Controlled-release and stratified cyclodextrin inclusion complex vehicles

Abstract

To provide biochemical constructs for delivery of bioactive agents, including delivery vehicles comprising molecules carried as inclusions within cyclodextrins that are delivered together with selected enzymes having cyclodextrin-degrading activity.SOLUTION: The invention provides cyclodextrin inclusion complex delivery vehicles, in which the cyclodextrin inclusion complex is provided together with enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin, so that upon delivery of a delivery vehicle to a target the enzyme is activated and releases a guest molecule from the cyclodextrin cavity.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention is in the field of biochemical constructs for the delivery of bioactive agents, comprising a delivery vehicle consisting of a molecule that is delivered together with a selected enzyme having cyclodextrin-degrading activity and carried as an inclusion within cyclodextrin.

Background Art

[0002] Cyclodextrins are non-reducing cyclic glucooligosaccharides, often the products of the catalytic degradation of starch by cyclomaltodextrin glucanotransferase (E.C. 2.4.1.19; CGTase). Cyclodextrins can have various structures, including three common cyclodextrins (α-, β- and γ-cyclodextrin, respectively) having 6, 7 or 8 D-glucopyranosyl residues linked within the ring by 1,4-glucosidic bonds (see: Saenger et al., Chem. Rev. 98 (1998) 1787-1802). The frustum shape of cyclodextrin forms a cavity or lumen, and the cavity has different diameters depending on the number of glucose units. Table 1 shows the structural hierarchy of selected cyclodextrins (CD). Larger cyclodextrins such as cyclomaltnonaoose (δ-CD) and cyclomaltodecaose (ε-CD), as well as supramolecular structures based on various cyclodextrins, are also possible (see: Zhang and Ma, Adv Drug Deliv Rev. 2013 Aug; 65(9): 1215-33).

[0003]

Table 1

[0004] Cyclodextrins are generally amphiphilic, having a wide rim of the cavity presenting 2-OH and 3-OH, and a narrow rim presenting 6-OH. These hydrophilic hydroxyl groups are thus on the outside of the cavity, whereas the inner surface is generally hydrophobic, with anomeric oxygen atoms and hydrogen atoms of C3-H and C5-H arranged along the inner surface. In aqueous solution, this hydrophobic cavity holds only a few water molecules, e.g., about 3 (α-CD), 7 (β-CD), or 9 (γ-CD), but has low entropy and can contain relatively easily replaceable water molecules. In addition, hydrophilic cyclodextrins can bind to and hold one or more molecules of appropriate size inside or partially inside the cavity of the CD to form cyclodextrin inclusion or clathrate compounds. For example, they can bind non-polar aliphatic and aromatic compounds, including drugs such as lipophilic drugs, usually increasing the water solubility of hydrophobic compounds or minimizing undesirable properties such as odor or taste in certain food additives. For this reason, cyclodextrin inclusion is widely used in the fields of pharmaceuticals, foods, and cosmetics (see Hedges, Chem. Rev. 98 (1998) 2035-2044). Cyclodextrins are used, for example, in various sustained-release pharmaceutical formulations such as inclusion compounds of pharmaceutical compounds with hydrophobic cyclodextrin derivatives (US4869904).

[0005] For example, cyclodextrin can be chemically modified in various ways to modify its inclusion specificity, physical, and chemical properties. For example, the hydroxyl groups of CD can be derivatized. For example, two modified CDs, sulfobutyl ether derivative of β-CD, a polyanionic variably substituted form, SBE-β-CD, i.e., Captisol, and HP-β-CD, a modified CD commercially developed by Janssen, are used in a number of pharmaceuticals. Further CD derivatives include Sugammadex, i.e., Org-25969, in which the 6-hydroxyl group of γ-CD is substituted by a carboxythioacetate ether bond and hydroxybutenyl-β-CD. Other forms of cyclodextrin include 2,6-di-O-methyl-β-CD (DIMEB), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), randomly methylated β-cyclodextrin (RAMEB), sulfobutyl ether-β-cyclodextrin (SBE-β-CD), sulfobutyl ether-γ-cyclodextrin (SBE-γ-CD), sulfobutylated β-cyclodextrin sodium salt, sulfobutylated β-cyclodextrin sodium salt, (2-hydroxypropyl)-α-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, DIMEB-50, heptakis(2,6-di-O-methyl)-β-cyclodextrin, TRIMEB, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, methyl-β-cyclodextrin, octakis(6-deoxy-6-iodo)-γ-cyclodextrin, and octakis(6-deoxy-6-bromo)-γ-cyclodextrin. CDs with such good pharmacological properties and toxicological profiles have been developed, but after administration, residual CD may disrupt the pharmacokinetic properties of drugs, particularly those co-administered drugs, especially after parenteral administration (see: Stella and He, Toxicol Pathol, January 2008, vol.36 no.1, 30-42).

[0006] Cyclodextrins such as α-CD and β-CD are resistant to gastric acid, saliva, and pancreatic enzyme digestion, but γ-CD has been observed to be only partially digested by amylases in the GIT, raising concerns about the physiological effects of residual CDs derived from therapeutic CD inclusion complexes. It is generally accepted that only relatively small amounts of orally administered CDs are absorbed, and the absorbed CDs are excreted in the urine without significant metabolism. Unabsorbed CDs are understood to be fermented by the gut microbiota.

[0007] Cyclodextrins are variably sensitive to enzymatic digestion. For example, γ-CD is relatively easily hydrolyzed by α-amylase, while α-cyclodextrin is hydrolyzed only poorly. CD-based therapeutic agents generally rely on the activity of endogenous amylases that digest CDs. However, there are significant variations in amylase activity among patients. For example, patients with pancreatic insufficiency, cystic fibrosis, celiac disease, or Crohn's disease may lack normal amounts of amylase. Similarly, patients, particularly elderly patients, may have insufficient gastric acid production and thus be unable to create appropriate low pH conditions in the duodenum to properly trigger the release of pancreatic amylase. Similar effects can occur due to the increasing common use of antacids, histamine 2 blockers, proton pump inhibitors, or alternative acid blockers.

[0008] Various microbial cyclodextrin digestive enzymes have been identified. CD degrading enzymes include cyclomaltodextrinase (or cyclodextrinase, or CDase, EC 3.2.1.54), maltogenic amylase (EC 3.2.1.313), neopullulanase (EC 3.2.1.135), and it has been reported that they can hydrolyze additional substrates such as CD, and in some cases, pullulan, starch, etc. Cyclodextrinase (CDase) catalyzes the hydrolysis of CD to form linear oligosaccharides with α-1,4-linkages, thereby releasing substances from the CD inclusion complex. CDase derived from Bacillus macerans was reported in 1968. Since then, many CDases derived from bacteria such as those from Bacillus sp., Thermoanaerobacter ethanolicus strain 39E, Flavobacterium sp., and Klebsiella oxytoca strain M5a1 have been characterized. CDases from Archaea derived from Archaeoglobus fuigidus, Thermococcus sp. B1001, Thermococcus sp. CL1, Thermofilum pendens, and Pyrococcus furiosus have been characterized. The structure of the CDase derived from Fiavobacterium sp. has been characterized in detail (see: Sun et al., Archaea, Volume 2015 (2015), Article ID 397924, reporting the identification of the gene encoding cyclodextrinase from Thermococcus kodakarensis KOD1 (CDase-Tk)).

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Non-Patent Documents

[0010]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0011] A cyclodextrin inclusion complex delivery vehicle, wherein the cyclodextrin in the cyclodextrin inclusion complex delivery vehicle has a cavity and a biologically active molecule that is at least partially retained as a guest molecule in the cavity to form a cyclodextrin inclusion complex. A biologically acceptable carrier for the cyclodextrin inclusion complex is provided, wherein the guest molecule is stably retained by the cyclodextrin in a biologically acceptable carrier. An enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin that retains the guest molecule may be included in the delivery vehicle. The enzyme may be formulated such that the cyclodextrin-degrading activity is activated upon delivery of the delivery vehicle to a target to release the guest molecule from the cavity of the cyclodextrin.

[0012] In another aspect of the delivery vehicle, the enzyme may be formulated with the cyclodextrin inclusion complex or the enzyme may be packaged with the cyclodextrin inclusion complex in the delivery vehicle. When the enzyme is packaged together, the delivery vehicle may further comprise a biochemically acceptable carrier for the enzyme.

[0013] The target may be, for example, a host organism such as a human patient or the target may be an abiotic environment such as a fabric or packaging material.

[0014] The enzyme may be, for example, amylase, cyclodextrinase, maltogenic amylase or neopullulanase. Amylase may be, for example, mammalian salivary amylase, mammalian pancreatic amylase or microbial amylase. The cyclodextrinase may be, for example, microbial cyclodextrinase.

[0015] The cyclodextrin may be, for example, a CD derivative such as a hydrophobic alkylated cyclodextrin or a mixed methylated / ethylated cyclodextrin.

[0016] The ratio of the cyclodextrin to the guest molecule may be, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4 or 1:5 and alternative values including a wide range of non-integer ratios of this parameter are also possible.

[0017] Cyclodextrin may be, for example, α-, β- or γ-cyclodextrin and a very wide range of alternative CD structures can also be used.

[0018] In the selected embodiment, the guest molecule may be a drug or a prodrug such as, for example, a flavonoid (quercetin), a cannabinoid or an anti-inflammatory drug (including acetaminophen). In this case, the biologically acceptable carrier may advantageously be a pharmaceutically acceptable carrier. This type of delivery vehicle may be formulated, for example, for delivery by parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, intraocular, intraventricular, intra-articular, intrathecal, subarachnoid, intracapsular, intraperitoneal, intranasal, inhalation, aerosol, topical, intratumoral, sublingual or oral routes. Similarly, the delivery vehicle may be formulated for sustained release of the drug or the prodrug.

[0019] In another aspect, the delivery vehicle may contain a guest molecule that is a herbicide, an insecticide, a fungicide, an animal repellent, a pheromone, or a plant growth regulator. In yet another aspect, the guest molecule may be, for example, a fragrance molecule.

[0020] In this way, the present invention provides another embodiment in which the delivery vehicle may be used as a pharmaceutical, a food ingredient, a medical food ingredient, a dietary supplement ingredient, a fragrance, a fabric or packaging, or in an agricultural environment as a herbicide, an insecticide, a fungicide, an animal repellent, a pheromone or a plant growth regulator.

[0021] In various aspects, the delivery vehicle accordingly provides a CD inclusion complex with an effective amount of an enzyme having CD-degrading activity, thereby facilitating the release of the guest molecule from the CD in a predictable manner.

[0022] In the selected embodiment, the drug or prodrug in the delivery vehicle may be a short-chain fatty acid or its ester derivative, such as butyric acid (butanoic acid), propionic acid, acetic acid, or their ester derivatives, such as glycerides. If a glyceride form is provided, lipase may be included in the delivery vehicle, for example. This type of formulation can be used for the treatment of gastrointestinal disorders such as colitis, diverticulitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, inflammation associated with an ostomy stoma, or granulation associated with an ostomy stoma.

[0023] Guest molecules can include various amino acids such as L-phenylalanine, N-acetylcysteine (and L-cysteine), L-methionine, L-isoleucine, and L-tryptophan. In the selected embodiment, N-acetylcysteine can be combined with acetaminophen in a hepatoprotective formulation, for example. Another hepatoprotective guest molecule may be derived from extracts of silymarin, curcumin, or tetrahydrocurcumin, for example.

[0024] A method of formulating a cyclodextrin inclusion complex delivery vehicle, comprising providing a cyclodextrin having a cavity; providing a biologically active molecule, wherein the biologically active molecule is at least partially retained within the cavity of the cyclodextrin as a guest molecule to form a cyclodextrin inclusion complex; providing a biologically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained by the cyclodextrin within the biologically acceptable carrier; and optionally providing an enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin that retains the guest molecule, wherein the enzyme is formulated with the cyclodextrin inclusion complex such that the cyclodextrin-degrading activity is activated upon delivery of the delivery vehicle to a target to release the guest molecule from the cavity of the cyclodextrin.

[0025] Also provided is a multi-component stacked cyclodextrin inclusion complex comprising, for example, a cyclodextrin having a cavity, an amino acid retained as a first guest molecule within the cavity of the cyclodextrin, and a biologically acceptable lipid at least partially retained as a second guest molecule within the cavity of the cyclodextrin. In selected embodiments, the multi-component stacked cyclodextrin inclusion complex may comprise, for example, N-acylcysteine (at least partially retained as a first guest molecule within the cavity of the cyclodextrin) and acetaminophen (at least partially retained as a second guest molecule within the cavity of the cyclodextrin). In these stacked inclusion complexes, the guest molecules may be present in any order, such that when the CD cavity is frustoconical, i.e., has a larger diameter opening and a smaller diameter opening disposed at an opposite end of the cavity, the first guest molecule may be closer to the smaller opening and the second guest molecule may be closer to the larger opening (or vice versa).

[0026] Provided is a method of treating a patient having an autism spectrum disorder, comprising administering to the patient an effective amount of a short-chain fatty acid cyclodextrin inclusion complex. Similarly, this type of method can be used to modulate the microbiome of a patient having a neurological disorder. The short-chain fatty acid may be, for example, butyric acid, and in some embodiments, the treatment method may comprise administering an effective amount of acetic acid (optionally as an inclusion complex). BRIEF DESCRIPTION OF THE DRAWINGS

[0027]

Figure 1

Figure 2

Figure 3

Mode for Carrying Out the Invention

[0028] A wide variety of biologically active compounds can be included in the form of pharmaceutical compositions in the delivery vehicle of the present invention, for example, docetaxel (US2014-0336149, US2013-0296268), carbamazepine (US2014-0080812), rifampicin (US7001893), cardiac glycosides, especially digoxin (US4555504), progesterone (see, Zoppetti et al., Journal of Inclusion Phenomena and Macrocyclic Chemistry, April 2007, Volume 57, Issue 1, pp 283-288), albendazole, mebendazole, ricobendazole, fenoprofen, ketoprofen, cocaine, glyclazide, digitoxin, macrocycle compounds (MCC), ibuprofen, procrolo-methazine, DY-9760e, NSC-639829, ETH-615, piroxicam, levomethadyl acetate hydrochloride, diprasidone mesylate, sulindac, mebendazole, sulindac, phenolphthalein, danazol (see, Challa et al., 2005, AAPS PharmSciTech 2005; 6(2) Article 43), itraconazole, nelfinavir mesylate, telmisartan, 5-fluorouracil and other nucleoside analogs, camptothecin, or flavonoids.

[0029] Similarly, in the field of pesticides, delivery vehicles can be provided that contain guest molecules with a variety of activities such as herbicides, insecticides, fungicides, repellents, pheromones, and growth regulators.

[0030] The cyclodextrin delivery vehicles of the present invention can also contain cyclodextrin inclusion complexes with fragrances or other bioactive molecules in fabrics, fabrics or packaging materials (see, Wang and Chen, 2005, Journal of Industrial Textiles, Vol 34, No.3, 157-166; US2015-0375521, US2015-0217896, US2015-0150256, US2014-0315780, US2013-0251926). For example, a cyclodextrin digestive enzyme can be incorporated into a fabric, and subsequently a cyclodextrin inclusion complex can be applied to the enzyme-containing fabric to form a delivery vehicle. Conversely, a CD inclusion complex can be incorporated into a fabric, and subsequently an enzyme can be applied to the fabric to form a delivery vehicle. Similarly, both the CD inclusion complex and the enzyme can be incorporated into the fabric during manufacture. The enzyme can be incorporated into the fabric by immobilization including layer-by-layer assembly and / or nanocoating while attached to the fabric substrate so as to retain catalytic activity (for example, as described in Wang et al, 2009, Bioprocess Biosyst Eng 32: 633-839, and overviewed in Advances in Textile Biotechnology, Nierstrasz and Cavaco-Paulo eds., Elsevier, 2010, a method similar to the process of antibacterial functionalization of wool by immobilization of lysozyme).

[0031] In addition to CDs and CD derivatives, supramolecular systems based on various cyclodextrins are available for the delivery of biologically active molecules in the above ranges (reviewed in Zhang and Ma, Adv Drug Deliv Rev. 2013 Aug; 65(9): 1215-33). Accordingly, aspects of cyclodextrin-based delivery vehicles include embodiments characterized as cyclodextrin-based nanosponges. These systems can be adapted, for example, to the context of the present invention for the controlled delivery of biologically active molecules such as drugs.

[0032] In selected embodiments, an enzyme contained in the vehicle may be formulated such that cyclodextrin-degrading activity is activated upon delivery of the vehicle to a target to release guest molecules from the cavity of the cyclodextrin. Activation of the enzyme can be achieved, for example, in a dry dosage form such as a capsule or tablet in which the enzyme is incorporated, in the case of a pharmaceutical for oral delivery, such that the enzyme is not active until it is activated by moisture in the gastrointestinal tract of the host. Similarly, a wide variety of time-release matrices and formulations are known, which can be adapted for use with CD delivery vehicles to orchestrate appropriate activation of the CD-degrading enzyme upon delivery to the target.

[0033] In various situations, the CD delivery vehicle may, for example, have an enzyme formulated with a cyclodextrin inclusion complex as described above, or the enzyme may be packaged with the cyclodextrin inclusion complex in the delivery vehicle. When packaged together, the delivery vehicle can include, for example, a biochemically acceptable carrier for the enzyme that is different from the carrier for the CD inclusion complex. For example, the delivery vehicle may be provided in separate compartments containing the CD inclusion complex and the CD-degrading enzyme, whereby the delivery vehicle is composed of a CD inclusion complex compartment linked to a CD-degrading enzyme compartment. A mechanism can be provided for the combined release of the CD inclusion complex and the CD-degrading enzyme from each compartment in the delivery vehicle. For example, a syringe having such separate compartments may be provided, which is discharged by a normal discharge mechanism, such as a mechanism that cooperatively moves pistons in each compartment, and a fixed amount of the CD inclusion complex and the CD-degrading enzyme is discharged, thereby mixing the enzyme and the CD inclusion complex to activate the enzymatic release of guest molecules from the CD. This type of vehicle may be used, for example, to disperse a topical cream or other surface-active formulation. This variety of delivery vehicles may be adapted, for example, from devices known as dispersible two-part compositions, such as epoxy resins, two-part pharmaceuticals or dental formulations, described in US4538920, US8100295, US8308340, US8875947, US8499976, WO2007 / 041266 and WO2000 / 021842.

[0034] For example, there are various techniques available for preparing CD inclusion complexes, such as those described in Chaudhary & Patel, IJPSR, 2013; Vol. 4(1): 68 - 78, US2009 - 0029020, US5070081, US5552378, and US8658692. As a kneading method that includes mixing CD with water or aqueous alcohol to obtain a paste, general methods are known. Then, a bioactive molecule can be added to the paste and kneaded for a specific time. Next, the kneaded mixture can be dried and, if necessary, passed through a sieve. Other known approaches for preparing CD inclusion complexes include freeze - drying, microwave irradiation, and supercritical fluid antisolvent technique.

[0035] The CD delivery vehicle of the present invention can be provided alone or in combination with other compounds (e.g., nucleic acid molecules, small molecules, peptides or peptide analogs) in the presence of carriers such as liposomes, adjuvants, or any pharmaceutically or biologically acceptable carrier. Selected embodiments include drugs in a form suitable for administration to a mammalian, e.g., human, animal host. As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The carrier can be suitable for any appropriate administration form, including topical, subcutaneous, intradermal, intravenous, parenteral, intraperitoneal, intramuscular, sublingual, inhalation, intratumoral, or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. The use of such media and drugs for pharmaceutically active substances is well - known in the art. The use thereof in the pharmaceutical compositions of the present invention is intended, except in cases where any conventional media or drugs are incompatible with the biologically active compound. Supplementary active compounds can also be incorporated into the composition.

[0036] Using conventional pharmaceutical practice, an appropriate formulation or composition for administration to a delivery vehicle can be provided. For example, any suitable route of administration such as parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intraarticular, intrathecal, subarachnoid, intracapsular, intraperitoneal, intranasal, inhalation, aerosol, topical, intratumoral, sublingual or oral can be used. The therapeutic formulation can be in the form of a liquid solution or suspension. In the case of oral administration, the formulation can be in the form of tablets or capsules. In the case of nasal drops, the formulation can be in the form of powders, intranasal drops or aerosols. In the case of sublingual formulations, the formulation can be in the form of drops, aerosols or tablets.

[0037] Cyclodextrin-degrading enzymes or digestive enzymes can be formulated, for example, for oral delivery. For example, enteric enzyme formulations such as submicron particle formulations prepared by the emulsification solvent evaporation method (Sharma et al., Pharm Dev Technol. 2013 May-Jun: 18(3): 560-9) can be provided. Similarly, the delivery vehicle may be formulated as a hydrogel (see US2014-0094433) or a medicinal gum (see US2013-0022652).

[0038] Methods well known in the art for manufacturing formulations can be found, for example, in “Remington's Pharmaceutical Sciences” (20th edition), ed. A. Gennaro, 2000, Mack Publishing Company, Easton, PA. Formulations for parenteral administration can include, for example, excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalene. The release of the compound can be controlled by using biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycolates, and deoxycholates, or may be in the form of nasal drops, or an oily solution for administration as a gel.

[0039] The pharmaceutical composition of the present invention can be in any form that enables the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid, or gas (aerosol). Typical routes of administration include, but are not limited to, oral, topical, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, epidural, intracardiac injection, or infusion techniques. The pharmaceutical composition of the present invention is formulated such that the active ingredient contained in the composition is biologically available when the composition is administered to a patient. The composition administered to the patient takes the form of one or more dosage units. For example, tablets, capsules, or cachets may be single dosage units, and a container of a compound in aerosol form may contain multiple dosage units.

[0040] The materials used to prepare the pharmaceutical composition must be pharmaceutically pure and non-toxic in the amounts used. The compositions of the present invention can include one or more compounds (active ingredients) known for particular desirable effects. It will be apparent to those skilled in the art that the optimal dosage of the active ingredient in the pharmaceutical composition depends on various factors. Relevant factors include, but are not limited to, the type of subject (e.g., human), the specific form of the active ingredient, the method of administration, and the composition used.

[0041] Generally, the pharmaceutical composition comprises the delivery vehicle of the present invention described herein, mixed with one or more carriers. The carrier may be particulate, for example, such that the composition is in the form of a tablet or powder. For example, in the case of a composition that is an oral syrup or an injection solution, the carrier may be liquid. Further, for example, to provide an aerosol composition useful for inhalation administration, the carrier may be gaseous.

[0042] When oral administration is intended, the composition is preferably either solid or liquid, and forms such as semi-solid, semi-liquid, suspension and gel are included within the forms contemplated herein as either solid or liquid.

[0043] As a solid composition for oral administration, the composition can be formulated in the form of powders, granules, compressed tablets, pills, capsules, cachets, chewing gums, wafers, lozenges, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. Further, one or more of the following adjuvants may be present: binders such as syrup, acacia, sorbitol, polyvinylpyrrolidone, carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacanth gum or gelatin, and mixtures thereof; excipients such as starch, lactose or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants such as magnesium stearate or Sterotex; fillers such as lactose, mannitol, starch, calcium phosphate, sorbitol, methyl cellulose, and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, etc.; wetting agents such as sodium lauryl sulfate; flow promoters such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate or orange flavor; and coloring agents.

[0044] When the composition is in the form of a capsule, for example, a gelatin capsule, the composition may contain a liquid carrier such as polyethylene glycol or fatty oil in addition to the materials of the above types.

[0045] The composition may be in the form of a liquid, such as an elixir, syrup, solution, aqueous or oily emulsion or suspension, or a dry powder that can be reconstituted with water and / or another liquid medium before use. The liquid may be, by way of two examples, for oral administration or for delivery by injection. When intended for oral administration, the preferred composition contains, in addition to the present compound, one or more of a sweetening agent, a thickening agent, a preservative (e.g., alkyl p-hydroxybenzoate), a coloring agent / colorant and a flavor enhancer (flavoring). In the composition administered by injection, it may contain one or more of a surfactant, a preservative (e.g., alkyl p-hydroxybenzoate), a wetting agent, a dispersing agent, a suspending agent (e.g., sorbitol, glucose or other sugar syrup), a buffering agent, a stabilizing agent and an isotonic agent. The emulsifier can be selected from lecithin and sorbitol monooleate.

[0046] The liquid pharmaceutical composition of the present invention, even in the form of a solution, suspension or other similar form, may contain one or more of the following adjuvants: water for injection, saline, preferably physiological saline, Ringer's solution, a sterile diluent such as isotonic sodium chloride; a synthetic mono- or diglyceride, polyethylene glycol, glycerin, propylene glycol or other solvent such as a non-volatile oil serving as a solvent or suspending medium; an antibacterial agent such as benzyl alcohol or methyl paraben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffering agent such as acetate, citrate or phosphate; and a tonicity adjusting agent such as sodium chloride or dextrose. The parenteral preparation can be enclosed in a glass or plastic ampoule, a disposable syringe or a multi-dose vial. Physiological saline is the preferred adjuvant. The pharmaceutical composition for injection is preferably sterile.

[0047] The pharmaceutical composition can be intended for topical administration, in which case the carrier can suitably include a base of solution, emulsion, ointment, cream or gel. The base can include, for example, diluents such as petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, water and alcohol, and one or more emulsifiers and stabilizers. A thickening agent may be present in the pharmaceutical composition for topical administration. If transdermal administration is intended, the composition can include a transdermal patch or an iontophoresis device. The topical formulation may contain the bioactive compound at a concentration of about 0.1 to about 25% w / v (weight per unit volume).

[0048] The composition can be intended for rectal administration, for example, in the form of a suppository that melts in the rectum to release the drug. The composition for rectal administration may contain an oily base as a suitable non-irritating excipient. Such bases include, but are not limited to, lanolin, cocoa butter and polyethylene glycol. Low melting point waxes are preferred for the preparation of suppositories, and a mixture of fatty acid glycerides and / or cocoa butter is a suitable wax. The wax is melted and stirred to uniformly disperse the aminocyclohexyl ether compound. Then, the melted uniform mixture is poured into a mold of a convenient size and cooled to solidify.

[0049] The composition can include various substances that change the physical form of the solid or liquid dosage unit. For example, the composition can include a material that forms a coating shell around the active ingredient. The material forming the coating shell is typically inert and can be selected from, for example, sugars, shellac, and other enteric coating agents. Alternatively, the active ingredient may be placed in a gelatin capsule or cachet.

[0050] The pharmaceutical composition of the present invention may be composed of gaseous dosage units and may be in the form of, for example, an aerosol. The term aerosol is used to denote various systems ranging from colloidal to pressurized packaging systems. Delivery can be effected by liquefied or compressed gas or by a suitable pump system for dispensing the active ingredient. The aerosol of the compound of the present invention can be delivered in a single-phase, two-phase or three-phase system for delivering the active ingredient. Delivery of the aerosol includes the necessary containers, activators, valves, sub-containers, etc. that can be formed into a kit together.

[0051] The biologically active compound may be in the form of the free base or in the form of a pharmaceutically acceptable salt such as hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate, or other salts known in the art. For appropriate embodiments (e.g., oral or parenteral administration routes), an appropriate salt is selected to enhance the bioavailability or stability of the compound.

[0052] The composition intended to be administered by injection can be prepared by combining the delivery vehicle of the present invention with water and preferably a buffer to form a solution. The water is preferably sterile pyrogen-free water. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension. The surfactant is a compound that non-covalently interacts with the aminohexyl ether compound to promote the dissolution or uniform suspension of the aminohexyl ether compound in the aqueous delivery system. Since the amino cyclohexyl ether compound according to the present invention can be hydrophobic, it is desirable for the surfactant to be present in the aqueous composition of the present invention. Other carriers for injection include, but are not limited to, ethyl oleate free of sterile peroxide, dehydrated alcohol, propylene glycol, and mixtures thereof.

[0053] Suitable pharmaceutical adjuvants for injection solutions include stabilizers, solubilizers, buffers, and viscosity modifiers. Examples of these adjuvants include ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity modifiers. These pharmaceutical formulations can be injected intramuscularly, epidurally, intraperitoneally, or intravenously.

[0054] The present invention also provides a kit comprising a pharmaceutical composition comprising one or more delivery vehicles. The kit also includes instructions for use of the pharmaceutical. Preferably, a commercially available package contains one or more unit doses of the pharmaceutical composition. For example, such unit doses may be an amount sufficient for the preparation of an intravenous injection. It will be apparent to those skilled in the art that photosensitive and / or air-sensitive compounds require special packaging and / or formulation. For example, packages that are opaque to light and / or sealed from contact with ambient air and / or formulated with a suitable coating agent or excipient can be used.

[0055] The "effective amount" of the CD inclusion complex delivery vehicle according to the present invention includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" represents an amount effective at the dosage and for the period required to achieve the desired therapeutic result. The therapeutically effective amount of the delivery vehicle can vary depending on factors such as the disease state, age, gender, and weight of the individual, and the ability of the compound to elicit the desired response in the individual. The dosing regimen can be adjusted to provide an optimal therapeutic response. The therapeutically effective amount may also be one in which the toxicity or adverse effects of the delivery vehicle or active compound do not exceed the therapeutically beneficial effects. A "prophylactically effective amount" represents an amount effective at the dosage and for the period required to achieve the desired prophylactic result. Typically, prophylactic doses are used in subjects prior to or at the early stages of the disease, whereby the prophylactically effective amount may be less than the therapeutically effective amount. For any particular subject, the timing and dosage of treatment can be adjusted over time (e.g., the timing can be daily, every other day, weekly, monthly) according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0056] In certain embodiments, the present invention provides a composition or pharmaceutical product comprising one or more biologically active compounds selected from biologically active compounds, solvates thereof, pharmaceutically acceptable salts, esters, amides, complexes, chelates, stereoisomers, mixtures of stereoisomers, geometric isomers, crystalline forms, amorphous forms, metabolites, metabolic precursors or prodrugs, isolated enantiomers, diastereomers and geometric isomers thereof, and mixtures thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient. Further provided is a method for producing such a composition or pharmaceutical product.

[0057] While various embodiments of the invention are disclosed herein, many adaptations and modifications can be made within the scope of the invention in accordance with the common general knowledge of those skilled in the art. Such modifications include substitutions of known equivalents for any aspect of the invention in order to achieve substantially the same result in substantially the same way. Numerical ranges include the numbers defining the range. The term "comprising" is used herein as an open-ended term substantially equivalent to the phrase "including but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes a plurality of such things.

[0058] The citation of references in this specification does not admit that such references are prior art to the present invention. Any priority documents and all publications, including but not limited to the patents and patent applications cited in this specification, are hereby incorporated by reference into this specification. All documents cited or referenced in the documents cited herein are hereby incorporated by reference into this specification, together with the manufacturer's instructions, descriptions, product specifications, and product sheets of any product described in any of the documents described herein or incorporated by reference into this specification, and may also be used in the practice of the present invention. More specifically, all referenced publications are hereby incorporated by reference into this specification to the same extent that each individual publication is specifically and individually incorporated by reference into this specification or is fully described herein. The present invention includes all embodiments and substantially the foregoing modifications, with reference to the examples and drawings.

[0059] In some embodiments, the present invention excludes steps including medical or surgical procedures.

Examples

[0060] Example 1: Extracts of Serenoa and Prunus γ-Cyclodextrin (GCD, Wacker Chemi, Germany) and inclusion complexes were prepared by a kneading method from the Serenoa repens purified seed extract (Indena, Italy) and the Prunus africana bark extract (Indena, France) at a ratio of 2:1, respectively. The Serenoa extract is rich in fatty acids and plant sterols. The Serenoa extract may contain, for example, oleic acid, lauric acid, caprylic acid, capric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, heptadecanoic acid, stearic acid, vaccenic acid, linoleic acid, linolenic acid, arachidic acid, gondoic acid, behenic acid, lignoceric acid, etc., triglycerides and / or free fatty acids. The plant sterols in the Serenoa extract may contain, for example, campesterol, β-sitosterol and stigmasterol. Similarly, the plant sterols of Prunus may contain, for example, a wide variety of such compounds. These may include, for example, N-butylbenzenesulfonamide, atraric acid, β-sitosterol, β-sitostenone, and fatty acids such as linoleic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, lauric acid, myristic acid, etc., and docosanol, behenic acid, ursolic acid, lignoceric acid, ferulic acid and friedelin.

[0061] The Serenoa extract oil is amber-colored. The Prunus extract resembles a "waste oil ball" containing an extract that is almost black and hardened and can be kneaded by hand. Both extracts have an almost pleasant deep fruity odor, which almost completely disappears when contained in the cyclodextrin inclusion complex.

[0062] After drying and pulverization, samples of the inclusion complex were assayed for their sensitivity to the enzyme release of the herbal extract. In this assay, 1 g of the inclusion complex was mixed with 20 ml of distilled water in container 1, and in container 2, the same amount of 1 g of the inclusion complex and 20 ml of distilled water were mixed with 20 mg of undiluted amylase powder (Enzyme Development Corporation, New York). Both containers were heated to 37 °C with stirring every 5 minutes.

[0063] At the 20-minute mark of the assay, the color change began to become apparent in container 2 and became quite pronounced at the 30-minute mark. In contrast, in container 1 where no enzyme was added, the off-white color was maintained (consistently for over 5 hours). The contents of container 2 became significantly darker as the amylase digested the GCD inclusion complex. After 30 minutes, the protective envelope of the GCD was decomposed by the enzyme, and the raw materials became visible again, so container 2 was showing some of the color of the main body of the extract. Furthermore, after 30 minutes, in container 2 rather than container 1, the odor of the two components became apparent again. At the 30-minute mark, no lipids were present, and the components in container 1 were not separated, as evidenced by the contents of the container remaining as small pieces of the inclusion complex. However, at the 30-minute mark in container 2, the decomposition of the inclusion complex was evident not only in the main body of the solution but also by a ring of serein extract and prunus extract that produced an oil film around the container as a lipid substance and oil droplets visible on the white ceramic surface of container 2.

[0064] This example illustrates the effective release of fatty acids and plant sterols from a plant extract formulated as a CD inclusion complex. Thus, this embodiment is representative of CD inclusion complexes containing one or more free fatty acids and / or plant sterols such as oleic acid, lauric acid, caprylic acid, capric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, heptadecanoic acid, stearic acid, vaccenic acid, linoleic acid, linolenic acid, arachidic acid, gondoic acid, behenic acid, lignoceric acid, campesterol, β-sitosterol, stigmasterol, N-butylbenzenesulfonamide, atraric acid, β-sitostenone, docosanol, behenic acid, ursolic acid, lignoceric acid, ferulic acid, and friedelin.

[0065] Example 2: Butyric acid An inclusion complex was prepared from α-cyclodextrin (ACD, Wacker Chemi, Germany) and butyric acid (Vigon, USA) using a kneading method. Butyric acid is a fatty acid (also known as butanoic acid) that is a clear, light oil at room temperature and has an unpleasant, somewhat putrid odor. This odor almost completely disappears when contained in the cyclodextrin inclusion complex. The odor of butyric acid is detected by the human nose at concentrations above 10 ppm and can irritate the skin, eyes, and respiratory system.

[0066] After drying and pulverization, a sample of the inclusion complex was assayed for its sensitivity to enzymatic release of butyric acid. In this assay, 1 g of the inclusion complex was mixed with 20 ml of distilled water in container 1, and in container 2, the same amount of 1 g of the inclusion complex and 20 ml of distilled water were mixed with 20 mg of undiluted amylase powder (Enzyme Development Corporation, New York). Both containers were heated to 37 °C with stirring every 5 minutes.

[0067] At the 25-minute mark, the odor of butyric acid began to become apparent in container 2 and became more pronounced at the 35-minute mark. In contrast, in container 1 without added enzyme, the same faint odor was maintained without increasing for over 5 hours.

[0068] Example 3: Cannabis oil extract An inclusion complex was prepared from γ-cyclodextrin (GCD, Wacker Chemi, Germany) and a purified cannabis oil extract (CV Sciences, USA) using a kneading method. Cannabis oil typically contains various fatty acids, plant sterols, and physiologically active components such as linoleic acid, α-linolenic acid, oleic acid, β-sitosterol, campesterol, phytol, cycloartenol, γ-tocopherol, and cannabidiol, as well as a small proportion of terpene-like substances. As discussed below, it was named "cannabis essential oil" for reference in this specification.

[0069] After drying and grinding, samples of the inclusion complex were assayed for their sensitivity to in vivo enzyme release of cannabis oil extract. In this assay, 390 mg of the inclusion complex was encapsulated in size 0 capsules. A second set of capsules was prepared containing 390 mg of the inclusion complex and 10 mg of undiluted amylase powder (Enzyme Development Corporation, New York).

[0070] A healthy 43-year-old male subject with a record of 912 sleep cycles was given two capsules of each preparation on different days, just before 11:30 p.m., the standard bedtime, without giving foods that induce salivary amylase after a sufficient dinner.

[0071] Figure 1 shows a typical sleep pattern of a subject with a duration and level of deep sleep. Figure 2 shows the sleep pattern after taking the inclusion complex without added amylase, showing a sleep pattern with slightly deeper sleep than the typical baseline of subjects who record average sleep by self-assessment. Figure 3 dramatically shows what the subject described as "the most peaceful sleep in years for him." Except for getting up briefly to go to the toilet and immediately returning to sleep, the overall sleep pattern reaches a depth of sleep and a duration of deep sleep that had not been achieved before.

[0072] This example shows the in vivo release of physiologically active components from an inclusion complex that utilizes amylase added to the inclusion complex formulation. An aspect of this example is the independence of the formulation from dependence on salivary or digestive amylase to release the active ingredient.

[0073] In a typical embodiment, alternative formulations may include cyclodextrin inclusion complexes of various biologically active molecules derived from cannabis or the cannabis plant, such as cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), and other cannabinoids.

[0074] Example 4: Glaucoma The subject of this example is a California medical doctor who has had experience using medical marijuana since 1996. The subject self-administered capsules prepared containing 390 mg of the cannabinoid inclusion complex and 10 mg of amylase powder, as described in Example 3. After several days of continuous use, the subject showed a marked improvement in glaucoma. These results from the use of the inclusion complex were better than any combination of isolated cannabidiol or standardized products the subject had used in the past.

[0075] Example 5: Stratified inclusion complex This example relates to the production of CD inclusion complex mixtures in which multiple alternative guest molecules form inclusion complexes with multiple alternative cyclodextrins, and each guest molecule matches in size and / or affinity a corresponding cyclodextrin having a cavity of a size or fit to stably hold the guest molecule. In this way, a complex mixture of discrete, e.g., biologically active substances of different sizes, can be formulated as a hierarchical inclusion complex mixture.

[0076] In an exemplary embodiment, cannabis essential oil (reference, Table 2, percentage ratio) was continuously formulated with α- and β-cyclodextrins. A sample of cannabis essential oil was first added to a slurry of α-cyclodextrin and water and kneaded over time to form an inclusion complex of guest molecules sized to fit within the cavities of α-cyclodextrin. Next, β-cyclodextrin, a cyclodextrin with larger cavities, was added over time along with additional water and kneaded to complete a size-stratified inclusion complex mixture by forming inclusion complexes of guest molecules that were too large to fit within the cavities of α-cyclodextrin. By first forming an inclusion complex with the cyclodextrin having the smaller cavities and then forming an inclusion complex with the cyclodextrin having the larger cavities, this method provides an inclusion complex mixture in which guest molecules are accommodated in the cyclodextrin in which they form the most stable inclusion complex and smaller molecules are avoided from being trapped by the larger CD which is not optimal. This method may be iterative using a series of larger or differently modified CDs that are used to form complex, size-stratified inclusion complexes in which guest molecules are continuously retained in cyclodextrins that are chemically or sterically compatible.

[0077] [Table 2]

[0078] [Table 3]

[0079] The synthetic mixture of the hierarchical inclusion complex can be formulated such that the ratio of the biologically active molecules is changed compared to the first mixture in which the inclusion complex is formed. To carry out the above exemplary embodiments, α-cyclodextrin inclusion complexes derived from a series of cannabis essential oils are pooled, and then a certain amount of β-cyclodextrin inclusion complex is added to this pooled α-cyclodextrin formulation to provide a formulation in which smaller biologically active molecules are enriched in the form of inclusion complexes compared to the composition of the first cannabis essential oil. Alternatively, as described above, a synthetic mixture of the hierarchical inclusion complex may be produced to recapture a relatively large amount of biologically active molecules in the selected starting material. In the exemplified embodiment, this was achieved by using α-cyclodextrin and β-cyclodextrin in a ratio of 4:1. This reflects the fact that approximately 80% of the cannabis essential oil sample is composed of biologically active molecules of a size that fits α-cyclodextrin, and most of the remaining 20% is of a size that fits within the β-cyclodextrin inclusion complex.

[0080] In typical embodiments, a synthetic mixture of stratified inclusion complexes is provided that contains adjusted ratios of cannabinoids and terpenes, for example, derived from a sample or extract of hemp or cannabis. These mixtures may include inclusion complexes of various cannabinoids such as cannabigerol (CBG), cannabinchromene (CBC), tetrahydrocannabivarin (THCV), tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The terpenes (isoprenoids) in these mixtures can include, for example, α-pinene, ocimene, caryophyllene (β-caryophyllene), camphene, camphor, eucalyptol, humulene (α-humulene), myrcene, γ-terpinene, cis-nerylol, caryophyllene, terpinolene, terpinol, trans-nerylol, cymene (p-cymene), linalool, farnesene, guaiol, limonene, isopulegol, cary oxide, α-terpinene, geraniol, valencene, fenchol, borneol (isoborneol), phytol, sabinene, menthol, cedrene, nerylol, isopulegol, geranyl acetate, pregeone, and bisabolol.

[0081] The stratified inclusion complex can be formulated for delivery with one or more enzymes having cyclodextrin-degrading activity that can digest the cyclodextrin that retains the guest molecule. In selected embodiments, for example, an enzyme can be selected that has preferential or exclusive activity against a subset of the cyclodextrins found in the mixture. In this way, the stratified cyclodextrin inclusion complex delivery vehicle is adapted to have two or more distinct enzymes, and the distinct enzymes are formulated to have distinct cyclodextrin-degrading activities that are activated when delivered to two or more distinct targets of the delivery vehicle, for example, two distinct portions of the gastrointestinal tract.

[0082] Example 6: Short-chain fatty acid inclusion complex This example relates to a pharmaceutical, nutraceutical, food or functional food formulation comprising an inclusion complex of individual or combined short-chain fatty acids (SCFAs) with hydrophobic or hydrophilic cyclodextrins (including α-, β- or γ-CD and modified CDs such as ethylated CD). The SCFAs may be present in the form of esters, salts or other pharmaceutically acceptable derivatives such as glycerides (mono-, di- or triglycerides). The SCFA inclusion complex may be provided in a dosage form having an enzyme with cyclodextrin-degrading activity capable of digesting the CD that retains the SCFA guest molecule such as α-, β- or γ-amylase. Similarly, lipase may be added to the formulation to release SCFA from lipids, for example to act on esters of SCFAs such as glycerides. These formulations can be prepared as an immediate-release dosage form or food form, or a sustained-release dosage form or food form. In the sustained-release dosage form, the dissolution and release of one or more components including the SCFA pharmaceutical ingredient, CD and / or amylase may be sustained or delayed at a controlled rate. For example, regardless of the presence or absence of the CD inclusion compound, amylase can be formulated in the form of beads or granules coated with a wide range of sustained-release coatings or in the form of a resin. Similarly, especially when lipase is included in the formulation, glycerides such as triglycerides can be provided on a matrix, for example spray-dried on a cellulose matrix in admixture with lipase. These formulations may be adapted to control or maintain the blood concentration of a pharmaceutical compound such as SCFA or its metabolite at an effective level for a longer period than in the absence of a sustained-release carrier.

[0083] One aspect of these formulations is the use of an administration form that provides SCFAs to the small and large intestines of a subject such as a human or mammal. The formulations may be used for adjuvant or therapeutic purposes in the treatment of gastrointestinal disorders such as, for example, colitis, diverticulitis, Crohn's disease, inflammatory bowel disease or irritable bowel syndrome (IBS). In another aspect, these formulations can be used to provide prophylactic or therapeutic treatment of neoplastic diseases of the gastrointestinal tract such as colon cancer. In a further aspect, these formulations may be used to provide prophylactic or therapeutic treatment to improve insulin sensitivity in diabetic patients. In a further aspect, these formulations may be used to provide prophylactic or therapeutic treatment to improve thermogenic activity with subsequent weight loss.

[0084] In selected embodiments, these formulations provide a pharmaceutical preparation comprising an inclusion complex containing at least one SCFA as an active ingredient that can be complexed as an inclusion compound with at least one hydrophobic cyclodextrin. In certain embodiments, the SCFA may be, for example, one or more of butyric acid (butanoic acid), propionic acid, and acetic acid. A plurality of SCFAs may be provided to a selected diet, for example, in a ratio of 9:1 to 1:9. The selected SCFAs can be formulated into an optimized formulation, for example, containing 75-95% butyric acid, 1-20% propionic acid, and 1-10% acetic acid, for example, containing approximately 85% butyric acid, approximately 10% propionic acid and approximately 5% acetic acid.

[0085] Example 7: Gastrointestinal treatment with butyric acid preparation This example relates to the treatment of common gastrointestinal disorders. A 48-year-old woman presenting with active and long-term symptoms of a clinically diverse gastrointestinal disorder was given 4 capsules twice a day of a 30 mg capsule of the butyric acid inclusion complex prepared as described in Example 2. Three weeks after the start of treatment, the attending physician reported that clinically relevant evidence of therapeutic effect was shown, namely that for the first time in 4 years the patient was characterized by normal gastrointestinal function.

[0086] Example 8: Gastrointestinal treatment with SCFA preparation This example describes the treatment of certain gastrointestinal symptoms with a formulation containing a mixture of SCFAs. The subject was presented as a 65-year-old male with intermittent liquid diarrhea and predictable symptomatic erythema after morning coffee (especially with morning citrus) or after eating a rich dinner. Treatment was initiated with capsules of an SCFA inclusion complex drug containing butyric acid (27 mg), propionic acid (2.5 mg), and acetic acid (2.5 mg) in an inclusion complex with α-cyclodextrin. The initial treatment plan was 4 capsules three times a day. This was later reduced to twice a day. Within 24 hours of the first dose, the liquid diarrhea stopped and did not recur during the entire 5-week treatment period. During treatment, the patient reported that his stools were completely consistent and the fecal output decreased dramatically. The patient also reported that he was able to discontinue his normal antacid treatment after meals and before bedtime and that his tolerance to moderate alcohol intake had improved.

[0087] Example 9: Treatment of IBD with butyric acid preparation This example describes the alleviation of symptoms of chronic inflammatory bowel disease (IBD). The patient was presented as a 52-year-old female who had had chronic IBD for 30 years and received symptomatic treatment with loperamide 2 - 4 times a day. Treatment was initiated during an IBD recurrence, starting with the butyric acid formulation of Example 2, 3 capsules twice a day, and without concomitant treatment with loperamide during the 7-day treatment with the butyric acid inclusion complex formulation. All diarrhea stopped within 48 hours. This patient also reported a definite appetite suppression after 7 days of treatment. Thus, this example demonstrates the therapeutic efficacy in the treatment of IBD and the use of the SCFA inclusion complex formulation as an appetite suppressant.

[0088] Example 10: Ostomy inflammation This example describes the treatment of stoma-related symptoms, including inflammation and granulation. This is a case of a physician with a 3-year history of recurrent stoma inflammation and infection. Prior to treatment with the butyrate CD formulation, the patient's clinical history was as follows. · Colectomy for ulcerative colitis in 1971. · Continuous unknown exposure to Stachybotrys from November 2012 to January 2014. ·Secondary immunodeficiency due to exposure to Stachybotrys. ·Recurrence of ileitis and enterocutaneous fistula from 01 / 13 to 08 / 15. Neither responded to multiple administrations of ciprofloxacin and metronidazole. Five laparotomies were performed during that period to reduce the damage. Finally, removal of the colonic reservoir and replacement with a standard Brooke ileostomy. ·Two surgeries for wound debridement due to non-healing skin wounds and relocation of the final ileostomy. ·Persistent granulation tissue around the stoma did not respond to two steroid injections combined with tacrolimus cream.

[0089] Treatment was initiated with an oral butyrate preparation prepared according to Example 2, 8 capsules twice a day. The capsules contained 30 mg of net butyric acid in a sustained-release CD preparation with amylase enzyme. Healing of the inflammation progressed until just before the decision that treatment was completed. Within one week of interruption of butyrate CD treatment, the lesions disintegrated again and began to grow. The lesions deteriorated for a total of two weeks. When butyrate CD treatment was resumed, healing began again.

[0090] Example 11: Myelofibrosis This example describes the treatment of symptoms associated with myelofibrosis. A patient suffering from myelofibrosis was treated with a quercetin CD preparation. The preparation was prepared from quercetin (Glanbia Nutritionais) powder as an inclusion complex with γ-cyclodextrin, dried, and mixed with amylase powder. At the start of quercetin CD treatment, the patient required transfusions approximately every 10 days. After the start of quercetin CD treatment, the patient was able to go 20 days between transfusions. The supervising physician, who had been practicing quercetin use since 1984, stated that this patient had not obtained this result after a standard quercetin supplementation dosing schedule.

[0091] This example demonstrates that the delivery vehicle of the present invention can be used to provide advantageous delivery of flavonoids, including bioflavonoids such as quercetin.

[0092] Example 12: Autism This example includes three cases of the treatment of autism spectrum disorder (ASD) in children using an α-cyclodextrin butyrate inclusion complex mixed with amylase.

[0093] A 5-year-old male O, who had received a confirmed diagnosis of ASD, was treated with an oral α-cyclodextrin butyrate inclusion complex combined with amylase, prepared using a kneading method. The dosage was 30 mg of net butyric acid administered twice a day. In a psychiatric evaluation, a dramatic improvement in ASD symptoms was observed within 10 days. This was consistent with the caregivers' assessment of a considerable improvement in the quality of life.

[0094] A 6-year-old male M, who had received a confirmed diagnosis on the autism spectrum, was treated daily with 1 / 4 teaspoon (tsp) of an α-cyclodextrin butyrate inclusion complex combined with amylase enzyme, prepared using a kneading method. M had previously generally been unable to make eye contact when speaking to anyone, even his mother, and had been unable to tie his shoelaces. Twenty-two hours after the start of butyrate-CD treatment, after two administrations, M tied his shoelaces and made direct eye contact with his mother when showing pride in his achievement.

[0095] A 17-year-old female, who had received a confirmed diagnosis on the non-verbal spectrum of autism, was treated with 3 capsules twice a day of an α-cyclodextrin butyrate inclusion complex combined with amylase enzyme and 180 mg of net butyrate, prepared using a kneading method. Within 3 days, the patient made better eye contact and became calmer. Now, even without being asked, she can point to animals and pictures in a picture book and even say the names of specific people in words.

[0096] Autism is associated with various gastrointestinal symptoms, and studies have found evidence of distinct characteristics of the gut microbiota in autistic patients, along with evidence of the beneficial effects of butyrate. Thus, in one aspect, the present invention provides an α-cyclodextrin butyrate inclusion complex preparation for use in modulating the gut microbiota of patients with neurological diseases.

[0097] Example 13: Low-allergy meal replacement formulation and elemental diet formulation This example relates to the production of a CD inclusion complex mixture in which individual amino acids or groups of amino acids form an inclusion complex with cyclodextrin, for example, to mask the taste of poorly soluble amino acids and improve their solubility.

[0098] In an exemplary embodiment, the CD inclusion complex may be formed from individual amino acids known to be bitter or sulfur dominant in taste, such as L-phenylalanine, N-acetylcysteine (and L-cysteine), L-methionine, L-isoleucine, and L-tryptophan. In one example, these amino acids were each individually included in β-cyclodextrin in an equimolar ratio using a kneading method. A second group was included in γ-cyclodextrin in an equimolar ratio using a kneading method. The material was then dried and pulverized. When added to tap water, these inclusion complexes were found to be completely soluble and to very well mask the unpleasant taste compared to the original materials.

[0099] In other embodiments, the same amino acids (L-phenylalanine, N-acetylcysteine (and L-cysteine), L-methionine, L-isoleucine, and L-tryptophan) were pre-mixed as one group and then included in β-cyclodextrin in an equimolar ratio using a kneading method. A second group was included in γ-cyclodextrin in an equimolar ratio using a kneading method. The material was then dried and pulverized. When added to tap water, these inclusion complexes as a combination were found to be completely soluble and also to very well mask the unpleasant taste.

[0100] Therefore, these methods can be used individually or in combination with naturally occurring or synthetic amino acids. β-Cyclodextrin inclusion complexes may be appropriate in some situations where the dosing requirements are restricted, for example, when the daily dose by oral administration is limited to a relatively small amount. Thus, in formulations intended for the administration of a small amount of a particular amino acid, β-cyclodextrin can be a suitable option for inclusion. β-Cyclodextrin may be advantageous from a cost perspective compared to α- or γ-cyclodextrin. Alternatively, if size permits, the amino acid can be included in an α-cyclodextrin inclusion complex.

[0101] Commercially available meal replacements such as Vivonex® Plus, which are packaged products of amino acids, soybean oil (for essential fats), maltodextrin / corn starch (carbohydrate source), and basic vitamins and minerals and preservatives, are available for use in gastrointestinal training. Five amino acids (L-phenylalanine, N-acetylcysteine (and L-cysteine), L-methionine, L-isoleucine, and L-tryptophan) having a bitter or sulfur-dominant taste can be recognized as improving the taste of this type of product. The components of this type of product and the corresponding products of the present invention containing one or more amino acids in the form of a CD inclusion complex are, for example, maltodextrin (derived from corn), L-glutamine, processed corn starch, L-leucine, L-arginine acetate, soybean oil, and less than 2% magnesium gluconate, L-lysine acetate, calcium glycerophosphate, L-isoleucine, L-valine, L-phenylalanine, sodium citrate, L-threonine, potassium citrate, L-cysteine hydrochloride, citric acid, L-methionine, L-tyrosine, L-histidine hydrochloride, L-aspartic acid, L-proline, L-tryptophan, disodium phosphate, potassium chloride, choline bitartrate, L-serine, L-alanine, glycine, ascorbic acid, polyglycerol ester of fatty acids, taurine, L-carnitine, α-tocopherol acetate, zinc sulfate, potassium sorbate, and BHA and BHT and tocopherol (to maintain freshness), ferrous sulfate, niacinamide, vitamin A palmitate, calcium pantothenate, copper gluconate, vitamin D3, pyridoxine hydrochloride, manganese sulfate, riboflavin, thiamine hydrochloride, folic acid, chromium chloride, biotin, potassium iodide, sodium molybdate, sodium selenite, phylloquinone, vitamin B12 may be included.

[0102] These meal replacements and component nutrients may be formulated, for example, to provide a single serving size of about 79.4 g: 13.5 g of protein (as amino acids), 2 g of fat, 57 g of carbohydrates, 6.9 g of vitamins, minerals, and other components.

[0103] The meal replacement may alternatively provide an amino acid ratio modeled on natural protein sources such as eggs.

[0104] In an exemplary embodiment, canola oil as a fatty acid source was included in a γ-cyclodextrin inclusion complex at an equimolar ratio using a kneading method. Subsequently, the material was dried and pulverized as a premix and added to the meal replacement. The amount of one portion of the premix contained was 2.0 of canola oil and 10.5 of carbohydrates derived from γ-cyclodextrin, expressed in g. In this embodiment, the amino acids: L-phenylalanine, N-acetylcysteine, L-methionine, L-isoleucine and L-tryptophan were pre-mixed as one group and then included in γ-cyclodextrin at an equimolar ratio using a kneading method. Subsequently, the material was dried and pulverized as a premix and added to the meal replacement. The ratio of one portion of the premix contained is as follows when expressed in g. <Amino acid> L-phenylalanine 0.85 N-acetylcysteine 0.5 L-methionine 0.5 L-isoleucine 0.85 L-tryptophan 0.42 Carbohydrates derived from γ-cyclodextrin 26.8

[0105] Subsequently, this material was added to the following amounts of amino acids (g). L-leucine 2.2 L-arginine 2.1 L-valine 1.0 L-tyrosine 0.5 L-histidine 0.5 L-lysine 0.76 L-threonine 0.6 L-aspartic acid 0.5 L-glutamine 3.2 L-proline 0.5 L-serine 0.85 L-alanine 0.85 Glycine 0.85 Taurine 0.34 L-Carnitine 0.34

[0106] The total weight of the amino acids present in the blend is 18.21 g. The total weight of γ-cyclodextrin in the blend is 37.3 g. The total weight of canola oil in the blend is 2 g.

[0107] A dry blend of this material was made and the following were added. Rice maltodextrin 19.7 g Sodium chloride 366 mg

[0108] The formulation may contain a variety of vitamins and minerals. For example, a multivitamin mineral premix containing highly absorbable biologically active ingredients (total of about 3 g) may be added and may include the following. Vitamin A (2,000 IU from β-carotene, 1,000 IU as palmitate) 3,000 IU Vitamin C (as ascorbic acid) 50 mg Vitamin D (as vitamin D3) 200 IU Vitamin E (as d-α-tocopheryl) 40 IU Thiamine (as thiamine hydrochloride) 5 mg Riboflavin (as riboflavin 5'-phosphate sodium) 2 mg Niacin (20 mg as niacinamide and 5 mg as niacin) 25 mg Vitamin B6 (as pyridoxal 5'-phosphate) 2 mg Folate (as L-5-methyltetrahydrofolate from L-5-methyltetrahydrofolate glucosamine salt) 200 μg Vitamin B12 (10 μg adenosylcobalamin and 10 μg methylcobalamin) 20 μg Biotin 100 μg Pantothenic acid (as calcium pantothenate) 20 mg Choline (as citrate) 100 mg Calcium (120 mg of calcium citrate and 90 mg of calcium malate) 210 mg Iron (as iron picolinate) 3 mg Iodine (as potassium iodide) 225 μg Magnesium (60 mg of magnesium citrate and 30 mg of magnesium malate) 90 mg Zinc (as zinc picolinate) 3 mg Selenium (as L-selenomethionine) 40 μg Copper (as copper picolinate) 0.3 mg Manganese (as manganese picolinate) 3 mg Chromium (nicotinic acid chromium glycinate chelate) * 40 μg Molybdenum (as molybdenum picolinate) 20 μg Potassium (30 mg of potassium citrate and 30 mg of potassium malate) 60 mg Boron (as boron picolinate) 0.5 mg Vanadium (as vanadium picolinate) 20 μg

[0109] According to the foregoing embodiments, a single-serving size of approximately 80 g is provided. This produces a palatable, low-allergenic Vivonex-type meal replacement that is free of the intolerable tastes characteristic of bitter or sulfurous amino acid residues. Alternative single-serving sizes, ingredients, and ingredient ratios are also provided. Additional or alternative ingredients may include, for example, nicotinamide riboside, butyric acid, and acetic acid.

[0110] In other embodiments, the amino acids: L-phenylalanine and L-tryptophan were individually included in the γ-cyclodextrin inclusion complex at an equimolar ratio using a kneading method. Then, each material was dried, pulverized and added to the premix, and further added to the meal replacement. In other variations of this, the two amino acids were repeated, premixed, and then added to obtain the same final product. Subsequently, the individual amino acids: N-acetylcysteine, L-methionine and L-isoleucine were each included in the γ-cyclodextrin inclusion complex at an equimolar ratio using a kneading method. For example, oil can also be supplied to the final product so as to reduce the space in the final formulation. For the purposes of this example, canola oil was added in the same amount as the amino acid to each amino acid inclusion and kneaded in each individual manufacturing process. 0.85 g of canola oil was added to formulate L-phenylalanine, 0.5 g of canola oil was added to formulate N-acetylcysteine, and 0.5 g of canola oil was added to formulate L-methionine. Surprisingly, when added in these amounts, the oil was clearly incorporated into the γ-cyclodextrin inclusion complex. Thus, cyclodextrin not only puts the amino acid in the cavity and masks the unpleasant taste of the amino acid, but the CD also encloses the amino acid in the CD by putting at least a part of the canola triglyceride and forming a conceptual plug in the CD cavity with the oil. Accordingly, the present invention provides this type of formulation that provides a soluble odor-masked amino acid in combination with a lipid. This example was repeated using individual fatty acids, capric acid, instead of canola oil, and the same surprising results were obtained. Thereby, a stacked double inclusion complex is obtained within a single cyclodextrin. Then, each of the materials treated with canola was dried, pulverized and added to the premix and further added to the meal replacement. In other variations of this, the same three amino acids were repeated, premixed, and then added, and further canola oil was added to obtain the same final product.

[0111] As described above, this example relates to a component nutrient having CD (regardless of the presence or absence of an enzyme that facilitates the decomposition of CD) for good taste. In this context, in some patients, enteral nutrition causes a decrease in pancreatic enzyme secretion, and there is evidence that the use of one or more enzymes in this formulation is particularly advantageous for patients in whom this is occurring.

[0112] Amino acid supplements can also be provided as CD inclusion complexes, regardless of the presence or absence of an enzyme that facilitates the decomposition of CD. This can be particularly advantageous for branched-chain amino acids such as leucine, isoleucine, and valine, for example. Accordingly, in this example, leucine and valine are formulated into a good-tasting α-CD inclusion complex, and isoleucine is formulated into a good-tasting γ-CD inclusion complex.

[0113] Example 14: Acetaminophen inclusion complex In one aspect, this example relates to the production of a CD inclusion complex mixture in which an anti-inflammatory drug or analgesic forms an inclusion complex with cyclodextrin as a stand-alone inclusion to mask the taste and improve solubility. In another embodiment, other substances may be included in the inclusion compound. These embodiments can be formulated regardless of the presence or absence of one or more enzymes that facilitate the decomposition of CD.

[0114] In an exemplary embodiment, acetaminophen was included in an α-cyclodextrin inclusion complex in an equimolar ratio using a kneading method. A second amount was included in a β-cyclodextrin inclusion complex in an equimolar ratio using a kneading method. A third amount was included in a γ-cyclodextrin inclusion complex in an equimolar ratio using a kneading method. The materials were then dried and pulverized. When added to tap water, these inclusion complexes were found to be completely soluble and to very effectively mask the unpleasant taste.

[0115] In a further embodiment, N-acetylcysteine was included in γ-cyclodextrin in an equimolar ratio using a kneading method as in Example 13 above. The material was then dried and pulverized. When added to tap water, this inclusion complex was found to be completely soluble and also to very effectively mask the normal unpleasant taste and odor.

[0116] Subsequently, acetaminophen / γ-cyclodextrin dry powder and N-acetylcysteine / γ-cyclodextrin dry powder were made into a mixture. When mixed with tap water, it provided a therapeutic dose of acetaminophen while providing the liver-protective function of N-acetylcysteine. The combination of the two components as an inclusion complex provides a delivery vehicle that more easily delivers acetaminophen due to increased solubility, but also provides a delivery form of N-acetylcysteine with a dramatically less odor and unpleasant taste. This type of formulation may be enhanced, for example, in the form of a powder, with the addition of a small amount of flavoring and sweetening compounds, regardless of the presence or absence of enzymes that facilitate the decomposition of the CD, or may be incorporated into other standard dosage forms such as capsules or tablets including sustained release forms.

[0117] Example 15: Hepatoprotective preparation This example relates to the production of a CD inclusion complex mixture in which a hepatoprotective substance forms an inclusion complex with cyclodextrin, for example, as a stand-alone inclusion or when added to other substances that may also be inclusion compounds, to mask taste and improve solubility.

[0118] In an exemplary embodiment, N-acetylcysteine was included in γ-cyclodextrin in an equimolar ratio using a kneading method as in Example 13 above. The material was then dried and pulverized. When added to tap water, this inclusion complex was found to be completely soluble and also to very effectively mask the unpleasant taste.

[0119] Silymarin extract (Indena SPA) was incorporated into γ-cyclodextrin at an equimolar ratio using a kneading method. Then, the material was dried and pulverized. When added to tap water, this inclusion complex was found to be completely soluble and to very effectively mask unpleasant tastes.

[0120] Curcumin extract (Sabinsa) was incorporated into γ-cyclodextrin at an equimolar ratio using a kneading method. Then, the material was dried and pulverized. When added to tap water, this inclusion complex was found to be completely soluble and to very effectively mask unpleasant tastes.

[0121] Curcumin extract (Sabinsa) was incorporated into γ-cyclodextrin at a ratio of 1:2 using a kneading method. Then, the material was dried and pulverized. When added to tap water, this inclusion complex was found to be completely soluble and to very effectively mask unpleasant tastes.

[0122] Tetrahydrocurcumin (Sabina) was incorporated into γ-cyclodextrin at an equimolar ratio using a kneading method. Then, the material was dried and pulverized. When added to tap water, this inclusion complex was found to be completely soluble and to very effectively mask unpleasant tastes.

[0123] Tetrahydrocurcumin (Sabina) was incorporated into γ-cyclodextrin at a ratio of 1:2 using a kneading method. Then, the material was dried and pulverized. When added to tap water, this inclusion complex was found to be completely soluble and to very effectively mask unpleasant tastes.

[0124] For example, N-acetylcysteine under the trademark name Mucomyst is administered in emergency room situations of acetaminophen overdose for patients having a hepatotoxic risk, for example, according to the Rumack-Matthew toxicity level nomogram. Most ER utilization is currently by the intravenous route due to the very unpleasant taste and odor of N-acetylcysteine. Accordingly, embodiments provide a mixture of N-acetylcysteine formulated to be administered to a patient with water or juice, for example, as a rescue therapeutic agent for acetaminophen poisoning, regardless of the presence or absence of a CD degrading enzyme such as amylase. Alternatively, such a formulation can be provided as a prophylactic agent, for example, in conjunction with daily or high-dose use of acetaminophen. Similarly, additional hepatoprotective agents can be provided that include silymarin, curcuminoids, and other known hepatoprotective agents. Such other known hepatoprotective agents include, but are not limited to, grapefruit, naringin, naringenin, blueberry, cranberry, flavonoids, catechins, epicatechins, anthocyanidins, proanthocyanidins, resveratrol, cactus pear, chamomile, spirulina, propolis, and β-glucan.

[0125] In an alternative aspect, acetaminophen itself can be formulated with an amino acid CD inclusion complex, regardless of the presence or absence of an enzyme that facilitates the degradation of the CD. For example, N-acetylcysteine CD inclusion complexes can be formulated for use, particularly as pediatric formulations, to prevent liver injury. In an alternative embodiment, acetaminophen can be included in the same CD as N-acetylcysteine, for example, in an alternative form of a multi-component stacked inclusion complex, for example, having acetaminophen as the first inclusion and an amino acid as the second inclusion, or vice versa. In a selected embodiment, γ-cyclodextrin can be utilized to include both acetaminophen and N-acylcysteine within the cavity of the CD.

[0126] Combinations of two or more components as inclusions provide a vehicle that more readily delivers the components by increasing solubility, may be easily formulated as a powder dosage form with the addition of small amounts of flavoring agents and sweetener compounds, or may be incorporated into other standard dosage forms such as capsules or tablets that include a sustained release form, providing a delivery form having dramatically less odor and unpleasant taste.

[0127] Example 16: Stacked inclusion complex This example relates to the production of a CD inclusion complex mixture in which a substance forms an inclusion complex as a stacked inclusion complex with cyclodextrin so as to mask the taste and improve solubility. In an exemplary embodiment, N-acetylcysteine was included in γ-cyclodextrin in an equimolar ratio using a kneading method as in Example 13. Acetaminophen was added to the N-acetylcysteine inclusion complex in an equimolar ratio to form a stacked inclusion complex. The material was then dried and pulverized. When added to tap water, these inclusion complexes were found to be completely soluble and to very well conceal the unpleasant taste. In selected embodiments, the stacked inclusion complex may be formulated to facilitate inclusion of multiple compounds in a single cyclodextrin and to reduce the dosage of the product.

Claims

1. A cyclodextrin inclusion complex delivery vehicle comprising: a cyclodextrin having a cavity; a biologically active molecule that is at least partially retained as a guest molecule within the cavity of the cyclodextrin to form a cyclodextrin inclusion complex; a biologically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained by the cyclodextrin within a biologically acceptable carrier; and an enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin that retains the guest molecule, the enzyme being formulated such that the cyclodextrin-degrading activity is activated upon delivery of the delivery vehicle to a target to release the guest molecule from the cavity of the cyclodextrin. A cyclodextrin inclusion complex delivery vehicle containing the above components.

2. The delivery vehicle according to claim 1, wherein the enzyme is formulated together with the cyclodextrin inclusion complex.

3. The delivery vehicle according to claim 1, wherein the enzyme is packaged together with the cyclodextrin inclusion complex in the delivery vehicle, and the delivery vehicle further includes a biochemically acceptable carrier for the enzyme.

4. The delivery vehicle according to any one of claims 1 to 3, wherein the target is a host organism.

5. The delivery vehicle according to any one of claims 1 to 3, wherein the target is an abiotic environment.

6. The delivery vehicle according to any one of claims 1 to 4, wherein the enzyme is amylase, cyclodextrinase, maltogenic amylase or neopullulanase.

7. The delivery vehicle according to claim 6, wherein the amylase is mammalian salivary amylase, mammalian pancreatic amylase or microbial amylase.

8. The delivery vehicle according to claim 6, wherein the cyclodextrinase is microbial cyclodextrinase.

9. The delivery vehicle according to any one of claims 1 to 8, wherein the cyclodextrin is a hydrophobic alkylated cyclodextrin.

10. The delivery vehicle according to any one of claims 1 to 9, wherein the cyclodextrin is a mixed methylated / ethylated cyclodextrin.

11. The delivery vehicle according to any one of claims 1 to 10, wherein the ratio of the cyclodextrin to the guest molecule is from 5:1 to 1:

5.

12. The delivery vehicle according to any one of claims 1 to 11, wherein the cyclodextrin is α-, β- or γ-cyclodextrin.

13. The delivery vehicle according to any one of claims 1 to 12, wherein the guest molecule is a drug or a prodrug, and the biologically acceptable carrier is a pharmaceutically acceptable carrier.

14. The delivery vehicle according to claim 13, wherein the delivery vehicle is formulated for delivery by a parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intra-articular, intrathecal, subarachnoid, intracapsular, intraperitoneal, intranasal, inhalation, aerosol, topical, intratumoral, sublingual or oral route.

15. The delivery vehicle according to claim 13 or 14, wherein the delivery vehicle is formulated for sustained release of a drug or a prodrug.

16. The delivery vehicle according to claim 13, 14 or 15, wherein the drug or the prodrug is a short-chain fatty acid or an ester derivative thereof.

17. The delivery vehicle according to claim 16, wherein the short-chain fatty acid is one or more of butyric acid (butanoic acid), propionic acid and acetic acid.

18. The delivery vehicle according to claim 16 or 17, wherein the ester derivative is a glyceride.

19. The delivery vehicle according to claim 18, further comprising lipase.

20. The delivery vehicle according to claim 13 or 14, wherein the drug is quercetin.

21. The delivery vehicle according to claim 20, wherein the cyclodextrin is γ-cyclodextrin.

22. The delivery vehicle according to claim 20 or 21, wherein the cyclodextrin-degrading enzyme is amylase.

23. The delivery vehicle according to any one of claims 1 to 12, wherein the guest molecule is N-acetylcysteine, the biologically acceptable carrier is a pharmaceutically acceptable carrier, and the delivery vehicle further comprises acetaminophen.

24. A method for treating gastrointestinal disorders, comprising administering an effective amount of the delivery vehicle according to any one of claims 16 to 19 to a subject in need thereof.

25. The method according to claim 24, wherein the subject is a human patient, the delivery route is oral, and the gastrointestinal disorder is colitis, diverticulitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, inflammation associated with an ostomy stoma or granulation associated with an ostomy stoma.

26. The method according to claim 25, wherein the short-chain fatty acid is butyric acid.

27. The delivery vehicle according to any one of claims 1 to 12, wherein the guest molecule is a herbicide, an insecticide, a fungicide, an animal repellent, a pheromone or a plant growth regulator.

28. The delivery vehicle according to any one of claims 1 to 12, wherein the guest molecule is a fragrance molecule.

29. Use of the delivery vehicle according to any one of claims 1 to 19 as a medicament.

30. Use of the delivery vehicle according to any one of claims 1 to 19 as a food ingredient, a medical food, a dietary supplement or a nutritional supplement.

31. Use of the delivery vehicle according to claim 27 as a herbicide, an insecticide, a fungicide, an animal repellent, a pheromone or a plant growth regulator.

32. Use of the delivery vehicle according to claim 28 as a fragrance.

33. Use of the delivery vehicle according to any one of claims 1 to 12 as a fabric or a packaging.

34. A method of formulating a cyclodextrin inclusion complex delivery vehicle, comprising: providing a cyclodextrin having a cavity; providing a biologically active molecule, wherein the biologically active molecule is at least partially retained within the cavity of the cyclodextrin as a guest molecule to form a cyclodextrin inclusion complex; providing a biologically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained by the cyclodextrin within the biologically acceptable carrier; and providing an enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin retaining the guest molecule, wherein the enzyme is formulated with the cyclodextrin inclusion complex such that the cyclodextrin-degrading activity is activated upon delivery of the delivery vehicle to a target to release the guest molecule from the cavity of the cyclodextrin.

35. A pharmaceutical formulation comprising an acetaminophen and N-acetylcysteine cyclodextrin inclusion complex in a pharmaceutically acceptable carrier.

36. The formulation according to claim 35, wherein the cyclodextrin is β- or γ-cyclodextrin.

37. The preparation according to claim 35 or 36, further comprising an enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin.

38. A method of formulating acetaminophen, comprising combining acetaminophen and an N-acetylcysteine cyclodextrin inclusion complex with a pharmaceutically acceptable carrier.

39. The delivery vehicle according to any one of claims 1 to 12, wherein the guest molecule is an amino acid and the biologically acceptable carrier is a pharmaceutically acceptable carrier.

40. The delivery medium according to claim 39, wherein the amino acid is one or more of L-phenylalanine, N-acetylcysteine, L-cysteine, L-methionine, L-isoleucine and L-tryptophan.

41. The delivery vehicle according to claim 39 or 40, wherein the delivery vehicle is formulated for delivery by a parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intra-articular, intrathecal, subarachnoid, intracapsular, intraperitoneal, intranasal, inhalation, aerosol, topical, intratumoral, sublingual or oral route.

42. A meal replacement or component nutrient containing an amino acid in a cyclodextrin inclusion complex, wherein the amino acid is one or more of L-phenylalanine, N-acetylcysteine, L-cysteine, L-methionine, L-isoleucine and L-tryptophan.

43. A meal replacement or component nutrient agent according to claim 42, comprising at least 10 of maltodextrin, L-glutamine, modified corn starch, L-leucine, L-arginine acetate, soybean oil, magnesium gluconate, L-lysine acetate, calcium glycerophosphate, L-isoleucine, L-valine, L-phenylalanine, sodium citrate, L-threonine, potassium citrate, L-cysteine hydrochloride, citric acid, L-methionine, L-tyrosine, L-histidine hydrochloride, L-aspartic acid, L-proline, L-tryptophan, disodium phosphate, potassium chloride, choline bitartrate, L-serine, L-alanine, glycine, ascorbic acid, polyglycerol ester of fatty acids, taurine, L-carnitine, α-tocopherol acetate, zinc sulfate, ferrous sulfate, niacinamide, vitamin A palmitate, calcium pantothenate, copper gluconate, vitamin D3, pyridoxine hydrochloride, manganese sulfate, riboflavin, thiamine hydrochloride, folic acid, chromium chloride, biotin, potassium iodide, sodium molybdate, sodium selenite, phylloquinone, vitamin B12.

44. Cyclodextrin having a cavity, an amino acid held as a first guest molecule within the cavity of the cyclodextrin, and a biologically acceptable lipid at least partially held as a second guest molecule within the cavity of the cyclodextrin, a multi-component stacked cyclodextrin inclusion complex.

45. Cyclodextrin having a cavity, N-acylcysteine at least partially held as a first guest molecule within the cavity of the cyclodextrin, and acetaminophen at least partially held as a second guest molecule within the cavity of the cyclodextrin, a multi-component stacked cyclodextrin inclusion complex.

46. The cavity is frustoconical, having an opening with a larger diameter and an opening with a smaller diameter disposed at an opposite end of the cavity, wherein the first guest molecule is proximate to the smaller opening and the second guest molecule is proximate to the larger opening, the multi-component stacked cyclodextrin inclusion complex according to claim 45.

47. The cavity is frustoconical and has a larger-diameter opening and a smaller-diameter opening disposed at an opposing end of the cavity. The multicomponent stacked cyclodextrin clathrate according to claim 45, wherein the first guest molecule is close to the larger opening, and the second guest molecule is close to the smaller opening.

48. The multicomponent stacked cyclodextrin clathrate according to any one of claims 44 to 47, further comprising an enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin holding the first and second guest molecules. The multicomponent stacked cyclodextrin clathrate, wherein the enzyme is formulated such that the cyclodextrin-degrading activity is activated upon delivery of the delivery vehicle to the target to release the guest molecule from the cavity of the cyclodextrin.

49. A method of treating a patient having an autism spectrum disorder, comprising administering to the patient an effective amount of a short-chain fatty acid cyclodextrin clathrate.

50. A method for modulating the microbiome of a patient having a neurological disorder, comprising administering to the patient an effective amount of a short-chain fatty acid cyclodextrin clathrate.

51. The method according to claim 49 or 50, wherein the short-chain fatty acid is butyric acid.

52. The method according to any one of claims 49 to 51, wherein the cyclodextrin is α-cyclodextrin.

53. The method according to any one of claims 49 to 52, further comprising administering to the patient an effective amount of acetic acid.

54. The method according to claim 53, wherein the acetic acid is formulated in the short-chain fatty acid cyclodextrin clathrate.

55. The method according to any one of claims 49 to 54, wherein the cyclodextrin clathrate is included in a formulation containing an enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin holding butyric acid.

56. The method according to claim 55, wherein the enzyme is amylase.

57. The delivery vehicle according to claim 13, 14 or 15, wherein the drug or the prodrug is a cannabinoid.

Images