Controlled release and layered cyclodextrin inclusion complex vehicles

Abstract

The present invention provides cyclodextrin inclusion complex delivery vehicles, wherein the cyclodextrin inclusion complex is provided with an enzyme having cyclodextrin-degrading activity capable of digesting cyclodextrin, such that upon delivery of the vehicle to a target, the enzyme is activated and releases the guest molecule from the cavity of the cyclodextrin. In alternative aspects, these cyclodextrin inclusion complex delivery vehicles are provided in the form of, for example, a drug, a food ingredient, a medical food ingredient, a nutritional supplement ingredient, a dietary supplement ingredient, a herbicide, a pesticide, a fungicide, an animal repellent, a pheromone, a plant growth regulator, a fragrance, a fabric or a packaging material.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201780017946.0, filed February 3, 2017, entitled "Controlled Release and Layered Cyclodextrin Inclusion Complex Vehicles."

[0002] Related Applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 291,202, filed February 4, 2016; U.S. Non-Provisional Application No. 15 / 232,647, filed August 9, 2016; U.S. Non-Provisional Application No. 15 / 285,264, filed October 4, 2016; and U.S. Provisional Application No. 62 / 444,036, filed January 9, 2017, the contents of which are incorporated herein by reference. TECHNICAL FIELD

[0004] The present invention is in the field of biochemical constructs for the delivery of biologically active agents, including delivery vehicles comprising molecules carried as inclusion complexes within cyclodextrins, which are delivered with selected enzymes having cyclodextrin-degrading activity. BACKGROUND

[0005] Cyclodextrins are non-reducing cyclic oligosaccharides of glucose, typically the product of starch degradation catalyzed by a cyclomaltodextrin glucanotransferase (E.C. 2.4.1.19; CGTase). Cyclodextrins can have a variety of structures (see Saenger et al., Chem. Rev. 98 (1998) 1787-1802), including three common cyclodextrins with 6, 7, or 8 D-glucopyranose acid residues linked into a ring through a-1,4 glycosidic bonds (a-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively). The truncated conical shape of the cyclodextrins forms a cavity or lumen, which has a different diameter depending on the number of glucose units. The sizes of selected cyclodextrin (CD) structures are listed in Table 1. Larger cyclodextrins such as cyclomaltodecaose (δ-CD) and cyclomaltoundecaose (ε-CD) are also possible, as are various cyclodextrin-based supramolecular structures (see Zhang and Ma, Adv Drug Deliv Rev. 2013 Aug;65(9):1215-33).

[0006] Table 1: Cyclodextrin Structures

[0007]

[0008]

[0009] Cyclodextrins are generally amphiphilic, with the wider rim of the cavity displaying 2- and 3-OH groups, and the narrower rim displaying 6-OH groups. Thus, these hydrophilic hydroxyl groups are on the outside of the cavity, while the inner surface is generally hydrophobic, and lined with an anomeric oxygen atom, as well as C3-H and C5-H hydrogen atoms. In aqueous solution, this hydrophobic cavity can contain water molecules, for example about 3 (α-CD), 7 (β-CD), or 9 (γ-CD) water molecules that are loosely held but of low entropy, and thus relatively easily displaced. Thus, hydrophilic cyclodextrins can bind one or more molecules of appropriate size within or partially within the CD cavity, forming a cyclodextrin inclusion or complex. For example, non-polar aliphatic and aromatic compounds, including pharmaceuticals such as lipophilic pharmaceuticals, can be bound, thereby increasing the water solubility of normally hydrophobic compounds, or minimizing undesirable properties such as odor or taste in certain food additives. Cyclodextrin inclusions are thus widely used in the pharmaceutical, food, and cosmetic arts (see Hedges, Chem. Rev. 98 (1998) 2035-2044). For example, cyclodextrins have been used in various sustained release pharmaceutical formulations, such as for inclusion complexes of medicinal compounds with hydrophobic cyclodextrin derivatives (U.S. Patent No. 4,869,904).

[0010] Cyclodextrins can be chemically modified in a number of ways. For example, to alter the inclusion specificity, physical and chemical properties of the cyclodextrin. For example, CD hydroxyl groups can be derivatized. For example, two modified CDs have been used in a number of pharmaceutical products: SBE-β-CD or Captisol (a poly-anionic variably substituted sulfobutyl ether of β-CD), and HP-β-CD (a modified CD commercialized by Janssen). Other CD derivatives include sugammadex or Org-25969 (in which the 6-hydroxyl on a γ-CD is replaced by a carboxyl thioacetate ether linkage), and hydroxybutenyl-β-CD. Alternative forms of cyclodextrins 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) and sulfobutyl ether-γ-cyclodextrin (SBEγCD), 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. Although CDs such as these have been developed to have good pharmacological and toxicological properties, there remains the possibility that residual CD, following administration, can interfere with the pharmacokinetic properties of the drug, including co-administered drugs, particularly following parenteral administration (see Stella and He, Toxicol Pathol 2008 Jan, vol. 36, no. 130-42).

[0011] Concerns about the physiological effects of residual CD from therapeutic CD inclusion complexes stem from the observation that CDs such as α-CD and β-CD are resistant to gastric acid and salivary and pancreatic enzyme digestion, and that γ-CD is only partially digested by amylase in the GIT. It is generally accepted that only a relatively small amount of orally administered CD is absorbed, and that absorbed CD is excreted in the urine without undergoing significant metabolism. Unabsorbed CD is believed to be fermented by intestinal microflora.

[0012] Cyclodextrins vary in their susceptibility to enzymatic digestion. For example, γ-CD is relatively easily hydrolyzed by α-amylase, while α-cyclodextrin is more resistant to hydrolysis. CD-based therapies generally rely on the activity of endogenous amylase to digest the CD. However, there are significant differences in amylase activity between patients. For example, patients with pancreatic insufficiency, cystic fibrosis, celiac disease, or Crohn’s disease can lack normal amounts of amylase. Similarly, patients, particularly aging patients, can have insufficient gastric acid production and thus cannot produce the appropriately low pH conditions in the duodenum to properly trigger the release of pancreatic amylase. Routine use of increased antacids, histamine-2 blockers, proton pump inhibitors, or alternative acid blockers can increase can have similar effects.

[0013] A number of microbial cyclodextrin digestion enzymes have been identified. CD-degrading enzymes include cyclomaltodextrinase (or cyclodextrinase, or CDase, EC 3.2.1.54), maltosaccharase (EC 3.2.1.133), neopullulanase (EC 3.2.1.135), which have been reported to be able to hydrolyze CD, and in some cases, other substrates such as pullulan and starch. Cyclodextrinases (CDases) catalyze the hydrolysis of CD to form linear oligosaccharides with α-1,4-linkages, and thus they can release substrates from CD inclusion complexes. CDase from Bacillus macerans was reported in 1968, and since then a number of CDases from bacteria have been characterized, such as enzymes from Bacillus sp., Thermoanaerobacter ethanolicus strain 39E, Flavobacterium sp., and Klebsiella oxytoca strain M5al. Archaeal CDases have been characterized by Archaeoglobus fulgidus, Thermococcus sp. B1001, Thermococcus sp. CL1, Thermofilum pendens, and Pyrococcus furiosus. The structure of a Flavobacterium sp. CDase has been characterized in detail (see Sun et al., Archaea, vol. 2015 (2015), article no. 397924, reporting the identification of a gene encoding a cyclodextrinase from Thermococcus kodakarensis KOD1 (CDase-Tk)). BRIEF DESCRIPTION OF DRAWINGS

[0014] Figure 1A typical baseline sleep cycle pattern for a subject is shown for a 912 sleep cycle.

[0015] Figure 2 A sleep cycle for a subject after administration of a cannabis oil cyclodextrin inclusion complex formulation without amylase is shown, which shows significantly less deep sleep than the sleep pattern for a subject after administration of a cannabis oil cyclodextrin inclusion complex formulation with amylase.

[0016] Figure 3 A sleep cycle for a subject after administration of a cannabis oil cyclodextrin inclusion complex formulation with amylase is shown, which shows significantly more deep sleep than the baseline sleep cycle pattern for the subject. SUMMARY

[0017] A cyclodextrin inclusion complex delivery vehicle is provided, wherein the cyclodextrin has a cavity, wherein a biologically active molecule is at least partially retained in the cavity as a guest molecule, forming a cyclodextrin inclusion complex. A biologically acceptable carrier can be provided for the cyclodextrin inclusion complex, such that the guest molecule is stably retained within the biologically acceptable carrier by the cyclodextrin. An enzyme can also be provided in the delivery vehicle, which has cyclodextrin-degrading activity, capable of digesting the cyclodextrin retaining the guest molecule. The enzyme can be formulated such that the cyclodextrin-degrading activity is activated upon delivery of the delivery vehicle to the target, thereby releasing the guest molecule from the cyclodextrin cavity.

[0018] In an alternative aspect of the delivery vehicle, the enzyme can be co-formulated with the cyclodextrin inclusion complex, or the enzyme can be co-packaged with the cyclodextrin inclusion complex in the delivery vehicle. When the enzyme is co-packaged, the delivery vehicle can also include a biochemically acceptable carrier for the enzyme.

[0019] For example, the target can be a host organism, such as a human patient, or the target can be an inanimate environment, such as a fabric or packaging material.

[0020] The enzyme, for example, can be an amylase, a cyclodextrinase, a maltogenic amylase, or a neopullulanase. The amylase, for example, can be a mammalian salivary amylase or pancreatic amylase, or a fungal or bacterial-derived amylase. The cyclodextrinase, for example, can be a microbial cyclodextrinase.

[0021] The cyclodextrin, for example, can be a CD derivative, such as a hydrophobic alkylated cyclodextrin or a mixed methylated / ethylated cyclodextrin.

[0022] The ratio of the cyclodextrin to the guest molecule can be, for example, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, or 1:5, although a variety of alternative values are possible for this parameter, including non-integer ratios.

[0023] The cyclodextrin, for example, can be an alpha, beta or gamma cyclodextrin, and likewise various different alternative CD structures can be used.

[0024] In selected embodiments, the guest molecule, for example, can be a drug or prodrug, such as a flavonoid (quercetin), a cannabinoid or an anti-inflammatory agent (including acetaminophen). In this case, the biocompatible carrier advantageously can be a pharmaceutically acceptable carrier. Such delivery vehicles can be formulated for delivery, for example, parenterally, intravenously, intradermally, subcutaneously, intramuscularly, intracranially, intraorbital, ophthalmically, intraventricularly, intracapsularly, intraspinally, intrathecally, intracisternally, intraperitoneally, intranasally, by inhalation, by spray, topically, intratumorally, sublingually or orally. Likewise, the delivery vehicle can be formulated for sustained release of the drug or prodrug.

[0025] In alternative aspects, the delivery vehicle can include a guest molecule that is a herbicide, a pesticide, a fungicide, an animal repellent, a pheromone or a plant growth regulator. In other alternatives, the guest molecule, for example, can be an aroma molecule.

[0026] In this manner, the present application provides alternative embodiments in which the CD delivery vehicle can be used as a pharmaceutical agent, a food ingredient, a medical food ingredient, a nutritional supplement ingredient, a dietary supplement ingredient, an aroma, a fabric or a packaging material, or in an agricultural environment as a herbicide, a pesticide, a fungicide, an animal repellent, a pheromone or a plant growth regulator.

[0027] Thus, in various aspects, the delivery vehicle is provided with an effective amount of an enzyme having CD-degrading activity to facilitate the predictable release of the guest molecule from the CD.

[0028] In selected embodiments, the drug or prodrug in the delivery vehicle can be a short chain fatty acid or an ester derivative thereof, such as butanoic (butane) acid, propionic acid, acetic acid or an ester derivative thereof, such as a glyceride. When provided in the form of a glyceride, for example, a lipase can be included in the delivery vehicle. Such formulations can be used to treat gastrointestinal disorders, such as colitis, diverticulitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, inflammation associated with a stoma or granulation associated with a stoma.

[0029] The guest molecule can include various amino acids, such as L-phenylalanine, N-acetyl-cysteine (and L-cysteine), L-methionine, L-isoleucine and L-tryptophan. In selected embodiments, N-acetyl-cysteine, for example, can be combined with acetaminophen, such as in a hepatoprotective formulation. Alternative hepatoprotective guest molecules, for example, can be derived from silymarin, curcumin or tetrahydrocurcumin extract.

[0030] Methods for formulating a cyclodextrin inclusion complex delivery vehicle are provided, comprising: providing a cyclodextrin having a cavity; providing a biologically active molecule as a guest molecule at least partially retained within the cavity of the cyclodextrin, forming a cyclodextrin inclusion complex; providing a biologically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained within the biologically acceptable carrier by the cyclodextrin; and, optionally, providing an enzyme having cyclodextrin degrading activity capable of digesting the cyclodextrin retaining the guest molecule, wherein the enzyme is co-formulated with the cyclodextrin inclusion complex such that the cyclodextrin degrading activity is activated upon delivery of the vehicle to a target, thereby releasing the guest molecule from the cavity of the cyclodextrin.

[0031] Also provided are multi-component layered cyclodextrin inclusion complexes, e.g., comprising: a cyclodextrin having a cavity; an amino acid as a first guest molecule retained within the cavity of the cyclodextrin; and a biologically acceptable lipid as a second guest molecule at least partially retained within the cavity of the cyclodextrin. In selected embodiments, e.g., a multi-component layered cyclodextrin inclusion complex can comprise N-acetyl-cysteine (as a first guest molecule at least partially retained within the cavity of the cyclodextrin), and acetaminophen (as a second guest molecule likewise at least partially retained within the cavity of the cyclodextrin). In these layered inclusion complexes, the guest molecules can be present in any order, such that the cavity of the CD is frustoconical, i.e., having a larger diameter opening and a smaller diameter opening disposed at opposite ends of the cavity, the first guest molecule can be proximal to the smaller opening, and the second guest molecule can be proximal to the larger opening (or vice versa).

[0032] Methods of treating a patient having an autism spectrum disorder are provided, comprising administering an effective amount of a short chain fatty acid cyclodextrin inclusion complex. Similarly, such methods can be used to modulate the microbiota of a patient having a neurological disease. For example, the short chain fatty acid can be butyric acid, and in some embodiments, the treatment can further comprise administering acetic acid (optionally as an inclusion complex). DETAILED DESCRIPTION

[0033] Various biologically active compounds can be included in the delivery vehicles of the present application, for example in the form of pharmaceutical compositions, such as: docetaxel (U.S. Patent Publications 20140336149, 20130296268); carbamazepine (U.S. Patent Publication 20140080812); rifampin (U.S. Patent No. 7001893); cardiac glycosides, particularly digoxin (U.S. Patent No. 4555504), progesterone (see Zoppetti et al., Journal of Inclusion Phenomena and Macrocyclic Chemistry, April 2007, Vol. 57, No. 1, pp. 283-288); albendazole, mebendazole, ricobendazole, fenoprofen, ketoprofen, cocaine, gliclazide, digitoxin, macrocyclic compounds (MCCs), ibuprofen, prochloro-methazine, DY-9760e, NSC-639829, ETH-615, piroxicam, levemopamil HCl, ziprasidone mesylate, surinamide, mebendazole, sulindac, phenothalin, 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.

[0034] Similarly, in the field of agrochemicals, delivery vehicles can be provided that include guest molecules with a variety of different activities, such as herbicides, pesticides, fungicides, repellents, pheromones, and growth regulators.

[0035] The cyclodextrin delivery vehicles of the present invention can also comprise cyclodextrin inclusion complexes of fragrance or other bioactive molecules in a textile or fabric or packaging material (see Wang and Chen, 2005, Journal of Industrial Textiles, Vol. 34, No. 3, 157-166; US patent publications: 20150375521, 20150217896, 20150150256, 20140315780, 20130251926). For example, cyclodextrin digestive enzymes can be incorporated into a textile, and subsequently cyclodextrin inclusion complexes can be applied to the enzyme-containing fabric to form the delivery vehicle. Conversely, CD inclusion complexes can be incorporated into a textile, and subsequently enzymes can be applied to the fabric to form the delivery vehicle. Similarly, both CD inclusion complexes and enzymes can be incorporated into a textile during manufacture. Enzymes can be incorporated into a textile, for example, by immobilization involving layered components and / or nanocoatings, in which the enzyme is attached to the textile substrate such that it remains catalytically active (similar to, for example, the method of achieving wool antibacterial functionalization by immobilizing lysozyme, as described in Wang et al., 2009, Bioprocess Biosyst Eng 32:633-639, and as reviewed in Nierstrasz and Cavaco-Paulo eds. Advances in Textile Biotechnology, Elsevier, 2010).

[0036] In addition to CDs and CD derivatives, a variety of cyclodextrin-based supramolecular systems are available for delivery of the range of bioactive molecules described above (reviewed in Zhang and Ma, Adv Drug Deliv Rev. 2013 Aug;65(9): 1215-33). Thus, aspects of cyclodextrin-based delivery vehicles include embodiments that have been characterized as cyclodextrin-based nanosponges. These systems can be adapted, for example, in the context of the present invention, for controlled delivery of bioactive molecules such as drugs.

[0037] In selected embodiments, the enzymes provided in the vehicles can be formulated such that cyclodextrin-degrading activity is activated upon delivery of the vehicle to the target, thereby releasing the guest molecules from the cavity of the cyclodextrin. For example, enzyme activation can be accomplished, for example, for orally delivered drugs, in a dry dosage form such as a capsule or tablet, in which the enzyme is mixed such that the enzyme is not active until activated by moisture in the host's gastrointestinal tract. Similarly, a variety of time-limited release matrices and formulations are known that can be adapted for use in CD delivery vehicles, such that appropriate activation of CD-degrading enzymes is coordinated upon delivery to the target.

[0038] In various aspects, the CD delivery vehicle can have the enzyme co-formulated with the cyclodextrin inclusion complex, e.g., as described above, or the enzyme can be co-packaged with the cyclodextrin inclusion complex in the delivery vehicle. In the case of co-packaging, the delivery vehicle may, for example, comprise a biochemically acceptable carrier for the enzyme that is different from the carrier for the CD inclusion complex. For example, the delivery vehicle can have separate compartments comprising the CD inclusion complex and the CD-degrading enzyme, such that the delivery vehicle consists of a CD inclusion complex compartment linked to a CD-degrading enzyme compartment. Mechanisms for the release of the CD inclusion complex and the CD-degrading enzyme from their respective compartments in the delivery vehicle can be provided. For example, a syringe having such different compartments can be provided that expels the CD inclusion complex and the CD-degrading enzyme through a common expelling mechanism, such as a mechanism that moves pistons in each compartment in coordination to expel an aliquot of the CD inclusion complex and the CD-degrading enzyme, such that the enzyme and complex can be subsequently mixed to activate the enzymatic release of the guest molecule from the CD. Such vehicles can be used, for example, for dispensing topical creams or other surface-activated formulations. A variety of such delivery vehicles can be adapted from known devices for dispensing two-component compositions such as epoxy resins, two-component pharmaceuticals or dental formulations, e.g., as disclosed in U.S. Patents Nos. 4,538,920; 8,100,295; 8,308,340; 8,875,947; 8,499,976, and International Patent Publications WO2007041266 and WO2000021842.

[0039] A variety of techniques are available for preparing CD inclusion complexes, e.g., as described in Chaudhary & Patel, IJPSR, 2013; Vol. 4(1): 68-76; U.S. Patent Publication US20090029020; U.S. Patents Nos. 5,070,081; 5,552,378; and 8,658,692. One common method is referred to as the kneading method, which involves mixing the CD with water or aqueous alcohol to provide a paste. The biologically active molecule can then be added to the paste and kneaded for a specific time. The kneaded mixture can then be dried and sieved as needed. Other known methods of preparing CD inclusions include lyophilization, microwave irradiation, and supercritical fluid antisolvent techniques.

[0040] The CD delivery vectors of the present application 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 a carrier such as a liposome, adjuvant, or any pharmaceutically or biologically acceptable carrier. Selected embodiments include pharmaceuticals in a form suitable for administration to an animal host, such as a mammal (e.g., a human). As used herein, "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for any desired route of administration, 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 extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the bioactive compounds, its use in the pharmaceutical compositions of the application is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0041] Conventional pharmaceutical practice can be employed to provide suitable formulations or compositions for administering the delivery vehicles to a subject. Any suitable route of administration can be employed, e.g., parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ocular, intraventricular, intracapsular, intraspinal, intrathecal, intracisternal, intraperitoneal, intranasal, inhalation, spray, topical, intratumoral, sublingual, or oral administration. The therapeutic agent can be in the form of a liquid solution or suspension; for oral administration, the formulation can be in the form of a tablet or capsule; for intranasal administration, in the form of a powder, nasal drops, or aerosol; for sublingual administration, in the form of drops, aerosol, or tablet.

[0042] Cyclodextrin-degrading or -digesting enzymes can be formulated, for example, for oral delivery. For example, enteric enzyme formulations can be provided, such as submicron particle formulations prepared by emulsion solvent evaporation (Sharma et al., Pharm Dev Technol. 2013 May-Jun; 18(3):560-9). Similarly, the delivery vehicles can be formulated as hydrogels (see U.S. Patent Publication 20140094433), or as pharmaceutical gums (see U.S. Patent Publication 20130022652).

[0043] Methods for preparing formulations well known in the art can be found, for example, in "Remington's Pharmaceutical Sciences" (20th ed.), ed. A. Gennaro, 2000, Mack Publishing Company, Easton, PA. Formulations for parenteral administration can, for example, contain excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils or hydrogenated napththenic oils. Biocompatible and biodegradable poly-lactide polymers, poly-lactide-co-glycolide, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds. Other possible useful parenteral delivery systems include ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation can contain excipients such as lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-dodecyl ether, glycocholate and deoxycholate, or can be oily solutions for administration in the form of nasal drops or as gels.

[0044] The pharmaceutical compositions of the present application can be in any form that allows the active ingredients to be delivered to a patient. For example, the compositions can be in solid, liquid, or gaseous (aerosol) form, for example. 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 injections, intravenous, intramuscular, epidural, intrasternal, intrastemal injection or infusion techniques. The pharmaceutical compositions of the present application are formulated to allow the active ingredients contained therein to be bioavailable upon administration to a patient. Compositions that will be administered to a patient should be in unit dosage forms by, for example, a tablet, capsule or cachet, or a container of aerosol formulation containing a plurality of doses. For example, the dosage unit form can contain from about 1 ng to about 1 g of active ingredient.

[0045] The materials used to prepare the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. The compositions of the present application can contain one or more compounds known to have a particular desired effect (active ingredients). It will be apparent to those of ordinary skill in the art that the optimal dosage of an active ingredient in a pharmaceutical composition will depend on a variety of factors. Relevant factors include, but are not limited to, the type of subject (e.g., human), the particular form of the active ingredient, the mode of administration, and the composition employed.

[0046] Typically, the pharmaceutical compositions comprise a delivery vehicle of the present application as described herein admixed with one or more carriers. The carrier can be particulate, such that the compositions are, for example, in tablet or powder form. The carrier can be liquid, in which case the compositions are, for example, oral syrups or injectable liquids. Alternatively, the carrier can be gaseous, to provide an aerosol composition useful for administration, for example, by inhalation.

[0047] When oral administration is desired, the composition is preferably in solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms included in the solid or liquid forms as contemplated herein.

[0048] As a solid composition for oral administration, the composition can be formulated into the form of powders, granules, compressed tablets, pills, capsules, cachets, chewing gum, wafers, lozenges and the like. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more adjuvants can be present such as binders (e.g., syrup, gum arabic, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, tragacanth or gelatin), and mixtures thereof; excipients (e.g., starch, lactose or dextrins); disintegrating agents (e.g., alginic acid, sodium alginate, Primogel, corn starch and the like); 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, silicon dioxide, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, flavoring agents such as peppermint, methyl salicylate or orange flavoring and coloring agents.

[0049] When the composition is in the form of a capsule, e.g., a gelatin capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.

[0050] The composition can be in liquid form, e.g., elixir, syrup, solution, aqueous or non-aqueous suspension or emulsion, or even a dry powder, which can be reconstituted with water and / or other liquid medium before use. As two examples, the liquid can be for oral administration or for delivery by injection. When intended for oral administration, preferred compositions contain, in addition to a synthetic of the present invention, one or more of a sweetening agent, a thickening agent, a preservative, a dye / colorant and a flavoring agent. In compositions intended to be administered by injection, one or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, an emulsifying agent, a buffer, a stabilizing agent and a isotonic agent can be included. The emulsifying agent can be selected from the group consisting of lecithin and sorbitan monooleate.

[0051] The liquid pharmaceutical compositions of the present application, whether they are solutions, suspensions or other like form, can include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono- or diglycerides, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile.

[0052] The pharmaceutical compositions can be used for topical administration, in which case the carrier will conveniently comprise a solution, emulsion, ointment, cream or gel base. The carrier, for example, can comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohols, and emulsifiers and stabilizers. Thickening agents can be present in the pharmaceutical compositions to increase the viscosity of the topical formulation. If intended for transdermal administration, the composition can include a transdermal patch or iontophoresis device. Topical formulations can include concentrations of the biologically active compound from about 0.1% to about 25% w / v (weight per unit volume).

[0053] The compositions can be used for rectal administration, for example, in the form of suppositories for melting in the rectum to release the medication. Compositions for rectal administration can include 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 waxes for example, a mixture of fatty acid glycerides and / or cocoa butter are suitable for the manufacture of suppositories. The wax can be melted and the aminocyclohexyl ether compound uniformly dispersed therein by stirring the molten material. The uniformly molten mixture is then poured into a convenient sized mold, allowed to cool and solidify.

[0054] The compositions can include various materials which modify the physical form of the solid or liquid dosage unit. For example, the composition can include a coating material, such as sugar, shellac, or other enteric coating agents. Alternatively, the active ingredient can be encased in a gelatin capsule or a cellulose capsule.

[0055] The pharmaceutical compositions of the present application can consist of gaseous dosage units, for example, they can be in the form of a gas mist. The term "gas mist" is used to indicate a variety of systems, ranging from those with colloidal properties to systems consisting of pressurized packages. Delivery can be by liquefied or compressed gas, or by a suitable pump system that dispenses the active ingredient. Gas mists of the compounds of the present application can be delivered in single phase, bi- or tri-phase systems, in order to deliver the active ingredient. Delivery of the gas mist includes the necessary containers, activators, valves, sub-containers, etc., which together can form a kit.

[0056] The biologically active compound can be in the form of a free base or a pharmaceutically acceptable salt, such as hydrochloride, sulfate, phosphate, citrate, fumarate, mesylate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate, and others known in the art. Suitable salts can be selected to improve bioavailability or stability of the compound, to achieve a suitable mode of application (e.g., oral or parenteral administration routes).

[0057] Compositions intended to be administered by injection can be prepared by forming a solution of the delivery vehicle of the present application with water, and preferably with a buffer. 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 aminocyclohexyl ether compound, thereby facilitating the dissolution or uniform suspension of the aminocyclohexyl ether compound in the aqueous delivery system. The presence of a surfactant is preferred in the aqueous compositions of the present application, as the aminocyclohexyl ether compounds according to the present application can be hydrophobic. Other injectable carriers include, but are not limited to, sterile pyrogen-free ethyl oleate, dehydrated alcohol, propylene glycol, and mixtures thereof.

[0058] Suitable pharmaceutical adjuvants for injectable 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.

[0059] The present application also provides kits comprising a pharmaceutical composition comprising one or more delivery vehicles. The kits also comprise instructions for using the pharmaceutical. Preferably, a commercial package will comprise one or more unit doses of the pharmaceutical composition. For example, such unit doses can be in amounts sufficient to prepare an intravenous injection. It will be apparent to one of ordinary skill in the art that light- and / or air-sensitive compounds can require special packaging materials and / or formulations. For example, the packaging materials can be light-protected and / or sealed from ambient air, and / or formulated with suitable coatings or excipients.

[0060] An "effective amount" of a CD inclusion delivery vehicle according to the present application includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a delivery vehicle can vary depending on such factors as the disease stage, age, sex, and weight of the individual, and the ability of the compound to elicit an intended response in the individual. Dosage regimens can be adjusted to provide the optimum therapeutic response. A therapeutically effective amount can also be the amount of the delivery vehicle or active compound that has therapeutic benefit with minimal, or no, toxic or deleterious effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Generally, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so a prophylactically effective amount can be less than a therapeutically effective amount. The duration and dosage of treatment for any particular subject can be adjusted according to individual need and professional judgment by the person administering or supervising the administration of the composition (e.g., time can be daily, every other day, weekly, monthly).

[0061] In selected embodiments, the present application provides a composition or medicament comprising one or more biologically active molecules selected from the group consisting of: a biologically active compound or solvate, a pharmaceutically acceptable salt, ester, amide, complex, chelate, stereoisomer, stereoisomer mixture, geometric isomer, crystal or non-crystal form, metabolite, metabolic precursor or prodrug thereof, including isolated enantiomers, diastereomers, and geometric isomers thereof, and mixtures of the foregoing, in combination with a pharmaceutically acceptable carrier, diluent, or excipient, and methods for making such compositions or medicaments.

[0062] While various embodiments of the present application are disclosed herein, many adaptations and modifications can be made within the scope of the application in accordance with the general principles disclosed. Such modifications include the substitution of known equivalents for any aspect of the application with the essential function of the application remaining the same. Numerical ranges include the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprise" 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 substance" includes more than one such substance.

[0063] The citation of references herein does not constitute an admission that such references are prior art. Any priority documents and all publications, including but not limited to patents and patent applications, cited in this specification are hereby incorporated by reference. Any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein are hereby incorporated by reference herein, and can be employed in the practice of the application. More specifically, all referenced files are incorporated by reference to the same extent as if each individual publication, application or patent was specifically and individually incorporated by reference. The application includes all embodiments and variations falling within the scope of the claims.

[0064] In some embodiments, the application does not include steps involving medical or surgical treatment. Examples

[0065] Example 1 : Serenoa and Prunus extracts

[0066] Gamma cyclodextrin (GCD, Wacker Chemi, Germany) inclusion complexes were prepared using seed extract purified from Serenoa repens (Indena, Italy) and Prunus Africana bark extract (Indena, France) in a 2:1 ratio using a kneading method. The Serenoa extract is rich in fatty acids and phytosterols. For example, the Serenoa extract can include triglycerides and / or free fatty acids such as: oleic acid, lauric acid, caprylic acid, capric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, vaccenic acid, linoleic acid, linolenic acid, arachidic acid, gadoleic acid, behenic acid, lignoceric acid. For example, the phytosterols in the Serenoa extract can include: campesterol, beta-sitosterol, and stigmasterol. Similarly, the Prunus extract includes a variety of such compounds, for example, it can include: N- butylbenzenesulfonamide, atraric acid, beta-sitosterol, beta-sitostenone, and fatty acids such as linoleic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, lauric acid and myristic acid, behenyl alcohol, behenic acid, ursolic acid, lignoceric acid, ferulic acid, and friedelin.

[0067] The Prunus extract was amber in color, while the Juglans extract resembled a "tar ball" and contained a nearly black hardened extract that could be kneaded by hand. Both extracts had a nearly pleasant deep fruit odor that was almost completely eliminated when included in the cyclodextrin inclusion complex.

[0068] After drying and grinding, the inclusion complex samples were tested for susceptibility to enzymatic release of the herbal extract. In this test, 1 g of inclusion complex was mixed with 20 ml of distilled water in container 1, and an equal amount of 1 g of inclusion complex and 20 ml of distilled water, along with 20 mg of undiluted amylase powder (Enzyme Development Corporation, New York) was mixed in container 2. Both containers were heated to 37°C and stirred every 5 minutes.

[0069] At the 20 minute time point of the test, the color change in container 2 became noticeable and very pronounced at the 30 minute time point. In contrast, container 1 remained off-white (consistent throughout the entire 5 hours that followed). The contents of container 2 became noticeably darker as the amylase digested the GCD inclusion complex. After 30 minutes, the raw ingredients were again visible as the protective coating of the GCD was destroyed by the enzyme, and container 2 showed some of the natural color of the extract. Additionally, after 30 minutes, the odor of both ingredients was again noticeable in container 2 but not in container 1. At the 30 minute time point, no separation of the ingredients occurred in container 1, which could be evidenced by the absence of lipid, as the contents of this container remained inclusion complex granules. However, in container 2, at 30 minutes, the destruction of the inclusion complex was more apparent, not only in the solution bulk, but also as an oily smooth ring of the Juglans and Prunus extracts as lipid material around the container, and oil droplets could be seen on the white ceramic surface of container 2.

[0070] This example demonstrates that fatty acids and phytosterols can be effectively released from plant extracts formulated as CD inclusion complexes. Thus, this embodiment is illustrated for inclusion complexes comprising one or more of the following fatty acids and / or phytosterols: oleic acid, lauric acid, caprylic acid, capric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, vaccenic acid, linoleic acid, linolenic acid, arachidic acid, cetoleic acid, behenic acid, lignoceric acid, campesterol, beta-sitosterol; stigmasterol; N-butylbenzenesulfonamide, arachidic acid, beta-sitosteroi, behenyl alcohol, behenic acid, ursolic acid, lignoceric acid, ferulic acid, and friedelin.

[0071] Example 2: Butyric acid

[0072] Alpha cyclodextrin (ACD, Wacker Chemi, Germany) inclusion complexes containing butyric acid (Vigon, USA) were prepared using the kneading method. Butyric acid is a fatty acid (also known as butanoic acid) which is a clear, light oil at room temperature with a somewhat nauseating odor which is almost completely eliminated in the cyclodextrin inclusion complex. At concentrations greater than 10 ppm, the odor of butyric acid can be detected by the human nose and can cause irritation to the skin, eyes and respiratory system.

[0073] After drying and grinding, the sensitivity of the inclusion complex samples to the enzymatic release of butyric acid was determined. In this assay, 1 g of inclusion complex was mixed with 20 ml of distilled water in container 1 and an equal amount of 1 g of inclusion complex and 20 ml of distilled water along with 20 mg of undiluted amylase powder (Enzyme Development Corporation, New York) was mixed in container 2. Both containers were heated to 37°C and stirred every 5 minutes.

[0074] At the 25 minute time point, the odor of butyric acid in container 2 became noticeable and more pronounced at the 35 minute time point. In contrast, container 1 which had no enzyme added remained with the same faint odor and did not increase for the next 5 hours.

[0075] Example 3: Hemp oil extract

[0076] Gamma cyclodextrin (GCD, Wacker Chemi, Germany) inclusion complexes were prepared using the kneading method with a purified hemp oil extract (CV Sciences, USA). Hemp oil typically contains a variety of fatty acids, phytosterols and physiologically active ingredients such as: linoleic acid, alpha-linolenic acid, oleic acid, beta-sitosterol, campesterol, phytol, cycloartenol, gamma-tocopherol and cannabidiol, as well as a smaller proportion of terpenes, which are referred to herein as "hemp essential oil" as described below.

[0077] After drying and grinding, the sensitivity of the inclusion complex samples to the in vivo enzymatic release of the hemp oil extract was determined. In this assay, 390 mg of inclusion complex was encapsulated in size 0 capsules. A second set of capsules was prepared containing 390 mg of inclusion complex along with 10 mg of undiluted amylase powder (Enzyme Development Corporation, New York).

[0078] A 43 year old male in good health with 912 recorded sleep cycles was given 2 capsules of each formulation 30 minutes before his standard bedtime of 11 PM on different days. The dosing was well after dinner so there was no food to induce salivary amylase.

[0079] Figure 1 The typical sleep pattern of the subject is shown, including duration and level of deep sleep. Figure 2 The sleep pattern after taking the inclusion complex without any added amylase is shown, which shows a sleep pattern with slightly deeper sleep compared to the typical baseline, where the subject reported average sleep in his rating. Figure 3 Significantly, the subject described "the quietest sleep of her life". The entire sleep pattern reached a previously unattained depth of sleep and duration of deep sleep, except for a brief use of the bathroom upon waking, and a quick return to sleep.

[0080] This example illustrates the in vivo release of a physiologically active ingredient from an inclusion complex with amylase added to the inclusion complex formulation. One aspect of this example shows the independence of the formulation in releasing the active ingredient from any dependence on salivary or digestive amylase.

[0081] In exemplary embodiments, the optional formulation can include a plurality of biologically active molecules derived from cannabis or cannabis genus plants, such as cyclodextrin inclusion complexes of various cannabinoids such as cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN).

[0082] Example 4: Glaucoma

[0083] The subject in this example is a California medical doctor with experience using medical cannabis since 1996. The subject self-administered capsules prepared as described in Example 3, containing 390 mg of cannabis oil inclusion complex and 10 mg of amylase powder. After several days of continuous use, the subject's glaucoma was significantly improved, with better results using the inclusion complex than the subject had experienced in the past using isolated cannabidiol or any combination of standardized products.

[0084] Example 5: Lamellar inclusion complexes

[0085] This example relates to the production of a CD inclusion complex mixture, in which a plurality of optional guest molecules form inclusion complexes with a plurality of optional cyclodextrins, in which the size and / or affinity of each guest molecule matches the corresponding cyclodextrin, which has a cavity of the appropriate size or adapted to stably retain the guest molecule. In this way, a unique, e.g., size- varied, mixture of biologically active molecules can be formulated into inclusion complex mixtures, resulting in layered inclusion complex mixtures.

[0086] In an exemplary embodiment, cannabis essential oil is formulated with alpha and beta cyclodextrins in sequence (see Table 2 for percentage ratios). Some cannabis essential oil is first added to a slurry of alpha cyclodextrin and water, and kneaded for a period of time to form guest inclusion complexes of a size that fit the alpha cyclodextrin cavity. Next, additional water is added to the beta cyclodextrin, which has a larger cavity, and kneaded to obtain a sizeable mixture of layered inclusions by forming guest inclusion complexes that are too large to fit the alpha cyclodextrin cavity. By forming inclusion complexes with cyclodextrins having smaller cavities first, and then with cyclodextrins having larger cavities, the process provides a mixture of inclusion complexes in which the guest molecules are encapsulated in cyclodextrins that form the most stable inclusion complexes with them, avoiding suboptimal capture of small molecules by larger CDs. This process can be repeated with a series of larger or differently modified CDs to form a composite layered inclusion complex in which the guest molecules are retained in chemically or sterically compatible cyclodextrins in sequence.

[0087] Table 2: Cannabis essential oil analysis

[0088]

[0089]

[0090]

[0091] A synthetic mixture of layered inclusion complexes can be formulated to provide a different ratio of bioactive molecules than the original mixture from which the inclusion complexes were prepared. To employ the exemplary embodiment described above, samples of alpha cyclodextrin inclusion complexes from a series of cannabis essential oils can be combined, and then a single aliquot of beta cyclodextrin inclusion complexes can be added to the combined alpha cyclodextrin preparation, thereby providing a preparation enriched in smaller bioactive molecules in the form of inclusion complexes compared to the original composition of cannabis essential oil. Alternatively, as described above, a synthetic mixture of layered inclusion complexes can be prepared to reproduce the relative abundance of bioactive molecules in a selected starting material. In an exemplary embodiment, this is achieved by using a ratio of alpha cyclodextrin to beta cyclodextrin of 4: 1, reflecting the fact that about 80% of a sample of cannabis essential oil consists of bioactive molecules that fit alpha cyclodextrin inclusion complexes, and the remaining 20% fit beta cyclodextrin inclusion complexes.

[0092] Exemplary embodiments provide synthetic mixtures of layered inclusion complexes comprising a tunable ratio of cannabinoids and terpenes, such as from a Cannabis or cannabis sample or extract. These mixtures can include inclusion complexes of different cannabinoids, such as cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV), tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). Terpenes (isoprenoids) in these mixtures can include, for example, a-pinene, ocimene, caryophyllene (β-caryophyllene), camphene, camphor, eucatyptol, humulene (a-humulene), myrcene, γ-terpinene, cis-nerolidol, carene, terpinolene, terpineol, trans-nerolidol, p-cymene, linalool, phellandrene, guaiol, limonene, iso-pulegol, cary-oxide, a-terpinene, geraniol, valencene, fenchol, citronellol, myrcenol, pinene, orange oil, isopulegol, geranyl acetate, pulegone, and bisabolol.

[0093] Layered inclusion complexes can be formulated for delivery with one or more enzymes having cyclodextrin-degrading activity that can digest cyclodextrin while preserving a guest molecule. In selected embodiments, for example, the enzymes can be selected from those having a preferential or exclusive activity on a sub-class of cyclodextrin in the mixture. In this way, a layered cyclodextrin inclusion complex delivery vehicle can be adapted to contain two or more unique enzymes and formulated to have unique cyclodextrin-degrading activity that is activated upon delivery of the vehicle to two or more unique targets, such as two different sites in the gastrointestinal tract.

[0094] Example 6: Short-chain fatty acid inclusion complexes

[0095] The present embodiments relate to pharmaceutical, dietary supplement, food or medical food formulations comprising inclusion complexes of short chain fatty acids (SCFAs) alone or in combination with hydrophobic or hydrophilic cyclodextrins (including alpha, beta or gamma CD, and modified CD such as ethylated CD). The SCFAs can be present in ester form, such as glycerides (mono, di or triglycerides), salts or other pharmaceutically acceptable derivatives. The SCFA inclusion complexes can be provided in dosage form with enzymes having cyclodextrin degrading activity, such as alpha, beta or gamma amylases, which are capable of digesting the CD while leaving the SCFA guest molecule intact. Similarly, lipases can be added to the formulation to release SCFAs from oils, for example, acting on the esters of SCFAs, such as glycerides. These formulations can be formulated as immediate release dosage or food forms, or sustained release dosage or food forms. In sustained release dosage forms, the dissolution and release of one or more of the compositions, including the SCFA pharmaceutical ingredient, CD and / or amylase, can be maintained or delayed at a controlled rate. For example, amylases with or without CD inclusion complexes can be formulated in the form of microparticles or granules coated in a variety of sustained release coatings or resins. Similarly, glycerides such as triglycerides can be provided on a matrix, for example, spray dried on a cellulose matrix, for example, mixed with lipases. For example, these formulations can be adjusted to control or maintain the blood concentration of a pharmaceutical compound or its metabolites, such as SCFAs, at effective levels for a longer period of time than would be the case without a sustained release carrier.

[0096] One aspect of these formulations is the use of the SCFA dosage forms to the small and large intestine of a subject, such as a human or mammal. For example, the formulations can be used for adjunctive or therapeutic purposes in the treatment of gastrointestinal disorders such as colitis, diverticulitis, Crohn's disease, inflammatory bowel disease or irritable bowel syndrome (IBS). In another aspect, the formulations can be used to provide prophylactic or therapeutic treatment of neoplastic diseases of the gastrointestinal tract, such as colon cancer. In yet another aspect, the formulations can be used to provide prophylactic or therapeutic treatment of insulin sensitivity in diabetes. In yet another aspect, the formulations can be used to provide prophylactic or therapeutic treatment to increase thermogenic activity and subsequent weight loss.

[0097] In selected embodiments, the formulations provide a pharmaceutical formulation comprising inclusion complexes consisting of at least one SCFA as an active ingredient, which is capable of complexing as an inclusion complex with at least one hydrophobic cyclodextrin. In particular embodiments, for example, the SCFA can be one or more of butyric (butane), propionic or acetic acid. For example, a plurality of SCFAs can be provided in selected proportions, for example, from 9:1 to 1:9. For example, selected SCFAs can be formulated in an optimal formulation, for example, comprising 75%-95% butyric acid, 1%-20% propionic acid and 1%-10% acetic acid, for example, about 85% butyric acid, 10% propionic acid and 5% acetic acid.

[0098] Example 7: Gastrointestinal treatment with butyric acid formulations

[0099] This example illustrates the treatment of general gastrointestinal dysfunction. A 48 year old female with a history of recurrent and chronic clinically distinct symptoms of gastrointestinal dysfunction was given 30 mg of the butyric acid inclusion complex capsules prepared as described in Example 2, 4 capsules per day, administered 3 times. After 3 weeks of treatment, her physician reported clinically relevant evidence of treatment efficacy and for the first time in 4 years the patient showed signs of normal GI function.

[0100] Example 8: Gastrointestinal treatment with SCFA formulations

[0101] This example illustrates the treatment of specific gastrointestinal symptoms with a formulation comprising a mixture of SCFAs. The subject was a 65 year old male with intermittent liquid diarrhea with predictable symptomatic flare-ups after drinking coffee in the morning (especially after eating citrus in the morning) or after eating a large evening meal. Treatment was initiated with SCFA inclusion complexes, which were capsules containing inclusion complexes of butyric acid (27 mg), propionic acid (2.5 mg), and acetic acid (2.5 mg) with alpha cyclodextrin. The initial treatment regimen was 4 capsules, 3 times per day. This was subsequently reduced to twice per day. Within 24 hours of the first dose, the liquid diarrhea ceased and did not recur during the entire 5 week treatment period. During the treatment period, the patient reported that the stools began to be completely formed and the volume of stool was significantly reduced. The patient was also able to discontinue his routine antacid therapy after meals and before sleep and reported an improvement in tolerance to moderate alcohol consumption.

[0102] Example 9: IBD treatment with butyric acid formulations

[0103] This example illustrates the amelioration of symptoms of chronic irritable bowel disease (IBD). The patient was a 52 year old female with a 30 year history of chronic IBD who was receiving symptomatic treatment with doses of loperamide 2-4 times per day. Treatment was initiated with the butyric acid formulation described in Example 2, 3 capsules, 2 times per day, during an IBD flare-up, with no concomitant loperamide treatment during the 7 day treatment period with the butyric acid inclusion complex formulation. Within 48 hours, all diarrhea ceased. The patient also reported a marked suppression of appetite after the 7 day treatment. Thus, this example demonstrates treatment efficacy in the treatment of IBD and the use of SCFA inclusion complex formulations as appetite suppressants.

[0104] Example 10: Ostomy inflammation

[0105] This example illustrates the treatment of symptoms associated with ostomy, including inflammation and granulation. This is a medical history of a patient with a 3 year history of recurrent inflammation and infection of an ostomy. Prior to treatment with the butyrate CD formulation, the patient's history was as follows:

[0106] • Colon resection for ulcerative colitis in 1971;

[0107] • Ongoing Stachybotrys infection from November 2012 - January 2014;

[0108] • Immune system dysfunction secondary to Stachybotrys infection;

[0109] • Recurrent pouchitis and enterocutaneous fistula from 01 / 13 - 06 / 15, unresponsive to multiple doses of ciprofloxacin and metronidazole; 5 laparotomies were performed to reduce damage during this period; the intestinal reservoir was finally removed and replaced with a standard Brooke ileosomy;

[0110] • Two surgeries to clean up and eventually remove the ileostomy due to non-healing skin wounds;

[0111] • Persistent granulation tissue around the stoma, unresponsive to two steroid injections administered in combination with tacrolimus cream.

[0112] Oral treatment was initiated with the butyric acid formulation prepared according to Example 2, 8 capsules twice a day. The capsules were formulated with 30 mg of neat butyric acid in a slow release CD with amylase. When treatment was stopped, the healing of the inflammation gradually plateaued. Within 1 week of stopping the butyrate CD treatment, the lesions began to break down and grow again. The lesions continued to worsen for 2 weeks. Upon reinitiation of butyrate CD treatment, healing began again.

[0113] Example 11 : Myelofibrosis

[0114] This example illustrates the treatment of symptoms associated with myelofibrosis. A patient with myelofibrosis was treated with a quercetin CD formulation. The formulation was made from quercetin (Glanbia Nutritionals) powder, complexed with gamma cyclodextrin, dried and mixed with amylase powder. At the initiation of quercetin CD treatment, the patient required a blood transfusion approximately every 10 days. Upon initiation of quercetin CD treatment, the patient was able to increase the time between blood transfusions to 20 days. The patient had not achieved this result with standard quercetin supplementation therapy, according to the attending physician who has been practicing with quercetin since 1984.

[0115] This example illustrates that the delivery vehicle of the present application can be used to provide delivery of flavonoids with advantages, including bioflavonoids such as quercetin.

[0116] Example 12: Autism

[0117] This example includes treatment cases of children with autism spectrum disorder (ASD) using butyric acid a-cyclodextrin inclusion complexes with mixed amylases.

[0118] A 5 year old boy, O, diagnosed with ASD, was treated orally with butyric acid a-cyclodextrin inclusion complexes prepared by the kneading method and mixed with amylase. The dose was 30 mg of net butyric acid, twice a day. Within 10 days, psychiatric evaluation found a substantial improvement in ASD symptoms. This was consistent with the evaluation of the caregivers that there was a great improvement in the quality of life.

[0119] A 6 year old boy, M, diagnosed with autism spectrum, was treated with butyric acid a-cyclodextrin inclusion complexes prepared by the kneading method and mixed with amylase in the amount of ¼ teaspoon per day. M was unable to make eye contact when speaking to people, even his mother, and was unable to tie his own shoelaces. 24 hours after starting butyrate CD treatment, after 2 doses, M tied his own shoelaces and made direct eye contact with his mother while expressing pride in his achievement.

[0120] A 17 year old girl, diagnosed with autism non-verbal spectrum, was treated with 3 pellets, twice a day, of butyric acid a-cyclodextrin inclusion complexes prepared by the kneading method and mixed with amylase, 180 mg of net butyrate. Within 3 days, the patient showed better eye contact, became calmer, and was now able to point out and recognize animals and pictures in a picture book, even saying the names of specific characters.

[0121] Autism is associated with a variety of gastrointestinal symptoms, and studies have found evidence of unique characteristics of the gut microbiome in autistic patients, as well as related evidence of the beneficial effects of butyrate. Therefore, the present invention provides, in one aspect, butyric acid cyclodextrin inclusion complex formulations for the modulation of the gut microbiome in patients with neurological disorders.

[0122] Example 13: Hypoallergenic meal replacement formulations and elemental diet formulations

[0123] This example relates to the preparation of CD inclusion complexes mixtures in which individual amino acids or groups of amino acids form inclusion complexes with cyclodextrins, for example, to mask the taste and improve the solubility of not easily soluble amino acids.

[0124] In exemplary embodiments, CD inclusion complexes can be formed from individual amino acids known to have bitter or sulfur-dominant tastes, such as: L-phenylalanine, N-acetyl-cysteine (and L-cysteine), L-methionine, L-isoleucine, and L-tryptophan. In one example, these amino acids are individually included in β-cyclodextrin in equimolar ratios using a kneading method. A second set is included in γ-cyclodextrin in equimolar ratios using a kneading method. The materials are then dried and ground. Upon addition of tap water, the inclusion complexes are found to dissolve completely and mask the objectionable tastes quite well compared to the base material.

[0125] In another embodiment, the same amino acids (L-phenylalanine, N-acetyl-cysteine (and L-cysteine), L-methionine, L-isoleucine, and L-tryptophan) are premixed as a group of amino acids and then included in β-cyclodextrin in equimolar ratios using a kneading method. A second set is included in γ-cyclodextrin in equimolar ratios using a kneading method. The materials are then dried and ground. Upon addition of tap water, the inclusion complexes are found to dissolve completely and mask the objectionable tastes quite well.

[0126] Thus, these methods can be used for naturally occurring or synthetic individual or group amino acids. In some cases, β-cyclodextrin inclusion complexes can have strict dosage requirements, such as being limited to relatively small amounts per day by oral administration. Thus, for formulations of small dosages of specific amino acids, β-cyclodextrin can be a suitable choice for inclusion complexes (which can be more cost effective than α or γ cyclodextrins). Alternatively, when size permits, the amino acids can be included in α-cyclodextrin inclusion complexes.

[0127] Commercially available meal replacements for gastrointestinal training are available, such as Vivonex TMPlus, pre-packaged products of amino acids, soy oil (for essential fats), maltodextrin / corn starch (carbohydrate source), and essential vitamins and minerals and preservatives. The taste of the 5 amino acids that are bitter or sulfur dominant (L-phenylalanine, N acetyl-cysteine (and L cysteine), L-methionine, L-isoleucine, and L-tryptophan) can be considered to make such products unpalatable. The ingredients of such products, and the corresponding products of the present invention that contain one or more amino acids in the form of CD inclusion complexes, can include, for example: maltodextrin (from corn), L-glutamine, modified corn starch, L-leucine, L-arginine acetate, soy 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-aspartate, L-proline, L-tryptophan, disodium phosphate, potassium chloride, choline tartrate, L-serine, L-alanine, glycine, ascorbic acid, polyglycerol ester of fatty acids, taurine, L-carnitine, alpha-tocopherol acetate, zinc sulfate, potassium sorbate, and bha and bht and tocopherols (to preserve 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, phytonadione, vitamin B12.

[0128] For example, these meal replacement and basic dietary formulations can be formulated in a serving size of about 79.4 g to provide: protein (as amino acids) 13.5 g; fat 2 g; carbohydrate 57 g; vitamins, minerals and other ingredients 6.9 g.

[0129] Alternatively, the meal replacement formulations can provide amino acid profiles that mimic natural protein sources, such as chicken eggs.

[0130] In one exemplary embodiment, rapeseed oil (a source of fatty acids) is included in a γ-cyclodextrin inclusion complex using a kneading method in equimolar proportions. The material is then dried and ground and added as a premix to the meal replacement formulation. The proportions of the included premix in grams are: rapeseed oil 2.0; carbohydrate from γ-cyclodextrin 10.5. In this embodiment, the amino acids L-phenylalanine, N acetyl-cysteine, L-methionine L-isoleucine and L-tryptophan are premixed as a group of amino acids and then included in γ-cyclodextrin using a kneading method in equimolar proportions. The material is then dried and ground and added as a premix to the meal replacement formulation. The proportions of the included premix in grams are:

[0131] Amino acids:

[0132]

[0133] Carbohydrate from gamma cyclodextrin 26.8

[0134] The material is then added in grams of the following amino acids:

[0135]

[0136] The total amount of amino acids present in the mixture is 18.21 g. The total amount of gamma cyclodextrin in the mixture is 37.3 g. The total amount of rapeseed oil in the mixture is 2 g.

[0137] A dry mix of the material is prepared and the following are added:

[0138] Rice maltodextrin 19.7 g

[0139] Sodium chloride 366 mg

[0140] The formulation can contain a wide variety of vitamins and minerals. For example, a multi-vitamin mineral premix containing highly absorbable bioactive ingredients can be added, totalling about 3 g, and can include:

[0141] Vitamin A (2,00 IU from beta carotene and 1,000 IU as palmitate) 3,000 IU.

[0142] Vitamin C (as ascorbic acid) 50 mg.

[0143] Vitamin D (as vitamin D3) 200 IU.

[0144] Vitamin E (as d-alpha tocopherol) 40 IU.

[0145] Thiamin (as thiamin HCl) 5 mg.

[0146] Riboflavin (as riboflavin 5'-phosphate sodium) 2 mg.

[0147] Niacin (20 mg as niacinamide and 5 mg as nicotinic acid) 25 mg.

[0148] Vitamin B6 (as pyridoxal 5'-phosphate) 2 mg.

[0149] Folic acid (200 meg as L-5-methyltetrahydrofolate, glucosamine salt) 200 meg.

[0150] Vitamin B12 (10 meg as adenosylcobalamin and 10 meg as methylcobalamin) 20 meg.

[0151] Biotin 100 meg.

[0152] Pantothenic acid (as calcium RAEte) 20 mg.

[0153] Choline (as citrate) 100 mg.

[0154] Calcium (120 mg as calcium citrate and 90 mg as calcium malate) 210 mg.

[0155] Iron (as ferric pyrrolidone carboxylate) 3 mg.

[0156] Iodine (as potassium iodide) 225 meg.

[0157] Magnesium (60 mg as magnesium citrate and 30 mg as magnesium malate) 90 mg.

[0158] Zinc (as zinc pyrrolidone carboxylate) 3 mg.

[0159] Selenium (as L-selenomethionine) 40 meg.

[0160] Copper (as copper pyrrolidone carboxylate) 0.3 mg.

[0161] Manganese (as manganese pyrrolidone carboxylate) 3 mg.

[0162] Chromium (chromium picolinate glycinate chelate) * 40 meg.

[0163] Molybdenum (as molybdenum pyrrolidone carboxylate) 20 meg.

[0164] Potassium (30 mg as potassium citrate and 30 mg as potassium malate) 60 mg.

[0165] Boron (as boron pyrrolidone carboxylate) 0.5 mg.

[0166] Vanadium (as vanadium pyrrolidone carboxylate) 20 meg.

[0167] According to the above embodiments, a total serving of about 80 g is provided. This results in a tasty, hypoallergenic, Vivonex-type meal replacement formulation without the typically intolerable bitter or sulfur amino acid residue taste. Alternative servings, ingredients, and ingredient ratios are also provided. For example, additional or alternative ingredients, such as, for example, can contain nicotinamide riboside, butyric acid, and acetic acid.

[0168] In another embodiment, the amino acids L-phenylalanine and L-tryptophan are each encapsulated in a γ-cyclodextrin inclusion complex using a kneading process in equimolar proportions. Each material is then dried and ground, added to a premix and further added to a meal replacement formulation. Another premixing and inclusion protocol is repeated with these two amino acids, with identical results. Subsequently, the amino acids N-acetyl-cysteine, L-methionine and L-isoleucine are each encapsulated in a γ-cyclodextrin inclusion complex using a kneading process in equimolar proportions. Oil can also be added to the final product, for example, to take up less space in the final formulation. For the purposes of this example, the same amount of rapeseed oil as the amino acid is added to each amino acid inclusion by kneading during each process. L-phenylalanine is formulated with 0.85 grams of rapeseed oil, N-acetyl cysteine with 0.5 grams of rapeseed oil and L-methionine with 0.5 grams of rapeseed oil. Surprisingly, when added in these amounts, the oil is apparently encapsulated in the γ-cyclodextrin inclusion complex. Thus, not only does the cyclodextrin allow the amino acid to enter the cavity, masking the pungent taste of the amino acid, but the CD also allows at least a portion of the rapeseed oil triglyceride to enter, forming a notional plug-like structure in the cavity of the CD, locking the amino acid in the CD. Thus, the present application provides this type of formulation in combination with oil, which provides a soluble, flavour-masked amino acid. This example is repeated with a single fatty acid, decanoic acid, instead of rapeseed oil, with identical surprising results. This forms a lamellar double inclusion complex within a single cyclodextrin. Each of the rapeseed oil-treated materials is then dried and ground for addition to a premix and further addition to a meal replacement formulation. Another premixing and inclusion protocol is repeated with these three identical amino acids, followed by the addition of rapeseed oil, with identical final results.

[0169] As mentioned above, this example relates to palatable basic dietary formulations containing CD (with and without enzymes to facilitate the breakdown of the CD). In this context, there is some evidence that a basic diet can cause a reduction in pancreatic enzyme secretion in some patients, and for patients in this situation, it can be particularly advantageous to use one or more of the enzymes in the formulations of the present application.

[0170] Amino acid supplements can also be provided as CD inclusion complexes with and without enzymes to facilitate the breakdown of the CD.

[0171] For example, this can be particularly advantageous for branched chain amino acids, such as leucine, isoleucine and valine. Thus, in this example, leucine and valine are formulated in a palatable αCD inclusion complex and isoleucine is formulated in a palatable γCD inclusion complex.

[0172] Example 14: Acetaminophen inclusion complexes

[0173] In one aspect, the present embodiments relate to the preparation of CD inclusion complex mixtures in which an anti-inflammatory agent or pain relieving substance forms an inclusion complex with a cyclodextrin, thereby masking the taste and increasing the solubility when taken as a separate inclusion. In alternative embodiments, other substances can be included in the inclusion complex. These embodiments can be formulated with and without one or more enzymes to facilitate the breakdown of the CD.

[0174] In an exemplary embodiment, a kneading method is used to enclose acetaminophen in an α cyclodextrin inclusion complex in an equimolar ratio. A kneading method is used to enclose a second amount in a β cyclodextrin in an equimolar ratio. A kneading method is used to enclose a third amount in a γ cyclodextrin in an equimolar ratio. Each material is then dried and ground. Upon addition of tap water, the inclusions are found to dissolve completely and mask the unpleasant taste quite well.

[0175] In another embodiment, a kneading method is used to enclose N-acetyl-cysteine in a γ cyclodextrin in an equimolar ratio as in Example 13 above. The material is then dried and ground. Upon addition of tap water, the inclusion is found to dissolve completely and greatly masks the normally unpleasant taste and odor.

[0176] A premix of acetaminophen / γ-cyclodextrin and N-acetyl-cysteine / γ cyclodextrin dry powders is then prepared. Upon mixing with tap water, it provides a therapeutic dose of acetaminophen, as well as the hepatoprotective efficacy of N-acetyl-cysteine. The combination of the two ingredients (as inclusions) not only provides a vehicle for easier delivery of acetaminophen due to increased solubility, but also a delivery form of N-acetyl-cysteine with significantly reduced odor and unpleasant taste. For example, small amounts of flavor and sweetener compounds can be added to enhance such formulations, for example, in powder form or incorporated into other standard dosage forms, such as capsules or tablets, including sustained release forms, with and without enzymes to facilitate the breakdown of the CD.

[0177] Example 15: Hepatoprotective agents

[0178] The present embodiments relate to the preparation of CD inclusion complex mixtures in which a hepatoprotective substance forms an inclusion complex with a cyclodextrin, either as a separate inclusion or added to other substances also in the form of an inclusion complex, for example, to mask the taste and improve solubility.

[0179] In an exemplary embodiment, a kneading method is used to enclose N-acetyl-cysteine in a γ cyclodextrin in an equimolar ratio as in Example 13. The material is then dried and ground. Upon addition of tap water, the inclusion is found to dissolve completely and mask the unpleasant taste quite well.

[0180] Using a kneading method, curcumin extract (Sabinsa) was encapsulated in γ-cyclodextrin in a 1 :2 molar ratio. The material was then dried and ground. Upon addition of tap water, the inclusion was found to be completely dissolved and the objectionable taste was quite well masked.

[0181] Using a kneading method, curcumin extract (Sabinsa) was encapsulated in γ-cyclodextrin in a 1 :2 molar ratio. The material was then dried and ground. Upon addition of tap water, the inclusion was found to be completely dissolved and the objectionable taste was quite well masked.

[0182] Using a kneading method, curcumin extract (Sabinsa) was encapsulated in γ-cyclodextrin in a 1 :2 molar ratio. The material was then dried and ground. Upon addition of tap water, the inclusion was found to be completely dissolved and the objectionable taste was quite well masked.

[0183] Using a kneading method, curcumin extract (Sabinsa) was encapsulated in γ-cyclodextrin in a 1 :2 molar ratio. The material was then dried and ground. Upon addition of tap water, the inclusion was found to be completely dissolved and the objectionable taste was quite well masked.

[0184] Using a kneading method, curcumin extract (Sabinsa) was encapsulated in γ-cyclodextrin in a 1 :2 molar ratio. The material was then dried and ground. Upon addition of tap water, the inclusion was found to be completely dissolved and the objectionable taste was quite well masked.

[0185] N-acetyl-cysteine, for example, the drug used in the emergency room against acetaminophen overdose, for example, for patients at risk of hepatotoxicity as determined by the Rumack-Matthew nomogram for toxicity levels. Most ERs currently administer N-acetyl-cysteine by intravenous injection due to the extremely objectionable taste and odor of N-acetyl-cysteine. Thus, one embodiment is to provide a mixture containing N-acetyl-cysteine with or without CD-degrading enzymes, such as amylase, for example, formulated for administration to patients with water or juice as a rescue strategy for acetaminophen poisoning. These formulations can also be used prophylactically, for example, with daily or high doses of acetaminophen. Similarly, other hepatoprotective agents can be provided, including silymarin, curcumin, and other known hepatoprotective agents, including but not limited to grapefruit, naringin, naringenin, blueberry, cranberry, flavonoids, catechins, epicatechin, anthocyanins, proanthocyanidins, resveratrol, prickly pear fruit, chamomile, spirulina, propolis, and beta glucan.

[0186] In another aspect, acetaminophen itself can be formulated with the amino acid CD inclusion complex, with and without enzymes to facilitate the breakdown of the CD. For example, N-acetyl-cysteine CD inclusion complexes can be formulated, particularly for pediatric formulations, to prevent liver damage. In alternative embodiments, acetaminophen can be included in the same CD as N-acetyl-cysteine, for example, in a multi-layer, multi-component inclusion complex, for example, with acetaminophen as the primary inclusion and the amino acid as the secondary inclusion, or vice versa. In selected embodiments, utilizing gamma cyclodextrin, both acetaminophen and N-acetyl-cysteine can be included within the cavity of the CD.

[0187] The combination of two or more ingredients (in inclusion complex form) provides a vehicle for easier delivery of the ingredients due to increased solubility, and provides a delivery form with significantly reduced odor and unpleasant taste, which can be easily adjusted by adding small amounts of flavoring and sweetening agents to the powder form or incorporated into other standard dosage forms, such as capsules or tablets, including sustained release forms.

[0188] Example 16: Lamellar inclusion complexes

[0189] This example relates to the preparation of CD inclusion complex mixtures, in which substrates form inclusion complexes with cyclodextrins to mask taste, improve solubility of the layered inclusion. In an exemplary embodiment, a kneading method is utilized to incorporate N-acetyl-cysteine, as in Example 13, in equimolar proportions in gamma cyclodextrin. Acetaminophen is added to the N-acetyl-cysteine inclusion in equimolar proportions, forming a layered inclusion. The material is then dried and ground. Upon addition of tap water, the inclusion complex is found to dissolve completely and mask the off-taste quite well. In selected embodiments, layered inclusion complexes can be formulated so as to incorporate multiple compounds into a single cyclodextrin, for example, to reduce the volume of product dosage.

Claims

1. A cyclodextrin inclusion complex delivery vehicle comprising: cyclodextrin having a cavity; N-acetylcysteine and acetaminophen, both at least partially retained as guest molecules within the cavity of the cyclodextrin, forming a multi-component layered cyclodextrin inclusion complex; a pharmaceutically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained within the pharmaceutically acceptable carrier; and an enzyme having cyclodextrin degrading activity capable of digesting the cyclodextrin retaining the guest molecules, wherein the enzyme is co-formulated with the cyclodextrin inclusion complex such that the cyclodextrin degrading activity is activated upon oral delivery of the vehicle to a human patient, thereby releasing the guest molecules from the cyclodextrin cavity; wherein the enzyme is an amylase, a cyclodextrinase, or a neopullulanase.

2. The delivery vehicle of claim 1, wherein the enzyme comprises one of: a maltogenic amylase, a mammalian salivary amylase, a mammalian pancreatic amylase, or a microbial amylase.

3. The delivery vehicle of claim 2, wherein the microbial amylase is a bacterial-derived amylase.

4. The delivery vehicle of claim 1, wherein the cyclodextrin is a beta cyclodextrin or a gamma cyclodextrin.

5. The delivery vehicle of claim 1, wherein the cyclodextrin is a mixed methylated / ethylated cyclodextrin or a hydrophobic alkylated cyclodextrin.

6. The delivery vehicle of claim 1, wherein the delivery vehicle is formulated for sustained release of the N-acetylcysteine and acetaminophen.

7. The delivery vehicle of any one of claims 1-6, further comprising one or more hepatoprotective agents, wherein the one or more hepatoprotective agents are at least partially retained as guest molecules within the cavity of the cyclodextrin.

8. The delivery vehicle of claim 7, wherein the one or more hepatoprotective agents are selected from silymarin, curcumin, a flavonoid, resveratrol, or a beta-glucan.

9. The delivery vehicle of claim 8, wherein the flavonoid is selected from naringin, naringenin, catechin, epicatechin, an anthocyanidin, or a proanthocyanidin.

10. Use of the delivery vehicle of any one of claims 1-9 in the manufacture of a medicament for the treatment of pain and / or inflammation.

11. Use of the delivery vehicle of any one of claims 1-9 in the manufacture of a medicament for the prevention of toxicity caused by acetaminophen use and / or overdose.

12. A method of formulating a cyclodextrin inclusion complex delivery vehicle comprising: providing cyclodextrin having a cavity; providing N-acetylcysteine and acetaminophen, both at least partially retained as guest molecules within the cavity of the cyclodextrin, forming a cyclodextrin inclusion complex; providing a pharmaceutically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecules are stably retained by the cyclodextrin within the pharmaceutically acceptable carrier; and providing an enzyme having cyclodextrin degrading activity capable of digesting the cyclodextrin retaining the guest molecules, wherein the enzyme is co-formulated with the cyclodextrin inclusion complex such that the cyclodextrin degrading activity is activated upon oral delivery of the vehicle to a human patient, thereby releasing the guest molecules from the cyclodextrin cavity, wherein the enzyme is an amylase, a cyclodextrinase, or a neopullulanase.

13. The method of claim 12, wherein the enzyme comprises one of the following: a maltogenic amylase, a mammalian salivary amylase, a mammalian pancreatic amylase, or a microbial amylase.

14. The method of claim 13, wherein the microbial amylase is a bacterial-derived amylase.

15. The method of claim 12, wherein the cyclodextrin is a beta cyclodextrin or a gamma cyclodextrin.

16. The method of claim 12, wherein the cyclodextrin is a mixed methylated / ethylated cyclodextrin or a hydrophobic alkylated cyclodextrin.

17. The method of claim 12, wherein the delivery vehicle is formulated for sustained release of the N-acetylcysteine and acetaminophen.

18. The method of any one of claims 12-17, further comprising providing one or more hepatoprotective agents, wherein the one or more hepatoprotective agents are at least partially retained as guest molecules within the cavity of the cyclodextrin.

19. The method of claim 18, wherein the one or more hepatoprotective agents are selected from silymarin, curcumin, a flavonoid, resveratrol, or a beta-glucan.

20. The method of claim 19, wherein the flavonoid is selected from naringin, naringenin, catechin, epicatechin, an anthocyanidin, or a proanthocyanidin.

21. A cyclodextrin inclusion complex delivery vehicle, comprising: a cyclodextrin having a cavity; a biologically active molecule at least partially retained as a guest molecule within the cavity of the cyclodextrin, forming a cyclodextrin inclusion complex, wherein the guest molecule is a drug or prodrug, and wherein the drug or prodrug is a flavonoid, a cannabinoid, or an anti-inflammatory agent; a pharmaceutically acceptable carrier for the cyclodextrin inclusion complex, wherein the guest molecule is stably retained within the pharmaceutically acceptable carrier by the cyclodextrin; the delivery vehicle is formulated for oral delivery; and an enzyme having cyclodextrin-degrading activity capable of digesting the cyclodextrin retaining the guest molecule, wherein the enzyme is co-formulated with the cyclodextrin inclusion complex such that the cyclodextrin-degrading activity is activated upon oral delivery of the vehicle to a human, thereby releasing the guest molecule from the cyclodextrin cavity.

22. The delivery vehicle of claim 21, wherein the enzyme is co-packaged with the cyclodextrin inclusion complex in the delivery vehicle, the delivery vehicle further comprising a biochemically acceptable carrier for the enzyme.

23. The delivery vehicle of claim 21 or 22, wherein the flavonoid is quercetin.

24. The delivery vehicle of claim 21 or 22, wherein the anti-inflammatory agent comprises acetaminophen.

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