US20030203853A1 - Preventatives/remedies for skin aging - Google Patents
Preventatives/remedies for skin aging Download PDFInfo
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- US20030203853A1 US20030203853A1 US10/405,701 US40570103A US2003203853A1 US 20030203853 A1 US20030203853 A1 US 20030203853A1 US 40570103 A US40570103 A US 40570103A US 2003203853 A1 US2003203853 A1 US 2003203853A1
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- substance
- prophylaxis
- therapy
- composition
- inhibitory activity
- Prior art date
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- 0 C*CCCC(*C(C(*)*)=O)C(*C(C(C)OC(C(*C(C(Cc1ccccc1)*(*)C(C(Cc1ccccc1)**)=O)=O)C(C)*)=O)C(*C(C(*)=O)=**)=O)=O Chemical compound C*CCCC(*C(C(*)*)=O)C(*C(C(C)OC(C(*C(C(Cc1ccccc1)*(*)C(C(Cc1ccccc1)**)=O)=O)C(C)*)=O)C(*C(C(*)=O)=**)=O)=O 0.000 description 6
- JWUKRHWKNAOXJT-UHFFFAOYSA-N C.C.CC1CCCN1C.CCN(C)C1CCC2=C1C=CC=C2 Chemical compound C.C.CC1CCCN1C.CCN(C)C1CCC2=C1C=CC=C2 JWUKRHWKNAOXJT-UHFFFAOYSA-N 0.000 description 3
- WDGHKQIEWJULLQ-UHFFFAOYSA-N C[NH+](CC1CC1)[O-] Chemical compound C[NH+](CC1CC1)[O-] WDGHKQIEWJULLQ-UHFFFAOYSA-N 0.000 description 2
- OSUCPJIQIVIONM-UHFFFAOYSA-N CC=C(NC(=O)C(NC(=O)C(CCCNC(C)C)NC(=O)C(C)C)C(C)OC(=O)C(NC(=O)C(CC1=CC=CC=C1)N(C)C(=O)C(CC1=CC=CC=C1)C(C)C)C(C)C)C(=O)C(C)C.CNC(C)C.CO.CO Chemical compound CC=C(NC(=O)C(NC(=O)C(CCCNC(C)C)NC(=O)C(C)C)C(C)OC(=O)C(NC(=O)C(CC1=CC=CC=C1)N(C)C(=O)C(CC1=CC=CC=C1)C(C)C)C(C)C)C(=O)C(C)C.CNC(C)C.CO.CO OSUCPJIQIVIONM-UHFFFAOYSA-N 0.000 description 1
- QMTLHKOTMPIZHO-UHFFFAOYSA-L CC=C(NC(=O)C(NC(=O)C(CCCNC(C)C)NC(=O)C(C)C)C(C)OC(=O)C(NC(=O)C(CC1=CC=CC=C1)N(C)C(=O)C(CC1=CC=CC=C1)C(C)C)C(C)C)C(=O)C(C)C.CNC(C)C.COS(=O)(=O)O[K].COS(=O)(=O)O[K] Chemical compound CC=C(NC(=O)C(NC(=O)C(CCCNC(C)C)NC(=O)C(C)C)C(C)OC(=O)C(NC(=O)C(CC1=CC=CC=C1)N(C)C(=O)C(CC1=CC=CC=C1)C(C)C)C(C)C)C(=O)C(C)C.CNC(C)C.COS(=O)(=O)O[K].COS(=O)(=O)O[K] QMTLHKOTMPIZHO-UHFFFAOYSA-L 0.000 description 1
- SPADMXARFMJWFD-UHFFFAOYSA-L CC=C(NC(=O)C(NC(=O)C(CCCNC(C)C)NC(=O)C(C)C)C(C)OC(=O)C(NC(=O)C(CC1=CC=CC=C1)N(C)C(=O)C(CC1=CC=CC=C1)C(C)C)C(C)C)C(=O)C(C)C.CNC(C)C.COS(=O)(=O)O[Na].COS(=O)(=O)O[Na] Chemical compound CC=C(NC(=O)C(NC(=O)C(CCCNC(C)C)NC(=O)C(C)C)C(C)OC(=O)C(NC(=O)C(CC1=CC=CC=C1)N(C)C(=O)C(CC1=CC=CC=C1)C(C)C)C(C)C)C(=O)C(C)C.CNC(C)C.COS(=O)(=O)O[Na].COS(=O)(=O)O[Na] SPADMXARFMJWFD-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/005—Enzyme inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- 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
Definitions
- This invention relates to a composition for prophylaxis and therapy of dermal aging which comprises a substance having human leukocyte elastase inhibitory activity as an active ingredient.
- the present inventors discovered that a substance having human leukocyte elastase inhibitory activity is effective in the prevention and treatment of dermal aging and has perfected this invention.
- This invention is directed to a composition for prophylaxis and therapy of dermal aging which comprises a substance having human leukocyte elastase inhibitory activity as an active ingredient.
- the substance having human leukocyte elastase inhibitory activity which can be used as the active ingredient of this composition for prophylaxis and therapy of dermal aging may be any substance that has human leukocyte elastase inhibitory activity.
- the substance having human leukocyte elastase activity which can be used in this invention includes not only substances which are direct inhibitors of that activity but also substances which inhibit leukocyte elastase activity indirectly through suppression of leukocyte infiltration and inhibition of elastase production.
- any novel substance that may have human leukocyte elastase inhibitory activity can also be employed. The following is a partial listing of the preferred compounds in this category.
- WS7622A mono- or disulfate and pharmaceutically acceptable salts thereof are known substances which have the following physicochemical properties (JP Kokai H4-279600).
- WS7622A disulfate ester disodium salt (hereinafter sometimes referred to briefly as FR134043):
- Solubility Soluble: water, methanol
- WS7622A disulfate ester disodium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid at 110° C. for 20 hours and, then, concentrated to dryness under reduced pressure, and the residue was analyzed with Hitachi 835 Automatic Amino Acid Analyzer.
- amino acids standard solution Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used.
- Solubility Soluble: water, methanol
- WS7622A disulfate ester dipotassium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110° C. for 20 hours and, then, concentrated to dryness under reduced pressure, and the residue was analyzed with Hitachi 835 Automatic Amino Acid Analyzer.
- amino acids standard solution Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used.
- the pharmaceutically acceptable salt of WS7622A mono- or disulfate ester there can be mentioned the mono- or di-salts with inorganic or organic bases, such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt etc.), ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and pyridine salt, among others.
- alkali metal salts e.g. sodium salt, potassium salt, etc.
- alkaline earth metal salts e.g. calcium salt etc.
- ammonium salt ethanolamine salt
- triethylamine salt triethylamine salt
- dicyclohexylamine salt and pyridine salt among others.
- Substance WS7622A which is a starting compound for synthesis of said WS7622A mono- or disulfate ester also has human leukocyte elastase inhibitory activity and can, therefore, be used as a prophylactic and therapeutic agent for wrinkles.
- This substance is known to have the following physicochemical properties (JP Kokai H3-218387, JP Kokai H4-279600).
- Acidity-alkalinity acidic
- Negative ninhydrin reaction, Molisch reaction, Dragendorff reaction
- Soluble methanol, ethanol, n-butanol
- WS7622A (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 m) at 110° C. for 20 hours and concentrated to dryness under reduced pressure, and the residue was analyzed with Hitachi 835 Automatic Amino Acid Analyzer.
- amino acids standard solution Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used.
- the salt of Substance WS7622A includes salts with inorganic or organic bases, such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt etc. ), ammonium salt, ethanolamine salt, triethylamine salt and dicyclohexylamine salt, among others.
- alkali metal salts e.g. sodium salt, potassium salt, etc.
- alkaline earth metal salts e.g. calcium salt etc.
- ammonium salt ethanolamine salt
- triethylamine salt triethylamine salt and dicyclohexylamine salt, among others.
- Substances WS7622B, C and D and derivatives thereof (JP Kokai H3-218387) , all of which have human leukocyte elastase inhibitory activity as well can also be used as prophylactic and therapeutic agents for wrinkles.
- Substance WS7622A (as well as Substances WS7622B, C and D) can be produced by growing Streptomyces resistomycificus No. 7622, which strain has been deposited with National Institute of Bioscience and Human Technology, one of the international culture collections under Budapest Treaty, with the accession number of FERM BP-2306 assigned.
- R 1 represents a lower alkyl group having 1 or 2 substituents selected from among carboxy, esterified carboxy and di-lower alkylcarbamoyl; a phenyl (lower) alkyl group which may optionally have halogen, amino or nitro on the phenyl moiety thereof and carboxy or esterified carboxy on the alkyl moiety thereof; a halophenyl group; a morpholino group; or a morpholino (lower) alkyl group; R 2 and R 3 each represents a lower alkyl group; X represents— or —NH—;
- the compounds mentioned in the above paragraphs (2) ⁇ (4) are known compounds as described in JP Kokai H4-297446, for instance.
- the pharmaceutically acceptable salts of said compounds (2) ⁇ (3) there can be mentioned the respective salts with organic or inorganic bases, such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. calcium salts etc.), ammonium salts, ethanolamine salts, triethylamine salts, dicyclo-hexylamine salts, etc. , methanesulfonates, and organic or inorganic acid addition salts such as hydrochlorides, sulfates, nitrates, phosphates and so forth.
- organic or inorganic bases such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. calcium salts etc.), ammonium salts, ethanolamine salts, trieth
- lower means 1 ⁇ 6 carbon atoms unless otherwise specified.
- halogen there can be mentioned fluoro, chloro, bromo and iodo.
- the preferred “lower alkyl group” includes residues of straight-chain or branched-chain alkanes containing 1 ⁇ 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and hexyl, preferably those having 1 ⁇ 4 carbon atoms.
- the preferred “esterified carboxy” includes, among others, alkyl esters, i.e. alkoxycarbonyl groups such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), and phenyl (lower) alkyl esters, i.e. phenyl (lower) alkoxycarbonyl groups such as benzyloxycarbonyl etc., and benzoyl (lower) alkyl esters, i.e. benzoyl (lower) alkoxycarbonyl groups such as benzoylmethoxycarbonyl and so forth.
- alkyl esters i.e. alkoxycarbonyl groups such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl
- the preferred “lower alkylene group” includes but is not limited to methylene, ethylene, propylene and isopropylene.
- the preferred “di-lower-alkylcarbamoyl group” includes N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl, among others.
- Substance FR901451 having the following physicochemical properties and its pharmaceutically acceptable salt:
- Soluble water, methanol, dimethyl sulfoxide
- Substance FR901451 is known as the substance elaborated by Substance FR901451-producing strains of organisms belonging to the genus Flexibacter (e.g. WO93/02203). Flexibacter sp. No. 758, which is among such producer strains, has been deposited with National Institute of Bioscience and Human Technology, an international culture collection under Budapest Treaty, with the accession number of FERM BP-3420 assigned.
- the pharmaceutically acceptable salt of the above Substance FR901451 includes the same kinds of salts as mentioned for the pharmaceutically acceptable salts of the compounds (2) ⁇ (3).
- ⁇ 1-antitrypsin secretory leukocyte protease inhibitor
- SLP1 secretory leukocyte protease inhibitor
- urinastatin colchicine
- erythromycin clarithromycin
- ICI200 erythromycin
- ONO-8046 American Journal of Respiratory and Critical Care Medicine Vol. 153, P391-397
- anti-elastase antibodies and so forth.
- a substance having human leukocyte elastase inhibitory activity is efficacious and can be administered for the prevention and treatment of dermal aging in general. More particularly, it can be indicated for the prevention and treatment of decreases in moistfulness, sheen, smoothness, and tonus of the skin and even increased wrinkling, or the prevention and treatment of skin flaccidity.
- dermal aging are suspected to arise from morphological and functional changes of the organs and tissues making up the skin, and actually, thinning of the horny layer of the epidermis and loss of oxytalan fiber in the papillary layer of the corium are noted.
- said substances are efficacious for promoting neogenesis of oxytalan fiber in the region of dermal papillae and neogenesis of collagen fibrils in the dermis immediately beneath the epidermis, and for increasing the thickness of the epidermis, among others.
- substances having human leukocyte elastase inhibitory activity are efficacious in various skin diseases such as scleroderma, elephantiasis, scars, steroid-induced thinning of the skin, keloids, pressure sores, wounds, refractory ulcers, psoriasis, spots, freckles, senile plaques, rough skin and pityriasis.
- neutrophil leukocyte
- Each drug was applied in one location (a total of 5 locations) on the back (5 ⁇ 5 cm) of each dog.
- the drug was applied in a dosing volume of about 4 ⁇ L/cm 2 once daily (except on Saturdays, Sundays and holidays) for 3 months.
- H-E hematoxylin-eosin stain
- van Gieson's stain staining of collagen fiber
- Weigert's stain staining of elastin fiber
- Neogenesis of a thin layer of collagen fiber was found across the boundary between the epidermis and dermis in the case of FK706 ⁇ 0.2% (Dog No. 8807)
- composition for prophylaxis and therapy of dermal aging as provided by this invention is usually applied in the form of a preparation for external application (e.g. lotion, ointment, patch, liniment, aerosol, suspension, emulsion, etc.) or an external powder (e.g. an enzyme facial cleanser) but may also be used in the conventional pharmaceutical dosage forms such as powders, fine granules, granules, tablets, sugar-coated tablets, parenteral preparations, inhalants, microcapsules, capsules, suppositories, solutions, syrups and so on. Furthermore, it can be used in such formulations as facial cleansers, facial wash-off/emolient preparations, and bath preparations.
- a preparation for external application e.g. lotion, ointment, patch, liniment, aerosol, suspension, emulsion, etc.
- an external powder e.g. an enzyme facial cleanser
- it can be used in such formulations as facial cleansers, facial wash-
- a diluent or disintegrator e.g. sucrose, lactose, starch, crystalline cellulose, low-substitution-degree hydroxypropylcellulose, synthetic aluminum silicate, etc.
- a binder e.g. cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, etc.
- a coloring agent e.g. magnesium stearate
- a lubricant e.g. magnesium stearate
- compositions for prophylaxis and therapy of dermal aging depends on the species of substance used, symptoms and other factors but, generally speaking, the recommended dose of an external dosage form, in terms of the concentration of the substance having human leukocyte elastase inhibitory activity or a pharmaceutically acceptable salt thereof, can be judiciously selected from the range of about 0.001 ⁇ 20%, preferably about 0.01 ⁇ 10%.
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
A composition for prophylaxis and therapy of dermal aging which comprises a substance having human leukocyte elastase inhibitory activity as an active ingredient.
Description
- This invention relates to a composition for prophylaxis and therapy of dermal aging which comprises a substance having human leukocyte elastase inhibitory activity as an active ingredient.
- Aging of the skin is said to begin after the third decade of life. Obvious signs of aging include decreases in the moistness, gloss, smoothness, tonus, etc. of the skin and an increased number of wrinkles. These are suspected to result from the morphological and functional changes of the organs and tissues making up the skin. Thus, aging is accompanied by thinning of the epidermis and loss of oxytalan fiber in the papillary layer of the dermis.
- Dermal aging, epitomized by wrinkling of the skin, is a serious beauty problem for women but no satisfactory remedy has been available to this day.
- The present inventors discovered that a substance having human leukocyte elastase inhibitory activity is effective in the prevention and treatment of dermal aging and has perfected this invention.
- This invention is directed to a composition for prophylaxis and therapy of dermal aging which comprises a substance having human leukocyte elastase inhibitory activity as an active ingredient.
- The substance having human leukocyte elastase inhibitory activity which can be used as the active ingredient of this composition for prophylaxis and therapy of dermal aging may be any substance that has human leukocyte elastase inhibitory activity. Furthermore, the substance having human leukocyte elastase activity which can be used in this invention includes not only substances which are direct inhibitors of that activity but also substances which inhibit leukocyte elastase activity indirectly through suppression of leukocyte infiltration and inhibition of elastase production. Thus, while many substances having such activity are known, any novel substance that may have human leukocyte elastase inhibitory activity can also be employed. The following is a partial listing of the preferred compounds in this category. (1) WS7622A mono- or disulfate and pharmaceutically acceptable salts thereof; among these, WS7622A disulfate ester disodium salt and WS7622A disulfate ester dipotassium salt are known substances which have the following physicochemical properties (JP Kokai H4-279600).
- WS7622A disulfate ester disodium salt (hereinafter sometimes referred to briefly as FR134043):
- Description: Colorless crystals
- Solubility: Soluble: water, methanol
- Insoluble: chloroform, n-hexane
- Melting point: 257˜263° C. (decomp.) Optical rotation: [α]23 D+37.5° (c=1, methanol) Molecular formula: C47H61N9O19S2Na2 Elemental analysis: Calcd.: (for C47H61N9O19S2Na2.6H2O): C, 44.30; H, 5.77; N, 9.89; S, 5.03; Na, 3.61% Found: C, 44.98; H, 5.90; N, 10.06; S, 5.00; Na, 3.98% Molecular weight: FAB-MS m/z 1188 (M+Na)+
- Thin-Layer Chromatography:
TABLE 1 Stationary Developer phase solvent Rf Silica gel CHCl3—CH3OH—H2O 0.11 (Merck Art. 5715) (65:25:4) n-butanol-acetic 0.29 acid-water (4:2:1) Infrared absorption spectrum: υKBr max: 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1380, 1250, 1200, 1060, 1030, 940, 890 cm−1 1H Nuclear magnetic resonance spectrum: (400 MHz, D2O) δ 7.50 (1H, s) 7.27 (1H, s) 7.33-7.24 (3H, m) 6.94 (1H, q, J=7 Hz) 6.85 (2H, br d, J=8 Hz) 5.53 (1H, m) 5.37 (1H, m) 4.80 (1H, br s) 4.63-4.57 (2H, m) 4.53 (1H, m) 4.06 (1H, m) 3.99 (1H, d, J=10 Hz) 3.56 (1H, br d, J=14 Hz) 3.46 (1H, m) 2.97 (3H, s) 2.97-2.88 (2H, m) 2.72 (1H, m) 2.59 (1H, m) 2.51-2.38 (2H, m) 2.09-1.91 (4H, m) 1.82-1.60 (3H, m) 1.77 (3H, d, J=7 Hz) 1.50 (3H, d, J=6.5 Hz) 1.40 (1H, m) 1.11 (6H, d, J=7 Hz) 0.99 (3H, d, J=6.5 Hz) 0.97 (3H, d, J=6.5 Hz) 13C Nuclear magnetic resonance spectrum: (100 MHz, D2O) δ 183.6 (s) 177.9 (s) 177.7 (s) 174.8 (s) 173.8 (s) 173.3 (s) 172.4 (s) 167.8 (s) 161.5 (s) 145.5 (s) 144.9 (s) 139.6 (d) 139.0 (s) 137.0 (s) 136.0 (s) 132.3 (d)×2 131.0 (d)×2 129.6 (d) 127.4 (d) 125.9 (d) 77.4 (d) 75.1 (d) 63.8 (d) 62.7 (d) 59.1 (d) 55.9 (d) 54.9 (d) 51.9 (d) 41.9 (t) 37.2 (d) 36.9 (t) 34.1 (q) 32.3 (d) 31.9 (t) 31.8 (t) 31.2 (t) 27.5 (t) 23.7 (t) 21.7 (q) 21.4 (q)×2 21.3 (q) 21.1 (q) 15.5 (q) - Amino Acid Analysis:
- WS7622A disulfate ester disodium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid at 110° C. for 20 hours and, then, concentrated to dryness under reduced pressure, and the residue was analyzed with Hitachi 835 Automatic Amino Acid Analyzer. As the amino acids standard solution, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used.
- As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive components were detected.
-
- WS7622A disulfate ester dipotassium salt:
- Description: Colorless amorphous powders
- Solubility: Soluble: water, methanol
- Insoluble: chloroform, n-hexane
- Melting point: 230˜237° C. (decomp.) Optical rotation: [α]23 D+34° (c=1, methanol) Molecular formula: C47H61N9O19S2K2 Elemental analysis: Calcd.: (for C47H61N9O19S2K2.6H2O ): C, 43.21; H, 5.63; N, 9.65; S, 7.91; Na, 5.99% Found: C, 43.96; H, 5.44; N, 9.97; S, 5.09; Na, 4.49% Molecular weight: FAB-MS m/z 1236 (M+K)+
- Thin-Layer Chromatography:
TABLE 2 Stationary Developer phase solvent Rf Silica gel CHCl3—CH3OH—H2O 0.13 (Merck Art. 5715) Infrared absorption spectrum: υKBr max: 3360, 2960, 1735, 1660, 1640, 1530, 1500, 1405, 1380, 1250, 1200, 1050, 1030, 940, 890 cm−1 1H Nuclear magnetic resonance spectrum: (400 MHz, D2O) δ: 7.52 (1H, s) 7.28 (1H, s) 7.34-7.25 (3H, m) 6.96 (1H, q, J=7 Hz) 6.87 (2H, br d, J=8 Hz) 5.56 (1H, m) 5.40 (1H, m) 4.84 (1H, br s) 4.70-4.55 (3H, m) 4.10 (1H, m) 4.03 (1H, m) 3.60 (1H, br d, J=14 Hz) 3.50 (1H, m) 3.00 (3H, s) 3.00-2.85 (2H, m) 2.76 (1H, m) 2.62 (1H, m) 2.55-2.40 (2H, m) 2.12-1.95 (4H, m) 1.90-1.65 (3H, m) 1.79 (3H, d, J=7 Hz) 1.53 (3H, d, J=6.5 Hz) 1.45 (1H, m) 1.14 (6H, d, J=7 Hz) 1.02 (3H, d, J=6.5 Hz) 1.00 (3H, d, J=6.5 Hz) - Amino Acid Analysis:
- WS7622A disulfate ester dipotassium salt (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 ml) at 110° C. for 20 hours and, then, concentrated to dryness under reduced pressure, and the residue was analyzed with Hitachi 835 Automatic Amino Acid Analyzer. As the amino acids standard solution, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used.
- As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive components were detected.
-
- As the pharmaceutically acceptable salt of WS7622A mono- or disulfate ester, there can be mentioned the mono- or di-salts with inorganic or organic bases, such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt etc.), ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and pyridine salt, among others.
- Substance WS7622A which is a starting compound for synthesis of said WS7622A mono- or disulfate ester also has human leukocyte elastase inhibitory activity and can, therefore, be used as a prophylactic and therapeutic agent for wrinkles. This substance is known to have the following physicochemical properties (JP Kokai H3-218387, JP Kokai H4-279600).
- Physicochemical properties of Substance WS7622A:
- Description: colorless prisms
- Acidity-alkalinity: acidic
- Color reactions:
- Positive: cerium sulfate reaction, iodine vapor reaction, ferric chloride reaction
- Negative: ninhydrin reaction, Molisch reaction, Dragendorff reaction
- Solubility:
- Soluble: methanol, ethanol, n-butanol
- Slightly soluble: chloroform, acetone, ethyl acetate
- Insoluble: water, n-hexane
- Thin-layer chromatography (TLC):
- Chloroform-methanol (5:1, v/v)
- Rf 0.51
- Acetone-methanol (10:1)
- Rf 0.62
- (Kieselgel 60F254 silica gel plate, Merck)
- Melting point: 250˜252° C. (decomp.) Optical rotation: [α]23 D+36° (c=1, methanol) UV absorption spectrum: λMeOH max 287 nm (ε=3600) λMeOH—HC1 max 287 nm λMeOH—NaOH max 298 nm Molecular formula: C47H63N9O13 Elemental analysis: Calcd.: (for C47H63N9O13.2H2O): C, 56.56; H, 6.77; N, 12.63% Found: C, 56.65; H, 6.62; N, 12.27% Molecular weight: FAB-MS m/z 984 (M+Na)+Infrared absorption spectrum: υKBr max: 3400, 3300, 3060, 2980, 2940, 1735, 1710, 1690, 1670, 1660, 1640, 1540, 1520, 1470, 1380, 1330, 1300, 1260, 1220, 1200, 1160, 1130, 1090, 1000, 980, 940, 920 cm−1
1H Nuclear magnetic resonance spectrum: (400 MHz, CD3OD) δ: 7.22-7.09 (3H, m) 6.88-6.77 (3H, m) 6.74 (1H, s) 6.46 (1H, s) 5.46 (1H, m) 5.18 (1H, s) 4.85 (1H, s) 4.77 (1H, m) 4.65 (1H, m) 4.50 (1H, m) 3.96 (1H, m) 3.91 (1H, d, J=9 Hz) 3.60-3.47 (2H, m) 3.03 (1H, m) 2.90 (3H, s) 2.86 (1H, m) 2.59-2.49 (2H, m) 2.39 (1H, m) 2.29-2.16 (2H, m) 2.00 (1H, m) 1.84 (1H, m) 1.74 (3H, d, J=6 Hz) 1.72-1.53 (4H, m) 1.44 (3H, d, J=6 Hz) 1.12 (1H, m) 1.10 (6H, d, J=6 Hz) 0.99 (3H, d, J=6 Hz) 0.94 (3H, d, J=6 Hz) 13C Nuclear magnetic resonance spectrum: (100 MHz, CD3OD) δ 179.7 (s) 176.3 (s) 174.7 (s) 173.3 (s) 172.4 (s) 171.4 (s) 170.3 (s) 165.8 (s) 160.2 (s) 145.7 (s) 145.6 (s) 137.5 (s) 134.0 (d) 131.4 (s) 130.6 (d)×2 129.8 (s) 129.1 (d)×2 129.1 (s) 127.6 (d) 119.1 (d) 118.0 (d) 76.0 (d) 73.4 (d) 63.1 (d) 61.4 (d) 57.1 (d) 53.6 (d) 52.7 (d) 50.5 (d) 39.9 (t) 36.1 (t) 35.8 (d) 31.8 (q) 31.0 (t) 30.8 (d) 29.9 (t) 29.7 (t) 25.2 (t) 22.3 (t) 20.2 (q) 20.0 (q)×2 19.7 (q) 19.5 (q) 13.3 (q) - Amino Acid Analysis:
- WS7622A (1 mg) was hydrolyzed with 6 N-hydrochloric acid (1 m) at 110° C. for 20 hours and concentrated to dryness under reduced pressure, and the residue was analyzed with Hitachi 835 Automatic Amino Acid Analyzer. As the amino acids standard solution, Wako Pure Chemical's Type H (Wako Code 013-08391) and Type B (016-08641) were used.
- As a result, threonine, valine, phenylalanine, ornithine, ammonia and several unknown ninhydrin-positive components were detected.
-
- The salt of Substance WS7622A includes salts with inorganic or organic bases, such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt etc. ), ammonium salt, ethanolamine salt, triethylamine salt and dicyclohexylamine salt, among others.
- Substances WS7622B, C and D and derivatives thereof (JP Kokai H3-218387) , all of which have human leukocyte elastase inhibitory activity as well can also be used as prophylactic and therapeutic agents for wrinkles.
- The above-mentioned Substance WS7622A (as well as Substances WS7622B, C and D) can be produced by growingStreptomyces resistomycificus No. 7622, which strain has been deposited with National Institute of Bioscience and Human Technology, one of the international culture collections under Budapest Treaty, with the accession number of FERM BP-2306 assigned.
-
-
-
- (wherein R1˜R3 have the same meanings as defined above (2)).
- (4) 3 (RS)-[[4-(carboxymethylaminocarbonyl) phenyl-carbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane or its sodium salt (this sodium salt will sometimes be referred to briefly as FK706).
- The compounds mentioned in the above paragraphs (2)˜(4) are known compounds as described in JP Kokai H4-297446, for instance. As the pharmaceutically acceptable salts of said compounds (2)˜(3) , there can be mentioned the respective salts with organic or inorganic bases, such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. calcium salts etc.), ammonium salts, ethanolamine salts, triethylamine salts, dicyclo-hexylamine salts, etc. , methanesulfonates, and organic or inorganic acid addition salts such as hydrochlorides, sulfates, nitrates, phosphates and so forth.
- The preferred examples relevant to the various definitions given hereinbefore are now set forth in detail. The term “lower” means 1˜6 carbon atoms unless otherwise specified. As the preferred examples of “halogen”, there can be mentioned fluoro, chloro, bromo and iodo. The preferred “lower alkyl group” includes residues of straight-chain or branched-chain alkanes containing 1˜6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and hexyl, preferably those having 1˜4 carbon atoms. The preferred “esterified carboxy” includes, among others, alkyl esters, i.e. alkoxycarbonyl groups such as lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), and phenyl (lower) alkyl esters, i.e. phenyl (lower) alkoxycarbonyl groups such as benzyloxycarbonyl etc., and benzoyl (lower) alkyl esters, i.e. benzoyl (lower) alkoxycarbonyl groups such as benzoylmethoxycarbonyl and so forth.
- The preferred “lower alkylene group” includes but is not limited to methylene, ethylene, propylene and isopropylene. The preferred “di-lower-alkylcarbamoyl group” includes N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl, among others.
- (5) Substance FR901451 having the following physicochemical properties and its pharmaceutically acceptable salt:
- Description: white powders
- Color reactions:
- Positive: cerium sulfate, iodine vapor, Ehrlich, and ninhydrin reactions
- Negative: Molisch reaction
- Solubility:
- Soluble: water, methanol, dimethyl sulfoxide
- Hardly soluble: acetate
- Insoluble: ethyl acetate
- Melting point: 243˜245° C. (decomp.) Optical rotation: [α]23 D−15° (c=0.65, H2O) Ultraviolet absorption spectrum: λMeOH max nm(ε): 275 (4300), 281 (4500), 290 (3900) Molecular formula: C60H79N13O18 Elemental analysis: Calcd.: (for C60H79N13 O18.10H2O): C, 49.68; H, 6.88; N, 12.55 Found: C, 49.95; H, 6.28; N, 12.42 Molecular weight: FAB-MS m/z 1270 (M+H)+
- Thin-Layer Chromatography:
TABLE 3 Stationary Developer phase solvent Rf Silica gel CHCl3:MeOH:NH4OH 0.60 (Merck) (15:11:5) RP-18 70% aqueous 0.32 (Merck) methanol FT-IR spectrum: υKBr max: 3390, 3070, 2970, 2880, 1740, 1660, 1530, 1450, 1410, 1380, 1350, 1250, 1190, 1110, 1080, 1010, 750, 700, 670, 660, 620, 600 cm−1 1H Nuclear magnetic resonance spectrum: (400 MHz, D2O) δ: 7.70 (1H, d, J=7 Hz) 7.52 (1H, d, J=7.5 Hz) 7.44-7.23 (7H, m) 7.22 (1H, s) 5.59 (1H, q, J=7 Hz) 4.94 (1H, t, J=4.5 Hz) 4.85-4.74 (3H, m) 4.58 (1H, dd, J=6 Hz, 10 Hz) 4.45-4.35 (3H, m) 4.30 (1H, dd, J=4 Hz, 7 Hz) 4.07 (1H, m) 3.99 (1H, dd, J=10 Hz, 4.5 Hz) 3.66-3.50 (3H, m) 3.44-3.25 (4H, m) 3.16-2.93 (4H, m) 2.87 (1H, d, J=18 Hz) 2.80-2.68 (2H, m) 2.56-2.48 (2H, m) 2.08 (1H, dd, J=16 Hz, 4 Hz) 1.87-1.53 (9H, m) 1.43 (3H, d, J=7 Hz) 1.30 (3H, d, J=6.5 Hz) 1.45-1.17 (4H, m) 0.95 (3H, d, J=6 Hz) 0.84 (3H, d, J=6 Hz) 13C Nuclear magnetic resonance spectrum: (100 MHz, D2O) δ 177.2 (s) 130.0 (d)×2 56.0 (d) 31.4 (t) 176.5 (s) 129.8 (d)×2 54.1 (d) 28.8 (t) 174.6 (s) 128.5 (d) 53.8 (d) 26.6 (t) 174.2 (s) 127.8 (s) 53.2 (d) 25.1 (d) 174.0 (s) 125.5 (d) 53.1 (d) 23.2 (q) 173.2 (s) 123.2 (d) 52.9 (d) 23.2 (t) 173.0 (s) 120.9 (d) 52.8 (d) 23.1 (t) 172.8 (s) 118.7 (d) 49.5 (d) 20.8 (q) 172.6 (s) 113.1 (d) 48.6 (t) 19.4 (q) 172.5 (s) 108.8 (s) 40.1 (t) 18.3 (q) 172.1 (s) 73.3 (d) 39.6 (t) 171.7 (s) 69.7 (d) 39.4 (t) 171.4 (s) 64.3 (t) 38.9 (t) 170.3 (s) 62.1 (d) 35.3 (t) 137.2 (s) 60.9 (d) 34.8 (t) 136.0 (s) 57.1 (d) 31.7 (t) - The above Substance FR901451 is known as the substance elaborated by Substance FR901451-producing strains of organisms belonging to the genus Flexibacter (e.g. WO93/02203). Flexibacter sp. No. 758, which is among such producer strains, has been deposited with National Institute of Bioscience and Human Technology, an international culture collection under Budapest Treaty, with the accession number of FERM BP-3420 assigned.
- The pharmaceutically acceptable salt of the above Substance FR901451 includes the same kinds of salts as mentioned for the pharmaceutically acceptable salts of the compounds (2)˜(3).
- In addition to the foregoing substances, the following can be mentioned as examples of the substance having elastase inhibitory activity: α1-antitrypsin, SLP1 (secretory leukocyte protease inhibitor) [American Review of Respiratory Diease Vol. 147, 1993, P442-446], urinastatin, colchicine, erythromycin, clarithromycin, ICI200, 880, ONO-8046 [American Journal of Respiratory and Critical Care Medicine Vol. 153, P391-397], anti-elastase antibodies, and so forth.
- For the purposes of this invention, a substance having human leukocyte elastase inhibitory activity is efficacious and can be administered for the prevention and treatment of dermal aging in general. More particularly, it can be indicated for the prevention and treatment of decreases in moistfulness, sheen, smoothness, and tonus of the skin and even increased wrinkling, or the prevention and treatment of skin flaccidity. These signs of dermal aging are suspected to arise from morphological and functional changes of the organs and tissues making up the skin, and actually, thinning of the horny layer of the epidermis and loss of oxytalan fiber in the papillary layer of the corium are noted.
- The signs of dermal aging being as mentioned above, the efficacy of a substance having human leukocyte elastase inhibitory activity is particularly pronounced for the elimination or diminution of wrinkles or prevention of increased wrinkling, improvement of skin texture (fineness, handle) and amelioration of the shade of the skin (shadowy complexion).
- Furthermore, said substances are efficacious for promoting neogenesis of oxytalan fiber in the region of dermal papillae and neogenesis of collagen fibrils in the dermis immediately beneath the epidermis, and for increasing the thickness of the epidermis, among others.
- In addition, substances having human leukocyte elastase inhibitory activity are efficacious in various skin diseases such as scleroderma, elephantiasis, scars, steroid-induced thinning of the skin, keloids, pressure sores, wounds, refractory ulcers, psoriasis, spots, freckles, senile plaques, rough skin and pityriasis.
- The following is an example of experimentation relevance to this invention.
- Object of Experiment:
- The therapeutic efficacy of neutrophil (leukocyte) elastase inhibitors in “dermal aging” was evaluated in hairless dogs.
- Experimental Animals:
- Two adult (old) experimental hairless dogs constructed by cross-breeding of a Mexican hairless dog and a beagle dog were used. Old dogs presenting with age-associated fine “wrinkles”, not observed in young dogs, on the body surface were used as subject animals.
- No. 8807 (10 yr old, male)
- No. 8808 (10 yr old, female)
- Investigational Drugs:
- 1) FK706·0.2%
- 2) FK706·0.02%
- 3) FR134043·0.2%
- 4) FR134043·0.02%
- 5) Polyethylene glycol (PEG) (solvent control) (PEG was used as the solvent for drugs 1˜4)
- Administration:
- Each drug was applied in one location (a total of 5 locations) on the back (5×5 cm) of each dog. The drug was applied in a dosing volume of about 4 μL/cm2 once daily (except on Saturdays, Sundays and holidays) for 3 months.
- Evaluation Items:
- 1) Skin condition: Gross observation and observation with a video macroscope
- 2) Histology: Observation of histological changes in biopsy samples by H-E (hematoxylin-eosin) stain (general staining), van Gieson's stain (staining of collagen fiber) and Weigert's stain (staining of elastin fiber)
- 3) Skin thickness: Using H-E stained tissue samples, changes in thickness of the epidermis (excluding the horny layer) were studied (only the location treated with FK706 0.2%, which showed a marked improvement in skin condition, was evaluated)
- Results:
- 1) Skin Condition (Remission of Wrinkles)
- (Gross Observation)
- No. 8807: In the elimination or remission of wrinkles, the order of efficacy was FK706·0.1%>FK706·0.02%>FR134043·0.2%=FR134043·0.02%. This finding of remission was accompanied by improvements in skin texture (fineness, handle) and paralleled depigmentation of the skin (change to fair˜rosy skin).
- No. 8808: The order of efficacy was FK706·0.2%>FK706·0.02%>FR134043·0.2%=FR134043·0.02%.
- In neither dog was found a side effect.
- (Observation with a Video Macroscope)
- The findings were substantially identical to the results of gross observation.
- No. 8807: The order of efficacy was FK706·0.2%>FK706·0.02%>FR134043·0.2%>FR134043·0.02%
- No. 8808: The order of efficacy was FK706·0.2%=FK706·0.02%>FR134043·0.2%=FR134043·0.02%.
- 2) Histological Findings
- Van Gieson's Stain:
- Neogenesis of a thin layer of collagen fiber was found across the boundary between the epidermis and dermis in the case of FK706·0.2% (Dog No. 8807)
- Weigert's Strain:
- Growth of elastin fibrils (suspected to be oxytalan fiber which is said to disappear as increasing age) was found across the boundary between the epidermis and dermis (Dog No. 8807).
- 3) Evaluation of Skin Thickness
- The thickness of the epidermis was increased significantly (p<0.05 in both Dog 8807 and Dog 8808).
- No. 8807: 17.0±1.9 μm→26.8±5.9 μm (mean±SD)
- No. 8808: 24.6±3.6 μm→42.0±9.0 μm
- The composition for prophylaxis and therapy of dermal aging as provided by this invention is usually applied in the form of a preparation for external application (e.g. lotion, ointment, patch, liniment, aerosol, suspension, emulsion, etc.) or an external powder (e.g. an enzyme facial cleanser) but may also be used in the conventional pharmaceutical dosage forms such as powders, fine granules, granules, tablets, sugar-coated tablets, parenteral preparations, inhalants, microcapsules, capsules, suppositories, solutions, syrups and so on. Furthermore, it can be used in such formulations as facial cleansers, facial wash-off/emolient preparations, and bath preparations. Where necessary, a diluent or disintegrator (e.g. sucrose, lactose, starch, crystalline cellulose, low-substitution-degree hydroxypropylcellulose, synthetic aluminum silicate, etc.), a binder (e.g. cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, etc.), a coloring agent, a sweetener and a lubricant (e.g. magnesium stearate), among others, can be additionally dispersed in such formulations.
- The level of use of the composition for prophylaxis and therapy of dermal aging according to this invention depends on the species of substance used, symptoms and other factors but, generally speaking, the recommended dose of an external dosage form, in terms of the concentration of the substance having human leukocyte elastase inhibitory activity or a pharmaceutically acceptable salt thereof, can be judiciously selected from the range of about 0.001˜20%, preferably about 0.01˜10%.
Claims (10)
1. A composition for prophylaxis and therapy of dermal aging which comprises a substance having human leukocyte elastase inhibitory activity as an active ingredient.
2. A composition for prophylaxis and therapy of wrinkles which comprises WS7622A mono- or disulfate ester or a pharmaceutically acceptable salt thereof as an active ingredient.
3. A composition for prophylaxis and therapy of dermal aging which comprises a trifluoromethylketone derivative of the following formula or a pharmaceutically acceptable salt thereof as an active ingredient.
[wherein R1 represents a lower alkyl group having 1 or 2 substituents selected from among carboxy, esterified carboxy and di-lower alkylcarbamoyl; a phenyl (lower) alkyl group which may optionally have halogen, amino or nitro on the phenyl moiety thereof and carboxy or esterified carboxy on the alkyl moiety thereof; a halophenyl group; a morpholino group; or a morpholino (lower) alkyl group; R2 and R3 each represents a lower alkyl group; X represents— or —NH—;
4. A composition for prophylaxis and therapy of wrinkles which comprises a trifluoromethylketone derivative of the following formula or a pharmaceutically acceptable salt thereof as an active ingredient.
[wherein R1 represents a lower alkyl group having 1 or 2 substituents selected from among carboxy, esterified carboxy and di-lower alkylcarbamoyl; a phenyl (lower) alkyl group which may optionally have halogen, amino or nitro on the phenyl moiety thereof and carboxy or esterified carboxy on the alkyl moiety thereof; a halophenyl group; a morpholino group; or a morpholino (lower) alkyl group; R2 and R3 each represents a lower alkyl group; X represents— or —NH—;
5. The composition for prophylaxis and therapy of dermal aging as claimed in claim 1 wherein the substance having human leukocyte elastase inhibitory activity is Substance FR134043.
6. The composition for prophylaxis and therapy of wrinkles as claimed in claim 2 wherein the substance having human leukocyte elastase inhibitory activity is Substance FR134043.
7. The composition for prophylaxis and therapy of dermal aging as claimed in claim 1 wherein the substance having human leukocyte elastase inhibitory activity is Substance FK706.
8. The composition for prophylaxis and therapy of wrinkles as claimed in claim 4 wherein the substance having human leukocyte elastase inhibitory activity is Substance FK706.
9. A method for prophylaxis and therapy of dermal aging which comprises administering a substance having human leukocyte elastase inhibitory activity to a patient for the prevention or treatment of dermal aging.
10. Use of a substance having human leukocyte elastase inhibitory activity for the production of a pharmaceutical composition for the prophylaxis and therapy of dermal aging.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/405,701 US20030203853A1 (en) | 1998-02-24 | 2003-04-03 | Preventatives/remedies for skin aging |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4147998 | 1998-02-24 | ||
JP10/41479 | 1998-02-24 | ||
US09/622,053 US6610748B1 (en) | 1998-02-24 | 1999-02-19 | Preventives/remedies for skin aging |
US10/405,701 US20030203853A1 (en) | 1998-02-24 | 2003-04-03 | Preventatives/remedies for skin aging |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/000761 Division WO1999043352A1 (en) | 1998-02-24 | 1999-02-19 | Preventives/remedies for skin aging |
US09/622,053 Division US6610748B1 (en) | 1998-02-24 | 1999-02-19 | Preventives/remedies for skin aging |
Publications (1)
Publication Number | Publication Date |
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US20030203853A1 true US20030203853A1 (en) | 2003-10-30 |
Family
ID=12609497
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/622,053 Expired - Lifetime US6610748B1 (en) | 1998-02-24 | 1999-02-19 | Preventives/remedies for skin aging |
US10/405,701 Abandoned US20030203853A1 (en) | 1998-02-24 | 2003-04-03 | Preventatives/remedies for skin aging |
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Application Number | Title | Priority Date | Filing Date |
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US09/622,053 Expired - Lifetime US6610748B1 (en) | 1998-02-24 | 1999-02-19 | Preventives/remedies for skin aging |
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---|---|
US (2) | US6610748B1 (en) |
EP (1) | EP1057491B1 (en) |
JP (1) | JP4320791B2 (en) |
ES (1) | ES2421505T3 (en) |
WO (1) | WO1999043352A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109310585A (en) * | 2016-06-24 | 2019-02-05 | 宝丽化成工业有限公司 | For improving the skin preparations for extenal use of wrinkle |
CN111315350A (en) * | 2017-11-15 | 2020-06-19 | 宝丽化成工业有限公司 | Oily composition |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4610832B2 (en) * | 1999-10-26 | 2011-01-12 | 株式会社 ジャパン・ティッシュ・エンジニアリング | Wound contraction inhibitor |
JP2002293738A (en) * | 2001-03-30 | 2002-10-09 | Sansho Seiyaku Co Ltd | Cosmetic for improving photoaged skin |
JP7047997B2 (en) * | 2017-12-21 | 2022-04-05 | ポーラ化成工業株式会社 | Composition |
US20220168370A1 (en) * | 2019-04-01 | 2022-06-02 | Mycology Techno.Corp. | Elastase activity inhibitor, elastase activity inhibiting topical agent, and elastase activity inhibiting food and beverage composition |
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- 1999-02-19 US US09/622,053 patent/US6610748B1/en not_active Expired - Lifetime
- 1999-02-19 EP EP99905256.6A patent/EP1057491B1/en not_active Expired - Lifetime
- 1999-02-19 WO PCT/JP1999/000761 patent/WO1999043352A1/en active Application Filing
- 1999-02-19 JP JP54338999A patent/JP4320791B2/en not_active Expired - Lifetime
- 1999-02-19 ES ES99905256T patent/ES2421505T3/en not_active Expired - Lifetime
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CN109310585A (en) * | 2016-06-24 | 2019-02-05 | 宝丽化成工业有限公司 | For improving the skin preparations for extenal use of wrinkle |
EP3476381A4 (en) * | 2016-06-24 | 2020-01-01 | Pola Chemical Industries Inc. | External preparation for skin for wrinkle improvement |
IL274153A (en) * | 2016-06-24 | 2020-06-30 | Pola Chem Ind Inc | External preparation for skin for wrinkle improvement |
TWI720214B (en) * | 2016-06-24 | 2021-03-01 | 日商寶麗化成工業股份有限公司 | External skin agent for wrinkle improvement |
TWI734647B (en) * | 2016-06-24 | 2021-07-21 | 日商寶麗化成工業股份有限公司 | External skin agent for wrinkle improvement |
CN113693965A (en) * | 2016-06-24 | 2021-11-26 | 宝丽化成工业有限公司 | External preparation for skin for improving wrinkles |
AU2017282393B2 (en) * | 2016-06-24 | 2022-06-02 | Pola Chemical Industries, Inc. | External preparation for skin for wrinkle improvement |
EP4008304A3 (en) * | 2016-06-24 | 2022-07-20 | Pola Chemical Industries Inc. | External preparation for skin for wrinkle improvement |
US11413224B2 (en) | 2016-06-24 | 2022-08-16 | Pola Chemical Industries, Inc. | External preparation for skin for wrinkle improvement |
CN111315350A (en) * | 2017-11-15 | 2020-06-19 | 宝丽化成工业有限公司 | Oily composition |
Also Published As
Publication number | Publication date |
---|---|
US6610748B1 (en) | 2003-08-26 |
JP4320791B2 (en) | 2009-08-26 |
EP1057491A1 (en) | 2000-12-06 |
ES2421505T3 (en) | 2013-09-03 |
EP1057491A4 (en) | 2006-04-12 |
EP1057491B1 (en) | 2013-06-19 |
WO1999043352A1 (en) | 1999-09-02 |
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