Bioactive agents and bioactive agent delivery systems

Abstract

Bioactive agents and / or bioactive agent delivery systems are disclosed. An example bioactive agent delivery system may include a metal ion complexed with a chelating agent. The bioactive agent delivery system may also include a protein.

Description

Bioactive Agents And Bioactive Agent Delivery SystemsCross Reference to Related Applications

[0001] This application claims the benefit of U.S. Patent Application Serial No. 63 / 561,387, filed March 5, 2024, the disclosure of which is incorporated herein by reference.Technical Field

[0002] The present disclosure pertains to bioactive agents and bioactive agent delivery systems.Background

[0003] A number of bioactive agents and / or bioactive agent delivery systems are known. Of the known bioactive agents and / or bioactive agent delivery systems, each has certain advantages and disadvantages. There is an ongoing need for new and different bioactive agents and / or bioactive agent delivery systems.Brief Summary

[0004] This disclosure provides design, material, manufacturing method, and use alternatives for bioactive agents and / or bioactive agent delivery systems. A bioactive agent delivery system is disclosed. The bioactive agent delivery system comprises: a native metal ion containing protein complexed with a chelating agent; and a protein.

[0005] Alternatively or additionally to any of the embodiments above, the native metal ion containing protein includes copper.

[0006] Alternatively or additionally to any of the embodiments above, the native metal ion containing protein includes zinc.

[0007] Alternatively or additionally to any of the embodiments above, the native metal ion containing protein includes magnesium.

[0008] Alternatively or additionally to any of the embodiments above, the chelating agent includes ethylenediaminetetraacetic acid.

[0009] Alternatively or additionally to any of the embodiments above, the chelating agent includes diethyldithiocarbamate.

[0010] Alternatively or additionally to any of the embodiments above, the protein includes sunflower protein.

[0011] Alternatively or additionally to any of the embodiments above, the protein includes soluble sunflower protein.

[0012] Alternatively or additionally to any of the embodiments above, the native metal ion containing protein includes a polyphenol oxidase.

[0013] Alternatively or additionally to any of the embodiments above, the native metal ion containing protein includes a polyphenol oxidase containing copper.

[0014] Alternatively or additionally to any of the embodiments above, the native metal ion containing protein complexed with a chelating agent is soluble.

[0015] Alternatively or additionally to any of the embodiments above, further comprising a capsule containing the native metal ion containing protein complexed with the chelating agent and the protein.

[0016] Alternatively or additionally to any of the embodiments above, the native metal ion containing protein complexed with the chelating agent and the protein are configured to be administered orally to a patient.

[0017] A bioactive agent delivery system is disclosed. The bioactive agent delivery system comprises: a native organometallic amino acid compound complexed with a chelating agent.

[0018] Alternatively or additionally to any of the embodiments above, the native organometallic amino acid compound includes a metal ion.

[0019] Alternatively or additionally to any of the embodiments above, the metal ion includes copper.

[0020] Alternatively or additionally to any of the embodiments above, the metal ion includes zinc.

[0021] Alternatively or additionally to any of the embodiments above, the metal ion includes magnesium.

[0022] Alternatively or additionally to any of the embodiments above, the chelating agent includes ethylenediaminetetraacetic acid.

[0023] Alternatively or additionally to any of the embodiments above, the chelating agent includes diethyldithiocarbamate.

[0024] Alternatively or additionally to any of the embodiments above, the native organometallic amino acid compound one or more sunflower proteins.

[0025] Alternatively or additionally to any of the embodiments above, the native organometallic amino acid compound one or more soluble sunflower proteins.

[0026] Alternatively or additionally to any of the embodiments above, the native organometallic amino acid compound includes a polyphenol oxidase.

[0027] Alternatively or additionally to any of the embodiments above, the native organometallic amino acid compound includes a polyphenol oxidase containing copper.

[0028] Alternatively or additionally to any of the embodiments above, the native organometallic amino acid compound complexed with the chelating agent is soluble.

[0029] Alternatively or additionally to any of the embodiments above, further comprising a capsule containing the native organometallic amino acid compound complexed with the chelating agent.

[0030] Alternatively or additionally to any of the embodiments above, the native organometallic amino acid compound complexed with the chelating agent is configured to be administered orally to a patient.

[0031] A method for manufacturing a bioactive agent delivery system is disclosed. The method comprises: isolating one or more soluble proteins from sunflower seeds; forming a solution comprising the one or more soluble proteins; and adding a chelating agent to the solution.

[0032] Alternatively or additionally to any of the embodiments above, the one or more soluble proteins include a metal ion.

[0033] Alternatively or additionally to any of the embodiments above, the metal ion includes copper.

[0034] Alternatively or additionally to any of the embodiments above, the metal ion includes zinc.

[0035] Alternatively or additionally to any of the embodiments above, the metal ion includes magnesium.

[0036] Alternatively or additionally to any of the embodiments above, the chelating agent includes ethylenediaminetetraacetic acid.

[0037] Alternatively or additionally to any of the embodiments above, the chelating agent includes diethyldithiocarbamate.

[0038] Alternatively or additionally to any of the embodiments above, the one or more soluble proteins include a polyphenol oxidase.

[0039] Alternatively or additionally to any of the embodiments above, the one or more soluble proteins include a polyphenol oxidase containing copper.

[0040] A bioactive agent delivery system is disclosed. The bioactive agent delivery system comprises: a metal ion complexed with a chelating agent; and a protein.

[0041] Alternatively or additionally to any of the embodiments above, the metal ion includes copper.

[0042] Alternatively or additionally to any of the embodiments above, the metal ion includes zinc.

[0043] Alternatively or additionally to any of the embodiments above, the metal ion includes magnesium.

[0044] Alternatively or additionally to any of the embodiments above, the chelating agent includes ethylenediaminetetraacetic acid.

[0045] Alternatively or additionally to any of the embodiments above, the chelating agent includes diethyldithiocarbamate.

[0046] Alternatively or additionally to any of the embodiments above, the protein includes sunflower protein.

[0047] Alternatively or additionally to any of the embodiments above, the protein includes soluble sunflower protein.

[0048] Alternatively or additionally to any of the embodiments above, the protein includes a polyphenol oxidase.

[0049] Alternatively or additionally to any of the embodiments above, the protein includes a polyphenol oxidase containing copper.

[0050] Alternatively or additionally to any of the embodiments above, the metal ion complexed with a chelating agent is soluble.

[0051] Alternatively or additionally to any of the embodiments above, further comprising a capsule containing the metal ion complexed with the chelating agent and the protein.

[0052] Alternatively or additionally to any of the embodiments above, the metal ion complexed with the chelating agent and the protein are configured to be administered orally to a patient.

[0053] A bioactive agent delivery system is disclosed. The bioactive agent delivery system comprises: an organometallic amino acid compound complexed with a chelating agent.

[0054] Alternatively or additionally to any of the embodiments above, the organometallic amino acid compound includes a metal ion.

[0055] Alternatively or additionally to any of the embodiments above, the metal ion includes copper.

[0056] Alternatively or additionally to any of the embodiments above, the metal ion includes zinc.

[0057] Alternatively or additionally to any of the embodiments above, the metal ion includes magnesium.

[0058] Alternatively or additionally to any of the embodiments above, the chelating agent includes ethylenediaminetetraacetic acid.

[0059] Alternatively or additionally to any of the embodiments above, the chelating agent includes diethyldithiocarbamate.

[0060] Alternatively or additionally to any of the embodiments above, the organometallic amino acid compound one or more sunflower proteins.

[0061] Alternatively or additionally to any of the embodiments above, the organometallic amino acid compound one or more soluble sunflower proteins.

[0062] Alternatively or additionally to any of the embodiments above, the organometallic amino acid compound includes a polyphenol oxidase.

[0063] Alternatively or additionally to any of the embodiments above, the organometallic amino acid compound includes a polyphenol oxidase containing copper.

[0064] Alternatively or additionally to any of the embodiments above, the organometallic amino acid compound complexed with the chelating agent is soluble.

[0065] Alternatively or additionally to any of the embodiments above, further comprising a capsule containing the organometallic amino acid compound complexed with the chelating agent.

[0066] Alternatively or additionally to any of the embodiments above, the organometallic amino acid compound complexed with the chelating agent is configured to be administered orally to a patient.

[0067] The above summary of some embodiments is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The Detailed Description, which follows, more particularly exemplify these embodiments.Detailed Description

[0068] For the following defined terms, these definitions shall be applied, unless a different definition is given in the claims or elsewhere in this specification.

[0069] All numeric values are herein assumed to be modified by the term “about”, whether or not explicitly indicated. The term “about” generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (e.g., having the same function or result). In many instances, the terms “about” may include numbers that are rounded to the nearest significant figure.

[0070] The recitation of numerical ranges by endpoints includes all numbers within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0071] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0072] It is noted that references in the specification to “an embodiment”, “some embodiments”, “other embodiments”, etc., indicate that the embodiment described may include one or more particular features, structures, and / or characteristics. However, such recitations do not necessarily mean that all embodiments include the particular features, structures, and / or characteristics. Additionally, when particular features, structures, and / or characteristics are described in connection with one embodiment, it should be understood that such features, structures, and / or characteristics may also be used connection with other embodiments whether or not explicitly described unless clearly stated to the contrary.

[0073] A number of processes have been developed to extract, isolate, and / or otherwise remove materials of interest from oil seeds. Example plants that produce oil seeds mayinclude almond, argan, borage, canola, castor, cherry, coconut, com, cotton, flax, grape, hemp, jojoba, macadamia, mango, mustard, neem, oil palm, rapeseed, safflower, sesame, shea, sunflower, tonka bean, moringa, rice (and / or rice bran), soy, and tung. At least some of the following description refers to processes for extracting and / or isolating one or more materials from sunflower seeds. This, however, is not intended to be limiting. Other processes are contemplated that may use different oils seeds and / or combinations of oil seeds.

[0074] Some of the materials of interest that may be extracted / isolated from sunflower seeds may include chlorogenic acid (CGA), phytic acid (PA), meals, and proteins. While not intending to be limiting, sunflower proteins (e.g., proteins extracted and / or isolated from sunflower seeds) can be classified generally into at least two groups: (a) group / class 001, corresponding generally to soluble proteins, low molecular weight proteins, albumins (e g., soluble albumins), combinations thereof, and / or the like and (b) group / class 002 corresponding generally to insoluble proteins, high molecular weight proteins, helianthinins, globulins, albumins (e.g., residual albumins and / or insoluble albumins), combinations thereof, and / or the like. For the purposes of this disclosure, the sunflower proteins of group 001 may be labeled in the disclosure as soluble proteins (e.g., one or more soluble proteins and / or a mixture of one or more soluble proteins) or albumins (e.g., soluble albumins) and the sunflower proteins of group 002 may be labeled in this disclosure as insoluble proteins (e.g., one or more insoluble proteins and / or a mixture of one or more insoluble proteins) or helianthinins.

[0075] Plant-based proteins have a growing utility in a variety of industries including the food industry and / or the manufacturing of food products. One aspect of sunflower proteins, for example group 001 soluble proteins, is that the proteins can have a sweetness or sweet flavor, which may be desirable for a number of different applications. Processes have been developed for extracting the desired protein (e.g., e.g., group 001 soluble proteins) from oil seeds, for example sunflower seeds. Processes have also been developed for extracting group 002 insoluble proteins, CGA, PA, and other materials.

[0076] A number of metal ions such as copper, zinc, magnesium, etc. are present in plants including sunflowers. Some of these metal ions may be complexed with proteins. For example, when sunflower proteins such as soluble proteins / albumins are isolated fromsunflower seeds (e g., as described herein), the soluble proteins may include organometallic amino acid compounds and / or organometallic polypeptide compounds and / or organometallic proteins such as, for example, polyphenol oxidases (PPOs). Polyphenol oxidases (PPOs) have metal ions such as copper complexed therewith, associated therewith, and / or bound therewith. As proteins are isolated, the relative amount of copper present in the isolated protein may become elevated. It may be desirable to remove some of the copper in order to reduce toxicity that may be associated with such metal ions and / or otherwise reduce the level of copper present in protein extracts.

[0077] One mechanism for removing metal ions and / or inorganic components is the use of a chelating agent. For example, ethylenediaminetetraacetic acid (EDTA), which can be used to treat lead poisoning, can form a complex with metal ions (e.g., Pb). When doing so, the EDTA forms a non-active lead complex that is adsorbed and then excreted from the body via the kidneys. Other chelating agents are capable of forming active biological agents when combined with inorganic elements or compounds including di ethyldithiocarbamate (DDTC).

[0078] In the processes described herein, proteins such as soluble proteins / albumins may be isolated from sunflower seeds. If the isolated proteins are intended to be used as part of a food product, it may be desirable to reduce the level of metal ions contained in the isolated product. For example, soluble proteins / albumins isolated from sunflower seeds may include PPOs which contain copper. Thus, processes are contemplated where the isolated soluble proteins / albumins may be combined with a chelating agent such as DDTC. The chelating agent may complex with the copper, allowing the copper to be removed efficiently. While removing copper from extracted / isolated proteins may be a desirable use process that involves DDTC, the use of DDTC has other applications of interest. For example, the medical literature includes reports of DDTC, particularly DDTC complexed with copper, having efficacy for treating cancerous tumors. Accordingly, copper-DDTC (Cu-DDTC) complexes may have a number of applications of interest.

[0079] One drawback of Cu-DDTC complexes is that the complexes have a relatively low aqueous solubility. Because of this, it may be challenging to administer Cu-DDTC complexes to patients, for example in a manner that allows the Cu-DDTC complexes to efficiently reach the tumors. When attempting to remove copper from sunflower proteinisolates, it was surprisingly found that Cu-DDTC complexes formed by the presence of copper containing protein (e.g., in isolated sunflower protein) remain soluble. In other words, copper that is natively part of the protein structure (e.g., in isolated sunflower protein) can form water soluble Cu-DDTC complexes. It can be appreciated that the increased solubility of the protein-based Cu-DDTC complexes may increase the ability of protein-based Cu-DDTC complexes to be used to treat cancerous tumors. For example, protein-based Cu-DDTC complexes may be an effective vehicle for delivery of bioactive Cu-DDTC complexes to cancer sites.

[0080] Disclosed herein are bioactive agents and / or bioactive agent delivery systems. For the purposes of this disclosure, a bioactive agent may be understood to be a substance that may have efficacy toward one or more conditions. A bioactive agent delivery system may be understood to be a vehicle that can be used in combination with the bioactive agent in order to more efficiently deliver the bioactive agent to a target. One example bioactive agent may include a Cu-DDTC complex. One example bioactive agent delivery system may include a Cu-DDTC complex mixed with protein. For example, a bioactive agent delivery system may include a Cu-DDTC complex mixed with soluble proteins / albumins. In some instances, a bioactive agent delivery system may include a Cu-DDTC complex mixed with soluble proteins / albumins isolated from sunflower proteins. In some of these and in other instances, a bioactive agent delivery system may include a native metal ion containing protein complexed with a chelating agent and a protein. For example, a native metal ion containing protein (e.g., natively and / or naturally found in sunflower protein) may include a PPO.

[0081] While Cu-DDTC complexes formed from soluble proteins naturally containing copper isolated from sunflower proteins may be one example of bioactive agent delivery system, other bioactive delivery systems are contemplated that may make use of different metal ions, different chelating agents, and / or different proteins. As another example, copper containing tyrosinase can be utilized to create a Cu-DDTC complex and act as a bioactive agent delivery system. In addition the bioactive agent need not be limited to copper. Zn-DDTC is as used an agent to reduce nickel poisoning in humans today and one of the many proteins containing zinc can be used to create a Zn-DDTC delivery system.

[0082] A number of processes are contemplated that include extracting / isolating a copper containing protein (e.g., a soluble sunflower protein such as the 001 sunflower protein) and adding a suitable chelating agent in order to produce a bioactive agent and / or bioactive agent delivery system. Some example processes for extracting / isolating a protein (e.g., a soluble sunflower protein such as the 001 sunflower protein) are disclosed herein. The isolated protein may be combined with a chelating agent, for example to form a bioactive agent delivery system. For example, a 10% solution of the extracted isolated protein (e.g., the 001 soluble sunflower protein) may be prepared in DI water and / or saline. The Cu content may be about 20 ppm in the solution, for example when utilizing the processes disclosed herein. DDTC (e.g., the sodium salt of DDTC, NaDDTC) may be added to the protein solution. For example, NaDDTC may be provided from a 1000 ppm stock solution in DI water. The protein solution and NaDDTC may be mixed at 25°C in 1 :5 Cu:NaDDTC proportion. Other ratios are contemplated including 1 :2 (Cu:NaDDTC) to 1: 10 (Cu:NaDDTC).

[0083] Mixing of NaDDTC and protein (e.g., which contain PPOs) may allow the DDTC to react / complex with PPOs in the protein solution to form a Cu-DDTC complex. The resultant product includes a Cu-DDTC protein complex in a protein solution. This product may be understood to be a bioactive agent delivery system as the product may be administered to a patient in order to deliver the Cu-DDTC complex (e.g., a bioactive agent).

[0084] The end product may comprise an aqueous mixture including the Cu-DDTC protein complex and protein. As indicated above, the Cu-DDTC protein complex remains soluble in the mixture. The mixture may be dried to form a powder form of the bioactive agent delivery system. The powder form may be reconstituted with saline or DI water to reform an aqueous mixture (e.g., where the Cu-DDTC complex remains soluble). In some instances, the powder form may be incorporated into a capsule or tablet for oral administration.

[0085] Example Isolation / Extraction Processes For Isolating / Extracting Proteins and / or Other Materials of Interest from Oil Seeds.

[0086] An example method for isolating materials of interest may include processing oil seeds, for example sunflower seeds. For example, sunflower seeds can be harvested and transported to a suitable processing facility. The seeds can be dehulled and coldpressed in a conventional manner, which may remove at least some of the oil from the sunflower seeds. For example, cold pressing (e.g., cold pressing at a temperature less than or equal to 140°F) may remove about 85% or so of the sunflower oil from the seed. After pressing, the resulting meal can be further processed.

[0087] The meal from the cold press can be subjected to one or more extractions. To extract the meal, the meal may be mixed with an aqueous solution, for example a saline solution. The amount of liquid added to the meal may include adding liquid at a ratio of about 5: 1-20:1 liquid (and / or the water component of the saline solution) to the dry weight of the meal. In some instances, the saline solution may include a NaCl solution (e.g., 0.5M NaCl). Other salts and / or concentrations are contemplated. In some instances, the saline solution may include an additive. For example, the saline solution may include ascorbic acid (e.g., about 0.1 wt-% ascorbic acid). In at least some instances, the use of an aqueous solution for the extraction(s) may be desirable because, for example, the use of organic solvents during extraction can adversely impact the proteins and / or other materials that may be extracted from the meal.

[0088] Adding the aqueous solution to the meal may form a mixture. The pH of the mixture may be adjusted to about pH of 5-5.5 or about 5.1-5.2 using a suitable acid (e.g., HC1). The pH adjusted mixture can be heated to a target temperature (e.g., about 120- 160°F, or about 135-145°F, or about 138°F) and mixed for a suitable time (e.g., about 1-4 hours, or about 1-3 hours, or about 2 hours). Heating and mixing the pH adjusted mixture may form a slurry.

[0089] The slurry may be separated using a suitable separating apparatus such as a decanting centrifuge. Separating the slurry may include multiple rounds of decanting (e.g., 1, 2, 3, 4, 5, 6 or more decanting steps). For example, the slurry may undergo a first decanting step (e.g., using a decanting centrifuge) in order to be separated into a solid stream and a liquid stream. A liquid or solution may be added back to the solid stream and the solid stream may be decanted again (e.g., a second decanting step). For example, the solid stream may be mixed with a solution (e.g., a 0.25M NaCl saline solution) at a suitable ratio of liquid to the dry weight and be decanted (e.g., using a decanting centrifuge). For example, the ratio of liquid to dry weight of the solids may be about 5 : 1-20: 1 or about 10: 1. In some instances, the solid stream from the second decanting step may be decanted again(e.g., a third decanting step). The third decanting step may include mixing the solid stream from the second decanting step with a saline solution similar to the first and second decanting steps, with water, or the like and decanting (e.g., using a decanting centrifuge). The solid stream from the third decanting step may be dried to form a sunflower meal. The liquid stream from the third decanting step may be sent to a reverse osmosis system to recover clean water that can be re-used.

[0090] The liquid streams from the first and second decanting steps may be combined. In some instances, CaCh may be added to the combined liquid streams. The amount of CaCk added may be about 1-5 wt-% or about 2.5 wt-% of the incoming meal (e.g., the meal coming off of the cold press). The pH may also be raised, for example using NaOH. For example, the pH may be raised to about 5-6 or about 5.6-5.8. The addition of CaCh and the increase in the pH may precipitate phytic acid present in the liquid streams. The phytic acid can be removed / recovered by sending the liquid to a decanter (e.g., a decanting centrifuge). The phytic acid decanting step may produce a solid stream (e.g., the phytic acid) and a liquid stream.

[0091] The liquid stream from the phytic acid decanting step may undergo one or more filtrations. This may include a microfiltration process. For example, the liquid stream from the phytic acid decanting step may be filtered using a microfiltration membrane (e.g., a 0.8-micron microfiltration membrane). This may include concentrating the liquid stream to a factor of about 10-30 or to a factor of about 20. The concentration factor, as used herein, may be understood as referring to how much the volume on the retentate side (e.g., what is retained on the filter, rather than passing through) has been concentrated by due to liquid passing through the filter. Diafiltration water may be added to the concentrated stream at up to about 0.15 times the volume of the initial volume of the concentrated stream. The retentate captured on the microfiltration membrane may include materials such as sunflower meal and any remaining oil, which may be discarded as waste. The permeate may include a number of other / additional target materials such as proteins, CGA, and salts.

[0092] The permeate from the microfiltration may be further processed. For example, the pH may be lowered in the permeate using an acid such as HC1. For example, the pH may be lowered to about 4.0-4.1. The temperature of the permeate may also be adjusted (e.g., cooled) to a temperature less than or equal to about 60°F. The adjustments to pH andtemperature may precipitate the insoluble proteins / helianthinins. In at least some instances, the pH-adjusted and cooled permeate may be filtered, for example using another microfiltration membrane (e.g., a second microfiltration step using, for example, a 0.1- micron microfiltration membrane) which may be the same or different from the microfiltration membrane used in prior microfiltration. When doing so, the retentate may be concentrated to a factor of about 8-15 or to a factor of about 11 of the starting volume. Diafiltration water may be added to the concentrated retentate at up to about 0.7 times the volume of material sent to the microfiltration membrane. This may help to de-salt the insoluble proteins / helianthinins in the retentate. The pH may be raised in the retentate to a pH of about 5.6-6.0 with a base (e.g., NaOH) and then be sent to an evaporator to concentrate the solids (e.g., up to about 20%). The concentrated solids can be sent to a flash dryer to create a dry, insoluble sunflower protein powder that is about 90 wt-% protein (Nx5.6).

[0093] The permeate (e.g., the permeate from the second microfiltration step, which may include soluble proteins / albumins, CGA, and salts) may be sent to a nanofiltration membrane (e.g., an 800 Da nanofiltration membrane). When doing so, the permeate may be adjusted, as needed, to a temperature at or below about 90°F and to a pH at or below 5.0 and filtered using the nanofiltration membrane. The retentate may be concentrated to a factor of about 50-100 or to a factor of about 75 of the starting volume and diafiltration water may be added at about 0.3-0.4, or about 0.36 times the volume of the material sent to the membrane. This may de-salt the soluble proteins / albumins. The retentate may include the soluble proteins / albumins along with some CGA whereas the permeate contained the remaining (e.g., majority) of the CGA and salts. The ratio (w / w) of protein to CGA in the retentate may be about 20: 1 to about 40: 1.

[0094] In some instances, the permeate (e.g., the permeate from the second microfiltration step) can be sent to an adsorption column, which may allow the proteins, salt, and some of the CGA to pass through while adsorbing a majority of the CGA. This may allow the CGA to be eluted, sent to an evaporator before going to a spray dray to produce a dry, CGA powder. This may be desirable for a number of reasons. For example, this may allow a substantial portion of the CGA to be removed (e.g., about 75%), which may help with product properties such as color. In addition, removing CGA at an earlierstage may allow for the nanofiltration (discussed below) to be more efficient. In other instances (e.g., instead of sending the permeate from the second microfiltration step to the adsorption column), the permeate from the nanofiltration step may be sent to an adsorption column, which may allow the saltwater to pass through while adsorbing the CGA. The CGA can be eluted and sent to an evaporator to concentrate to 10% solids before going to a spray dryer where a dry, CGA powder as produced that was 60 wt% CGA.

[0095] It can be appreciated that other processes / steps may be utilized to remove CGA from the permeate (e.g., the permeate from the second microfiltration step and / or other permeates, retentates, etc.). For example, CGA can be hydrolyzed into quinic acid and caffeic acid using an appropriate enzyme such as an esterase (e.g., a general esterase), lipase, or a specific CGA esterase. This hydrolysis can be done at any point in the process prior to the nanofiltration step and will allow the CGA (or rather its component acids) to be more easily removed via nanofiltration.

[0096] The retentate (e.g., from the nanofiltration step) may be adjusted to raise the pH to about 5.6-6.0 with a base (e.g., NaOH) and be sent to an ion exchange column to remove additional CGA. When doing so, the output of the ion exchange column may be tuned to hit a target protein to CGA ratio (w / w) that is greater than or equal to about 40: 1, or greater than or equal to about 50:1, or greater than or equal to about 60:1, or greater than or equal to about 70: 1, or greater than or equal to about 80: 1, or greater than or equal to about 90: 1, or greater than or equal to about 100:1, or greater than or equal to about 150:1, or greater than or equal to about 200:1, or greater than or equal to about 250: 1, or greater than or equal to about 300: 1, or greater than or equal to about 350: 1, or greater than or equal to about 400: 1, or greater than or equal to about 450: 1, or greater than or equal to about 500: 1. In other instances, the retentate (e.g., from the nanofiltration step) may be sent to an adsorption column (e.g., instead of an ion exchange column) to remove CGA.

[0097] U.S. Patent Application No. 18 / 259, 677 is herein incorporated by reference.

[0098] WO 2022 / 115784 is herein incorporated by reference.

[0099] U.S. Patent Application No. 63 / 555,312 is herein incorporated by reference.

[0100] It should be understood that this disclosure is, in many respects, only illustrative. Changes may be made in details, particularly in matters of shape, size, and arrangement of steps without exceeding the scope of the disclosure. This may include, tothe extent that it is appropriate, the use of any of the features of one example embodiment being used in other embodiments. The invention's scope is, of course, defined in the language in which the appended claims are expressed.

Claims

ClaimsWhat is claimed is:

1. A bioactive agent delivery system, comprising: a native metal ion containing protein complexed with a chelating agent; and a protein.

2. The bioactive agent delivery system of claim 1, wherein the native metal ion containing protein includes copper.

3. The bioactive agent delivery system of claim 1, wherein the native metal ion containing protein includes zinc.

4. The bioactive agent delivery system of claim 1, wherein the native metal ion containing protein includes magnesium.

5. The bioactive agent delivery system of claim 1, wherein the chelating agent includes ethylenediaminetetraacetic acid.

6. The bioactive agent delivery system of claim 1, wherein the chelating agent includes diethyldithiocarbamate.

7. The bioactive agent delivery system of claim 1, wherein the protein includes sunflower protein.

8. The bioactive agent delivery system of claim 1, wherein the protein includes soluble sunflower protein.

9. The bioactive agent delivery system of claim 1, wherein the native metal ion containing protein includes a polyphenol oxidase.

10. The bioactive agent delivery system of claim 1 , wherein the native metal ion containing protein includes a polyphenol oxidase containing copper.

11. The bioactive agent delivery system of claim 1, wherein the native metal ion containing protein complexed with a chelating agent is soluble.

12. The bioactive agent delivery system of claim 1, further comprising a capsule containing the native metal ion containing protein complexed with the chelating agent and the protein.

13. The bioactive agent delivery system of claim 1, wherein the native metal ion containing protein complexed with the chelating agent and the protein are configured to be administered orally to a patient.

14. A bioactive agent delivery system, comprising: a native organometallic amino acid compound complexed with a chelating agent.

15. The bioactive agent delivery system of claim 14, wherein the native organometallic amino acid compound includes a metal ion.

16. The bioactive agent delivery system of claim 15, wherein the metal ion includes copper.

17. The bioactive agent delivery system of claim 15, wherein the metal ion includes zinc.

18. The bioactive agent delivery system of claim 15, wherein the metal ion includes magnesium.

19. The bioactive agent delivery system of claim 14, wherein the chelating agent includes ethylenediaminetetraacetic acid.

20. The bioactive agent delivery system of claim 14, wherein the chelating agent includes diethyldithiocarbamate.

21. The bioactive agent delivery system of claim 14, wherein the native organometallic amino acid compound one or more sunflower proteins.

22. The bioactive agent delivery system of claim 14, wherein the native organometallic amino acid compound one or more soluble sunflower proteins.

23. The bioactive agent delivery system of claim 14, wherein the native organometallic amino acid compound includes a polyphenol oxidase.

24. The bioactive agent delivery system of claim 14, wherein the native organometallic amino acid compound includes a polyphenol oxidase containing copper.

25. The bioactive agent delivery system of claim 14, wherein the native organometallic amino acid compound complexed with the chelating agent is soluble.

26. The bioactive agent delivery system of claim 14, further comprising a capsule containing the native organometallic amino acid compound complexed with the chelating agent.

27. The bioactive agent delivery system of claim 14, wherein the native organometallic amino acid compound complexed with the chelating agent is configured to be administered orally to a patient.

28. A method for manufacturing a bioactive agent delivery system, the method comprising: isolating one or more soluble proteins from sunflower seeds; forming a solution comprising the one or more soluble proteins; and adding a chelating agent to the solution.

29. The method of claim 28, wherein the one or more soluble proteins include a metal ion.

30. The method of claim 29, wherein the metal ion includes copper.

31. The method of claim 29, wherein the metal ion includes zinc.

32. The method of claim 29, wherein the metal ion includes magnesium.

33. The method of claim 28, wherein the chelating agent includes ethylenediaminetetraacetic acid.

34. The method of claim 28, wherein the chelating agent includes di ethyl di thi oc arb am ate .

35. The method of claim 28, wherein the one or more soluble proteins include a polyphenol oxidase.

36. The method of claim 28, wherein the one or more soluble proteins include a polyphenol oxidase containing copper.

37. A bioactive agent delivery system, comprising: a metal ion complexed with a chelating agent; and a protein.

38. The bioactive agent delivery system of claim 37, wherein the metal ion includes copper.

39. The bioactive agent delivery system of claim 37, wherein the metal ion includes zinc.

40. The bioactive agent delivery system of claim 37, wherein the metal ion includes magnesium.

41. The bioactive agent delivery system of claim 37, wherein the chelating agent includes ethylenediaminetetraacetic acid.

42. The bioactive agent delivery system of claim 37, wherein the chelating agent includes diethyldithiocarbamate.

43. The bioactive agent delivery system of claim 37, wherein the protein includes sunflower protein.

44. The bioactive agent delivery system of claim 37, wherein the protein includes soluble sunflower protein.

45. The bioactive agent delivery system of claim 37, wherein the protein includes a polyphenol oxidase.

46. The bioactive agent delivery system of claim 37, wherein the protein includes a polyphenol oxidase containing copper.

47. The bioactive agent delivery system of claim 37, wherein the metal ion complexed with a chelating agent is soluble.

48. The bioactive agent delivery system of claim 37, further comprising a capsule containing the metal ion complexed with the chelating agent and the protein.

49. The bioactive agent delivery system of claim 37, wherein the metal ion complexed with the chelating agent and the protein are configured to be administered orally to a patient.

50. A bioactive agent delivery system, comprising: an organometallic amino acid compound complexed with a chelating agent.

51. The bioactive agent delivery system of claim 50, wherein the organometallic amino acid compound includes a metal ion.

52. The bioactive agent delivery system of claim 51, wherein the metal ion includes copper.

53. The bioactive agent delivery system of claim 51, wherein the metal ion includes zinc.

54. The bioactive agent delivery system of claim 51, wherein the metal ion includes magnesium.

55. The bioactive agent delivery system of claim 50, wherein the chelating agent includes ethylenediaminetetraacetic acid.

56. The bioactive agent delivery system of claim 50, wherein the chelating agent includes diethyldithiocarbamate.

57. The bioactive agent delivery system of claim 50, wherein the organometallic amino acid compound one or more sunflower proteins.

58. The bioactive agent delivery system of claim 50, wherein the organometallic amino acid compound one or more soluble sunflower proteins.

59. The bioactive agent delivery system of claim 50, wherein the organometallic amino acid compound includes a polyphenol oxidase.

60. The bioactive agent delivery system of claim 50, wherein the organometallic amino acid compound includes a polyphenol oxidase containing copper.

61. The bioactive agent delivery system of claim 50, wherein the organometallic amino acid compound complexed with the chelating agent is soluble.

62. The bioactive agent delivery system of claim 50, further comprising a capsule containing the organometallic amino acid compound complexed with the chelating agent.

63. The bioactive agent delivery system of claim 50, wherein the organometallic amino acid compound complexed with the chelating agent is configured to be administered orally to a patient.