Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/42—Amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
  • A61K8/447—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof containing sulfur
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/005—Preparations for sensitive skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• N-ACETYLCYSTEINE AMIDE NACA
• (2R.2R )-3.3 -DISl EI A ⁇ FDIYE BIS(2- ACETAMIDOPROPANAMIDE) DIYAC.A
• the present invention relates in general to the use of N-acetylcysteine amide (NACA) or (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (diNACA) for the prevention and treatment of radiation dermatitis, radiation damage to the skin, skin lightening, whitening or to improve skin health.
• NACA N-acetylcysteine amide
• diNACA 2-acetamidopropanamide
• Radiation dermatitis is one of the most common adverse events in radiotherapy for cancer, and 95% of patients receiving radiotherapy show this symptom.
• the dermatitis not only decreases quality of life, but also hampers the conducting of necessary additional radiotherapy.
• Nrf2 activators seem appropriate for combating the progress of radiation dermatitis.
• Skin aging is a complex biological phenomenon that includes two independent clinically and biologically distinct processes, namely“intrinsic aging” and“extrinsic aging.
• Extrinsic aging is the result of exposure to outdoor elements, primarily ultraviolet (UV) irradiation.
• Photoaged skin shows a variety of age-associated clinical alterations, including deep wrinkles, sallow discoloration, and irregular pigmentation.
• ROS reactive oxygen species
• UVB-induced H2O2 in keratinocytes causes melanocyte degeneration in the skin of patients with vitiligo.
• NO ⁇ induces melanogenesis by increasing the amounts of tyrosinase and tyrosinase-related protein.
• Melanogenesis associated with ROS is suppressed by antioxidant treatment.
• NO ⁇ production via the stabilization of NO synthase contributes partly to the suppression of melanogenesis by ascorbic acid.
• N-acetyl cysteine (a precursor of glutathione) inhibits alpha-melanocyte-stimulating hormone induction by UVB irradiation.
• Glutathione a tripeptide of cysteine, glycine, and glutamate, is a primary antioxidant in the body and plays important roles in maintaining intracellular thiol status and in detoxification.
• glutathione exists in both reduced (GSH) and oxidized (GSSG) states, the majority of its pool in the body is in the reduced form.
• GSH exerts antioxidant activity by acting as a free- radical scavenger during the reductive detoxification of hydrogen peroxide and lipid peroxide.
• GSH serves as an electron donor.
• GSH nicotinamide adenine dinucleotide phosphate.
• GSH has a variety of physiological effects. Importantly, it inhibits melanogenesis by suppressing the activity of tyrosinase, and oral administration of GSH in humans reduces melanin production in the skin. GSH in aqueous solution is highly unstable and easily decomposed. For this reason, there have been no reported investigations of the skin-whitening effect of GSH in topical formulations, unlike in oral formulations.
• GSSG is less susceptible to decomposition in aqueous solution and is suitable for use in liquid form, although the skin-whitening effect of topical GSSG is unknown.
• Watanabe et al. (2014) demonstrated topical GSSG safely and effectively whitens the skin and improves skin condition.
• the present invention provides a method for the use of N-acetylcysteine (NAC), N-acetylcysteine amide (NACA) or (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (diNACA) for the prevention and/or treatment of at least one of: radiation dermatitis, radiation damage to the skin, skin lightening, whitening or to improve skin health in an animal or human that comprises administering to the animal or human a therapeutically effective amount of N-acetylcysteine amide NAC, NACA, or diNACA.
• NAC N-acetylcysteine
• NACA N-acetylcysteine amide
• diNACA (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide)
• the NAC, NACA or diNACA is provided in or with a pharmaceutically acceptable carrier.
• the NACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, topically, sublingually, by injection into the skin, or rectally.
• the NAC, NACA or diNACA is administered in daily doses of about 0.5 to 150 mg/Kg.
• NAC, NACA or diNACA is administered two or three times daily.
• NAC, NACA or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.
• a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine t
• the dose for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.
• the does for administration is 0,1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per dose.
• the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid.
• the NACA is administered prophylactically to prevent and/or treat radiation dermatitis, skin lightening, whitening or to improve skin health.
• the animal is a human.
• the method further comprises adding NACA or diNACA into a formulation to prevent radiation damage to the skin from sun exposure.
• the method further comprises adding NACA or diNACA into a formulation to prevent exposure to bioweapons, chemical bums, heat bums, contact damage caused by friction.
• the method further comprises adding NACA or diNACA into a formulation to treat xeroderma pigmentosa.
• the method further comprises adding NACA or diNACA into a formulation to treat other skin disorders caused by oxidative stress.
• the present invention includes a method for the prevention and/or treatment of radiation dermatitis, skin lightening, whitening or to improve skin health comprising: identifying a human in need of prevention and/or treatment of radiation dermatitis, skin lightening, whitening or to improve skin health ; and administering to the human a therapeutically effective amount of NAC, NACA or diNACA sufficient to prevent and/or treat the radiation dermatitis, skin lightening, whitening or to improve skin health .
• the NAC, NACA or diNACA is provided in or with a pharmaceutically acceptable carrier.
• the NAC, NACA or diNACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, topically, sublingually, cutaneously, subcutaneously, by injection into the skin, or rectally.
• the NAC, NACA or diNACA is administered in daily doses of about 0.5 to 150 mg/Kg.
• NAC, NACA or diNACA is administered two or three times daily.
• NAC, NACA or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.
• a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine t
• the dose for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.
• the does for administration is 0,1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per dose.
• the NAC, NACA or diNACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid.
• the NAC, NACA or diNACA is administered prophylactically to prevent and/or treat radiation dermatitis, skin lightening, whitening or to improve skin health.
• the method further comprises adding NACA or diNACA into a formulation to prevent radiation damage to the skin from sun exposure.
• the method further comprises adding NACA or diNACA into a formulation to prevent exposure to bioweapons, chemical bums, heat bums, contact damage caused by friction.
• the method further comprises adding NACA or diNACA into a formulation to treat xeroderma pigmentosa.
• the method further comprises adding NACA or diNACA into a formulation to treat other skin disorders caused by oxidative stress.
• FIGURE 1 shows that GSSG, NPI-001 (NACA) and NPI2 (diNACA) treatments decreased RHE Pigmentation.
• FIGURE 2 is a graph that shows that GSSG, NPI-001 (NACA) and NPI2 (diNACA) treatments decreased melanin extraction.
• FIGURE 3 is a graph that shows that NPI-001 (NACA) and (diNACA) increased levels of GSSG production in human skin exposed to UVA-induced oxidative skin damage.
• N-acetylcysteine also known as 2-acetamido-3-sulfanylpropanoic acid or NAC, has the structure:
• NACA N-acetyl-L-cysteine amide
• NAC N-acetyl-L-cysteine amide
• (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (diNACA), is the dimer form of N-acetyl-L-cysteine amide, acts as a carrier of NAC or cysteine has the structure:
• Gluthathione is a tripeptide, c-L-glutamyl-L-cysteinyl-glycine, found in all mammalian tissues. It has several important functions including detoxification of electrophiles, scavenging ROS ⁇ maintaining the thiol status of proteins, and regeneration of the reduced forms of vitamins C and E. GSH is the dominant non-protein thiol in mammalian cells; as such it is essential in maintaining the intracellular redox balance and the essential thiol status of proteins. Also, it is necessary for the function of some antioxidant enzymes such as the glutathione peroxidases.
• Intracellular GSH levels are determined by the balance between production and loss. Production results from de novo synthesis and regeneration of GSH from GSSG by GSSG reductase. Generally there is sufficient capacity in the GSSG reductase system to maintain all intracellular GSH in the reduced state, so little can be gained by ramping up that pathway. The major source of loss of intracellular GSH is transport out of cells. Intracellular GSH levels range from 1-8 mM while extracellular levels are only a few mM; this large concentration gradient essentially precludes transport of GSH into cells and once it is transported out of cells, it is rapidly degraded by g-glutamyltranspeptidase.
• GSH transporters could theoretically increase intracellular GSH levels, but is potentially problematic because the transporters are not specific for GSH and their suppression could lead imbalance of other amino acids and peptides. Thus, intracellular GSH levels are modulated primarily by changes in synthesis.
• GSH is synthesized in the cytosol of virtually all cells by two ATP-requiring enzymatic steps: L-glutamate + L-cysteine + ATP [ ] g-glutamyl-L-cysteine + ADP + Pi and g-glutamyl- L-cysteine + L-glycine + ATP [ ] GSH + ADP + Pi.
• the first reaction is rate-limiting and is catalyzed by glutamate cysteine ligase (GCL, EC 6.3.2.2).
• GCL is composed of a 73Kd heavy catalytic subunit (GCLC) and a 30Kd modifier subunit (GCLM), which are encoded by different genes.
• the apparent K m of GLC for glutamate is 1.8 mM and intracellular glutamate concentration is roughly 10-fold higher so that glutamate is not limiting, but the Km for cysteine is 0.1-0.3 mM, which approximates its intracellular concentration.
• the second reaction is catalyzed by GSH synthase (GS, EC 6.3.2.3), which is 118 Kd and composed of two identical subunits.
• EAAT sodium-dependent excitatory amino acid transporter
• GTRAP3-18 glutamate transporter associated protein 3-18
• NAC N-acetylcysteine
• NAC is used for the treatment of acetaminophen overdose at a dose of 140 mg/kg as the loading dose, followed by 70 mg/kg every 4 hours for 17 doses, starting 4 hours after the loading dose.
• NAC has been administered orally from 400 to 1000 mg once daily and from 200 to 600 mg three times daily.
• NAC is rapidly absorbed and then rapidly cleared.
• the plasma half-life of NAC has been reported to be 2.5 hours and no NAC is detectable 10-12 hours after administration.
• NAC is rapidly metabolized to cysteine, which is a direct precursor of glutathione.
• the present invention provides a method for the prevention, amelioration, or treatment of a disease or condition associated with oxidative stress in a subject comprising administration of a therapeutically effective amount of NACA, to increase the amount of glutathione expressed in the tissues of the subject.
• “active oxygen species” or“reactive oxygen species” are understood as transfer of one or two electrons produces superoxide, an anion with the form O2”, or peroxide anions, having the formula O2-” or compounds containing an 0-0 single bond, for example hydrogen peroxides and lipid peroxides.
• Such superoxides and peroxides are highly reactive and can cause damage to cellular components including proteins, nucleic acids, and lipids.
• agent refers to a therapeutically active compounds or a potentially therapeutic active compound, e.g., an antioxidant.
• An agent can be a previously known or unknown compound.
• an agent is typically a non-cell based compound, however, an agent can include a biological therapeutic agent, e.g., peptide or nucleic acid therapeutic, e.g., siRNA, shRNA, cytokine, antibody, etc.
• the terms“amelioration” or“treatment” is understood as meaning to lessen or decrease at least one sign, symptom, indication, or effect of a specific disease or condition.
• prevention, amelioration or treatment of radiation dermatitis, skin lightening, whitening or to improve skin health can be to reduce, delay, or eliminate one or more signs or symptoms of radiation dermatitis, skin lightening, whitening or to improve skin health including, but not limited to, improved skin health, a reduction in radiation induced dermatitis, skin lightening, and/or whitening; or any other clinically acceptable indicators of disease state or progression.
• Amelioration and treatment can require the administration of more than one dose of an agent, either alone or in conduction with other therapeutic agents and interventions. Amelioration or treatment does not require that the disease or condition be cured.
• Antioxidant refers to a molecule for slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Such reactions can be promoted by or produce superoxide anions or peroxides. Oxidation reactions can produce free radicals, which start chain reaction that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols, ascorbic acid or polyphenols.
• Antioxidants include, but are not limited to, a-tocopherol, ascorbic acid, Mn(III)tetrakis (4-benzoic acid) porphyrin, a-lipoic acid, and n-acetylcysteine.
• the terms“effective amount” or“effective doses” refer to that amount of an agent to product the intended pharmacological, therapeutic or preventive results.
• the pharmacologically effective amount results in the amelioration of one or more signs or symptoms of a disease or condition or the advancement of a disease or conditions, or causes the regression of the disease or condition.
• a therapeutically effective amount preferably refers to the amount of a therapeutic agent that decreases vision loss, the loss of overall visual acuity, the loss of visual field, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or more as compared to an untreated control subject over a defined period of time, e.g., 2 weeks, one month, 2 months, 3 months, 6 months, one year, 2 years, 5 years, or longer. More than one dose may be required to provide an effective dose.
• the terms“effective” and“effectiveness” includes both pharmacological effectiveness and physiological safety.
• Pharmacological effectiveness refers to the ability of the treatment to result in a desired biological effect in the patient.
• Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (often referred to as side-effects) resulting from administration of the treatment.
• side-effects the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (often referred to as side-effects) resulting from administration of the treatment.
• the term “ineffective” indicates that a treatment does not provide sufficient pharmacological effect to be therapeutically useful, even in the absence of deleterious effects, at least in the unstratified population.
• Treatment may be ineffective in a subgroup that can be identified by the expression profile or profiles.
• “Less effective” means that the treatment results in a therapeutically significant lower level of pharmacological effectiveness and/or a therapeutically greater level of adverse physiological effects, e.g., greater liver toxicity.
• a drug which is“effective against” a disease or condition indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in disease signs or symptoms, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.
• peroxidases or“a peroxide metabolizing enzyme” refer to a large family of enzymes that typically catalyze a reaction of the form:
• the optimal substrate is hydrogen peroxide, wherein each R is H, but others are more active with organic hydroperoxides such as lipid peroxides.
• Peroxidases can contain a heme cofactor in their active sites, or redox -active cysteine or selenocysteine residues.
• the term phrase“pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
• the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be“acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• pharmaceutically acceptable carriers for administration of cells typically is a carrier acceptable for delivery by injection, and do not include agents such as detergents or other compounds that could damage the cells to be delivered.
• materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ring
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BEIT), lecithin, propyl gallate, a- tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BEIT), lecithin
• Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, intramuscular, intraperotineal, intraocular, intravitreal, subretinal, and/or other routes of parenteral administration.
• the specific route of administration will depend, inter alia, on the specific cell to be targeted.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect.
• plurality is understood to mean more than one.
• a plurality refers to at least two, three, four, five, or more.
• a“polypeptide” or“peptide” is understood as two or more independently selected natural or non-natural amino acids joined by a covalent bond (e.g., a peptide bond).
• a peptide can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more natural or non-natural amino acids joined by peptide bonds.
• Polypeptides as described herein include full-length proteins (e.g., fully processed proteins) as well as shorter amino acids sequences (e.g., fragments of naturally occurring proteins or synthetic polypeptide fragments).
• small molecule refers to a compound, typically an organic compound, having a molecular weight of no more than about 1500 Da, 1000 Da, 750 Da, or 500 Da. In an embodiment, a small molecule does not include a polypeptide or nucleic acid including only natural amino acids and/or nucleotides.
• the term“subject” refers to living organisms, in particular, humans.
• the living organism is an animal, in certain preferred embodiments, the subject is a mammal, in certain embodiments, the subject is a domesticated mammal or a primate including a non-human primate.
• Examples of subject include humans, monkeys, dogs, cats, mice, rates, cows, horses, goats, and sheep.
• a human subject may also be referred to as a subject or patient.
• “superoxide dismutase” is understood as an enzyme that dismutation of superoxide into oxygen and hydrogen peroxide. Examples include, but are not limited to SOD1, SOD2, and SOD3. Sodl and SOD3 are two isoforms of Cu-Zn-containing superoxide dismutase enzymes exists in mammals. Cu-Zn-SOD or SOD1, is found in the intracellular space, and extracellular SOD (ECSOD or SOD3) predominantly is found in the extracellular matrix of most tissues.
• the term“therapeutically effective amount,” refers to an amount of an agent which is effective, upon single or multiple does administration to the cell or subject, in prolonging the survivability of the patient with such a disorder, reducing one or more signs or symptoms of the disorder, preventing or delaying and the like beyond that expected in the absence of such treatment.
• An agent or other therapeutic intervention can be administered to a subject, either alone or in combination with one or more additional therapeutic agents or interventions, as a pharmaceutical composition in mixture with conventional excipient, e.g., pharmaceutically acceptable carrier, or therapeutic treatments.
• the pharmaceutical agents may be conveniently administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical arts, e.g., as described in Remington’s Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1985).
• Formulations for parenteral administration may contain as common excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
• biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of certain agents.
• the present invention is directed to the use of NACA to improve skin health, and/or prevent, reduce, or treat radiation-induced dermatitis, skin lightening, and/or whitening.
• the present invention includes a method for use of N-acetylcysteine amide (NACA) or (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (diNACA) for the prevention and treatment of radiation dermatitis in a human that comprises administering to the human therapeutically effective amount of NACA.
• the NACA is provided in or with a pharmaceutically acceptable carrier.
• the NACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, topically, sublingually, or rectally.
• the embodiments of this invention are defined to include pharmaceutically acceptable derivatives thereof.
• A“pharmaceutically acceptable derivative” means any pharmaceutically salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention.
• Particularly favored derivatives are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood, to increase serum stability or decrease clearance rate of the compound) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
• Derivatives include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein.
• the embodiments of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
• modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
• Suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecylsulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, methanesulfonate, 2- napthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, and undeconaoate.
• Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)4+ salts.
• alkali metal e.g., sodium
• alkaline earth metal e.g., magnesium
• ammonium e.g., sodium
• N-(alkyl)4+ salts e.g., sodium
• This invention also envisions the quatemization of any basic nitrogen- containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quatemization.
• the embodiments of the invention can, for example, be administered by injection, intraocularly, intravitreally, subretinal, intravenously, intraarterially, subdermally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, directly to a diseased organ by catheter, topically, or in an ophthalmic preparation, with a dosage ranging from about 0.001 to about 100 mg/kg of body weight, or according to the requirements of the particular drug and more preferably from 0.5-10 mg/kg of body weight. It is understood that when a compound is delivered directly to the eye, considerations such as body weight have less bearing on the dose.
• Frequency of dosing will depend on the agent administered, the progression of the disease or condition in the subject, and other considerations known to those of skill in the art. For example, pharmacokinetic and pharmacodynamics considerations for compositions delivered to the eye, or even compartments within the eye, are different, e.g., clearance in the subretinal space is very low. Therefore, dosing can be as infrequent as once a month, once every three months, once every six months, once a year, once every five years, or less.
• the dosing frequency of the antioxidant will be higher than the expression construct, e.g., one or more times daily, one or more times weekly.
• FIG. 1 GSSG, NPI-001 and diNACA treatments decreased RHE Pigmentation.
• FIG. 2 GSSG, NPI-001 and diNACA treatments decreased melanin extraction.
• FIG. NPI-001 and diNACA increased levels of thiol production in human skin exposed to UVA-induced oxidative skin damage.
• RHE Reconstructed human epithelium
• RHE human epithelium
• MatTek MatTek (MelanoDermTM cat #MEL-300B).
• RHE were cultured for 14 days with reapplication of media with basolateral treatment every other day. Day 0, Day 7 and Day 14 RHE were photographed and frozen for melanin extraction.
• NPI-001 (NACA lOmM) successfully inhibited the pigmentation of MelanoDermTM RHE cultures over 14 days to a greater extent than both the 2% GSSG and lOmM diNACA treatments by both visual scoring and melanin extraction.
• NPI-001 NACA lOmM
• diNACA lOmM
• Dosing may be determined in conjunction with radiation dermatitis, radiation damage to the skin, skin lightening, whitening or to improve skin health.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• a typical preparation will contain from about 1% to about 95% active compound (w/w).
• such preparations contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required.
• Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity ad course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms and the judgment of the treating physician.
• NACA or diNACA may be useful agents in a topical product, e.g, a sunscreen product, thereby acting to protect skin cells from radiation damage.
• NACA or diNACA could be used alone, or in combination with each other or other agents in a sunscreen product.
• NACA or diNACA may be useful agents to treat xeroderma pigmentosa or protect patients with xeroderma pigmentosa from skin damage caused by exposure to the sun or other radiation
• NACA or diNACA may be useful in prevention or treatment of the effects of agents that cause skin damage attributed to oxidative stress in the skin. This includes, but is not limited to, bioweapons, chemical bums, heat bums, contact damage caused by friction, contact dermatitis, hypersensitivity reactions and skin wrinkles and dehydration.
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, TWEEN® 80) and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• suitable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
• NAC, NACA or diNACA is administered in daily doses of about 0.5 to 150 mg/Kg. In other embodiments, NACA is administered two or three times daily.
• NAC, NACA or diNACA is administered with a second active agent selected from ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, a-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• EDTA ethylenediamine tetraacetic acid
• the dose of NAC, NACA or diNACA for administration is, 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.
• the dose for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 102, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per dose.
• the NAC, NACA or diNACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid.
• the NACA is administered prophylactically to improve skin health, and/or prevent, reduce, or treat radiation induced dermatitis, skin lightening, and/or whitening.
• the present invention includes a method for the treatment of radiation-induced dermatitis, skin lightening, and/or whitening and to improve skin health comprising: identifying a human in need of treatment for age-related macular degeneration; and administering to the human a therapeutically effective amount of NAC, NACA or diNACA sufficient to treat improve skin health, and/or prevent, reduce, or treat radiation induced dermatitis, skin lightening, and/or whitening.
• NAC, NACA or diNACA is administered in daily doses of about 0.5 to 150 mg/Kg.
• NAC, NACA or diNACA is administered two or three times daily.
• NACA is administered with a second active agent as disclosed above.
• the dose of NAC, NACA or diNACA for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.
• the dose for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 102, 1- 3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per dose.
• the NAC, NACA or diNACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid.
• NACA is administered prophylactically to prevent improve skin health, and/or prevent, reduce, or treat radiation induced dermatitis, skin lightening, and/or whitening.
• “susceptible to” or“prone to” or“predisposed to” a specific disease or condition or the like refers to an individual who based on genetic, environmental, health, and/or other risk factors is more likely to develop a disease or condition than the general population.
• An increase in likelihood of developing a disease may be an increase of about 10%, 20%, 50%, 100%, 150%, 200% or more.
• the present invention provides a method for the use of N-acetylcysteine (NAC), N-acetylcysteine amide (NACA) or (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide) (diNACA) for the prevention and/or treatment of at least one of: radiation dermatitis, radiation damage to the skin, skin lightening, whitening or to improve skin health in an animal or human that comprises, consisting essentially or, consisting of: administering to the animal or human a therapeutically effective amount of N-acetylcysteine amide NAC, NACA, or diNACA.
• NAC N-acetylcysteine
• NACA N-acetylcysteine amide
• diNACA (2R,2R’)-3,3’-disulfanediyl bis(2-acetamidopropanamide)
• the NAC, NACA or diNACA is provided in or with a pharmaceutically acceptable carrier.
• the NACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, topically, sublingually, by injection into the skin, or rectally.
• the NAC, NACA or diNACA is administered in daily doses of about 0.5 to 150 mg/Kg.
• NAC, NACA or diNACA is administered two or three times daily.
• NAC, NACA or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.
• a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine t
• the dose for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.
• the does for administration is 0,1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per dose.
• the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid.
• the NACA is administered prophylactically to prevent and/or treat radiation dermatitis, skin lightening, whitening or to improve skin health.
• the animal is a human.
• the method further comprising adding a topical agent to protects skin cells from radiation damage.
• the method further comprising adding an active agent for the treatment of xeroderma pigmentosa or protect that protects the skin of patients with xeroderma pigmentosa from skin damage caused by exposure to sun or other radiation.
• the method further comprising adding an active agent for the treatment of bioweapons, chemical bums, heat bums, contact damage caused by friction, contact dermatitis, hypersensitivity reactions and skin wrinkles and dehydration.
• the present invention includes a method for the prevention and/or treatment of radiation dermatitis, skin lightening, whitening or to improve skin health comprising, consisting essentially or, consisting of: identifying a human in need of prevention and/or treatment of radiation dermatitis, skin lightening, whitening or to improve skin health; and administering to the human a therapeutically effective amount of NAC, NACA or diNACA sufficient to prevent and/or treat the radiation dermatitis, skin lightening, whitening or to improve skin health .
• the NAC, NACA or diNACA is provided in or with a pharmaceutically acceptable carrier.
• the NAC, NACA or diNACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, topically, sublingually, cutaneously, subcutaneously, by injection into the skin, or rectally.
• the NAC, NACA or diNACA is administered in daily doses of about 0.5 to 150 mg/Kg.
• NAC, NACA or diNACA is administered two or three times daily.
• NAC, NACA or diNACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid.
• a second active agent selected from at least one of ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytouene (BHT), lecithin, propyl gallate, a-tocopherol, citric acid, ethylenediamine t
• the dose for administration is 100, 150, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose.
• the does for administration is 0,1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, 7-10 grams per dose.
• the NAC, NACA or diNACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, dual release, mixed release, sachet, powder, or liquid.
• the NAC, NACA or diNACA is administered prophylactically to prevent and/or treat radiation dermatitis, skin lightening, whitening or to improve skin health.
• the method further comprising adding a topical agent to protects skin cells from radiation damage.
• the method further comprising adding an active agent for the treatment of xeroderma pigmentosa or protect that protects the skin of patients with xeroderma pigmentosa from skin damage caused by exposure to sun or other radiation.
• the method further comprising adding an active agent for the treatment of bioweapons, chemical bums, heat bums, contact damage caused by friction, contact dermatitis, hypersensitivity reactions and skin wrinkles and dehydration.
• the words“comprising” (and any form of comprising, such as“comprise” and“comprises”),“having” (and any form of having, such as “have” and“has”),“including” (and any form of including, such as“includes” and“include”) or “containing” (and any form of containing, such as“contains” and“contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
• “comprising” may be replaced with “consisting essentially of’ or“consisting of’.
• the phrase consisting essentially of’ requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention.
• the term“consisting” issued to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), propertie(s), method/process steps or limitation(s)) only.
• words of approximation such as, without limitation, “about”, “substantial” or“substantially” refer condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
• the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skill in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
• a numerical value herein that is modified by a word of approximation such as“about” may vary from the stated value by at least ⁇ 1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
• compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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