BACKGROUND

[0001] Human intestinal microbiota include microorganisms such as bacteria that inhabit and maintain homeostasis of the gastrointestinal tract. These microorganisms contribute to the symbiotic ecosystem of the gastrointestinal tract. One benefit of the symbiosis is the metabolic activity of the microorganisms on exogenous and endogenous substrates, forming nutrients that arc useable by the human host.

[0002] The presence of diverse metabolic activity in the human gastrointestinal tract allows the intestinal microbiota to fill available ecological niches and competitively inhibit colonization by pathogens. The gastrointestinal tract may have elevated concentrations of mostly acidic fermentation byproducts compared to other areas of the human body. These elevated concentrations of byproducts may reduce pH locally to create an inhospitable environment for pathogens. The gastrointestinal tract metabolites and byproducts formed from intestinal microorganisms may be called “intestinal microbial metabolites.”

[0003] Intestinal microbial metabolites may also modulate the immune system through impacting the physiology of host cells, gene expression, or both. Specific fermentation pathways carried out by intestinal microorganisms can result in the formation of toxic compounds that have the potential to damage the host epithelium and cause inflammation. In other instances, formation of intestinal microbial metabolites may exacerbate diseases and conditions related to human health.

SUMMARY

[0004] This summary is provided to introduce a selection of concepts that are further described below in the detailed description. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used as an aid in limiting the scope of the claimed subject matter.

[0005] In one aspect, one or more embodiments herein relate to a pharmaceutical formulation for treating a patient with an elevated serum level of an intestinal microbial metabolite. The pharmaceutical formulation may include an effective amount of a macrocyclic molecule selected from the group consisting of a cucurbituril, a cucurbituril derivative, a cucurbituril conjugate, a pharmaceutically acceptable salt of cucurbituril, an isomer of cucurbituril, a tautomer of cucurbituril, a solvate of cucurbituril, an isotopic variation of cucurbituril, and a combination thereof, wherein the macrocyclic molecule comprises 5 to 20 glycoluril monomers.

[0006] In another aspect, one or more embodiments herein relate to a method of treating a patient with an elevated serum level of an intestinal microbial metabolite. The method may include administering a dose of a macrocyclic molecule to the patient with the elevated serum level of the intestinal microbial metabolite. The macrocyclic molecule may be selected from the group consisting of a cucurbituril. a cucurbituril derivative, a cucurbituril conjugate, a pharmaceutically acceptable salt of cucurbituril, an isomer of cucurbituril, a tautomer of cucurbituril, a solvate of cucurbituril, an isotopic variation of cucurbituril, and a combination thereof, and wherein the macrocyclic molecule comprises 5 to 20 glycoluril monomers.

[0007] In another aspect, one or more embodiments herein relate to a method of treating a disease. The method may include administering an effective amount of a macrocyclic molecule to a patient suffering from the disease. The disease may be selected from the group consisting of a cardiovascular disease, a cerebrovascular disease, a kidney disease, a psychiatric disorder, a gastrointestinal disorder, and a combination thereof. The macrocyclic molecule is selected from the group consisting of a cucurbituril, a cucurbituril derivative, a cucurbituril conjugate, a pharmaceutically acceptable salt of cucurbituril, an isomer of cucurbituril, a tautomer of cucurbituril, a solvate of cucurbituril, an isotopic variation of cucurbituril, and a combination thereof.

[0008] In another aspect, one or more embodiments herein relate to a biocompatible material. The biocompatible material may include a macrocyclic molecule selected from the group consisting of a cucurbituril, a cucurbituril derivative, a cucurbituril conjugate, a pharmaceutically acceptable salt of cucurbituril, an isomer of cucurbituril, a tautomer of cucurbituril, a solvate of cucurbituril, an isotopic variation of cucurbituril, and a combination thereof. The biocompatible material may include a solid carrier component selected from the group consisting of polyvinylchloride (PVC), polysulfone (PS), polycthcr sulfone (PES), polyphcnylsulfonc (PPSU), polycthcr ether ketone (PEEK), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyethylene (PE), polyurethane (PU), polyetherimide (PEI), polycarbonate (PC), polypropylene (PP), polyoxymethylene (POM), polymethyl methacrylate (PMMA), polyester polymer alloy (PEPA), polyglycolic acid (PGA), cellulose triacetate, ethylene vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), polyphenol, polyamide, nylon, polystyrene, polyacrylate, polycarbonate, polymer containing acrylonitrile, sodium acrylonitrile metarylsulfonate copolymer (AN69), polymer containing methylallylsulfonate salt, cellulose triacetate (CTA), a copolymer thereof, and a combination thereof.

[0009] In another aspect, one or more embodiments herein relate to a method of treating a patient having an elevated serum level of an intestinal microbial metabolite. The method may include passing blood from the patient to an article or a product containing a biocompatible material. The biocompatible material may include a macrocyclic molecule selected from the group consisting of a cucurbituril, a cucurbituril derivative, a cucurbituril conjugate, a pharmaceutically acceptable salt of cucurbituril, an isomer of cucurbituril, a tautomer of cucurbituril, a solvate of cucurbituril, an isotopic variation of cucurbituril, and a combination thereof. The biocompatible material may include a solid carrier component selected from the group consisting of polyvinylchloride (PVC), polysulfone (PS), polyether sulfone (PES), polyphenylsulfone (PPSU), polyether ether ketone (PEEK), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyethylene (PE), polyurethane (PU), polyetherimide (PEI), polycarbonate (PC), polypropylene (PP), polyoxymethylene (POM), polymethyl methacrylate (PMMA), polyester polymer alloy (PEPA), polyglycolic acid (PGA), cellulose triacetate, ethylene vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), polyphenol, polyamide, nylon, polystyrene, polyacrylate, polycarbonate, polymer containing acrylonitrile, sodium acrylonitrile metarylsulfonate copolymer (AN69), polymer containing methylallylsulfonate salt, cellulose triacetate (CTA), a copolymer thereof, and a combination thereof. The method may include allowing the intestinal microbial metabolite to contact the macrocyclic molecule, thereby capturing the intestinal microbial metabolite with the cucurbituril in an inclusion complex. [0010] In another aspect, one or more embodiments herein relate to a molecular composite.

The molecular composite may include a macrocyclic molecule selected from the group consisting of a cucurbituril, a cucurbituril derivative, a cucurbituril conjugate, a pharmaceutically acceptable salt of cucurbituril, an isomer of cucurbituril, a tautomer of cucurbituril, a solvate of cucurbituril, an isotopic variation of cucurbituril, and a combination thereof. The molecular composite may include an additional macrocyclic molecule selected from the group consisting of a cyclic oligosaccharide, a pillararene, a calixarene, a derivative thereof, and a combination thereof.

[0011] Other aspects and advantages of the claimed subject matter will be apparent from the following description and the appended claims.

BRIEF DESCRIPTION OF DRAWINGS

[0012] Specific embodiments of the disclosed technology will now be described in detail with reference to the accompanying figures. Where the figures include like elements between them, the elements are denoted by like reference numerals. They may be differentiated by letters appended to reference numerals.

[0013] FIG. 1A shows a chemical formula of cucurbituril with “n” number of units, according to one or more embodiments.

[0014] FIG. IB shows a chemical formula of cucurbituril, illustrated with five units of the chemical formula of FIG. 1A, according to one or more embodiments.

[0015] FIG. 2 shows a dialyzer, according to one or more embodiments.

[0016] FIG. 3 shows a dialyzer, according to one or more embodiments.

DETAILED DESCRIPTION

[0017] In the following detailed description of embodiments of the disclosure, numerous specific details arc set forth to provide a more thorough understanding of the disclosure. However, it will be apparent to one of ordinary skill in the art that the disclosure may be practiced without these specific details. In other instances, well-known features have not been described in detail to avoid unnecessarily complicating the description. [0018] A biochemical in the body may be processed by gastrointestinal bacteria to produce a metabolized biochemical, such as one or more intestinal microbial metabolite. An intestinal microbial metabolite may be further processed in the liver. An intestinal microbial metabolite or a downstream product and/or conjugate thereof (including, but not limited to those formed in the liver) may be grouped under the phrase intestinal microbial metabolite.

[0019] Intestinal microbial metabolites have been implicated as exacerbating factors in various diseases and conditions. In other words, one or more intestinal microbial metabolites may aggravate or deteriorate a disease or a health condition. When a patient experiences an elevated serum level (concentration) of an intestinal microbial metabolite compared with a normal serum level of the intestinal microbial metabolite, the metabolite may correlate with increased risk, exacerbation, or manifestation of a disease.

[0020] In one or more embodiments, compositions comprising cucurbituril are provided to sequester, capture, or otherwise associate with one or more biomolecules. A biomolecule may be removed once captured by the cucurbituril. Methods herein may include removing a captured biomolecule from the body of a patient, for example.

[0021] A biomolecule may include at least one macronutrient that is consumed in the human diet including, but not limited to, a carbohydrate, a protein, a fat, and a vitamin. A macronutrient may be broken down by a metabolic process in the gastrointestinal tract of the body, as previously described. In one or more embodiments, a biomolecule is an intestinal microbial metabolite.

[0022] A macronutrient such as a protein may include amino acids such as tyrosine, phenylalanine, and tryptophan. An amino acid may be a protein-derived amino acid in the diet. Some amino acids are not able to be created by the human body, which are called essential nutrients (such as essential amino acids). Suitable examples of other macronutrients include a vitamin including, but not limited to, choline; an acid including, but not limited to, a short chain fatty acid such as acetic acid, propionic acid, and butyric acid, and a bile acid such as taurocholic acid, glycolic acid, deoxycholic acid; carnitine; dietary fiber; and combinations thereof. [0023] One or more biomolecules such as a macronutrient may be metabolized by intestinal bacteria to produce an intestinal microbial metabolite. For example, intestinal microbial metabolites produced from tyrosine, phenylalanine, or tryptophan include, but are not limited to, indole, indolacetic acid, indoxyl sulfate, skatole, trimethylamine, p- cresol, 4-ethyl phenol, phenol, phenol derivative(s), homocysteine, 3-carboxy-4-methyl-5- propyl-2-furanopropionic acid, urofuranic acid(s), hippuric acid, p-hydroxyhippuric acid, and a combination thereof.

[0024] Generally, when a biomolecule is broken down to a metabolite, the metabolite may be further processed by oxidation, hydrolysis, reduction, glutathione conjugation, sulfation, acetylation, glucuronidation, another known metabolic process, and a combination thereof. Thus, an intestinal microbial metabolite may be further metabolized in the liver to produce another compound. The compound that has been further metabolized may still be called an intestinal microbial metabolite. For example, intestinal microbial metabolites that have been further metabolized may include, but are not limited to, indoxyl sulfate, hippuric acid, p-cresyl sulfate, p-cresol glucuronide, 4-ethylphenol sulfate (4EPS), trimethylamine-N trimethylamine-N-oxide (TMAO), and other suitable downstream metabolic products.

[0025] As a non-limiting example of how an elevated serum level of a metabolite is linked to health conditions, when an elevated TMAO level is present in the serum of a patient, the elevated serum TMAO level may correlate with cardiovascular disease. Likewise, an elevated serum 4EPS level may correlate with psychological conditions, such as autism spectrum disorder (ASD). In addition, an elevated serum indoxyl sulfate and/or p-cresyl sulfate level may correlate with kidney disease, such as chronic kidney disease. Chronic kidney disease may be prevalent in, for example, a dialysis patient.

[0026] Some conventional methods may be used to remove an intestinal microbial metabolite directly from the blood of patients with end-stage renal failure, such as dialysis. However, a protein-bound intestinal microbial metabolite, such as indoxyl sulfate and/or p-cresyl sulfate that is bound to albumin, is not removed sufficiently by dialysis to reduce the serum level of the metabolite. In some instances, intestinal microbial metabolite may be difficult to remove from the body by conventional means because of its structure, such as a protein-bound or a conjugate structure. In other instances, free intestinal microbial metabolites (not protein-bound or conjugated) may also be difficult to remove from the body by conventional means.

[0027] Regarding intestinal microbial metabolites (whether protein-bound or free), factors that affect dialysis efficiency include size (molecular weight), solubility in water (hydrophilic/hydrophobic), protein binding rate (if any), and volume of distribution. In general, intestinal microbial metabolites that have low solubility in water (that are hydrophobic) are more likely to bind to proteins including, but not limited to, albumin. Conversely, intestinal microbial metabolites that have high solubility in water (that are hydrophilic) are less likely to bind to proteins including, but not limited to, albumin. The molecular weight of molecules that may be removed by dialysis are up to a size of 10,000 (10 ⁴ ) grams per mole (g/mol) molecular weight. However, dialysis used alone for the removal of molecules with a molecular weight greater than 1 ,000 g/mol may not be as efficient as other techniques. Hemodiafiltration and hemofiltration techniques may remove molecules with a size greater than 10,000 g/mol.

[0028] For example, indoxyl sulfate has a molecular weight of about 213 g/mol and p- cresyl sulfate has a molecular weight of about 210 g/mol (in sodium salt form, or about 188 g/mol as p-cresol sulfate); intestinal microbial metabolites such as these are easily removed by dialysis if not bound to proteins. However, the molecular weight of albumin that is about 66,500 (6.65 x 10 ⁴ ) g/mol (or 66.5 kilodalton) shows that protein-bound intestinal microbial metabolites may be difficult to remove by dialysis alone.

[0029] Thus, one or more embodiments of the present disclosure relates to removal of an intestinal microbial metabolite (or a further downstream metabolite) using a macrocyclic compound such as cucurbituril. Compositions and methods according to one or more embodiments herein may have fewer side effects and/or greater efficacy compared to conventional compositions and methods to remove a metabolite. Here, greater efficacy relates to removing an intestinal microbial metabolite sufficiently to reduce a serum level of the metabolite (whether protein-bound or free).

[0030] Conventional compositions and methods to remove a metabolite may include activated carbon, macrocycles (macrocyclic hosts), and uses thereof. For example, activated carbon may be used as an oral adsorbent and blood purification device, but it does not allow specific control of the size of the substance that is to be adsorbed. Conventional compositions also adsorb many components that arc useful to the body. Among macrocycles, cyclodextrins may be used. However, cyclodextrins are reported to have low selectivity and low affinity due to their low binding constant (such as binding constant, Ka, of <10 ⁴ M ¹ (1/M)) (as reported in Rekharsky, M. V., and Inoue, Y. (1998), Complexation thermodynamics of cyclodextrins. Chem. Rev. 98, 1875-1917. doi: 10.1021/cr970015o).

[0031] Due to the low binding constant, excess concentration of cyclodextrin (and other macrocycles) may be needed to form host-guest complexes with, for example, intestinal microbial metabolites. Furthermore, cyclodextrins and other conventional macrocycles may be nephrotoxic when administered in an unmetabolized form.

[0032] Relating to host-guest complexes of cucurbituril and an intestinal microbial metabolite, the binding constant (Ka) of cucurbituril is several orders of magnitude greater than those of cyclodcxtrins in aqueous medium (as reported by: Cao, L., Sckutor, M., Zavalij, P. Y., Mlinaric-Majerski, K., Glaser, R., and Isaacs, L. (2014), Cucurbit[7]uril*guest pair with an attomolar dissociation constant; Angew. Chem. Int. Ed. 53, 988-993, doi: 10.1002/anie.201309635; Assaf, K. I., and Nau, W. M. (2015), Cucurbiturils: from synthesis to high-affinity binding and catalysis, Chem. Soc. Rev. 44, 394-418, doi: 10.1039/C4CS00273C; Barrow, S. J., Kasera, S., Rowland, M. J., del Barrio, J., and Scherman, O. A. (2015). Cucurbituril-based molecular recognition, Chem. Rev. 115, 12320-12406, doi: 10.1021/acs.chemrev.5b00341; and Shetty, D„ Khedkar, J. K., Park, K.M., and Kim, K. (2015), Can we beat the biotin-avidin pair? cucurbit[7]uril- based ultrahigh affinity host-guest complexes and their applications, Chem. Soc. Rev. 44, 8747-8761, doi: 10.1039/C5CS00631G.)

[0033] Compared to conventional compositions and methods, cucurbiturils may be nontoxic and biocompatible (as reported by: Montes-Navajas, P., Gonzalez-Bejar, M., Scaiano, J. C., and Garcia, H. (2009), Cucurbituril complexes cross the cell membrane, Photochem. Photobiol. Sci. 8, 1743-1747, doi: 10.1039/b9pp00041k; Hettiarachchi, G., Nguyen, D., Wu, J., Lucas, D., Ma, D., Isaacs, L., et al. (2010), Toxicology and drug delivery by cucurbit[n]uril type molecular containers, PLoS ONE 5:el0514, doi: 10.1371 /journal .pone.0010514; Uzunova, V. D., Cullinane, C., Brix, K., Nau,W.M., and Day, A. I. (2010), Toxicity of cucurbit[7]uril and cucurbit[8]uril: an exploratory in vitro and in vivo study. Org. Biomol. Chem. 8, 2037-2042, doi: 10.1039/b925555a; Zhang, X., Xu, X., Li, S., Wang, L.-H., Zhang, J., and Wang, R. (2018b), A systematic evaluation of the biocompatibility of cucurbit[7]uril in mice, Sci. Rep. 8:8819, doi: 10.1038/s41598- 018-27206-6; and Das D, Assaf KI and Nau WM (2019), Applications of Cucurbiturils in Medicinal Chemistry and Chemical Biology, Front. Chem. 7:619, doi: 10.3389/fchem.2019.00619.)

[0034] Cucurbituril is described as follows. As shown in FIG. 1A, cucurbituril is a macrocyclic molecule made of glycoluril (=C4H2N40I=) units linked by methylene (-CH2-) bridges. Cucurbituril may be a condensation product (polymerization) of glycoluril monomers and formaldehyde.

[0035] The name cucurbituril is derived from the cyclic molecule’s resemblance with a pumpkin of the family Cucurbitaceae . When viewed thrcc-dimcnsionally, cucurbituril has a pumpkin-like shape with an exterior band and an interior cavity. Cucurbituril has no bottom and no top. Thus, cucurbituril has an interior cavity that is accessible from the top and the bottom. The oxygen atoms in cucurbituril are located along the edges of the exterior band and are tilted inwards, forming a partly enclosed interior cavity. The exterior of cucurbituril is made up of a band of glycoluril molecules that are linked by methylene bridges.

[0036] The interior cavity of cucurbituril may capture a molecule within the interior cavity. When a molecule or a portion of a molecule is in the interior cavity, the molecule or portion thereof may be called a “guest” where the cucurbituril is the “host.” The cucurbituril molecule may function as a macrocyclic host in host-guest chemistry and supramolecular chemistry. One of ordinary skill in the art would appreciate the interaction between a host and a guest in host-guest and supramolecular chemistry to the extent that such chemical concepts would apply to cucurbituril chemically associating with and/or capturing a molecule. An inclusion complex (also known as an inclusion compound) is formed from a cucurbituril and a molecule that is captured in the cucurbituril. [0037] In one or more embodiments, the interior cavity of cucurbituril is hydrophobic. Because the interior cavity of cucurbituril may be hydrophobic, the guest molecule may easily be incorporated into the interior cavity when the guest molecule is also hydrophobic. In one or more embodiments, a guest molecule is an intestinal microbial metabolite.

[0038] In one or more embodiments, the interior cavity of cucurbituril is lipophilic. Because the interior cavity of cucurbituril may be lipophilic, the guest molecule may easily be incorporated into the interior cavity when the guest molecule is also lipophilic. Thus, a guest molecule that is hydrophobic, lipophilic, or both hydrophobic and lipophilic may be water insoluble.

[0039] The number of glycoluril monomers in cucurbituril is represented by the letter n in FIG. 1A. In one or more embodiments, n is from 5 to 20 glycoluril monomers. A suitable cucurbituril molecule herein may have glycoluril monomers in an amount of, for example, n = 5, 6, 7, 8, 10, 13, 14, 15. As a non-limiting example, FIG. IB shows cucurbituril having 5 glycoluril monomers.

[0040] A composition comprising cucurbituril according to one or more embodiments may include cucurbituril molecules having different n number of glycoluril monomers. Sometimes, cucurbituril is described as cucurbit[n]uril (or CB[n] or CBn), where n is the number of glycoluril monomers.

[0041] When n = 5, 6, or 7 (glycoluril monomers), the interior cavity in cucurbituril is from about 4.4 angstroms (A) to about 7.3 A in diameter. When n = 8, 9, 10, 11, or 12, the interior cavity in cucurbituril is from about 8.8 A to about 15.0 A in diameter at its widest point. When n = 13, 14, or 15, the interior cavity in cucurbituril is from about 16.4 A to about 20 A in diameter at its widest point. When n = 16, 17, 18, 19, or 20, the interior cavity in cucurbituril is from about 21 A to about 28 A in diameter at its widest point.

[0042] The cucurbituril may have an interior cavity that is suitably sized for a guest molecule or a portion of a guest molecule. Meaning, the formation of the inclusion complex of cucurbituril and the guest molecule depends on the size of the cucurbituril interior cavity. [0043] The exterior dimensions of the cucurbituril are slightly larger than the interior cavity size. For example, a cucurbituril having n-6 has a height of about 9.1 angstroms (A) and an outer diameter of about 5.8 A, while having an inner diameter of about 3.9 A.

[0044] In one or more embodiments, cucurbituril may range from about 830 to about 3,320 grams per mole (g/mol) (or from about 0.83 to about 3.32 kilodalton (KDa)). In one or more embodiments, the cucurbituril may be in a range of from about 0.5 to about 5 KDa. Thus, cucurbituril may be in a range having a lower limit of any of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, or 3.5 KDa, and an upper limit of any of 1.0, 1.5, 2.0. 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 KDa, where any lower limit may be combined with any mathematically allowed upper limit. One factor that is included in the size of cucurbituril is the n number of glycoluril monomers. For example, a single glycoluril monomer with two methylene bridges has a molecular weight of about 166 g/mol. Another factor that is included in the size of the cucurbituril is whether the cucurbituril is a conjugate, derivative, or another suitable form of cucurbituril.

[0045] In one or more embodiments, the cucurbituril is resistant to acidic pH. Resistant to acidic pH means that the cucurbituril retains its function at acidic pH, which is to trap a molecule or portion thereof as a guest molecule within the interior cavity without, for example, decomposing or breaking apart. An acidic pH may be less than 7.0. such as a pH having a lower limit of any of 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 3.5, and an upper limit of any of 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, and 7.0, where any lower limit may be combined with any mathematically allowed upper limit.

[0046] Acidic pH may be representative of a gut, stomach, intestine, colon, or other gastrointestinal location. Acidic physiological pH may be from 1.0 to 4.0, such as from 1.5 to 3.5. Such areas of the body are known to include strong acids such as hydrochloric acid (HC1). Other compounds may be mixed with HC1 in an acidic mixture within the stomach or gut including, but not limited to, compounds such as a salt, an enzyme, and a combination thereof. A salt may include, but is not limited to potassium chloride, sodium chloride, and a combination thereof. These acidic mixtures may also have an acidic pH.

[0047] The cucurbituril may be in a form selected from the group consisting of a crystalline product, an amorphous powder product, a syrup, a gel, and a combination thereof. The cucurbituril may be a commercially available product or may be produced by a conventional method.

[0048] In one or more embodiments, a composition comprising cucurbituril herein is a pharmaceutical formulation. A pharmaceutical formulation herein includes cucurbituril as an active ingredient. A pharmaceutical formulation may include more than one active ingredient. For example, depending on what disease or health condition that the pharmaceutical formulation is used to treat, there may be one or more additional active ingredient. Examples of active ingredients in addition to cucurbituril include, but are not limited to: sodium polystyrene sulfonate and/or calcium polystyrene sulfonate corresponding with hyperpotassemia, chronic kidney disease, dialysis, and a combination thereof; cholestyramine corresponding with dyslipidemia, diarrhea (such as due to inhibition of endotoxin activity), vitamin D3 overdose, and a combination thereof; one or more of sevelamer hydrochloride, lanthanum carbonate hydrate, bixaromer, ferric citrate hydrate preparations, precipitated calcium carbonate, and sucrooxy iron hydroxide corresponding to hyperpotassemia, chronic kidney disease, dialysis, and combinations thereof; and activated charcoal corresponding to chronic kidney disease and/or acute drug poisoning.

[0049] In one or more embodiments, compositions herein include different forms of cucurbituril. For example, the term “cucurbituril” herein may refer to cucurbituril, a cucurbituril derivative, a cucurbituril conjugate, a pharmaceutically acceptable salt of cucurbituril, an isomer of cucurbituril, a tautomer of cucurbituril, a solvate of cucurbituril, an isotopic variation of cucurbituril, or a combination thereof.

[0050] A cucurbituril conjugate may include a chemically modified cucurbituril where one or more carbonyl carbon of cucurbituril is an attachment point for another molecule or chemical moiety. Thus, a cucurbituril conjugate may include an ester linkage, or other suitable linkage known in the ail to chemically and physically bind the cucurbituril.

[0051] In one or more embodiments, a pharmaceutical formulation herein includes an inactive ingredient. A pharmaceutical formulation herein may include one or more component that is orally administered. For example, a pharmaceutical formulation comprising cucurbituril may include glycoluril, formaldehyde, and a combination thereof. In one or more embodiments, a pharmaceutical formulation substantially does not include formaldehyde. Formaldehyde is generally harmful to the body of living animals including humans, and the pharmaceutical formulation including less formaldehyde is preferable. The cucurbituril may be formed from a formaldehyde-free reaction subjecting to react glycoluril monomers with a methylene bridging agent instead of formaldehyde or its precursor in the presence of an acid. The methylene bridging agent can be a dialkoxymethane, preferably diethoxymethane or dipropoxymethane. Another formaldehyde-free reaction can be a reaction of a fully alkoxy methylated glycoluril with unsubstituted glycoluril in the presence of an acid.

[0052] In one or more embodiments, the pharmaceutical formulation comprising cucurbituril is in a suitable dosage form for oral administration. Oral administration is where a substance is taken through the mouth. Examples of suitable dosage forms of a pharmaceutical formulation comprising cucurbituril include, but are not limited to, a tablet, a chew (a dissolvable solid or tablet), a capsule (hard capsule, soft capsule, gel capsule, microcapsule, or chewable capsule), a liquid, a gel, a powder, a granule (such as a fine granule), a round, a pastille, an osmotic delivery system, a decoction, an elixir, an electuary, an emulsion, an effervescent, a solution, a suspension, a tincture, a syrup, a food product including, but not limited to, a drink, and a combination thereof. The dosage form may be time-release, extended-release, or sustained release.

[0053] As a non-limiting example, the cucurbituril may be released in the colon to adsorb intestinal microbial metabolites from enteric bacteria. For such a time delay (or locationspecific) release, cellulase derivatives such as cellulase acetate phthalate (CAP) and cellulose hydroxy propyl methyl phthalate may be used. Further, a dosage form that dissolves in alkaline intestinal juice (and not, for example, in acidic gastric juice) may be used as a material in a cap, capsule, film, or other suitable dosage form where the dosage form is made from enteric soluble material.

[0054] One or more embodiments of the present disclosure relate to a method of administering a composition comprising cucurbituril to a patient in need thereof. The composition comprising cucurbituril may be a pharmaceutical composition. The method may include administering a dose of cucurbituril by oral administration or by other means to a gastrointestinal tract, such as by a feeding tube.

[0055] The method may include administering a single dose or multiple doses in an effective amount to treat a patient having an elevated serum level of an intestinal microbial metabolite. An effective amount reduces an elevated level (concentration) of the intestinal microbial metabolite to a safe or normal level of the intestinal microbial metabolite, where concentration may be measured in a patient’s serum. The effective dose and number of doses of cucurbituril may vary depending on the type of administration, the patient’s age, body weight, nature, or severity of symptoms to be treated, overall health, other health conditions, additional medicines, and other factors.

[0056] Depending on the factors previously mentioned, a maximum allowable dose for a human is up to about 1,000 milligrams per kilogram of body weight (mg/kg/body weight) per day of cucurbituril that is orally administered.

[0057] As described previously, one or more embodiments of the method include treating a patient having an elevated scrum level of an intestinal microbial metabolite. For example, indoxyl sulfate (produced from indole in intestine) has a normal concentration of 0.53 milligrams per liter (mg/L) with a standard deviation of about 0.29 mg/L and a standard deviation of 0.29 (SD: 0.29), a mean uremic concentration of about 23.1 mg/L (SD: 13.0), and a greatest uremic concentration of about 44.5 mg/L (SD: 15.3). P-cresyl sulfate (produced from phenol in intestine) has a normal concentration of about 1.9 mg/L (SD: 1.3), a mean uremic concentration of about 20.9 mg/L (SD: 12.2), a greatest uremic concentration of about 41 mg/L (SD: 13.3).

[0058] In general, it is assumed that blood concentrations are normally distributed, and the mean value ± 2 SD is the normal value (the range in which about 95% of people are distributed). Therefore, when looking to indoxyl sulfate, about 0 to about 1.11 (0.53+0.29 x 2) mg/L is the normal value, and if this value is exceeded, this is considered an elevated serum level of the intestinal microbial metabolite (indoxyl sulfate). Similar reasoning applies to p-cresyl sulfate and other intestinal microbial metabolites. [0059] An effective amount of cucurbituril is administered to the patient when the dose concentration is sufficient to lower an elevated serum level of an intestinal microbial metabolite to a normal serum level of the same metabolite.

[0060] The method may include allowing the cucurbituril (or derivative, etc.) to associate with the intestinal microbial metabolite, thereby capturing the intestinal microbial metabolite with the cucurbituril. Without wanting to be bound by theory, an inclusion complex may be formed by inclusion of the intestinal microbial metabolite in the cucurbituril (as a host-guest complex). As a result, a concentration (level) of an intestinal microbial metabolite in the gastrointestinal tract and serum are thought to decrease to a normal or a healthy level as compared to an elevated level, which may suppress the progression of various diseases and human health conditions.

[0061 ] In one or more embodiments, the method includes removing the intestinal microbial metabolite from the patient. Removing the intestinal microbial metabolite may include removing an inclusion complex (metabolite with cucurbituril), unused cucurbituril that may not be part of an inclusion complex, as well as free intestinal microbial metabolite.

[0062] The patient to be treated may be suffering from a disease, a disorder, or have a condition that is exacerbated by the elevated serum level of the intestinal microbial metabolite. Thus, the patient’s condition may include an elevated serum level of an intestinal microbial metabolite. For example, the condition may be selected from the group consisting of a cardiovascular disease, a cerebrovascular disease, a kidney disease, a psychiatric disorder, a gastrointestinal disorder, and other metabolic diseases and disorders, and a combination thereof.

[0063] The cardiovascular disease and/or the cerebrovascular disease is selected from the group consisting of coronary heart disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, pulmonary embolism, stroke, cerebral infarction, and a combination thereof.

[0064] An example intestinal microbial metabolite that exacerbates a cardiovascular disease and/or cerebrovascular disease includes trimethylamine N-oxide. Phosphatidylcholine in food is metabolized to trimethylamine N (TMA) by intestinal bacteria. Trimethylamine N (TMA) is further metabolized to trimethylamine N-oxide (TMAO) by the enzyme flavin-containing monooxygenase 3 (FMA3) in the liver. Trimethylamine N-oxide (TMAO) induces the development of atherosclerosis and cardiovascular disease by, among other things, inducing macrophages to form (as reported in Koeth RA, et al.'. Intestinal microbiota metabolism of L-camitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19 : 576 to 585, 2013; and Tang WH, etal:. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368 : 1575 to 1584, 2013.)

[0065] The kidney disease is selected from the group consisting of chronic kidney disease, IgA nephropathy, and a combination thereof.

[0066] An example intestinal microbial metabolite that exacerbates a kidney disease includes indoxyl sulfate, p-cresyl sulfate, and combinations thereof. Indoxyl sulfate induces renal tubular cell injury and cell death through production of oxidative stress, among other things. Further, indoxyl sulfate stimulates renal fibrosis through TGF-bcta overexpression and activates mesangial cell proliferation. P-cresyl sulfate also causes renal tubular cell damage by inducing oxidative stress, among other things.

[0067] The psychiatric disorder is selected from the group consisting of an autism spectrum disorder, an anxiety disorder, and a combination thereof.

[0068] An example intestinal microbial metabolite that exacerbates a psychiatric disorder includes 4-ethylphenyl sulfate (4EPS). 4-Ethylphenyl sulfate (4EPS) is produced when tyrosine is metabolized by intestinal bacteria to 4-ethylphenol, which is then sulfate conjugated in liver. 4-Ethylphenol (4EP) and 4-ethylphenyl sulfate (4EPS) prevent oligodendrocyte maturation, inhibit neuronal myelin formation, and decrease connectivity in the brain, among other things. Such changes may be strong in anxiety disorders.

[0069] The gastrointestinal disorder is selected from the group consisting of irritable bowel disease, irritable bowel syndrome, intestinal permeability, colon cancer, gastrointestinal cancer, and a combination thereof.

[0070] An example intestinal microbial metabolite that exacerbates a gastrointestinal disorder includes skatole (produced from dietary tryptophan, metabolized by intestinal microbes) and tryptamine. Skatole plays a role in the disturbance of intestinal homeostasis and in the development of intestinal bowel disease via inhibition of CYP11A1 expression and glucocorticoid production, among other things. Tryptamine is a ligand for trace amine- associated receptors and potentiates the inhibitory effect of serotonin that is involved in intestinal bowel disease, among other things.

[0071] Another example of an intestinal microbial metabolite that exacerbates a gastrointestinal disorder includes a short chain fatty acid (SCFA). Short chain fatty acids (SCFAs) include, but are not limited to, propionic acid, butyric acid, valeric acid, and combinations thereof. Short chain fatty acids (SCFAs) are produced in various parts of the intestinal tract. Among short chain fatty acids (SCFA), concentrations of acetic acid, propionic acid, and total organic acids in the feces of irritable bowel syndrome patients are greater than those of patients without irritable bowel syndrome. Excessive production of acetic acid and propionic acid in the feces of irritable bowel syndrome patients leads to decreased expression of adhesion factors and mucus production followed by increased mucosal permeability, among other things. These changes may lead to or contribute to irritable bowel syndrome.

[0072] Other conditions include, but are not limited to dementia, obesity, diabetes, dyslipidemia, malignancies, allergies, and chronic inflammatory diseases. Examples of an intestinal microbial metabolite that exacerbates dementia include, but are not limited to ammonia, p-cresol, isovaleric acid, indole, butyric acid, phenol, skatole. Examples of intestinal microbial metabolites that exacerbate diabetes, autoimmune disease(s), and infections are short chain fatty acids. Other intestinal microbial metabolites that may contribute to diabetes include trimethylamine and trimethylamine oxide. Other conditions may include liver cancer, exacerbated by an intestinal microbial metabolite such as secondary bile acids.

[0073] In one or more embodiments, a material having a composition comprising cucurbituril is biocompatible or blood-compatible, and an article at least partially formed from the material may be used in biological and medical arts. The article may include from about 0.1 to about 50 weight % of macrocyclic molecule (cucurbituril). “Biocompatible” means an ability to act and perform without impairing basic immunological functions of the body or causing injurious, negative physiological, or toxic reactions. “Blood- compatiblc” means a feature suitable for direct contact with blood without causing an injurious, negative physiological, allergic, or toxic reaction. For example, ISO 10993-4 is a standardized method to test for blood compatibility. Under this standard, thrombogenicity, blood coagulation, platelets, hematologic items, and complement activation systems are evaluated. Saline extracts are used for hemolytic testing, immunologic testing (through complement activation), and devices in direct contact with blood. Hemolysis studies such as thrombogenicity testing should be performed using direct and indirect methods; thrombogenicity should be evaluated as part of safety studies performed in relevant animal models. As an alternative, a 4-hour canine venous heparinization model can be used to evaluate thrombogenicity.

[0074] A product to be used in biological and medical arts may be formed from the article. An example of the product is a dialysis membrane. In one or more embodiments, a method is provided that includes removing an intestinal microbial metabolite from the body of a dialysis patient using the dialysis membrane. The dialysis membrane may adsorb an intestinal microbial metabolite that may be free or bound to a protein. The intestinal microbial metabolite may be adsorbed during a dialysis process.

[0075] The article according to one or more embodiments herein further comprises a solid carrier component. The solid carrier component may be a constituent of the composition of the material comprising cucurbituril and may be another component of the article than a component made of the material comprising cucurbituril. The weight ratio between the macrocyclic molecule (cucurbituril) and the solid carrier component may be from about 1:1000 to about 1:1.

[0076] The dialysis membrane according to one or more embodiments herein may include a conventional dialysis membrane as the solid carrier component. By combination of cucurbituril with the conventional dialysis membrane, intestinal microbial metabolites may be removed by size as well as adsorption. For example, a coating of cucurbituril on a surface of the conventional dialysis membrane (that interacts with the blood) allows adsorption of intestinal microbial metabolites and the conventional dialysis membrane allows removal of components by size. Thus, cucurbituril may be used to enhance adsorption capacity of the dialysis membrane.

[0077] The solid carrier component may comprise a polymer or other suitable solid carrier.

Suitable examples of the polymer for the solid carrier component include, but are not limited to, polyvinylchloride (PVC), polysulfone (PS), polyether sulfone (PES), polyphenylsulfone (PPSU), polyether ether ketone (PEEK), polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polyethylene (PE), polyurethane (PU), polyetherimide (PEI), polycarbonate (PC), polypropylene (PP), polyoxymethylene (POM), polymethyl methacrylate (PMMA), polyester polymer alloy (PEPA), polyglycolic acid (PGA), cellulose triacetate, ethylene vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), polyphenol, polyamide including, but not limited to, nylon, polystyrene, polyacrylate, polycarbonate, polymer containing acrylonitrile including, but not limited to, sodium acrylonitrile metarylsulfonate copolymer (AN69) (a copolymer of acrylonitrile and sodium methallyl sulfonate), polymer containing methylallylsulfonate salt, cellulose triacetate (CTA), a copolymer thereof, and a combination thereof. An example of the other suitable solid carrier is an activated charcoal (activated carbon).

[0078] One of ordinary skill in the art would appreciate that one or more additional component may be included in the article. Thus, one or more additional components may be included in the article.

[0079] The solid carrier component may be from about 0.1 to about 50 weight % of the total article.

[0080] The cucurbituril may be affixed to the solid carrier component. For example, the cucurbituril may be physically or chemically mixed, bound, and/or associated with the solid carrier component. When the solid carrier component is a polymer, the cucurbituril and the polymer may be cross-linked or otherwise attached to form a polymer including cucurbituril.

[0081] In one or more embodiments, the article has a form that may include but is not limited to a sheet, a membrane, a hollow fiber, a porous material, a particle, a foam, a textile, a granule, a non-woven, a gel, and a combination thereof. [0082] The article may have a surface that includes cucurbituril. The cucurbituril may be exposed at the surface of the article. That is, the cucurbituril in the article may host small molecule guests to form an inclusion complex with an intestinal microbial metabolite and cucurbituril at the surface. The surface of the article may be smooth, porous, semiporous, or a combination thereof.

[0083] The article may include one or more layer that cucurbituril may be embedded in or may be exposed at the surface of the one or more layer, to an extent that a small molecule such as an intestinal microbial metabolite is accessible to the cucurbituril of each layer.

[0084] The article according to one or more embodiments may be formed by a method comprising one of coating, mixing, layering, and a combination thereof.

[0085] The article according to one or more embodiments may be formed by applying a coating comprising cucurbituril on a surface of a substrate comprising the solid carrier component. The coating may cover a part or whole of the substrate. Traditional coating techniques that are known in the art may be used.

[0086] The article according to one or more embodiments may be formed of a mixture of cucurbituril and the solid carrier component. Traditional mixing techniques that are known in the art may be used.

[0087] The article according to one or more embodiments may be formed by layering a plurality of layers. The composition formed of each of the layers may be same or different. Thus, traditional layering techniques that are known in the art may be used. Layering techniques include but are not limited to a layer-by-layer application.

[0088] In one or more embodiments, a product is provided that includes an article according to one or more embodiments.

[0089] The product may be a blood-compatible adsorbent. In one or more embodiments, the blood-compatible adsorbent may be a porous membrane such as a dialysis membrane comprising the article according to one or more embodiments. The cucurbituril contained in the article may be exposed on at least one surface of the dialysis membrane so that the cucurbituril is able to host a toxic substance in a fluid. [0090] The product may be made from, in whole or in part, the article according to one or more embodiments. The article may also be on a portion of or the entirety of the product. For example, when the product is a catheter, the article may be provided on part of the catheter or the entire body of the catheter. As well, the catheter may be made from the article. Thus, the product may be tailored for an application depending on where the cucurbituril and adsorption effects are needed.

[0091] One or more embodiments of the present disclosure relate to a dialysis apparatus comprising an article herein. Thus, a dialysis apparatus may include a product comprising an article having cucurbituril and a solid carrier component.

[0092] One or more embodiments of a composition comprising cucurbituril and a method of use herein may be associated with an extracorporeal treatment. The dialysis apparatus may be a hemodialysis apparatus. This type of dialysis is sometimes called hemodialysis and removes extracorporeal waste and frees water from the blood, for example, when kidneys are in a state of failure in a patient. Other extracorporeal treatments include peritoneal dialysis, and adsorption with sorbents, such as charcoal or another adsorbent, and filtration that are suitable for use with one or more embodiments herein.

[0093] In a healthy person, an intestinal microbial metabolite in serum may be excreted via the kidneys with urine or by other biological mechanisms. However, in patients with a health condition, an intestinal microbial metabolite may remain in the patient’s blood, to be removed by dialysis. The intestinal microbial metabolite may be difficult to remove when bound to a protein, such as albumin. In some instances, one or more additional components may be added to the blood of a patient to separate a protein (such as albumin) from a metabolite during dialysis. However, conventional methods of separation may be inefficient, may increase general dosage of medications for a patient, and may decrease the patient’ s quality of life compared to one or more embodiments of a dialyzer herein and methods of use.

[0094] In one or more embodiments, a protein-bound intestinal microbial metabolite may be efficiently removed with articles and products described herein without administering medicine, or an additional medicine that disrupts the protein-metabolite complex (inclusion complex), to a patient in need of dialysis. [0095] As previously mentioned, an intestinal microbial metabolite present in serum may be in a protein-bound form. This is because the intestinal microbial metabolite alone may have poor or low water solubility (is hydrophobic). When the intestinal microbial metabolite is bound to a protein, then transport of the metabolite may occur in aqueous medium, serum, blood, and other biological fluids via the carrier protein. The protein that binds the intestinal microbial metabolite includes but is not limited to albumin.

[0096] An intestinal microbial metabolite that is bound to a protein has a larger molecular mass than the metabolite alone that is not protein-bound. A low molecular mass intestinal microbial metabolite may be less than 50 g/mol. An average molecular mass may be between 50 and 5,000 g/mol. A large molecular mass may be greater than 5,000 g/mol. A protein-bound intestinal microbial metabolite may fall within the large molecular mass range.

[0097] One or more embodiments of the present disclosure includes removing a proteinbound intestinal microbial metabolite from serum. Thus, the protein-bound intestinal microbial metabolite may be effectively removed even at sizes that do not readily diffuse across a dialysis membrane, such as a (large) molar mass from about 65,000 to 70,000, which is about the size of albumin present in serum and a metabolite bound thereto.

[0098] FIG. 2 shows a cucurbituril-containing dialyzer 200 with a cucurbituril-containing dialysis bag 202, according to one or more embodiments. The cucurbituril-containing dialyzer is depicted as a simplified version for clarity. A person of ordinary skill in the art would appreciate variations of dialyzers that are known in the art.

[0099] As shown in FIG. 2, blood is introduced into a blood inlet 210 where it passes to the blood compartment 206. From the blood compartment, the blood passes to the blood outlet 212, through which the blood exits the cucurbituril-containing dialyzer 200. Likewise, dialysate is introduced into a dialysate inlet 214 where it passes to the dialysate compartment 208. From the dialysate compartment, the dialysate passes to the dialysate outlet 216, through which the dialysate exits the cucurbituril-containing dialyzer 200.

[00100] In the cucurbituril-containing dialyzer 200, the dialysis membrane includes or is made from an article (containing cucurbituril) according to one or more embodiments and is called a cucurbituril-containing dialysis membrane 204. The cucurbituril-containing dialysis membrane separates the blood compartment 206 from the dialysate compartment 208. The cucurbituril-containing dialysis membrane 204 allows free intestinal microbial metabolite 220 (unbound to a protein 222) to pass over the cucurbituril-containing dialysis membrane 204. Once the free intestinal microbial metabolite 220 crosses the dialysis membrane, it may pass from the dialysate compartment 208 through the dialysate outlet 216 and exit the dialyzer 200 for further processing and/or removing steps. The dialysate may be recycled and reintroduced, or removed and fresh dialysate may be introduced into the dialysate inlet 214.

[00101] However, as shown in FIG. 2 (and FIG. 3) a protein-bound intestinal microbial metabolite 224 may not pass through a dialysis membrane because the holes in the membrane are too small for the protein-bound intestinal microbial metabolite to pass through.

[00102] In some instances, the cucurbituril-containing dialysis membrane 204 may also trap an intestinal microbial metabolite that is protein-bound. In other instances, the cucurbituril-containing dialysis membrane 204 may trap a free intestinal microbial metabolite. When the cucurbituril in the cucurbituril-containing dialysis membrane 204 associates with a protein-bound intestinal microbial metabolite 224, the binding affinity of the metabolite for the protein decreases from its protein-bound state to an extent that the metabolite may separate from the protein. As the metabolite separates or frees from the protein, cucurbituril in the cucurbituril-containing dialysis membrane may bind with the free intestinal microbial metabolite to form an inclusion complex 207. In one or more embodiments, the cucurbituril in the cucurbituril-containing dialysis membrane may retain a protein-bound intestinal microbial metabolite without separation of the metabolite from the protein. Meaning, an inclusion complex may be formed between the cucurbituril in the membrane and the protein-bound metabolite. Nonetheless, even in this case the intestinal microbial metabolite may be efficiently captured for later removal in the blood compartment of a dialyzer according to one or more embodiments.

[00103] Removing the free metabolite may occur via the dialysate outlet during filtration.

Removing the inclusion complex of the intestinal microbial metabolite (protein-bound or free) and the cucurbituril may occur by removing the dialyzer from the apparatus and cither replacing with a new dialyzer or flushing the dialyzer with an appropriate fluid to remove the intestinal microbial metabolite that may be bound to the cucurbituril in an inclusion complex.

[00104] The cucurbituril-containing dialysis membrane may be integrated into any suitable portion of the dialysis apparatus that contacts blood or serum, including, but not limited to, a bag, a blood cap, a fiber membrane, and a combination thereof. As shown in FIG. 2, the cucurbituril-containing dialysis membrane may be included in a dialyzer. Alternatively, or in addition, the cucurbituril-containing dialysis membrane may be a separate bag or a cartridge that is upstream of a dialyzer.

[00105] A method of treating a patient having an elevated serum level of a microbial metabolite may include the following steps. First, the method may include identifying an elevated serum level of an intestinal microbial metabolite in a patient. Second, the method may include passing blood from the patient to a product containing an article. Third, the method may include allowing the intestinal microbial metabolite to contact the cucurbituril, thereby capturing the intestinal microbial metabolite with the cucurbituril in an inclusion complex. Fourth, the method may include removing the captured microbial metabolite, thereby forming an inclusion complex and an intestinal microbial metabolite- depleted blood. The method may include passing the metabolite-depleted blood back to the patient.

[00106] In one or more embodiments, the article is effective when the metabolite to be removed is bound to a protein as carrier protein. The protein may be a serum protein including, but not limited to albumin (such as human albumin), oci-acid glycoprotein, alpha 1-acid glycoprotein (AGP), a lipoprotein, an immunoglobulin, and mixtures thereof. In one or more embodiments, the article is effective when the metabolite to be removed is free, or is not protein bound.

[00107] An amount of intestinal microbial metabolite in serum that may be removed based on a safe dose (or effective amount of cucurbituril) may vary based on the individual’s health condition. For example, in the case of indoxyl sulfate, the average concentration in healthy subjects is less than 10 micromolar (pM), but in patients with end-stage chronic renal failure, the average concentration is about 250 pM and may reach up to about 550 pM (117.27 mg/L for a molecular weight of 213.21 g/mol). A 60 kilogram (kg) person has a blood volume of approximately 4.6 liters (L), which means that about 539 milligrams (mg) of cucurbituril may be present in the blood according to the aforementioned concentration(s). During removal of intestinal microbial metabolite, amino acids and vitamins may also be adsorbed. Such amino acids and vitamins may also be replenished in the patient.

[00108] In one or more embodiments, a composition called a “molecular composite” is provided that comprises cucurbituril and one or more macrocyclic compound in addition to the cucurbituril. The molecular composite may be biocompatible. The molecular composite is an adsorbent for the removal of a protein-bound intestinal microbial metabolite. Methods herein may be used to support an extracorporeal treatment including dialysis (or hemodialysis) with a dialyzer, filtration with a hemofiltration apparatus, and other techniques that are known to one of ordinary skill in the art.

[00109] The one or more macrocyclic compound in addition to cucurbituril may include a cyclic oligosaccharide such as a pillararene, a calixarene, a derivative thereof, and a combination thereof.

[00110] As previously mentioned, an intestinal microbial metabolite may bind to a protein in human blood and serum. The metabolite may also bind to a protein in other biological fluids such as interstitial fluid, peritoneal fluid, third space fluid, including cerebrospinal fluid, gastrointestinal tract fluid, urinary tract fluid, gland fluid, cavity fluid, and other biological liquids. When an intestinal microbial metabolite is present at an elevated level in a patient’s serum, this metabolite may be a toxic substance. One of ordinary skill in the art would appreciate other toxic substances that may be present in serum.

[001 1 1 ] A displacer is a substance that may bind to a protein, such as a protein in human blood or serum, and displace a toxic substance such as an intestinal microbial metabolite. A displacer may be natural, such as bilirubin, and/or albumin, or it may be synthetic such as acetaminophen. A displacer may competitively bind to a protein while displacing a metabolite that was previously bound to the protein. [00112] In one or more embodiments, the cucurbituril may be mixed in a molecular composite that is added to pre-dialysis blood. Macrocyclic components in the molecular composite may form an inclusion complex with the toxic substance such as an intestinal microbial metabolite. The inclusion complex may be removed by dialysis, filtration, or another suitable extracorporeal treatment of removal including, but not limited to, extracorporeal renal replacement therapy.

[00113] FIG. 3 shows a molecular composite dialyzer 300 with a molecular composite dialysis bag 302, according to one or more embodiments herein. The molecular composite dialyzer 300 includes a molecular composite distributor 303 that is coupled to the blood compartment 206.

[00114] In FIG. 3, the molecular composite distributor 303 is affixed to the blood compartment. However, a molecular composite distributor may be accessible to the blood compartment by a conduit such as a tube or a pipe. A molecular composite distributor may also be a means of introducing a molecular composite into the blood compartment such as an injection. The molecular composite may also be a combination of the above-mentioned molecular composites. In FIG. 3, the dialysis membrane 304 may be a conventional dialysis membrane or it may be a cucurbituril-containing dialysis membrane (as shown in FIG. 2).

[00115] As shown in FIG. 3, blood is introduced into a blood inlet 210 where it passes to the blood compartment 206. From the blood compartment, the blood passes to the blood outlet 212through which the blood exits the molecular composite dialyzer 300. Likewise, dialysate is introduced into a dialysate inlet 214 where it passes to the dialysate compartment 208. From the dialysate compartment, the dialysate passes to the dialysate outlet 216 through which the dialysate exits the molecular composite dialyzer 300.

[00116] As the molecular composite including cucurbituril passes from the molecular composite distributor 303 to the blood compartment 206, the cucurbituril 305 in the molecular composite may intermingle with a protein-bound intestinal microbial metabolite 224 or a free intestinal microbial metabolite (not protein-bound). As the molecular composite associates with the toxic substance or intestinal microbial metabolite, the protein may dissociate from the captured toxic substance upon binding and formation of an inclusion complex. As previously described, an inclusion complex 306 may be formed between the cucurbituril (and/or molecular composite) and the toxic substance or the intestinal microbial metabolite. In one or more embodiments, the inclusion complex 306 is much smaller than the protein-bound intestinal microbial metabolite 224 so that it can pass through the pore of the dialysis membrane 304. The inclusion complex formed of at least one of cucurbituril formed from 5 to 10 glycoluril monomers is especially preferable with its size. The inclusion complex 306 formed in the blood compailment 206 may pass through the dialysis membrane 304 to the dialysate compartment 208 following the concentration gradient.

[00117] In one or more embodiments, the method includes removing the captured toxic substances from the blood of a patient. A free intestinal microbial metabolite may pass through the dialysis membrane 304 to the dialysate compartment 208. Inclusion complexes including cucurbituril and a toxic substance such as an intestinal microbial metabolite may pass through the dialysis membrane 304 (in the case of, for example, hemodiafiltration where this process removes inclusion complexes with proteins such as albumin). Thus, the intestinal microbial metabolite may pass from the molecular composite dialyzer 300 via the dialysate outlet 216 and exit the system. The method may include flushing the dialysate compartment with further dialysate, thereby removing the toxic substances from the dialyzer.

[00118] Benefits of the method of introducing the molecular composite in pre-dialysis blood include an increased efficiency of protein-bound metabolite removal compared to without the molecular composite. Toxicity is reduced (and safety is improved) compared to when using bilirubin, cyclodextrin or other conventional macrocycle, or another compound that displaces intestinal microbial metabolites bound to albumin. Cost is also reduced; for example, conventional displacement methods such as administering albumin is expensive and impractical on a daily basis, whereas cucurbituril is lower cost. Cucurbituril is also more efficient in binding intestinal microbial metabolites compared to cyclodextrin (and other conventional macrocycles). [00119] Unless defined otherwise, all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the art to which these systems, apparatuses, methods, processes, and compositions belong.

[00120] The singular forms “a,” “an,” and “the” include plural referents, unless the context clearly dictates otherwise.

[00121] As used here and in the appended claims, the words “comprise,” “has,” and “include” and all grammatical variations thereof are each intended to have an open, nonlimiting meaning that does not exclude additional elements or steps.

[00122] “Optionally” means that the subsequently described event or circumstances may or may not occur. The description includes instances where the event or circumstance occurs and instances where it does not occur.

[00123] When the word “approximately” or “about” is used, this term may mean that there can be a variance in value of up to ±10%, of up to 5%, of up to 2%, of up to 1%, of up to 0.5%, of up to 0.1%, or up to 0.01%.

[00124] The term “substantially” as used refers to a majority of, or mostly, as in at least about 50%. 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

[00125] Ranges may be expressed as from about one particular value to about another particular value, inclusive. When such a range is expressed, it is to be understood that another embodiment is from the one particular value to the other particular value, along with all particular values and combinations thereof within the range.

[00126] Although only a few example embodiments have been described in detail above, those skilled in the ail will readily appreciate that many modifications are possible in the example embodiments without materially departing from this invention. Accordingly, all such modifications are intended to be included within the scope of this disclosure as defined in the following claims.