, New Jersey Tea, New Zealand Green-lipped Mussel, Niacin, Nicotinamide, Neolix Oil, Nickel, Nicotinamide Nucleoside, Sunflower Maple, Noni Fruit, Northern Sichuan Pepper, Norway Spruce, Nutmeg, Strychnos nux-vomica, Oakmoss, Oats, Octacosanol, Octoamine, Oleander, Oleic Acid, Olive, Olive Oil, Omega-6 Fatty Acid, Onion, Oolong Tea, Orchid Extract, Oregano, Oregon Grape, Oriental Arborvitae, Ornamental Marigold, Ornithine, Ornithine Ketoglutarate (OKG), Iris, OslocoSure, Osha, Ostallin, Ostrich Fern, Oswick Tea, Oxeye Daisy, Cinnamomum Caulis, Pagoda Tree, Palm Oil, Palmitoyl Glycolamide (PEA), Ginseng, Panax Notoginseng, Pancreatic Enzyme Products, Pantothenic Acid, Pantothenic Acid Pantothenic acid, Morinda officinalis, Papain, Papaya, Para-aminobenzoic acid (PABA), Parsley, Wild Lady's Mantle, Saposhnikovia divaricata, Gynostemma pentaphyllum, Passionflower, Bauhinia purpurea, Patchouli oil, Pink Lapachoe, Pea protein, Peanut oil, Pear, Pectin, Peppermint, Wall grass, Corpse grass, Peppermint, Peony, Peppermint, Perilla, Perilla alcohol, Vinca minor, Peru balsam, Cactus, Common bean, Red daffodil, Phellodendron bark, Phenethylamine (PEA), Phenyribote, Amphetamine, Phenylalanine, Phlorizin, Phosphatidylcholine, Phosphatidylserine, Phytase, Picamilone, Picrorhiza scrophulariiflora, Coptis chinensis, Pinellia ternata, Prunus armeniaca, Piracetam, Pitcher plant, Phytosterols, Pleurotus ostreatus, Prunus persica, Podophyllum hexandrum, Poison ivy, Phytolacca acinosa, Polar therapy, Polyol Polydextrose, dragon fruit, pomegranate, poppy, poppy seed, poria cocos, potassium, potato, cinnamon, pregnenolone, radish from *Gnaphalium affine*, cactus, procaine, progesterone, proline, propionyl-L-carnitine, propolis, proteolytic enzyme (protease), psilocybin, Pu-erh tea, Pulsatilla chinensis, pumpkin, *Lysimachia christinae*, *Cyperus rotundus*, *Pyrethrum salicaria*, pyrethrum, pyruvate, *Paspalum notatum*, white oak, *Sapium sebiferum*, quercetin, *Gnaphalium affine*, *Platycladus orientalis*, quinoa, *Rabdosia rubescens*, radish, raspberry ketone, emetic *Rauvolfia purpurea*, *Rauvolfia purpurea*, red clover, red maple, red raspberry, sandalwood, red soapberry, red yeast rice, red valerian, reed, rehmannia, ganoderma lucidum, resveratrol, latani, rhodiola rosea, rhubarb, riboflavin, ribose, rice bran, rice bran arabinoxylan compounds, rice protein.RNA and DNA, rock rose, Roman chamomile, South African rooibos, rose geranium oil, rosehip, rosemary, royal jelly, rue, *Rhododendron simsii*, rust-leaved rhododendron, rutin, ryegrass, S-23, *Saccharomyces boulardii*, safflower, saffron, sage, Saigon cinnamon, *Dracaena sanderiana*, glycerides, orchid stem powder, sacred sage, SAMe, sea peltata, immortelle, dragon's blood croton, *Croton tiglium*, *Smilax china* root, *Sassafras scabra*, sandy juniper, saw palmetto, sea green, strychnine, schisandra, catnip, scopolamine, broom, Scottish thistle, scurvy, sea buckthorn, nori, secretin, *Impatiens balsamina*, selenium, *Prunella vulgaris*, *Imperata cylindrica*, senna, serine, serase, sesame, sesame seed, sesame bark, shark cartilage, shark liver oil, shea butter Shellac, shepherd's purse, shiitake mushroom, Siberian cocklebur, heart-leaved yellow clover, silicon, simia lappa, sitosterol, scutellaria baicalensis, skunk cabbage, slippery elm, knotweed, smooth alder, snake skin, sodium, sodium bicarbonate, sodium tetrachloroaurate, polygonatum, sorghum, oxalis, soybean, soybean oil, Spanish broom, Spanish oregano oil, spearmint, spinach, prickly violet, spleen extract, spotted geranium, horn Squalamine, squid, St. John's wort, star anise, Bethlehem star, ranunculus, sildenafil, pinnatifida, stevia, nettle, rock root, styrax, strawberry, Streptococcus thermophilus, strontium, celandine, succinate, subuthylamine, sulforaphane, sulfur, suma, sulphur, summer peppermint, sunflower, sunflower oil, superoxide dismutase (SOD), sage root, marsh milkweed, sweet almond Artemisia annua, sweet cherry, European myrrh, sweet osmanthus, fragrant bayberry, sweet orange, sweet sumac, sweet spring grass, fragrant violet, fragrant clover, camel thorn, tamarind, tamarisk, citrus, tannic acid, tansy, ragweed, cassava, tarragon, sour cherry, tartaric acid, taurine, tea tree oil, tea saponin, terminalia kernel, testosterone, tetrahydrocannabinol (THCV), tea essence, theaflavins, theanine, thiamine, threonine, cypress, thunder vine, thyme, thymus extract, thyroid extract, tianeptine, timothy, tin, heart-leaved scarab beetle, tiramisu, tocotrienol, toluene, tomato, tonka bean, tooth moss, upright cinnamon, yarrow gum, cranberry, transfer factor, grape-leaved clematis, paradise tree, tree tobacco, tree turmeric, estrogenic 4,9,11-triene-3,17- Diketone, Tribulus terrestris, *Eupatorium fortunei*, *Abutilon theophrasti*, trypsin, tung seed, corydalis, *Trametes versicolor*, turmeric, turpentine, *Gnaphalium affine*, *Eupatorium fortunei*, tyramine, tyramine, ubiquinone, *Eupatorium fortunei* drops, Usnea, bearberry, *Uzala root*, valerian, vanadium, vanilla, verbena, *Veronica* (Plantago asiatica), vetiver, Vietnamese coriander, vinca, vitamin A, vitamin B1, vitamin B2, vitamin B12, vitamin B6, vitamin C, vitamin D, vitamin E, vitamin K, vitamin O, elm, *Symplocos edulis*, wallflower, mustard, water oats, water sorrel, water hemlock, watercress, wheat bran, wheat straw, whey protein, white nettle flower, white sedge, white summer solstice grass, white lily, white mulberry, white mustard, white oak, white pepper, white sandalwood, wild carrot, wild cherry.Wild daisy, wild indigo, wild lettuce, wild mint, wild thyme, wild yam, Willard water, willow bark, wine, winter cherry, winter jasmine, holly, witch hazel, five-leaved anemone, wood sage, oxalis, *Triticum* species, wormwood, xanthan gum, coarse yellow plum, xylitol, yarrow, wrinkled sorrel, loosestrife, yellow willow catkins, houttuynia root, yerba mate, North American sage, yew, artemisia capillaris, ylang-ylang oil, yogurt, yohimbine, zeaxanthin, turmeric, zinc, jujube seed, carnitine or its salt, ester or amide suitable for human consumption, acetyl-L-carnitine or its salt, ester or amide suitable for human consumption, propionyl-L-carnitine or its salt, ester or amide suitable for human consumption, alpha-lipoic acid, alpha-GP C. Aniracetam, Piracetam, Phenylacetylpiracetam, Apocarpus zebrin, Artichoke, Ashwagandha, Astaxanthin, False Portulaca, Cat's Claw, Caduceus, Cannabidiol (CBD), Celastrus orbiculatus, Meclofenac Hydrochloride, Citicoline, Butterfly Pea, Cobraracetam, Codonopsis pilosula, Ubiquinone (e.g., Coenzyme Q10), Creatine or its salts, esters or amides suitable for human consumption, Choline or its salts, esters or amides suitable for human consumption, Docosahexaenoic acid (DHA), Dimethylethanolamine (DMAE), Trichosanthes kirilowii, Ginkgo biloba, Ginseng, Centella asiatica, Guarana, Canna indica, Kava, Caramel, L-Glutamine or its salts, esters or amides suitable for human consumption, L-Phenylalanine or its... Salts, esters, or amides suitable for human consumption; L-theanine or its salts, esters, or amides suitable for human consumption; L-tryptophan or its salts, esters, or amides suitable for human consumption; lecithin or its salts, esters, or amides suitable for human consumption; lemon balm; lion's mane mushroom; magnolia; medium-chain triglycerides; reduced nicotinamide adenine dinucleotide (NADH); nelfecitratan; nicotine; arecoline; norepinephrine; oat straw; piracetam; passionflower; fenibour; phosphatidylcholine; phosphatidylserine; picocamidoside; pine bark extract; plasracetam; pyrrolizine quinoline quinone (PQQ); pterostilbene; resveratrol; rosemary; rhodiola rosea; S-adenosylmethionine (SAMe); schisandrol-A; St. John's wort Subuthiamine, taurine or its salts, esters or amides suitable for human consumption, turmeric, L-tyrosine or its salts, esters or amides suitable for human consumption, N-acetyl-L-tyrosine or its salts, esters or amides suitable for human consumption, uridine, valerian, vinpocetine, thiamine or its salts, esters or amides suitable for human consumption, niacin or its salts, esters or amides suitable for human consumption, pantothenic acid or its salts, esters or amides suitable for human consumption, vitamin B6 or its salts, esters or amides suitable for human consumption, vitamin B8 or its salts, esters or amides suitable for human consumption, vitamin B9 or its salts, esters or amides suitable for human consumption, vitamin B12 or its salts, esters or amides suitable for human consumption, and Paraguayan tea.

[0069] The compositions and / or formulations disclosed herein may be administered in any form, including, for example, capsules, pouches, pills, tablets, powders, granules, pills, beads, granules, lozenges, tablets, granules, solutions, elixirs, syrups, tinctures, suspensions, emulsions, mouthwashes, sprays, drops, ointments, creams, gels, pastes, transdermal patches, suppositories, pessaries, creams, gels, pastes, foams, and combinations thereof. The compositions and / or formulations disclosed herein may also include acceptable additives (e.g., solubilizers, enzyme inhibitors, anticoagulants, defoamers, antioxidants, colorants, coolants, cryoprotectants, hydrogen-bonding agents, flavoring agents, plasticizers, preservatives, sweeteners, thickeners, and combinations thereof) and / or acceptable carriers (e.g., excipients, lubricants, binders, disintegrants, diluents, extenders, solvents, suspending agents, solubilizers, isotonic agents, buffers, soothing agents, amphiphilic lipid delivery systems, and combinations thereof).

[0070] Curcumin or curcuminoid ammonium phenolate salts can be conveniently produced in unit dosage forms. Unit dosage forms can be those containing daily doses or units, daily fractions, or suitable portions thereof of the administration components as described herein.

[0071] Dosage units may include ammonium phenolate salts of curcumin or curcuminoids and, for example, at least one solubilizer, such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate, copper carbonate, and ferric carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, zinc bicarbonate, copper bicarbonate, and / or ferric bicarbonate. Additionally, dosage units may include ammonium phenolate salts of curcumin or curcuminoids mixed with pharmaceutically acceptable additives.

[0072] The oral dose of curcumin or curcumin-like ammonium phenolate salts can be from 1 mg to 30,000 mg daily, divided into one or more doses. For the purpose of enhancing athletic performance, the formulation is administered (e.g., orally) before exercise, for example, at any time between 3 days and immediately before exercise. In some implementations, the formulation is administered one hour before exercise.

[0073] Dosage units may be in a form suitable for administration via standard routes. Typically, dosage units may be administered, as non-limiting examples, via local (including buccal and sublingual), transdermal, oral, rectal, ocular (including intravitreal or anterior chamber), nasal, vaginal, and / or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal, and epidural) routes.

[0074] For the purposes of this disclosure, oral delivery may be a particularly advantageous delivery route for administering pharmaceutical compositions to humans and animals, the pharmaceutical compositions optionally being formulated with appropriate pharmaceutically acceptable additives to facilitate administration.

[0075] It should be understood that any component of a particular realization of curcumin or curcuminoid ammonium phenolate may be used in commercially available form, or may be pretreated by any method and technique known in the art, depending on the desired dosage form, such as agglomeration, air suspension cooling, air suspension drying, pelleting, coagulation, pulverization, compression, granulation, freeze granulation, extrusion, pelletizing, homogenization, inclusion compounding, freeze drying, melting, mixing, molding, pan coating, solvent dehydration, ultrasonication, spheronization, spray cooling, spray condensation, spray drying, and / or other processes known in the art. Various components may also be pre-coated or encapsulated as known in the art. Those skilled in the art will also appreciate that suitable additives may be introduced into the composition or during the process to facilitate the preparation of the dosage form, depending on the needs of the individual process.

[0076] Those skilled in the art will be able to readily select manufacturing equipment and pharmaceutically acceptable additives or inert ingredients to manufacture the implementation of curcumin or curcumin-like ammonium phenolate salts. For illustrative purposes, examples of pharmaceutically acceptable additives or inert ingredients and manufacturing processes are included below, particularly those relating to the manufacture of implementations of curcumin or curcumin-like ammonium phenolate salts in tablet form. Although specific examples are given, it should be understood that those skilled in the art will readily understand how to manufacture implementations of curcumin or curcumin-like ammonium phenolate salts according to other administration and delivery methods disclosed in this document.

[0077] Specific implementations of curcumin or curcumin-like ammonium phenolate salts may include lubricants. Lubricants are any anti-sticking agents, flow aids, flow promoters, and similar materials that perform numerous functions in tablet manufacturing, such as improving the flow rate of tablet granulation, preventing tablet material from adhering to the surfaces of the die and punch, reducing intergranular friction, and facilitating tablet ejection from the die cavity. Lubricants may contain, for example, magnesium stearate, calcium stearate, talc, and colloidal silica.

[0078] Specific realizations of curcumin or curcuminoid ammonium phenolate salts may also include binders. A binder is any agent used to impart cohesive properties to a powder material through particle-to-particle bonding. Binders may include, for example, matrix binders (e.g., dry starch, dry sugar), membrane binders (e.g., cellulose, bentonite, sucrose), and chemical binders (e.g., polymeric cellulose derivatives such as methylcellulose, carboxymethylcellulose, and hydroxypropylcellulose); and other sugar, gelatin, non-cellulose binders, etc.

[0079] Disintegrants can be used in specific implementations of curcumin or curcuminoid ammonium phenolate salts to promote the breakage or disintegration of tablets after administration. Disintegrants may include, for example, starch, starch derivatives, clay (e.g., bentonite), alginate, gum (e.g., guar gum), cellulose, cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose), croscarmellose sodium, croscarmellose cellulose, and other organic and inorganic materials.

[0080] The realization of curcumin or curcumin-like ammonium phenolate salts may include a diluent or any inert substance added to increase the volume of the curcumin-ammonium phenolate salt so that the tablet has the actual size for compression. Diluents may include, for example, calcium phosphate, calcium sulfate, lactose, mannitol, magnesium stearate, potassium chloride, and citric acid, as well as other organic and inorganic materials.

[0081] The buffer may be contained in curcumin-ammonium phenolate and may be either an acid or a base, wherein the acid is, for example, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, or toluenesulfonic acid, and the base is, for example, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, and other organic and inorganic chemicals.

[0082] Curcumin or curcumin-like ammonium phenolate salts can also be administered using amphiphilic lipid delivery systems (such as liposomes and monolayer vesicles), tablet systems, oral liquid systems, parenteral and / or intravenous systems, local systems (creams, gels, transdermal patches, etc.), intranasal systems, rectal or vaginal systems, and many other delivery methods and / or systems known to those skilled in the art.

[0083] Those skilled in the art will be able to readily select additional pharmaceutically acceptable additives to enable the delivery of the pharmaceutical compositions disclosed in this document.

[0084] For the illustrative purposes of this disclosure, tablets can be used for the delivery of specific implementations of curcumin or curcuminoid ammonium phenolate salts. A tablet is any solid pharmaceutical dosage form containing one or more pharmaceutically acceptable active agents, administered with or without suitable pharmaceutically acceptable additives, and prepared by compression or molding methods well known in the art. Tablets have been widely used and remain popular as a dosage form because they offer advantages to manufacturers (e.g., simplicity and economy of preparation, stability, and convenience of packaging, transport, and dispensing) and patients (e.g., accuracy of dosage, compactness, portability, mild taste, and ease of administration). Although the most common shape of tablets is disc-shaped, they can also be, for example, round, oval, rectangular, cylindrical, or triangular. Tablets may optionally be scored so that they can be divided into different doses. They can vary considerably in size and weight depending on the amount of one or more pharmaceutically acceptable active agents present and the intended route of administration. They fall into two main categories: compressed tablets and molded tablets.

[0085] For example, tablets and other oral discrete dosage forms, such as capsules, flat capsules, pills, granules, pills, beads, and granules, can optionally be coated with one or more enteric coatings, sealing coatings, film coatings, barrier coatings, compression coatings, rapidly disintegrating coatings, or enzyme-degradable coatings. Multiple coatings can be applied to achieve the desired properties. Furthermore, as a non-limiting example, dosage forms can be designed for immediate release, pulsed release, controlled release, extended release, delayed release, targeted release, simultaneous release, or targeted delayed release. To control release / absorption, the carrier can be made from various component types and coatings of varying levels or thicknesses. Such different carriers can be mixed in the dosage form to achieve the desired properties. Furthermore, the dosage form release profile can be influenced by polymer matrix compositions, coating matrix compositions, multi-particle compositions, coated multi-particle compositions, ion exchange resin-based compositions, permeation-based compositions, or biodegradable polymeric compositions.

[0086] While the manufacture of curcumin or curcumin-like ammonium phenolate salts has been described in the examples with specific sequences of steps and / or specific forms, it will be understood that such manufacture is not limited to the specific order of the disclosed steps or forms. For example, solvents other than water can be used, where ammonia and curcumin are readily soluble and can be evaporated. Any steps or sequences of steps in the manufacture of any form of curcumin or curcumin-like ammonium phenolate salts are given as examples of possible steps or sequences of steps or potential forms, and not as limitations, as many possible manufacturing processes and sequences of steps can be used to manufacture a wide variety of forms of curcumin-ammonium phenolate salts.

[0087] In other aspects, this disclosure relates to methods for treating curcumin-amylated conditions in a subject. The methods may include administering to the subject an ammonium phenolate of curcumin or an ammonium phenolate of curcumin metabolites. Therefore, the use of an ammonium phenolate of curcumin or an ammonium phenolate of curcumin metabolites for treating curcumin-amylated conditions is disclosed. In some aspects, the use of an ammonium phenolate of curcumin or an ammonium phenolate of curcumin metabolites in the manufacture of pharmaceuticals, therapeutic compositions, or nutritional compositions is disclosed.

[0088] In some respects, the methods and uses disclosed herein include reducing inflammation in human subjects, reducing lactic acid production in human subjects during or after exercise, increasing endurance in human subjects, increasing strength in human subjects, lowering total cholesterol in subjects, lowering LDL cholesterol in subjects, treating depression in subjects, treating allergic rhinitis in subjects, lowering triglycerides in subjects, treating hyperlipidemia in subjects, treating non-alcoholic fatty liver disease in subjects, treating alcoholic fatty liver disease in subjects, treating stomatitis in subjects, treating osteoarthritis in subjects, treating pruritus in subjects, treating Alzheimer's disease in subjects, treating peptic ulcers in subjects, treating acne in subjects, and treating age-related disorders in subjects. Cognitive decline, treatment of amenorrhea, treatment of ankylosing spondylitis, treatment of asthma, improvement of motor performance, treatment of benign prostatic hyperplasia, treatment of β-thalassemia, treatment of bruising and enhanced healing, treatment of cachexia, treatment of oral ulcers, treatment of chemotherapy-induced acral erythema, treatment of chemotherapy-induced constipation, treatment of chemotherapy-induced diarrhea, treatment of chemotherapy-induced nausea and vomiting (CINV), treatment of chemotherapy-induced peripheral neuropathy, treatment of chronic kidney disease (CKD), treatment of colorectal adenoma, treatment of colorectal cancer, reduction of coronary artery bypass graft migration. Risk of cardiac injury after CABG surgery, relief of COVID-19 symptoms in subjects, treatment of Crohn's disease in subjects, treatment of denture stomatitis in subjects, treatment of diabetes in subjects, treatment of diabetic foot ulcers in subjects, treatment of diabetic nephropathy in subjects, treatment of dysmenorrhea in subjects, treatment of indigestion in subjects, treatment of erythema in subjects, treatment of exercise-induced muscle soreness in subjects, treatment of gingivitis in subjects, treatment of gout in subjects, treatment of Helicobacter pylori in subjects, treatment of impaired glucose tolerance (prediabetes) in subjects, treatment of irritable bowel syndrome (IBS) in subjects, treatment of arthralgia in subjects, treatment of juvenile idiopathic arthritis (JIA) in subjects, treatment of... Knee pain, treatment of lichen planus, treatment of metabolic syndrome, treatment of migraine, reduction of myocardial damage after myocardial infarction (MI), treatment of obesity, reduction of body fat percentage, increase of body mass index, treatment of oral submucosal fibrosis, treatment of acute pain, treatment of periodontitis, treatment of polycystic ovary syndrome (PCOS), treatment of postoperative pain, treatment of premenstrual syndrome (PMS), treatment of prostate cancer, treatment of psoriasis, improvement of quality of life for chronic diseases, treatment of radiation dermatitis, treatment of radiation-induced rectal disease, and treatment of respiratory infections.Curcumin was used to treat rheumatoid arthritis (RA), sarcopenia, schizophrenia, sepsis, stress, systemic lupus erythematosus (SLE), tuberculosis, ulcerative colitis, uveitis, and / or improve wound healing in subjects. For simplicity, the above uses are referred to herein as "conditions that curcumin can improve."

[0089] The realization of curcumin or curcumin-like ammonium phenolates is particularly useful in improving athletic performance and alleviating the various ailments discussed above. For all the conditions that curcumin can improve, the curcumin-ammonia complexes and related formulations described herein deliver the beneficial effects of curcumin at lower doses than curcumin alone. In other respects, the curcumin-ammonia complexes and related formulations are more potent than equivalent doses of curcumin.

[0090] Curcumin, which can be relieved by application of curcumin and the formulations described herein, improves the symptoms and etiology of the condition, as described in Springhouse Corporation's "Handbook of Diseases," 3rd edition, which is incorporated herein by reference in its entirety. Furthermore, all references, patents, and published patent applications cited throughout this application (if any) are incorporated herein by reference in their entirety for all purposes.

[0091] Example

[0092] The following examples further illustrate the content of this disclosure and should not be construed as limiting.

[0093] Example 1:

[0094] At room temperature, 95% curcumin powder (2.68 mol or 987.26 g curcumin) was slowly dissolved in a glass beaker containing 1000 ml of 10% ammonia solution (5.36 mol concentration, 91.12 g ammonia) while stirring. The mixture was dried under vacuum at 60 °C. The resulting product (ammonium phenolate of curcumin) was then ground. The powder was then mixed with sodium carbonate at a ratio of 2:1.

[0095] like Figure 5 As shown, the visible appearance of the ammonium phenolate of curcumin (top) is compared with that of regular curcumin, and the phenolate is significantly darker in color. Figure 6 This shows the low solubility of curcumin in water. On the other hand, Figure 7 and Figure 8This shows that the ammonium phenolate of curcumin is more soluble in water. Even without stirring, the dissolution of the ammonium phenolate of curcumin in water is visible one minute after combining 1 g of the ammonium phenolate of curcumin with 100 ml of water without any stirring. Figure 7 On the other hand, even 10 minutes after combining 95% curcumin powder with water, there was no visible sign of curcumin dissolving in the water. With stirring (using a magnetic stirrer at 1200 rpm), it took less than 10 seconds to completely dissolve 1 gram of curcumin ammonium phenolate in 100 ml of water. Figure 9 ).like Figure 10 As shown, a solution containing 1 g of 95% curcumin powder in 100 ml of water did not exhibit any solubility even with stirring. After centrifuging the solution at 1000 rpm for 10 seconds and then passing it through a filter, all the curcumin powder remained on the filter paper, and the filtrate was clear and colorless. On the other hand, the filtrate produced by centrifuging a solution of 1 g of curcumin ammonium phenolate in 100 ml of water was curcumin-colored, and no solids remained on the filter paper. Figure 11 ).

[0096] Example 2:

[0097] A 60-year-old man with chronic knee and shoulder pain experienced no effect on his pain levels after using 1 to 4 grams of curcumin products daily. These curcumin products included those from leading curcumin brands containing piperine, which reportedly made curcumin more bioavailable at a daily dose of 2 grams of 95% curcumin. Once the subject began taking curcumin ammonium phenolate at a dose of 1 gram twice daily, he began noticing symptom improvement the following day. He continued to show improvement in pain reduction over the next 30 days of taking the new formulation.

[0098] Example 3:

[0099] A 42-year-old male subject who trained regularly ingested curcumin ammonium phenolate salt at a dose of 1 gram in the morning and 1 gram in the evening the day before training. On training days, he ingested curcumin ammonium phenolate salt 1 hour before starting training. The subject experienced longer time to failure on the treadmill (if the treadmill was set to 0 height and 5 mph): his time to failure increased from 13 minutes to 15.5 minutes. For the bicep curl test using 40-pound dumbbells (the maximum number of bicep curl repetitions performed in 30 seconds with appropriate weight), the number of repetitions increased from 11 to 14. On the second day after training, his soreness was significantly lower. In addition, he recovered from exercise at almost half the usual rate (measured by muscle soreness and discomfort, 1 day vs. 2 days).

[0100] After a 3-day washout period (curcumin has a half-life of approximately 7 hours), he took 1 gram of 95% curcumin extract the night before another training day and another gram one hour before training. His time to failure on the treadmill was 13 minutes. His maximum number of bicep curls with 40-pound dumbbells in 30 seconds was 11 repetitions. His recovery time (measured by muscle soreness and discomfort) was 2 days after training. Therefore, regular curcumin had no effect on his athletic performance and recovery, while the ammonium phenolate of curcumin increased his athletic performance and reduced the recovery time required.

[0101] The beneficial effects of curcumin ammonium phenolate on athletic performance are surprising, given that ammonium has long been identified as associated with fatigue and is considered a metabolic toxin contributing to its development. See Mutch and Banister, Ammoniametabolism in exercise and fatigue: a review, Med Sci Sports Exerc., 1983, 15(1): 41-50. Specifically, ammonia production has been observed in stimulated nerves, and the direct source of ammonia from muscles appears to be a result of AMP deamination, and this is more pronounced in fast twitching fibers than in slow twitching fibers. Elevated blood ammonia levels have also been reported in rats after swimming and in humans after arm work, maximal dynamometer, and treadmill exercise. In addition to exercise and fatigue, elevated blood ammonia has been associated with a surprising number of functional and metabolic neurological disorders, including the development of hepatic coma, ammonia-induced seizures due to hyperbaric oxygen respiration, epileptic seizures, and decreased neuronal excitability. Furthermore, elevated blood ammonia concentrations are characteristic of many genetic diseases with neurological dysfunction. Therefore, the fact that curcumin ammonium phenolate can enhance endurance and shorten recovery time, while curcumin itself cannot, is a surprising effect of the soluble form of curcumin.

[0102] Example 4:

[0103] Although curcumin is almost insoluble in water, its solubility is even lower in acidic environments. For example, the solubility of curcumin in water, phosphate buffer, and 0.1 mol / L hydrochloric acid are 1.622 μg / ml, 0.310 μg / ml, and 0.675 μg / ml, respectively (Lu Y, Lin M, Zong J, Zong L, Zhao Z, Wang S, Zhang Z, and Han M, Highly bioavailable curcumin preparation with a co-grinding and solvent-free process, Food Sci Nutr. 2020 Oct 7;8(12):6415-6425. doi: 10.1002 / fsn3.1930.PMID: 33312527; PMCID: PMC7723189.). Therefore, it is of interest to investigate whether curcumin ammonium phenolate also exhibits enhanced solubility at acidic pH. Therefore, 2 grams of curcumin ammonium phenolate was added to 200 ml of saturated citric acid solution (pH=3). The resulting acidic solution was then filtered out. The liquid passing through the filter had the characteristic orange color of curcumin. Figure 12 Then, 2 grams of 95% curcumin were added to 200 ml of saturated citric acid solution (pH=3). The resulting acidic solution was then filtered out. The liquid passing through the filter was completely clear, like water with a neutral pH. Figure 13 The slight yellow tint in the water comes from residues from previous use of the filter. Therefore, curcumin ammonium phenolate exhibits increased solubility even at acidic pH.

Claims

1. A composition comprising: ammonia; and Curcumin or curcuminoids.

2. The composition according to claim 1, wherein the composition comprises curcumin and ammonia as an ammonium phenolate of curcumin.

3. The composition according to claim 2, wherein the ammonium phenolate of curcumin comprises the following structure: 。 4. The composition according to claim 2, wherein the curcumin or curcuminoid is selected from at least one of the group consisting of: curcumin glucoside, tetrahydrocurcumin, curcumin sulfate, hexahydrocurcuminol, demethoxycurcumin, bisdemethoxycurcumin, and cyclocurcumin.

5. The composition according to any one of claims 1 to 4, wherein the composition further comprises a solubility enhancer.

6. The composition according to claim 5, wherein the solubility enhancer is sodium carbonate.

7. The composition according to any one of claims 1 to 6, wherein the composition further comprises dietary ingredients, food additives, or pharmaceutically acceptable additives.

8. The composition of claim 7, wherein the pharmaceutically acceptable additive comprises one or more of the following: solubilizer, enzyme inhibitor, anticoagulant, defoamer, antioxidant, colorant, coolant, cryoprotectant, diluent, hydrogen bonding agent, flavoring agent, flow agent, plasticizer, preservative, sweetener, thickener, and carrier.

9. The composition of claim 7, wherein the pharmaceutically acceptable additive comprises one or more of the following: calcium phosphate, cellulose, stearic acid, croscarmellose cellulose, magnesium stearate, and silicon dioxide.

10. The composition according to any one of claims 1 to 9, wherein the composition further comprises an adhesive.

11. The composition according to any one of claims 1 to 10, wherein the composition is in the form of capsules, flat capsules, pills, tablets, powders, granules, pills, beads, granules, lozenges, tablets, solutions, elixirs, syrups, tinctures, suspensions, emulsions, mouthwashes, sprays, drops, ointments, creams, gels, pastes, transdermal patches, suppositories, pessaries, creams, gels, pastes, or foams.

12. The composition according to any one of claims 1 to 11, wherein the composition further comprises a lubricant.

13. The composition of claim 12, wherein the lubricant comprises one or more of the following: magnesium stearate, calcium stearate, talc, and colloidal silica.

14. The composition according to any one of claims 1 to 4, wherein the composition comprises 5% to 95% by weight of curcumin and 5% to 95% by weight of ammonia.

15. The composition according to any one of claims 1 to 4, wherein the composition further comprises human saliva, human gastric juice, human intestinal juice, or any combination thereof.

16. A method for forming an ammonium phenolate of curcumin or curcuminoid, the method comprising dissolving the curcumin or curcuminoid in an ammonia solution.

17. The method of claim 16, wherein the molar ratio of ammonia to the curcumin or curcuminoid is about 1:1 to about 2:

1.

18. The method according to claim 16 or 17, the method further comprising drying the ammonia solution comprising the dissolved curcumin or curcuminoid to produce a dried product.

19. The method of claim 18, the method further comprising grinding the dried product to produce a powder.

20. The method according to any one of claims 16 to 19, wherein the ammonia solution comprises about 5% by weight to about 40% by weight of ammonia.

21. The method according to any one of claims 16 to 21, wherein the ammonium phenolate of curcumin comprises the following structure: 。 22. The method according to any one of claims 16 to 21, wherein the curcumin or curcuminoid is selected from at least one of the group consisting of: curcumin glucoside, tetrahydrocurcumin, curcumin sulfate, hexahydrocurcuminol, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin.

23. A method for treating a condition that can be improved by curcumin, the method comprising administering to a subject curcumin or an ammonium phenolate of curcumin-like compounds.

24. The method of claim 23, wherein the method reduces lactic acid in human subjects during exercise, increases endurance in human subjects, increases strength in human subjects, lowers total cholesterol in subjects, lowers LDL cholesterol in subjects, treats depression in subjects, treats allergic rhinitis in subjects, lowers triglycerides in subjects, treats hyperlipidemia in subjects, treats non-alcoholic fatty liver disease in subjects, treats alcoholic fatty liver disease in subjects, treats stomatitis in subjects, treats osteoarthritis in subjects, treats pruritus in subjects, treats Alzheimer's disease in subjects, treats peptic ulcers in subjects, reduces acne in subjects, treats age-related cognitive decline in subjects, and treats amenorrhea in subjects. The treatments included: reducing age-related cognitive decline in subjects; reducing ankylosing spondylitis symptoms in subjects; improving asthma in subjects; improving athletic performance in subjects; treating benign prostatic hyperplasia in subjects; treating β-thalassemia in subjects; treating bruises and enhancing their healing in subjects; treating cachexia in subjects; treating oral ulcers in subjects; treating chemotherapy-induced acral erythema in subjects; treating chemotherapy-induced constipation in subjects; treating chemotherapy-induced diarrhea in subjects; treating chemotherapy-induced nausea and vomiting (CINV) in subjects; treating chemotherapy-induced peripheral neuropathy in subjects; treating chronic kidney disease (CKD) in subjects; treating colorectal adenoma in subjects; treating colorectal cancer in subjects; and reducing coronary artery disease. Risk of cardiac injury after CABG surgery, relief of COVID-19 symptoms in subjects, treatment of Crohn's disease in subjects, treatment of denture stomatitis in subjects, treatment of diabetes in subjects, treatment of diabetic foot ulcers in subjects, treatment of diabetic nephropathy in subjects, treatment of dysmenorrhea in subjects, treatment of indigestion in subjects, treatment of erythema in subjects, treatment of exercise-induced muscle soreness in subjects, treatment of gingivitis in subjects, treatment of gout in subjects, treatment of Helicobacter pylori infection in subjects, treatment of impaired glucose tolerance (prediabetes) in subjects, treatment of irritable bowel syndrome (IBS) in subjects, treatment of arthralgia in subjects, treatment of juvenile idiopathic arthritis (JIA) in subjects, treatment of subjects Knee pain, lichen planus, metabolic syndrome, migraine, myocardial damage after myocardial infarction (MI), obesity, body fat percentage, body mass index, oral submucosal fibrosis, acute pain, periodontitis, polycystic ovary syndrome (PCOS), postoperative pain, premenstrual syndrome (PMS), prostate cancer, psoriasis, quality of life with chronic diseases, radiation dermatitis, radiation-induced rectal disease, and respiratory infections.Treatment of subjects with rheumatoid arthritis (RA), sarcopenia, schizophrenia, sepsis, stress, systemic lupus erythematosus (SLE), tuberculosis, ulcerative colitis, uveitis, and / or improvement of wound healing.

25. The method of claim 23 or 24, wherein administration of curcumin or curcumin-like ammonium phenolate comprises administering curcumin ammonium phenolate to the subject at a dose of 1 mg to 30,000 mg per day.

26. The method according to any one of claims 23 to 25, wherein administering curcumin ammonium phenolate comprises administering the curcumin ammonium phenolate in multiple doses daily.

27. The method according to any one of claims 23 to 26, wherein the application of curcumin or curcumin-like ammonium phenolate comprises the application of the curcumin or curcumin-like ammonium phenolate in the form of capsules, pouches, pills, tablets, powders, granules, pills, beads, granules, lozenges, pills, solutions, elixirs, syrups, tinctures, suspensions, emulsions, mouthwashes, sprays, drops, ointments, creams, gels, pastes, transdermal patches, suppositories, pessaries, creams, gels, pastes, foams, and combinations thereof.

28. The method according to any one of claims 23 to 27, wherein the application of curcumin or curcumin-like ammonium phenolate comprises topical, transdermal, oral, rectal, ocular, nasal, vaginal, parenteral, and combinations thereof application of the curcumin or curcumin-like ammonium phenolate.

29. The method according to any one of claims 23 to 28, wherein the ammonium phenolate of curcumin comprises the following structure: 。 30. The method according to any one of claims 23 to 29, wherein the curcumin or curcuminoid is selected from at least one of the group consisting of: curcumin glucoside, tetrahydrocurcumin, curcumin sulfate, hexahydrocurcuminol, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin.

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