KR100953386B1 - Method for ameliorating pruritus - Google Patents

Abstract

The present invention relates to a method for preventing, treating or ameliorating pruritis caused by a skin, mucosal or systemic disorder. The method comprises administering to a subject suffering from pruritus an effective amount of a pharmaceutical composition consisting primarily of phenylbutyric acid or short-chain fatty acid derivatives and a pharmaceutically acceptable carrier, salt or solvate thereof, or topically applying to the site of pruritus invasion. It includes.

Phenylbutyric acid derivatives, pruritus, pharmaceutical compositions

Description

How to improve pruritus {METHOD FOR AMELIORATING PRURITUS}

The present invention relates to a method of improving pruritus, and more particularly to a method of using phenylbutyric acid or short-chain fatty acid derivatives for preventing, treating or ameliorating pruritus associated with local or systemic diseases or disorders.

As is known, the skin sensation called pruritus is characterized by the unpleasant pruritus of the skin causing a scratch. Scratching is sometimes severe enough to sting the affected subject's skin and cause inflammation. Pruritus can also be characterized as a constant response to a wide range of physical, chemical and / or biological stimuli, which is an allergic response to drugs, insect bites and environmental allergens, or hyperthyroidism, diabetes, uremia, iron deficiency It may be an endogenous or exogenous characteristic that may be associated with certain skin diseases such as anemia, paranoid parasites, polycythemia rubra vera, cholestasis and Hodgkin's disease. Pruritus can usually occur in the skin, but can also occur in non-skin areas, such as mucous membranes. Thus, the cause of pruritus may be multifactorial or may be due to a single underlying disease. Pathophysiology of pruritus includes the central and peripheral nervous system as well as multiple cytokine release and molecular mediators.

When the origin of pruritus is in the skin, sensory nerve endings in the dermal epidermal junction are stimulated. The sensation of pruritus is carried along a dedicated anhydrous C fiber that is separate from the fibers that deliver pain and feel. The inflamed skin will transmit a feeling of pruritus by stimulating local nerves in the spinal cord. From this, the stimulus is transmitted through the thalamic spinal cord thalamus, and then to the cerebral cortex, causing a sensation of pruritus (Weldon D. Allergy Asthma Proc 28: 153-62, 2007). Gastrin-releasing peptide receptor (GRPR), histamine, substance P and tumor necrosis factor α (TNF-α) are believed to play a significant role in the recognition of pruritus (Sun YG, et. al. Nature 448: 700-703, 2007). In addition, for central nervous system in which itching is detected, opiate-like peptides and μ receptors have been implicated in causing bile pruritus, which responds to intravenous naloxone (Jones EA, et al. JAMA 268: 3359-). 62, 1992). On the other hand, serotonin reuptake inhibitors can enhance systemic pruritus caused by cholestasis, suggesting that serotonergic pathways are also important for the recognition of itching (Mayo MJ, et al. Hepatology 45: 666-74, 2007). .

On the other hand, histamine, tachykinin, serotonin (5-hydroxytryptamine (5-HT)) and interferon (secreted from activated macrophages, mast cells or T cells at the site of prutitoceptive origin) Topical secretory agents, including IFN) -gamma, interleukin 2 (IL-2) and IL-4, are implicated in causing syndromes and signs of itching sensation, scratching, swelling, rash, urticaria and / or scaling. Greaves MW, et al. Lancet 348: 938-40, 1996; Inagaki N, et al. Eur J Pharmacol 546: 189-96, 2006). Subjects with pruritus caused by a dermatological disorder or systemic disease are likely to exacerbate pruritus by excessively scratching the extensively invasive areas such that excessive scratching causes irritation, inflammation, wound formation and possibly infection. With regard to the peripheral mechanisms of pruritus, the role of numerous cytokine secretion and molecular mediators in the onset of syndromes and signs of pruritus in diseased skin or mucous membranes is defined. Histamine-induced pruritus includes the H1 receptor (Davies MG, et al. Br J Clin Pharmacol 9: 461-65, 1980). Takkinin, including the neuropeptide substance P, calcitonin gene related peptides and vascular functional enteropeptides, is found in anhydrous cutaneous free nerve endings of anchovy nociceptors neurons that initiate the sensation of pruritus. Intradermal 5-HT can cause itching and scratching by acting on 5-HT2 and 5-HT3 receptors (Nojima H, et al. J Pharmacol Exp Ther 306: 245-52, 2003). These observations resulted in the use of 5-HT2 or 5-HT3 receptor antagonists to treat pruritus (Schworer H, et al. Lancet 341: 1277, 1993). IL-2, when given subcutaneously, causes strong local itching in both atopic and normal subjects (Wahlgren CF, et al. Arch Dermatol Res 287: 572-80, 1995). Inhibition of IL-2 biosynthesis by immunosuppressants such as cyclosporin A alleviates pruritus of atopic dermatitis (Wahlgren CF, et al. Acta Derm Venereol (Stockh) 70: 323-29, 1990).

Antihistamines are widely used to suppress pruritus, but the extent to which the inhibition is due to side effects of central sedation rather than local histamine antagonism on the skin is unclear (Krause L, et al. BMJ 287: 1199-200, 1983). Many patients report persistent pruritus even with current antihistamine therapies, 5-HT receptor antagonists, and / or immunosuppressants, which are largely ineffective against chronic pruritus, and only provide short-term relief from side effects. Pruritus can be significantly weakened for some patients. As such, there is a continuing need for the development of new and improved methods and compositions for preventing, treating or improving pruritus resulting from a wide range of causes.

Phenylbutyrate, a short-chain fatty acid, has been approved by the FDA as a rare drug for congenital disorders with urea cycle disorders for the treatment of hyperammonemia (Brusilow SW, et al. N Engl J Med 310: 1630-4, 1984). . In the human body, phenylbutyrate is metabolized to phenylacetate via β-oxidation. Phenyl acetate is then conjugated with glutamine to form phenylacetylglutamine, which acts as a vehicle of waste nitrogen secretion. Recently, phenylbutyrate also inhibits deacetylases, increasing acetylation for histone and non-histone proteins, reformulating chromatin structure, and also altering the activity of multiple transcription factors, thereby simultaneously regenerating many genes. Genetic regulation has been shown to have the ability to control disease (Marks PA, et al. J Natl Cancer Inst 92: 1210-6, 2000). In preclinical and clinical studies, the gene-modulating effects of phenylbutyrate have been found in many hematological and solid tumors such as cystic fibrosis, sickle cell anemia, β-thalassemia, X-related adrenal white matter dysplasia, spinal muscular atrophy and neuropathic disorders. Therapeutic potential in inflammatory diseases such as genetic disorders, aging, and autoimmune diseases (Kemp S, et al. Nat Med 4: 1261-8, 1998; 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). In addition, phenylbutyrate may also act as a chemical chaperone to protect normal cells from oxidative stress damage and prevent neurotoxicity (Yam GH, et al. Invest Ophthalmol Vis Sci 48: 1683-90, 2007).

Summary of the Invention

The present invention provides pharmaceutical compositions and methods for the prevention, treatment or amelioration of pruritus associated with skin, mucosal or systemic diseases or disorders. The method comprises administering to a subject suffering from pruritus an effective amount of a pharmaceutical composition consisting primarily of phenylbutyric acid or short-chain fatty acid derivatives and a pharmaceutically acceptable carrier, salt or solvate thereof, or topically applying to the site of pruritus invasion. It includes.

The invention also provides pharmaceutical compositions and methods for the prevention, treatment or amelioration of pruritis associated with skin, mucosal or systemic diseases or disorders. This method may be used in combination with other antipruritic agents to administer to the subject suffering from pruritus an effective amount of a pharmaceutical composition comprising 2 to 6 phenylbutyric acid or short-chain fatty acid derivatives and pharmaceutically acceptable carriers, salts or solvates thereof. Or topically applying to the area affected by pruritus.

Hereinafter, detailed description is given in the following embodiments with reference to the accompanying drawings.

A method of administering an effective amount of a pharmaceutical composition comprising a phenylbutyric acid or short-chain fatty acid derivative of the present invention and a pharmaceutically acceptable carrier, salt or solvate thereof to a subject suffering from pruritus or topically applying to a site in which pruritus is invaded. It is therefore possible to prevent, treat or ameliorate pruritis associated with local or systemic diseases or disorders.

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

The present invention is broadly used, for example, allergic skin diseases, pruritic skin diseases, vascular skin diseases, sebaceous gland disorders, autoimmune disorders, rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, Sjogren's syndrome, dermatitis, mixed connective tissue diseases, papule scales Skin disease, bacterial skin disease, viral skin disease, mycolic acid skin infection, granulomatous skin disease, parasitic skin disease, dropout dermatitis, bullous skin disease, pigmented skin disease, photosensitive skin disease, skin disease caused by collagen disease, skin disease caused by internal disease, dryness , Urticaria, atopic dermatitis, eczema, vasculitis, simple chronic thyroiditis, psoriasis, scabies, dyslexia and schizophrenia, multiple sclerosis, hyperthyroidism, diabetes, renal failure, uremia, iron deficiency anemia, parasitic delusions, true hematocytosis , Cholestasis, cuts, sunburn, herpes simplex, acne, insect bites, radiotherapy or chemotherapy-derived dermatitis or moles Phenylbutyric acid to prevent, treat or ameliorate various types of pruritus from various diseases or disorders, including but not limited to salts, edema, malignancies, primary skin cancers and metastatic skin cancers, including but not limited to those illustrated. It is intended for the use of short chain fatty acids and their pharmaceutically acceptable derivatives.

In the present invention, the compound of the phenylbutyric acid derivative is phenylbutyric acid, phenylproprioric acid, phenylacetic acid, phenylbutyrate , phenylproprionate, phenylacetate, phenylacetylglutamine, phenoxybutyric acid, phenoxyproprioric acid, phenoxy Acetic acid, phenoxybutyrate, phenoxypropionate, phenoxyacetate, bromophenylbutyric acid, bromophenylproprioric acid, bromophenylacetic acid, bromophenylbutyrate, bromophenylproprionate, bromophenyl Acetate, Chlorophenylbutyric Acid, Chlorophenylproprioric Acid, Chlorophenylacetic Acid, Chlorophenylbutyrate, Chlorophenylproprionate, Chlorophenyl Acetate, Fluorophenylbutyric Acid, Fluorophenylproprioric Acid, Fluorophenylacetic Acid, Fluoro Phenylbutyrate, fluorophenylpropionate, fluorofe Acetate, iodophenylbutyric acid, iodophenylproprioric acid, iodophenylacetic acid, iodophenylbutyrate, iodophenylproprionate, iodophenylacetate, hydroxyphenylbutyric acid, hydroxyphenylproprioric acid, Hydroxyphenylacetic acid, hydroxyphenylbutyrate, hydroxyphenylproprionate, hydroxyphenylacetate, methylphenylbutyric acid, methylphenylproprioric acid, methylphenylacetic acid, methylphenylbutyrate, methylphenylproprionate, methylphenylacetate, ethylphenylbutyric acid, Ethyl phenyl propionate, ethyl phenyl acetic acid, ethyl phenyl butyrate, ethyl phenyl propionate, ethyl phenyl acetate, naphthyl butyric acid, naphthyl proprioric acid, naphthyl acetic acid, naphthyl butyrate, naphthyl propionate, Naphthyl Acetate and Trad Ibutyrins include but are not limited to these. In addition, other short-chain fatty acids having 2 to 6 carbon atoms include butyric acid, butyrate, 2,2-dimethyl butyric acid, α-methylhydrocinnamic acid, 3,5-dimethoxy-4-hydrocinnamic acid, cinnamic acid, butyryl Hydroxamate, propionate, bromopropionate, E-3-3 pyridyl-2-propene acid, levulinic acid, Kemp triacid, isovalerate, valerate, butylimide, eye Sobutyramid, valproic acid and valproate, but are not limited to these.

Second compounds for use with phenylbutyric acid or short-chain fatty acid derivatives include antihistamines, anticholiners, nonsteroidal anti-inflammatory agents, steroids, antioxidants, vitamins, leukotriene modulators, interleukin antagonists, mast cell inhibitors, anti-IgE antibodies, SSRIs (selective serotonin reuptake inhibitors), 5-hydroxytryptamine (5-HT) receptor antagonists, antibiotics, calcineurin inhibitors, histone deacetylase inhibitors, gastrin secreting peptide receptor antagonists, gabapentin and naloxone However, it is not limited to these.

The compounds of the present invention can be formulated as pharmaceutical compositions. Such compositions are orally, parenterally, inhaled, inhaled, rectal, intravaginal, intradermal, transdermal or topical in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired. By administration. Topical administration may also include the use of transdermal administration, such as transdermal patches or ion transport devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular or intrasternal. Formulations of the drug are described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Penn. (1975) and Lierman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).

In one embodiment, the skin pruritus treatment formulation is generally aimed at providing conditions that increase skin manageability. For example, a range of formulations for skin care compositions including creams, ointments, gels, sprays, lotions, skin tonics, shampoos or mousses are tolerated, as referenced above. Skin sprays are generally composed of aerosolized copolymers such as polyvinylpyrrolidone and vinyl acetate, and may also function as a setting lotion. Skin gel formulations are similar to sprays in compositions, but are in the form of gels and alcohols and may coat the skin. Skin mousse is a bubble released under pressure from an aerosolization can. The phenylbutyric acid derivative or short-chain fatty acid active ingredient in the topical skin care composition according to the invention is preferably present at a concentration of 0.00001 to 100.00% by weight or at a dose of 1 to 1000 mg relative to the total weight of the composition. . Skin protection compositions for the treatment of pruritus according to the invention are suitably hydrophobic or hydrophilic creams, ointments, gels, skin as described above together with further ingredients suitable for use in skin protection compositions of the type known in the art. It can be formulated as an emollient, spray, lotion, skin tonic, shampoo or mousse, and such additional ingredients include petrolatum, wax, lanolin, silicone, liposomes, vegetable oils, mineral oils, plasticizers, fragrances, preservatives, penetration enhancers, pH adjusters or And other suitable ingredients for topical skin compositions. These ingredients moisturize the skin, stabilize the active compounds, increase drug-skin contact and local concentration, control the sustained release of the drug, and / or reduce skin damage, prevent skin atopy, fibrosis and infection, skin It can help promote wound healing.

The present invention also provides a method of treating skin pruritus as described herein, which method is an antihistamine, anticholinergic, nonsteroidal anti-inflammatory agent, steroid, antioxidant, vitamin, leukotriene modulator, interleukin antagonist, mast cell inhibitor With at least one other agent, including anti-IgE antibodies, SSRIs, 5-hydroxytryptamine (5-HT) receptor antagonists, antibiotics, calcineurin inhibitors, histone deacetylase inhibitors, gabapentin and naloxone These active ingredients are present in free form or in the form of pharmaceutically acceptable salts and optionally at least one pharmaceutically acceptable carrier) at least phenylbutyric acid derivatives or short chain fatty acids thereof, systemically or locally simultaneously, or Compositions that are provided individually or for sequential use.

Suitable salts for the components to be used according to the subject matter also include, for example, alkali metal salts, especially those having inorganic cations such as sodium, potassium, or ammonium salts, alkaline earth metal salts, in particular magnesium salts or calcium salts, as well as divalent or four. Salts with valent cations such as zinc, aluminum or zirconium salts. Examples of salts that can be assumed include salts having an organic base such as dicyclohexylamine salt; Methyl-D-glucamine; And salts with amino acids such as arginine, lysine, histidine, glutamine and the like. In addition, basic nitrogen-containing groups include lower halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfate; Long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; Quaternized by such agents as aromatic halides such as benzyl, phenethyl bromide and the like. Salting agents such as low molecular weight alkylamines such as methylamine, ethylamine or triethylamine can also be used. In this way, water soluble or oil soluble or dispersible products can be obtained.

The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the subject and the particular dosage mode. The dose required will vary depending upon a number of factors known to those skilled in the art, including but not limited to the compound or compounds used, the type of subject, the size of the subject and the severity of the associated disease state causing pruritus, and the like. . The compound may be administered in a single dose, in multiple doses over 24 hours or by continuous infusion. When administered by continuous infusion, the compound may be supplied by methods known in the art, such as but not limited to intravenous gravity drop, intravenous infusion pump, implantable infusion pump or other local routes. Can be. The duration of treatment will vary depending on many factors, such as the duration and severity of the skin, mucosal or systemic disease or disorder causing the local or generalized pruritus. Treatment of a subject with phenylbutyric acid derivatives or short-chain fatty acid derivatives alone or in combination with other agents of the invention can be maintained until pruritus disappears, or the treatment will continue for the life of the subject.

Example

Example  1: Various Topical Compositions-Oily Ointments, Creams and Gels

A. Preparation of Oily Ointment of Phenylbutyrate:

65 g of white Vaseline (Riedel-de Haen), 15 g of cetyl alcohol (Riedel-de Haen), 260 g of soft paraffin (Merck), 155 g of liquid paraffin (Merck) and 5 g of 4-phenylbutyrate (Merck) in the beaker Mixed at and heated at 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 Phenylbutyrate Cream:

Part I: Tefose 63.RTM. 70 g, Superpolystate. RTM. 20 g, Coaster 5000.RTM. 10 g, Myriyol 318.RTM. 15 g, coaster 5088.RTM. 15 g and GMS SE.RTM. 15 g (all available from local suppliers) were mixed in a beaker and heated at 70 ° C.

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

Part II was slowly added to Part I and stirred continuously at 400 rpm for 5 minutes to form a mixture. 2% Stabilase QM.RTM. (Prepared by dissolving 2 g of Stabilase QM.RTM. In 98 g of deionized water, stirring by heating at 70 ° C. to form a paste and cooling at room temperature) It was added to the mixture and stirred for 5 minutes. The pH of this mixture was adjusted to 5.34 with 0.85% phosphoric acid (Merck) and stirred at 600 rpm for 20 minutes. This mixture was cooled at room temperature.

C. Preparation of Gels of Phenylbutyrate:

Part I: Stabilase QM.RTM. 10 g and 232.035 g deionized water were mixed in a beaker and heated at 70 ° C.

Part 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 in a beaker And heated at 70 ° C.

Part II was slowly added to Part I and stirred continuously at 400 rpm for 20 minutes to form a mixture. This mixture was cooled at room temperature.

D: Preparation of Liposome Formulation of Phenylbutyrate:

In liposome formulations, eg phosphatidylcholine (EPC) and cholesterol were used at equimolar or different molar concentrations as primary lipid components. The lipid: phenylbutyrate ratio was varied to obtain various liposomes in which 4-phenylbutyrate was located. Liposomes were prepared by thin film hydration, sized by membrane extraction, and physically evaluated.

Example  2: to skin with different disorders involved to treat pruritus Phenylbutyric acid  Topical administration

2.5% phenylbutyric acid gel was applied to the affected skin six times per day for one week. There were 4 patients in each group, and for these, 0 (no pruritus) to 10 (presumably worst) using the visual analog scale (VAS) to the point where facial expression was fixed to guide their selection. The severity of their pruritus was graded against a continuous scale of pruritus), completing a daily itching journal.

Referring to FIG. 1, 2.5% phenylbutyric acid gel rapidly relieves pruritus within 2 to 10 minutes, thus averaging VAS in each patient with radiation-induced dermatitis, sunburn, surgical wound healing, psoriasis or atopic dermatitis. Was improved from 7.25, 7, 6.75, 8 and 7.75 to 2, 1, 1.5, 2.5 and 2.25 on days 1-2. Pruritus-related syndromes of erythema, urticaria, swelling and desquamation were also alleviated simultaneously.

Example  3: 4- Phenylbutyrate  Inhibition of Multiple Itch-related Molecular Mediators by Sodium

Itching is the most important problem in many allergic and inflammatory skin diseases. The skin barrier (stratum corneum) is a major factor in determining the immune response to allergens present on the skin surface.

Abnormalities in skin barrier function can result in Th1, Th2 and Th3 responses against infectious agents, drugs or protein antigens that cause several cytokines and molecular mediators in skin lesions that cause syndromes and signs of pruritus. The resulting cytokine profile depends on the type of allergen stimulation. Individual subsets of helper T cell activation have been identified by the cytokines they produce. Activated Th1 cells produce IFN-gamma and IL-2. Th1 cells regulate delayed forms of hypersensitivity reactions. The Th1 response is promoted 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. Th2 response is synergistically favored by local production of IL-4, IL-33 and IL-18. Several cytokines such as IL-3, GM-CSF (CSF2) and TNF-alpha are produced by both Th1 and Th2 subsets. IL-6, on the other hand, is a pro-inflammatory cytokine secreted by T cells that is activated to stimulate an immune response to trauma, in particular to burns or other skin damage that causes inflammation. Th3 cells are involved in the negative regulation of the immune response.

To demonstrate whether phenylbutyrate can inhibit multiple itch-related cytokines, molecular mediators or markers at once, RT ² Profiler ™ PCR Array Human Th1-Th2-Th3: APHS-034, SuperArray Bioscience Corporation) was used to analyze gene expression profiling panels.

Jurkat T cells were treated with increasing concentrations of 4-phenylbutyrate, ionomycin and / or phorbol 12-myristate 13-acetate (PMA) at 37 ° C. for 24 to 72 hours. It was. Flow cytometry, cytotoxicity and control extracellular treated cells in cell proliferation after incubation at a dose of 1 mM 4-phenylbutyrate for 48 hours and PMA of 1 mM ionomycin + 10 ng / ml for 24 hours. No significant difference was found by liver apoptosis. However, 48 hours after stimulation with ionomycin (1 mM) + PMA (10 ng / ml), T cells were circulated totally, resulting in cell cycle S due to survival factors (interleukin) and T cell growth induction, While progressing through the G2 and M phases, pretreatment with phenylbutyrate (1 mM) for 24 hours almost completely prevented entry of cells into the S phase of the cell cycle.

Jurkat T-cells were stimulated for 6 hours with ionomycin (1 mM) and PMA (10 ng / ml) with or without pre-culture with 4-phenylbutyrate sodium (1 mM) for 24 hours. Or stimulated, RNA was extracted and RT-PCR was performed to profile the expression of 84 genes associated with the Th1-Th2-Th3 response shown in the gene table (FIG. 2).

Referring to Figures 2A-2E and Table 1, phenylbutyrate is a Th1 cytokine and related genes (CCR5, CSF2, IFN-gamma, IL12B, IL12RB2, in PMA / inomycin-induced Jurkat T-cell activation) IL18, IL18R1, IL2, IL2RA, IRF1, STAT4, TLR4, TLR6), Th2 cytokines and related genes (CCL11, CCL7, CCR2, CCR4, IL13, IL13RA1, IL1R1, IL1R2, IL4R, IL9, IRF4, MAF), T9 Cell activity markers (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 (L18) , IL4R, IRF4) and completely inhibit or significantly reduce the induction of antimicrobial humoral responses (CCL7, CCR2, IL12B, IL13, SFTPD). Phenylbutyrate, on the other hand, upregulates more expression of SOCS1, an inhibitor of cytokine signaling as a Th3 response implicated in the negative regulation of cytokines.

IL-1 and IL-6 are proinflammatory cytokines. Antigen binding to T cell receptors stimulates secretion of IL-2 and expression of IL-2 receptors. The IL-2 / IL-2R interaction then stimulates the growth, differentiation and survival of antigen-selected cytotoxic T cells. IL-4 stimulates activated B-cells and T-cell proliferation and differentiation of CD4 + T-cells into Th2 cells, leading to the switching of the B-cell family to IgE. IL-9 has been thought to function in asthma by eliciting many functions on lymphoid and mast cell lineages. IL-12 is known as a T cell stimulating factor in response to antigenic stimulation, which can stimulate the growth and function of T cells. IL-13 secreted by many cell types, especially Th2 cells, is an important mediator of allergic inflammation. IL-18 works in conjunction with IL-12 to induce cell mediated immunity following infection by microbial products such as lipopolysaccharide. Inhibition of Complex Correlation Signal Network Pathway of IL-1, IL-2, IL-4, IL-6, IL-9, IL-12, IL-13 and IL-18 and of SOCS1 (Inhibitor of Cytokine Signaling) Considering the effects of phenylbutyrate on upregulation, phenylbutyrate correlates with the novel knowledge in the present invention that has the ability to improve pruritus in some allergic and inflammatory dermatitis-related pruritus.

Inhibitory effect of at least 2-fold difference and phenylbutyrate induced by T-cell stimulation when compared to control Th1 cytokine and related genes Mitogen stimulation Phenylbutyrate + Mitogen Stimulation CCR5 2.68 0.98 CSF2 229.13 88.77 IFN-gamma 126.24 99.18 IL12B 2.68 0.98 IL12RB2 2.68 0.98 IL18 2.68 0.98 IL18R1 19.97 0.98 IL2 831.75 304.86 IL2RA 151.17 64.98 IRF1 5.86 1.7 SOCS1 4.82 8.59 STAT4 7.89 3.32 TLR4 2.68 0.98 TLR6 29.04 10.43 Th2 cytokine and related genes CCL11 2.68 0.98 CCL7 2.68 1.04 CCR2 4.20 0.84 CCR4 7.41 1.93 IL13 2.68 0.98 IL13RA1 2.68 0.98 IL1R1 11.31 3.92 IL1R2 2.25 0.82 IL4R 42.81 9.53 IL9 2.68 0.98 IRF4 26.17 16.50 MAF 2.68 0.98 Other T-cell Activity Markers BCL3 58.08 19.73 CD69 87.43 48.57 IL6 2.68 0.98 IL6R 2.68 0.98 JAK2 4.72 2.27 LAT 3.12 1.57 SFTPD 2.68 0.98 TNFRSF9 89.26 13.01

Induction of a number of cytokine expressions typically depends 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 the induction of cytokines is mainly regulated by the level of transcription, 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. Jurkat T cells were either unstimulated or stimulated with ionomycin (1 mM) and PMA (10 ng / ml) for 6 hours with or without 24-hour preculture of 4-phenylbutyrate sodium (1 mM). Subsequently, formaldehyde crosslinking between the protein and DNA and ChIP was performed using anti-NFκB, NF-AT, AP-1, Sp1 or acetyl H3 antibody (Santa Cruz). PCR primers were designed to amplify the human IL-2 promoter: F5'-GAGTTACTTTTGTATCCCCACCCCC (-317 to -292 in IL-2 promoter), R5'-CCTGTACATTGTGGCAGGAGTTGAGG (+33 to 58). PCR amplification was performed 35 times using a three-step protocol of 90 ° C. (30 sec) denaturation temperature, 59 ° C. (45 sec) primer annealing temperature, and 72 ° C. (30 sec) enzyme reaction temperature. Referring to FIG. 3, phenylbutyrate affects chromatin structure by altering the acetyl H3 state, reducing the DNA binding of NFκB, NF-AT and AP-1 to the IL-2 promoter, which affects the promoter of the transcription factor. It was suggested that the inhibition of phenylbutyrate on cytokine expression during T-cell activation could be mediated by reducing the binding of.

As mentioned above, although this invention was demonstrated through the preferable embodiment as an example, it is necessary to understand that this invention is not limited to these disclosed embodiment. In this regard, the present invention is intended to cover various modifications and similar arrangements (as will be apparent to one skilled in the art). Accordingly, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such variations and similar configurations.

1 shows the results of administration of a topical 2.5% phenylbutyric acid gel that rapidly alleviates pruritis associated with skin disorders caused by radiation dermatitis, sunburn, surgical wound healing, psoriasis and atopic dermatitis;

2A-2C show human Th1-Th2-Th3 gene expression profiles to demonstrate phenylbutyrate which simultaneously inhibits the induction of multiple cytokine expression in activated T cells stimulated by PMA and ionomycin Drawing. Jurkat T cells were pre-cultured with phenylbutyrate (1 mM) for 24 hours and then stimulated with ionomycin (1 mM) and PMA (10 ng / ml) for 6 hours. Real-time PCR was used to analyze the expression of a panel of genes associated with helper T cells with or without T-cell stimulation and phenylbutyrate treatment. The array consists of cytokine genes representing Th1, Th2 and Th3 cells, gene coding transcription factors that regulate the expression of cytokines and other markers of CD4 + T lymphocytes, genes involved in immune cell activation in Th1 and Th2 type immune responses, and Genes associated with antimicrobial humoral responses. Results are SE of mean ± 3 results (fold induction (expressed as observed experimental relative unit / reference control relative unit without any stimulation or treatment));

2D and 2E disclose various human Th1-Th2-Th3 genes;

Figure 3 shows the results of chromatin immunoprecipitation (ChIP) assays demonstrating the regulatory effect of phenylbutyrate on the binding of transcription factors that regulate histone status and gene expression to remodel chromatin structure. The result is that 4-phenylbutyrate sodium not only regulates histones but also the IL-2 promoter of transcription factors of NF-κB, NFAT and AP-1 in activated Jurkat T cells stimulated by ionomycin and PMA. It is effective to reduce the binding of. Anti-Sp1 antibodies were used as negative controls because Sp1 did not bind to the IL-2 promoter.

Claims (16)

A pharmaceutical composition for the prevention, treatment or amelioration of pruritus associated with a skin, mucosal or systemic disease or disorder, comprising phenylbutyric acid and a pharmaceutically acceptable carrier, salt or solvate thereof, wherein the disease or disorder is allergic Skin disease, pruritic skin disease, vascular skin disease, sebaceous gland disorders, autoimmune disorders, rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, Sjogren's syndrome, dermatitis, mixed connective tissue disease, papulosquamous dermatose, bacterial skin disease, Viral skin disease, mycolic acid skin infection, granulomatous skin disease, parasitic skin disease, dropout dermatitis, bullous skin disease, pigmented skin disease, photosensitive skin disease, skin disease caused by collagen disease, skin disease caused by internal diseases, dryness, hives, atopic dermatitis, Eczema, Vasculitis, Simple Chronic Psoriasis, Psoriasis, Scabies, Myticosis and Schizophrenia, Multiple Cirrhosis Syndrome, hyperthyroidism, diabetes, renal failure, uremia, iron deficiency anemia, cholestasis, parasitic delusions, intrinsic hematocytosis, wounds, sunburn, herpes simplex, acne, insect bites, radiotherapy or dermatitis or mucositis derived from chemotherapy , Edema tumor, malignant tumor, primary skin cancer and metastatic skin cancer. delete delete The pharmaceutical composition of claim 1, wherein the phenylbutyric acid is present in an amount of 0.00001% to 100.00% by weight based on the weight of the formulation. The method of claim 1, wherein the pharmaceutical composition is a cream, gel, lotion, paste, ointment, emollients, liposomes, nanospheres, skin tonic, mouthwash, oral rinse, shampoo, mousse, spray, pack, Pharmaceutical compositions formed from capsules, tablets, powders, granules, solutions, suspensions, patches or sealed skin conditioning agents. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises a pH adjuster or a penetration enhancer to provide a formulation pH in the range of 3.0 to 13.0. According to claim 1, wherein the pharmaceutical composition is an antihistamine, anticholinergic, nonsteroidal anti-inflammatory, steroid, antioxidant, vitamin, leukotriene modulator, interleukin antagonist, mast cell inhibitor, anti-IgE antibody, SSRI (selective serotonin reuptake) in combination with a second agent, including 5-hydroxytryptamine (5-HT) receptor antagonist, antibiotic, calcineurin inhibitor, histone deacetylase inhibitor, gastrin secreting peptide receptor antagonist, gabapentin, naloxone or combinations thereof Pharmaceutical compositions administered. 8. A pharmaceutical composition according to claim 7, wherein said pharmaceutical composition and said second agent are administered systemically or topically simultaneously or sequentially. A pharmaceutical composition for the prevention, treatment or amelioration of pruritus associated with a skin, mucosal or systemic disease or disorder, comprising a short-chain fatty acid having 2 to 6 carbon atoms and a pharmaceutically acceptable carrier, salt or solvate thereof Or disorders include allergic skin disease, pruritic skin disease, vascular skin disease, sebaceous gland disorders, autoimmune disorders, rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, Sjogren's syndrome, dermatitis, mixed connective tissue disease, papular scale skin disease, bacterial skin disease , Viral skin disease, mycolic acid skin infection, granulomatous skin disease, parasitic skin disease, dropout dermatitis, bullous skin disease, pigmented skin disease, photosensitive skin disease, skin disease caused by collagen disease, skin disease caused by internal disease, dryness, hives, atopic dermatitis , Eczema, vasculitis, simple chronic salivary glands, psoriasis, scabies, dyskinesia and schizophrenia, multiple sclerosis Hyperthyroidism, diabetes, renal failure, uremia, iron deficiency anemia, cholestasis, parasitic delusions, nephropathy, wounds, sunburn, herpes simplex, acne, insect bites, radiotherapy or chemotherapy-derived dermatitis or mucositis Pharmaceutical composition, selected from the group consisting of edema tumors, malignancies, primary skin cancers and metastatic skin cancers. delete 10. The method of claim 9, wherein the short chain fatty acids and pharmaceutically acceptable salts thereof are butyric acid, butyrate, 2,2-dimethyl butyric acid, propionate, bromopropionate, levulinic acid, isovalerate and valerate Pharmaceutical composition selected from the group consisting of. The pharmaceutical composition of claim 9, wherein the short chain fatty acid is present in an amount of 0.00001% to 100.00% by weight based on the weight of the formulation. The method of claim 9, wherein the pharmaceutical composition is a cream, gel, lotion, paste, ointment, emollient, liposomes, nanospheres, skin tonic, mouthwash, mouthwash, shampoo, mousse, spray, pack, capsule, tablet A pharmaceutical composition formed of a patch dosage device with a powder, granule, liquid, suspension, patch, sealed skin conditioning agent, or microneedles. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition further comprises a pH adjusting agent or a penetration enhancer to provide a formulation pH in the range of 3.0 to 13.0. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is an antihistamine, anticholinergic, nonsteroidal anti-inflammatory agent, steroid, antioxidant, vitamin, leukotriene modulator, interleukin antagonist, mast cell inhibitor, anti-IgE antibody, SSRI, 5 Pharmaceutically administered in combination with a second agent comprising a hydroxytrytamine (5-HT) receptor antagonist, an antibiotic, a calcineurin inhibitor, a histone deacetylase inhibitor, a gastrin secreting peptide receptor antagonist, gabapentin, naloxone or a combination thereof Composition. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition and the second agent are administered systemically or locally simultaneously or sequentially.

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