JPH09216815A - Skin ointment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin ointment which stably contains a water-soluble or hydrophobic polymer or chain substance, is compoundable even to a base composed mainly of powder and highly biocompatible and safe to the skin. SOLUTION: This ointment contains a water-soluble polymer, a water-soluble chain substance or a polyrotaxane derived from a hydrophobic polymer or a hydrophobic chain substance and a cyclodextrin. The water-soluble polymer or the chain substance is e.g. polyethylene glycol, polypropylene glycol or peptide and the hydrophobic polymer or the chain substance is e.g. a hydrocarbon such as squalane, an oil-soluble vitamin or a prostaglandin. The preparation may be incorporated with an anti-inflammatory agent, a water-soluble vitamin, a pigment, an ultraviolet absorber, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention is characterized by containing a highly biocompatible polyrotaxane formed from a water-soluble polymer or chain substance, or a hydrophobic polymer or chain substance and cyclodextrin, The present invention relates to a new skin external preparation.

[0002]

2. Description of the Related Art Inclusion with cyclodextrin or the like has been conventionally applied for the purpose of stabilizing or solubilizing drugs or physiologically active substances, or nonvolatilizing volatile substances.
Also in the field of cosmetics, squalane is included in cyclodextrin for inclusion (JP-A-63-6852).
0), a technique for encapsulating a fragrance in hydroxypropylated cyclodextrin (Journal of Japanese Cosmetic Science 17 73-83 (199)
3), JP-A-7-241333, etc.) are disclosed.

Further, a method using a cyclodextrin polymer has been proposed in order to solubilize a particularly insoluble substance in a stable manner (Japanese Patent Laid-Open No. 97025/1986). The production of polycyclodextrin beads has been studied for the purpose of expanding its application such as use as a column packing (JP-A-61-28360).
1).

However, it is difficult to stably include a long-chain polymer or a chain-like substance in cyclodextrin. Therefore, if it is simply included in a cyclodextrin polymer as described above, an external preparation containing powder as a main component is used. It was difficult to mix it into the base or solid cosmetics. On the other hand, it is almost impossible to encapsulate the polymer and the like in the insolubilized cyclodextrin beads. Further, since the inside of the cyclodextrin cyclic structure exhibits hydrophobicity, it has been difficult to stably include a water-soluble polymer.

[0005]

In the present invention, a water-soluble or hydrophobic polymer or chain substance is stably contained, and it is also compounded in a powder-based external preparation base or cosmetics. It is an object of the present invention to obtain a skin external preparation which is capable of being treated, has high biocompatibility and is safe for the skin.

[0006]

[Means for Solving the Problems] Recently, synthesis of polyrotaxane in which many cyclic molecules are confined in one molecule has been reported (Pharmacia 31 (11) 1258-1267 (199).
5), Nature 370 (14) 126-128 (1994)), and this time, they found that good results were obtained by applying this polyrotaxane, and completed the present invention.

The polyrotaxane used in the present invention is a water-soluble polymer or water-soluble chain substance, or a polymer formed from a hydrophobic polymer or hydrophobic chain substance and cyclodextrin, from the viewpoint of biocompatibility. Is also preferable.

Examples of the water-soluble polymer or water-soluble chain substance include polyethylene glycol, polypropylene glycol, peptides and the like which are generally used as moisturizers.

The peptides include hydrolysates of keratin, collagen, elastin, etc., which are skin constituent proteins, adrenocorticotropic hormone releasing hormone, thyroid stimulating hormone releasing hormone, growth hormone releasing hormone, melanocyte stimulating hormone releasing hormone. Examples include physiologically active peptides such as hypothalamic hormone, thyroid stimulating hormone, adrenocorticotropic hormone, gonadotropin, growth hormone, and hormones such as pituitary hormone such as melanocyte stimulating hormone.

Further, dyes, vitamins, antihistamines, anti-inflammatory agents, ultraviolet absorbers and the like can be attached to the ends of the above water-soluble polymers such as polyethylene glycol or water-soluble chain substances.

Examples of dyes include nitro dyes, azo dyes, nitroso dyes, triphenylmethane dyes, xanthene dyes, quinoline dyes, anthraquinone dyes, indigo dyes, pyrene dyes and phthalocyanine dyes.

The vitamins include thiamine (vitamin B ₁ ), thiamine pyrophosphate, riboflavin (vitamin B ₂ ), pyridoxine (vitamin B ₆ ), pyridoxal, pyridoxamine, pyridoxal phosphate, pyridoxamine phosphate, nicotinic acid, Nicotinamide, folic acid,
Water-soluble vitamins such as ascorbic acid (vitamin C), biotin, and pantothenic acid are preferable.

Examples of the antihistamine include diphenhydramine, pyrilamine, hydroxyzine, promethazine, chlorpheniramine, etc., and examples of the anti-inflammatory agent include allantoin, salicylic acid derivative, indoleacetic acid derivative, pyrazolidinedione derivative, anthranilic acid derivative. , Propionic acid derivatives, phenylacetic acid derivatives and the like.

Examples of the ultraviolet absorber include paraaminobenzoic acid derivatives such as ethyl paraaminobenzoate and 2-ethylhexyl paradimethylaminobenzoate, methoxycinnamic acid derivatives such as ethyl paramethoxycinnamate and 2-ethylhexyl paramethoxycinnamate, and 2-hydroxy. Benzophenone derivatives such as 4-methoxybenzophenone, octyl salicylate, salicylate derivatives such as phenyl salicylate, 4-tert
-Butyl-4'-methoxydibenzoylmethane and the like can be mentioned.

Hydrophobic polymers or hydrophobic chain substances include hydrocarbon oils such as paraffin, isoparaffin and squalane, saturated higher alcohols such as cetanol, stearyl alcohol and behenyl alcohol, oleyl alcohol, linoleinyl alcohol and linole. Unsaturated higher alcohols such as nyl alcohol, saturated higher fatty acids such as myristic acid, palmitic acid, stearic acid, and behenic acid, unsaturated higher fatty acids such as linoleic acid and linolenic acid, and long-chain α-hydroxy acids, Examples include retinol (vitamin A), retinal, α-carotene, β-carotene, γ-carotene, α-tocopherol (vitamin E), fat-soluble vitamins such as vitamin K, and prostaglandins.

Further, the above-mentioned dyes, ultraviolet absorbers and the like can also be bound to the above hydrophobic polymer or chain substance.

On the other hand, as the cyclodextrin forming the polyrotaxane, α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin can be used, and the appropriate inclusion property can be obtained depending on the structure of the polymer or chain substance forming the complex. Use what is shown.

[0018]

In the external preparation for skin of the present invention, even a liquid polymer such as liquid oil or a chain substance can be stably blended in a base containing powder as a main component, and vitamins can be added. First, a physiologically active substance can be stably mixed. When dyes are bound to a polymer or a chain substance, good and stable color development is obtained. Furthermore, when the external preparation for skin according to the present invention is applied to the skin, the cyclodextrin which forms the polyrotaxane under the action of the enzyme on the skin is gradually decomposed, and the polymer or chain substance clathrated in the cyclodextrin is reduced. Since it is released gradually, various actions can be continuously exerted.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention can be preferably carried out particularly as a skin external preparation containing powder as a main component of a base. It can also be carried out in a form in which polyrotaxane is dispersed in an aqueous base or a gel base. Further, it can be carried out in the form of powder cosmetics, lotion, gel cosmetics, emulsions and the like.

[0020]

EXAMPLES The present invention will be described in more detail with reference to Examples.

First, Table 1 shows the polyrotaxanes compounded in the external preparation for skin in the examples of the present invention. Table 1
In the above, polyethylene glycol, polypropylene glycol and polymethoxy vinyl ether having a molecular weight of 1,000, 1,000 and 2,000 were used.

[Table 1]

An example of the method for preparing the polyrotaxane shown in Table 1 is as follows. For the polyrotaxanes 1 to 6 formed by forming a complex with a water-soluble polymer or a chain substance, an aqueous solution of the polymer or the like and an aqueous cyclodextrin solution. It can be obtained by mixing and and collecting the precipitated complex. For polyrotaxanes 7 to 10 formed by forming a complex with a hydrophobic polymer or chain substance, the polymer or chain substance is solubilized in an aqueous solution of cyclodextrin, the liquid one is solubilized as it is, and the solid one is solubilized in an organic solvent. Then, gradually add it and incorporate it into cyclodextrin,
Obtained by collecting the precipitated complex. Regarding the polyrotaxanes 11, 12, and 13 containing polyethylene glycol to which an ultraviolet absorbing group and a dye are bound, the polyethylene glycol is dissolved in a polar organic solvent and mixed with an aqueous cyclodextrin solution to collect the precipitated complex. It can be obtained by

Example 1 Dermatitis powder (1) Talc 53.0 (wt%) (2) Zinc oxide 3.0 (3) Magnesium stearate 4.0 (4) Polyrotaxane 1 40.0 Manufacturing method: (1) to (3) are mixed with a blender and passed through a crusher for crushing, and then (4) is added and mixed uniformly.

Example 2 Skin Lotion (1) Ethanol 5.0 (wt%) (2) Hydroxyethyl Cellulose 1.0 (3) Polyrotaxane 2 10.0 (4) Polyrotaxane 3 3.0 (5) Polyrotaxane 5 6.0 (6) Purified water 75.0 Production method: After mixing (1), (2) and (6) to homogenize, (3)-
(5) is sequentially added and dispersed.

[Example 3] Emulsion for skin (1) Stearic acid 0.2 (wt%) (2) Cetanol 1.5 (3) Vaseline 3.0 (4) Liquid paraffin 7.0 (5) Polyoxy Ethylene (10 E.O.) monooleic acid 1.5 ester (6) Glycerin 5.0 (7) Methyl paraoxybenzoate 0.2 (8) Triethanolamine 1.0 (9) Polyrotaxane 2 5.0 (10 ) Polyrotaxane 5 5.0 (11) Polyrotaxane 9 5.0 (12) Polyrotaxane 10 5.0 (13) Purified water 60.6 Method: Mix the oil phase components (1) to (5) and heat to homogeneity Dissolve in and keep at 70 ° C. On the other hand, the water phase components (6) to (8) and (13) are mixed and heated to homogenize the mixture to 70 ° C. The above oil phase component is gradually added to this water phase component while stirring to emulsify, and after cooling, (9) to (12) are added and dispersed at room temperature.

Example 4 Gel Skin Agent (1) Dipropylene Glycol 10.0 (wt%) (2) Carboxyvinyl Polymer 0.5 (3) Potassium Hydroxide 0.1 (4) Paraoxybenzoic Acid Methyl 0.1 (5) Polyrotaxane 7 6.0 (6) Polyrotaxane 9 6.0 (7) Polyrotaxane 10 6.0 (8) Purified water 71.3 Manufacturing method: (2) is uniformly dissolved in (8) Then, (4) is dissolved in (1) and added, and then (3) is added to increase the viscosity, and (5) to (7)
To disperse.

Example 5 Whitening Lotion (1) Ethanol 14.0 (wt%) (2) 1,3-Butylene Glycol 4.0 (3) Methyl Paraoxybenzoate 0.1 (4) Polyrotaxane 4 10 .0 (5) Perfume 0.1 (6) Purified water 71.8 Manufacturing method: (1) to (3) and (5) are mixed and dissolved, and together with (4)
Add to (6) and mix.

Example 6 Moisturizing Emulsion (1) Squalane 5.0 (wt%) (2) Vaseline 2.0 (3) Beeswax 0.5 (4) Sorbitan sesquioleate 0.8 (5) Poly Oxyethylene (20E.O.) sorbitan 1.2 Monolauric acid ester (6) Propylene glycol 5.0 (7) Carboxyvinyl polymer 1.0 wt% aqueous solution 20.0 (8) Potassium hydroxide 0.1 (9) Methyl paraoxybenzoate 0.1 (10) Polyrotaxane 6 3.0 (11) Polyrotaxane 7 3.0 (12) Perfume 0.1 (13) Purified water 59.2 Process: Oil phase of (1) to (5) The ingredients are mixed and heated to 70 ° C. On the other hand, the water phase components (6), (9) and (13) were mixed and heated to 70 ° C., the oil phase was added to this to pre-emulsify, and then (7) was added to uniformly mix them. After that, add (8) to neutralize,
Emulsify uniformly with a homomixer and cool. After cooling,
Add (10) to (12) at 40 ° C. and mix and disperse uniformly.

[Example 7] Emollient face powder (1) Talc 51.2 (% by weight) (2) Kaolin 15.0 (3) Precipitated calcium carbonate 5.0 (4) Zinc oxide 10.0 (5) Stearine Magnesium acid 5.0 (6) Red iron oxide 1.0 (7) Yellow iron oxide 2.5 (8) Black iron oxide 0.2 (9) Polyrotaxane 8 10.0 (10) Perfume 0.1 Manufacturing method: (1) (6) ~ (8) is added to and mixed in a blender, (2) ~ (5) is added to this and mixed (10) is sprayed,
Mix evenly. After crushing this through a crusher,
Add (9) and mix evenly.

[Example 8] Emollient powder foundation (1) Talc 38.8 (wt%) (2) Mica 15.0 (3) Titanium oxide 10.0 (4) Nylon powder 10.0 (5) Red iron oxide 3 0.0 (6) Yellow iron oxide 2.5 (7) Black iron oxide 0.5 (8) Liquid paraffin 5.0 (9) Octyldodecyl myristate 2.5 (10) Vaseline 2.5 (11) Paraoxybenzoic acid Methyl acid 0.1 (12) Polyrotaxane 6 10.0 (13) Perfume 0.1 Manufacturing method: Mix (1) to (7) and grind through a grinder. This is transferred to a blender, (8) to (11) and (13) are added and mixed uniformly, and after pulverizing again, (12) is added and uniformly dispersed. This is filled in a gold plate and compression molded.

[Example 9] Two-way foundation for sunscreen (1) Silicone treated talc 20.2 (wt%) (2) Silicone treated sericite 20.0 (3) Silicone treated Kaolin 5.0 (4) Silicone treated Titanium oxide 10.0 (5) Silicone-treated red iron oxide 2.5 (6) Silicone-treated yellow iron oxide 2.0 (7) Silicone-treated black iron oxide 0.1 (8) Polyethylene powder 10.0 (9) Liquid paraffin 4 0.0 (10) Squalane 2.0 (11) Methylphenylpolysiloxane 4.0 (12) Methyl paraoxybenzoate 0.1 (13) Polyrotaxane 11 10.0 (14) Polyrotaxane 12 10.0 (15) Perfume 0 .1 Production method: (1) to (8) are mixed and pulverized through a pulverizer. This is transferred to a blender, (9) to (12) and (15) are added and uniformly mixed, and after pulverizing again, (13) and (14) are added and uniformly dispersed. This is filled in a gold plate and compression molded.

Example 10 Bath Agent (1) Sodium Sulfate 46.8 (wt%) (2) Sodium Bicarbonate 50.0 (3) Polyrotaxane 13 3.0 (4) Perfume 0.2 Manufacturing Method: (1 ) ~ (4) are mixed and homogenized.

Among the above-mentioned examples, first of all, the skin preparations of Examples 1 to 4 were evaluated for stability and therapeutic effect on dermatitis. At this time, the polyrotaxane in the example was replaced with the drug contained in the complex, and the one prepared as shown in Table 2 was used as a comparative example. In addition, in Comparative Examples 1 to 4 shown in Table 2, the same amount of the drug as the calculated value of the drug component contained in each example was contained.

[Table 2]

Regarding the stability, after storage at 25 ° C. for 3 months, the appearance and the state were changed and the presence or absence of a decrease in the activity of the drug was observed.
"○: No change in appearance and condition and decrease in drug activity", "△: Some change in appearance and condition or decrease in drug activity", "X: Change in appearance, condition or drug" The activity was markedly reduced. " Regarding the therapeutic effect on dermatitis, 20 patients with dermatitis were set as one group, and each group was allowed to use the Example and Comparative Example once a day for 1 week in a blind, and the improvement situation of dermatitis was observed. .
The results were evaluated in three grades of "improved", "slightly improved" and "no change", and the number of panelists who accepted each evaluation was shown. The above results are summarized in Table 3.

[0035]

[Table 3] From Table 3, in all of the examples of the present invention, good stability was observed, and the stabilizing effect of vitamins was particularly remarkable. Further, a good therapeutic effect on dermatitis was observed in the group used in Examples. It is considered that this is because the drug component is well retained on the skin in the present invention and is gradually released from the polyrotaxane. On the other hand, especially in Comparative Examples 3 and 4 in which oil-soluble vitamins were mixed, the stability was poor, and in each Comparative Example, the degree of treatment of dermatitis was significantly lower than that in the corresponding Example.

Next, in Example 5, the stability and the effect of improving the pigmentation symptom were evaluated. 25 ° C for stability
After storage for 3 months, the presence or absence of changes in appearance and state was observed, and when these changes were not observed, it was expressed as ◯, when some changes were recognized as Δ, and when significant changes were recognized as x. Regarding the effect of improving pigmentation symptoms, 1 panel of 20 panelists with skin pigmentation symptoms such as spots and freckles
Each group was used as a group once a day for one week in the blinds for one week, and the effect of improving pigmentation symptoms was observed. The results were evaluated in three grades of "improved", "slightly improved" and "no change", and the number of panelists who accepted each evaluation was shown. The above results are summarized in Table 4. In addition,
In Example 5, instead of polyrotaxane 4, ascorbic acid phosphoric acid ester was blended in an amount of 0.5% by weight, which was almost the same as the effective amount in Example, and the total amount was 100.
What made 0 weight% was made into the comparative example 5.

[0037]

[Table 4] From Table 4, Example 5 of the present invention showed good stability, 8
A clear improvement in pigmentation symptoms was observed in 0% of panelists. On the other hand, in Comparative Example 5, the stability was poor, and therefore the pigmentation symptom was not sufficiently improved.

Subsequently, in Example 6, stability was evaluated in the same manner as described above, and a usage test was conducted for feeling of use. In the use test, 20 female panelists aged 20 to 50 were used as one group, and the examples and the comparative examples were used blindly to perform a sensory evaluation on the moist feeling, refreshing feeling, and sticky feeling of the emulsion. The results are "yes; 5 points" and "somewhat;
4 points "," neither can be said; 3 points "," somewhat not;
"2 points", "no; 1 point", "no"; 5 points "," somewhat not; 4 points "," neither can be said; 3 points ","somewhat; 2 points "," yes " Scored as "1 point", and the average value of 20 persons was calculated and shown. These results are summarized in Table 5. In Example 6, instead of polyrotaxanes 6 and 7, 0.15% by weight and 0.10% by weight of a collagen-derived peptide and a long-chain α-hydroxy fatty acid were blended, and the total amount was 100.00% by weight with purified water. Was used as Comparative Example 6.

[0039]

[Table 5] From Table 5, good stability was observed in Example 6 of the present invention, but in Comparative Example 6, alteration of collagen-derived peptide and precipitation of long-chain α-hydroxy acid were observed. Also in the results of the use test, Example 6 had a refreshing feeling in addition to a sufficient moist feeling, and almost no sticky feeling was recognized. On the other hand, in Comparative Example 6, few panelists recognized a refreshing feeling, and a slight sticky feeling was also recognized.

Next, a usage test was conducted on Examples 7 and 8 of the present invention. A group of 20 female panelists aged 20 to 50 was used as a group, and each of the examples and comparative examples was blindly used, and sensory evaluation was performed on moist feeling, dry feeling, sticky feeling and makeup lasting. The results are "yes; 5 points" for moist and dry feeling,
"Somewhat; 4 points", "Neither can be said; 3 points",
"Slightly no; 2 points", "No, 1 point", "No; 5 points", "Slightly No; 4 points", "Neither can be said; 3 points", "Slightly; 2 points" for sticky feeling ","is there;
1 point ", for makeup lasting"good; 5 points "," somewhat good; 4 points ","normal; 3 points "," somewhat bad; 2 points ",
"Poor; 1 point" was scored and the average value of 20 persons was calculated and shown in Table 6. In Example 7, polyrotaxane 8 was replaced with 0.5 wt% of squalane, and polyrotaxane 6 was replaced with 0.5 wt% of a peptide derived from collagen in Example 8, and the total amount was 100.0 wt% with talc. And Comparative Example 7 and Comparative Example 8, respectively.

[0041]

[Table 6] As is clear from Table 6, in Examples 7 and 8 of the present invention, moderate moisturizing feeling, good dry feeling and makeup lasting property were observed, and sticky feeling was not recognized by most panelists. It was On the other hand, in Comparative Examples 7 and 8, the evaluation of the dry feeling was rather poor, a slight sticky feeling was also observed, and the makeup durability was insufficient.

For Example 9 of the present invention, a sun protection factor (Sun Protection Factor,
SPF) and skin irritation were evaluated.

For the measurement of SPF, 20 adult males of skin types I to III were used as subjects, and the minimum erythema dose (MED) in the uncoated area of the back was determined in advance, and then 2 mg was applied to the back.
/ In ratio of cm ² and the sample was applied to a portion of 20 cm ^2, using a xenon arc solar simulator as a light source,
The sample was irradiated with the SPF value equal to or higher than the expected SPF value in 5 steps at a common ratio of 1.3, and the MED of the sample application portion was obtained.
The SPF value was calculated by the following equation (1) and expressed as the average value of each subject.

[Equation 1]

On the other hand, for skin irritation, a clogging test was conducted for 48 hours using 30 male panelists for each sample.
The results were evaluated according to the criteria shown in Table 7, and the average value of the skin irritation index of 30 persons was obtained.

[Table 7]

In Example 9, polyrotaxane 1
1 and 12 are 2-ethylhexyl paramethoxycinnamate,
2-Ethylhexyl Paradimethylaminobenzoate 1.0 each
Replace with wt% and use silicone-treated talc for a total of 10
What was made into 0.0 weight% was made into the comparative example 9.

[0046]

[Table 8] Table 8 summarizes the above results. From Table 8, in Example 9 of the present invention, although the actual content of the ultraviolet absorbing group was smaller than that in Comparative Example 9, the SP was almost the same.
The F value is shown, while no skin irritation is observed. On the other hand, in Comparative Example 9, some skin irritation was observed. Thus, when the UV-absorbing group is introduced into the polymer forming the polyrotaxane, the dispersibility of the UV-absorber is improved and the skin absorption of these is suppressed, and the UV-absorbing effect and the safety to the skin are improved. It is thought that both can be improved.

Finally, in Example 10 of the present invention, the dispersibility of the dye and the color stability of the bath water were evaluated. Example 10
Polyrotaxane 13 in yellow 403 (1) 0.0
Replace with 2% by weight and use sodium sulfate to make the total amount 100.0.
The amount of 0% by weight was used as Comparative Example 10, and the dispersibility of the dye in the preparations of Examples and Comparative Examples and the stability of the color tone after immersing in the 42 ° C bath water for 3 hours were observed. It was expressed as “Good; ○”, “Slightly bad; Δ”, “Poor; ×”. The results are shown in Table 9.

[0048]

[Table 9] From Table 9, it was clear that in Example 10 of the present invention, the dispersibility of the dye and the stability of the color tone were better than those of Comparative Example 10.

[0049]

INDUSTRIAL APPLICABILITY As described in detail above, according to the present invention, a water-soluble or hydrophobic polymer or a chain substance is stably contained, and it is also compounded in a powder-based external preparation base or cosmetics. It was possible to obtain a skin preparation for external use which is highly biocompatible and safe for the skin. Further, in the present invention, various effects such as stabilization of unstable physiologically active ingredients and drugs, improvement of sustainability due to sustained release of active ingredient, and the like could be obtained.

Claims (4)

[Claims] 1. An external preparation for skin, which comprises a polyrotaxane. 2. The external skin preparation according to claim 1, wherein the polyrotaxane is formed from cyclodextrin and a water-soluble polymer or a chain substance. 3. The external preparation for skin according to claim 1, wherein the polyrotaxane is formed of cyclodextrin and a hydrophobic polymer or a chain substance. 4. The external preparation for skin according to claim 1, wherein the external preparation for skin is a cosmetic.