Patent Application
20100324096
This application claims the priority of Japanese Patent Application No. 2008-29106 filed on Feb. 8, 2008 and Japanese Patent Application No. 2008-199606 filed on Aug. 1, 2008, which are incorporated herein by reference.
The present invention relates to a whitening agent and a skin external preparation, and particularly, to an active ingredient thereof.
Pigmentation in the skin such as pigmented spots and freckles are resulted from hyperpigmentation of melanin in the epidermis. The hyperpigmentation is caused by acceleration of melanin production in epidermal melanocytes triggered by hormone abnormality or UV stimulation.
A whitening agent has been mixed into a skin external preparation with an aim to prevent and improve such abnormal melanin pigmentation. At present, as ingredients that are mixed into a skin external preparation as a whitening agent, there are vitamin C derivative, kojic acid, arbutin (4-hydroxyphenyl-β-D-glucopyranoside), Rucinol (4-n-butylresorcinol), ellagic acid, etc., which are known to have an inhibitory action on melanin production.
However, a whitening agent fully satisfactory in terms of the effect, safety, and the like has not yet been obtained, and therefore development of a new whitening agent has been demanded.
On the other hand, Patent Literature 1 describes a 2-aminothiazole compound having an antibacterial or bactericidal effect.
Also, Patent Literature 2 describes a thiazole compound having a C17,20-lyase inhibitory effect.
Further, Patent Literature 3 describes a thiazoline compound having a pest control effect on a harmful organism.
However, these literatures are totally silent on an inhibitory action on the melanin production and a whitening effect.
Patent Literature 1: Japanese Patent No. 3033178
Patent Literature 2: Japanese Unexamined Patent Publication No. 2005-532983
Patent Literature 3: Japanese Unexamined Patent Publication No. H6-25197
The present invention has been accomplished in view of the aforementioned problem of the conventional art. An object of the present invention is to provide a compound having an excellent inhibitory action on melanin production and being useful as a whitening agent, and a skin external preparation containing the compound.
The present inventors conducted thorough research to solve the aforementioned problem. As a result, they have found that a specific thiazoline or oxazoline compound has an excellent inhibitory action on melanin production and also has extremely low cytotoxicity, thereby completing the present invention.
That is, the whitening agent of the present invention comprises, as an active ingredient, a heterocyclic compound represented by the following formula (1) or a pharmacologically acceptable salt thereof:
wherein
A is C1-6 alkyl, C5-6 cycloalkyl, benzyl, benzylcarbonyl, benzoyl, or a group represented by formula (A1):
wherein
X1 is CR1 or N, wherein R1 is H, C1-6 alkyl, C1-6 alkoxy, or OH;
X2 is CR2 or N, wherein R2 is H, C1-6 alkyl, C1-6 alkoxy, or OH;
R5 is C1-6 alkyl, C1-6 alkoxy, or OH; and
p is an integer of 0 to 3, wherein when p is 2 or 3, R5 may be the same or different;
Ra is H, C1-6 alkyl, or C2-6 alkenyl;
“” represents a single bond that leads n=2 or a double bond that leads n=1, wherein when n=2, two R3 may be the same or different, and two R4 may also be the same or different;
Y is S or O; and
R3 and R4 are each independently H, C1-6 alkyl, hydroxy-C1-6 alkyl, C2-7 acyl, or the group (A1), or
one R3 and one R4 may together form a saturated or unsaturated 5- or 6-membered hydrocarbon ring condensed with the hetero ring to which R3 and R4 are bound, or
C(R3)2 or C(R4)2 may each independently be C═CH2;
with the proviso that at least one R3 is a group other than C1-3 alkyl in the case where: the hetero ring containing Y is a thiazoline ring; R4═Ra═H; X1═X2═CH; and p=0 or R5═C1-6 alkyl.
The present invention also provides the whitening agent, wherein Y is S.
The present invention also provides the whitening agent, wherein A is the group (A1).
The present invention also: provides the whitening agent, wherein is a single bond.
The present invention also provides the whitening agent, wherein is represented by formula (1-1):
wherein R3, R4, R5, and Ra are as defined in the formula (1).
The present invention also provides the whitening agent, wherein R3 in the formula (1-1) is each independently H or C1-6 alkyl.
The present invention also provides the whitening agent, wherein R4 in the formula (1-1) is each independently H or C1-6 alkyl, or C(R4)2 is C═CH2.
The present invention also, provides the whitening agent, wherein is represented by formula (1-2):
wherein R3, R4, R5, and Ra are as defined in the formula (1).
The present invention also provides the whitening agent, wherein R3 and R4 in the formula (1-2) are each independently H or C1-6 alkyl.
The present invention also provides the whitening agent, wherein is a double bond.
The present invention also provides the whitening agent, wherein is represented by formula (1-3):
wherein, R3, R4, R5, and Ra are as defined in the formula (1).
The present invention also provides the whitening agent, wherein is represented by formula (1-4):
wherein, R3, R4, R5, and Ra are as defined in the formula (1).
The present invention also provides the whitening agent, wherein R3 in the formula (1-3) or (1-4) is C1-6 alkyl or the group (A1).
The present invention also provides the whitening agent, wherein R4 in the formula (1-3) or (1-4) is H or C1-6 alkyl.
The present invention also provides the whitening agent, wherein Ra is H.
The present invention also provides the whitening agent, wherein R5 is C1-6 alkyl.
The present invention also provides the whitening agent, wherein the active ingredient inhibits melanin production.
The present invention also, provides a skin external preparation or a cosmetic comprising any of the aforementioned heterocyclic compounds or a pharmacologically acceptable salt thereof.
The whitening agent of the present invention has an excellent inhibitory action on melanin production and also has extremely low cytotoxicity; therefore, it can be suitably mixed into a skin external preparation as a whitening agent.
The whitening agent of the present invention is represented by the following formula (1):
In the formula (1), A is C1-6 alkyl, C5-6 cycloalkyl, benzyl, benzylcarbonyl, benzoyl, or a group represented by the following formula (A1):
In the group (A1), X1 is CR1 or N, wherein R1 is H, C1-6 alkyl, C1-6 alkoxy, or OH.
X2 is CR2 or N, wherein R2 is H, C1-6 alkyl, C1-6 alkoxy, or OH.
Accordingly, an unsaturated 6-membered ring containing X1 and X2 is a benzene ring, a pyridine ring, or a pyrimidine ring.
R5 is C1-6 alkyl, C1-6 alkoxy, or OH, and preferred examples thereof include C1-6 alkyl.
p is an integer of 0 to 3. When p is 2 or 3, R5 can be the same or different.
Ra is H, C1-6 alkyl, or C2-6 alkenyl, and preferred examples thereof include H.
“” represents a single bond or a double bond. When it is a single bond, n=2, When it is a double bond, n=1. When n=2, two R3 may be the same or different, and two R4 may also be the same or different.
Y is S or O. Accordingly, in the formula (1), an unsaturated 5-membered hetero ring containing Y is thiazole, thiazoline, oxazole, or oxazoline.
R3 and R4 can each independently be H, C1-6 alkyl, hydroxy-C1-6 alkyl, C2-7 acyl, or the aforementioned group (A1). Also, one R3 and one R4 may together form a saturated or unsaturated 5- or 6-membered hydrocarbon ring condensed with the hetero ring to which R3 and R4 are bound. Alternatively, C(R3)2 or C(R4)2 may each independently be C═CH2.
However, in the present invention, at least one R3 is a group other than C1-3 alkyl, in the case where: a hetero ring containing Y is a thiazoline ring; R4═Ra═H; X1═X2═CH; and either p=0 or R5═C1-6 alkyl.
An example of the preferred compound represented by the formula (1) is a compound wherein Y═S.
Another example of the preferred compound represented by the formula (1) is a compound wherein A is the group (A1).
An example of the preferred compound wherein A is a group (A1) is a compound wherein is a single bond. Preferred examples of such a compound include a compound represented by the following formula (1-1) or formula (1-2).
In the formula (1-1) and formula (1-2), R3, R4, R5, and Ra are as defined in the formula (1).
A preferred example of the compound represented by the formula (1-1) is a compound wherein R3 is each independently H or C1-6 alkyl.
Another preferred example of the compound represented by the formula (1-1) is a compound wherein R4 is each independently H or C1-6 alkyl, or a compound wherein C(R4)2 is C═CH2.
A preferred example of tho compound represented by the formula (1-2) is a compound wherein R3 and R4 are each independently H or C1-6 alkyl.
It is to be noted that compounds of the formula (1) wherein is a single bond and Ra═H can be tautomers as shown below. In the present invention, such tautomers are also included in the compound of the formula (1).
Also, a preferred example of the compound wherein A is the group (A1) is a compound wherein is a double bond. Preferred examples of such a compound include a compound represented by the following formula (1-3) or formula (1-4).
In the formula (1-3) and formula (1-4), R3, R4, R5, and Ra are as defined in the formula (1).
A preferred example of the compound represented by the formula (1-3) or formula (1-4) is a compound wherein R3 is C1-6 alkyl or the group (A1).
Another preferred example of the compound represented by the formula (1-3) or (1-4) is a compound wherein R4 is H or C1-6 alkyl.
The compound of the formula (1) can be synthesized by a known method or commercially available.
In the case of synthesis, when the molecule has a functional group which blocks or might block a reaction, an appropriate protecting group is preferably used to allow the reaction to proceed efficiently. The use of the protecting group can be carried out according to, for example, Protective Groups in Organic Synthesis by Theodora W. Greene and Peter G. M. Wuts.
Further, when an isomer such as a conformational isomer, a geometric isomer, and an optical isomer is present, a pure isomer or geometric isomer can be obtained by appropriately selecting a raw material and a reaction condition and performing a separation operation. In the present invention, a pure isomer of the compound of the formula (1) as well as a mixture thereof are also included.
A compound wherein is a single bond and Ra═H in the formula (1) can be obtained by, for example, a reaction shown in the following scheme 1.
In scheme 1, a reaction of an iso(thio)cyanate compound (2) with an ethanolamine compound (3) can be carried out, for example, in an appropriate solvent such as chloroform, while heating as needed. A ring closure reaction of the (thio)urea compound (4) thus obtained can be carried out, for example, in the presence of an acid catalyst, while heating. The above reaction can be carried out according to, for example, a method described in Japanese Unexamined Patent Publication No. S62-228089.
Alternatively, as a method described in Japanese Unexamined Patent Publication No. H6-25197, a reaction of 2-imino (or 2-amino) thiazoline compound (or oxazoline compound) with a compound represented by A-X (X is a halogen) can also be adopted. This reaction can typically be carried out in an appropriate solvent in the presence of a base such as triethylamine, while heating as needed.
A compound wherein is a double bond and Ra═H in the formula (1) can be obtained by, for example, a reaction shown in the following scheme 2.
In scheme 2, a reaction of a (thio)urea compound (5) with a α-haloketone compound (6) can be carried out in an appropriate solvent such as methanol, at room temperature or while heating, in the presence of a base such as triethylamine as needed. This reaction can be carried out according to, for example, a method described in Japanese Unexamined Patent. Publication No. 2005-532983 and Japanese Patent No. 3023178.
Alternatively, as a method described in Japanese Patent No. 3023178, a reaction of 2-aminothiazole compound (or 2-aminooxazol compound) with a compound represented by A-X (X is a halogen) can also be adopted. This reaction can typically be carried out in an appropriate solvent in the presence of a base such as triethylamine, while heating as needed.
The compound of the formula (1) can be converted into an acid-addition salt by an ordinary method as needed. Examples of acid in the acid-addition salt include an inorganic salt such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and an organic acid such as acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, and methanesulfonic acid.
Many of the compounds of the formula (1) are commercially available and can be obtained from various suppliers such as Enamine Ltd. (Ukraine), Pharmeks Ltd. (Russia), Labotest (Germany), Scientific Exchange Inc. (U.S.A), Life Chemicals Inc. (Ukraine), Asinex Ltd. (Russia), Vitas-M Laboratory Ltd. (Russia), ACB Blocks Ltd. (Russia), Bionet (U.S.A), and Princeton Biomolecular Research Inc. (U.S.A).
The compound of the formula (1) has an excellent inhibitory action on melanin production while exhibiting extremely low eytotoxieity. Therefore, the present compound is useful as a whitening agent and can be suitably mixed into various skin external preparations, particularly a skin external preparation intended to improve or prevent pigmented spots, freckles, skin dullness, and the like.
When the compound of the formula (1) is mixed into the skin external preparation as the whitening agent, the compound amount is, in the total amount of the external agent, typically 0.0002% by mass or more, preferably 0.002% by mass or more. When it is too low, the effect cannot be fully exerted. Although no limitation is imposed on the upper limit, it is typically 30% by mass or less, preferably 20% by mass or less, and more preferably 5% by mass or less. When the compound is excessively mixed in, not only a remarkable effect reasonably expected from the increased amount may not be obtained but also formulation designing and usability may be affected.
Other than adding the compound of the formula (1), the skin external preparation of the present invention can be produced by an ordinary method.
In addition to the compound of the formula (1), other ingredients normally used in a skin external preparation such as a cosmetic product and a pharmaceutical product can be appropriately added to the skin external preparation of the present invention as needed as far as the effect of the present invention is not adversely affected. Examples of such an ingredient include oil, a humectant, an ultraviolet protective agent, an antioxidant, a metal ion chelating agent, a surfactant, a preservative, a moisturizer, a fragrance, water, an alcohol, a thickener, powder, a colorant, a crude drug, and various kinds of medicinal ingredients.
Further, other whitening agents such as vitamin C, magnesium ascorbyl phosphate, ascorbyl glucoside, arbutin, kojic acid, Rucinol, ellagic acid, tranexamic acid, and linoleic acid can be appropriately added.
The skin external preparation of the present invention is widely applicable to the fields of cosmetics, drugs, and quasi drugs. No particular limitation is imposed on the form of the skin external preparation as long as it is applicable to the skin. Any form such as a solution, an emulsion, a solid, a semi-solid, a powder, a powder dispersion, a water-oil-separated two-phase liquid, a water-oil-powder-separated three-phase liquid, an ointment, a gel, an aerosol, a mousse, and a stick can be applied. Further, the skin external preparation can be provided in any use form including a facial cosmetic such as a lotion, an emulsion, a cream, a pack, an essence, and a gel, and a makeup cosmetic such as a foundation, a makeup base, and a concealer.
Hereinbelow, the present invention will be further described with specific examples. However, the present invention is not limited thereto.
A test for melanin production inhibition by the compounds of the formula (1) was conducted. The test method is as follows.
Melanin Production Inhibition Test
Mouse B16 melanoma cells were inoculated in a six well plate at 100,000 cells/well. The next day, test substance solutions (solvent: DMSO) were added.
Three days after the addition of the test substance solution, the medium was removed by aspiration. Then 1 ml of EMEM medium containing 10% Alamar Blue solution was added, and a reaction was allowed to proceed at 37° C. After 30 minutes, 100 μL of the reaction mixture was transferred to a 96 well plate and fluorescence was measured at an excitation wavelength of 544 nm and a measurement wavelength of 590 nm. Using the value thus measured as a relative value of cell count, a ratio of the cell count (% cell count) of the test substance-added group to the test substance-absent group (group in which only the solvent was added) was calculated. The higher the % cell count, the lower the cytotoxicity. It was determined that a compound having the % cell count of 80% or more was non-cytotoxic, and that a compound having the % cell count of less than 80% was cytotoxic.
The cells after the cell proliferation test were washed with PBS three times, and then lysed by addition of 200 μL of 1M NaOH to measure an absorbance at 475 nm. Using the value thus measured as a relative value of the melanin amount, a ratio of the melanin amount (%) of the test substance-added group to the test substance-absent group (group in which only the solvent was added) was calculated. The lower the ratio of the melanin amount, the higher the melanin production-inhibitory effect. In the final concentrations of the test substances at which the compound was determined to be non-cytotoxic, the minimum final concentration of the test substance at which the ratio of the melanin amount (%) was 80% or less was provided as a minimum concentration for inhibition of melanin production (ppm). The inhibitory effect on melanin production was evaluated according to the following criteria.
⊚: the minimum concentration for inhibition of melanin production was 1 ppm or less.
◯: the minimum concentration for inhibition of melanin production was more than 1 ppm and 10 ppm or less.
×: no inhibitory effect on melanin production was exhibited at 10 ppm or less
The results of melanin production inhibition test using the compounds of the present invention are shown in Table 1.
Any of the compounds shown in Table 1 was acknowledged to have an inhibitory effect on melanin production, and most of them exhibited the effect at such an extremely low concentration as 1 ppm or less.
It is to be noted that symbols in Tables represent the following groups.
Hereinbelow, representative Synthesis Examples of the heterocyclic compounds used for the whitening agent of the present invention will be shown. Various heterocyclic compounds can be obtained by carrying out a reaction according to the below-described Synthesis Examples using a corresponding raw material.
To p-anisidine (0.60 g, 4.86 mmol) and methanol (4.0 mL) in a 50 mL recovery flask was added methallyl isothiocyanate (0.50 g, 4.42 mmol) dropwise at room temperature, and then the resulting mixture was stirred for 12 hours at room temperature. Upon completion of the reaction, the mixture was extracted with ethyl acetate once. The organic phase thus obtained was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.79 g of 1-(4-methoxyphenyl)-3-(2- methylallyl)thiourea (yield 76%).
1-(4-Methoxyphenyl)-3-(2-methylallyl)thiourea (0.50 g, 2.11 mmol) and 35% hydrochloric acid (5.0 mL) were added in a pressure resistant reaction container, and the resulting mixture was stirred at 140° C. for five hours in the sealed container. Upon completion of the reaction, a 3N aqueous solution of sodium hydroxide was added to the reaction mixture to adjust the pH up to 14, and the resulting mixture was extracted with ethyl acetate twice. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give 0.19 g of 4-(5,5-dimethyl-4,5-dihydrothiazol-2-ylamino)phenol (Compound 41) (yield 40%).
(Hetero)arylaminothiazolines as shown in Table 6 were each synthesized in the same manner as in Synthesis Example 1-1 except that raw material A was used instead of anisidine.
1H-NMR (DMSO-d6): 1.46 (6 H, s), 3.51 (2 H, br-s), 6.61 (2 H, dd), 7.07 (2 H, br-s), 8.67 (2 H, br-s)
1H-NMR (DMSO-d6): 1.47 (6 H, s), 3.64 (2 H, br-s), 6.31 (1 H, d), 6.83 (2 H, br-s), 6.97 (1 H, t), 9.17 (2 H, br-s)
1H-NMR (DMSO-d6): 1.49 (6 H, s), 3.53 (2 H, br-s), 7.23 (1 H, dd), 7.66 (1 H, br-s), 8.12 (1 H, dd), 8.35 (1 H, br-s), 9.10 (1 H, br-s)
To 975 mL of methanol were added triethylamine (14.0 g, 137 mmol), o-toluylthiourea (11.54 g, 69.4 mmol), and 2-(bromoacetyl)pyridine hydrobromide (19.5 g, 69.4 mmol), and the resulting mixture was stirred for 15 hours at room temperature. Upon completion of the reaction, 1,950 mL of water was added to the mixture and precipitated crystals were collected by filtration. The solid thus collected was crystallized from a mixed solvent of water and methanol to give the title compound (14.0 g, 76%).
1H-NMR (DMSO-d6): 2.30(3H, s), 7.01-7.04(1H, m), 7.22-7.30(3H, m), 7.46(1H, s), 7.82-7.91(2H, m), 7.97(1H, d), 8.56(1H, d), 9.32(1H, s)
In 500 g of chloroform was dissolved 2-amino-2-methyl-1-propanol (61.6 g, 0.69 moL). Then, 300 g of chloroform solution containing phenyl isothiocyanate (81.6 g, 0.6 moL) was slowly added dropwise to the mixture over one hour, while stirring. Upon completion of the addition, the resulting mixture was stirred for 12 hours at room temperature. The precipitated crystals were refluxed with heat to be dissolved and then recrystallized. The crystals thus obtained were collected by filtration, washed with 20 mL of diethyl ether three times, and then dried under reduced pressure at room temperature to give 80.1 g of N-(1-hydroxy-2-methylpropan-2-yl)-N′-phenylthiourea (yield 60%).
N-(1-hydroxy-2-methylpropan-2-yl)-N′-phenylthiourea (80.1 g, 0.36 mol) was dissolved in 2,400 mL of 35% HCl, and the resulting mixture was stirred while heating at 90° C. for 1.5 hours. After cooling, the mixture was neutralized with NaOH and extracted with diethyl ether. The extract was washed with saturated brine and then anhydrous sodium sulfate was added. The organic phase was distilled off under reduced pressure and the residue was washed three times with hexane. The crystals thus obtained were dried under reduced pressure at room temperature, and then recrystallized from methanol twice to give 22.4 g of the title compound (yield 18%).
1H-NMR (CDCl3): 1.39(6H, s), 3.08(2H, s), 7.01-7.09(3H, m), 7.26-7.30(2H, m)
Hereinbelow, Formulation Examples of the skin external preparation of the present invention are shown. In each Formulation Example, one or more compounds of the present invention can be used. Any of the skin external preparations shown in Formulation Examples below exerts a whitening effect because of the by the addition of the compound of the present invention.
(Production Method)
Propylene glycol and caustic potash were dissolved in ion-exchanged water, and the resulting mixture was heated to and maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was gradually added to the aqueous phase, and after the complication of the addition, the resulting mixture was maintained at 70° C. for some time to allow a reaction to proceed. Subsequently, the mixture was homogeneously emulsified by a homomixer, and cooled to 30° C. while thoroughly stirring.
(Production Method)
Propylene glycol and disodium ethylenediaminetetraacetate were dissolved in ion-exchanged water and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was gradually added to the aqueous phase. The mixture was preliminarily emulsified at 70° C., homogeneously emulsified by a homomixer, and then cooled to 30° C. while thoroughly stirring.
(Production Method)
Powder soap and borax were added to ion-exchanged water and dissolved with heat, and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). While stirring, the oil phase was gradually added to the aqueous phase to allow a reaction to proceed. Upon completion of the reaction, the mixture was homogeneously emulsified by a homomixer, and then cooled to 30° C. while thoroughly stirring.
(Production Method)
Carboxyvinyl polymer was dissolved in a small amount of ion-exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water and dissolved with heat, and the resulting mixture was maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). The oil phase was added to the aqueous phase and preliminarily emulsified. After addition of phase A, the resulting mixture was homogeneously emulsified by a homomixer and then cooled to 30° C. while thoroughly stirring.
(Production Method)
Propylene glycol was added to ion-exchanged water, and the resulting mixture was heated and maintained at 70° C. (aqueous phase). Other components were mixed and melted by heat, and maintained at 70° C. (oil phase). While stirring the oil phase, the aqueous phase was gradually added to the oil phase. The resulting mixture was homogeneously emulsified by a homomixer and then cooled to 30° C. while thoroughly stirring.
(Production Method)
Carboxyvinyl polymer was homogeneously dissolved in ion-exchanged water. Separately, the compound of the present invention and POE (50) oleyl ether were dissolved in 95% ethanol and then added to the aqueous phase. After addition of the remaining components, the resulting mixture was neutralized by caustic soda and L-arginine to increase the viscosity.
(Production Method)
Each of Phase A and Phase C was homogeneously dissolved, and Phase A was added to Phase C to be solubilized. After addition of Phase B, the resulting mixture was packed in a container.
(Production Method)
Each of Phase A, Phase B, and Phase C was homogeneously dissolved, and Phase B was added to Phase A to be solubilized. After addition of Phase C, the resulting mixture was packed in a container.
(Production Method)
Powdery components from talc to black iron oxide shown above were thoroughly mixed by a blender. To this mixture were added oily components from squalane to isocetyl octanoate shown above, the compound of the present invention, preservative, and fragrance. The resulting mixture was thoroughly kneaded, packed in a container, and then formed.
(Production Method)
The aqueous phase was stirred with heat and then the powder part, which had been fully mixed and pulverized, was added. The mixture was treated with a homomixer and then the oil phase, which had been mixed with heat, was added. The mixture was treated with a homomixer and then fragrance was added while stirring. The mixture thus obtained was cooled to room temperature.
(Production Method)
(2), (4), (5), (9), and (10) were dissolved in (12) to provide a purified water solution, Separately, (1), (3), (7), (8), and (11) were dissolved in (6), and the resulting mixture was added to the aforementioned the purified water solution to be solubilized. The mixture thus obtained was filtrated to provide a lotion.
(Production Method)
Alcohol phase A was added to Aqueous phase B and solubilized to provide a lotion.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2008-029106 | Feb 2008 | JP | national |
| 2008-199606 | Aug 2008 | JP | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/JP2009/052079 | 2/6/2009 | WO | 00 | 8/6/2010 |
