TW201036947A - Composition for treating atopic dermatitis - Google Patents

Abstract

Disclosed is a composition for treating atopic dermatitis comprising montelukast or a salt thereof and resveratrol. The composition exhibits significantly potent pharmaceutical effects on atopic skin diseases, such as atopic dermatitis, allergic diseases, without inducing any severe side effects.

Description

201036947 VI. Description of the Invention: [Technical Field] The present invention relates to a composition comprising montelukast or a salt thereof and resveratrol for treating atopic dermatitis. More specifically, the present invention relates to a composition comprising montelukast or a salt thereof and resveratrol for treating atopic dermatitis, which is different in, for example, atopic dermatitis and allergic diseases. More excellent relief and treatment effects on the skin disease. 〇 [Prior Art] Atopic dermatitis is a representative atopic skin disease, which is a chronic dermatitis that causes severe itching and consequent secondary infection. Atopic dermatitis is often found in Westerners, and about 10% of children suffer from atopic dermatitis, and the effects of the disease are increasing. In Korea, the effects of atopic dermatitis are rapidly increasing. However, due to the high incurability and the unexplained cause of Q, most treatments have focused on symptomatic treatment of the disease. Recent studies have pointed out that atopic dermatitis caused by immune abnormalities has led to attempts to create new therapeutic avenues. An immune abnormality is characterized by an allergic manifestation, which is an immune response in which the body is too large or inappropriate for foreign media. Allergic reactions to allergic reactions of the first type are caused by antigen-specific IgE antibodies, but when the patient is exposed to the same antigen, it may or may not trigger an allergic reaction depending on the person. For this reason, this reaction is called "atopy", which means an idiosyncratic reaction. Examples of specific reactions include allergic rhinitis, asthma, food over 201036947, atopic dermatitis, etc. Helper T cells (Th) are responsible for the immune response and differentiate into Th1 and Th2 cells, which show a balance of each other and secrete mutually antagonistic substances. However, patients with atopic dermatitis have more Th2 cells than Th1 cells. There is an imbalance between the two. That is, the secretion of eosinophils associated with allergic reactions and the secretion of interleukin (IL)_4, IL-5 and IL-10 which can stimulate IgE antibodies are increased in Th2-type cells. However, the secretion of IgE-secreting substances in Th1 type cells is reduced. The degree of increase in IgE leads to the activation of the eosinophils and obese cells. IgE binds to the IgE receptor (FcsRI), and then cross-links allergens and FcsRI. /IgE binds to the complex, triggering the activation of basophilic spheres and obese cells. This leads to a process called degranulation. At this time, for example, the physiologically active substance of histamine is secreted outside the cell, thus producing, for example, itching. Symptoms of atopic dermatitis with erythema, edema, and k disease (Cellular and Molecular Immunology, Abbas et al., 2nd Edition, Saunders,

Philadelphia, and Journal of Dermatological Science, 36, 1-9, 2004). Meanwhile, 'steroidal and antihistamine drugs are now widely used for the treatment of allergic diseases of atopic dermatitis, and they are administered immunosuppressive agents in severe cases. Unfortunately, these agents exhibit only transient therapeutic effects and are highly susceptible to adverse side effects such as osteoporosis, avascular necrosis, atherosclerosis, glaucoma, tumor growth, and the like. Therefore, there is an urgent need to develop a novel therapeutic agent for symptomatic relief and treatment of atopic dermatitis, which provides a strong and long-lasting therapeutic effect with minimal adverse side effects. 201036947 SUMMARY OF THE INVENTION Accordingly, the present invention has been made to solve the above problems and other unresolved technical problems. SUMMARY OF THE INVENTION One object of the present invention is to provide a composition comprising montelukast or a salt thereof and resveratrol for treating atopic dermatitis. Another object of the present invention is to provide a food, a cosmetic, and a medicament containing the composition. [Embodiment] In one aspect, the present invention is directed to a composition comprising montelukast or a salt thereof and resveratrol for treating atopic dermatitis. Montelukast is a leukotriene receptor antagonist that inhibits the cysteine-based leukotriene (CysLTl) receptor. Leukotrienol and bronchial constriction and inflammation are associated with fluid accumulation in the lungs. Among the montelukast salts, montelukast sodium is known as a therapeutically effective agent for the treatment of respiratory diseases such as asthma Q and allergic rhinitis. The composition of the present invention may, if appropriate, be used with montelukast and montelukast salts or a combination thereof. Therefore, the term "Montelup or its salts" as used herein is intended to cover all of the above forms. Examples of the montelukast salt may include, but are not limited to, montelukast sodium, montelukast potassium, montelukast ammonium, montelukast calcium, and montelukast magnesium. The montelukast salt can be used alone or in combination. Among the montelukast salts, montelukast sodium is particularly preferred, and its chemical name is [R-(E)]-l-[[[l-3-2-[(7-chloro-) 2-quinolinyl]]vinyl]benzene 201036947 】][2(1*yl·1-methyl-ethyl)phenylpropionate] continued acid propyl]acetic acid monosodium salt, and is represented by the following formula.

Resveratrol is a multi-drug anti-gasification agent with 3,5,4_3 via its ethylene structure, and rib cis isomers or trans isomers are widely found in alcohols. For gymnosperms and dicots. Even if it can be present and the glycoside material is present, (iv) ruthenol is present in the form of a sucrose form in which the sputum alcohol (non-sugar component) is attached to the sugar component. In addition, the alcohol is present as a trans-alcoholic alcohol, wherein the trans isomer is in a stable form in nature. The naturally occurring trans-resveratrol (IV) table can inhibit: carcinogenic effects and anticancer activity (Science, 275, 218_2汕 1997), and a lot of research has been actively carried out on the white sterol alcohol. Alum has been found to have various beneficial effects such as an anticancer effect, an antioxidant effect, an anti-inflammatory activity, a cholesterol lowering activity, a preventive effect against cardiovascular diseases, and the like. According to the present invention, trans-resveratrol (trans-3,5,4'-dihydroxymonostyrene) found in nature is preferred in the trans isomer. Regarding the source of resveratrol, a resveratrol-containing extract obtained from any suitable plant species or resveratrol itself can be used. This plant species may be gymnosperms and dicots, and examples thereof 201036947 include grapes, polygonum cuspidatum, eucalyptus, spruce, Scottish pine, peanuts, lilies, etc. . Trans-resveratrol is abundantly present in grape fruit, grape skin, grape seed, grape stem and grape leaf, especially vitis vinifera, Vitis rotundifolia and Vitis labrusca grapes. The raw material of resveratrol, the extract of the above plant species may be used singly or in combination, or a sputum extract containing a small amount of resveratrol may be used. Preferably, a purified resveratrol extract having a high purity of greater than 90% is used. As can be seen from the results of the following experimental examples, it was found that the combined use of montelukast or its salt and resveratrol exerted an unpredictable therapeutic effect when compared with the separate components. More specifically, it can be seen in the experimental examples described below that the composition of the present invention exerts an improvement of 4 times or more in pharmacodynamics when compared with the separation using montelukast or its salt. In addition, it is confirmed that the composition of the present invention exhibits excellent treatment for atopic dermatitis, in view of the fact that the dose of the alcohol produced by Baili alone does not exert the desired effect, and the improvement effect is generally unpredictable by those skilled in the art. Drug effect. The composition of the present invention exhibits efficacy comparable to or superior to those of tacrolimus (t_limUS), regardless of the superior efficacy of tacrolimus in the treatment of chronic dermatitis and atopic dermatitis, which is a use side effect (1) Immunosuppressive agents that are restricted by tumorigenicity. Considering the fact that the montelukast or resveratrol present in the composition of the present invention is less toxic and irritating to humans, in view of the elimination of other uses as a specific reaction, the immunoprecipitate 7 201036947 formulation or steroid preparation, The fact that the composition of the invention exhibits an effect comparable to or superior to that of a conventional medicament represents an unexpectedly superior effect. Regarding the ratio of montelukast or its salt and resveratrol, it can be seen in the experimental examples. Although the leucovorol is added in a very small amount, it still synergizes with montelukast, and thus exerts the desired effect of the present invention. Specifically, the ratio of montelukast or its salt to resveratrol (v/v) may be 1:0.001 to 1:3 for the composition containing montelukast or its salt and resveratrol. 'It is preferably 1: 0.01 to 1: 2, more preferably 1: 0.05 to 1:1. The composition of the present invention can be used in various forms including pharmaceutical, food, and cosmetic compositions. In a specific embodiment, when the composition of the present invention is used as a medical composition, a therapeutically effective amount of montelukast or a salt thereof and resveratrol are present in the composition. As used herein, the term "therapeutically effective amount" means the amount of active ingredient that will alleviate or reduce the symptoms or disease of one or more pre-treatments or delay the onset of clinical signs or symptoms of the desired prevention. Thus, the term "therapeutically effective amount" means a compound (1) that delays disease progression, (2) inhibits subsequent disease progression, and/or (3) relieves (preferably removes) one or more diseases associated with the disease. The number of symptoms. A therapeutically effective amount can be determined by testing the compound in vivo and in vitro mode systems using the desired therapeutic condition. Examples of therapeutically effective amounts can be found in the examples described below. The pharmaceutical composition can be formulated into various oral or parenteral formulations of the type 201036947. The oral preparation can be formulated into a solid preparation such as a powder, granule, lozenge, capsule or the like, or formulated into a liquid preparation such as a suspension, an emulsion, a syrup or the like. The parenteral preparation can be formulated into a topical preparation such as a cream, an ointment, a gel, a lotion, a patch, or the like, or a sorbent, an aerosol, a test, or the like. The pharmaceutical composition may comprise a pharmaceutically acceptable excipient, and in particular may further comprise a predetermined solvent or oil to increase the solubility of resveratrol, if desired, and may further comprise a dispersing agent. Examples of the solvent which can be used in the present invention include, but are not limited to, water, ethanol, isopropanol, 1,3-1,3-butanediol, propylene glycol, glycerin and the like. Examples of the oil which can be used in the present invention include corn oil, sesame oil, cotton abalone oil, soybean oil, peanut oil, mono-glycerin vinegar, di-glycerin S and triglyceride, mineral oil, squalene, Jojoba oil, olive oil, evening primrose oil, Borage Oil, grape oil, and any combination thereof, but not limited to this. The solvent and the oil may be used singly or in any combination thereof, and preferably contain less than 10% (w/v) based on the amount of the q composition. Examples of useful dispersing agents may include, but are not limited to, egg fat, organic monoglyceride, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, sorbitan stearate, and the like. These materials may also be used singly or in any combination thereof, and may contain less than 5% (w/v) based on the amount of the composition. If desired, the composition may further comprise additional materials such as antibacterial agents or preservatives. Meanwhile, the conventional active ingredient can be used together with the composition as long as it has no adverse effect on the pharmaceutical activity of the composition of the present invention. For example, such as 201036947 nerve reliance (ee_ide), skin cream is usually used as a traditional atopic dermatitis drug or liquid scalpel, such as hydroxycortisol steroids, vitamin A and other organisms such as lycopene vitamins and / Or fertility can be used with the composition. * When the pharmaceutical composition is used as an external preparation, an appropriate external skin preparation can be used as a base material, and an aqueous solution, a nonaqueous solvent, a suspension, an emulsion or a lyophilized preparation can be used, which is sterilized by a conventional method. In the compositions of the present invention which are actually administered or administered, the dosage can be determined depending on various factors such as the route of administration, age, sex, and the body weight of the patient, the severity of the disease, and the dosage form as an active ingredient. Where the composition of the invention may be a food or cosmetic composition, the composition may be prepared by the appropriate addition of at least one food nourishing or cosmetically acceptable carrier. The food composition can be used or added to, for example, a health food. As used herein, the term "healthy food" means a food product containing the composition of the present invention having an improved function as compared to a general food. The health food can be prepared by adding the composition to a general food, or by encapsulation, powdering or suspension liquefaction. The cosmetic composition may be added by itself or together with other cosmetic ingredients, or may be suitably used according to other conventional methods. Cosmetics include aftershaves, lotions, creams, masks and make-up, but not limited to them. The cosmetic composition can be formulated into various compositions such as gels, creams, ointments and the like. The composition in the form of a gel, a cream and an ointment can be suitably prepared according to the composition in a known manner by adding a conventional softener, an emulsifier 201036947, and a thickener or other materials known in the art. The composition in the form of a gel can be prepared, for example, by adding a softening agent such as trimethylolpropane, polyethylene glycol, and glycerin, a solvent such as propylene glycol, ethanol, and cetyl alcohol, and pure water. The composition of the milk phase form can be prepared, for example, by the addition of a fatty alcohol such as hard decyl alcohol, 1 sterol, behenyl al C〇h〇l, arachidyl alcohol, isostearyl alcohol and isocetyl alcohol; Emulsifiers such as lipids such as lecithin, phosphorus

Lipid test, glucosamine, phosphatidylamine, _lipid inositol and its derivatives 'stearic acid glycerin, palm sorbitol §|, sorbitan stearate [natural fats and oils, For example, pear oil, almond oil, baba tree oil, ceramide, cholesterol, fatty acid, planting agent such as propylene glycol, etc.; and pure water. (4) Preparation of a composition in the form of a cold ointment such as a month or the like, such as microcrystalline wax, paraffin wax, self-added softener, milk Vaseline, and the like. The mouth is also woven (squeaking, candied, recorded sputum, on the other hand, the present invention provides a method for treating the course or symptom of the disease or ameliorating the agent for atopic dermatitis, and the preparation of the preparation is used for Treatment "treatment or relief, - the word is intended to be used by patients (4) as used herein, when, refers to stopping or delaying the embodiment. The present invention will now be described with reference to the following examples, and should not be In the following, these embodiments are intended to limit the scope and spirit of the present invention. Example & Example 1 Preparation of a sample containing various contents of montelukastol via a mixed solvent dissolved in ethanol and propylene glycol (7:3) Prepare the sample. Knowing that 'there is an immunosuppressive agent, which exhibits excellent anti-inflammatory effects,' is therefore used as a therapeutic agent for chronic atopic dermatitis. However, the use of tacrolimus is due to side effects. Limitations, such as immunosuppressive pro-tumor growth have been published (Cancer, Vol. 80, ρ·1141 (1997)). In this experiment, 'in order to confirm the medical effect of the experimental group on atopic dermatitis' Tacros Positive control group. The montelukast sodium used herein was obtained from Teva, Ltd., the purity was 99.5% or higher, and the white saponin used herein was obtained from Xi'an Tianxing Natural Bio-products, purity. 99% or higher, as shown in Table 1. Table 1 —- — ---— Composition and content (w/v%) Positive control group 1 tacrolimus 0.03% Control group 2 tacrolimus 1% __ί Test group 1 montelukast sodium 0.5% ___^ test group 2 Montelukner 1% __ experimental group 3 montelukast sodium 2% experimental group 4 white indigo alcohol 1% __ experimental group 5 Menglu Sinter sodium 0.5% + resveratrol 1% __f test group 孟 montelukast sodium 1% + resveratrol 1% __f test group 7 montelukast sodium 1.5% + resveratrol 1% _ test Group 8 montelukast sodium 2% + resveratrol 1% Experimental Example 1: Mouse ear edema inhibition test 12 201036947 To confirm the relief and therapeutic effect of atopic dermatitis, a mouse ear edema model (a kind) Atopic animal model) was tested. The ear edema model is an animal model that demonstrates the therapeutic effect of atopic dermatitis, which is an allergen via sensitization of incomplete haptens in the ear of mice (binding to proteins) It Molecular weight chemical substances) specifically to initiate the reaction, the ear swelling over time and measuring the amount of increase of the thickness in mice, to measure the effect of suppressing the swelling of the ear (Journal of Dermatological Science, 36,1-9,2004; Ο ο

Journal of Dermatological Science, 37, 159-167, 2005). In this experiment, 'Balb/C mice (male, 8 weeks) and as incomplete antigen D1 1 06 (1-chloro-2,3,4-trinitro-benzene, 84111 phantom, and painful one) Group 6 mice were tested. The mouse abdomen was shaved with animal scissors and general razor, and one week later, 100 μ 17% ΤΝ (: Β solution (mixture solvent of acetone and olive test (4: 1)) was applied to Mouse abdomen. After 5 days, the mice were anesthetized with halothane, the thickness of the bilateral external ear was measured by thick error _Ut〇yo N〇.7309), and 1〇μ1 1% Take / (C = tatsan oil (4: 1) solution) to the inside of the bilateral external ear. At the top of the application (3) Γ = a sample of 1 〇 μ1 was applied to the bilateral external ear of the mouse. 24-hour odometer _. Ear thickness after induction of edema minus ear thickness of induced water (4), meter # edema inhibition "The following public car count, and the simple case of Xiang Xiang (four) and the table = inhibition (%) = a control group increased X100 Table 2 13 201036947 - position) Inhibition (%) Basic control group 0 Positive control group 1 ~ Moss 3 43% *** Positive control group 2 ... - Division 100 67%... Experimental group 1 Montelukast sodium 50 14 %... experimental group 2 Montelukast sodium 100 26%*"* experimental group 3 montelukast sodium 200 36%*** experimental group 4 ... resveratrol 100 -7% experimental group 5 montelukast sodium 50 + white peony Resveratrol 1〇〇49%"* Experimental Group 6 Montelukast Sodium 100+ White Gourd Xue 1〇〇49%"* Experimental Group 7 Montelukner 150+ Resveratrol 1〇〇52 〇/,* Experimental group 8 montelukast sodium 2〇0 + resveratrol 1〇〇77%***: P<0.001, DUnnett, s Multiple Comparison Test, compared to the control group. ί. As seen in Table 2 above, the experimental examples (test groups 1 to 3) administered alone with montelukast showed 14 to 36% inhibition of ear edema, which increased with the content of montelukast. The experimental group 4 administered with resveratrol alone showed no inhibition of ear edema. However, Experimental Examples 5 to 8 using both monutuk and resveratrol exhibited an edema inhibition of 4 9 to 7 7 %, which represents a significant improvement effect as compared with the case where the compound was used alone. As seen in the experimental groups 1 and 5, Menglu (10) (50 tons) alone showed 14% ear edema inhibition, while (4) Menglu (4) and resveratrol showed 49% ear edema inhibition, which increased 4 times. Or higher. Therefore, in the animal model of atopic dermatitis, a significant improvement effect on atopic dermatitis is exerted by the combination of each compound (4) ❹' due to the synergistic effect of the combination of 孟 # 司 及 and 藜 醇 醇. 14 201036947 agent] seen in the electricity 'compared to tacrolimus (immunosuppression 5 to 8) presenting deaf group 1 to 2), the experimental example of the present invention (experimental group J exhibits ear edema inhibition. Example 2 Preparation of samples containing various contents of self-purinol - To confirm the various levels of resveratrol in atopic dermatitis, prepare a sample by dissolving in a mixed solvent of ethanol and propylene glycol (7:3) as follows As shown in Table 3, reference is made to pimecr〇limus, an immunosuppressant similar to tacrolimus, which exhibits an excellent anti-inflammatory effect and thus is used as a therapeutic agent for chronic atopic dermatitis. The use of pimecrolimus is limited by side effects'. For example, immunosuppressive growth-promoting tumor growth has been published (Cancer, Vol. 80, p. 1141 (1997)). In this experiment, in order to confirm the experimental group of the present invention In the medical effect on atopic dermatitis, this pimecrolimus was used as a positive control group. The montelukast sodium used herein was obtained from Teva, Ltd., purity 99.5% or higher, and used herein. Resveratrol is obtained from

Xi’an Tianxing Natural Bio-products, purity 99% or higher. Table 3 Composition and content (w/v%) Positive control group 3 Pimecrolimus 1% Experimental group 9 Montelukast sodium 1% Experimental group 10 Resveratrol 1% Experimental group 11 Montelukast sodium 1% + Resveratrol 1% Experimental group 12 Montelukast sodium 1% + resveratrol 0.1% Experimental group montelukast sodium 1% + resveratrol 0.01% 15 201036947 Experimental Example 2: Mice Ear edema inhibition test In order to confirm the relief and therapeutic effect of atopic dermatitis, the test was carried out in the same manner as in Experimental Example 1 using a mouse ear edema nuclear type (an animal model for atopic dermatitis). Experimental Example 2 was tested in the same manner as Experimental Example 除了 except for the sample used in Example 2. The test was repeated to determine the inhibition of edema of the ear, and the results obtained are shown in Table 4 below. --------- Inhibition (%) Basic control group ----- VP57 UL and / a 0 positive Control group 3 _Memos 100 69%*" Experimental group 9 ... Montelukast sodium 100 30%... Experimental group 10 ____ Resveratrol 100 -5% "* _Experiment group 11 _ Meng Russet sodium 100 + white gourd yeast 100 67% *** experimental group 12 montelukast sodium 100 + resveratrol 10 57% *** experimental group 13 montelukast sodium 100 + resveratrol 1 63% . P < 0.001, Dunnett's Multiple Comparison Test, compared to the control group.比较 Comparing the experimental group 11 and the experimental group 13 as seen in the above Table 4, although a small amount of resveratrol was added, the experimental group 13 exhibited inhibition corresponding to the experimental group U. This confirms that although a very small amount of resveratrol is synergistically acted upon with montelukast, it has a significant improvement effect on atopic dermatitis compared to the separation of each compound. Further, as seen in the above Table 4, the experimental examples of the present invention (experimental group η to 13) 16 201036947 exhibited ear edema inhibition as compared with indomethacin (immunosuppressive agent) (positive control group 3). These results show that the combined use of montelukast and resveratrol has not been published to produce side effects such as immunosuppressive growth-promoting tumor growth, and atopic dermatitis exhibits superior therapeutic effects comparable to immunosuppressive agents. Industrial Applicability As described above, the present invention provides a composition for treating atopic dermatitis comprising montelukast or a salt thereof and resveratrol as an active ingredient. The composition exhibits an unpredictable therapeutic effect on an atopic skin disease such as atopic dermatitis, and thus it can be used in various forms for treating atopic skin diseases. Although the preferred embodiment of the invention has been disclosed for purposes of illustration and description, it will be understood that ❹ [Simple description of the diagram] No 0 [Description of main component symbols] No 0 17

Claims (1)

201036947 VII. Patent application scope: 1. A composition for treating atopic dermatitis, comprising montelukast or its salt and resveratrol (resveratr〇1). 2. The composition of the first item of the Shenqing Special Case, wherein the montelukast salt is montelukast sodium. 3. For the composition of the full-time enclosure, the resveratrol is trans • resveratrol (trans-3,5,4-trihydroxystilbene). 4. If the composition of the special case No. 3 is applied, the (tetra) ruthenol is purified to a purity of 90% or higher. 5. If you apply for the scope of the special case! The composition of the item, wherein the weight ratio of the montelukast or its salt to the 5 resveratrol is 1: 〇.〇〇 1 to 1:3. 6. For the composition of the scope of the special case, the weight ratio of the montelukast or its salt to the resveratrol is 1: 〇 01 to 1: 2. 7. For the composition of the scope of the special case, further comprising a solvent or an oil to increase the solubility of the resveratrol. 8. The composition of claim 7, wherein the solvent is selected from the group consisting of ethanol, isopropanol, 1,3-butylene glycol, propylene glycol, glycerin, and combinations thereof. 9. For the composition of the scope of the special case, item 7, wherein the oil is selected from the group consisting of corn oil, sesame oil, cotton abalone oil, soybean oil, peanut oil, mono-glyceride, glycerol and triglyceride, minerals A group of oil, squaliene, jojoba oil, eucalyptus oil, evening primrose oil, borage oil (B〇rage 〇il), grape oil, and any combination thereof. 10. If the composition of claim 7 of the scope of the application is applied, it further comprises a dispersing agent. 18 201036947 11. The composition of claim 10, wherein the dispersant is selected from the group consisting of lecithin, organic monoglyceride, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, sorbitan stearate Group of anhydride esters and any combination thereof. 12. A method of using the pharmaceutical composition of claim 1 to prepare a medicament for treating or ameliorating atopic dermatitis. 19 201036947 IV. Designated representative map: (1) The representative representative of the case is: None. (2) A brief description of the symbol of the representative figure: None. 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: