Information
-
Patent Application
-
20040122103
-
Publication Number
20040122103
-
Date Filed
December 09, 200320 years ago
-
Date Published
June 24, 200420 years ago
-
Inventors
-
Original Assignees
-
CPC
-
US Classifications
-
International Classifications
Abstract
The present invention relates to a composition for external application, a humectant and a skin barrier function reinforcing agent, each containing a diamide derivative represented by the following formula (1):
1
Description
TECHNICAL FIELD
[0001] The present invention relates to compounds capable of maintaining normal barrier functions of the horny layer of the skin and improving its water retaining ability, thereby exhibiting skin roughness lessening effects and the like, and compositions for external application containing these compounds.
BACKGROUND ART
[0002] When the water retaining ability or barrier functions of the horny layer are weakened by some internal or external reasons, the skin suffers from various troubles accelerating skin roughness or aging. Lowering in the water retaining ability and barrier functions of the horny layer can also be recognized in the roughened skin resulting from various skin diseases such as atopic dermatitis, psoriasis or xeroderma. Therefore, the maintenance • reinforcement of the water retaining ability and barrier functions of the horny layer are highly important for our healthy daily life.
[0003] With the foregoing in view, the present applicants found, as a dermatologic preparation for external application having effects of basically improving (maintaining, reinforcing) the barrier functions of the horny layer, dermatologic preparations for external application containing amide derivatives represented by the below-described formula (2) and applied for a patent (Japanese Patent Laid-Open No. Hei 4-12825).
2
[0004] (wherein, Ra represents a linear or branched, saturated or unsaturated C10-40 hydrocarbon group, Rb represents a linear or branched, divalent C3-39 hydrocarbon group, and Rc represents a hydrogen atom, a linear or branched, saturated or unsaturated C10-40 hydrocarbon group or an acyl group)
[0005] Although such amide derivatives bring about excellent effects as described above, their solubility in a base ingredient or stability therewith is not always sufficient. There is therefore a room left for improvement in miscibility or mixing stability of the derivative to be incorporated in a dermatologic preparation for external application. These amide derivatives are accompanied with another problem that necessity of multi-stage reaction upon preparation inevitably leads to a rise in the production cost.
[0006] An object of the present invention is to provide a composition for external application which is capable of basically improving the water retaining ability and barrier functions of the horny layer, excellent in miscibility and mixing stability, and available efficiently at a low cost.
DISCLOSURE OF THE INVENTION
[0007] The present inventors have carried out a further investigation on amide derivatives. As a result, it has been found that diamide derivatives represented by the below-described formula (1) are effective for reinforcing the water retaining ability of the horny layer and improving the barrier functions of it and at the same time, have excellent miscibility and mixing stability so that they are useful as compositions for external application having preventive • remedial effects for skin troubles such as chapping, and hair protective effects.
[0008] In the present invention, there are thus provided compositions for external application, each containing a diamide derivative represented by the following formula (1):
3
[0009] (wherein, R1a and R1b are the same or different and each represents a C1-23 hydrocarbon group, R2a and R2b are the same or different and each represents a divalent C1-6 hydrocarbon group, R3s are the same or different and each represents a divalent C2-6 hydrocarbon group and n stands for 1 to 100); compositions for external application, each containing said diamide derivative and an intercellular lipid component of the horny layer; and humectants and skin barrier function reinforcing agents each having the diamide derivative as an effective ingredient.
[0010] In the present invention, there are also provided a method for reinforcing the water retaining ability of the horny layer and a method for reinforcing the skin barrier functions, each comprising applying an effective amount of said diamide derivative to the skin.
[0011] In the present invention, there is also provided a method for relieving excessive hair dryness or improving the touch feel of the hair, which comprising applying an effective amount of said diamide derivative to the hair.
[0012] In the present invention, there is also provided the use of said diamide derivative for the preparation of compositions for external application.
[0013] In the present invention, there is also provided a diamide derivative represented by the following formula (1′):
4
[0014] (wherein, R1a and R1b are the same or different and each represents a branched C4-23 hydrocarbon group, R2a and R2b are the same or different and each represents a divalent C1-6 hydrocarbon group, R3s are the same or different and each represents a divalent C2-6 hydrocarbon group and n stands for 1 to 100).
BEST MODE FOR CARRYING OUT THE INVENTION
[0015] In the diamide derivative (1) of the present invention, as the C1-23 hydrocarbon group represented by R1a and R1b, preferred are linear or branched C5-17 alkyl or alkenyl groups, with the case wherein R1a and R1b represent the same group being more preferred. Particularly preferred examples of the hydrocarbon group include pentyl, heptyl, nonyl, undecyl, tridecyl, pentadecyl, heptadecyl, 1-ethylheptyl, 2,4,4-trimethylpentyl, 1-heptyldecyl, isoheptadecyl, methyl-branched isoheptadecyl, 8-heptadecenyl and 8,11-heptadecadienyl groups.
[0016] The compound represented by the formula (1′) wherein R1a and R1b each represents a branched hydrocarbon group having at least 4 carbon atoms is a novel one.
[0017] As the divalent C1-6 hydrocarbon group represented by R2a and R2b, linear or branched C2-6 alkylene groups are preferred, with the case wherein R2a and R2b represent the same group being more preferred. Particularly preferred examples of the divalent hydrocarbon group include ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1-methylethylene and 2-methylethylene groups, of which 1-methylethylene and 2-methylethylene groups are more preferred.
[0018] As the divalent C2-6 hydrocarbon group represented by R3, linear or branched C2-6 alkylene groups are preferred. Of these, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1-methylethylene, 2-methylethylene and 2,2-dimethyltrimethylene groups are preferred, with ethylene, 1-methylethylene and 2-methylethylene groups are especially preferred.
[0019] Preferably, n stands for 1 to 50, more preferably 1 to 10, with the number less than 4 being especially preferred.
[0020] As the diamide derivative (1), compounds of the formula (1) having, in combination, the above-exemplified preferred groups as R1a, R1b, R2a, R2b, R3 and n, respectively are preferred. Among them, compounds wherein some or all of the hydrocarbon groups as R1a, R1b, R2a, R2b and R3 are branched are preferred to compounds whose hydrocarbon groups are all linear, because the former ones have a low melting point and therefore have excellent miscibility.
[0021] The diamide derivatives (1) to be used for the composition for external application according to the present invention can be prepared by a known amide synthesizing process. It can be prepared efficiently at a low cost, for example, by the below-described process.
5
[0022] (wherein, R1a, R1b, R2a, R2b, R3 and n have the same meanings as described above).
[0023] The target diamide derivative (1) is available efficiently by reacting the corresponding diamine (3) with a carboxylic acid (4a) and/or (4b) or reaction derivative (ester, acid halide, acid anhydride or the like) thereof.
[0024] The reaction is preferably effected at room temperature to 300° C. under reduced pressure of 1.3 Pa to normal pressure in the presence or absence of a dehydrating agent such as dicyclohexyl carbodiimide or a base, for example, an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkaline earth metal carbonate such as calcium carbonate, an alkali metal alcoholate such as sodium methoxide, sodium ethoxide or potassium-tert-butoxide, or a tertiary amine such as triethylamine or pyridine. Upon this reaction, the carboxylic acid (4a) and/or (4b) or reaction derivative thereof is preferably used in an excess amount, that is, at least 2 equivalents relative to the diamine (3). Reaction while removing the resulting water out of the system is preferred, because it permits rapid progress of the reaction. The diamide derivative (1) thus available can be purified by the known method such as washing with water, liquid-liquid extraction, column chromatography, distillation, crystallization, recrystallization or pulverization.
[0025] Examples of the diamine (3) include polyoxyethylene diamine, polyoxypropylene diamine and polyoxyethyleneoxypropylene diamine, more specifically, polyoxyalkylene diamines “JEFFAMINE” (trade marks product of HUNTSMAN CORPORATION).
[0026] The diamide derivatives (1) of the present invention thus available have effects of maintaining and improving the barrier functions of the skin horny layer and improving water retaining ability of the horny layer so that they are useful as humectants or skin barrier function reinforcing agents. Compositions for external application containing them are effective for remedial effects for skin trouble such as chapping.
[0027] In the present invention, use in combination with a water soluble humectant selected from polyhydric alcohols, organic acids or salts thereof, or derivatives thereof and plant extracts makes it possible to synergistically heighten the water retaining ability of the horny layer.
[0028] Examples of the polyhydric alcohol include polyglycerins such as glycerin, diglycerin, triglycerin and tetraglycerin, ethylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, propylene glycol, dipropylene glycol, polyethylene glycol, 1,3-propanediol, glucose, maltose, maltitol, sucrose, fructose, xylitol, sorbitol, maltotriose, threitol, erythritol, starch degraded and reduced alcohol, sorbitol, polyoxyalkylene alkyl glucosides. Of these, glycerin, 1,3-butylene glycol, propylene glycol and dipropylene glycol are preferred.
[0029] Two or more of these polyhydric alcohols may be used in combination. When they are incorporated in the composition of the present invention for external application in an amount ranging from 0.001 to 50 wt. % (which will hereinafter be called “%”, simply), preferably from 0.01 to 40%, especially from 0.1 to 30%, the water retaining ability of the horny layer can be heightened synergistically.
[0030] Examples of the organic acid and organic acid derivatives include C2-28 oxycarboxylic acids such as glycolic acid, lactic acid, citric acid and 2-hydroxyoctanoic acid, C2-12 dicarboxylic acids such as succinic acid, fumaric acid, maleic acid, malonic acid and 1,3-propanedicarboxylic acid, amino acids and derivatives thereof such as aspartic acid, asparagine, glycine, glutamic acid, glutamine, γ-aminobutyric acid, arginine, cysteine and alanine; dicarboxylic monoesters such as octyl succinate and methyl maleate; nicotinic acid or salts thereof, or derivatives thereof such as nicotinic acid, methyl nicotinate, ethyl nicotinate, benzyl nicotinate, nicotinamide, tocopherol nicotinate, quinolinic acid, pyridine-3,5-dicarboxylic acid, nicotinamide adenine dinucleotide phosphate (NADP), nicotinic acid mononucleotide, nicotinyl alcohol and nicotinyl alcohol tartrate; and sterine derivatives represented by the following formula (5):
6
[0031] [wherein, R4 represents —(CH2)1— (1 stands for 2 to 10), —CH2—CH— or —CH—CH2— (in which R6 represents a linear or
7
[0032] branched C6-20 alkyl or alkenyl group), and R5 represents natural sterine or a residue obtained by removing a hydroxyl group proton from the hydrogenated product of the natural sterine].
[0033] As the sterine derivative, those of the formula (5) wherein 1 stands for 2 to 5, R6 represents hexadecenyl or octadecenyl and R5 represents cholesteryl or sitosteryl are preferred.
[0034] As the organic acid or organic acid derivative, preferred are α-hydroxycarboxylic acid, amino acid and nicotinic acid and derivatives thereof, with glycolic acid, lactic acid, citric acid, succinic acid, aspartic acid, glycine, arginine, nicotinamide, tocopherol nicotinate and glycine betaine being especially preferred.
[0035] Examples of the salt of the organic acid include potassium salt, magnesium salt, calcium salt, aluminum salt and basic amino acid salts of lactic acid, citric acid and succinic acid. When the organic acid has a basic group, examples include acid addition salts of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
[0036] At least two of these organic acids or salts thereof, or derivatives thereof may be used in combination. They are preferably incorporated in the invention composition for external application in an amount of 0.0001 to 10%, especially 0.001 to 5%.
[0037] As the plant extract, those described in Japanese Patent Laid-Open No. Hei 9-165313 can be mentioned as examples. Of these, especially preferred are extracts, steam distillates or compressed products of eucalyptus, hops, ginger, balloonflower, GANPIRUNOKI, wild rose, angelica, lily, adlay, cattail, loquat, gardenia, ginseng, soapwort, birch, hydrangea, cloves, safflower, burnet, iris or Sophora flavewscens. As an extracting solvent, water, ethanol, 1,3-butylene glycol or the like is usable.
[0038] Two or more of these plant extracts may be used in combination. They are preferably incorporated in the composition of the present invention in an amount of 0.0001 to 10%, especially 0.0001 to 5% in terms of a dry solid content.
[0039] In the present invention, use in combination of an intercellular lipid component of the horny layer selected from ceramides, pseudoceramides, sphingoglycolipids, sphingophospholipids, sphingosines and derivatives thereof, sphinganines and derivatives thereof, higher fatty acids, cholesterols and derivatives thereof makes it possible to synergistically heighten the barrier functions of the horny layer.
[0040] The ceramides include natural ceramides extracted from the brain or skin, followed by purification and synthetic ceramides synthesized by the microbiological or chemical method.
[0041] Examples of the natural ceramide include ceramides of Types I to VII, N-oleoyl-sphingosine, N-(12-hydroxyoctadecanoyl)sphingosine, N-(16-hydroxyhexadecanoyl)sphingosine and bovine brain ceramide.
[0042] As the synthesizing method of a synthetic ceramide, that described, for example, in Japanese Patent Laid-Open No. Sho 59-7118, Japanese Patent Laid-Open No. Hei 4-342553 or WO93/22281 can be employed.
[0043] Pseudoceramides can be prepared in accordance with the method described, for example, in Japanese Patent Laid-Open No. Sho 62-228048 or Japanese Patent Laid-Open No. Sho 63-216852. Particularly preferred examples of the pseudoceramide include compounds represented by the following formula (6):
8
[0044] (wherein, R7 represents a C9-17 alkyl group and R8 represents a C10-18 alkyl group)
[0045] Similar to the above-described ceramides, sphingoglycolipids and sphingophospholipids include natural and synthetic ones. Examples of the sphingoglycolipids include those having, as a constituent sugar, glucose, mannose, galactose, glucuronic acid and glucosamine. They also include selebroside and sulfate esters thereof. As the sphingophospholipids, sphingomyelin can be exemplified.
[0046] As the sphingosines preferably used in combination, as well as ceramides, pseudoceramides, sphingoglycolipids and sphingophospholipids, preferred are sphingosines disclosed in Japanese Patent Laid-Open No. Hei 5-85924, compounds disclosed in Japanese Patent Laid-Open No. Hei 6-271446 and represented by the formula (7), compounds disclosed in Japanese Patent Laid-Open No. Hei 5-194185 and represented by the formula (8).
[0047] Examples of the sphingosines disclosed in Japanese Patent Laid-Open No. Hei 5-85924 include sphingosine (sphingenine), dihydrosphingosine (sphinganine), phytosphingosine, dehydrosphingosine, dehydrophytosphingosine, and sphingadienine and N-methyl derivatives or N,N-dimethyl derivatives thereof. The hydrocarbon group of these compounds preferably has 12 to 24 carbon atoms and it may be either linear or branched, and either saturated or unsaturated.
[0048] The compound (7) disclosed in Japanese Patent Laid-Open No. Hei 6-271446 is represented by the following formula:
9
[0049] (wherein, R9 represents a C1-40 hydrocarbon group which may have a hydroxyl group, Z represents —CH2OH, —CO2H or
10
[0050] and W represents —NH2, —NHCH3, —N(CH3)2 or —N+(CH3)3).
[0051] The compound (8) disclosed in Japanese Patent Laid-Open No. Hei 5-194185 is represented by the following formula:
11
[0052] (wherein, R10 represents a linear, branched or cyclic, saturated or unsaturated C4-40 hydrocarbon group, R11, R12, R13, R14 and R15 each independently represents a hydrogen atom or a C1-10 hydrocarbon group which may be substituted by at least one hydroxyl group).
[0053] As the higher fatty acid, those having 12 or more carbon atoms are preferred, with those having 12 to 24 carbon atoms being especially preferred. Specific examples include myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid and behenic acid. Monoglycerides, diglycerides or triglycerides rich in such a higher fatty acid may be incorporated.
[0054] As the cholesterol ester, those composed of a higher fatty acid having 12 or more carbon atoms, especially 12 to 24 carbon atoms are preferred. Specific examples include cholesteryl palmitate, cholesteryl isostearate, di(cholesterol, 2-octyldodecyl) N-lauroyl-L-glutamate, lanoline fatty acid cholesterol and macadamia nut oil fatty acid cholesterol.
[0055] Two or more of these intercellular lipid components of the horny layer may be used in combination. They may be incorporated in the composition of the present invention preferably in an amount of 0.001 to 20%, especially 0.005 to 10%.
[0056] The content of the diamide derivative (1) in the composition of the present invention is preferably 0.001 to 50% of the whole composition when the composition is an emulsion type dermatologic preparation for topical application. It is preferably 0.01 to 50% of the whole composition when the composition is an oily type dermatologic external preparation containing a liquid hydrocarbon such as squalane as a base ingredient. In either case, addition of it in an amount of 0.01 to 20% is especially preferred. Particularly for the prevention or remedy of skin roughness, addition of it in an amount of 0.1 to 20% is preferred.
[0057] The composition for external application according to the present invention can be classified roughly, from the viewpoint of its type of usage, into a medicinal dermatologic external preparation and a cosmetic composition. It is preferred to use as a cosmetic composition, in particular as a cosmetics for skin.
[0058] As the medicinal dermatologic external preparation, various ointments containing a pharmaceutically effective ingredient can be mentioned by way of example. As the ointment, either one of an ointment having an oily base or a water-in-oil or an ointment having an oil-in-water emulsion base can be used. Examples of the oily base include vegetable oils, animal oils, synthetic oils, fatty acids, natural and synthetic glycerides and the like. As the pharmaceutically effective ingredient, an analgesic anti-inflammatory agent, antipruritic, disinfectant antiseptic, astringent, skin softening agent, hormone or the like can be used, for example, as needed.
[0059] When used as a cosmetic composition (including skin cosmetic composition and hair cosmetic composition), on the other hand, generally-employed cosmetic ingredients such as oily ingredient, surfactant, humectant, ultraviolet absorber, whitening agent, wrinkle remedy, alcohol, chelating agent, pH regulator, antiseptic, thickener, colorant and perfume can be added in any combination to the diamide derivative (1) which is an essential ingredient.
[0060] As a cosmetic composition, it is possible to use it in various forms such as water-in-oil or oil-in-water emulsified cosmetic composition, cream, milky lotion, skin lotion, oily cosmetic composition, lip stick, foundation, bath agent, skin cleanser, nail care agent, and hair cosmetic compositions. Specific examples of the hair cosmetic compositions include hair tonic, hair dressing, hair rinse, hair treatment, hair conditioner, hair styling agent, shampoo, baldness remedy and hair growth accelerator.
[0061] In the medicinal dermatologic external composition or skin cosmetic composition among the compositions for external application according to the present invention, surfactants such as anionic surfactants, cationic surfactants, nonionic surfactants and amphoteric surfactants can be incorporated. Of these, nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, fatty acid monoglycerides and glyceryl ether are preferred. The surfactant is preferably added in an amount of 0.01 to 20%, especially 0.1 to 10%, based on the composition.
[0062] When the composition of the present invention is used as a hair cosmetic composition, the diamide derivative (1) is preferably added in an amount of 0.001 to 5% for shampoo or the like, 0.1 to 20% for rinse, treatment, conditioner, styling agent or the like, and 0.01 to 5% for hair liquid, hair tonic or the like.
[0063] In the hair cosmetic composition, surfactants such as anionic surfactants, cationic surfactants, nonionic surfactants and amphoteric surfactants and ingredients ordinarily employed for hair cosmetic compositions can be incorporated. When the hair cosmetic composition is a shampoo, an anionic surfactant such as alkyl ether sulfate, alkyl sulfate or olefin sulfonate salt can be incorporated as a main surfactant. Its content is preferably 5 to 30% in the composition, with 10 to 20% being especially preferred.
[0064] When the cosmetic composition of the present invention is a hair rinse, conditioner, hair treatment or hair styling agent, a cationic surfactant such as mono- or di-(longer chain)alkyl quaternary ammonium salt, a nonionic surfactant such as polyoxyethylene alkyl or alkenyl ether, or an oil or fat such as liquid paraffin can be incorporated in order to impart the hair with good touch feel. The cationic and nonionic surfactants are preferably added in an amount of 0.1 to 50%, especially 0.5 to 20% in the composition.
[0065] When the hair cosmetic composition is a hair liquid, hair tonic or the like, a nonionic surfactant such as polyoxyethylene can be incorporated in it. The nonionic surfactant is preferably added in an amount of 0.01 to 20%, especially 0.1 to 5% in the whole composition.
Preparation Example 1
[0066] Preparation of Compound (A)
12
[0067] In a flask equipped with a stirrer, a nitrogen inlet tube and a distillation apparatus, 317 g of caprylic acid (“LUNAC 8-98(E)”, product of Kao Corp.) was charged, followed by dropwise addition of 228 g of “JEFFAMINE D-230” (product of Huntsman Corp.) over 2.5 hours at 220° C. under stirring in a nitrogen gas stream. Under the same conditions, the reaction mixture was matured for 5 hours. The dropwise addition and maturation were conducted under a nitrogen gas stream, made it possible to conduct them while distilling off the water byproduced. After completion of the reaction, the reaction mixture was subjected to molecular distillation (160 to 210° C., 0.5 Pa), whereby 262 g of the title compound (A) was obtained. The resulting Compound (A) has physical properties as follows:
[0068] Colorless oil
[0069]
1
H-NMR (CDCl3, δ): 0.80-1.00(m), 1.00-1.50(m), 1.50-1.80(m), 2.13(t,J=7.5 Hz), 3.00-3.75(m), 4.00-4.30(m), 5.60-6.10(m).
Preparation Examples 2 to 11
[0070] In a similar manner to Preparation Example 1 except for the use of the compounds shown in Table 1 instead of Diamine (3) and Carboxylic acid (4a) or (4b), the below-described Compounds (B)-(k) were prepared. The physical properties of each of the diamide derivatives are also shown in Table 1 and Table 2.
131TABLE 1
|
|
DiamideCarboxylic acid
derivative (1)Diamine (3)(4a or 4b)Physical propertices
|
|
Prep.Compound (B)JEFFAMINE D-230Lauric acidWhite solid, melting point: 74° C.
EX. 21H-NMR(CDCl3, δ): 0.80-1.00(m), 1.00-
1.50(m), 1.50-1.80(m), 2.13(t, J=7.5Hz),
3.00-3.75(m), 4.00-4.30(m), 5.60-6.10(m)
Prep.Compound (C)JEFFAMINE D-2302-EthylhexanoicColorless oil
Ex. 3acid1H-NMR(CDCl3, δ): 0.80-10.5(m), 1.05-
1.75(m), 1.75-2.20(m), 3.30-3.75(m),
4.10-4.30(m), 5.50-6.00(m).
Prep.Compound (D)JEFFAMINE D-2303,5,5-Colorless oil
Ex. 4Trimethylhexanoic1H-NMR(CDCl3, δ): 0.88(s),
acid0.94(d, J=6.2Hz), 1.00-1.35(m), 1.85-
2.25(m), 3.30-3.70(m), 4.00-4.30(m),
5.50-6.20(m).
Prep.Compound (E)JEFFAMINE XFJ-511Octanoic acidColorless oil
Ex. 5(polyoxyethylene-1H-NMR (CDCl3, δ): 0.75-1.00(m), 1.00-
oxypropylene1.45(m), 1.45-1.75(m), 2.11(t, J=7.6Hz),
diamine, product of3.35-3.75(m) 3.42(d, J=4.3Hz), 4.00-
HUNTSMAN CORP)4.30(m), 5.60-6.30(m).
Prep.Compound (F)JEFFAMINE XFJ-511Lauric acidWhite solid, Melting point: 61° C.
Ex. 61H-NMR (CDCl3, δ): 0.75-1.00(m), 1.00-
1.45(m), 1.45-1.75(m), 2.14(t, J=7.6Hz),
3.40-3.70(m), 3.42(d, J=4.3Hz), 4.00-
4.30(m), 5.60-6.20(m).
Prep.Compound (G)JEFFAMINE XFJ-5112-EthylhexanoicColorless oil
Ex. 7acid1H-NMR (CDCl3, δ): 0.75-1.00(m), 1.00-
1.75(m), 1.75-2.00(m), 3.40-3.70(m),
3.40(d, J=4.4Hz), 4.05-4.35(m), 5.50-
6.20(m).
Prep.Compound (H)JEFFAMINE XFJ-5113,5,5-Colorless oil
Ex. 8Trimethylhexanoic1H-NMR(CDCl3, δ): 0.87(s),
acid0.93(d, J=6.4Hz), 1.00-1.35(m), 1.80-
2.25(m), 3.42(d, J=4.3Hz), 3.50-3.70(m),
4.00-4.30(m), 5.55-6.25(m).
|
[0071]
2
TABLE 2
|
|
|
Diamide
Carboxylic acid
|
derivative (1)
Diamine (3)
(4a or 4b)
Physical properties
|
|
|
Prep.
Compound (I)
JEFFAMINE EDR-
Lauric acid
White solid, melting point: 116° C.
|
Ex. 9
148 (polyoxyethylene
1
H-NMR(CDCl3, δ): 0.85(t, J=6.4H, 6H),
|
diamine; product of
1.10-1.40(m, 32H), 1.50-1.70(m, 4H),
|
HUNTSMAN CORP)
2.15(t, J=7.6Hz, 4H), 3.45(t, J=5.3Hz, 4H),
|
3.50-3.65(m, 4H), 3.59(s, 4H), 5.80-6.00(m, 2H).
|
Prep.
Compound (J)
JEFFAMINE EDR-
2-Ethylhexanoic
White solid, melting point: 91° C.
|
Ex. 10
148
acid
1
H-NMR(CDCl3, δ): 0.75-1.05(m, 12H),
|
1.10-1.75(m, 16H), 1.75-2.05(m, 2H), 3.40-3.65(m, 8H),
|
3.59(s, 4H), 5.80-6.00(m, 2H)
|
Prep.
Compound (K)
JEFFAMINE EDR-
3,5,5-
Colorless oil
|
Ex. 11
148
Trimethylhexanoic
1
H-NMR(CDCl3, δ): 0.87(s, 12H),
|
acid
0.93(d, J=6.3Hz, 6H),
|
1.06(dd, J=6.1, 14.0Hz, 2H),
|
1.21(dd, J=3.6, 14.0Hz, 2H), 1.90(dd, J=7.5,
|
12.2Hz, 2H), 1.95-2.15(m, 2H),
|
2.17(dd, J=5.1H, 14.0Hz, 2H), 3.40-3.65(m, 8H),
|
3.58(s, 4H), 5.85-6.00(m, 2H)
|
|
[0072] Test 1
[0073] Compositions for external application according to the present invention (invention products) containing the diamide derivatives prepared in Preparation Examples 1 to 11 and having the compositions as shown in Tables 3 to 5 were prepared and their percutaneous water transpiration amount and percutaneous absorption amount were measured and evaluated by the methods described below.
[0074] (Testing Method)
[0075] Male Wister rats were raised using only feed free of essential fatty acids. Those rats showing symptoms of essential fatty acid deficiency were used for the test. After the back of each rat suffering from the essential fatty acid deficiency was shaved thoroughly, the composition for external application was applied to the shaved part once a day for 12 days. A group consisting of five rats was tested for each composition to be evaluated. Three days after completion of the application, the below-described items of the compositions were measured and evaluated.
[0076] (1) Percutaneous Water Transpiration
[0077] The water transpiration amount from the skin of the back of each rat was measured by TEVAMETER, and inhibitory effects on percutaneous water transpiration were found by the below-described formula:
[0078] Degree of percutaneous water transpiration inhibition by the invention product=Percutaneous water transpiration amount of the rat to which Comparative Product 1 has been applied−percutaneous water transpiration amount of the rat to which the invention product has been applied (g/m2/hr).
[0079] (2) Percutaneous Absorption
[0080] The dorsal skin of the test rat was cut off and fixed on a percutaneous absorption chamber with the epidermis side up. The lower receiver was filled with a phosphate buffer solution. Onto the epidermis, a phosphate buffer solution containing 14C-salicylic acid of 37 KBq was added, which was then allowed to stand. Nineteen hours later, a fixed amount of the phosphate buffer solution was drawn from the lower receiver and the radioactivity of the 14C-salicylic acid penetrated into the solution was measured. In accordance with the below-described formula, percutaneous absorption inhibitory effects were determined.
[0081] Degree of percutaneous absorption inhibition of the invention product=percutaneous absorption amount of the rat to which Comparative Product 1 has been applied−percutaneous absorption amount of the rat to which the invention product has been applied (dpm)
3TABLE 3
|
|
InventionInventionInventionInvention
Composition (%)product 1product 2product 3product 4
|
Compound (A)10———
Compound (B)—10——
Compound (C)——10—
Compound (D)———10
1,3-Butylene glycol 62.9 62.9 62.9 62.9
Ethanol27272727
Isostearyl glyceryl ether 0.1 0.1 0.1 0.1
|
[0082]
4
TABLE 4
|
|
|
Invention
Invention
Invention
Invention
|
Composition (%)
product 5
product 6
product 7
product 8
|
|
Compound (E)
10
—
—
—
|
Compound (F)
—
10
—
—
|
Compound (G)
—
—
10
—
|
Compound (H)
—
—
—
10
|
1,3-Butylene glycol
62.9
62.9
62.9
62.9
|
Ethanol
27
27
27
27
|
Isostearyl glyceryl ether
0.1
0.1
0.1
0.1
|
|
[0083]
5
TABLE 5
|
|
|
Invention
Invention
Invention
Comparative
|
Composition (%)
product 9
product 10
product 11
product 1
|
|
Compound (I)
10
—
—
—
|
Compound (J)
—
10
—
—
|
Compound (K)
—
—
10
—
|
1,3-Butylene glycol
62.9
62.9
62.9
62.9
|
Ethanol
27
27
27
30
|
Isostearyl glyceryl
0.1
0.1
0.1
0.1
|
ether
|
|
[0084]
6
TABLE 6
|
|
|
Percutaneous water
Percutaneous
|
transpiration
absorption
|
inhibition degree
inhibition degree
|
|
|
Invention product 1
1.5
2563
|
Invention product 2
1.3
1564
|
Invention product 3
1.8
2706
|
Invention product 4
1.3
2890
|
Invention product 5
1.4
1363
|
Invention product 6
1.2
1731
|
Invention product 7
1.4
1184
|
Invention product 8
1.1
1088
|
Invention product 9
0.3
532
|
Invention product 10
0.8
516
|
Invention product 11
0.9
739
|
|
[0085] It has been found that the invention products 1 to 11 are superior to Comparative product 1 in effects of inhibiting percutaneous water transpiration and percutaneous absorption and also superior in skin roughness lessening effects.
[0086] Test 2
[0087] Compositions for external application according to the present invention (invention products) containing the diamide derivative and having the composition as shown in Tables 7 and 8 were prepared and their percutaneous water transpiration and skin conductance were measured and evaluated by the below-described methods. For comparison, a composition for external application (Comparative Product 2) containing Vaseline, which is known to have high skin occlusive property and is therefore used for external dermatological preparations for medical use or skin cosmetic compositions, was subjected to similar measurement and evaluation. Results are shown in Table 9.
[0088] (Testing Method)
[0089] Ten normal volunteers were washed at the inside of the forearms (both arms), followed by acetone/ether (1/1) treatment to remove the intercellular lipid of the horny layer to roughen their skin. The composition for external application was applied to the test site twice a day for three days. On the next day after final application, the site was washed. After rest for 20 minutes at room temperature of 20° C. and humidity of 30%, the below-described items were measured and evaluated.
[0090] (2) Percutaneous Water Transpiration
[0091] The percutaneous water transpiration amount was measured by TEVAMETER. In accordance with the below-described formula, effects for inhibiting percutaneous water transpiration were determined.
[0092] Degree of percutaneous water transpiration inhibition by the invention product=percutaneous water transpiration amount of the site to which the base ingredient has been applied−percutaneous water transpiration amount of the site to which the invention product has been applied (g/m2/hr)
[0093] (2) Water Content in the Horny Layer
[0094] The water content in the horny layer was measured by a skin conductance meter. The higher the conductance, the greater the water content in the horny layer. In accordance with the below-descried formula, effects for improving water retaining ability of the horny layer were determined.
[0095] Water retaining ability improving degree of the invention product=conductance of the site to which the invention product has been applied−conductance of the site to which the base ingredient has been applied (μS)
7TABLE 7
|
|
InventionInventionInventionInvention
Composition (%)product 12product 13product 14product 15
|
Compound (A)5—
Compound (C)—5——
Compound (D)——5—
Compound (E)———5
Squalane2222
Neopentyl glycol3333
dicaprate
Cetanol3333
Stearyl alcohol2222
Polyoxyethylene1111
hydrogenated castor oil
(40E.O.)
Polyoxyethylene sorbitan 0.5 0.5 0.5 0.5
monostearate
(20E.O.)
Sorbitan monostearate 2.5 2.5 2.5 2.5
Methyl paraoxybenzoate 0.3 0.3 0.3 0.3
WaterBalanceBalanceBalanceBalance
|
[0096]
8
TABLE 8
|
|
|
Invention
Invention
Comparative
|
Composition (%)
product 16
product 17
Product 2
|
|
Compound (G)
5
—
|
Compound (K)
—
5
—
|
Vaseline
—
—
5
|
Squalane
2
2
2
|
Neopentyl glycol dicaprate
3
3
3
|
Cetanol
3
3
3
|
Stearyl alcohol
2
2
2
|
Polyoxyethylene hydrogenated
1
1
1
|
castor oil (40E.O.)
|
Polyoxyethylene sorbitan
0.5
0.5
0.5
|
monostearate (20E.O.)
|
Sorbitan monostearate
2.5
2.5
2.5
|
Methyl paraoxybenzoate
0.3
0.3
0.3
|
Water
Balance
Balance
Balance
|
|
[0097]
9
TABLE 9
|
|
|
Inhibition degree
Water
|
of percutaneous
retaining ability
|
water transpiration
improving degree
|
|
|
Invention product 12
2.2
4.7
|
Invention product 13
2.8
5.6
|
Invention product 14
2.1
4.0
|
Invention product 15
2.2
5.2
|
Invention product 16
2.0
4.1
|
Invention product 17
1.3
3.7
|
Comparative Product 2
0.6
0.1
|
|
[0098] It has been found that the invention products 12 to 17 were superior to the comparative product 2 in effects for increasing the water content in the horny layer, percutaneous water transpiration inhibiting effects and skin roughness remedial effects.
[0099] Test 3
[0100] Compositions for external application according to the present invention (invention products) having the compositions shown in Tables 10 to 12 were prepared and their percutaneous water transpiration, skin conductance and skin roughness were evaluated. For comparison, a Vaseline-containing composition for external application (comparative product 2) was subjected the similar evaluation. Results are shown in Tables 11 and 13.
[0101] (Testing method)
[0102] (1) Percutaneous Water Transpiration
[0103] It was evaluated in a similar manner to Test 2.
[0104] (2) Water Content in the Horny Layer
[0105] It was evaluated in a similar manner to Test 2.
[0106] (3) Score of Skin Roughness
[0107] Skin roughness was visually observed and ranked in accordance with the below-described standards. The score was indicated by an average value.
[0108] 0: No skin roughness is observed.
[0109] 1: Slight skin roughness is observed.
[0110] 2: Skin roughness is observed.
[0111] 3: Rather severe skin roughness is observed.
10TABLE 10
|
|
Comp.
Product
Invention Products2
131819202122232425262
|
Diamide compound (C)5555555555—
Ceramide II (product—0.5———0.50.50.50.50.5—
of sederma)
Ceramide III (product——0.5————————
of cosmoferm)
Sofcareceramide———0.5———————
Kao (Jap. Pat. Laid-
Open No. Sho 62-
228048)
Sphingoglycolipid————0.5——————
(Kibun Food Chemifa
Co., Ltd.)
Phytosphingosine—————0.5—————
Palmitic acid——————0.5————
Sunflower oil———————0.5———
Cholesterol————————0.5——
Cholesteryl—————————0.5—
isostearate
Vaseline——————————5
Squalane22222—22222
Neopentyl glycol33333333333
dicaprate
Cetanol33333333333
Stearyl alcohol22222222222
Polyoxyethylene11111111111
hydrogenated castor
oil (40E.O.)
Polyoxyethylene0.50.50.50.50.50.50.50.50.50.50.5
sorbitan monostearate
(20E.O.)
Sorbitan monostearate2.52.52.52.52.52.52.52.52.52.52.5
Methyl paraoxybenzoate0.30.30.30.30.30.30.30.30.30.30.3
WaterBal-Bal-Bal-Bal-Bal-Bal-Bal-Bal-Bal-Bal-Bal-
anceanceanceanceanceanceanceanceanceanceance
|
[0112]
11
|
|
Inhibition degree
Score
|
of percutaneous
of skin
|
water transpiration
roughness
|
|
|
Invention product 13
2.8
1.6
|
Invention product 18
3.3
1.2
|
Invention product 19
3.2
1.3
|
Invention product 20
3.4
1.1
|
Invention product 21
2.9
1.6
|
Invention product 22
4.5
0.3
|
Invention product 23
3.9
0.5
|
Invention product 24
3.5
0.9
|
Invention product 25
4.2
0.4
|
Invention product 26
4.1
0.4
|
Comparative product 2
0.6
2.7
|
|
[0113] The invention products 13 and 18 to 26 were superior to Comparative Product 2 in effects for inhibiting percutaneous water transpiration from the horny layer and skin roughness remedial effects.
12TABLE 12
|
|
Comp.
Invention productsProduct
13272829303132332
|
Diamide55555555—
compound (C)
Glycerin—0.5———————
1,3-Butylene——0.5——————
glycol
Eucalyptus extract———0.5—————
(Ichimaru Pharcos
Co., Ltd.)
Ginger extract————0.5————
(Maruzen Pharma-
ceuticals Co., Ltd.)
Sodium lactate—————0.5———
Sodium aspartate——————0.5——
Trimethylglycine———————0.5—
Vaseline————————5
Squalane222222222
Neopentyl glycol333333333
dicaprate
Cetanol333333333
Stearyl alcohol222222222
Polyoxyethylene111111111
hydrogenated castor
oil (40E.O.)
Polyoxyethylene0.50.50.50.50.50.50.50.50.5
sorbitan mono-
stearate (20E.O.)
Sorbitan mono-2.52.52.52.52.52.52.52.52.5
stearate
Methyl paraoxy-0.30.30.30.30.30.30.30.30.3
benzoate
WaterBal-Bal-Bal-Bal-Bal-Bal-Bal-Bal-Bal-
anceanceanceanceanceanceanceanceance
|
[0114]
13
TABLE 13
|
|
|
Water retaining ability improving
Score of skin
|
degree
roughness
|
|
Invention product 13
5.6
1.6
|
Invention product 27
7.0
1.3
|
Invention product 28
6.1
1.4
|
Invention product 29
8.8
0.7
|
Invention product 30
8.5
0.7
|
Invention product 31
7.9
1.0
|
Invention product 32
7.5
1.1
|
Invention product 33
8.1
0.9
|
Comparative product 2
0.1
2.7
|
|
[0115] The invention products 13 and 27 to 33 were superior to Comparative Product 2 in effects for increasing the water content in the horny layer and skin roughness remedial effects.
[0116] Test 4
[0117] Hair rinses of the present invention (invention products) containing the diamide derivatives and having the 10 compositions as listed in Tables 14 and 15 were prepared and excessive dryness and touch feel of the hair after treated with the resulting hair rinses were evaluated by a panel of 5 experts in accordance with the below-described criteria. The results are shown in Tables 16 and 17.
[0118] −2: Bad
[0119] −1: slightly bad
[0120] 0: neither good nor bad
[0121] +1: Slightly good
[0122] +2: Good
14TABLE 14
|
|
InventionInventionInvention
Composition (%)product 34Product 35Product 36
|
Distearyl dimethylammonium222
chloride
Propylene glycol333
Compound (A)1——
Compound (C)—1—
Compound (D)——1
WaterBalanceBalanceBalance
|
[0123]
15
TABLE 15
|
|
|
Invention
Invention
Comparative
|
Composition (%)
product 37
Product 38
Product 3
|
|
Distearyl dimethylammonium
2
2
2
|
chloride
|
Propylene glycol
3
3
3
|
Compound (E)
1
—
—
|
Compound (G)
—
1
—
|
Water
Balance
Balance
Balance
|
|
[0124]
16
TABLE 16
|
|
|
Invention
Invention
Invention
|
Evaluation items
product 34
product 35
product 36
|
|
Excessive dryness of the hair
+1.8
+1.8
+1.2
|
Favorable touch feel
+1.6
+2.0
+1.6
|
|
[0125]
17
TABLE 17
|
|
|
Invention
Invention
Comparative
|
Evaluation items
product 37
product 38
Product 3
|
|
Excessive dryness of the hair
+1.6
+1.6
−1.2
|
Favorable touch feel
+1.6
+1.8
−1.0
|
|
[0126] The invention products 34 to 38 were superior to Comparative product 3 in the effects of alleviating excessive hair dryness and improving the touch feel of the hair.
Example 1
[0127] A skin lotion having the composition shown in Table 18 was prepared in a conventional manner. The resulting 10 hair lotion exhibited excellent effects for preventing or remedying skin roughness. Compounds (A), (C), (D), (E), (G) and (K) were excellent in miscibility and mixing stability.
18TABLE 18
|
|
(Composition)(%)
|
Compound (A), (C), (D), (E), (G) or (K)1.0
Glycerin monostearate1.0
Propylene glycol4.0
Isopropyl palmitate3.0
Lanolin1.0
Methyl paraoxybenzoate0.1
PerfumeTrace
ColorantTrace
WaterBalance
|
Example 2
[0128] An O/W cream having the composition shown in Table 19 was prepared in a conventional manner. The resulting O/W cream exhibited excellent effects for preventing or remedying skin roughness. Compounds (A), (C), (D), (E), (G) and (K) were excellent in miscibility and mixing stability.
19TABLE 19
|
|
(Composition)(%)
|
Compound (A), (C), (D), (E), (G) or (K)3.5
Squalane2.0
Neopentyl glycol dicaprate3.0
Cetostearyl alcohol3.0
Polyoxyethylene sorbitan monostearate (20E.O.)2.1
Sorbitan monostearate0.9
Polyoxyethylene hydrogenated castor oil (40E.O.)1.0
Isostearyl glyceryl ether0.2
Ceramide 20.5
86% Glycerin5.0
Methyl paraoxybenzoate0.3
WaterBalance
|
Example 3
[0129] A shampoo having the composition as shown in Table 20 was prepared in a conventional manner. This shampoo improved the touch feel of the hair and prevented remedied the roughened skin of the scalp. Compound (A), (C), (D), (E), (G) and (K) were excellent in miscibility and mixing stability.
20TABLE 20
|
|
(Composition)(%)
|
Polyoxyethylene (25) lauryl ether sulfate sodium salt15.0
Coconut oil fatty acid diethanolamide 3.0
Compound (A), (C), (D), (E), (G) or (K) 2.0
Perfume 0.5
ColorantTrace
Citric acidTrace
WaterBalance
|
Example 4
[0130] A hair liquid composition having the composition shown in Table 21 was prepared in a conventional manner. The resulting hair liquid composition imparted the hair with excellent style retention and manageability and good touch feel. Compounds (A), (C), (D), (E), (G) and (K) were excellent in miscibility and mixing stability.
21TABLE 21
|
|
(Composition)(%)
|
Compound (A), (C), (D), (E), (G) or (K) 1.0
Polyoxypropylene (30) butyl ether15.0
Ethanol40.0
WaterBalance
Perfume 0.3
|
Example 5
[0131] A night cream having the composition as described below was prepared. The resulting night cream was effective for recovering a deterioration in the barrier functions of the skin horny layer and reinforcing the functions, heightened the water retaining ability of the horny layer and exhibited skin roughness preventive remedial effects. Compounds (A), (C), (D), (E), (G) and (K) were excellent in miscibility and mixing stability.
22TABLE 22
|
|
(Composition)(%)
|
|
Diamide compound (A), (C), (D), (E), (G) or (K)10.0
Ceramide 2 (Takasago International Corp.)1.0
Bovine brain lipid (Q. P. Corp.)0.5
Sofcare ceramide SLE (Kao Corp.)3.0
Macadamia nut oil fatty acid cholesterol (Nippon Fine2.0
Chemical Co., Ltd.)
Dimethylpolysiloxane 10cSt5.0
Polyether-modified silicone2.0
Polyoxyethylene hydrogenated castor oil1.0
Cyclic silicone7.0
Glycerin5.0
Magnesium sulfate0.5
Nicotinic amide0.2
Dipotassium glycyrrhizinate0.1
Amur cork tree extract (Ichimaru Pharcos Co., Ltd.)0.1
Heavy liquid isoparaffin0.5
Polyvinyl alcohol0.3
Methyl paraoxybenzoateq.s.
Perfumeq.s.
Purified waterBalance
|
Example 6
[0132] A sunscreen emulsion having the below-described composition was prepared. The sunscreen emulsion thus obtained was effective for recovering a deterioration in barrier functions of the skin horny layer and reinforcing the function, heightened water retaining ability of the horny layer and exhibited skin roughness preventive • remedial effects. Compounds (A), (C), (D), (E), (G) and (K) were each excellent in miscibility and mixing stability.
23TABLE 23
|
|
(Composition)(%)
|
|
Diamide compound (A), (C), (D), (E), (G) or (K)3.0
Cetyloxypropylglyceryl methoxypropyl myristamide (Example1.0
1 of Japanese Patent Laid-Open No. Hei 08-319263)
Phytosphingosine (product of cosmoferm)0.1
Stearic acid0.2
Palmitic acid0.3
Lanoline fatty acid cholesterol0.5
2-Ethylhexyl p-methoxycinnamate5.0
Silicon-coated titanium dioxide7.0
Silicon-coated zinc oxide3.0
Polyether-modified silicone2.0
Alkyl-modified silicone2.0
Cyclic silicone15.0
Sodium silicate1.0
Glycerin2.0
Dipropylene glycol3.0
Kitin1.0
Cysteine0.2
Burnet extract (Maruzen Pharmaceutical Co., Ltd.)0.3
Stearyl glycyrrhizinate0.2
Methyl paraoxybenzoateq.s.
Perfumeq.s.
Purified waterBalance
|
[0133] Industrial Applicability
[0134] Diamide derivatives (I) of the present invention penetrate into the lipid layer between horny cells, thereby exerting effects of improving (maintaining • reinforcing) water retention capacity and barrier functions of the horny layer or penetrate into the hair, thereby heightening hair protecting effects and at the same time, they have good solubility and excellent stability in a base ingredient. The compositions for external application, humectants and skin barrier function reinforcing agents according to the present invention therefore exhibit effects in prevention treatment of chapping, anti-aging of the skin, improvement in the touch feel of the hair, and prevention and remedy of the chapping of the scalp and are useful as pharmaceuticals, cosmetics or quasi-drugs excellent in stability. The compositions for external application according to the present invention can be prepared efficiently at a low cost.
Claims
- 1. A composition for external application, which comprises a diamide derivative represented by the following formula (1):.
- 2. A composition for external application, which comprises a diamide derivative represented by the following formula (1):
- 3. A composition for external application according to claim 2, wherein the intercellular lipid component of the horny layer is at least one selected from ceramides, pseudoceramids, sphingoglycolipids, sphingophospholipids, sphingosines and derivatives thereof, sphinganines and derivatives thereof, higher fatty acids, and cholesterols and derivatives thereof.
- 4. A composition for external application according to any one of claims 1 to 3, which is a cosmetic composition.
- 5. A humectant, which comprises, as an effective ingredient, a diamide derivative represented by the following formula (1):
- 6. A skin barrier function reinforcing agent, which comprises, as an effective ingredient, a diamide derivative represented by the following formula (1):
- 7. A method for reinforcing the water retaining ability of the horny layer, which comprises applying, to the skin, an effective amount of a diamide derivative as claimed in claim 1.
- 8. A method for reinforcing skin barrier functions, which comprises applying, to the skin, an effective amount of a diamide derivative as claimed in claim 1.
- 9. A method for remedying excessive hair dryness or improving touch feel of the hair, which comprises applying, to the hair, an effective amount of a diamide derivative as claimed in claim 1.
- 10. Use of a diamide derivative as claimed in claim 1 for the preparation of a composition for external application.
- 11. Use according to claim 10, wherein the composition for external application serves as cosmetics.
- 12. A diamide derivative represented by the following formula (1′):
- 13. A diamide derivative according to claim 12, wherein R1a′ and R1b′ each represents a branched C5-17 alkyl group, R2a and R2b each represents a C2-6 alkylene group, R3 represents a C2-6 alkylene group and n stands for 1 to 10.
- 14. A diamide derivative according to claim 12, which is represented by the following formula (C):
Priority Claims (1)
Number |
Date |
Country |
Kind |
2001-061695 |
Mar 2001 |
JP |
|
Divisions (1)
|
Number |
Date |
Country |
Parent |
10082115 |
Feb 2002 |
US |
Child |
10730048 |
Dec 2003 |
US |