TW201102059A - Pharmaceutical composition for treating or ameliorating mucocutaneous or ocular toxicities or side effects - Google Patents

Abstract

A pharmaceutical composition for treating or ameliorating mucocutaneous, ocular toxicities, or side effects induced by blocking cellular growth and survival signal transduction pathways. The composition comprises an effective amount of a histone deacetylase inhibitor and a pharmaceutically acceptable carrier, salt or solvate thereof, wherein the cell growth and survival signal transduction pathways are blocked by an antibody targeted therapy agent, antibody fragment, targeted small-molecule chemical compound, low-molecular-weight tyrosine kinase inhibitor, peptide mimetic, anti-sense oligonucleotide (DNA and/or RNA), or ribozyme.

Description

201102059 VI. OBJECTS OF THE INVENTION </ RTI> The present invention relates to the treatment of skin disorders, and in particular to the treatment of skin/mucosa or ocular toxicity with a tissue protein deacetylase inhibitor (HDACi). [Prior Art] In many diseases, such as cancer, inflammatory diseases, immune diseases, and degenerative diseases, 'abnormal message transmission affects cell behavior, growth, survival, and apoptosis, and finds, for example, EGFR. VEGF, tyrosine kinase, serine/synamic acid kinase and MAPK/ERK play an important role in molecular target therapy. (Lacouture ME. Nat Rev Cancer 6:803-812, 2006). Molecular target treatment techniques that have been developed include monoclonal antibodies, small molecule compounds, peptide mimetic, and antisense oligonucleotides. However, molecularly targeted drugs also affect the normal activity of EGFR receptor, tyrosine kinase activity or MApK/ERK signaling in message delivery pathways (Perez-Soler R, et al. J Clin Oncol 23:5235-5246, _ 2005). Therefore, when the EGFR, tyrosinase and MAPK/ERK pathways in the skin, mucous membranes and eyes are inhibited, undesirable side effects occur in the skin/mucosa or the eye area. It is known that when Egfr, tyrosine kinase activity or MAPK/ERK pathway is inhibited, it inhibits DNA synthesis, hinders cell growth, and promotes early-onset differentiation of primary keratinocytes (10). &amp;&amp;ι 376:337-341, 1995). Since cell survival is associated with CY, if EGFR is inhibited, it will inhibit cell growth and lead to fineness. The reason may be related to the inhibition of its downstream pathway, for example, ΜΑρκ pathway, 201102059 PI3K (phosphatidylinositol 3-kinase)-Akt-mTOR pathway, pressure-activated protein kinase pathway, which includes protein kinase C and Janus kinase (Jak)-STAT (transcribed message transmitter and activator) pathway. Therefore, if the inhibition of EGFR occurs in the basal layer of the epidermis, the sub-basal layer or the primary keratinocytes in the outer layer of the hair follicle in the undifferentiated or proliferating, the epidermal layer will become thinner, thereby reducing its function as a barrier and making the epidermis Cells are more sensitive to UV and radiation. On the other hand, when promoting the activity of EGFR, it can increase the expression of CXCL8 and attenuate the expression of CCL2, CCL.5 and CXCL10 (Mascia F, et al. Am J Pathol 163: 303-312, 2003). Conversely, when the activity of EGFR is inhibited, the opposite happens. In mouse experiments, selective EGFR tyrosine kinase inhibitors lead to more severe contact allergic reactions, the expression of CCL2, CCL5 and CXCL10 in the epidermis, and mononuclear/macrophage and T lymphocytes in the skin. The number has increased. This result indicates that EGFR can regulate skin response by affecting the expression of chemokines in primary keratinocytes. EGFR regulates the physiological balance, repair and response of epidermal tissue. Therefore, many standard-labeled drugs are designed to interfere with EGFR, MAPK/ERK signaling or valine activity's and cause skin state changes, including rashes, dry skin, hardening, itching, epidermal redness and pain , paronychia, hand-foot reaction or symptoms, telangiectasia, hair growth or skin color changes (Galimont-Collen AFS, et al. Eur J Cancer 43: 845-851., 2007). This change in skin condition is a side effect of the normal individual on the target drug, rather than a simple drug allergy. This side effect can cause chronic eczema and increase the risk of secondary infection. The initial symptoms are tenderness of the hands and feet. Then, redness and swelling occur in the palms and soles of the feet. The most common skin condition is pustules 201102059, which looks like acne and occurs on the scalp, face, chest and upper back. In severe cases, it affects other parts of the body and can cause pain when the pustule ruptures. Skin rashes are usually most severe in the weeks when the target = substance is administered. At 4 weeks after the target drug treatment, the skin usually hardens and becomes very dry and red. After a few weeks, a round, flat or raised erythema is produced, as well as a white-headed acne in the center. Skin rash can be oysters. The cause of the hand-foot reaction or symptoms is still unknown, and it may be accompanied by damage to the micro-vessels of the hands and feet, or damage to the tissue caused by leakage of the drug from the blood vessels. Other uncommon side effects of target treatment may also occur in the mucous membranes and eyes, including diarrhea, nausea, vomiting, mouth ulcers, coughing and trichomegaly. Long eyelashes can affect the eye and may cause conjunctivitis and other eyes. Symptoms, which in turn cause discomfort and blurred vision. Skin/mucosal or ocular side effects caused by target drugs include pain, physical and mental, and physiological disorders, and can affect the patient's walking, diet, and normal activities. As a result, many patients discontinue or delay the treatment of targeted drugs due to skin/mucosal or ocular side effects. In view of this, there is a need in the industry for a composition and method for treating skin/mucosal or ocular toxicity or side effects. SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects, comprising an effective amount of a tissue protein deacetylase inhibitor and/or its pharmaceutically acceptable carrier, salt A class or solvent in which the mucosal/skin or eye toxicity or side effects are caused by inhibition of signalling pathways for cell growth and survival. 201102059 The present invention further provides a pharmaceutical composition for treating or slowing the side effects of skin or epidermis, comprising an effective amount of a tissue protein deacetylase inhibitor and a pharmaceutically acceptable carrier, salt or solvent thereof, wherein the skin or epidermis Side effects include skin rash, dry skin, itching, dermatitis, hand and foot syndrome, mucositis, hair loss, hyperplasia of eyelashes and facial hair, and/or embrittlement and nail swelling, which are caused by Molecular standard treatment of epidermal growth factor receptor, MAPK/ERK, vascular endothelial growth factor and/or pi3K (phosphatidylinositol 3-kinase)-Akt-mTOR pathway, with or without radiation and/or chemotherapy, And the tissue protein deacetylase inhibitor includes valproic acid, phenyl butyrate, arginine butyrate, depudecin, trapoxin A, depsipeptide 'oxamflatin, octanoic acid-based basic amine oxo acid (+SAHA), mastedatin A, scriptaid, MS-27-275 or a combination thereof. The above and other objects, features and advantages of the present invention will become more <RTIgt; When the tissue EGFR, tyrosine kinase or MAPK/ERK pathway is inhibited, it will cause abnormal proliferation, metastasis, differentiation and apoptosis of tissues and epidermal cells, and then destroy the integrity of the skin, mucous membranes and eyes and lead to inflammatory cells. Hyperplasia. Therefore, it is indicated that the local side effects of the skin/mucosa and eyes are related to EGFR, tyrosine kinase and MApK/ERK pathways in the epidermis, hair follicle, nail, mucosa and eye tissues. 201102059 The present invention demonstrates that tissue protein deacetylase inhibitors (hereinafter referred to as HDAC inhibitors, or hdACi) are effective in alleviating skin abnormalities caused by EGFR inhibitors. Therefore, HDAC inhibitors are effective in treating skin toxicity caused by EGFR, tyrosine kinase and MAPK/ERK inhibitors. Accordingly, the present invention provides a pharmaceutical composition and a pharmaceutically acceptable carrier which can treat or slow down mucosal/skin or eye toxicity or side effects caused by inhibition of signal transmission pathways for cell growth and survival. "EGFR, tyrosine kinase and MAPK/ERK inhibitors" as used in the present invention refers to any EGFR, valine kinase or MApK/ERK inhibitor that is currently known or may be discovered in the future, and which has an inhibitory individual Biological activity of the EGFR, tyrosine kinase or MApK/ERK pathway. EGFR, tyrosine kinase and MAPK/ERK inhibitors can bind to or inhibit the biological response downstream of egfR. Travel EGFR, tyrosine kinase or MAPK/ERK inhibitors include any agent that blocks the EGFR, tyrosine kinase or Mapk/erk pathway, or a downstream biological response associated with EGFR or tyrosine kinase responses, and its Z is used to treat healthy cancers. Inflammatory _, secretory disease or degenerative body. The above inhibitors can be inhibited by extracellular or intracellular growth factors by inhibiting (tetra) acid kinase activity, or via serine/sodium chlorination. Its associated downstream message-transport chain. In addition, urethane stimulating agents inhibit downstream informers associated with tyrosine kinase. The "nitramine kinase inhibitors" described in the invention include natural Or a compound f preparation Cool to teach or hinder enzyme alanine, leucine armpit kinase inhibition by Qi = two binding sites. EGFR, acid kinase or MAPK/ERK 匕, not limited to, low molecular weight inhibitors, antibodies or antibody fragments 201102059, antisense DNA or RNA structures, mimetic peptides and ribose enzymes.

A group of (HDACi) gene-regulating compounds called tissue protein deacetylase inhibitors activate and inhibit a gene subpopulation that reconstitutes chromatin structure by altering tissue protein acetylation (Marks et al, J. Natl. Cancer Inst., 92: 1210-1216, 2000; Kramer et al, Trends Endocrinol. Metab” 12: 294-300, 2001). Tissue protein over-acetylation causes cell cycle inhibitors (p21Cipl ' p27Kipl ' and P16INK4 Up-regulation, downregulation of oncogenes (Myc and Bcl_2), inhibition of inflammatory cytokines (interleukin-1 (IL)-1 'IL-S 'TNF-α ' and TGF-β), or no change (GAPDH and y-actin) (Lagger et al, EMBO J., 21: 2672-2681, 2002;

Richon et al, Clin. Cancer Res., 8: 662-667, 2002; Richon et al, Proc. Natl. Acad. Sci. USA., 97: 10014-10019, 2000; Van Lint et al, Gene Expr., 5: 245-243, 1996; Huang et al, Cytokine, 9: 27-36, 1997; Mishra et al, Proc. Natl. Acad. Sci. USA., 98: 2628-2633, 2001; Stockhammer et al, J Neurosurg., 83: 672-681, 1995; Segain et al, Gut, 47: 397-403, 2000; Leoni et al, Proc. Natl. Acad. Sci. USA, 99: 2995-3000, 2002). In addition to causing tissue protein over-acetylation, HDAC inhibitors also induce per-acetylation of non-tissue proteins such as ribosomal S3, p53 or NF-κΒ Rel-A subunits, regulate protein kinase C (PKC) activity, and inhibit proteins. Prenylation reduces DNA methylation and binding to nuclear receptors (Webb et al, J. Biol. Chem., 274: 14280-14287, 1999; Chen et al, Science, 293: 1653-1657, 2001) 'HDAC inhibitors have been shown to have the ability to initiate cell cycle arrest, cell differentiation, and cell death in tumor cells, and have the ability to reduce inflammation and fibrosis in immune diseases (Warrell et al, J. Natl. Cancer Inst., 90: 1621-1625, 1998;

Vigushin et al, Clin. Cancer Res., 7: 971-976, 2001; Saunders et al, Cancer Res., 59: 399-404, 1999; Gottlicher et al, EMBO J., 20: 6969-6978, 2001; Rombouts et al, Acta Gastroenterol. Belg., 64: .239-246, 2001). Although the effect of HD AC inhibitors triggers a large amount of tissue protein acetylation, resulting in tumor cell death, terminal differentiation, and growth arrest, it is not toxic to normal cells (Garber et al, J. Natl.

Cancer Inst., 94: 793-795, 2002). In addition, the regulation of chromatin structure by HDAC 抑制 inhibitors can also make radiation-sensitive tumor cells more radiation-sensitive and make tumor cells more sensitive to chemotherapy (Ferrandina et al, Oncol. Res., 12 : 429-440, 2001; Miller et al, Int. J. Radiat.

Biol., 72: 211-218, 1997; Biade et al, Int. J. Radiat. Biol., 77: 1033-1042, 2001) ° The active compound used in the practice of the present invention is usually a tissue protein peracetate. (histone hyperacetylating agents), such as tissue protein deacetylation inhibitors. Tissue protein deacetylase inhibitors include hydroxamic acid derivatives, fatty acids, cyclic tetrapeptides, benzamides derivatives, or electrophilic ketone derivatives. . A variety of such compounds are known, see, for example, P. Dulski, Histone Deacetylase as Target for Antiprotozoal Agents, PCT Application WO 97/11366 (Mar. 27, 1997). Examples of such compounds include, but are not limited to: A. Trichostatin A and its analogs, such as: Maastatin A (TSA); Tri. chostatin C ( Koghe et al. 1998. Biochem. Pharmacol. 56: 1359-1364) (Isolated Mauss 201102059, Dachstatin B has not been shown to have an HDAC inhibitor effect). B. peptides such as: Aussie Flittin (transliteration 〇xamflatin) [(2E)-5-[3-[(本基醯))aminophenyl]pentyl_2_稀_4_氢Oxy- tyrosine (Kim et al. Oncogene, 18: 2461-2470 (1999)); trans-Pulsin A (TPX)-cyclotetrapeptide (cyclo-(L-phenylaminobenzoic acid) ·L_Phenylaminobenzoic acid ~〇-hexahydropyridinecarboxylic acid 丄-2-amino-oxo-9,1〇-epoxy_mercapto))(Kijima et al" J. Biol· Chem 268, 22429-22435 (1993)); FR901228, Depsipeptide (Nakajima et al., Ex. Cell

• Res. 241,126-133 (1998)); FR225497, H. Mori et al., PCT Application WO 00/08048 (Feb. 17, 2000); Epistin (Apicidin) , cyclotetrapeptide [ring (N--0-methyl-L-tryptophan-L-isoleucine-D-hexahydropyridinecarboxylic acid-L-2-amino-8--oxopurine醯基)] (Darkin-Rattray et al., Proc. Natl. Acad. Sci. USA 93, 13143-13147 (1996)); Epistin la, Epistin lb, Epistin Ic' Ai Pistin Ila, and Epstein lib (P. Dulski et al., PCT Application WO 97/11366); HC-toxin, cyclosporin (Bosch et al., Spring Plant Cell 7, 1941-1950 ( 1995)); WF27082, Cyclosporin (PCT)

Application WO 98/48825); and chlamydocin (Bosch et al "supra) ° C. Hydroxy-acid-based heteropolar compounds (HPCs), such as: Salicylhydroxamie acid (SBHA) (Andrews et al., International J. Parasitology 30, 761-768 (2000)); Suberoylanilide Hydroxamic Acid (SAHA) (Richon et al., Proc. Natl. Acad. Sci USA 95, 3003-3007 (1998)); Azelaic Bishydroxamic Acid (201102059 ABHA) (Andrews et al., supra), 壬di-1-hydroxyl-9-aminobenzene (Azelaic-l-Hydroxamate-9-Anilide, AAHA) (Qiu et al., Mol. Biol Cell 11, 2069-2083 (2000)); M-Carboxycinnamic Acid Bishydroxamide, CBHA (Ricon et al., supra); 6-(3-Chlorophenylureido) carpoic Hydroxamic Acid, 3-C1-UCHA (Richon et Al., supra); MW2796 (Andrews et al., supra); and MW2996 (Andrews et al) supra. In addition, such analogues do not have the effect of HDAC inhibitors: Hexamethylene bisacetamide (HBMA) (Richon et al. 1998, PNAS, 95:3003_3007); and diethyl bis(pentamethylene-N,N-dimethyl sulfhydryl) succinic acid (Diethyl bis(pentamethylene-N, N-dimethylcarboxamide) malonate, EMBA) (Richon et al. 1998, PNAS, 95:3003-3007) D. Short-chain fatty acid (SCFA) compounds such as sodium butyrate (Cousenset al J. Biol. Chem. 254, 1716-1723 (1979)); Isovalerate (McBaiii et al., Biochem. Pharm. 53: 1357-1368 (1997)); Valproic Acid); Valerate (McBain et al., supra); 4-Phenylbutyrate, 4-PBA (Lea and Tulsyan, Anticancer Research, 15, 879-873 (1995) )); Phenylbutyrate (PB) (Wang et al., Cancer Research, 59, 2766-2799 (1999)); Propionate (McBain et al., supra); Butylamine ( Butrymide) (Lea and Tulsyan, supra); Isobutyramide (Lea and Tulsyan, supra); Phenylacetate (Lea and Tulsyan, supra); Propionic acid 3 Desert 12 201102059 (3-Bromop Roponate) (Lea and Tulsyan, supra); and Tributyrin (Guan et al., Cancer Research, 60, 749-755 (2000)). E. Benzoamide derivatives, W :MS-27-275 [N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl) aminomethyl] benzamide] (Saito et al" Proc. Natl. Acad. Sci. USA 96, 4592 -4597 (1999)); and its 3,-amino derivative (Saito et al., supra) ° F. Other inhibitors, such as: low-dutydin (depudecin) [its analogues (single-MTM- Low dydoxine and chlorhexidine bis (diethyl ether) do not inhibit HDAC] (Kwon et al, 1998. PNAS 95: 3356-3361); and Scriptaid (Su et al. 2000 Cancer Research, 60:3137-3142). Second agents for use in combination with HDACi include, but are not limited to, cytokines, cytokine inhibitors, interleukins, interleukin inhibitors, growth factors, angiogenesis agents, anti-angiogenic agents, anti-cancer agents, anti-drugs Inflammatory agents, steroids, immunosuppressants, non-steroidal immunosuppressants, analgesics, antihistamines, anti-cholestases, antipruritic agents, antibacterial agents, antiviral agents, antifungals, antiparasitic agents, antibiotics An oxidizing agent, an acid, an anti-fibrotic agent, a vasoactive agent, an adenine receptor antagonist, a vitamin, a leukotriene modifier, a chemical hormone antagonist, an obese cell inhibitor, an anti-IgE antibody, Selective serotonin recovery inhibitor (SSRI), serotonin (5·ΗΤ) beneficial antagonist, peroxisome proliferator-activated receptor (ppAR) antagonist, calcineurin inhibitor, gastrin receptor antagonist, ρ38 river Gossip kinase inhibitor, keratinocyte growth factor (KGF) 'HDAC inhibitor, steroid 13 201102059 pigment (retinoid), NFkB regulator, gabapentin, sucralfate and nagak (Naloxone). The compound of the present invention may be a pharmaceutical composition. The pharmaceutical composition is administered by oral, parenteral, inhalation, anal suppository, vaginal suppository, transdermal absorption or topical. This agent comprises a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and carrier. Topical administration includes the use of percutaneous absorption, such as dermal patches or iontophoretic elements. Gastrointestinal administration includes subcutaneous injection, intravenous injection, intramuscular injection or chest _ injection, or injection technique. For the type of medicament, please refer to Hoover, John E.,

Remington’s Pharmaceutical Sciences, Mack Publishing Co.,

Easton, Penn (1975), Liberman, H. A. and Lachman, L” Eds”

Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).

In one embodiment, the agent can be formulated to generally treat skin side effects resulting from the use of EGFR, tyrosine kinase or MAPK/ERK inhibitors, making the agent suitable for skin treatment. Skin coating formulations include, but are not limited to, emulsions, ointments, gels, sprays, lotions, shampoos or sess. In general, the skin spray can be composed of a spray copolymer such as 'polyvinylpyrrolidone, vinyl acetate and the like, and it can function as a makeup water. The skin gel is prepared in a manner similar to that of a spray, but its presence and absence of ethanol can adhere to the skin. The skin is for people to release the bubble. The HDACi of the present invention is in the topical skin coating agent S, ., 0.00001 00 00% by weight, or its dosage is 】 to i amount = skin emulsion is - hydrophobic or hydrophilic emulsion, ointment, gel, moist Skin, _, paint, skin conditioning water, shampoo or curtains. In addition, 14 201102059

It is also possible to add suitable ingredients to skin emulsions. This additional ingredients include petrolatum, earth, lanolin, #, microlipids, vegetables, oils, plasticizers, fragrances, preservatives, penetration enhancers, pH. A value adjuster or other ingredient suitable for topical skin. This extra mu is called skin, stabilizing the active compound, increasing drug-skin contact, localized area concentration, controlling drug release and/or reducing skin damage, preventing L skin atrophy, fibrosis or infection, and promoting skin wounds. repair. The pH adjuster can control the pH of the agent between about 3. 〇 and 13 〇. The present invention further provides a composition for treating skin by-products, which is a skin serine/synthesis effect produced by EGFR, tyrosine kinase, VEGF, acid kinase or MAPK/ERK inhibitor. Including an effective amount of tissue protein peracetic acid, or in combination with at least one or more other agents, including cytokines, cytokine inhibitors, interleukins, interleukin inhibitors, growth factors, angiogenesis agents , anti-angiogenic agents, anti-cancer agents, anti-inflammatory agents, steroids, immunosuppressive agents, non-sterols

Immunosuppressants, analgesics, antihistamines, anticholinergic agents, antipruritic agents, antibacterial agents, antiviral agents, antifungal agents, antiparasitic agents, antioxidants, A acids, antifibrotic agents, vasoactive agents (vas〇active t-shirt), adenine receptor antagonist, vitamins, leukotriene modifiers, chemical hormone antagonists, obesity cytostatics, anti-IgE antibodies, selective serotonin recovery inhibitors (SSRI), Serotonin (5-HT) receptor antagonist, peroxisome leaner activation receptor (PPAR) antagonist, calcineurin inhibitor, gastrin receptor antagonist, p3 8 MAP kinase inhibitor, keratinocyte growth factor (KGF), HDAC inhibitor, retinoid, NFkB modulator, gabapentin, sucralfate, and naloxone, the active ingredient may be from 15 201102059 by type or its pharmaceutically acceptable salt or solvent, and selected Optionally, there is at least one pharmaceutically acceptable carrier which can be used simultaneously or separately, systemically or locally, with other agents. Mucosa/skin, eye toxicity or side effects including skin rash, dry skin, itching, dermatitis, hand and foot syndrome, mucositis, hair loss, hyperplasia of eyelashes and facial hair, and/or nail embrittlement, nail enlargement, etc. Epithelial side effects. EGFR, tyrosine kinase, VEGF, serine/synamic acid kinase or MAPK/ERK inhibitor can be an antibody standard therapeutic agent, antibody fragment, small molecule target compound, low molecular weight tyrosine inhibitor, A mimetic peptide, an antisense oligonucleotide (DNA and/or RNA), or a ribozyme (Hbozyme) that inhibits epidermal growth factor receptor (EGFR), mitogen-activated protein kinase/extracellular regulated kinase (MAPK/) ERK), vascular endothelial growth factor (VEGF) and/or PI3K (phosphatidylinositol 3-kinase)-Akt-mTOR pathway. Suitable salts in the present invention include inorganic cations, for example, metal salts such as sodium, potassium or amine salts, alkaline earth metal salts such as magnesium, calcium salts, salts containing divalent or tetravalent cations, such as Zinc, aluminum or zirconium salt. In addition, it may also be an organic salt such as dicyclohexylamine salt, methyl-D-glucosamine, an amine acid salt such as arginine, lysine, histidine, glutamine. . In another aspect, the nitrogen-containing salt group can be a lower alkyl halide such as a mercapto group, an ethyl group, a propyl group, a gas butane, a bromide, and an iodide, a dihydrocarbon sulfate such as a diindenyl group, a diethyl group, Dipropyl and dipentane sulfides, long chain halides such as fluorenyl, dodecyl, tetradecyl, octadecyl chloride, evolutions and moths, asthma halides, Benzoyl, phenethyl bromide or the like. A reagent for forming a salt, including a low molecular weight alkyl amine, for example, 16 201102059 methylamine, ethylamine or triethylamine. Water or oil soluble agents or dispersing agents can also be used. The active ingredient of the present invention may be present in an amount such that the active ingredient may be combined with other carriers to form a single dosage. This dose can be adjusted according to different parameters. The above parameters include, but are not limited to, the type of individual, the size of the individual, and the severity of the disease. The active ingredient of the present invention can be administered at a time, administered multiple times or continuously within 24 hours. When the mode of administration is continuous, a suitable conventional method may be used, including, but not limited to, intravenous drip, intravenous drip, implantable injection or topical administration. The duration of treatment can be adjusted according to different conditions, for example, the course and severity of the skin, and localized pruritus caused by mucosal or systemic diseases. In the case of HDACi alone or in combination with other agents of the invention until skin/mucosal or ocular damage ends, or for continued treatment for life. In one embodiment, a biocompatible polymer can be used in the treatment of mucosal damage. When this bioacceptable polymer is added to the group of the present invention, the viscosity of the composition of the present invention increases with the physiological temperature around it, and generally, the physiological temperature is 37 °C. In this embodiment, the composition of the present invention exhibits a low viscosity liquid when administered at a low temperature, and its viscosity increases as the temperature increases to a physiological temperature. In a preferred embodiment, the compositions of the present invention have a reverse-thermal viscosity having a temperature in the range of at least 1 °C to the physiological temperature of the individual (e.g., 37 ° C for humans). In the present invention, bioacceptable polymers generally include bioadhesive polymers, cationic polymers, viscous polymer colloids, water gels, natural polymers, polyoxyalkylene block copolymers, and inverse 17 201102059 heat. Gel poly σ. In addition to the biologically acceptable polymer, the compositions of the present invention may further comprise an additional I-occupant which increases the viscosity of the compositions of the present invention. In general, adhesives are often used as the second polymer, and they have a higher bioadhesive property. / In a thicker gel, the composition of the present invention may further comprise si^alfate which can enter and coat a plurality of digestive tracts via silver food. The agent of this month can be made into different dosage forms depending on the location of the administration. For example, the dosage form of the present invention may include an oral solution, a bladder rinse, a colloid, a slurry (- Μ, mouthwash, throat lozenge, lozenge, flakes, shells, lollipops, sprays, or suppositories). For example, when treating the surface of the rectum or vaginal mucosa, the gel can be prepared as a relaxant. The slurry or oral solution can be used to treat the mucosal surface of the oral cavity, esophagus and/or digestive tract. [Examples] 1. Inhibition of CCL2 by HDACi The performance of φ EGFR is lightly inhibited and promotes the expression of epidermal CCL2. Therefore, in this case, skin keratinocytes were treated with EGFR inhibitor PD168393 and/or different HDACi, and ELISA was used to measure keratin. The amount of CCL2 in the cell culture medium is formed. Referring to Figure 1, the content of the chemokine CCL2 is increased after 24 hours of treatment with the EGFR inhibitor (PD168393), but if different HDACi (valproic acid (5 mM) is used separately ), butyric acid butyrate (5 mM), and grossin A (5 nM) treatment for 2 hours can inhibit the induced CCL2. This result is expressed as the mean ± quasi-standard deviation of the three experimental data. 18 201102059 2. A variety of skin with HDACi combination Preparation A. Preparation of Butyl Acetate Gel First component: 10 g of stabileze QM®, 380.561 g of deionized water in a beaker and heated to 70 ° C. Second component: 5.739 g of 4-butyric acid benzene Sodium esterification (Merck), 0.125 g of methylparaben (Merck), 0.075 g of propylparaben (Merck), 83.5 g of 1,2-propanediol, and 20 g of 10% NaOH in a beaker Mix and heat to 70 ° C. Slowly add the second component to the first component and continue to stir at 400 rpm for 20 minutes until a mixture is formed. The mixture is cooled to room temperature. B. Butyric acid ester liposome formula Prepared in such a liposome formula, egg phosphatidylcholine (EPC) and cholesterol are used as primary lipid fractions of equivalent or different _ molar concentration. Different fats can be obtained in a ratio of different fats: butyric acid - The liposome of phenyl butyrate. The microlipid system is prepared by film hydration, extruded by film, and evaluated. C. Preparation of Maastatin A ointment will be 2.5 g of white petrolatum (Riedel-de Haen), 27 g stone sample 50/52 (locally supplied Obtained), and 0.5 g of mascara A (sigma) placed in a beaker and heated to a thief-forming paste. The paste was stirred at 400 rpm for 1 hour and cooled to room temperature. Preparation of Maastatin A ointment 201102059 67.5 g of white petrolatum (Riedel-de Haen), 16 g of octadecyl alcohol (Riedel-de Haen), 260.5 g of soft paraffin (Merck), 155.5 g of liquid paraffin ( Merck), and 克.5 g of Maastatin A (Sigma) were placed in a beaker and heated to 70 ° C to form a paste. The paste was stirred at 400 rpm for 1 hour and cooled to room temperature. E. Preparation of valproic acid emulsion. One component: 70 g Tefose 63®, 20 g Superpolystate®, Φ 10 g Coster 5000d), 15 g Myriyol 318®, 15 g Coster 5088 (1), and 15 g GMS SE® (all available from local suppliers) Mix in a beaker and heat to 70 °C. The second component: 5.739 g of valproic acid (Sigma), 0.125 g of methylparaben (Merck), 〇.75 propylparaben (Merck), and 149.061 g of deionized water. Mix in a beaker and heat to 70 °C. The second component was slowly added to the first component and continued to be scrambled at 4 rpm for 5 minutes until a mixture was formed. 2% Stabileze QM® (prepared by dissolving 2 g of Stabileze QM® in 98 g of deionized water and heating to form a paste and cooling to room temperature) was added to the mixture and stirred for 5 minutes. The pH of the mixture was adjusted to $34 with 0.85% acid (mock) and stirred at 600 rpm for 20 minutes. The mixture was cooled to room temperature. 3. Inhibition of EGFR inhibitor by HDACi In an EGFR inhibitor-induced skin reaction test, 5 BALB/c small papers (body weight of about 22 ± 2 g) were grouped with ι〇μ: 20 201102059 Body (DMSO dissolved in ethanol at a ratio of 1/10) or PD168393 solution (4 mmol/L) for 30 minutes after treatment of mouse ears with 10 μί 0.5% 2,4-diafluorofluoronitrobenzene (DNFB) The right ear of the mouse was stimulated (Pastore S, et al. J Immunol 174: 5047-5056, 2005). Before the 0th and 1st day, the right ear was treated with 2.5% 4-butyric acid phenyl ester gel or placebo (general colloid), treated once every 3 hours, and treated a total of 3 times to treat EGFR inhibitors. Induced skin reaction. On day 1, the right ear of the mice was treated topically with PD168393 after 60 minutes of the first phenyl butyrate or placebo treatment and 30 minutes before the 0.5% DNFB stimulation. Treatment of the 2nd and 3rd phenyl butyrate or placebo was performed 1 and 3 hours after the 0.5% DNFB stimulation. Ear enlargement at 0, 3, 6, 8, 24, and 48 hours after DNFB stimulation was measured by Dyer's micrometer. In an experimental control group, mouse ears were treated with steroid dexamethasone (0.3 mg) 60 minutes before DNFB stimulation and 15 minutes after stimulation. The thickness of the left and right ears of the mice was measured by Dyer's micrometer. The condition of ear edema was expressed as the thickness of the left ear (normal control group) minus the thickness of the right ear (experimental group). Referring to Figures 2 and 3, when only 4 mM of PD168393, DMSO, placebo (general colloid), or 25% phenyl butyrate was administered topically, it did not affect the thickness of the mouse's ears and did not cause normal skin. Organizational changes. In contrast, 30 minutes before DNFB stimulation, 4 mM PD168393

Treatment will aggravate DNFB-induced skin reactions. However, compared to prior placebo (general colloid) pretreatment, if pre-treated with 25% phenylbutyrate gel, 3, 6, 8, 24, and 48 hours after DNFB stimulation, EGFR inhibitors The induced ear swelling is significantly reduced (Figures 2 and 3). In addition, although the steroid dexamethasone did not inhibit the skin reaction at 3, 6, and 8 21 201102059 after DNFB stimulation, it significantly inhibited skin swelling 24 hours after DNFB stimulation. It can be seen that the inhibitory effect of steroid dexamethasone is only observed 24 hours after DNFB stimulation, which is much later than that of phenyl butyrate, indicating that steroid does not act on skin reactions induced by EGFR inhibitors, while 2.5% butyric acid benzene Ester can treat skin symptoms (side effects) caused by EGFR inhibitors. Although the present invention has been described above by way of a preferred embodiment, it is not intended to limit the invention, and it is to be understood that those skilled in the art can make some modifications and refinements without departing from the spirit and scope of the invention. The scope of the invention is defined by the scope of the appended claims.

22 201102059 [Simple description of the diagram] Figure 1 shows the different mitigation of EGFR by different HDACi

The current effect, the performance of chemokines is related to skin side effects, 'Figure 2 shows that local treatment with HDACi can alleviate skin swelling caused by small gas. Students can use the ί test to analyze the statistic to suppress the statistical difference between the 2.5% phenyl butyrate gel. After one-way ANOVA, Dunnett's assay was used to analyze differences in EGFR inhibition. &gt;&lt; 0.05 indicates a significant difference to PD168393 (EGFR inhibitor). Figure 3 shows the results of staining (H&amp;E) of each experimental tissue. Skin reactions induced by EGFR inhibitor (PD168393) were treated with placebo or 2.5% phenyl butyrate 48 hours after stimulation with DNFB. [Main component symbol description] None.

twenty three

Claims (1)

201102059 VII. Patent application scope: 1. A pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects, comprising an effective amount of tissue protein deacetylase inhibitor and / ' or its pharmaceutically acceptable carrier , a salt or a solvent in which the mucosal/skin or eye toxicity or side effects are caused by inhibition of signal transmission pathways for cell growth and survival. 2. A pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects as described in claim 1 wherein the tissue protein deacetylase inhibitor comprises hydroxamic acid derivative , fatty acid, cyclic tetrapeptide, benzamides derivative, or electrophilic ketone derivative. 3. A pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects as described in claim 1 wherein the tissue protein deacetylase inhibitor comprises valproic acid, phenyl butyrate, butyric acid. Arginine butyrate, depudecin, trapoxin A, depsipeptide, oxamflatin, ginsenoic acid aniline oxime acid (SAHA) ), Mausdatin A, scriptaid, MS-27-275, or a combination thereof. 4. A pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is a non-oral composition. 5. A pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects as described in claim 1, wherein the tissue protein deacetylase inhibitor comprises 0.00001-100.00 of the total weight of the pharmaceutical composition. %. 24 201102059 6·If you apply for a medical composition as described in item 1 of the full-time occupation or to slow down the mucosa/skin• or eye toxicity, the agent is an emulsion, • Qi 1 coating, paste, oil Agent, softener, fat body plastic, nano granules, lotion, mouthwash, shampoo, lotion, mouth, suppository, capsule, powder, granule, solution, suspension, patch or closed type Apply. 7. A pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects as described in the scope of the patent application, further comprising a penetration promoting agent, or a pH adjusting agent for the pharmaceutical composition The pH is maintained at about 3.0 to 13,0. 8. A pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects as described in the application, wherein the pharmaceutical composition is combined with a second agent selected from the following The group consisting of: cytokines, cytokine inhibitors, interleukins, interleukin inhibitors, growth factors, angiogenesis agents, anti-angiogenic agents, anticancer agents, anti-inflammatory agents, steroids, immunosuppressants, non- Sterol immunosuppressants, analgesics, antihistamines, anticholinergic agents, antipruritic agents, antibacterial agents, antiviral agents, antifungal agents, antiparasitic agents, antioxidants, A acids, antifibrotic agents, Vasoactive agent, adenine receptor antagonist, vitamin, leukotriene modifier, chemical hormone antagonist, obesity cytostatic, anti-IgE antibody, selective serotonin recovery inhibitor (SSRI), 5 - serotonin (5-HT) receptor antagonist, peroxisome proliferator-activated receptor (PPAR) antagonist, calcineurin inhibitor, gastrin receptor antagonist, p38 MAP kinase inhibitor, fine keratin Growth factor (KGF), HDAC inhibitors, retinoids (retinoid), NFkB modulators, gabapentin 25 201102059 (gabapentin), sucralfate and that La Eriksson (nai〇x〇ne). 9. A pharmaceutical composition as claimed in claim 8 or for ameliorating mucosal/skin or ocular toxicity or side effects, wherein the pharmaceutical composition is administered simultaneously or separately with the second or the same (10) route. 10. The pharmaceutical composition for treating or slowing mucosa/skin or ocular toxicity or vice sensation as described in claim 1, wherein the signal transmission pathway for cell growth and survival is--the antibody (four) therapeutic agent, antibody fragment, Small well-hidden compounds, low molecular weight _ acid suppression, mimetic, antisense nucleic acid, or ribozyme inhibition. 11. A pharmaceutical composition for treating or slowing mucosal/skin or eye toxicity or side effects as described in Shenqing Patent Co., Ltd., wherein the antibody is a therapeutic agent, an antibody fragment, a small molecule, or a low molecular weight. Amino acid inhibitor, mimetic peptide, antisense oligo, or nuclear-inhibiting epidermal growth factor receptor, MAPK/ERK, vascular endothelial growth factor and/or Η3Κ (fatinositol 3-kinase)-Akt- mTOR pathway. 12. If you apply for a full-time (4) 〗 〖 韵 诚 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 减缓 、 、 、 、 、 、 、 、 、 、 、 、 、 Mucositis, hair loss, hyperplasia of eyelashes and facial hair, and/or embrittlement of nails and nail enlargement. 13. A pharmaceutical composition for treating or slowing the side effects of the skin or epidermis, comprising - an effective amount of tissue egg serotonin and a carrier, a salt or a solvent thereof, wherein the skin or epidermal side effect package: skin treatment , dry skin, return, dermatitis K syndrome, sticky hair, eyelash and facial hair hyperplasia, and / or nail embrittlement deformation and only t A 26 201102059 swelling, the skin or epidermal side effects are affected by epidermal growth factor Molecular target treatment of body, MAPK/ERK, vascular endothelial growth factor and/or Π3Κ (lipinositol 3-kinase)-Akt-mTOR pathway, and caused by combined or no combined radiation and/or chemotherapy, and the tissue Protein deacetylase inhibitors include aprotic acid, butyl succinate, arginine butyrate, depudecin, trapoxin A, depsipeptide, AO Oxalflatin, decyl sulphonyl sulfonate (SAHA), mastedatin a, scriptaid, MS-27-275, or a combination thereof. 27