Curcuminoid cyclodextrin complexes and methods for preparing the same

Abstract

Curcuminoid cyclodextrin complexes, process for preparing the same along with products utilizing the curcuminoid cyclodextrin complexes formed. The process includes providing an amount of one or more curcuminoids, one or more cyclodextrins, one or more bases and / or one or more acids. A first mixture is prepared by combining the one or more curcuminoids, the one or more cyclodextrins and / or the one or more bases with water. An amount of the one or more acids are added to the first mixture to modify the pH and form a second mixture. Throughout the process, the one or more curcuminoids and the one or more cyclodextrins form one or more curcuminoid cyclodextrin complexes. Subsequently, the second mixture is subjected to drying process(es) reducing the overall amount of water and increase the bond, interaction and / or complexation between the one or more curcuminoids and the one or more cyclodextrins within the complexes formed.

Description

[0001] TITLE

[0002] CURCUMINOID CYCLODEXTRIN COMPLEXES

[0003] AND METHODS FOR PREPARING THE SAME

[0004] FIELD OF THE DISCLOSURE

[0005] The present disclosure relates to curcuminoid cyclodextrin complexes along with methods and / or processes for producing the same.

[0006] BACKGROUND OF THE DISCLOSURE

[0007] Curcumin is a bright yellow bioactive that is naturally produced by plants belonging to the Curcuma longa species. Currently, tetrahydrocurcumin (THC), which is a beta-diketone, a polyphenol and a diarylheptanoid that is derived from curcumin, has been shown to have medical and / or dietary benefits, however due to its poor bioavailability the overall effectiveness and usability of THC in these applications has been inhibited. In pharmacology, the bioavailability of a substance has to deal with absorption characteristics of a substance within a body. In particular, it has to deal with the percent fraction of an administered drug that reaches the systemic circulation or the portion of the cardiovascular system which transports oxygenated blood away from the heart to the rest of the body.

[0008] Tetrahydrocurcumin (hereinafter “THC”) is a beta-diketone, a polyphenol and a diarylheptanoid that is derived from and is a metabolite of curcumin. While THC is a natural product, it has poor solubility and dissolution due to its hydrophobic nature. As a result, various solvents are typically used throughout the manufacturing processes for products containing THC therein as a component or an ingredient. This is undesirable as the use of one or more solvents in the production of a food, medical, pharmaceutical, nutraceutical, bioceutical, recreational, supplement and / or other product typically results in an amount of a solvent residue that retained within the final product. Exposure to the remaining solvent residue can be harmful for users and is therefore undesirable. Solvent exposure can result in various issues such as toxicity to the nervous system, reproductive damage, liver and kidney damage, respiratory impairment, cancer, and dermatitis. All of which are undesirable. Additionally, production or manufacturing processes that utilize one or more solvents to produce a product are typically slower, more hazardous and more expensive than a solvent-free process. Furthermore, the use of solvents within the manufacturing process carries with it various environmental contamination and health risks. This is due to the solvents ability to quickly migrate great distances within the soil after a spill resulting in wide-spread soil contamination that negatively effects the surrounding plant, animal and human population.

[0009] It would therefore be advantageous to develop a complex that increases the overall solubility, dissolution and / or bioavailability of THC. Additionally, it would be advantageous to develop a THC complex and process for manufacturing or producing the same in such a manner that no solvents are used and a solvent- free product is obtained.

[0010] SUMMARY OF THE DISCLOSURE

[0011] Curcuminoid cyclodextrin complexes, process for preparing the curcuminoid cyclodextrin complexes along with products utilizing the curcuminoid cyclodextrin complexes formed. The process includes the step of providing an amount of one or more curcuminoids, one or more cyclodextrins, one or more bases and / or one or more acids. A first mixture is prepared by combining the one or more curcuminoids, the one or more cyclodextrins and / or the one or more bases with water. An amount of the one or more acids are added to the first mixture to modify the pH and form a second mixture. Throughout the process, the one or more curcuminoids and the one or more cyclodextrins form one or more curcuminoid cyclodextrin complexes. Subsequently, the second mixture is subjected to drying process(es) reducing the overall amount of water and increase the bond, interaction and / or complexation between the one or more curcuminoids and the one or more cyclodextrins within the one or more curcuminoid cyclodextrin complexes formed using the process.

[0012] According to an embodiment of the disclosure and as a non-limiting example, the one or more acids may be added to reduce the pH of the second mixture to approximately 3 to approximately 5.

[0013] According to an embodiment of the disclosure and as a non-limiting example, the first mixture may be mixed in a high shear mixer for approximately 20 minutes to approximately 2 hours.

[0014] According to an embodiment of the disclosure and as a non-limiting example, the one or more cyclodextrins may be one or more alpha-cyclodextrins and their derivatives, one or more beta-cyclodextrins and their derivatives and / or one or more gamma-cyclodextrins and their derivatives.

[0015] According to an embodiment of the disclosure and as a non-limiting example, the one or more curcuminoids may be tetrahydrocurcumin (THC).

[0016] According to an embodiment of the disclosure and as a non-limiting example, the one or more curcuminoid cyclodextrin complexes formed using the process may have a tetrahydrocurcumin content of approximately 7% by weight to approximately 20% by weight.

[0017] According to an embodiment of the disclosure and as a non-limiting example, the one or more bases may be one or more strong bases. According to an embodiment of the disclosure and as a non-limiting example, the one or more strong bases may be potassium hydroxide, sodium hydroxide, magnesium hydroxide and / or calcium hydroxide.

[0018] According to an embodiment of the disclosure and as a non-limiting example, the one or more curcuminoid cyclodextrin complexes formed using the process may have approximately 0.5% to approximately 5% by weight of a potassium chloride therein, preferably approximately 1% to approximately 3% by weight potassium chloride therein or more preferably approximately 1 % to approximately 2% by weight potassium chloride therein.

[0019] According to an embodiment of the disclosure and as a non-limiting example, the one or more acids may be one or more strong acids.

[0020] According to an embodiment of the disclosure and as a non-limiting example, the one or more strong acids may be hydrochloric acid, nitric acid, hydroiodic acid, perchloric acid, chloric acid, phosphoric acid and / or citric acid.

[0021] According to an embodiment of the disclosure and as a non-limiting example, the water is deionized water.

[0022] According to an embodiment of the disclosure and as a non-limiting example, where the process further includes the step of adding one or more anti-caking agents.

[0023] According to an embodiment of the disclosure and as a non-limiting example, the one or more anti-caking agents may be tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminium silicate, calcium aluminosilicate, bentonite, aluminium silicate, stearic acid and / or poly dimethylsiloxane. According to an embodiment of the disclosure and as a non-limiting example, during the drying step the second mixture is dried using one or more spray drying processes.

[0024] According to an embodiment of the disclosure and as a non-limiting example, after the drying step the one or more curcuminoid cyclodextrin complexes formed using the process may have approximately 2% to approximately 15% water by weight or preferably approximately 5% to approximately 10% water by weight.

[0025] According to an embodiment of the disclosure and as a non-limiting example, the one or more drying processes may occur at approximately 160°C to approximately 200°C.

[0026] According to an embodiment of the disclosure and as a non-limiting example, the one or more curcuminoid cyclodextrin complexes formed using the process may be a free-flowing off- white powder.

[0027] According to an embodiment of the disclosure and as a non-limiting example, the one or more curcuminoid cyclodextrin complexes formed using the process are suitable for use within a food, a medical, a pharmaceutical, a nutraceutical, a bioceutical, a recreational and / or a supplement products.

[0028] BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The above, as well as other advantages of the present disclosure, will become readily apparent to those skilled in the art from the following detailed description when considered in light of the accompanying drawings in which:

[0030] FIG. 1 is a flow chart illustrating a process for preparing or manufacturing cyclodextrin and tetrahydrocurcumin (THC) complexes;

[0031] FIG. 2 is a chart illustrating the amount of THC in parts per million within various samples obtained at pre-determined time intervals according to Example 5; and FIG. 3 is a chart illustrating the amount of THC cyclodextrin complexes in parts per million within various samples obtained at pre-determined time intervals according to Example 6.

[0032] DETAILED DESCRIPTION

[0033] It is to be understood that the invention may assume various alternative orientations, formulations, compositions and / or step sequences, except where expressly specified to the contrary. It is also understood that the specific devices, compositions, formulations and / or processes illustrated within the attached drawings and described within the specification are simply exemplary embodiments of the inventive concepts disclosed and defined herein. Hence, specific dimensions, formulations, compositions, directions and / or other physical characteristics relating to the various embodiments disclosed are not to be considered as limiting, unless expressly stated otherwise.

[0034] It is within the scope of this disclosure and as a non-limiting example that the complexes disclosed herein may be used within a food, medical, pharmaceutical, nutraceutical, bioceutical, recreational, supplement and / or other product.

[0035] The present disclosure relates to a method or process for preparing or otherwise manufacturing a complex of a curcuminoid with a cyclodextrin or a cyclodextrin derivative. Cyclodextrins are cyclic oligosaccharides containing six (a-), seven (B-) or eight (y-) D- glucopyranose units connected to one another via a-(l,4) bonds and which are obtained by enzymatic conversion (or enzymatically) from starch. Due in part to their molecular structure, cyclodextrins have a hydrophilic outer surface and a hydrophobic inner surface or cavity (not shown). As a result, cyclodextrins can form reversible complexes that may contain one or more hydrophobic guest molecules therein. Because cyclodextrins have a hydrophilic outer surface, they can be used to improve the overall water solubility of various substances that may be hydrophobic and therefore resistant to dissolving in or being mixed with water in a safe and environmentally friendly way. At the same time, it is possible to reduce the volatility of various volatile substances by forming complexes with cyclodextrins and to achieve delayed release of a guest molecule. Furthermore, cyclodextrins have been approved by the United States Food and Drug Administration (hereinafter “FDA”) and is generally recognized as being safe to use in food, medical, pharmaceutical, nutraceutical, bioceutical, recreational, supplement and / or other such products.

[0036] Curcuminoids are a linear diarylheptanoid, which is a class of plant secondary metabolites that includes curcumin, demethoxycurcumin, and bisdemethoxycurcumin, all of which are isolated from turmeric and / or other plants of the curcuma longa species. These compounds are natural phenols and produce a pronounced yellow color that is often used to color foods, medicines and / or other products. Curcumin is obtained from the root of turmeric and as a phenolic pigments is responsible for the yellow color of turmeric. Additionally, curcumin has also been used as a flavoring ingredient for various food products. However, due to the unstable nature and its poor bioavailability, laboratory and clinical research has not been able to confirm whether or not curcumin has any medical or dietary benefits and / or uses.

[0037] Tetrahydrocurcumin (hereinafter “THC”) is a beta-diketone, a polyphenol and a diarylheptanoid that is derived from curcumin. In THC, both of the double bonds have been reduced to single bonds and it has a role as a metabolite. In biochemistry, metabolites are an intermediate product or end product of metabolism which is a life sustaining chemical reactions in an organism. The term metabolite is often used when referring to a small molecule and they have various functions, including but not limited to fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, catalytic activity, defense and / or interactions with other organisms for example as pigments, odorants, and / or pheromones. A primary metabolite is directly involved in normal "growth", development, and / or reproduction, while a secondary metabolite is not directly involved in those processes, but usually has an important ecological function.

[0038] While THC is reported to have various therapeutic properties, such as but not limited to anti-inflammatory, anti-microbial, anti-carcinogenic and / or antioxidant properties, due to its unstable nature and its poor bioavailability, laboratory and clinical research has not been able to confirm whether or not curcumin has any medical or dietary benefits and / or uses. Additionally, due to the hydrophobic nature of THC, it has poor water solubility making it difficult to be absorbed within the body. This has a negative effect on the overall bioavailability of THC.

[0039] FIG. 1 provides a flow chart illustrating an exemplary and non-limiting process for preparing or otherwise manufacturing 100 cyclodextrin THC complexes according to an embodiment of the disclosure. The process 100 first includes a providing step 102 where an amount of one or more curcuminoids 104, an amount of one or more cyclodextrins 106 and / or derivatives thereof, an amount of one or more bases 108 and / or an amount of one or more acids 110 are provided for use within the process 100. As used herein, the one or more cyclodextrins 106 may be referred to as one or more host molecules and the one or more curcuminoids 104 may also be referred to as one or more guest molecules. It is within the scope of this disclosure and as a non- limiting example that the one or more curcuminoids 104 may be THC due in part to its improved bioavailability over that of pure curcumin. Additionally, it is within the scope of this disclosure and as a non- limiting example that the one or more cyclodextrins 106 may be one or more alpha-cyclodextrins, one or more beta-cyclodextrins and / or one or more gammacyclodextrins. Preferably, the one or more cyclodextrins 106 are un-complexed and therefore able to be complexed with the one or more curcuminoids 104. As a non-limiting example, the one or more cyclodextrins 106 may be one or more alpha-cyclodextrins and / or one or more gamma- cyclodextrins due to the fact that currently there are not any restrictions for these cyclodextrins with respect to their accepted daily intake (or ADI).

[0040] In accordance with an embodiment of the disclosure and as a non-limiting example, the derivatives of the one or more cyclodextrins 106 may be one or more hydroxy propyl beta cyclodextrins (HPB), one or more carboxymethyl-cyclodextrins and / or one or more methyl beta cyclodextrins.

[0041] The one or more cyclodextrins 106 are desirable as a carrier for the one or more curcuminoids 104 due to the fact that they are metabolized by the body like a starch, a fiber or a carbohydrate. This means that the one or more cyclodextrins 106 have increased bio-acceptability over other types of carriers.

[0042] In particular, it is within the scope of this disclosure and as a non-limiting example that the one or more cyclodextrins 106 may be one or more beta-cyclodextrins and / or one or more gamma-cyclodextrins. The one or more beta-cyclodextrins and the one or more gammacyclodextrins are particularly desirable given the size of the molecules in general, in combination with the overall size of the hydrophobic inner surface or cavity (not shown) of the gammacyclodextrin molecule, a more stable, effective and efficient curcuminoid cyclodextrin complex (not shown) is formed between the one or more curcuminoids 104 and the one or more beta- cyclodextrins and / or the one or more gamma-cyclodextrins. Additionally, given the increased responsiveness to pH modification that is exhibited by the one or more beta-cyclodextrins and the one or more gamma-cyclodextrins, the overall yield or quantity of the curcuminoid cyclodextrin complexes (not shown) obtained is increased. Furthermore, the one or more beta-cyclodextrins and the one or more gamma-cyclodextrins respond well to spray drying processes which is also desirable. Still further, the one or more beta-cyclodextrins and the one or more gamma- cyclodextrins have improved dissolution properties over those exhibited by alpha-cyclodextrins which again makes the one or more beta-cyclodextrins and the one or more gamma-cyclodextrins more desirable. As a result, the overall about of time associated with manufacturing a predetermined quantity or amount of the curcuminoid cyclodextrin complexes (not shown) using the one or more beta-cyclodextrins and / or the one or more gamma-cyclodextrins is decreased thereby providing a more efficient process 100. This also results in a decrease in the overall costs associated with manufacturing the curcuminoid cyclodextrin complexes (not shown).

[0043] Additionally, in particular, the one or more cyclodextrins 106 may be one or more alphacyclodextrins. The alpha-cyclodextrins are particularly desirable given their ability to be metabolized with the body like a fiber. Because fiber is not digested or absorbed within the body it does not build up or create additional undesirable side-effects making it an ideal candidate as a carrier for the one or more curcuminoids 104 in food and / or medical related applications.

[0044] In accordance with an embodiment of the disclosure and as a non-limiting example, the one or more bases 108 provided may be one or more strong bases. Strong bases are basic chemical compounds that can remove a proton from a molecule or a weak acid in an acid-base reaction. It is within the scope of this disclosure and as a non-limiting example that the one or more bases 108 may be one or more strong bases that are a hydroxide of an alkali metal and / or an alkaline earth metal. These are use due to the fact that they are food grade materials and due to the fact that the one or more bases 108 ionize completely when reacted with the one or more acids 110 as part of the process 100. As a non-limiting example that the one or more bases 108 may be a strong base such as but not limited to potassium hydroxide (KOH), sodium hydroxide (NaOH), magnesium hydroxide (Mg(OH)2) and / or calcium hydroxide (Ca(OH)2).

[0045] Potassium hydroxide (KOH) is a prototypical strong base and is used due to its reactivity toward and with various acids. Since the by-product of the process 100 when using sodium hydroxide (NaOH) as the one or more bases 108 results in an increase in the overall amount of sodium chloride (NaCl) within the final product, potassium hydroxide (KOH) is preferred as it reduces the overall sodium intake by the user within the final product produced according to the process 100. As a result, potassium hydroxide (KOH) is a more desirable strong base for use within the process 100. Especially when the cyclodextrin curcuminoid complexes (not shown) produced using the process 100 are used in the food and / or medical industries.

[0046] The one or more acids 110 used within the process 100 may be any acids that are capable of acidifying a mixture. Meaning that the one or more acids 110 may be any acids that are capable of lowering the pH of a mixture a predetermined amount. In accordance with an embodiment of the disclosure and as a non- limiting example, the one or more acids 110 may be one or more strong acids. Strong acids disassociate completely into their ions in water. Because strong acids are capable of complete or substantially complete ionization in water, it makes them ideal candidates for the process 100. As a result, it is within the scope of the disclosure and as a non- limiting example, that the one or more acids 110 used may be one or more strong acids such as hydrochloric acid (HC1), nitric acid (HNO3), hydroiodic acid (Hl), perchloric acid (HCIO4), chloric acid (HCIO3), phosphoric acid (H2PO4) and / or citric acid (CAI I O? ).

[0047] As a non-limiting example, the one or more strong acids 110 used within the process 100 may preferably be hydrochloric acid (HC1), phosphoric acid (H2PO4) and / or citric acid (GJ EC)?). Due to the pH and overall strength of hydrochloric acid (HC1), a smaller amount of the acid is needed to achieve the same result during a neutralization step 114 of the process 100 when compared to other strong acids. That in combination with hydrochloric acid (HC1) being a food grade material and is used within the body’s digestion system as a gastric acid makes it highly desirable for use within the process 100 described and illustrated herein.

[0048] As illustrated within FIG. 1 of the disclosure and as a non-limiting example, after the providing step 102, a complex preparation step 112 may occur. During the complex preparation step 112, an amount of the one or more curcuminoids 104, an amount of the one or more cyclodextrins 106 and an amount of the one or more bases 108 are combined together with an amount of water (not shown) to form a first mixture 113. It is within the scope of this disclosure and as a non-limiting example that the water (not shown) may be an amount of deionized water. Deionized water is used due to the fact that all or substantially all of the mineral ions and other impurities that are typically found within the water have been removed and are no longer present. This aids in ensuring that the chemical reactions that take place during the process 100 are conducted in a controlled and predictable manner. Thereby ensuring that the process yields a product (not shown) of a desired composition, quality and / or yield.

[0049] Once the first mixture 113 has been prepared, a complexing process (not shown) may begin. During the complexing process, an amount of the one or more curcuminoids 104 are received and / or retained within at least a portion of the inner surface or cavity (not shown) of the one or more cyclodextrins 106. Due to the geometry, polarity and hydrophobicity of the inner surface or cavity (not shown) of the one or more cyclodextrins 106 and hydrophobic nature or properties of the one or more curcuminoids 104, at least a portion of the one or more curcuminoids 104 are received and / or retained within at least a portion of the inner surface or cavity (not shown) of the one or more cyclodextrins 106 thereby forming a curcuminoid cyclodextrin complex (not shown). The one or more curcuminoids 104 and the one or more cyclodextrins 106 are held together by van der Waals force. This combination of the geometery and the polarity of the one or more curcuminoids 104 and the one or more cyclodextrins 106 is that draws or othereise attracts the one or more curcuminoids 104 to the one or more cyclodextrins 106 and then the one or more curcuminoids 104 and the one or more cyclodextrins 106 are heldtogether due due to van der Waals force. The curcuminoid cyclodextrin complex formed as a result of the process 100 aids in improving the overall, dispersibility, solubility and / or dissolution within the body when compared to a pure or substantially pure curcuminoid thereby providing an improved overall bioavailability. This is due to the fact that a higher dispersibility results in an increase in bioavailability.

[0050] By adding the one or more bases 108 to the first mixture 113, it increases the overall pH of the mixture (not shown). This is done to increase the overall solubility of the first mixture 113 and is referred to as a pH modification process. In particularly, it aids in increasing the overall solubility of the one or more curcuminoids 104. This aids in ensuring that the overall amount of the one or more curcuminoids 104 and the one or more cyclodextrins 106 that interact with each other within the first mixture 113 is maximized thereby providing an overall increase in the yield of the curcuminoid cyclodextrin complexes formed as a result of the process 100.

[0051] During the pH modification process, the one or more curcuminoids 104 are deprotonated thereby converting it to its more ionic form which aids in improving the overall solubility of the one or more curcuminoids 104 within the curcuminoid cyclodextrin complexes (not shown) formed using the process 100. This increase in the solubility of the one or more curcuminoids 104 within the curcuminoid cyclodextrin complexes (not shown) formed is achieved without the inclusion of one or more acid groups (not shown) with the one or more curcuminoids 104 (or the guest molecule). This is particularly desirable as it makes the process 100 more cost and time efficient. As a result, the increased solubility of the one or more curcuminoids 104 within the curcuminoid cyclodextrin complexes (not shown) formed using the process 100 was surprising and unexpected.

[0052] It is within the scope of this disclosures and as a non-limiting example that the one or more curcuminoids 104 may include one or more alcohol groups (not shown). The one or more alcohol groups (not shown) may be deprotonated during the pH modification process to make the one or more curcuminoids 104 more ionic thereby further aiding in increasing the overall solubility of the one or more curcuminoids 104. It is within the scope of this disclosure and as a non-limiting example that the one or more alcohol groups (not shown) may be one or more food grade alcohols. This increase in the overall solubility and the susceptibility of the one or more curcuminoids 104 to pH modification again is achieved without the inclusion of an acid group along with the one or more curcuminoids 104 provided which is desirable. Again, these results were surprising and unexpected.

[0053] The first mixture 113 obtained is then mixed together within a mixer (not shown) for a pre-determined period of time. It is within the scope of this disclosure and as a non-limiting example that the mixer utilized during the preparation step 112 may be a high shear mixer. High sheer mixers are used in order to disperse or transport one phase or ingredient of the mixture into a main continuous phase with which it would normally be immiscible. It is within the scope of this disclosure and as a non-limiting example that the mixture (not shown) may be mixed for a period of time from as little as a matter of minutes to a period of hours. A balance needs to be struck as longer mixing times at a higher pH results in an undesirable amount of the one or more curcuminoids 104 breaking down which negatively affects the overall yield or amount of the curcuminoid cyclodextrin complexes that are able to be formed as a result of the process 100. As a non-limiting example, the mixture (not shown) may be mixed from approximately 5 minutes to approximately 3.5 hours. It is within the scope of this disclosure and as a non-limiting example, that the first mixture 113 may be mixed from approximately 20 minutes to approximately 2 hours. The term approximately as used herein shall mean plus or minus 15% percent of the number or value associated therewith.

[0054] It is within the scope of this disclosure and as a non-limiting example that the curcuminoid cyclodextrin complexes (not shown) may continue to form throughout the mixing process. After the mixing process has been completed, a neutralization step 114 may occur. During the neutralization step 114, a pre-determined amount of the one or more acids 110 may be added to the first mixture 113 to form a second mixture (not shown). Acids and bases react quantitatively with each other to neutralize or lower the pH of the second mixture. The pH of the neutralized mixture depends on the acid strength of the reactants. As part of the pH modification process the one or more acids 110 are added in order to bring the pH of the second mixture (not shown) to a more stable and safe state for subsequent processing and consumption in medical and / or food related applications. Additionally, this is done in order to reduce the overall amount of decomposition of the one or more curcuminoids 104, the one or more cyclodextrins 106 and / or the curcuminoid cyclodextrin complexes (not shown) formed as a result of being exposed to a higher pH for too long of a period of time. It is within the scope of this disclosure and as a nonlimiting example that a second mixing step may occur after the neutralization step 114 to aid in ensuring even distribution of the one or more acids 110 therein. According to an embodiment of the disclosure and as a non-limiting example, the curcuminoid cyclodextrin complexes may continue to form throughout the second mixing process.

[0055] According to an embodiment of the disclosure and as a non-limiting example the during the neutralization step 114 the pH of the second mixture is lowered or reduced to approximately 3 to approximately 5.

[0056] During the neutralization step 114, a salt is formed as a by-product of the process 100. One advantage to using potassium hydroxide (KOH) over other strong bases, such as sodium hydroxide (NaCl), is that potassium hydroxide (KOH) aids in reducing the overall amount of sodium chloride (NaCl) that is created as a result of a neutralization step 114 in comparison to other strong bases. Due to the mixed opinions relating to the dietary acceptability of sodium chloride (NaCl), from a commercialization and nutritional point of view, it is desirable to limit the overall intake of sodium chloride (NaCl) within the body. It is within the scope of this disclosure and as a non- limiting example that the curcuminoid cyclodextrin complexes formed by the process 100 may have approximately 0.5% to approximately 5% by weight of a potassium chloride (KC1) therein, preferably approximately 1% to approximately 3% by weight potassium chloride (KC1) therein or more preferably approximately 1 % to approximately 2% by weight potassium chloride (KC1) therein.

[0057] After the neutralization step 114, one or more spray drying steps 116 may occur. During the one or more spray drying process 116, an amount of the water within the second mixture is removed in order to form a free-flowing powder of curcuminoid cyclodextrin complexes. When water is removed from the curcuminoid cyclodextrin complexes during the one or more spray drying steps 116, the binding or attraction between the one or more curcuminoids 104 and the one or more cyclodextrins 106 increases because they are no longer in dynamic equilibrium like they were when in the presence of water. The presence of too much water after the one or more spray drying processes 116 tends to result in the curcuminoid cyclodextrin complexes clumping together or forming agglomerates which tend to create packaging issues and reduces the overall shelf life of the final curcuminoid cyclodextrin complex product formed by the process 100. It is within the scope of this disclosure and as a non-limiting example that the there may be approximately 2% to approximately 15% water by weight after the one or more spray drying processes 116 or preferably approximately 5% to approximately 10% water by weight after the one or more spray drying processes 116. Additionally, it is within the scope of this disclosure and as a non- limiting example that the one or more spray drying processes 116 may occur at approximately 160°C to approximately 200°C.

[0058] It is within the scope of this disclosure and as a non-limiting example that the inlet temperature of the one or more spray dryers (not shown) utilized within the one or more spray drying processes 116 may be approximately 160°C to approximately 190°C. More specifically, it is within the scope of this disclosure and as a non-limiting example that the inlet temperature of the one or more spray dryers (not shown) may be approximately 180°C

[0059] According to an embodiment of the disclosure and as a non-limiting example, the curcuminoid cyclodextrin complexes produced by the process 100 may have a particle size of approximately 1 micron to approximately 100 microns. This aids in ensuring that the curcuminoid cyclodextrin complexes produced is in the form of a free-flowing powder.

[0060] It is within the scope of this disclosure and as a non-limiting example that the one or more curcuminoid cyclodextrin complexes (not shown) formed using the process 100 have a THC content of approximately 7% by weight to approximately 20% by weight.

[0061] In order to aid in preventing the curcuminoid cyclodextrin complexes from clumping together or forming agglomerates, it is within the scope of this disclosure that one or more anticaking agents (not shown) may be used. This aids in obtaining curcuminoid cyclodextrin complexes that are in the form of a free-flowing powder after the one or more spray drying processes 116. The one or more anti-caking agents (not shown) may be added as needed throughout the process 100. It is within the scope of this disclosure and as a non- limiting that one or more of the one or more anti-caking agents may be added during the complex preparation step 112, the mixing of the first mixture 113, the neutralization step 114, the one or more spray drying steps 116 and / or at an intermediate step (not shown) between the completion of the one or more spray drying processes 116 and the packaging 118 of the curcuminoid cyclodextrin complexes (not shown) formed from the process 100. It is within the scope of this disclosure and as a nonlimiting example that the one or more anti-caking agents (not shown) may tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminium silicate, calcium aluminosilicate, bentonite, aluminium silicate, stearic acid and / or polydimethylsiloxane.

[0062] It is within the scope of this disclosure and as a non-limiting example that the curcuminoid cyclodextrin complexes (not shown) may continue to form throughout the one or more spray drying processes 116.

[0063] Once the one or more spray drying processes 116 have been completed curcuminoid cyclodextrin complexes (not shown) may then be packaged 118 and shipped to the customer 120 in any suitable manner.

[0064] Having generally described the various embodiments of the disclosure, a further understanding may be obtained by referencing certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified

[0065] EXAMPLE 1

[0066] Tetrahydrocurcumin (THC) Gamma-Cyclodextrin Complexes

[0067] In accordance with this example, a mixture including approximately 20g of THC supplied by Sabinsa Corp, and approximately 76.6g by dry basis of a gamma-cyclodextrin were mixed together within approximately 235ml of deionized water. Approximately 3.0g of potassium hydroxide (KOH) was mixed along with the THC, the gamma-cyclodextrin and the deionized water using a high shear mixer for approximately 10 minutes at approximately 3600 rpm. With continued mixing, 5.4g of concentrated HC1 solution was added resulting in a pH between 3 and 5. The resulting mixture was then spray dried (Lab Plant) at approximately 180°C to yield approximately 63g of a THC gamma-cyclodextrin complex. The THC gamma-cyclodextrin complex obtained was a fine off-white free-flowing powder. Water content by loss on drying was 7.2%. An assay of the complex by high performance liquid chromatography (HPLC) indicated a THC content of 15% by weight.

[0068] EXAMPLE 2

[0069] Tetrahydrocurcumin (THC) Beta-Cyclodextrin Complexes

[0070] In accordance with this example, a mixture of approximately 22g of THC supplied by Sabinsa Corp, and approximately 73.8g on dry basis of a beta-cyclodextrin were mixed with approximately 234ml of deionized water. Approximately 3.3g of potassium hydroxide (KOH) was then mixed along with the THC, beta-cyclodextrins and the water using a high shear mixer for approximately 10 minutes at approximately 3600rpm. With continued mixing, 6.0g of concentrated hydrochloric acid (HC1) solution was added resulting in a pH between 3 and 5. The mixture was then spray dried (Lab Plant) at approximately 180°C to yield approximately 58g of a THC beta-cyclodextrin complex as a fine free-flowing off-white powder. The water content by loss on drying was 7.4% and the THC content was determined by high-performance liquid chromatography (HPLC) to be 16.5% THC. An assay of the complex by high performance liquid chromatography (HPLC) indicated a THC content of 16.5% by weight.

[0071] EXAMPLE 3

[0072] Tetrahydrocurcumin (THC) Alpha-Cyclodextrin Complexes

[0073] In this example, a mixture of approximately 25g of THC supplied by Sabinsa Corp, and approximately 71.8g on dry basis of an alpha-cyclodextrin were mixed together in approximately 238ml of deionized water. Along with the THC, the alpha-cyclodextrin and the water, approximately 3.8g potassium hydroxide (KOH) was mixed using a high shear mixer for approximately 10 minutes at approximately 3600 rpm. With continued mixing, 6.8 g of concentrated hydrochloric acid (HC1) solution was added resulting in a pH between 3 and 5. The resulting mixture was then spray dried (Lab Plant) at approximately 180°C to yield approximately 30g of a THC alpha-cyclodextrin complex as a fine free-flowing off-white powder. Water content by loss on drying was approximately 6.9%. The THC content of the complex was measured by High performance liquid chromatography (HPLC) to be 9.8% THC. An assay of the complex by high performance liquid chromatography (HPLC) indicated a THC content of 9.8% by weight. According to this Example 3, a THC content of 9.8% by weight is below the theoretical values thereby indicating that while THC alpha-cyclodextrin complexes were successfully formed, the resulting THC content is less than the THC content obtained when forming THC beta-cyclodextrin complexes and THC gamma-cyclodextrin complexes.

[0074] EXAMPLE 4

[0075] Tetrahydrocurcumin (THC) Gamma-Cyclodextrin Complexes

[0076] In this example, approximately THC 25g supplied by Sabinsa Corp, and approximately 95.8g on dry basis of a gamma-cyclodextrin was dispersed or mixed within approximately 235ml of deionized water. The gamma-cyclodextrin, THC and deionized water were mixed together using a high shear mixer for approximately 15 minutes and at approximately 3600 rpm. During this Example, the pH modification process described and illustrated herein was not used. The prepared mixture was then spray dried (Lab Plant) at approximately 180°C to yield approximately 52g of THC gamma-cyclodextrin complexes as a fine free-flowing off-white powder. Water content by loss on drying was determined to be approximately 7.4%. High performance liquid chromatography (HPLC) testing indicated 11.8% THC. Assay of the complex by high performance liquid chromatography (HPLC) indicated a THC content of 11.8% by weight. A THC content of 11.8% by weight is below the theoretical values. As a result, this Example 4 illustratively shows that the use of the pH modification process described and illustrated herein provides benefits over conventional methods.

[0077] EXAMPLE 5

[0078] Solubilization of Tetrahydrocurcumin (THC) Complexes and pure THC within a Simulated Gastric Fluid (SGF)

[0079] In this example, the tetrahydrocurcumin (THC) supplied by Sabinsa Corp, was pre-tested for solubility. During this solubility testing approximately 0.5% of a sodium dodecyl sulfate solution was prepared by dissolving approximately 5.0g within approximately 1000ml of deionized water. Then approximately 90ml aliquots were placed into beakers. The THC complexes were added to the aliquots prepared to give a concentration of approximately 50mg to approximately 300mg per 90ml of the aliquots. Gamma-cyclodextrin (W8) THC was used at approximately 20.0% THC as confirmed by high performance liquid chromatography (HPLC). The mixtures prepared were then stirred at room temperature for approximately 2 hours. During this time a haze begins to appear which indicates the solubilization limit for the mixture. By HPLC, this concentration was found to be 564ppm THC thus subsequent testing was then performed with this relative amount of THC. For the Comparative dissolution testing that occurred, an approximately 3.7L volume of a simulated gastric fluid (SGF) was combined with approximately 0.5% of sodium dodecyl sulfate (SDS). The SGF mixture included: approximately 7.4g of NaCl approximately 18.5g of Sodium Dodecyl Sulfate approximately 24.1ml of concentrated HC1 acid solution, and approximately 3700ml of deionized water.

[0080] Once the components were dissolved, through pH modification as described and illustrated herein, the pH was adjusted to 1.2 with IM of an aqueous hydrochloric acid (HC1) solution. For sampling and testing, approximately 900ml of the SGF was placed within a 2L jacketed beaker. The mixture was stirred using an overhead mixer that was equipped with a paddle at approximately 70rpm for a period of 2 hours. The mixture was maintained at 37°C using a recirculating bath. The THC cyclodextrin complexes formed for this Example used alphacyclodextrins (W6), beta-cyclodextrins and gamma-cyclodextrins (W8) and pure THC (obtained from Sabinsa Corp.) was added to give the maximum THC level determined and obtained. At various pre-determined time intervals, approximately 2ml samples were removed from the mixture and filtered using a 1.0pm glass fiber syringe filter. The pre- determined time intervals where the testing samples were obtained were at approximately 5, 10, 20, 30, 45, 60, 90 and 120 minutes from the introduction of the THC samples into the mixture. The filtered samples were then analyzed using high performance liquid chromatography (HPLC) to determine the amount of dissolved THC within each sample in parts per million (ppm). As illustrated within FIG. 2 of the disclosure and as a non- limiting example, it can be seen that the gamma-cyclodextrin (W8) THC complexes formed and beta-cyclodextrin (W7) THC complexes formed and sampled had the best dissolution given the increased parts per million of THC found within the samples obtained and tested. Additionally, as it can be seen in FIG. 2 of the disclosure and as a non-limiting example, the gamma-cyclodextrin (W8) THC complexes and the beta-cyclodextrin (W7) THC complexes formed and sampled achieved their max solubility and max concentration in parts per million in a shorter amount of time when compared to the alpha-cyclodextrin (W6) THC complexes and the pure THC samples tested.

[0081] EXAMPLE 6

[0082] Solubilization of Tetrahydrocurcumin (THC) Cyclodextrin Complexes within a Simulated Intestinal Fluid (S1F)

[0083] In this example, testing with S1F was performed and the same concentration of THC was used as described in relation to Example 5 above.

[0084] For the comparative testing performed in relation to this example, a 3.7L volume of a S1F with approximately 0.5% SDS was prepared. The S1F mixture included: approximately 22.2g Monosodium Phosphate (Nal I2PO4) approximately 18.5g Sodium Dodecyl Sulfate (SDS) approximately 3.29 g Sodium Hydroxide (NaOH), and approximately 3700ml of deionized water.

[0085] Once the components were dissolved, through pH modification as described and illustrated herein, the pH was adjusted or modified to 6.8 using IM phosphoric acid (H2PO4) solution. For testing approximately 900ml of the S1F was placed in a 2L jacketed beaker. The mixture was then stirred using an overhead mixer that was equipped with a paddle at approximately 70 rpm for a period of 2 hours. The mixture was maintained at approximately 37°C using a recirculating bath. The THC cyclodextrin complexes formed for this Example used alpha-cyclodextrins (W6), betacyclodextrins and gamma-cyclodextrins (W8) and pure THC (obtained from Sabinsa Corp.) was added to give the maximum THC level determined and obtained. At various pre-determined time intervals, approximately 2ml samples were removed from the mixture and filtered using a 1.0pm glass fiber syringe filter. The pre-determined time intervals where the testing samples were obtained were at approximately 5, 10, 20, 30, 45, 60, 90 and 120 minutes from the introduction of the THC samples into the mixture. The filtered samples were then analyzed using high performance liquid chromatography (HPLC) to determine the amount of THC within each sample in parts per million (ppm). As illustrated within FIG. 3 of the disclosure and as a non-limiting example, it can be seen that the gamma-cyclodextrin (W8) THC complexes formed and the betacyclodextrin (W7) THC complexes formed achieved their max solubility and max concentration in parts per million in a shorter amount of time when compared to the alpha-cyclodextrin (W6) THC complexes formed and pure THC samples tested. Additionally, as it can be seen within FIG. 3 of the disclosure, the alpha-cyclodextrin (W6) THC complexes formed and the pure THC samples were found to have achieved a higher max concentration in parts per million when compared to the alpha-cyclodextrin (W6) THC complexes formed and the pure THC samples set forth within Example 5 of the disclosure.

[0086] In light of the foregoing, it can be seen that the cyclodextrin complexes obtained in accordance with the process 100 have a faster dissolution when compared to non-complexed samples. As a result, the cyclodextrin complexes prepared in accordance with the process 100 described and illustrated herein provide an improved overall functionality over their non- complexed counterparts when used in food, medical, pharmaceutical, nutraceutical, bioceutical, recreational, supplement and / or other similar products or applications.

[0087] It is to be understood that the various embodiments described in this specification and as illustrated in the attached drawings are simply exemplary embodiments illustrating the inventive concepts as defined in the claims. As a result, it is to be understood that the various embodiments described and illustrated may be combined to from the inventive concepts defined in the appended claims.

[0088] In accordance with the provisions of the patent statutes, the present invention has been described to represent what is considered to represent the preferred embodiments. However, it should be noted that this invention can be practiced in other ways than those specifically illustrated and described without departing from the spirit or scope of this invention.

Claims

What is claimed is1. A process for preparing curcuminoid cyclodextrin complexes, comprising: providing an amount of one or more curcuminoids, one or more cyclodextrins and their derivatives, one or more bases and / or one or more acids; preparing a first mixture by combining the one or more curcuminoids, the one or more cyclodextrins and / or the one or more bases with an amount of water; modifying the pH of the first mixture by adding an amount of the one or more acids to the first mixture to form a second mixture; allowing the one or more curcuminoids and the one or more cyclodextrins to form one or more curcuminoid cyclodextrin complexes; and drying the second mixture to reduce the overall amount of water therein and to increase the bond between the one or more curcuminoids and the one or more cyclodextrins.

2. The process of claim 1, wherein the one or more acids are added to reduce the pH of the second mixture to approximately 3 to approximately 5.

3. The process of claim 1, wherein the first mixture is mixed in a high shear mixer for approximately 20 minutes to approximately 2 hours.

4. The process of claim 1, wherein the one or more cyclodextrins are one or more betacyclodextrins and / or one or more gamma-cyclodextrins.

5. The process of claim 1, wherein the one or more curcuminoids is tetrahydrocurcumin.

6. The process of claim 5, wherein the one or more curcuminoid cyclodextrin complexes formed have a tetrahydrocurcumin content of approximately 7% by weight to approximately 20% by weight.

7. The process of claim 1, wherein the one or more bases are one or more strong bases.

8. The process of claim 7, wherein the one or more strong bases are potassium hydroxide, sodium hydroxide, magnesium hydroxide and / or calcium hydroxide.

9. The process of claim 7, wherein the one or more curcuminoid cyclodextrin complexes formed have approximately 0.5% to approximately 5% by weight of a potassium chloride therein, preferably approximately 1% to approximately 3% by weight potassium chloride therein or more preferably approximately 1% to approximately 2% by weight potassium chloride therein.

10. The process of claim 1, wherein the one or more acids are one or more strong acids.

11. The process of claim 10, wherein the one or more strong acids are hydrochloric acid, nitric acid, hydroiodic acid, perchloric acid, chloric acid, phosphoric acid and / or citric acid.

12. The process of claim 1, wherein the water is deionized water.

13. The process of claim 1, further comprising the step of adding one or more anti-caking agents.

14. The process of claim 13, wherein the one or more anti-caking agents are tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminium silicate, calcium aluminosilicate, bentonite, aluminium silicate, stearic acid and / or poly dimethylsiloxane.

15. The process of claim 1, wherein during the drying step the second mixture is dried using one or more spray drying processes.

16. The process of claim 1, wherein after the drying step the one or more curcuminoid cyclodextrin complexes formed have approximately 2% to approximately 15% water by weight or preferably approximately 5% to approximately 10% water by weight.

17. The process of claim 1, wherein the drying step occurs at approximately 160°C to approximately 200°C.

18. The process of claim 1, wherein the one or more curcuminoid cyclodextrin complexes formed are a free-flowing off-white powder.

19. The process of claim 1, wherein the one or more curcuminoid cyclodextrin complexes formed are suitable for use within a food, a medical, a pharmaceutical, a nutraceutical, a bioceutical, a recreational and / or a supplement products.

Images