Compositions and therapeutic methods using glutathione

Abstract

A topical composition comprising nanoized L-glutathione and a cyclodextrin complex in a weight ratio of glutathione to ascorbic acid of 7:1 to 15:1 and 1:1 to 1:15, and ascorbic acid and an additional compound comprising dexpanthenol, thiamine, benzalkonium chloride, sodium hyaluronate, or acetyl-L-cysteine, wherein the composition is administered topically to treat symptoms of viral infections, including COVID-19 and influenza, as well as to treat herpes simplex, shingles, postherpetic neuralgia, genital herpes, alcohol detoxification, high triglycerides, age spots or melasma, and lupus.

Description

[Technical Field]

[0001] Related applications This application claims the interests of U.S. Provisional Application No. 63 / 029,240 filed on 22 May 2020 and U.S. Provisional Application No. 61 / 790,234 filed on 15 March 2013, both of which are incorporated herein by reference. Technical field The subject matter disclosed herein relates to the field of pharmacotherapy. In particular, the subject matter relates to compositions and therapeutic methods characterized by glutathione. [Background technology]

[0002] Glutathione (c-glutamylcysteinylglycine, GSH) is a major thiolated small peptide found in living cells. Due to its reducing and nucleophilic properties, GSH functions as a redox buffer, preventing oxidative damage. Glutathione depletion has been observed in many medical conditions, including acute respiratory diseases, lung diseases such as Parkinson's disease, and neurological disorders. Glutathione is indicated in the treatment of alcoholism and drug addiction, as well as for protection against cytotoxic chemotherapy and radiation trauma, and in the treatment of AIDS-related cachexia. It is desirable to apply the therapeutic effects of glutathione to the treatment of other conditions. [Overview of the project]

[0003] This specification provides topical compositions comprising: non-esterified, non-acetylated, and non-fatty acid-bonded reduced, nano-sized L-glutathione; gamma cyclodextrin; ascorbic acid; and one or more compounds selected from the group consisting of dexpanthenol, thiamine, benzalkonium chloride, sodium hyaluronate, and acetyl-L-cysteine; wherein the weight ratio of glutathione to ascorbic acid is between about 7:1 and 15:1. In another embodiment, the weight ratio of glutathione to ascorbic acid is between about 1:1 and 1:15. In yet another embodiment, one or more compounds are selected from the group consisting of dexpanthenol, thiamine, benzalkonium chloride, sodium hyaluronate, acetyl-L-cysteine, and potassium sorbate. [Modes for carrying out the invention]

[0004] Detailed description In some embodiments of the compositions described herein, the weight ratio of glutathione to ascorbic acid is about 7:1. In some embodiments, the weight ratio is about 10:1. In some embodiments, the weight ratio is in the range of about 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, or any ratio in between.

[0005] Some embodiments described herein relate to methods for treating a subject, comprising administering a topical composition to a region of the skin of the subject, wherein the composition comprises non-esterified, non-acetylated, and non-fatty acid-bonded reduced, nano-sized L-glutathione; gamma cyclodextrin; and ascorbic acid; the weight ratio of glutathione to ascorbic acid is between about 7:1 and 15:1; and the composition is administered 1 to 10 times per day. In some embodiments, the weight ratio of glutathione to ascorbic acid is between about 1:1 and 1:15.

[0006] In some embodiments, the composition further comprises one or more of dexpanthenol, thiamine, benzalkonium chloride, sodium hyaluronate, and acetyl-L-cysteine. In some embodiments, the composition further comprises one or more of dexpanthenol, thiamine, benzalkonium chloride, sodium hyaluronate, acetyl-L-cysteine, and potassium sorbate. In some embodiments, about 0.15 ml of the composition per dose is administered to the skin. In some embodiments, about 0.5 ml of the composition per dose is administered to the skin. In some embodiments, about 1.25 ml of the composition per dose is administered to the skin. Some embodiments further comprise a preservative blend which is a mixture of glycerin, leuconostoc / radish root ferment filtrate, Lonicera japonica (honeysuckle) flower extract, Lonicera caprifolium (honeysuckle) extract, Poplar tremuloides bark extract, and gluconolactone.

[0007] In some embodiments, the composition is administered once. In some embodiments, the composition is administered once daily. In some embodiments, the composition is administered twice daily. In some embodiments, the composition is administered every four hours.

[0008] In some embodiments, the administration period is 1 day. In some embodiments, the administration period is 2 weeks. In some embodiments, the administration period is 60 days. In some embodiments, the administration period is 4 months.

[0009] In some embodiments, the composition is applied to the skin at a depth of approximately 0.8 cm. 2 The composition is administered to a surface area of ​​approximately 24 square inches of skin. In some embodiments, the composition is administered to a surface area of ​​approximately 25 square inches of skin. Depending on the embodiment, any surface area between the above can be used.

[0010] In some embodiments, the patient is being treated for one or more of the following conditions: influenza, COVID-19, herpes simplex, shingles, postherpetic neuralgia, genital herpes, alcohol detoxification, high triglycerides, age spots or melasma, and lupus.

[0011] A therapeutic method is provided herein, comprising administering a composition comprising cyclodextrin and nano-sized L-glutathione to a patient in need of treatment. The composition may optionally contain other molecules, such as antioxidants.

[0012] In certain embodiments, the cyclodextrin is gamma cyclodextrin. The composition contains L-glutathione and nano-sized reduced glutathione (RealGSH). TM ) may include one or more of the above. In some embodiments, a native molecule is present, which comprises at least one of the following: a protein, a fragment thereof, and a polypeptide.

[0013] Gamma-cyclodextrin further enhances the transdermal and transmucosal delivery of the molecule, bypassing the gastrointestinal tract and eliminating the need for intravenous administration. Transdermal stabilized glutathione is a novel form of glutathione stabilized using encapsulation within a gamma-cyclodextrin ring structure to prevent oxidation of reduced glutathione by atmospheric oxygen.

[0014] In some embodiments, the native molecule comprises at least one nucleic acid and its fragments. The fragments may include at least one oligonucleotide, DNA, and RNA.

[0015] antioxidants Antioxidants are molecules that can inhibit the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. These radicals can then initiate a chain reaction. If a chain reaction occurs within a cell, it can lead to cell damage or cell death. Antioxidants terminate these chain reactions by removing free radical intermediates and inhibit other oxidation reactions. Antioxidants are often reducing agents containing thiols, such as GSH, ascorbic acid, or polyphenols, as they do this by being oxidized themselves. Thiol groups are present in animal cells at a concentration of about 5 mM. Glutathione reduces disulfide bonds formed within cytoplasmic proteins to cysteine ​​by acting as an electron donor. In the process, glutathione is converted to its oxidized form, glutathione disulfide (GSSG).

[0016] Oxidation is essential for life, but it can also be harmful, and oxidative stress appears to be a significant part of many human diseases. Therefore, plants and animals maintain a complex system of multiple types of antioxidants, such as GSH, vitamin C, and vitamin E, as well as enzymes such as catalase, superoxide dismutase, and various peroxidases. Low levels of antioxidants or inhibition of antioxidant enzymes can lead to oxidative stress, potentially damaging or killing cells.

[0017] In certain embodiments, the antioxidant comprises alpha-lipoic acid, ascorbic acid, uric acid, β-carotene, α-tocopherol, dimethylethanolamine (DMAE), coenzyme Q10, vitamin E, carnosine, colloidal silver, and at least one of the enzymes catalase, superoxide dismutase, and peroxidase. The composition may be a liquid, spray, aerosol, cream, serum, tablet, capsule, suppository, lotion, aqueous solution, powder, paste, ointment, jelly, wax, oil, lipid, or lipid (cationic or anionic) containing vesicles (Lipofectin TMetc.), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions, Carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and one or more carriers including semi-solid mixtures containing Carbowax.

[0018] The antioxidant has antioxidant activity and can be a soluble compound containing a mixture of two or more of ascorbic acid, ascorbic acid derivatives, L-cysteine, N-acetylcysteine, L-carnitine, acetyl-L-carnitine, riboflavin, and curcuminoids. The antioxidant can be in the range of 0.001 mol to 100 mol per mole of nano-sized L-glutathione, and in certain embodiments, the antioxidant is 0.01 mol or more and 10 mol or less per mole of nano-sized L-glutathione.

[0019] The antioxidant, such as ascorbic acid, can be present at a concentration of 1000 mg / ml, 900 mg / ml, 800 mg / ml, 700 mg / ml, 600 mg / ml, 500 mg / ml, 450 mg / ml, 400 mg / ml, 350 mg / ml, 300 mg / ml, 250 mg / ml, 225 mg / ml, 200 mg / ml, 175 mg / ml, 150 mg / ml, 100 mg / ml, 90 mg / ml, 80 mg / ml, 70 mg / ml, 60 mg / ml, 50 mg / ml, 40 mg / ml, 30 mg / ml, 20 mg / ml, 10 mg / ml, 8 mg / ml, 6 mg / ml, 5 mg / ml, 4 mg / ml, 3 mg / ml, 2 mg / ml, 1 mg / ml, or any amount between the above concentrations. The antioxidant, such as ascorbic acid, may be present between about 350 and 150 mg / ml. Table 1 shows the sample composition of the antioxidant present at a concentration of 250 mg / ml.

[0020] Table 1: Sample Composition

Table 1

[0021] Cyclodextrin Cyclodextrin (also called cycloamylose) is a family of compounds (cyclic oligosaccharides) in which sugar molecules are linked cyclically and is produced from starch by enzymatic conversion. Cyclodextrin is used in the food, pharmaceutical, chemical industries, as well as in agriculture and environmental engineering.

[0022] Cyclodextrin is composed of five or more (1,4)-linked α-D-glucopyranose units. In terms of conformation, cyclodextrin forms a torus with a hydrophobic interior and a hydrophilic exterior. Typical cyclodextrins contain a number of glucose monomers in the range of 6 to 8 units in the ring and form a conical shape. α-Cyclodextrin is a 6-membered sugar ring molecule, β-cyclodextrin is a 7-sugar ring molecule, and γ-cyclodextrin is an 8-sugar ring molecule. Cyclodextrin can be conformationally represented as a toroid, with the large and small openings of the toroid exposed to the second and first hydroxyl groups of the solvent, respectively. This arrangement makes the interior of the toroid not hydrophobic but considerably less hydrophilic than the aqueous environment and thus able to host other hydrophobic molecules. In contrast, the exterior is hydrophilic enough to confer water solubility to cyclodextrin (or its complex).

[0023] Thereby, cyclodextrin functions as a host molecule to form an inclusion complex with hydrophobic guest molecules. Cyclodextrin is known to enhance the effectiveness at the absorption site and affect the transdermal absorption of therapeutic agents by improving the transdermal penetration of therapeutic agents through solubilization of the drug and interaction with free lipids present in the stratum corneum.

[0024] The formation of inclusion compounds significantly alters the physical and chemical properties of the guest molecule, primarily in terms of water solubility. Thus, cyclodextrin inclusion compounds with hydrophobic molecules can penetrate biological tissues and be used to release biologically active compounds under specific conditions. The controlled degradation mechanism of such complexes may be based on changes in the solution's pH, causing the cleavage of hydrogen or ionic bonds between the host and guest molecules. Alternative means of disrupting the complex may include heating or the action of enzymes capable of cleaving the α-1,4 bond between glucose monomers.

[0025] In cyclodextrin inclusion, one or more guest molecules interact with the cavity of the cyclodextrin molecule to form a stable association. Molecules or functional groups of molecules less hydrophilic than water can be included in the cyclodextrin cavity in the presence of water. The "guest molecule" can be housed in the cyclodextrin cavity, at least partially. The size of the cavity and possible chemical modifications determine the affinity of the cyclodextrin to various molecules. For some low molecular weight molecules, multiple guest molecules can be housed in the cavity. Conversely, some high molecular weight molecules can bind to multiple cyclodextrin molecules. Therefore, a 1:1 molar ratio is not always achieved. The γ-cyclodextrin provided herein exhibits compatibility with glutathione, adequately protecting the glutathione molecule and effectively extending the glutathione half-life in the bloodstream.

[0026] In the solid state, guest molecules, even gaseous guest molecules, are molecularly dispersed within the cyclodextrin matrix. Therefore, guest molecules are effectively protected from all types of reactions, except for the hydroxyl group of the cyclodextrin. In aqueous solutions, the concentration of sparingly soluble guest molecules in the dissolved phase increases significantly. In most cases, the reactivity of guest molecules decreases.

[0027] Cyclodextrins can form inclusion complexes with a wide range of hydrophobic molecules, with larger γ-cyclodextrins accepting bulkier compounds. As provided herein, cyclodextrins and γ-cyclodextrins can form compounds with peptides, polypeptides, proteins, amino acids, nucleic acids, polynucleotides, DNA, and RNA, antioxidants such as ascorbic acid, carnosine, α-lipoic acid, DMAE, and coenzyme Q10, while other molecules such as colloidal silver can enhance the protective function of the complex and perform a variety of other functions.

[0028] Cyclodextrin complexes of drugs enhance drug stability, maintain release, and minimize photodegradation of the complexed drug. Cyclodextrin complex formation is useful for improving the chemical, physical, and thermal stability of drugs. Chemical reactions are necessary for the active molecule to decompose when exposed to oxygen, water, radiation, or heat. Once molecules are incorporated into cyclodextrin cavities, it becomes difficult for reactants to diffuse into the cavities and react with the protected guest.

[0029] The stabilized cyclodextrin-glutathione compound is provided in the form of a topically applied gel. The cyclodextrin ring structure is broken down by enzymes naturally present in the skin, and reduced glutathione is absorbed transdermally and enters the bloodstream.

[0030] Glutathione The glutathione (GSH) provided herein is natural, unesterified, unacetylated, and fatty acid-free, promoting high bioavailability. Glutathione is a tripeptide containing a unique peptide bond between the amine group of cysteine ​​and the carboxyl group of the glutamic acid side chain. It is an antioxidant that prevents damage to various cellular components caused by reactive oxygen species such as free radicals and peroxides. Glutathione is the most abundant low molecular weight thiol tripeptide synthesized intracellularly and helps maintain other antioxidants (such as vitamin C) in their active reduced form. Due to the unstable nature of the cysteine ​​moiety of glutathione, the clinical use of glutathione in medicine is limited. Therefore, when glutathione is administered intravenously, much of it is oxidized to GSSG within the IV bag during storage, transport, or infusion. Although spray forms are also used, the odor and taste reduce patient compliance, and it is counterintuitive to suggest that aerosolizing a highly reactive compound in the presence of atmospheric oxygen is an effective strategy.

[0031] In vivo, glutathione is almost without exception found in its reduced form, because glutathione reductase, the enzyme that reverts glutathione from its oxidized form, is constitutively active and induceable in response to oxidative stress. In fact, the ratio of reduced to oxidized glutathione in cells is often used as a measure of cytotoxicity. Glutathione helps prevent damage to cells by neutralizing harmful molecules produced during energy production. Glutathione also plays a role in processing pharmaceuticals and cancer-causing compounds (carcinogens), as well as in the construction of DNA, proteins, and other essential cellular components.

[0032] Glutathione is known as a substrate for both binding and reduction reactions catalyzed by the glutathione S-transferase enzyme in the cytosol, microsomes, and mitochondria. However, it can also participate in non-enzymatic conjugation with some chemicals. Glutathione is involved in leukotriene synthesis and is a cofactor for the enzyme glutathione peroxidase. It is also important as a hydrophilic molecule added in the liver during biotransformation before lipophilic toxins and waste products become part of bile. Glutathione also helps detoxify methylglyoxal, a toxin produced as a metabolic byproduct.

[0033] Low glutathione levels are strongly associated with depletion and negative nitrogen balance, as seen in cancer, AIDS, sepsis, trauma, burns, and even overtraining in athletics. Glutathione supplementation can counteract this process, leading to improved survival rates in AIDS, for example. Schizophrenia and bipolar disorder are associated with low glutathione levels. Accumulated data suggest that oxidative stress may be an underlying factor in the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione is a major free radical scavenger in the brain. Low glutathione levels increase cellular vulnerability to oxidative stress, which is characterized by the accumulation of reactive oxygen species. Glutathione supplementation with N-acetylcysteine ​​has been shown to alleviate symptoms of these disorders.

[0034] Glutathione is an antidote to overdose in the case of N-acetyl-p-benzoquinone imine (NAPQI), a reactive cytochrome P450 reactive metabolite formed by paracetamol (known as acetaminophen in the United States), which becomes toxic when glutathione is depleted due to excessive intake of acetaminophen. Glutathione conjugates to NAPQI and aids in detoxification. In this ability, glutathione protects the thiol groups of cellular proteins that would otherwise be covalently modified; once all glutathione is consumed, NAPQI begins to react with cellular proteins, killing the cells in the process.

[0035] Preliminary results in isolated cells suggest that glutathione may alter reactive oxygen species levels and reduce cancer development. Additional evidence indicates that appropriate levels of glutathione help control levels of tumor necrosis factor (TNF), a group of cytokines that can cause cell death. However, once cancer develops, elevated GSH levels in tumor cells confer resistance to many chemotherapy drugs, thus protecting cancer cells in bone marrow, breast, colon, laryngeal, and lung cancers.

[0036] Excessive synaptic glutamate release, which may occur in conditions such as traumatic brain injury, can interfere with the uptake of cysteine, a necessary component of glutathione. Without glutathione's protection against oxidative damage, cells could be damaged or killed.

[0037] Raising glutathione levels through direct supplementation is difficult. Studies suggest that orally ingested glutathione is broken down by digestive enzymes and not adequately absorbed from the gastrointestinal tract. Furthermore, natural GSH can oxidize very rapidly when exposed to air. Several attempts have been made to stabilize glutathione by acetylating or esterifying its thiol group.

[0038] The nano-sized L-glutathione and gamma-cyclodextrin complex protects glutathione from degradation and oxidation without altering the natural glutathione molecule.

[0039] Nano-sized L-glutathione-cyclodextrin complex Nano-encapsulation of pH-stabilized glutathione-cyclodextrin complexes may facilitate rapid absorption into the bloodstream. In some embodiments, sodium hydroxide, hydrochloric acid, or other acids are added to the stabilized glutathione and gamma cyclodextrin to adjust the pH of the solution. In various embodiments, the pH is adjusted to a range of 4.00 or higher and 7.8 or lower. In certain embodiments, the adjusted pH is 5.00 or higher and 7.2 or lower. The solution can be nano-encapsulated using ultrasound in the range of about 100 watts known in the art. Ultrasound may be applied for 1 minute or more and 10 minutes or less. In certain embodiments, ultrasound is applied for 3 minutes or more and 6 minutes or less.

[0040] The resulting nanoparticle sizes may range from 2 nanometers to 200 nanometers. In certain embodiments, the nanoparticles have sizes in the ranges of 2-20 nanometers, 20-40 nanometers, 40-60 nanometers, 60-80 nanometers, 80-100 nanometers, 100-120 nanometers, 120-140 nanometers, 140-160 nanometers, 160-180 nanometers, and 180-200 nanometers. In some embodiments, the nanoparticles may be of mixed sizes.

[0041] Therapeutic administration and formulations The compositions described herein may be effective outpatient treatments for COVID-19. Early treatment may prevent cytokine storm syndrome, which may be associated with COVID-19, shorten the time to complete symptom resolution, and restore patient well-being.

[0042] The compositions provided herein may be formulated as liquids, creams, serums, solids, lotions, oils, emulsions, sprays, aerosols, dissolving strips, boluses, suppositories, tablets, capsules, or other formulations using formulations and other methods known in the art. In certain embodiments, guest molecules such as gamma cyclodextrin and GSH are mixed in an aqueous solution containing ascorbic acid and benzalkonium chloride, mixed at a pH between about 3.0 and about 7.0, and then capped under vacuum. In some embodiments, the pH is about 5.5. In certain embodiments, the pH is about 3.0 to about 4.0, about 4.0 to about 5.0, about 5.0 to about 6.0, or about 6.0 to about 7.0.

[0043] The percentage of cyclodextrin can range from 1% to 50%. The percentage of cyclodextrin may be 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, or 45% to 50%. The percentage of glutathione or other guest molecules can range from 0.1% to 80%. In certain embodiments, the percentage of glutathione or other guest molecules is 0.1% to 1%, 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 85%, 85% to 90%, or 90% to 95% (or any percentage between the above).

[0044] In some embodiments, cyclodextrin is present at concentrations of approximately 69 mg / ml, 120 mg / ml, 155 mg / ml, or 250 mg / ml. In various embodiments, glutathione is present at concentrations of approximately 200 mg / ml, 350 mg / ml, or 550 mg / ml. The molar ratio of glutathione to cyclodextrin may be 26:1. The molar ratio of GSH to cyclodextrin may be between 1:15 and 30:1. As a non-limiting example, the molar ratio of glutathione or other guest molecule to cyclodextrin may be 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, and 1:1, or any of the aforementioned ratios. In certain embodiments, the molar ratio of GSH or other guest molecule:cyclodextrin may be 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10-1, 11:1, 12:1, 13:1, 14, to 15:1, 16:1, 17:1, 18:1, 19:1, 20-1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, and 30-1, or any of the aforementioned ratios. In certain embodiments, the glutathione concentration is 950 mg / ml. In various embodiments, the concentration of cyclodextrin is 150 mg / ml. The cyclodextrin may be gammacyclodextrin. In some embodiments, the combined concentration percentage is 95% GSH in 15% gammacyclodextrin.

[0045] Various natural molecules can bind to cyclodextrin in a similar manner to form inclusion complexes. In certain embodiments, antioxidants and other molecules, including but not limited to ascorbic acid, alpha-lipoic acid, uric acid, alpha-tocopherol, beta-carotene, or any other antioxidant molecule, may be added.

[0046] Specifically, the compositions of certain embodiments disclosed herein include nano-sized L-glutathione in a stabilized solution that may contain antioxidants. The antioxidants may be any soluble compounds having antioxidant activity, which may be a mixture of two or more of ascorbic acid, ascorbic acid derivatives, L-cysteine, N-acetylcysteine, L-carnitine, acetyl-L-carnitine, riboflavin, and curcuminoids. In some embodiments, the antioxidant may be between 0.001 moles and 100 moles per mole of reduced L-glutathione, and between 1 mole and 10 moles of reduced L-glutathione.

[0047] The compositions and methods may be administered under a physician's prescription or through retail stores, depending on the natural molecules and other components constituting the composition and the condition being treated. The routes of administration may follow known methods, including but not limited to: oral, sublingual, transdermal, transcutaneous, transmucosal, transmucosal, inhalation, intrafocal, oral cavity, or by the sustained-release systems described below. In some embodiments, the compositions provided herein are administered via small strips or other forms of substance that can dissolve in the patient's mouth. This allows for the convenience of solid therapy while maintaining the advantages of sublingual or mucosal delivery. Human oral enzymes can dissolve carbohydrates but cannot break down peptides or proteins, or many kinds of organic molecules. Therefore, compositions may be delivered directly into the bloodstream without exposure to digestive enzymes, without crossing the intestinal barrier, and without the need for intravenous delivery.

[0048] The therapeutic compositions disclosed herein are formulations comprising liquids, creams, serums, lotions, oils, emulsions, gels, pastes, powders, and liquid or powder aerosols (lyophilized) that can be administered through the skin, mucous membranes, nose, eyes, or lungs. The compositions may be administered parenterally or subcutaneously as needed. The compositions may be systemically administered and may be sterile, pyrogenically free, and parenterally acceptable solutions with appropriate consideration to pH, isotonicity, and stability. These conditions are known to those skilled in the art. Briefly speaking, the administration formulations of the compounds described herein are prepared for storage or administration by mixing the compounds of desired purity with physiologically acceptable carriers, excipients, or stabilizers, such as cyclodextrins and gammacyclodextrins. Such substances are nontoxic to the recipient at the dosage and concentration used and may include buffers such as TRIS HCl, phosphates, citrates, acetates and other organic acid salts; antioxidants such as ascorbic acid, carnosine, and alpha-lipoic acid; peptides such as polyarginine, proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidinone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; other carbohydrates including monosaccharides, disaccharides, and cellulose or its derivatives, glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and / or nonionic surfactants such as TWEEN, PLURONICS, and polyethylene glycol.

[0049] A suitable example of a sustained-release formulation includes a semipermeable matrix of a solid hydrophobic polymer containing the composition provided, the matrix being in the form of a molded article, film, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate)), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, and degradable lactic acid-glycolic acid copolymers such as poly-D-(-)-3-hydroxybutyrate.

[0050] Polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid allow for molecular release for over 100 days, while certain hydrogels release proteins in shorter periods. If encapsulated proteins remain in the body for extended periods, exposure to humidity at 37°C can result in denaturation or aggregation, leading to loss of bioactivity and altered immunogenicity. Depending on the relevant mechanism, rational strategies can be devised for protein stabilization. For example, if the aggregation mechanism is found to be intermolecular SS bond formation via disulfide exchange, stabilization can be achieved through modification of sulfhydryl residues, lyophilization from acidic solutions, control of water content, use of appropriate additives, and development of specific polymer matrix compositions.

[0051] The dosage of the composition herein for a given patient is determined by a therapist or physician, taking into account the natural molecules comprising the composition, and various factors known to alter the action of the drug, such as the severity and type of disease, body weight, sex, diet, time and route of administration, other pharmaceuticals, and other relevant clinical factors. A therapeutically effective dosage can be determined either in vitro or in vivo.

[0052] The effective dose of the therapeutically used compositions herein depends, for example, on the therapeutic purpose, the route of administration, and the patient's condition. Therefore, the therapist may escalate the dose and change the route of administration as needed to obtain the optimal therapeutic effect. The daily dose may range from approximately 0.001 mg / kg to a maximum of 100 mg / kg or more, depending on the factors described above. In some embodiments, the dose is 50, 100, or 200 mg of GSH administered as a topical gel. In some embodiments, the dose is administered twice daily, once in the morning and once in the afternoon. The clinician may administer the therapeutic compositions provided herein until a dose is reached that achieves the desired effect. The progress of this treatment can be monitored by conventional assays or as described herein.

[0053] In some embodiments, about 0.15 ml, 0.5 ml, or 1.25 ml of the composition is applied topically. In some embodiments, the composition is applied to about 0.5 cm 2 ~Approximately 25 square inches (for example, 0.8 cm) 2 It is applied to an area of ​​skin measuring 24 square inches or 25 square inches. In some embodiments, the composition is applied once a day, twice a day, or every four hours. In some embodiments, the composition is applied for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 20, 30, 40, 50, or 60 days. In some embodiments, the composition is applied for about 3, 4, 5, or 6 months, or about 1 year.

[0054] It is understood that the therapeutic substances administered by the compositions and methods herein may be administered together with appropriate carriers, excipients, and other agents incorporated into the formulation to improve mobility, delivery, tolerance, etc. Examples of such formulations include powders, pastes, ointments, jellies, waxes, oils, lipids (cationic or anionic), lipid-containing vesicles (such as Lipofectin®), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixture-containing carbowaxes. Any of the aforementioned mixtures may be suitable for treatment and therapy with the compositions herein, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable through the route of administration, as is known in the art.

[0055] The embodiments may be carried out in other specific forms. The embodiments described should be considered in all respects to be illustrative and not limiting. Accordingly, the scope of the invention is indicated by the appended claims rather than by the foregoing description. All modifications that fall within the meaning and scope of equivalence of the claims shall be included within that scope.

[0056] In some embodiments, therapeutic methods are further provided herein that include administering a composition of cyclodextrin, nano-glutathione, and antioxidants to a patient in order to treat a particular condition. The patient may be an animal selected from the group consisting of mammals, birds, reptiles, amphibians, and fish. Mammals may also be humans.

[0057] In certain embodiments, the conditions treated include one or more of the following: alcohol or drug addiction, intoxication, alcohol hangover, toxicity from cytotoxic chemotherapy, radiation trauma, AIDS-related cachexia, HIV / AIDS, herpes zoster, frostbite, heavy metal poisoning, laser burns, sunburn, traumatic burns, burns, burns including chemical burns, acne, pressure ulcers, autism, scar tissue, Parkinson's disease, hepatitis B, hepatitis C, upper respiratory tract viral infections (common cold), cystic fibrosis, insect bites (mosquito, spider, etc.), limb pain, neuropathy, reflex sympathetic dystrophy (RSD), rheumatoid arthritis, multiple sclerosis, osteoarthritis, psoriasis, psoriatic arthritis, jet lag, kidney disease (CRF, CKD), akathisia, and tardive dyskinesia.

[0058] In various embodiments, the conditions treated include: obesity, immunosuppression, inflammation, angina, heart disease, and cardiac reperfusion injury; lung and neurological diseases such as acute respiratory diseases, emphysema, pulmonary fibrosis and associated muscle wasting, asthma, and migraines; Parkinson's disease, herpes zoster, HSV, hepatitis B and C, as well as influenza, fibromyalgia; osteoporosis / osteomalacia; cancers including but not limited to those of the brain, head and neck, thyroid, lung, esophagus, stomach, intestines, liver, pancreas, kidneys, uterus, ovaries, prostate, leukemia (acute and chronic), lymphoma, multiple myeloma, and others; and systemic sclerosis. (Scleroderma) syndrome, sepsis, trauma, wrinkles, sagging skin, acne, atopic dermatitis and eczema, hyperactivity and muscle fatigue; schizophrenia, bipolar disorder, major depressive disorder, dementia, autism, attention deficit hyperactivity disorder (ADHD); acetaminophen overdose, low energy, drug toxicity; eye diseases such as cataracts, glaucoma, macular degeneration, macular dystrophy, diabetic retinopathy, decreased visual acuity, diabetic retinopathy, and contrast sensitivity; biomolecular imbalances due to traumatic brain injury or other causes, as well as one or more of male and female infertility.

[0059] In some embodiments, the conditions to be treated include one or more of COVID-19, herpes simplex, postherpetic neuralgia, genital herpes, high triglycerides, age-related or melasma, and lupus.

[0060] This specification further provides embodiments of a kit for topical application, comprising a cyclodextrin and nano-sized L-glutathione complex, a container for dispensing the composition, a composition applicator, and one or more instructions for use.

[0061] Throughout this specification, any reference to “several embodiments,” “specific embodiments,” “various embodiments,” or similar terms means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment. Thus, any appearance of “several embodiments,” “specific embodiments,” “various embodiments,” and similar terms throughout this specification means, but not necessarily, the same embodiments, but unless otherwise explicitly specified, “one or more embodiments, not all embodiments.” The terms “including,” “comprising,” “having,” and their variations mean “including, but not limited to,” unless otherwise explicitly specified. An enumerated list of items does not mean that some or all items are mutually exclusive and / or mutually exclusive unless otherwise explicitly specified. The terms “a,” “an,” and “the” also mean “one or more,” unless otherwise explicitly specified.

[0062] Furthermore, the features, structures, or properties described in the embodiments can be combined in any suitable manner. However, those skilled in the art will understand that the embodiments can be carried out without one or more specific details, or using other methods, components, materials, etc. Rather, the terms referring to features and advantages are understood to mean that a particular feature, advantage, or property is included in at least one embodiment. Thus, the descriptions of features and advantages, and similar terms, may, but not necessarily, refer to the same embodiments throughout this specification. In other examples, well-known protocols, reagents, materials, or procedures are not illustrated or described in detail to avoid obscuring aspects of the embodiments. [Examples]

[0063] Randomized controlled trial for the treatment of COVID-19 virus with glutathione composition A sample size of 186 adults was selected for the study. Inclusion criteria for subjects were: positive for SARS-CoV-2 laboratory testing (RT-PCR), 60 years of age or older, willingness to participate in a randomized controlled trial, SaO2 / SpO2 ratio greater than 95%, and AST / ALT less than 5 times normal. Exclusion criteria for subjects were: asymptomatic COVID-19 positive patients, pulmonary pneumonia secondary to bacterial infection, pregnant patients, patients with severe or serious illnesses, and patients with severe or renal failure with a GFR less than 50. Selected subjects exhibited minimal symptoms of fever, shortness of breath, or dry cough. Subjects may experience additional symptoms such as body aches and fatigue.

[0064] Half of the subjects (control group) were given a placebo, and the other half (experimental group) were given the following topical glutathione composition: Glutathione 350 mg / ml; Ascorbic acid 50 mg / ml; Dexpanthenol 2 mg / ml; and Cyclodextrin 155 mg / ml

[0065] Each subject receives 0.5 ml of the composition (or placebo) every 4 hours for 5 days, or until symptoms subside. Subsequently, subjects apply 0.5 ml twice daily for 14 days.

[0066] All subjects will be monitored for the time to clinical recovery, defined as the resolution of fever and cough that lasts for at least 72 hours. Fever is considered resolved when the subject's body temperature reaches 36.6°C on the surface, 37.2°C in the armpit and mouth, or 37.8°C in the rectum and eardrum. Cough is considered resolved when the subject reports having a mild cough or no cough. Temperature and cough will be checked three times a day.

[0067] Only 7% of the control group subjects developed serious illness, in contrast to the estimated 13.8% in the untreated group. Furthermore, only 3% of the control group subjects required mechanical ventilation, in contrast to the estimated 6.1% in the untreated group. [Examples]

[0068] Randomized controlled trial for the treatment of COVID-19 virus with glutathione composition Ten individuals participated in this experiment. After the risks and benefits were discussed through telemedicine visits, they received glutaryl. TM The patient was advised to self-manage their condition. Data was collected during the first telemedicine visit to record symptoms, age, sex, and chronic diseases. Documented symptoms followed World Health Organization (WHO) standards. Until July 2020, nausea was not yet recognized by the WHO, so no individual questions were asked. The administration protocol was 4 sprays 5 times a day for 5 days, followed by 4 sprays 2 times a day for 2 weeks. The spray was administered to the abdomen and absorbed into the systemic circulation. Glutarlyl TM Clinical responses were monitored via telemedicine 3, 7, and 10 days after administration of the spray.

[0069] Glutarlyl TM The spray contains the following ingredients: glutathione 200 mg / ml, ascorbic acid 20 mg / ml, and cyclodextrin 69 mg / ml.

[0070] result Table 2 summarizes the responses of 10 individuals. The outcome determination was the number of days from the onset of illness and participation in the study until the symptoms resolved. In all cases, the resolution of all symptoms and the restoration of a sense of well-being were achieved within 2 to 8 days after using Glutaryl TM . No subjects required hospitalization.

[0071] Cases 2, 4, 5, 7, and 8 had early treatment and recovered within 3 days. In the cases of 1, 3, 6, 9, and 10, it took a total of 10 to 12 days from onset to recovery, which may reflect the influence of chronic diseases, advanced age, and / or delayed treatment.

Table 2

Claims

1. Reduced, nano-sized L-glutathione that is non-esterified, non-acetylated, and non-fatty acid bound; Gamma cyclodextrin; Ascorbic acid; and One or more compounds selected from the group consisting of dexpanthenol, thiamine, and sodium hyaluronate; Includes, Here, the weight ratio of glutathione to ascorbic acid is 10:1, in a topical composition.

2. The composition according to claim 1 for use in a method for treating COVID-19.

3. The composition for use according to claim 2, wherein the composition is administered once to ten times per day.

4. The composition for use according to claim 2 or 3, wherein 0.15 ml, 0.5 ml, or 1.25 ml of the composition is administered to the skin per dose.

5. The composition for use according to any one of claims 2 to 4, wherein the composition is administered once, once daily, or twice daily.

6. The composition for use according to any one of claims 2 to 4, wherein the composition is administered every four hours.

7. A composition for use according to any one of claims 2 to 6, wherein the administration period is 1 day, 2 weeks, 60 days, or 4 months.

8. The composition is applied to 0.8 cm of skin. 2 A composition for use according to any one of claims 2 to 7, administered to a surface area of ​​24 square inches or 25 square inches.

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