CN101380317B - Pharmaceutical composition for easing pruritus - Google Patents
Pharmaceutical composition for easing pruritus Download PDFInfo
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- CN101380317B CN101380317B CN2007101490690A CN200710149069A CN101380317B CN 101380317 B CN101380317 B CN 101380317B CN 2007101490690 A CN2007101490690 A CN 2007101490690A CN 200710149069 A CN200710149069 A CN 200710149069A CN 101380317 B CN101380317 B CN 101380317B
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Abstract
The invention relates to a pharmaceutical composite which inhibits and/or relieves pruritus caused by dermatosis, mucosa disease or systemic disease or lesion, and is made from derivatives, salt or solvate of phenyl butyric acid and short chain fatty acid with effective dose and a carrier which is acceptable pharmaceutically.
Description
Technical field
The invention relates to the pharmaceutical compositions of a kind of inhibition and/or easing pruritus, and be particularly to utilize phenylbutanoic acid derivatives or short-chain fat acid derivative to suppress and/or the pharmaceutical compositions of easing pruritus.
Background technology
Pruritus can produce the uncomfortable and symptom such as scratch where it itches of other people, causes the redness and the pain of patient skin sometimes.Pruritus is considered to the stimulation on a kind of physics widely, chemistry and/or the biology, and it can be the inherence or external environment causes.Pruritus is classified in a kind of special skin condition, for example, anaphylactogen in drug allergy, mosquito bite, the environment or systemic disease, for example thyrotoxicosis, diabetes, uremia, iron deficiency anemia, delusion of parasitosis, polycythemia vera, cholestasis, Hodgkin ' s disease.Though pruritus is sent out in skin well, but still might betide noncutaneous position, for example, mucosal tissue.Therefore, the pruritic origin cause of formation can be a plurality of factors or single pathological changes.Pruritic pathophysiology relates to maincenter and peripheral nervous system and multiple cytokine and discharges and molecular media (molecular mediator).
When pruritus was begun by skin, the sensory nerve ending that is positioned at corium and epidermis intersection also can be stimulated, and the sensation of scratching where it itches can prolonged exclusive no myelin C fiber (unmyelinated C fibers) and transmitted, and it is different from the fiber that transmits pain and touching.The sensation that the skin of pain can be scratched where it itches by the local nerve transmission that stimulates in the spinal cord.Wherein, the transmission of stimulation comprises via lateral spinothalamic tract and reaches thalamus, then reaches cerebral cortex, and causes the sensation (Weldon D.Allergy Asthma Proc28:1 53-62,2007) of scratching where it itches at this.Histamine, P material (substance P), gastrin releasing peptide receptor (gastrin-releasing peptide receptor) and tumor necrosis factor (Tumor necrosis factor, as if TNF-α) sensuously playing the part of important role (Sun YG what scratch where it itches, Deng Nature448:700-703,2007).In addition, the urticant sensation of nervus centralis, opioid peptides and Opium (μ) are subjected to physical ability to cause the symptom of scratching where it itches of cholestasis, and it can utilize intravenous injection naloxone (naloxone) to treat (Jones EA, et al.JAMA 268:3359-62,1992).Serotonin reuptake inhibitors also may improve scratching where it itches of the general that causes because of cholestasis, this shows, the serotonin approach is sensuously equally also being played the part of important role (Mayo MJ, et al.Hepatology 45:666-74,2007) what scratch where it itches.
On the other hand, the material that is discharged at macrophage, mastocyte or the T cell of itching property regional area, for example, histamine, tachykinin (tachykinins), serotonin (5-hydroxy tryptamine, 5-HT), interferon-, interleukin-22 (IL-2) and IL-4 can cause scratching where it itches, swelling, eruption, urticaria and/or flaky sensation and symptom (Greaves MW, et al.Lancet 348:93 8-40,1996; Inagaki N, et al.Eur JPharmacol546:189-96,2006).When suffering the institute of scratching where it itches that dermatosis or systemic disease cause bitter, more may be excessive scratch this zone and cause pain, inflammation, wound and infection.For pruritic peripheral mechanism, have been found that institute's role on the release of multiple cytokine and sensation that molecular media is scratched where it itches and the symptom at present in ill skin and mucosa.Scratching where it itches that histamine caused relates to H1 receptor (Davies MG, et al.Br J Clin Pharmacol9:461-65,1980).Tachykinin (tachykinins), comprise that neuropeptide substance p (neuropeptides substance P), calcitonin-gene-related peptide (calcitonin gene-related peptide) and vasoactive intestinal peptide (vasoactive intestinalpeptide) are present in the skin free nerve endings of no myelin pain nerve unit, it can cause the generation of the consciousness of scratching where it itches.Intradermal 5-HT can cause the sensation (Nojima H, et al.J Pharmacol Exp Ther 306:245-52,2003) of scratching where it itches by activation 5-HT2 and 5-HT3 receptor.Therefore, can utilize the antagonist of 5-HT2 and 5-HT3 receptor to treat pruritus (Schworer H, et al.Lancet 341:1277,1993).When subcutaneous can on atopy patient and normal individual, cause after giving IL-2 the part of strong row scratch where it itches (Wahlgren CF, et al.Arch Dermatol Res 287:572-80,1995).Therefore utilize immunosuppressant, the biosynthesis that suppresses IL-2 as ciclosporin-A (cyclosporine A) can relax the symptom of scratching where it itches (Wahlgren CF, et al. Acta Derm Venerol (Stockh) 70:323-29,1990) of atopic dermatitis.
Suppress to scratch where it itches symptom though the antihistamine medicament is widely used in, this inhibitory action is the side effect of generation maincenter abirritative, rather than the antagonism of the local histamine in the skin, also unclear (the Krause L of its effect degree, et al, BMJ 287:1199-200,1983).Many patients confirm, even and treat with antihistamine medicament, 5-HT receptor antagonist and/or immunosuppressant, the persistent symptom of scratching where it itches is still arranged, because these therapeutic agents only are fit to the treatment of short time and side effect is arranged, and be not suitable for chronic sufferer of scratching where it itches.Therefore, be badly in need of a kind of novelty and effective compositions of preventing, treating or improving the symptom of scratching where it itches at present.
Phenylbutyric acid salt (phenylbutyrate), fatty acid for a kind of short chain, it is one of seldom used medicine of U.S. food and FAD (FDA) approval, it is used for the treatment of birth defect (the Brusilow SW with urea cycle disorder, et al N Engl J Med 310:1630-4,1984).In human body, phenylbutyric acid salt is metabolized to phenylacetic acid salt by beta-oxidation, and then phenylacetic acid salt can combine with glutamine to form phenylacetylglutamine, and it can be used as a kind of carrier to drain unnecessary nitrogen.Find also at present that phenylbutyric acid salt has the ability of inhibition deacetylase to increase histone and nonhistones acetylation; to change chromatin Structure and to influence the activity of a plurality of transcription factor; thereby can cause the back Radix Rehmanniae to regulate and control a plurality of gene control disease (Marks PA simultaneously; et al.J Natl Cancer Inst 92:1210-6,2000).Before clinical and in the clinical research, phenylbutyric acid salt is in the regulation and control of gene, have treatment blood and solid-state property tumor, hereditary, as fibrosis cyst, sicklemia, β-thalassemia, the chain adrenoleukodystrophy of X, spinal cord muscular dystrophy and neurodegenerative disease, wear out, reach inflammatory diseases, potentiality (Kemp S, et al.Nat Med 4:1261-8,1998 as autoimmune disease; Et al Proc Natl Acad Sci USA 102:11023-8,2005; Kang HL, et al.ProcNatl Acad Sci USA 99:838-43,2002; Blanchard F, et al. Drug Discov Today 10:197-204,2005).In addition, phenylbutyric acid salt also can be used as a kind of chemical accompaniment (chemicalchaperone) and suffers the injury of oxidative stress and neuron excitotoxicity to prevent normal cell.(Yam?GH，et?al.Invest?Ophthalmol?Vis?Sci?48：1683-90，2007)。
Summary of the invention
The invention provides a kind of pruritic pharmaceutical compositions that skin, mucosa or systemic disease or pathological changes are followed that suppresses and/or slow down, comprise the phenylbutyric acid or the C of effective dose
2-6Short-chain fat acid derivative, salt or solvate, with and pharmaceutically acceptable carrier.
The present invention provides a kind of pruritic pharmaceutical compositions that skin, mucosa or systemic disease or pathological changes are followed that suppresses and/or slow down in addition, comprises the phenylbutyric acid or the C of effective dose
2-6Short-chain fat acid derivative, salt or solvate with and pharmaceutically acceptable carrier, suppress pruritic medicament with other.
For above and other objects of the present invention, feature and advantage can be become apparent, preferred embodiment cited below particularly, and cooperate appended diagram, be described in detail below:
Description of drawings
Fig. 1 shows that topical 2.5% phenylbutyric acid gel can slow down dermatosis apace, the symptom of following as radiodermatitis, sunburn, surgical incision, psoriasis and atopic dermatitis of scratching where it itches.
Fig. 2 A-2C shows people Th1-Th2-Th3 gene expression situation, with inducing that proof phenylbutyric acid salt suppresses simultaneously that multiple cytokine in the activating T cell that PMA and ionomycin stimulate expresses.Jurkat T cell was handled 24 hours with phenylbutyric acid salt (1mM) earlier, then stimulated 6 hours with ionomycin (ionomycin) (1 μ M) and PMA (10ng/ml).Utilize PCR in real time, analyze the helper T cell Expression of Related Genes that is with or without T cytositimulation and the processing of phenylbutyric acid salt.The gene that in this array, comprises the transcription factor of the cytokine gene of representing Th1, Th2, Th3 cell, the adjustable cytokine-expressing of coding and other CD4+T lymphocyte sign, gene relevant and the gene relevant in Th1 and the immunoreation of Th2 type with the antimicrobial humoral response with activated immune cell.The result shows the axonometric chart of the meansigma methods ± SE of each numerical value, represents (relative unit of observed empirical value/without any the relative unit of the substrate contrast that stimulates or handle) with multiple.
The gene of Fig. 2 D-1,2D-2 displayed map 2A-2C representative.
Fig. 3 shows that chromatin immuno-precipitation (ChIP) analytical proof phenylbutyric acid salt pair changes the state of histone of STRUCTURE OF CHROMATIN and the bonded regulating action of the transcription factor that regulator gene is expressed.The result shows that the 4-phenylbutyrate sodium not only can change histone, and can reduce the NF-к B in the activation Jurkat T cell that stimulates with ionomycin and PMA, and NFAT and AP-1 transcription factor combine with the IL-2 promoter.Because Sp1 can not combine with the IL-2 promoter, therefore with anti-Sp1 antibody as negative matched group.
Embodiment
The present invention utilizes phenylbutyric acid or short-chain fatty acid and pharmaceutically acceptable derivates thereof to suppress or alleviate the pruritus of the form of ownership that rises because of disease or pathological changes, relevant disease or pathological changes comprise, but be not limited to allergic dermatosis (allergic dermatoses), pruritus (pruritic dermatoses), vascular dermatosis (vascular dermatoses), sebaceous gland pathological changes (sebaceous gland disorders), autoimmune pathological changes (autoimmune disorders), rheumatoid arthritis (rheumatoid arthritis), systemic lupus erythematosus (sle) (systemic lupus erythematosus), progressive systemic sclerosis (progressive systemic sclerosis), siogren's syndrome (sjogren ' s syndrome), dermatomyositis (dermatomyositis), mixed connective tissue disease (mixed connective tissuedisease), papulosquamous dermatosis (papulosquamous dermatoses), bacterial dermatosis (bacterial dermatoses), viral dermatosis (viral dermatoses), mycete skin infection (mycolic skin infections), granuloma dermatosis (granulomatous dermatoses), malis (parasitic skin dermatoses), exfoliative dermatitis (exfoliative dermatitis), bullous dermatosis (bullous dermatoses), coloring dermatosis (pigmented dermatoses), light sensitive dermatoses (photosensitive dermatoses), the caused dermatosis of collagenosis (dermatosescaused by collagen diseases), because of the caused dermatosis of internal disease (dermatoses due tointernal diseases), xerosis (xerosis), urticaria (urticaria), atopical dermatitis (atopicdermatitis), eczema (eczyma), vasculitis (vasculitis), lichen simplex chronicus disease (lichen simplexchronicus), psoriasis (psoriasis), scabies (scabies), pediculosis corporis and pubic louse (pediculosiscorporis and pubis), multiple sclerosis (multiple sclerosis), thyrotoxicosis (thyrotoxicosis), diabetes (diabetes), renal insufficiency (renal insufficiency), uremia (uremia), iron deficiency anemia (iron deficiency anemia), cholestasis (cholestasis), delusion of parasitosis (delusions of parasitosis), polycythemia vera (polycythemia rubravera), wound (wound), sunburn (sun bum), herpes labialis (cold sores), acne (acne), insect bite (insect bite), caused dermatitis of radiation cure or chemotherapy or mucositis (radiotherapy or chemotherapy-induced dermatitis or mucositis), tumor association syndrome (paraneoplastic syndrome), malignant tumor (malignancy), primary cutaneous cancer (primaryskin cancer) and transitivity skin carcinoma (metastatic skin cancer).
Phenylbutanoic acid derivatives of the present invention comprises, but be not limited to phenylbutyric acid (phenylbutyricacid), phenylpropionic acid (phenylproprionic acid), phenylacetic acid (phenylacetic acid), phenylbutyric acid salt (phenylbutyrate), phenylpropionic acid salt (phenylproprionate), phenylacetate (phenylacetate), phenylacetylglutamine (phenylacetylglutamine), phenoxy butyric acid (phenoxybutyric acid), phenoxy propionic acid (phenoxyproprionic acid), phenoxy acetic acid (phenoxyacetic acid), phenoxy butyric acid salt (phenoxybutyrate), phenoxy propionic acid salt (phenoxyproprionate), phenoxy acetate (phenoxyacetate), bromophenyl butanoic acid (bromophenylbutyric acid), bromophenyl propanoic acid (bromophenylproprionic acid), bromophenyl acetic acid (bromophenylacetic acid), bromophenyl butyrate (bromophenylbutyrate), bromophenyl propionate (bromophenylproprionate), bromophenyl acetate (bromophenylacetate), chlorphenyl butanoic acid (chlorophenylbutyric acid), chlorphenyl propanoic acid (chlorophenylproprionic acid), chlorophenylacetic acid (chlorophenylacetic acid), chlorphenyl butyrate (chlorophenylbutyrate), chlorphenyl propionate (chlorophenylproprionate), chlorophenylacetic acid salt (chlorophenylacetate), fluorophenyl butanoic acid (fluorophenylbutyric acid), fluorophenyl propanoic acid (fluorophenylproprionicacid), fluorophenyl acetic acid (fluorophenylacetic acid), fluorophenyl butyrate (fluorophenylbutyrate), fluorophenyl propionate (fluorophenylproprionate), fluorophenyl acetate (fluorophenylacetate), iodophenyl butanoic acid (iodophenylbutyric acid), iodophenyl propanoic acid (iodophenylproprionic acid), iodophenyl acetic acid (iodophenylacetic acid), iodophenyl butyrate (iodophenylbutyrate), iodophenyl propionate (iodophenylproprionate), iodophenyl acetate (iodophenylacetate), hydroxyphenyl butanoic acid (hydroxyphenylbutyric acid), hydroxyphenylpropionic acid (hydroxyphenylproprionic acid), hydroxyphenyl acetic acid (hydroxyphenylacetic acid), hydroxyphenyl butyrate (hydroxyphenylbutyrate), hydroxyphenylpropionic acid salt (hydroxyphenylproprionate), hydroxyphenyl acetate (hydroxyphenylacetate), aminomethyl phenyl butanoic acid (methylphenylbutyricacid), aminomethyl phenyl propanoic acid (methylphenylproprionic acid), aminomethyl phenyl acetic acid (methylphenylacetic acid), aminomethyl phenyl butyrate (methylphenylbutyrate), aminomethyl phenyl propionate (methylphenylproprionate), aminomethyl phenyl acetate (methylphenylacetate), ethylphenyl butanoic acid (ethylphenylbutyric acid), ethylphenyl propanoic acid (ethylphenylproprionicacid), ethylphenyl acetic acid (ethylphenylacetic acid), ethylphenyl butyrate (ethylphenylbutyrate), ethylphenyl propionate (ethylphenylproprionate), ethylphenyl acetate (ethylphenylacetate), naphthyl butanoic acid (naphthylbutyric acid), naphthyl propionic acid (naphthylproprionic acid), naphthyl acetic acid (naphthylacetic acid), naphthyl hydrochlorate (naphthylbutyrate), naphthyl propionic acid salt (naphthylproprionate), naphthyl acetic acid salt (naphthylacetate) and tributyrin (tributyrin).
Short-chain fat acid derivative of the present invention comprises; but be not limited to; butanoic acid (butyric acid); butyrate (butyrate); 2; 2-acid dimethyl (2; 2 dimethyl butyric acid); Alpha-Methyl hydrocinnamic acid (α-methylhydrocinnamic acid); 3; 5-dimethoxy-4 '-hydrocinnamic acid (3,5dimethoxy-4-hydrocinnamic acid); cinnamic acid (cinnamic acid); bytyry hydroxamate (butyryl hydroxamate); propionate (propionate); bromo-propionic acid salt (bromopropionate); E-3-3 pyridine radicals-2-acrylic acid (E-3-3 pyridyl-2-propenoic acid); levulic acid (levulinic acid); Kemp ternary acid (Kemp triacid); isovalerate (isovalerate); valerate (valerate); the inferior amide (butrymide) of fourth; isobutyramide (isobutyramide); valproic acid (valproic acid) and valproate (valproate).
Chemical compound of the present invention can be a kind of pharmaceutical compositions.That the mode that gives of this pharmaceutical compositions comprises is oral, parenteral formula, suction-type, anus suppository, vagina suppository, percutaneous absorbs or local.This medicament comprises the avirulent pharmaceutically acceptable carrier of tradition, adjuvant and carrier.Topical administration then comprises the mode that gives of using percutaneous to absorb, for example, and transdermal patches or iontophoresis assembly etc.The parenteral formula gives then to comprise subcutaneous injection, intravenous injection, intramuscular injection or breastbone injection, or infusion techn etc.The preparation of medicament can be with reference to Hoover, John E., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Penn (1 975), Liberman, H.A.and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).
In one embodiment, medicament can be made into and generally be used for the treatment of pruritic form to be used on the skin.The skin varniss pattern includes, but not limited to Emulsion, unguentum, gel, spray, astringent, shampoo or mousse etc.In general, the skin spray can be made up of the spray form copolymer, for example, and polyvinylpyrrolidone, vinyl acetate and analog thereof, and it can have the function of astringent.The preparation method and the spray of skin gel are similar, but it is gel and do not have alcoholic acid existence, can be attached on the skin.The skin mousse discharges foam for utilizing pressure.Phenylbutanoic acid derivatives of the present invention or short-chain fatty acid composition content in partial skin varniss is 0.00001 to 100.00 weight %, or its dosage 1 to 1000mg.Skin cream is hydrophobicity or hydrophilic Emulsion, unguentum, gel, emollient, spray, varnish, skin condition water, shampoo or mousse.In addition, more can add suitable composition to skin cream, this extra composition that adds comprises vaseline, wax, lanoline, siloxanes, liposome, vegetable oil, mineral oil, plasticizer, spice, antiseptic, short penetrating agent, pH value adjusts agent or other is suitable for the composition of local skin.The wettable skin of this extra composition, the stabilizing active chemical compound increases the contact of medicine-skin and the concentration of regional area, and the control drug slow discharges and/or reduce the infringement of skin, prevent atrophoderma, fibrosis or infection, and the reparation that promotes skin wound.
Contain at least a phenylbutanoic acid derivatives or short-chain fatty acid in the pharmaceutical compositions of the present invention, and can follow one or more second medicaments.This second medicament comprises; but be not limited to; antihistamine drug; anticholinergic agents; NSAID (non-steroidal anti-inflammatory drug); steroid; antioxidant; vitamin; the leukotriene dressing agent; the interleukin antagonist; the mastocyte inhibitor; anti-IgE antibodies; the selective serotonin reuptake inhibitor; 5-hydroxy tryptamine (5-hydroxytryptamine) receptor antagonist; antibiotic; the neurocalcin inhibitor; histone deacetylase inhibitors; gastrin releasing peptide receptor (gastrin-releasing peptidereceptor); gabapentin and naloxone etc.; above-mentioned active ingredient can comprise or not comprise its pharmaceutically acceptable salt class; and selectivity uses at least a pharmaceutically acceptable carrier; compositions of the present invention can general or topical administration, can be simultaneously; give respectively or successively.
Salt suitable among the present invention comprises inorganic cation, for example, alkaline metal salt, as sodium, potassium or ammonium salt, the alkaline-earth metal salt as magnesium, calcium salt, contains the salt of bivalence or quadrivalent cation, as zinc, aluminum or zirconates.In addition, be organic salt also, as hexanamine salt, methyl D-glycosamine, amidates is as arginine salt, lysinate, histidine salt, glutamate, Glu etc.And alkaline nitrogen-containing group can be quaternized with following reagent: low alkyl halide, as methyl, ethyl, propyl group and butyl chloride, bromide and iodide; Dialkylsulfates is as dimethyl, diethyl, dibutyl and diamyl sulfuric ester; Long-chain halogenide is as decyl, dodecyl, myristyl, stearyl chloride, bromide and iodide; Asthma halogenide (asthma halides) is as benzyl, phenethyl bromination thing or other analog.Form the reagent of salt, comprise low-molecular-weight alkylamine, for example, methyl amine, ethylamine or triethylamine.Also can make water or oil-soluble reagent or dispersant.
The content of active ingredient of the present invention can be according to Different Individual and the mode that gives, and this active ingredient can merge to form single dose with other carrier.This dosage can be done suitable adjustment according to different parameters.Above-mentioned parameter includes, but not limited to employed chemical compound, individual kind, individual size, causes the severity of disease of scratching where it itches.Active component of the present invention can once give, and repeatedly gives in 24 hours or transfusion continuously.When the mode that gives is transfusion continuously, can select suitable usual way for use, include, but not limited to gravity drip infusion, amedrop, implantation type infusion pump or any partial approach.The time of treatment can be done suitable adjustment according to different situations, and for example, the course of disease of skin and seriousness cause part or general the scratch where it itches mucosa or the systemic disease of symptom.Finish up to pruritus separately or with other medicament combined treatment individuality of the present invention with phenylbutanoic acid derivatives or short-chain fat acid derivative, or continued treatment is lifelong.
Embodiment
1. the preparation of oily ointment, cream and the gel of various different types
A. the preparation of phenylbutyric acid salt oil ointment
65 gram white vaseline (Riedel-de Haen), 15 gram spermols (Riedel-de Haen), 260 gram soft paraffins (Merck), 155 gram liquid paraffin (Merck) and 5 gram 4-phenylbutyric acid salt (Merck) are placed a beaker to mix and be heated to 70 ℃ form pastel.This pastel was stirred 1 hour in 400rpm, and be cooled to room temperature.
B. the preparation of phenylbutyric acid salt Emulsion
First composition: 70 gram Tefose63
, 20 the gram Superpolystate
, 10 the gram Coster 5000
, 15 the gram Myriyol 318
, 15 the gram Coster 5088
, and 15 gram GMS SE
(all can be obtained by the local supplier) mixed in a beaker and is heated to 70 ℃.
Second composition: 5.739 gram 4-phenylbutyrate sodiums (Triple CrownAmerica, Inc.), 0.125 gram methyl parahydroxybenzoate (methylparaben) (Merck), 0.075 gram propyl p-hydroxybenzoate (propylparaben) (Merck) and 149.061 gram deionized waters in a beaker, mix and be heated to 70 ℃.
Add second composition in first composition lentamente and continue and stir 5 minutes up to forming mixture with 400rpm.With 2%Stabileze QM
(with 2 gram Stabileze QM
Be dissolved in 98 gram deionized waters, and form a pastel, and be cooled to room temperature and be prepared in 70 ℃ of heated and stirred) add this mixture and stirred 5 minutes.With the pH value to 5.34 of 0.85% phosphoric acid (Merck) adjustment mixture, and with 600rpm stirring 20 minutes.Mixture is cooled to room temperature.
C. the preparation of phenylbutyric acid salt gel
First composition: 10 gram Stabileze QM
, 232.035 gram deionized waters mix in beaker and are heated to 70 ℃.
Second composition: 5.739 gram 4-phenylbutyrate sodiums (Triple CrownAmerica, Inc.), 0.125 gram methyl parahydroxybenzoate (methylparaben) (Merck), 0.075 gram propyl p-hydroxybenzoate (propylparaben) (Merck), 232.035 gram deionized waters and 20 gram 10%NaOH mix in beaker and are heated to 70 ℃.
Add second composition in first composition lentamente and continue and stir 20 minutes up to forming mixture with 400rpm.Mixture is cooled to room temperature.
D. the preparation of phenylbutyric acid liposome of salt preparation
In this kind Liposomal formulation, egg lecithin (egg phosphatidylcholine, EPC) and cholesterol be as being equal to-or the main lipid component of difference-molar concentration.With different lipids: the ratio of phenylbutyric acid salt can obtain the liposome of the multiple 4-of containing phenylbutyric acid salt.Liposome be via thin film hydration preparation and with film extrusion molding and actual assessment it.
2. the local application phenylbutyric acid is to pruritic inhibition effect that various disease produced
2.5% phenylbutyric acid gel is applied to patient skin, and also continue a week every day 6 times.Every group has 4 patients, and every patient's of record every day the degree of scratching where it itches.The degree of scratching where it itches is utilized visual analogue scale (Visual Analogue Scale, VAS) be divided into the 0th grade (nothing scratch where it itches situation) to 10 grades (the most serious situations of scratching where it itches that can imagine) according to seriousness, related content can wait Hepatology45:666-74,2007 with reference to Mayo MJ..
2.5% phenylbutyric acid gel is in about 2-10 minute, can slow down the sensation of scratching where it itches apace, and the VAS meansigma methods reduced to 2,1,1.5,2.5,2.25 respectively by 7.25,7,6.75,8,7.75 in two days, wherein respectively organize patient and be respectively radiodermatitis, sunburn, surgical incision, psoriasis, atopic dermatitis, shown in the 1st figure.At the same time, equally also eliminate and the relevant symptom of scratching where it itches, as erythema, urticaria, enlargement, decortication etc.
3.4-phenylbutyrate sodium suppresses the relevant molecular media of multiple pruritus
Scratching where it itches is one of great puzzlement of many skin allergy and inflammation.The protective layer of skin (horny layer) is vitals of differentiating the nature anaphylactogen on the skin surface.
If the function of protective layer of skin is undesired; can cause Th1, Th2 and Th3 cell that infectious agent (infectious agents), chemical substance or proteantigen are produced reaction; it can bring out the various kinds of cell factor and thereby molecular media causes the symptom of scratching where it itches in the skin wound generation, and produces different cytokines according to the kind of different anaphylactogens stimulations.Different helper T cell (helper T cell) activation can be differentiated by the cytokine that it produced.Activated T h1 cell can produce INF-γ and IL-2.Th1 cell may command delayed hypersensitivity (Delayed type hypersensitiveity reaction), and can promote the Th1 cell effect by the IL-12 Superfamily cytokine that the part discharges.These reactions more can be subjected to the generation of IL-15 and IL-18 and strengthen.Activated T h2 cell can produce IL-4 and IL-10.The Th2 cell is relevant with allergy and antibody response, and can promote the Th2 cell effect with synergism by IL-4, IL-33 and the IL-18 that the part produces.Th1 and Th2 hypotype can produce some cytokine, for example, and IL-3, GM-CSF (CSF2) and TNF-α.On the other hand, IL-6 is a kind of proinflammatory cytokine (pro-inflammatory cytokines), and it is discharged by the activated T cell, can promote the immunoreation of wound, and especially burn waits the inflammation that tissue necrosis caused.But Th3 cell negative regulation immunoreation.
For proof phenylbutyric acid salt can suppress multiple and relevant cytokine, molecular media or the sign (marker) of scratching where it itches simultaneously, utilize PCR in real time (RT
2Profiler
TMPCR Array HumanTh1-Th2-Th3:APHS-034, SuperArray Bioscience Coporation) the many groups of analysis expression of gene situations.
Handled Jurkat T cell 24 to 72 hours with 4-phenylbutyric acid salt, ionomycin (ionomycin) and/or 12-tetradecylic acid Buddhist ripple ester-13-acetate (PMA) that concentration increases down in 37 ℃.Found that the matched group of flow cytometer detection and cell proliferation, cytotoxicity and the apoptosis of processed group do not have significant difference after handling 48 hours, the ionomycin of the 1 μ M PMA with 10ng/ml with the 4-phenylbutyric acid salt of 1mM and handling 24 hours.Yet, after stimulating 48 hours with PMA (10 ng/ml) with ionomycin (1 μ M), because the growth of T cell and inducing of survival factors (interleukin), the T cell can carry out the cell cycle of complete S phase, G2 phase, M phase, otherwise the T cell of handling 24 hours with phenylbutyric acid salt (1mM) in advance then almost completely can't enter the cell cycle S phase.
Fig. 2 A-2C shows the JurkatT cell of handling in advance with 4-phenylbutyrate sodium processing 24 hours or nothing in advance, stimulated 6 hours or do not stimulate with ionomycin (1 μ M) and PMA (10ng/ml), extract its RNA, and analyze and 84 kinds of relevant expression of gene of Th1-Th2-Th-3 reaction with RT-PCR.2D figure shows the gene of 2A-2C figure representative.
With reference to Fig. 2 and table 1, phenylbutyric acid salt can suppress fully or reduce significantly the PMA/ ionomycin Th1 cytokine and related gene (CCR5, CSF2, the IFN-γ in the inductive Jurkat T cell activation, IL12B, IL12RB2, IL18, IL18R1, IL2, IL2RA, IRF1, STAT4, TLR4, TLR6), Th2 cytokine and related gene (CCL11, CCL7, CCR2, CCR4, IL13, IL13RA1, IL1R1, IL1R2, IL4R, IL9, IRF4, MAF), T cell activation sign (BCL3, CD69, IL6, IL6R, JAK2, LAT, TNFRSF9), t helper cell 1 type immunoreation (IL12B, IL1 8, IRF4, SFTPD, TLR4, TLR6), t helper cell 2 type immunoreation (IL18, IL4R, IRF4) and antimicrobial humoral response (CCL7, CCR2, IL12B, IL13, generation SFTPD).On the other hand, phenylbutyric acid salt can increase the expression of SOCS1.SOCS1 is a kind of inhibitor of cytokine signaling, is the Th3 reaction, but its negative regulation cytokine.
IL-1 and IL-6 are for inspiring inflammatory cytokines.The antigen that is attached to TXi Baoshouti can stimulate secretion and the IL-2 receptor expression of IL-2.But growth, differentiation and the survival of the cytotoxic T cell (antigen-selected cytotoxic T cells) that the reaction stimulator antigen of IL-2/IL-2R is selected.IL-4 can stimulate the propagation of activatory B cell, T cell,, and make the CD4+T cell differentiation become the Th2 cell, and induce the B cell category to be transformed into IgE.IL-9 can bring out the function of many lymphoid cells and mast cell line, and is considered to relevant with asthma.IL-12 is known as a kind of T cell stimulating factor, and to the antigenic stimulus reaction, it can stimulate the growth and the function of T cell.IL-13 can be by the emiocytosis of many kinds, Th2 cell particularly, and IL-13 is a kind of important irritated inflammation medium.After infecting by microbial product such as lipopolysaccharide, IL-18 can with the work immunity of inducing cell mediation of IL-12 one.The present invention finds that phenylbutyric acid salt can suppress the relevant signal network path of complexity of IL-1, IL-2, IL-4, IL-6, IL-9, IL-12, IL-13, IL-18, and raise SOCS1 (a kind of cytokine signaling inhibitor), and phenylbutyric acid salt can improve the symptom of scratching where it itches that allergy and inflammation dermatitis are followed.
Table 1, in the inducing of T cytositimulation, compare gene or the cytokine that has 2 times of differences at least and the inhibition effect of phenylbutyric acid salt with matched group
| Th1 cytokine and relevant gene | Mitogen stimulates | Phenylbutyric acid salt+mitogen stimulates |
| ?CCR5 | 2.68 | ?0.98 |
| ?CSF2 | 229.13 | ?88.77 |
| IFN-γ | 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 relevant gene | ||
| 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 |
| The activation sign of other T cell | ||
| 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 |
Induce the expression of multiple cytokine to depend on the coordinate active of transcription factor, transcription factor comprises NF к B mostly, NF-AT, and AP-1 (Sancho R, et al.J Immunol 172:2341-51,2004; Li-Weber M, et al.Eur J Immunol34:1111-18,2004).Because inducing of cytokine mainly is to regulate at transcriptional level, so utilize chromatin immuno-precipitation (ChromatinImmunoprecipitation, ChIP) analyze Jurkat T cell to determine NF к B, whether NF-AT or AP-1 have on the promoter that is bonded to the IL-2 gene.Handled 24 hours or do not have the Jurkat T cell of prior processing in advance with the 4-phenylbutyrate sodium; stimulated 6 hours or do not stimulate with ionomycin (1 μ M) and PMA (10ng/ml), utilize anti-NF к B, NF-AT, AP-1, Sp1 or acetyl group H3 antibody (SantaCruz) to carry out the formaldehyde crosslinking of protein and DNA and ChIP then.Design PCR primer human IL-2's promoter: the F 5 '-GAGTTACTTTTGTATCCCCACCCCC (in the IL-2 promoter-317 to-292) that increases, R 5 '-CCTGTACATTGTGGCAGGAGTTGAGG (+33 to 58).Pcr amplification uses 3 step designs, has the denaturation temperature of 90 ℃ (30 seconds), and the enzyme reaction temperature of the primer annealing temperature of 59 ℃ (45 seconds) and 72 ℃ (30 seconds) carries out 35 circulations altogether.With reference to Fig. 3, phenylbutyric acid salt can influence STRUCTURE OF CHROMATIN by the state that changes acetyl group H3, and reduces NF к B, NF-AT and AP-1 and combine with DNA to the IL-2 promoter.Show that in the T cell activation phase inhibition of phenylbutyric acid salt pair cytokine-expressing can mediate with combining of promoter by reducing transcription factor.
Though the present invention discloses as above with preferred embodiment; right its is not in order to qualification the present invention, any those skilled in the art, without departing from the spirit and scope of the present invention; when can doing a little change and retouching, so protection scope of the present invention should be with being as the criterion that claim was defined.
Claims (10)
1. a compositions that comprises the phenylbutyric acid or derivatives thereof purposes that is used for suppressing and/or slows down the pruritic medicine that skin, mucosa or systemic disease or pathological changes follow in preparation, wherein this phenylbutanoic acid derivatives is selected from: phenylbutyric acid salt, bromophenyl butanoic acid, bromophenyl butyrate, chlorphenyl butanoic acid, chlorphenyl butyrate, fluorophenyl butanoic acid, fluorophenyl butyrate, iodophenyl butanoic acid, iodophenyl butyrate, hydroxyphenyl butanoic acid, hydroxyphenyl butyrate, aminomethyl phenyl butanoic acid, aminomethyl phenyl butyrate, ethylphenyl butanoic acid, ethylphenyl butyrate.
2. purposes as claimed in claim 1, wherein this disease or pathological changes are selected from: allergic dermatosis, pruritus, the vascular dermatosis, the sebaceous gland pathological changes, the autoimmune pathological changes, rheumatoid arthritis, systemic lupus erythematosus (sle), progressive systemic sclerosis, siogren's syndrome, dermatomyositis, mixed connective tissue disease, papulosquamous dermatosis, bacterial dermatosis, viral dermatosis, the mycete skin infection, the granuloma dermatosis, malis, exfoliative dermatitis, bullous dermatosis, the coloring dermatosis, light sensitive dermatoses, the caused dermatosis of collagenosis, because of the caused dermatosis of internal disease, xerosis, urticaria, atopical dermatitis, eczema, vasculitis, lichen simplex chronicus disease, psoriasis, scabies, pediculosis corporis and pubic louse, multiple sclerosis, thyrotoxicosis, diabetes, renal insufficiency, uremia, iron deficiency anemia, cholestasis, delusion of parasitosis, polycythemia vera, wound, sunburn, herpes labialis, acne, insect bite, caused dermatitis of radiation cure or chemotherapy or mucositis, tumor association syndrome, malignant tumor, primary cutaneous cancer and transitivity skin carcinoma.
3. purposes as claimed in claim 1, wherein this phenylbutyric acid or derivatives thereof accounts for the 0.00001-100.00% of this medicine total weight.
4. purposes as claimed in claim 1, wherein this medicine is that Emulsion, unguentum, gel, pastel, emulsion, spray, suppository, capsule, lozenge, powder, granule, solution, suspension, paster or enclosed type are applied ointment or plaster.
5. purposes as claimed in claim 1 also comprises a kind of penetration enhancer, or a kind of pH value regulator is so that the pH of this medicine maintains 3.0 to 13.0.
6. purposes as claimed in claim 1; wherein said composition and a kind of second medicament merge use, and this second medicament is selected from: hydryllin, anticholinergic, NSAID (non-steroidal anti-inflammatory drug), steroid, antioxidant, vitamin, leukotriene dressing agent, interleukin antagonist, mastocyte inhibitor, anti-IgE antibodies, selective serotonin reuptake inhibitor (SSRI), 5-hydroxy tryptamine (5-HT) receptor antagonist, antibiotic, neurocalcin inhibitor, histone deacetylase inhibitors, gastrin releasing peptide receptor, gabapentin and naloxone or its combination.
7. purposes as claimed in claim 6, wherein said composition and this second medicament are that general or locality give.
8. purposes as claimed in claim 6, wherein said composition and this second medicament are for giving at the same time or separately.
9. purposes as claimed in claim 1, wherein this medicine makes an addition to emollient, astringent, collutory and shampoo.
10. purposes as claimed in claim 1, wherein this medicine is nano-particle, oil preparation, varnish or liposome dosage form.
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| US6093740A (en) * | 1997-04-30 | 2000-07-25 | Eli Lilly And Company | Therapeutic treatment for skin disorders |
| CN1414856A (en) * | 1999-12-28 | 2003-04-30 | 帝国制药株式会社 | Antiprurity agents for external use |
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| US6093740A (en) * | 1997-04-30 | 2000-07-25 | Eli Lilly And Company | Therapeutic treatment for skin disorders |
| CN1414856A (en) * | 1999-12-28 | 2003-04-30 | 帝国制药株式会社 | Antiprurity agents for external use |
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