JP4974813B2 - Ways to relieve itch - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for the remission of itching. <P>SOLUTION: A method for the prevention, treatment or remission of the itching caused by a disease of skin, mucosa or whole body is provided. The method comprises a step of administering an effective amount of a medicinal composition comprising phenylacetic acid, its short chain fatty acid derivative and pharmaceutically acceptable carrier, salt or solvent of the same, on a subject having itchiness, or a step of locally applying the same to a lesion having the itchiness. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention relates to a method for ameliorating itch, and in particular, a method of using phenylbutyric acid or a single chain fatty acid derivative to prevent, treat, or ameliorate itch associated with a local or systemic disease or disorder. About.

  As is known, the skin sensation called itching is characterized by an unpleasant, itching sensation of the skin, which induces scratching behavior. Scratching behavior can be so severe that the subject's suffering skin becomes tingling or reddening. Itching is also characterized by a heterogeneous response to a wide range of physical, chemical, and / or biological stimuli, which may include allergic reactions to drugs, insect bites, and environmental allergens, or Endogenous associated with specific dermatological conditions such as thyroid poisoning, diabetes mellitus, uremia, iron deficiency anemia, parasitosis delusions, true transient erythrocytosis, cholestasis, and Hodgkin's disease May depend on gender or exogenous nature. Itching usually occurs in the skin but can also occur in non-skin areas such as mucous membranes. Thus, the cause of itching can be multifactorial or can be due to a single underlying disease. The pathophysiology of pruritus involves central and peripheral nervous systems, multiple cytokine release, and molecular mediators.

  When the origin of itching is in the skin, sensory nerve endings at the dermal-epidermal junction are stimulated. The itch sensation is transmitted along a dedicated indefinite C fiber, which is different from the fiber that transmits pain and touch. The irritated skin is thought to transmit the sensation of itching by stimulating local nerves in the spinal cord. From here, the stimulation proceeds through the lateral spinal thalamic tract to the thalamus, and then reaches the surface of the cerebral cortex, where it causes a sense of itchiness (Non-Patent Document 1). Gastrin-releasing peptide receptor (GRPR), histamine, substance P, and tumor necrosis factor α (TNF-α) are thought to have an important role in the recognition of itch (Non-patent Document 2). Furthermore, with respect to the central nervous mechanism in which pruritus is detected, opioid peptides and μ receptors are involved in the induction of cholestasis itch, which responds to intravenous naloxone (Non-Patent Document 3). On the other hand, serotonin reuptake inhibitors can improve systemic itching induced by cholestasis, suggesting that the serotonergic pathway is also important for pruritus recognition (Non-Patent Document 4).

  On the other hand, histamine, tachykinin, serotonin (5-hydroxytryptamine (5-HT)), interferon (IFN) -γ, released from activated macrophages, mast cells, or T cells at the site of pruritoceptive origin Locally released substances are involved, including interleukin 2 (IL-2) and IL-4, and symptoms of pruritus, scratching, bumps, skin rash, hives and / or scaling Causes symptoms (Non-patent document 5; Non-patent document 6). Since subjects suffering from itch caused by dermatological or systemic illness can exacerbate itching by excessively scratching the affected area over a very wide area, excessive scratching behavior can cause irritation, inflammation, wounding Can lead to formation and possibly infection. With regard to the peripheral mechanism of itching, the role of multiple cytokine release and molecular mediators in the development of signs and symptoms of itching in the affected skin or mucosa has been defined. Histamine-induced itching requires the H1 receptor (Non-patent Document 7). Tachykinins, including neuropeptides such as substance P, calcitonin gene-related peptides, and vasoactive intestinal peptides, have been found in the skin free nerve endings of innocuous nociceptor neurons where the sensation of itch begins. Intradermal 5-HT can induce pruritus and scratching behavior by acting on 5-HT2 and 5-HT3 receptors (Non-patent Document 8). These findings have led to the use of 5-HT2 or 5-HT3 receptor antagonists to treat itch (9). When administered subcutaneously, IL-2 causes highly localized pruritus in both atopic patients and normal subjects (10). Inhibition of IL-2 biosynthesis by immunosuppressive agents such as cyclosporin A reduces the itch of atopic dermatitis (Non-patent Document 11).

  Antihistamines are widely used to suppress itching, but it is unclear to what extent the suppression is a result of side effects of central nerve sedation rather than local histamine antagonism in the skin (Non-patent Document 12). ). It has been reported in many patients that itching persists even with current antihistamine treatments, 5-HT receptor antagonists, and / or immunosuppressants, but this is Because most are ineffective and can only provide short-term relief with side effects. Itching can be quite debilitating for some patients. Accordingly, there is a continuing need to develop new and improved methods and compositions for preventing, treating or reducing itch caused by various causes.

  Phenylbutyrate, a short chain fatty acid, has been approved by the FDA as a rare drug for congenital abnormalities with urea cycle disease to treat hyperammonia (Non-patent Document 13). In the human body, phenylbutyrate is metabolized and converted to phenylacetate via β-oxidation. Phenyl acetate subsequently joins with glutamine to form phenylacetylglutamine, which serves as a medium for unwanted nitrogen emissions. Recently, phenylbutyrate has also been found to have the ability to inhibit deacetylation, increase acetylation in histone and non-histone proteins, reconstruct chromatin structures, and alter the action of multiple transcription factors. As a result, many genes are modified simultaneously and epigenetically, thus controlling the disease (Non-patent Document 14). In preclinical and clinical studies, the genetic modification effect of phenylbutyrate has been shown to affect many hematological and solid tumors, cystic fibrosis, sickle cell anemia, β-Mediterranean anemia, X-linked adrenoleukodystrophy, spinal muscular atrophy, Therapeutic potential in genetic genetic diseases such as neurodegenerative diseases, aging, and inflammatory diseases such as autoimmune diseases has been shown (Non-Patent Document 15; Non-Patent Document 16; Non-Patent Document 17; Non-Patent Document Reference 18). In addition, phenylbutyrate may also serve as a chemical chaperone to protect normal cells from oxidative stress damage and to prevent neurotoxicity (Non-Patent Document 19).

Weldon D. Allergy Asthma Proc 28: 153-62, 2007 Sun YG, et al. Nature 448: 700-703, 2007 Jones EA, et al. JAMA 268: 3359-62, 1992 Mayo MJ, et al. Hepatology 45: 666-74, 2007 Greaves MW, et al. Lancet 348: 938-40, 1996 Inagaki N, et al. Eur J Pharmacol 546: 189-96, 2006 Davies MG, et al. Br J Clin Pharmacol 9: 461-65, 1980 Nojima H, et al. J Pharmacol Exp Ther 306: 245-52, 2003 Schworer H, et al. Lancet 341: 1277, 1993 Wahlgren CF, et al. Arch Dermatol Res 287: 572-80, 1995 Wahlgren CF, et al. Acta Derm Venereol (Stockh) 70: 323-29, 1990 Krause L, et al. BMJ 287: 1199-200, 1983 Brusilow SW, et al. N Engl J Med 310: 1630-4, 1984 Marks PA, et al. J Natl Cancer Inst 92: 1210-6, 2000 Kemp S, et al. Nat Med 4: 1261-8, 1998 Borovecki F, et al. Proc Natl Acad Sci USA 102: 11023-8, 2005 Kang HL, et al. Proc Natl Acad Sci USA 99: 838-43, 2002 Blanchard F, et al. Drug Discov Today 10: 197-204, 2005 Yam GH, et al. Invest Ophthalmol Vis Sci 48: 1683-90, 2007

  An object of the present invention is to provide a method for ameliorating itch.

The present invention provides pharmaceutical compositions and methods for preventing, treating, or ameliorating itch associated with skin, mucosal, or systemic diseases and conditions. The method comprises administering or itching an effective amount of a pharmaceutical composition comprising phenylbutyric acid or a short chain fatty acid derivative and a pharmaceutically acceptable carrier, salt, or solvate thereof to a subject with itch. Including locally applying to the affected area.

The invention further provides pharmaceutical compositions and methods for preventing, treating, or ameliorating itch associated with skin, mucosal, or systemic diseases and conditions. The method comprises an effective amount of a pharmaceutical composition comprising a short chain fatty acid derivative of 2 to 6 carbons in combination with phenylbutyric acid or other antipruritic agent and a pharmaceutically acceptable carrier, salt, or solvate thereof. Is administered to a subject with itching or is applied topically to the affected area with itching.

  A detailed description is given in the following aspects with reference to the accompanying drawings.

  Specifically, the present invention provides the following.

The present invention (1) is a pharmaceutical composition for preventing, treating or ameliorating itch associated with skin, mucous membrane, or systemic diseases or disorders, comprising an effective amount of phenylbutyric acid derivative and pharmaceutically A pharmaceutical composition comprising an acceptable carrier, salt, or solvate thereof.
In the present invention (2), the disease or disorder is allergic skin disease, pruritic skin disease, vascular skin disease, sebaceous gland disease, autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, systemic progressive sclerosis Disease, Sjogren's syndrome, dermatomyositis, mixed connective tissue disease, papule scale skin disease, bacterial skin disease, viral skin disease, mycolic skin infections, granulomatous skin disease, parasitic skin disease (parasitic) skin dermatoses), exfoliative dermatitis, bullous skin disease, pigmented skin disease, photosensitivity skin disease, skin disease caused by collagen disease, skin disease due to internal disease, xeroderma, hives, atopic dermatitis, Eczema, vasculitis, vidar lichen, psoriasis, scabies, body lice and lice parasites, multiple sclerosis, thyroid poisoning, diabetes, renal failure, uremia, iron deficiency anemia, bile Stagnant, parasitosis delusion, true primary erythrocytosis, wounds, sunburn, cold sores, acne, insect bites, radiation therapy or chemotherapy induced dermatitis or mucositis, paraneoplastic syndrome, malignant disease The pharmaceutical composition of the present invention (1), selected from the group consisting of primary skin cancer, and metastatic skin cancer.
In the present invention (3), the phenylbutyric acid derivative is phenylbutyric acid, phenylpropionic acid, phenylacetic acid, phenylbutyrate, phenylpropionate, phenylacetate, phenylacetylglutamine, phenoxybutyric acid, phenoxypropionic acid, phenoxyacetic acid, phenoxybutyrate , Phenoxypropionate, phenoxyacetate, bromophenylbutyric acid, bromophenylpropionic acid, bromophenylacetic acid, bromophenylbutyrate, bromophenylpropionate, bromophenylacetate, chlorophenylbutyric acid, chlorophenylpropionic acid, chlorophenylacetic acid, chlorophenylbutyrate, Chlorophenylpropionate, chlorophenylacetate, fluorophenylbutyric acid, fluorophenylpropionic acid, fluoro Phenylacetic acid, fluorophenylbutyrate, fluorophenylpropionate, fluorophenylacetate, iodophenylbutyric acid, iodophenylpropionic acid, iodophenylacetic acid, iodophenylbutyrate, iodophenylpropionate, iodophenylacetate, hydroxyphenylbutyric acid, hydroxyphenylpropionate On acid, hydroxyphenylacetic acid, hydroxyphenylbutyrate, hydroxyphenylpropionate, hydroxyphenylacetate, methylphenylbutyric acid, methylphenylpropionic acid, methylphenylacetic acid, methylphenylbutyrate, methylphenylpropionate, methylphenylacetate, ethylphenyl Butyric acid, ethylphenylpropionic acid, ethylphenylacetic acid, ethylphenylbutyrate , Ethylphenylpropionate, ethylphenylacetate, naphthylbutyric acid, naphthylpropionic acid, naphthylacetic acid, naphthylbutyrate, naphthylpropionate, naphthylacetate, and tributyrin according to the present invention (1) It is a composition.
The present invention (4) is the pharmaceutical composition of the present invention (1), wherein the phenylbutyric acid derivative is present in an amount of about 0.00001% to about 100.00% by weight of the formulation.
The present invention (5) includes creams, gels, lotions and pastes, ointments, emollients, liposomes, nanospheres, skin tonics, mouth washes, oral rinses, According to the invention (1) formed into shampoos, mousses, sprays, poultices, capsules, tablets, powders, granules, solvents, suspensions, patches or occlusive skin conditioning agents A pharmaceutical composition.
The present invention (6) is the pharmaceutical composition of the present invention (1), further comprising a penetration enhancer or a pH adjuster for providing a formulation pH in the range of about 3.0 to 13.0.
The present invention (7) includes antihistamines, anticholinergics, non-steroidal anti-inflammatory agents, steroids, antioxidants, vitamins, leukotriene modulators, interleukin antagonists, mast cell inhibitors, anti-IgE antibodies, selective serotonin reactivation. Uptake inhibitors (SSRI), 5-hydroxytryptamine (5-HT) receptor antagonists, antibiotics, calcineurin inhibitors, histone deacetylase inhibitors, gastrin releasing peptide receptor antagonists, gabapentin, naloxone, or combinations thereof It is a pharmaceutical composition of the present invention (1) administered in combination with a second substance containing.
The present invention (8) is the pharmaceutical composition of the present invention (7), wherein the pharmaceutical composition and the second substance are administered systemically or locally simultaneously or sequentially.
The present invention (9) is a pharmaceutical composition for preventing, treating or ameliorating itch associated with skin, mucous membrane, or systemic diseases or disorders, comprising a short-chain fatty acid derivative having 2 to 6 carbon atoms And a pharmaceutically acceptable carrier, salt, or solvate thereof.
In the present invention (10), the disease or disorder is allergic skin disease, itchy skin disease, vascular skin disease, sebaceous gland disease, autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, systemic progressive sclerosis, Sjögren Syndrome, dermatomyositis, mixed connective tissue disease, papule scale skin disease, bacterial skin disease, viral skin disease, micole skin infection, granulomatous skin disease, parasitic skin disease, exfoliative dermatitis, bullous skin disease , Pigmentary skin disease, photosensitivity skin disease, skin disease caused by collagen disease, skin disease caused by internal diseases, xerosis, hives, atopic dermatitis, eczema, vasculitis, bidar lichen, psoriasis, scabies Body lice and lice infestation, multiple sclerosis, thyrotoxicosis, diabetes, renal failure, uremia, iron deficiency anemia, cholestasis, parasitosis delusion, true primary erythrocytosis, wound Selected from the group consisting of: tanning, cold sores, acne, insect bites, radiation therapy or chemotherapy-induced dermatitis or mucositis, paraneoplastic syndrome, malignant disease, primary skin cancer, and metastatic skin cancer This is the pharmaceutical composition of the present invention (9).
According to the present invention (11), the short-chain fatty acid derivative contains butyric acid, butyrate, 2,2 dimethylbutyric acid, α-methylhydrocinnamic acid, 3,5 dimethoxy-4-hydrocinnamic acid, cinnamic acid, butyryl hydroxamate, propionate Selected from the group consisting of bromopropionate, E-3-3 pyridyl-2-propenoic acid, levulinic acid, Kemp triacid base, isovalerate, valerate, butrymide, isobutyramide, valproic acid, and valproate This is the pharmaceutical composition of the present invention (9).
The present invention (12) is the pharmaceutical composition of the present invention (9), wherein the short chain fatty acid derivative is present in an amount from about 0.00001% to about 100.00% by weight of the formulation.
The present invention (13) includes creams, gels, lotions, pastes, ointments, emollients, liposomes, nanospheres, skin tonics, mouth washes, oral rinses, shampoos, mousses, sprays, poultices , Capsules, tablets, powders, granules, solvents, suspensions, patches, occlusive skin improvers, or a pharmaceutical composition of the present invention (9) formed into a patch-type administration device equipped with a fine needle It is a thing.
The present invention (14) is the pharmaceutical composition of the present invention (9), further comprising a penetration enhancer or a pH adjuster for providing a formulation pH in the range of about 3.0 to 13.0.
The present invention (15) includes antihistamines, anticholinergics, non-steroidal anti-inflammatory agents, steroids, antioxidants, vitamins, leukotriene modulators, interleukin antagonists, mast cell inhibitors, anti-IgE antibodies, selective serotonin reactivation. Uptake inhibitors (SSRI), 5-hydroxytryptamine (5-HT) receptor antagonists, antibiotics, calcineurin inhibitors, histone deacetylase inhibitors, gastrin releasing peptide receptor antagonists, gabapentin, naloxone, or combinations thereof It is a pharmaceutical composition of the present invention (9) administered in combination with a second substance containing.
The present invention (16) is the pharmaceutical composition of the present invention (15), wherein the pharmaceutical composition and the second substance are administered systemically or locally simultaneously or sequentially.

  The present invention provides a method for ameliorating itch.

  The following description is the best mode contemplated for carrying out the invention. This description is provided for the purpose of illustrating the general principles of the invention and should not be taken in a limiting sense. The scope of the invention is best determined with reference to the appended claims.

  The present invention generally includes phenylbutyric acid or short chain fatty acids and pharmaceutically acceptable thereof for preventing, treating, or ameliorating all types of itch caused by various diseases or disorders including, but not limited to: Intended to use: allergic skin disease, pruritic skin disease, vascular skin disease, sebaceous gland disease, autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, systemic progressive sclerosis, Sjogren's syndrome Dermatomyositis, mixed connective tissue disease, papule scale skin disease, bacterial skin disease, viral skin disease, mycolic skin infections, granulomatous skin disease, parasitic skin dermatoses, Exfoliative dermatitis, bullous skin disease, pigmented skin disease, photosensitivity skin disease, skin disease caused by collagen disease, skin disease due to internal disease, xeroderma, Urticaria, atopic dermatitis, eczema, vasculitis, vidar lichen, psoriasis, scabies, body lice and lice parasites, multiple sclerosis, thyroid poisoning, diabetes, renal failure, uremia, iron deficiency Anemia, parasitosis delusions, true primary erythrocytosis, cholestasis, wounds, sunburn, cold sores, acne, insect bites, radiation therapy or chemotherapy-induced skin disease or mucositis, neoplasm associated Syndrome, malignant disease, primary skin cancer, and metastatic skin cancer.

  In the present invention, compounds of phenylbutyric acid derivatives include but are not limited to: phenylbutyric acid, phenylpropionic acid, phenylacetic acid, phenylbutyrate, phenylpropionate, phenylacetate, phenylacetylglutamine, phenoxybutyric acid, phenoxy Propionic acid, phenoxyacetic acid, phenoxybutyrate, phenoxypropionate, phenoxyacetate, bromophenylbutyric acid, bromophenylpropionic acid, bromophenylacetic acid, bromophenylbutyrate, bromophenylpropionate, bromophenylacetate, chlorophenylbutyric acid, chlorophenylpropionate Acid, chlorophenylacetic acid, chlorophenylbutyrate, chlorophenylpropionate, chlorophenylacetate, fluoropheny Butyric acid, fluorophenylpropionic acid, fluorophenylacetic acid, fluorophenylbutyrate, fluorophenylpropionate, fluorophenylacetate, iodophenylbutyric acid, iodophenylpropionic acid, iodophenylacetic acid, iodophenylbutyrate, iodophenylpropionate, iodophenyl Acetate, hydroxyphenylbutyric acid, hydroxyphenylpropionic acid, hydroxyphenylacetic acid, hydroxyphenylbutyrate, hydroxyphenylpropionate, hydroxyphenylacetate, methylphenylbutyric acid, methylphenylpropionic acid, methylphenylacetic acid, methylphenylbutyrate, methylphenylpropio Nate, methylphenylacetate, ethylphenylbutyric acid, ethylphenylpropion , Ethylphenyl acetate, ethyl phenylbutyrate, ethyl propionate, ethyl phenylacetate, naphthyl butyrate, naphthyl propionic acid, naphthylacetic acid, naphthyl butyrate, naphthyl propionate, naphthyl acetate, and tributyrin. Similarly, other short chain fatty acids of 2 to 6 carbons include, but are not limited to: butyric acid, butyrate, 2,2 dimethylbutyric acid, α-methylhydrocinnamic acid, 3,5 dimethoxy-4-hydrocinnamic Acid, cinnamic acid, butyryl hydroxamate, propionate, bromopropionate, E-3-3 pyridyl-2-propenoic acid, levulinic acid, Kemp triacid base, isovalerate, valerate, butrimide, isobutyramide, valproic acid, And valproate.

  Second compounds for combination with phenylbutyric acid or short chain fatty acid derivatives include, but are not limited to: antihistamines, anticholinergics, non-steroidal anti-inflammatory agents, steroids, antioxidants, vitamins, Leukotriene modulator, interleukin antagonist, mast cell inhibitor, anti-IgE antibody, selective serotonin reuptake inhibitor (SSRI), 5-hydroxytryptamine (5-HT) receptor antagonist, antibiotic, calcineurin inhibitor, histone Acetylase inhibitors, gastrin releasing peptide receptor antagonists, gabapentin, and naloxone.

  The composition of the present invention can be formulated as a pharmaceutical composition. Such compositions can be administered orally, parenterally, by inhalation spray, rectal as a dosage unit formulation containing conventional pharmaceutically acceptable non-toxic carriers, adjuvants, and vehicles, if desired. It can be administered internally, intravaginally, intradermally, transdermally or topically. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. Drug formulation is described, for example, by Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Penn. (1975) and Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New Considered in York, NY (1980).

  In certain embodiments, preparations for treating skin itching are generally planned to provide conditions for increasing the manageability of the skin. As mentioned above, categories of formulations for skin care compositions are recognized, including creams, ointments, gels, sprays, lotions, skin tonics, shampoos or mousses. Skin sprays are generally composed of aerosolized copolymers such as polyvinylpyrrolidone, vinyl acetate and can also function as set lotions. The skin gel preparation is similar in composition to the spray, but is in a gel-like and alcohol-free form and can coat the skin. Skin mousse is a foam that is released under pressure from an aerosolized can. The phenylbutyric acid derivative or short-chain fatty acid active ingredient in the topical skin care composition according to the present invention is preferably present at a concentration of 0.00001-100.00% by weight, or at a dose of 1-1000 mg, relative to the total weight of the composition To do. A skin care composition for treating itch according to the present invention comprises a hydrophobic or hydrophilic cream, ointment as described above, suitably comprising additional ingredients suitable for use in skin care compositions of the type known in the art. , Gels, emollients, sprays, lotions, skin tonics, shampoos, or mousses, such additional ingredients include petrolatum, wax, lanolin, silicone, liposomes, vegetable oils, mineral oils , Plasticizers, fragrances, preservatives, penetration enhancers, pH adjusters, or other suitable ingredients for topical skin compositions. Such ingredients moisturize the skin, stabilize the active compound, increase drug-skin contact and topical concentration, control the delayed release of the drug and / or reduce skin destruction, skin atrophy, It can help prevent fibrosis and infection, and promote skin wound healing.

  The present invention also provides a method for treating skin itching as described herein, wherein the method comprises at least one phenylbutyric acid derivative or a short chain fatty acid thereof, as well as an antihistamine, an anticholinergic agent, Non-steroidal anti-inflammatory agent, steroid, antioxidant, vitamin, leukotriene modulator, interleukin antagonist, mast cell inhibitor, anti-IgE antibody, selective serotonin reuptake inhibitor (SSRI), 5-hydroxytryptamine receptor antagonist A composition that provides at least one or more other substances, including antibiotics, calcineurin inhibitors, histone deacetylase inhibitors, gabapentin, and naloxone, wherein the active ingredient is systemic or topical Free, for simultaneous, separate or sequential use, or Present in the form of at least one pharmaceutically acceptable carrier in a pharmaceutically acceptable salt thereof, and optionally.

  Also suitable salts for the components to be used by the subject of the present invention are salts with inorganic cations, such as alkali metal salts, especially sodium salts, potassium salts, or ammonium salts, especially alkali salts such as magnesium salts or calcium salts. It may be an earth metal salt and a salt having a divalent or tetravalent cation, such as a zinc salt, an aluminum salt, or a zirconium salt. Also contemplated are salts with organic groups such as dicyclohexylamine salts, methyl-D-glucamine, and salts with amino acids such as arginine, lysine, histidine, glutamine. Similarly, basic nitrogen-containing groups can be quaternized with materials such as: chloride, bromide and methyl iodide, chloride, bromide and ethyl iodide, chloride, bromide and iodide. Propyl and lower alkyl halides such as chloro, bromide and butyl iodide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; chloride, bromide and decyl iodide, chloride, bromide and iodine Long chain halides such as lauryl chloride, bromide, bromide and iodide, and stearyl chloride, bromide and iodide; aralkyl halides such as benzyl bromide and phenethyl bromide. Salt-forming substances such as low molecular weight alkylamines such as methylamine, ethylamine, or triethylamine can also be used. Thereby a product which is generally soluble or dispersible in water or oil is obtained.

  The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form can vary depending upon the subject and the particular mode of administration. The required dosage will depend on a number of factors known in the art including, but not limited to, the compound used, the species of the subject, the size of the subject, and the severity of the associated disease state that causes itching. Can vary. The compounds can be administered in a single dose, in multiple doses over a 24-hour period, or by continuous infusion. When administered by continuous infusion, the compound is supplied by methods known in the art such as, but not limited to, intravenous gravity drops, intravenous infusion pumps, implantable infusion pumps, or any local route. it can. The length of the treatment can vary depending on many factors, such as the duration and severity of the skin, mucous membrane, or systemic disease or disorder that causes local or systemic itching. Treatment of a subject with a phenylbutyric acid derivative or a short chain fatty acid derivative, alone or in combination with other substances of the present invention, can be continued until the itch disappears, or treatment can be continued for the lifetime of the subject. .

Example 1: Various topical compositions-oily ointments, creams and gels
A. Preparation of oily ointment of phenylbutyrate
65 g white petrolatum (Riedel-de Haen), 15 g cetyl alcohol (Riedel-de Haen), 260 g soft paraffin (Merck), 155 g liquid paraffin (Merck), and 5 g 4-phenylbutyrate The rate (Merck) was mixed in a beaker and heated to 70 ° C. to form a paste. The paste was stirred at 400 rpm for 1 hour and then cooled at room temperature.

B. Preparation of Phenyl Butyrate Cream Ingredient I: 70 g Tefose 63®, 20 g Superpolystate®, 10 g Coster 5000®, 15 g Myriyol 318® , 15 g of Coster 5088®, and 15 g of GMS SE® (all commercially available from a local supplier) were mixed in a beaker and heated at 70 ° C.

  Ingredient II: 5.739 g sodium 4-phenylbutyrate (Triple Crown America, Inc.), 0.125 g methylparaben (Merck), 0.075 g propylparaben (Merck), and 149.061 g deionized water were mixed in a beaker. And heated at 70 ° C.

  Component II was slowly added to Component I followed by stirring at 400 rpm for 5 minutes to form a mixture. 2% Stabileze QM® (2 g Stabileze QM® dissolved in 98 g deionized water, heated, stirred at 70 ° C. to form a paste, then cooled at room temperature To the mixture and stirred for 5 minutes. The pH of the mixture was adjusted to 5.34 using 0.85% phosphoric acid (Merck) and stirred at 600 rpm for 20 minutes. The mixture was cooled at room temperature.

C. Preparation of Phenyl Butyrate Gel Component I: 10 g Stabileze QM® and 232.035 g deionized water were mixed in a beaker and heated at 70 ° C.

  Ingredient II: 5.739 g sodium 4-phenylbutyrate (Triple Crown America, Inc.), 0.125 g methylparaben (Merck), 0.075 g propylparaben (Merck), 232.035 g deionized water, and 20 g 10% NaOH was mixed in a beaker and heated at 70 ° C.

  Component II was slowly added to Component I followed by stirring at 400 rpm for 20 minutes to form a mixture. The mixture was cooled at room temperature.

D. Preparation of Phenylbutyrate Liposome Formulation In this liposome formulation, egg phosphatidylcholine (EPC) and cholesterol were used as primary lipid components at equimolar or different molar concentrations. Various liposomes arranged with 4-phenylbutyrate were obtained by changing the lipid: phenylbutyrate ratio. Liposomes were prepared by thin-layer film hydration, and were physically evaluated after their sizes were aligned by membrane extrusion.

Example 2: Topical phenylbutyric acid on affected skin of different diseases to treat itching
2.5% phenylbutyric acid gel was applied to the affected skin 6 times a day for 1 week. Each group consisted of 4 patients who completed a daily pruritic diary. Here, they use a visual analog scale (VAS) with points fixed to facial expressions to guide the selection, and the severity of the itch is 0 (not considered to be 痒) ~ Graded on a continuous scale of 10 (worst imaginable itch) (Mayo MJ, et al. Hepatology 45: 666-74, 2007).

  Referring to Figure 1, 2.5% phenylbutyric acid gel quickly relieves pruritus sensation within 2 to 10 minutes, in each patient with radiation-induced skin disease, sunburn, surgical wound healing, psoriasis, or atopic dermatitis In 1-2 days, the average VAS was improved from 7.25, 7, 6.75, 8, and 7.75 to 2, 1, 1.5, 2.5, and 2.25. Erythema, hives, swelling, and itching related symptoms of desquamation also subside at the same time.

Example 3: Inhibition of multiple pruritus-related molecular mediators by sodium 4-phenylbutyrate Pruritus is the most serious problem in many allergic and inflammatory skin diseases. The skin barrier (stratum corneum) is a key factor in determining the nature of the immune response to the allergen presented on the skin surface.

  Abnormal skin barrier function can lead to Th1, Th2, Th3 responses to infectious agents, chemicals, or protein antigens, which induce several cytokines and molecular mediators in skin lesions to cause itching symptoms and signs cause. Subsequently, depending on the type of allergen stimulation, a cytokine profile is generated. Separate subsets of helper T cell activation were identified by the cytokines that produced them. Activated Th1 cells produce IFN-γ and IL-2. Th1 cells regulate delayed type hypersensitivity reactions. The Th1 response is facilitated by local release of the IL-12 superfamily of cytokines. These responses are further enhanced by IL-15 and IL-18 production. Activated Th2 cells produce IL-4 and IL-10. Th2 cells mediate allergic and antibody responses. The Th2 response is synergistic and favors local production of IL-4, IL-33, and IL-18. Some cytokines such as IL-3, GM-CSF (CSF2), and TNF-α are produced by both Th1 and Th2 subsets. IL-6, on the other hand, is a pro-inflammatory cytokine secreted by activated T cells to stimulate an immune response to trauma, particularly burns or other tissue damage that results in inflammation. Th3 cells are associated with negative regulation of the immune response.

To demonstrate whether phenylbutyrate can suppress multiple pruritus-related cytokines, molecular mediators, or markers at once, a series of gene expression profiles were generated using real-time PCR (RT ² Profiler ™ PCR Array Human Th1 -Th2-Th3: APHS-034, SuperArray Bioscience Corporation).

  Jurkat T cells were treated for 24-72 hours at 37 ° C. in the presence of increasing concentrations of 4-phenylbutyrate, ionomycin, and / or phorbol 13-acetate 12-myristate (PMA). Cell growth, cytotoxicity, and apoptosis between control and treated cells by flow cytometry at 4-phenylbutyrate 1 mM at 48 hours and ionomycin 1 μM and PMA 10 ng / ml incubated for 24 hours No significant difference was found. However, 48 hours after stimulation with ionomycin (1 μM) and PMA (10 ng / ml), T cells are completely cycled by T cell proliferation and survival factor (interleukin) induction, and the cell cycle Developed through S, G2, and M phases. On the other hand, pretreatment with phenylbutyrate (1 mM) for 24 hours almost completely prevented the cells from entering the S phase of the cell cycle.

  Jurkat T cells were stimulated with ionomycin (1 μM) and PMA (10 ng / ml) for 6 hours with or without 24-hour sodium 4-phenylbutyrate (1 mM) preincubation, and RNA was not stimulated. Extraction was followed by RT-PCR to profile the expression of 84 genes related to the Th1-Th2-Th3 response shown in the gene table (Figure 2).

  Referring to FIGS. 2A-2D and Table 1, phenylbutyrate is used in ThA cytokines and related genes (CCR5, CSF2, IFN-γ, IL12B, IL12RB2, IL18, IL18R1, IL2 in PMA / ionomycin-induced Jurkat T cell activation. , IL2RA, IRF1, STAT4, TLR4, TLR6), Th2 cytokines and related genes (CCL11, CCL7, CCR2, CCR4, IL13, IL13RA1, IL1R1, IL1R2, IL4R, IL9, IRF4, MAF), T cell activation marker (BCL3 , CD69, IL6, IL6R, JAK2, LAT, TNFRSF9), T-helper type 1 immune response (IL12B, IL18, IRF4, SFTPD, TLR4, TLR6), T-helper type 2 immune response (IL18, IL4R, IRF4), In addition, the induction of antimicrobial humoral response (CCL7, CCR2, IL12B, IL13, SFTPD) is either completely suppressed or significantly reduced. On the other hand, phenylbutyrate further upregulates the expression of SOCS1, which is a suppressor of cytokine signaling as a Th3 response, involved in the negative regulation of cytokines.

  IL-1 and IL-6 are proinflammatory cytokines. Antigens that bind to the T cell receptor stimulate IL-2 secretion and IL-2 receptor expression. The IL-2 / IL-2R interaction then stimulates the proliferation, differentiation, and survival of cytotoxic T cells selected for antigen. IL-4 stimulates the proliferation of activated B and T cells and the differentiation of CD4 + T cells into Th2 cells and induces a class switch of B cells to IgE. IL-9 induces many functions on lymphoma cells and mast cell lineages and is thought to have a role in asthma. IL-12 is known as a T cell stimulator that responds to antigenic stimulation and can stimulate T cell proliferation and function. IL-13 secreted by many cell types, especially Th2 cells, is an important mediator of allergic inflammation. IL-18 works with IL-12 to induce cellular immunity after infection with microbial products such as lipopolysaccharide. Taken together, the inhibition of complex and interrelated signaling network pathways of IL-1, IL-2, IL-4, IL-6, IL-9, IL-12, IL-13, and IL-18, And the effect of phenylbutyrate on the upregulation of SOCS1 (an inhibitor of cytokine signaling) is the book that phenylbutyrate has the ability to ameliorate itch in some allergic and inflammatory skin-related itch. It correlates with new findings in the invention.

(Table 1) Induction by T-cell stimulation and phenylbutyrate inhibitory effect at least 2 times different from control

Induction of multi-cytokine expression depends primarily on coordinated activation of transcription factors including NFκB, NF-AT, and AP-1 (Sancho R, et al. J Immunol 172: 2341-51, 2004; Li -Weber M, et al. Eur J Immunol 34: 1111-18, 2004). Since cytokine induction is primarily regulated at the transcriptional level, chromatin immunoprecipitation (ChIP) analysis in Jurkat T cells was performed to determine the binding of NFκB, NF-AT, and AP-1 to the IL-2 promoter . With or without pre-incubation of sodium 4-phenylbutyrate (1 mM) for 24 hours, Jurkat T cells were stimulated or unstimulated with ionomycin (1 μM) and PMA (10 ng / ml) for 6 hours, and then Anti-NFκB, anti-NF-AT, anti-AP-1, anti-Sp1, or anti-acetyl H3 antibody (Santa Cruz) was used to formaldehyde crosslinks between protein and DNA, as well as ChIP. PCR primers were designed to amplify the human IL-2 promoter:
F 5'-GAGTTACTTTTGTATCCCCACCCCC (-317 to -292 in the IL-2 promoter),
R 5'-CCTGTACATTGTGGCAGGAGTTGAGG (+33 to 58).
PCR amplification used the following three-step protocol: 35 cycles of denaturation temperature 90 ° C (30 seconds), primer annealing temperature 59 ° C (45 seconds), and enzyme reaction temperature 72 ° C (30 seconds). Referring to FIG. 3, phenylbutyrate affects chromatin structure by altering acetyl H3 status and reduces DNA binding between NFκB, NF-AT, and AP-1 and IL-2 promoters. This suggests that suppression of cytokine expression of phenylbutyrate upon T cell activation can be mediated by decreasing the binding between the transcription factor and the promoter.

  While the invention has been described in terms of preferred embodiments using examples, it is to be understood that the invention is not limited to the disclosed embodiments. On the contrary, it is intended to encompass various modifications and similar combinations (as would be apparent to one skilled in the art). Accordingly, the scope of the appended claims should be accorded the maximum interpretation so as to include all such modifications and similar combinations.

The present invention will be better understood by reading the detailed description and examples herein with reference to the accompanying drawings.
Figure 3 shows a topical 2.5% phenylbutyric acid gel that quickly relieves itch related to skin diseases caused by radiation dermatitis, sunburn, surgical wound healing, psoriasis, and atopic dermatitis. Human Th1-Th2-Th3 gene expression profiling showing phenylbutyrate that simultaneously suppresses induction of multiple cytokine expression in activated T cells stimulated with PMA and ionomycin. Jurkat T cells were preincubated with phenylbutyrate (1 mM) for 24 hours. Real-time PCR was used to analyze the expression of a series of genes associated with helper T cells by phenylbutyrate treatment. Arrays are cytokine genes representing Th1, Th2, and Th3 cells, genes encoding transcription factors that regulate cytokine expression and other CD4 + T lymphocyte markers, immune cell activity in Th1 and Th2 type immune responses Genes associated with oxidization, as well as genes associated with antimicrobial humoral responses. Results are the mean ± SE of three trials expressed as fold induction (experimental relative units / stimulus and basal control relative units without treatment). Human Th1-Th2-Th3 gene expression profiling showing phenylbutyrate that simultaneously suppresses induction of multiple cytokine expression in activated T cells stimulated with PMA and ionomycin. Jurkat T cells were stimulated with ionomycin (1 μM) and PMA (10 ng / ml) for 6 hours. Real-time PCR was used to analyze the expression of a series of genes associated with helper T cells upon T cell stimulation. Arrays are cytokine genes representing Th1, Th2, and Th3 cells, genes encoding transcription factors that regulate cytokine expression and other CD4 + T lymphocyte markers, immune cell activity in Th1 and Th2 type immune responses Genes associated with oxidization, as well as genes associated with antimicrobial humoral responses. The results are the mean ± SE of three trials expressed as induction ratios (observed experimental relative units / stimulus and basal control relative units without treatment). Human Th1-Th2-Th3 gene expression profiling showing phenylbutyrate that simultaneously suppresses induction of multiple cytokine expression in activated T cells stimulated with PMA and ionomycin. Jurkat T cells were preincubated with phenylbutyrate (1 mM) for 24 hours and then stimulated with ionomycin (1 μM) and PMA (10 ng / ml) for 6 hours. Real-time PCR was used to analyze the expression of a series of genes associated with helper T cells upon T cell stimulation and phenylbutyrate treatment. Arrays are cytokine genes representing Th1, Th2, and Th3 cells, genes encoding transcription factors that regulate cytokine expression and other CD4 + T lymphocyte markers, immune cell activity in Th1 and Th2 type immune responses Genes associated with oxidization, as well as genes associated with antimicrobial humoral responses. The results are the mean ± SE of three trials expressed as induction ratios (observed experimental relative units / stimulus and basal control relative units without treatment). Various human Th1-Th2-Th3 genes are disclosed. Chromatin immunoprecipitation (ChIP) analysis showing the regulatory effects of phenylbutyrate on histone status remodeling chromatin structure and on the binding of transcription factors that regulate gene expression. This resulted in not only histone modification but also reduced binding of NF-κB, NFAT, and AP-1 transcription factors to the IL-2 promoter in activated Jurkat T cells stimulated by ionomycin and PMA. It has been shown that sodium 4-phenylbutyrate was effective. Anti-Sp1 antibody was used as a negative control since Sp1 does not bind to the IL-2 promoter.

Claims (7)

  A pharmaceutical composition for preventing, treating, or ameliorating itch associated with skin, mucous membrane, or systemic diseases or disorders, comprising an active ingredient phenylbutyric acid or a pharmaceutically acceptable salt thereof Composition.   The disease or disorder is allergic skin disease, pruritic skin disease, vascular skin disease, sebaceous gland disease, autoimmune disease, rheumatoid arthritis, systemic lupus erythematosus, systemic progressive sclerosis, Sjogren's syndrome, dermatomyositis , Mixed connective tissue disease, papule scale skin disease, bacterial skin disease, viral skin disease, mycolic skin infections, granulomatous skin disease, parasitic skin dermatoses, exfoliative skin Inflammation, bullous skin disease, pigmented skin disease, photosensitivity skin disease, skin disease caused by collagen disease, skin disease due to internal disease, xerosis, hives, atopic dermatitis, eczema, vasculitis, bidar Lichen, psoriasis, scabies, body lice and lice parasites, multiple sclerosis, thyroid poisoning, diabetes, renal failure, uremia, iron deficiency anemia, cholestasis, parasitic disease Thoughts, true primary erythrocytosis, wounds, sunburn, cold sores, acne, insect bites, radiation therapy or chemotherapy induced dermatitis or mucositis, paraneoplastic syndromes, malignant diseases, primary skin cancer, and 2. The pharmaceutical composition according to claim 1, selected from the group consisting of metastatic skin cancer.   The pharmaceutical composition of claim 1, wherein phenylbutyric acid or a pharmaceutically acceptable salt thereof is present in an amount of 0.00001% to 100.00% by weight of the pharmaceutical composition.   Creams, gels, lotions and pastes, ointments, emollients, liposomes, nanospheres, skin tonics, mouth washes, oral rinses, shampoos, mousses, sprays, 2. The pharmaceutical composition of claim 1 formed into a poultice, capsule, tablet, powder, granule, solvent, suspension, patch, or occlusive skin conditioning agent.   The pharmaceutical composition according to claim 1, further comprising a penetration enhancer or a pH adjuster for providing the pH of the pharmaceutical composition in the range of 3.0 to 13.0.   Antihistamines, anticholinergics, nonsteroidal anti-inflammatory agents, steroids, antioxidants, vitamins, leukotriene modulators, interleukin antagonists, mast cell inhibitors, anti-IgE antibodies, selective serotonin reuptake inhibitors (SSRI), In combination with a second substance including a 5-hydroxytryptamine (5-HT) receptor antagonist, antibiotic, calcineurin inhibitor, histone deacetylase inhibitor, gastrin releasing peptide receptor antagonist, gabapentin, naloxone, or combinations thereof 2. The pharmaceutical composition of claim 1, wherein 7. The pharmaceutical composition according to claim 6 , wherein the pharmaceutical composition and the second substance are administered systemically or locally, simultaneously or sequentially.

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