WO2006107184A1 - Composition pharmaceutique contenant un 4-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-2-oxiranyl]-1-oxaspiro [2,5]octan-6-one pour le traitement de la dermatite atopique - Google Patents

Composition pharmaceutique contenant un 4-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-2-oxiranyl]-1-oxaspiro [2,5]octan-6-one pour le traitement de la dermatite atopique Download PDF

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Publication number
WO2006107184A1
WO2006107184A1 PCT/KR2006/001284 KR2006001284W WO2006107184A1 WO 2006107184 A1 WO2006107184 A1 WO 2006107184A1 KR 2006001284 W KR2006001284 W KR 2006001284W WO 2006107184 A1 WO2006107184 A1 WO 2006107184A1
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Prior art keywords
methyl
oxaspiro
octan
oxiranyl
butenyl
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PCT/KR2006/001284
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English (en)
Inventor
Cheol-Sik Yoon
Hyun-Soo Park
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Mycoplus Co., Ltd.
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Publication date
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Publication of WO2006107184A1 publication Critical patent/WO2006107184A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A41—WEARING APPAREL
    • A41C—CORSETS; BRASSIERES
    • A41C3/00—Brassieres
    • A41C3/12—Component parts
    • A41C3/14—Stiffening or bust-forming inserts
    • A41C3/142—Stiffening inserts
    • A—HUMAN NECESSITIES
    • A41—WEARING APPAREL
    • A41C—CORSETS; BRASSIERES
    • A41C3/00—Brassieres
    • A41C3/0007—Brassieres with stay means
    • A—HUMAN NECESSITIES
    • A41—WEARING APPAREL
    • A41C—CORSETS; BRASSIERES
    • A41C3/00—Brassieres
    • A41C3/12—Component parts
    • A41C3/122—Stay means
    • A41C3/128—Stay means using specific materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of atopic dermatitis, which comprises 4-hydroxy-5-methoxy-4- [2-methyl- 3- (3-methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one in a pharmaceutically effective amount.
  • Atopic dermatitis is a common skin disease, which is complicatedly related to hereditary, environmental or immune causes and frequently occurs on infancy and childhood. Prevalence of atopic dermatitis is about 3 to 15% and has been increased since World War II. The research has been undergone extensively in dynamics and in domestic (Hanifin, J.M. et al., Diagnostic features of atopic dermatitis, Acta Derm Venereol, 1980, Suppl 92, 44-47; Diepgen, T. L. et al., Recent epidemiological and genetic studies in atopic dermatitis, Acta Derm Venereol, 1992, Suppl 176, 13-18; Diepgen, T. L. et al., Evaluation and relevance of atopic base and minor features in patients with atopic dermatitis and in the general population, Acta Derm Venereol, 1989, Suppl 144, 50-54) .
  • Atopic dermatitis is a chronic, recurrent skin disease with intensive pruritus, a distinctive mark and dispersion, and genetic predisposition such as a personal or familiar history of atopy. Recently, atopic dermatitis is increased by food additives and environmental pollutions. The exact etiopogy is unknown yet but it is presumed that it is caused by a complex connection between genetic, environmental and immune factors. (Leung, D. Y.M. et al., In:Fitzpatrick T. B. et al., eds, Dermatology in general medicine, 4 th ed, New York: McGraw-Hill, 1993, 1543-1564; Morren, M.A. et al., Atopic dermatitis: triggering factors, J Am Acad Dermatol, 1994, 31, 467-473) .
  • CD8+ T lymphocyte of peripheral blood decreases and consequently a ratio of CD4:CD8 increases .
  • virus or bacterial infection frequently occurs due to a decline of skin immunity and reaction against contact allergen decreases.
  • ThI which participates in cell- mediated immunity by secreting INF- ⁇ and TNF- ⁇
  • Th2 which helps a production of IgE secreting IL-4 and causing allergy and participates in allergic reaction directly
  • the object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of atopic dermatitis, which contains a pharmaceutically effective amount of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2,5] octan-6-one.
  • Figs.l to 5 are a graph describing pruritus inhibiting effects (a ⁇ e) with various concentrations of 4-hydroxy-5- methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan-6-one of the present invention in animal models having atopic dermatitis .
  • Figs.6 and 7 are a result of infiltration of pleomorphic nuclear leucocyte from a skin of atopic dermatitis animals.
  • Fig.6 is a photograph showing the atopic dermatitis skin caused by injection of compound 48/80.
  • Fig.7 is a photograph showing 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2,5] octan-6-one of the present invention with the anti-infiltration effects of pleomorphic nuclear leucocyte caused by injection of compound 48/80.
  • Figs.8 and 9 are a result of infiltration of eosinophile from a skin of atopic dermatitis animals.
  • Fig.8 is a photograph showing the atopic dermatitis skin caused by injection of compound 48/80.
  • Fig.9 is a photograph in a case pretreated with 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl- 2-butenyl) -2-oxiranyl] -1-oxaspiro [2,5] octan- ⁇ -one of the present invention.
  • Figs.10 and 11 are a photograph showing degranulated mast cells in a skin of atopic dermatitis.
  • Fig.10 is a photograph showing the atopic dermatitis skin caused by injection of compound 48/80.
  • Fig.11 is a photograph showing anti-degranulation effects of mast cells due to injection of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -1-oxaspiro [2, 5] octan-6-one of the present invention.
  • Fig.12 is a graph describing an effect of different concentrations of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2,5] octan-6-one in mast cells.
  • Fig.13 is a graph describing an effect of different concentrations of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan-6-one toward degranulation of mast cells.
  • Fig.14 is a graph describing an effect of different concentrations of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2,5] octan-6-one in mast cells toward the isolation of histamine.
  • Fig. 15 is a graph describing an effect of different concentrations of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan-6-one toward Calcium inflow in mast cells.
  • Fig.16 is a graph describing an effect of different concentrations of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan-6-one toward cAMP in mast cells .
  • Fig.17 is a graph describing the level of the improvement of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one measured by dermatologists' naked eyes.
  • Fig.18 is a graph describing the level of the improvement of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one measured by SCORAD INDEX.
  • Fig.19 is a graph describing the level of the improvement of insomnia and pruritus evaluated by subjects having atopic dermatitis .
  • Fig.20 is a graph describing the change of water evapotransiration at skin of atopic dermatitis.
  • Fig.21 is a graph describing the change of water- holding capacity at skin of atopic dermatitis .
  • Fig.22 is a graph describing the pH change at skin of atopic dermatitis.
  • the pharmaceutical composition for treatment of atopic dermatitis in the present invention comprises 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan-6-one as an active ingredient.
  • pharmaceutically effective amount means the amount of a pharmaceutical composition, which is effective for the prevention or treatment of skin conditions, upon its application to skin.
  • composition refers to pharmaceutical preparation, detergents, or cosmetics comprising a pharmaceutically effective amount of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -1-oxaspiro [2, 5] octan-6-one as an active ingredient for the prevention and treatment of skin conditions caused by atopic dermatitis.
  • skin condition refers to conditions present on any region of skin affected by atopic dermatitis, and includes conditions considered as cutaneous diseases as well those not considered as cutaneous diseases.
  • treatment means an application result of the pharmaceutical composition of the present invention to atopic dermatitis not only with the complete recovery of symptoms of atopic dermatitis but also with the partial recovery, improvement and alleviation.
  • prevention means that symptoms of atopic dermatitis do not develop due to inhibition or prevention of infection and growth of atopic dermatitis through application of the pharmaceutical composition of the present invention to the skin, especially the one with atopic dermatitis.
  • the compound, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one, represented by the chemical formula 1, is a derivative of oxaspiro[2, 5] octane, and can be prepared by chemical synthesis methods as disclosed in Corey' s thesis (Corey, E.J. et al . , J. Am. Chem. Soc, 1985, 107, 256-257; Corey, E.J. et al., J. 7Am. Chem. Soc, 1994, 116, 12109-12110) .
  • oxaspiro [2, 5] octane 4-hydroxy-5- methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan-6-one can be used as a pharmaceutical material, as described in Corey's dissertation (Corey, E.J. et al., J. Am. Chem. Soc, 1985, 107, 256-257; Corey, E.J. et al., J. Am. Chem. Soc, 1994, 116, 12109-12110) and also has been used for the treatment of solid tumors and immunosuppressive drugs.
  • the present invention is achieved by discovering that 4- hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -1-oxaspiro [2, 5] octan-6-one, which has been used only as an anti-cancer medicine or an immunosuppressive drug, has an excellent effect against atopic dermatitis.
  • the pharmaceutical composition of the present invention for the treatment of atopic dermatitis contains 4- hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -l-oxaspiro[2, 5] octan-6-one as an active ingredient and is not limited by a formulation.
  • transepidermal drugs including ointment, cream, pastes, lotion, liniments, external use, tinct, glycerogelatins, external powders, aerosol and plasters; oral drugs including capsule, tablet, pills, powder and granules; detergents including soap, hair soap, hair conditioner, body cleanser and shampoo; and cosmetics including skin lotion, lotion, cream, essence and body lotion.
  • a pharmaceutical composition comprising 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -1-oxaspiro [2, 5] octan-6-one
  • a pharmaceutical composition for the prevention or treatment of atopic dermatitis which comprises 4-hydroxy-5- methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan- ⁇ -one as an active ingredient.
  • a pharmaceutical composition of the present invention is not limited particularly, but it may be a transepidermal or oral form, for example, ointment, cream, pastes, lotion, liniments, external use, kapsel, tablet, pills, powder and the like.
  • Such formulations are described in a prescription, which is generally known in the pharmaceutical industry
  • an ointment is provided as a preferable formulation.
  • the ointment of the present invention can be prepared from hydrocarbon base such as petrolatum, white petrolatum, yellow ointment and mineral oil, absorbent base such as hydrophilic petrolatum, anhydrous lanolin, lanolin and cold cream; water washable bases such as hydrophilic ointment; or water-soluble bases such as achieved depending on various factors including the release rate of a drug from a base, the effect of a base on enhancement of percutaneous adsorption, the moisture sealing effect of a base on water in skin, the stability of a drug in a base and the influence of a drug on a base, and is a common skill of experts in the pharmaceutical preparation field.
  • a cream is also provided as a preferable formulation.
  • the cream according to the present invention include water in oil (w/o) types, such as cold creams and emollient creams; and oil in water (o/w) types, which may be exemplified by shaving creams, vanishing creams, hand creams and cleansing creams. More preferable are vanishing creams, which typically contain water and stearic acid.
  • a cream form is preferable.
  • a lotion is provided as a preferable form.
  • a lotion may be prepared in the form of suspension, emulsion or solution, and this preparation is a common skill for experts in the pharmaceutical preparation field.
  • a white lotion which may be prepared by dissolving sulfated potash in water to a content of 4% and then filtering, and adding a solution of zinc sulfate to the solution with gentle agitation at a constant velocity.
  • a liniment is provided as a preferable formulation.
  • a liniment may be prepared by any of oil liniments and ethanol liniment. More preferable is an oil liniment causing little irritation to skin.
  • the oil liniment include non-volatile oils, which may be exemplified by almond oils, peanut oils, cottonseed oils, etc., mixtures of non-volatile oils and volatile oils, which may be exemplified by wintergreen, turpentine, etc.
  • detergents and cosmetics containing 4-hydroxy-5- methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan- ⁇ -one as an active ingredient, which is capable of preventing or treating skin conditions caused by atopic dermatitis .
  • the pharmaceutical composition according to the present invention can be formulated as various detergents and cosmetics, but are not limited thereto, including skin toiletry, hair toiletry and hairdressing.
  • the formulations of the detergent and cosmetics can be exemplified by soap and cleansing compositions in the form of solid, liquid, or powder, liquid creams and skin gels, skin oils, face lotions, body shampoos, astringents, essence/deodorants, soap, hair creams, aqueous and aqueous-alcoholic hair lotions, waving-setting lotions (hair fixer) , hairdressing creams/gels, hair sprays, hair tonics, hair oils, hair pomades, hair brilliants, and especially, hair conditioners and shampoos .
  • soap and cleansing compositions in the form of solid, liquid, or powder, liquid creams and skin gels, skin oils, face lotions, body shampoos, astringents, essence/deodorants, soap, hair creams, aqueous and aqueous-alcoholic hair lotions, waving-setting lotions (hair fixer) , hairdressing creams/gels, hair sprays, hair tonics, hair oils, hair pomades, hair brilliants, and especially
  • the detergent and cosmetics compositions containing 4-hydroxy-5- methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan-6-one as an active ingredient may include at least one of auxiliary agents, which are selected from the group consisting of surfactants, stabilizers, preservatives, moisturizers, anti-inflammatory agents, anti-oxidants, coloring agents, water and mixtures thereof.
  • auxiliary agents mentioned above can be contained in an amount of about 90.0 to 99.99999% of the composition.
  • the surfactant useful in preparation of the detergent and cosmetics of the present invention may be present in an anionic, a cationic, or zwitterionic form, typically, contained in an amount of at least 30%wt, and preferably, at least 70wt%.
  • the skilled experts in this field can easily determine a type and an amount of the surfactant .
  • the stabilizer useful in preparation of the detergent and cosmetics of the present invention contains, preferably, glycol stearate, but is not limited to this.
  • the stabilizer is typically contained in an amount of about 0.1 to 5wt% of the composition.
  • the preservative useful in preparation of the detergent and cosmetics of the present invention includes, but is not limited to, tetrasodium ethylenediamine tetraacetate (tetrasodium EDTA), 1- (3-chloroaryl) -3, 5, 7- traaza-1-adamanthane, parabene, methyl parabene, a mixture of 5-chloro-2-methyl-4-isothiazoline-3-one and 2-methyl-4- isothiazoline-3-one, phenoxyethanol, benzylalcohol, benzophenone-4, methylchloroisothiazolinone, methylisothiazolinone and mixtures thereof.
  • the preservative is, when used, typically contained in about 0.01 to 6wt% of
  • the moisturizer useful in preparation of the detergents and cosmetics of the present invention includes wheat proteins (e.g., laurdimonium hydroxypropyl hydrolyzed, wheat protein) , hair keratin amino acids, sodium peroxylin carbonic acid, pantenole, tocopherol (Vitamin E) , dimethicone and mixture of thereof.
  • the moisturizer is typically used in an amount of about 0.01 to 10wt% of the composition, preferably 0.05 to 1.5wt%, and more preferably about 0.01 to lwt%.
  • the coloring agent useful in preparation of the detergents and cosmetics of the present invention includes FD&C green No.3, Ext. D&G violet No.2, FD&C yellow No.5, FD&C red No.40 and mixtures thereof, and is, when used, typically used in an amount of about 0.001 to 0. lwt% of the cleaning and cosmetic composition, and more preferably, about 0.005 to 0.05wt%.
  • the anti-inflammatory agent useful in preparation of the detergents and cosmetics of the present invention the preferable one is an anti-inflammatory agent suitable for local administration and being pharmaceutically permeable, and the most preferable one is alatonin.
  • the anti- inflammatory agent may be, when used, used in an amount sufficient to inhibit or alleviate inflammation, typically about 0.01 to 2wt% of the composition, preferably, about 0.3 to 1.5wt%, and more preferably, about 0.3 to lwt%.
  • Anti-oxidants of both enzymatic and non-enzymatic types may be used in the detergent and cosmetic preparations of the present invention.
  • natural enzymatic antioxidants include superoxide dismutase (SOD) , catalase, and glutathione peroxidase
  • suitable non-enzymatic antioxidants include vitamin E (e.g., tocopherol), vitamin C (ascorbic acid) , carotenoides, echinacoside and cafeoyl derivatives, oligomeric proanthocyanidins or proanthanols
  • Carotenoids are powerful anti-oxidants, and they include beta-carotene, canthaxanthin, zeaxanthin, lycopen, letein, crocetin, capsanthin and the like.
  • the anti-oxidant component includes Vitamin E, Vitamin C or a carotenoid.
  • the anti-oxidant component when used, is present in an amount sufficient to inhibit or reduce the effects of free radicals at the scalp.
  • the anti-oxidant component may be present in an amount from about 0.001 to lwt%, preferably from about 0.01 to 0.5wt% of the composition.
  • the detergent and cosmetic compositions may contain other auxiliary agents well known to those skilled experts in the art.
  • auxiliary agents include perfumes, pigments, which include all those coloring hair concurrently or separately supplying color, solvents, opacificers or pearlescent agents (e.g., ester of fatty acid and polyol, magnesium salt and iron salt of fatty acid), copolymer dispersions, thickeners (e.g., sodium chloride, potassium chloride, ammonium chloride, sodium sulfate) , alkylolamide fatty acids, cellulose derivatives, natural gums, plant extracts, albumin derivatives (e.g., gelatin) , collagen hydrolysis products, natural or synthesized polypeptides, yolks, lecithin, lanoline and its derivatives, fats, oils, fatty alcohols, silicon, deodorant, antimicrobial agents, anti-seborrhea agents, keratolytic agents (e.g., sulfur, salicylic acid, benzo
  • thickeners
  • the magnitude of a prophylactic or therapeutic dose of the pharmaceutical preparation, cleansing and cosmetic preparations according to the present invention may be depending on the severity of the condition to be pretreated and their formulations .
  • the dose frequency may also vary according to the age, body weight, and physical constitution of patients.
  • the compound used as an active ingredient in the pharmaceutical composition of the present invention 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl]-l-oxaspiro[2,5]octan- ⁇ -one, can be present in the preparation described above in an amount of 0.00001 to 10wt%, preferably, 0.005 to 2wt%, and more preferably, 0.01 to lwt%.
  • the concentration of the compound in a specific preparation may be determined according to the use of the preparation.
  • a specific preparation such as a concentrated preparation, which should be diluted before use, may contain a much higher concentration of the compound.
  • All of the preparations according to the present invention may be manufactured using ordinary skill in the art by mixing 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- butenyl) -2-oxiranyl] -l-oxaspiro[2, 5] octan- ⁇ -one and each component, and formulating the mixture in a suitable form.
  • arioso preparations containing 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one may be used according to typical methods, and preferably, by applying or massaging to the skin areas afflicted with atopic dermatitis .
  • the pharmaceutical composition of the present invention for the treatment of atopic dermatitis contains 4- hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one as an active ingredient and is not limited by a formulation.
  • transepidermal drugs including ointment, cream, pastes, lotion, liniments, external use, tinct, glycerogelatins, external powders, aerosol and plasters; oral drugs including kapsel, tablet, pills and powder; deodorants including soap, hair soap, hair conditioner, body cleanser and shampoo; and cosmetics including skin lotion, lotion, cream, essence and body lotion.
  • the pharmaceutical composition of the present invention can be provided as a form of ointment, lotion, cream, soap, body cleanser, shampoo, conditioner and etc.
  • a temperature of skin surface, pH of skin, a value of transepidermal water loss and total epidermal lipid should be concerned and the ointment is mixed with such as oily, water-soluble or suspended materials including Vaseline, liquid paraffin, paraffin, plastibase, silicon, lard, vegetable tallow, wax, and purified lanolin.
  • additives such as antioxidant (e.g. tocopherol, BHA, BHT, NDGA), antiseptic (e.g.
  • moisturizer glycerol, propylene glycol, sorbitol
  • solubility aid ethanol, propylene glycol
  • softening aid liquid paraffin, glycerol, propylene glycol, surfactant
  • lotion In a formulation of lotion, it can be formulated as soluble, suspended or oily materials. In case of transepidermal lotion, a viscosity can be measured from 200cps to 500 cps and humectants such as glycerin and propylene Glycol can be mixed for a smooth application. In a formulation of spray, it may be mixed with a propellant to disperse concentrates or moist powder.
  • a shampoo or body cleanser is provided as the most preferable formulation of the pharmaceutical composition according to the present invention.
  • a shampoo may be formulated in the form of transparent liquids, opaque liquids, gels, creams, or powders.
  • the interactions of shampoo with hair, skin or scalp are dependent on the kind of surfactant, as a base of the shampoo, which may be an anionic, a cationic, a nonionic surfactant or a mixture thereof.
  • the shampoo composition of the present invention typically, comprises at least 30wt% of surfactant, and at least 70wt%.
  • the shampoo or body cleanser composition of the present invention also includes a foaming agent such as fatty acid mono- and di-alkaneolamide, which may be exemplified by cocamide MEA (a mixture of coconut acid monoethanolamides having a chemical formula of R-CO-NHCH 2 CH 2 OH, wherein the R group may be residue remaining after removal of a carboxyl group of a coconut fatty acid) , cocamide DEA (a mixture of diethanolamide having a chemical formula of R-CO-N(CH 2 CH 2 ON), wherein the R group is the same as above) , oleamide MEA, and oleamide DEA.
  • cocamide MEA a mixture of coconut acid monoethanolamides having a chemical formula of R-CO-NHCH 2 CH 2 OH, wherein the R group may be residue remaining after removal of a carboxyl group of a coconut fatty acid
  • cocamide DEA a mixture of diethanolamide having a chemical formula of R-CO-N(CH 2 CH 2 ON
  • the shampoo or body cleanser composition of the present invention also includes a thickening agent in order to give viscosity ranging from about 4,000 to 9,000 cps.
  • the thickening agent include aryl ester of sucrose, ClO-30 alkyl acrylate, and carbopol 1342 as a copolymer of acrylic acid/methacrylic acid.
  • the thickening agent useful in the shampoo or body cleanser may also include cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and the like.
  • an addition of a small amount of a salt ranged from about 0.25 to 0.6wt% controls the viscosity of final preparation.
  • the shampoo or body cleanser composition of the present invention may also include perfumes, coloring agents, opacifiers, conditioners (e.g., polyquaternium-7 [polymeric quaternary ammonium salt of acrylamide and dimethyl diaryl ammonium chloride] ) , and the like, which are standard components in shampoo or cleanser.
  • perfumes e.g., coloring agents, opacifiers, conditioners (e.g., polyquaternium-7 [polymeric quaternary ammonium salt of acrylamide and dimethyl diaryl ammonium chloride] ) , and the like, which are standard components in shampoo or cleanser.
  • the shampoo or body cleanser composition of the present invention may include acid, base, and buffering agents in order to maintain its pH in the range of from 4 to 10, preferably, 6.5 to 8, and more preferably, 6.9 to 7.4.
  • acid, base, and buffering agents in order to maintain its pH in the range of from 4 to 10, preferably, 6.5 to 8, and more preferably, 6.9 to 7.4.
  • neutral pH is preferred. Properties of such compounds for controlling pH values and manner of using them are well known in the art.
  • the embodiments indicate preparations of materials containing 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one as an active ingredient.
  • the present invention is not limited to the embodiments .
  • a frequency of scratching the neck with a hind leg was about 30 ⁇ 40/each 10 minutes for first 30 minutes, and then decreased as the time passed.
  • a frequency of scratching a neck with a hind neck due to compound 48/80 was significantly decreased concentration- dependently by pretreating with 4-hydroxy-5-methoxy-4- [2- methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan-6-one.
  • Fig. 6 and 7 The level of infiltration at polymorphic nuclear leukocytes, PMNL is observed with an optical microscope and filmed with a video camera. The results are illustrated in Fig. 6 and 7. As shown in Fig. 6 and 7, in a skin having atopic dermatitis due to compound 48/80, lots of infiltration at polymorphic nuclear leukocytes were observed (Fig. 6) , but infiltration at polymorphic nuclear leukocytes were significantly reduced by insertion of 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan-6-one (Fig. 7).
  • 4-hydroxy-5- methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro[2,5]octan- ⁇ -one is effective to inhibit the infiltration at polymorphic nuclear leukocytes by compound 48/80.
  • a skin was dyed toluidine blue and then a level of infiltration at mast cells and an existence of degranulation were observed with an optical microscope.
  • the results are illustrated in Fig. 10 and 11.
  • Fig. 10 and 11 lots of degranulated mast cells were observed in skin having atopic dermatitis due to compound 48/80, but degranulation of mast cells were significantly inhibited by insertion of 4-hydroxy-5-methoxy- 4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan- ⁇ -one.
  • 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan- ⁇ -one is effective to inhibit a degranulation of mast cells, which is caused by compound 48/80.
  • HEPES-Tyrode 25 ⁇ g was controlled or various concentrations of 4-hydroxy-5-methoxy-4- [2 ⁇ methyl-3- (3- methyl-2-butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one was controlled and cultured at 37 ° C for 4hours. After cultivation, 50 ⁇ g of lmg/lml MTT was added and cultured at 37 " C for 1 hour and then separated centrifugally again.
  • a method of Cocharane and Douglas was modified and supplemented (Cochrane, et al . , Calcium-induced extrusion of secretory granule (exocytosis) in the mast cells exposed to 48/80 or the inopores A23187 and X-537A, Proc. Natl. Acd. Sci. U.S.A., 71, 408, 1974).
  • Abdominal cleansing lotion was obtained by inserting about 10ml of Ca-Locke solution (15OmM NaCl, 5mM KCl, 2mM CaCl 2 , 1.
  • mast cells activated by various stimulations have a degranulation in mast cells by increase of calcium concentration in cells and decrease of a level of cAMP.
  • mast cells Once the mast cells are activated, Histamine, proteolytic enzymes, heparin and chemotactic factors, which were already formed in mast cells are separated, and new compounds such as prostaglandin, leukotriens, thromboxane are separated from activation of phospholipase A2 at the cell membrane.
  • Various mediated materials separated from mast cells have allergic symptoms caused by increase of vascular permeability, edema, pruritus, a bronchial smooth muscle contraction.
  • mast cells from 2-2 180 ⁇ g re-suspended solution of mast cells from 2-2 was fixed at room temperature for 10 minutes allowing cells to precipitate in a chamber of inverted microscope.
  • 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- butenyl) -2-oxiranyl] -1-oxaspiro [2, 5] octan- ⁇ -one inhibits a degranulation due to compound 48/80
  • mast cells were pretreated with various concentrations of 4-hydroxy-5- methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan-6-one for 10 minutes and then compound 48/80 was added.
  • a morphemic change of mast cells was observed under 1000 magnifications. The results are illustrated in Fig. 6.
  • Harvima A modified and supplemented method of Harvima was used (Harvima, R.J, Optimization of histamine radiolenzymatic assay with purified histamind N-methyltransferase, Clinica Chimica Acta, 171, 247, 1998) .
  • a 180 ⁇ l suspended solution of mast cells (10 6 cells/ml) which was separated through pure isolation method as descried above, was added with 20 ⁇ l of 4- hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -l-oxaspiro[2, 5] octan-6-one solution and the amount of histamine radiolenzymatic assay was estimated.
  • Mast cells were separated with a method of pure mast cells isolation to control the number of cells l*10 6 cells/ml in suspended solution and then 200 ⁇ l of them was obtained.
  • Embodiment 1 Shampoo preparation for normal hair
  • a shampoo was prepared using the ingredients in Table 1 below.
  • An original solution containing 1.64% of carbopol 1342 manufactured by uniformly dispersing copolymer powder using a Quadro distributor and then pushing into aqueous vapor under a vacuum condition) and deionized water were put into a vessel, and heated to about 70 ° C.
  • surfactants sodium laureth sulfate and sodium cocoil sarcocinate were added, a foaming agent, cocamide MEA, and a pearlescent agent, ethylene glycol disterate were subsequently added, and then completely dissolved.
  • Embodiment 2 Shampoo preparation for dry or damaged hair
  • the additional amount of sodium hydroxide can be slightly modified in order to maintain the pH in the more preferable range from 6.9 to 7.4. Also, the additional amount of sodium chloride can be slightly modified to accomplish a desired viscosity.
  • Embodiment 4 Hydrophilic ointment preparation
  • a hydrophilic ointment washable with water was prepared using the following ingredients .
  • Stearyl alcohol and white petrolatum were dissolved using steam, and then heated to 75 ° C
  • Sodium lauryl sulfate, propylene glycol, methylparabene and propylparabene were added to water, which was hated to 75 ° Cin advance.
  • An active ingredient, 4-hydroxy- 5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2-oxiranyl] -1- oxaspiro [2, 5] octan- ⁇ -one was added to a water phase, and mixing was continued to reach coagulation state, generating an ointment .
  • a cream of oil-in-water (O/W) type was prepared using the following ingredients . After an oil phase and a water phase were separately heated to 70 "Q the oil phase was slowly added to the water phase with stirring to generate a crude emulsion. The emulsion was cooled to about 55 ° C and then homogenized, followed by shaking incubation until coagulation, giving a cream.
  • Embodiment 6 Vanishing cream preparation
  • a cream of oil-in-water (0/W) type was prepared using the following ingredients. After, an oil phase and a water phase were separately heated to about 65 ° C the oil phase was slowly added to the water phase with stirring to generate a crude emulsion. The emulsion was cooled to about 50 ° C and then homogenized, followed by shaking incubation until coagulation, giving a cream.
  • a lubricating jelly was prepared using the following ingredients. Metocel 90 H. C. 4000 was dispersed in 40ml of hot water (80 to 90 ° (J, and cooled in a refrigerator overnight. Separately, carbopol 934 was dispersed in 20ml of water, adjusted in pH to 7.0 using a sufficient amount of 1% sodium hydroxide solution and then supplemented with water to give a final volume of 40ml. Also, separately, methylparabene and 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2-butenyl) -2- oxiranyl] -l-oxaspiro[2, 5] octan-6-one were dissolved in propylene glycol . The three solutions were carefully mixed to avoid aeration to generate a gel.
  • Test for skin irritation A test for skin irritation was performed according to the paper published by Genji Imokawa, et al . , and a closed path test was conducted using Finn Chamber of Norgesplaster A/S Company. lO ⁇ l of the formulations prepared in Embodiment 1-7 were put onto paper discs suitable for Finn Chamber, allowed to absorb, and transferred to Finn Chamber, and then attached onto skin of ten adult males for 48 hours. After 48 hours, the Finn Chamber was removed therefrom, and skin was washed with running water and dried. After 2 hours, skin conditions were evaluated according to the following criteria. The results are shown in Table2, below.
  • the dermal preparations of the present invention were found to cause no irritation to skin, and thus have no toxicity.
  • Male/Female subjects including infant and teenager aged 4 to 30, having Atopic dermatitis were selected first. After sustaining the living style and skin care for two weeks, final 20 subjects were selected by physical tests, interview, and dermatologists' clinical evaluation according to Hanifin&Rajka diagnostic criteria examining the existence of atopic dermatitis. Basic information of subjects is described in Table 9. Configurations, categories of symptoms are described in Table 10-12 below. Most of the subjects were suffering from dryness, lichenification, and excoriation. Edema or papulations were also partially observed and some of them had oozing or crusting due to scratching.
  • Embodiment 6 containing 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methyl-2- butenyl) -2-oxiranyl] -l-oxaspiro[2, 5] octan-6-one all over the body twice a day and after showering with lukewarm water as possible and removing the water, they put the product over skin having atopic dermatitis in five minutes.
  • the experiment was processed for 2 weeks and the effectiveness of the product was evaluated by dermatologists' naked eyes, noninvasive measuring equipment and subjective evaluations at weekO, 1, 2.
  • a degree of Atopic dermatitis is evaluated by dermatologists (KNS or MTK) using SCORAD Index (European Task Force on Atopic Dermatitis, Severity scoring of atopic dermatitis, The SCORAD Index, Dermatology, 1993, 186, 23-31) .
  • SCORAD Index is a score table grading the degree of Atopic dermatitis' severity.
  • a composition and a criterion are as follows . The SCORAD Index is consisted of 3 subdivided scores .
  • A (Score of an area based on a surface area of body)
  • Severity is based on average severity of body parts where atopic dermatitis is typically observed.
  • the level was scaled by visual sequence ranging from 0 to 3.
  • Excoriation 6 symptoms are graded from 0 to 3 with the most damaged part chosen for each criterion.
  • TEWL Trans Epidermal Water Loss
  • capacitance of moisture, and pH were measured at week 0, 1, 2 on the non- diseased part and the most damaged part among 11 parts having atopic dermatitis .
  • Table 17-22 illustrates the overall results.
  • lichenification was the most improved among 6 symptoms at week 1 of using the product compared to weekO .
  • Oozing or crusting, edema or papulations, erythema, excoriation and dryness also showed the improvement respectively.
  • oozing or crusting was the most improved compared to week 0, and lichenification and excoriation were also improved.
  • Excoriation and dryness and erythema also improvement and symptoms showed improvements overall.
  • transepidermal water loss is reduced 7.9% for diseased parts, and 4.8% for non-diseased parts.
  • it is also reduced 12.9% for diseased parts and even increased 9.0% for non-diseased parts.
  • Table 13 the experiment using Corneometer (CM825, Courage&Khazaka, Germany) showed 16.28+8.3 ⁇ g/m 2 h of hydration for diseased parts and 24.25+8.84g/m 2 h for non-diseased parts.
  • the pharmaceutical composition containing the compound, 4-hydroxy-5-methoxy-4- [2-methyl-3- (3-methy1-2- butenyl)-2-oxiranyl]-l-oxaspiro[2,5]octan- ⁇ -one, as an active ingredient has an excellent effect of preventing and treating Atopic dermatitis, which is caused by a complicated correlation between genetic, environmental and immune factors. Therefore, the pharmaceutical composition of the present invention may be greatly useful in industrial application.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant le composé 4 -hydroxy- 5 -méthoxy- 4- [2-méthyl-3- (3-méthyl-2-butényl) -2-oxiranyl] -1- oxaspiro [2, 5] octan-6-one en t ant que principe actif en dose pharmaceutiquement efficace pour la prévention et le traitement de la dermatite atopique, pathologie due à une corrélation complexe entre facteurs génétiques, envrionnementaux et immunes.
PCT/KR2006/001284 2005-04-07 2006-04-07 Composition pharmaceutique contenant un 4-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-2-oxiranyl]-1-oxaspiro [2,5]octan-6-one pour le traitement de la dermatite atopique WO2006107184A1 (fr)

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KR1020050029062A KR100528033B1 (ko) 2005-04-07 2005-04-07 4-하이드록시-5-메톡시-4-[2-메틸-3-(3-메틸-2-부테닐)-2-옥시란닐]-1-옥사스피로[2,5]옥탄-6-온을 함유한 아토피 피부염 치료용 약제학적 조성물
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008152127A1 (fr) * 2007-06-14 2008-12-18 Instituto Biomar, S.A. Terpènes exerçant une activité antifongique contre les levures du genre malassezia
JP2015199731A (ja) * 2014-04-01 2015-11-12 株式会社ポーラファルマ 皮膚外用剤の使用性の評価法及び該評価法で使用性に優れると判別される皮膚外用剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09309859A (ja) * 1996-05-20 1997-12-02 Asahi Chem Ind Co Ltd 新規化合物ａｍ６８９８及びその製法
JPH1129561A (ja) * 1997-07-07 1999-02-02 Asahi Chem Ind Co Ltd 新規化合物ａｍ６１０５及びその製法
WO2003094908A1 (fr) * 2002-05-13 2003-11-20 Mycoplus Co., Ltd. Composition pharmaceutique destine au traitement de la seborrhee contenant 4-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-2-oxiranyl]-1-oxaspiro[2,5]octane-6-one

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09309859A (ja) * 1996-05-20 1997-12-02 Asahi Chem Ind Co Ltd 新規化合物ａｍ６８９８及びその製法
JPH1129561A (ja) * 1997-07-07 1999-02-02 Asahi Chem Ind Co Ltd 新規化合物ａｍ６１０５及びその製法
WO2003094908A1 (fr) * 2002-05-13 2003-11-20 Mycoplus Co., Ltd. Composition pharmaceutique destine au traitement de la seborrhee contenant 4-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)-2-oxiranyl]-1-oxaspiro[2,5]octane-6-one

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Title
HOLM ET AL.: "Atopy patch test with house dust mite allergen - an IgE-mediated reaction", ALLERGY, vol. 59, no. 8, August 2004 (2004-08-01), pages 874 - 882 *
JACKOLA ET AL.: "Evidence for two independent distributions of serum immunoglobulin E in atopic families", HUM. IMMUNOL., vol. 65, no. 1, January 2004 (2004-01-01), pages 20 - 30 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008152127A1 (fr) * 2007-06-14 2008-12-18 Instituto Biomar, S.A. Terpènes exerçant une activité antifongique contre les levures du genre malassezia
JP2015199731A (ja) * 2014-04-01 2015-11-12 株式会社ポーラファルマ 皮膚外用剤の使用性の評価法及び該評価法で使用性に優れると判別される皮膚外用剤

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