JPH09216810A - Composition for skin and oral cavity application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a water-based composition which is applied to the skin and oral cavity, stably contains an oil-soluble substance and a peptide and is highly biocompatible and safe to the skin and the mucous membrane of oral cavity. SOLUTION: One or more kinds of oil-soluble substances or peptides are selected, included in a cyclodextrin polymer tube and compounded. The oil- soluble substance is e.g. a chain hydrocarbon, higher aliphatic alcohol, higher fatty acid, terpenoid, steroid, oil-soluble vitamin, prostaglandin, phospholipid, sphingolipid, oil soluble dye or ultraviolet-absorber. The peptide is e.g. a physiologically active peptide such as hydrolyzed product of skin-constituting protein, peptide hormone, interleukin, epidermal proliferation factor or fibroblast growth factor.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel skin and oral composition comprising a cyclodextrin polymer tube containing an oil-soluble substance or a peptide.

[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 of including a fragrance in hydroxypropylated cyclodextrin (Journal of the Japanese Cosmetic Science Society 17 (1) 73-83
(1993), JP-A-7-241333, etc.) is disclosed.

Further, in order to solubilize a particularly insoluble substance in a stable manner, a method using a cyclodextrin polymer produced by crosslinking cyclodextrin with epichlorohydrin or the like has been proposed (Japanese Patent Laid-Open No. 61-9702).
5).

However, it is difficult to stably include a long-chain polymer or a chain-like substance in cyclodextrin, and in the polymer formed by simply crosslinking cyclodextrin as described above, cyclodextrin is randomly distributed. It is difficult to efficiently arrange the above-mentioned polymers and the like in order to arrange them, and it is also impossible to arrange the oil-soluble substances in a linear arrangement.

[0005]

DISCLOSURE OF THE INVENTION In the present invention, an aqueous skin external preparation or cosmetic or oral composition stably containing an oil-soluble substance or peptide, which has biocompatibility and skin or oral cavity It is intended to provide a highly safe mucous membrane.

[0006]

[Means for Solving the Problems] Recently, a cyclodextrin polymer tube synthesized from polyrotaxane in which many cyclic molecules are confined in one molecule has been reported (Pharmacia 31 (11) 1258-1267 (1995), Natur
e 364 516-518 (1993)), this time, they found that good results were obtained by applying this cyclodextrin polymer tube, and completed the present invention.

The cyclodextrin polymer tube used in the present invention can be prepared, for example, as follows. First, a complex of α-cyclodextrin and a polymer such as polyethylene glycol bisamine is formed and isolated, dried and then reacted with dinitrofluorobenzene or the like in a polar solvent such as dimethylformamide to form a bulky substituent. Thus, polyrotaxane having both ends blocked is obtained. This polyrotaxane is dissolved in a thin alkaline solution, and after cyclodextrin is crosslinked with epichlorohydrin or the like, by heating in a concentrated alkaline solution to cleave the terminal substituents, the polymer inside also escapes, and the desired polymer A tube is obtained.

In the above, when a polyrotaxane is formed, a polypropylene glycol derivative is used as a polymer to obtain a β-cyclodextrin polymer tube, and a polymethyl vinyl ether derivative is used to obtain a γ-cyclodextrin polymer tube. it can.

As the oil-soluble substance to be encapsulated in the cyclodextrin polymer tube, chain hydrocarbons, higher aliphatic alcohols, higher fatty acids, terpenoids, steroids, oil-soluble vitamins, prostaglandins, phospholipids, sphingolipids, Examples thereof include oil-soluble dyes and ultraviolet absorbers.

Examples of the chain hydrocarbons include saturated or unsaturated hydrocarbons such as liquid paraffin, isoparaffin, squalene, squalane, pristane and the like.

Examples of the higher aliphatic alcohol include saturated 1-decanol (capryl alcohol) to 1-docosanol (behenyl alcohol) having a carbon number of about 10 to 22.
1-alcohol, 2-decanol to 2-docosanol, etc., saturated 2-alcohol having 10 to 22 carbon atoms, undecenol to docosenol, linoleyl alcohol, linolenyl alcohol, etc., having 10 to 22 carbon atoms, unsaturated Examples include alcohol.

The higher fatty acid has 10 to 2 carbon atoms such as decanoic acid (capric acid) to docosanoic acid (behenic acid).
About 2 linear saturated fatty acids, about 10 to 22 carbon linear monoenoic acids such as decenoic acid to docosenoic acid, and about 10 to 22 carbon atoms such as linoleic acid, linoelaidic acid, linolenic acid, and arachidonic acid. Tri and tetraenoic acid, carbon number 1
Α-hydroxy fatty acid of about 0 to 22 and the like can be mentioned.

Examples of the above-mentioned terpenoids include aromas such as myrcene, limonene, geraniol, menthol and farnesol, flavor components, α-carotene, β-carotene and γ-carotene.

Examples of the steroids include sterols such as cholesterol, dihydrocholesterol, cerebrosterol and phytosterol, triterpene alcohols such as lanosterol and dihydrolanosterol,
Examples thereof include steroid hormones such as estrone, estradiol, pregnenolone, and corticosteroids, and steroid analogs such as glycyrrhizic acid and glycyrrhetinic acid can also be preferably used.

Examples of the oil-soluble vitamins include retinol (vitamin A), retinal, ergocalciferol (vitamin D), α-tocopherol (vitamin E), vitamin K and the like.

Examples of the above prostaglandins include prostaglandins (PG) E ₁ , PGE ₂ , PGD ₂ ,
PGI _{2 and the} like can be mentioned.

Examples of the phospholipid include phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidylinositol and phosphatidylglycerol.

Examples of the sphingolipid include sphingomyelin, cerebroside, sulfatide, ceramide oligohexoside, globoside, ganglioside and the like. In addition, sphingosine and ceramide, which compose the sphingolipid, can be included in the cyclodextrin polymer tube.

The above oil-soluble dyes include rhodamine B.
Stearate (red 215), tetrabromofluorescein (red 223), Sudan III (red 225)
No.), dibromofluorescein (daidai 201
No.), Fluorescein (Yellow No. 201), Quinoline Yellow WS (Yellow No. 204), Azulin Purple SS (Purple No. 201), Oil Red XO (Red No. 505), Orange SS (Daidai No. 403), Yellow AB (Yellow) No. 404), yellow OB (yellow 405), sudan blue (blue 403) and the like.

Examples of the UV absorber include para-aminobenzoic acid derivatives such as ethyl para-aminobenzoate and 2-ethylhexyl para-dimethylaminobenzoate, methoxy-cinnamic acid derivatives such as ethyl para-methoxycinnamate and 2-ethylhexyl para-methoxycinnamate, 2- Benzophenone derivatives such as hydroxy-4-methoxybenzophenone, octyl salicylate, salicylate derivatives such as phenyl salicylate, 4-te
Examples include rt-butyl-4′-methoxydibenzoylmethane.

On the other hand, as the peptides which can be encapsulated in the cyclodextrin polymer tube, in particular, hydrolysates of keratin, collagen, elastin, etc., which are skin constituent proteins, adrenocorticotropic hormone releasing hormone, thyroid stimulating hormone releasing hormone, growth hormone. Hormones such as hypothalamic hormones such as releasing hormone, melanocyte stimulating hormone, thyroid stimulating hormone, adrenocorticotropic hormone, gonadotropin, growth hormone, melanocyte stimulating hormone, interleukins, epidermal growth factor (EGF), fibroblast growth factor (FGF), and other physiologically active peptides.

The cyclodextrin polymer tube for encapsulating the above oil-soluble substance or peptides is more suitable than the polymer tube for α-cyclodextrin than the polymer tube for γ-cyclodextrin, depending on the size and bulkiness of the substance to be encapsulated. Select and use the appropriate one.

[0023]

In the composition for skin and oral cavity of the present invention,
An oil-soluble substance can be stably and satisfactorily dispersed and mixed in an aqueous base, and the sustainability of the activity of physiologically active substances such as vitamins can be increased. Furthermore, it is possible to reduce the skin or oral mucous membrane irritation of physiologically active substances such as peptides.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention can be preferably carried out particularly as an aqueous or gel-type external preparation for skin.
Furthermore, it can be carried out in the form of an aqueous cosmetic such as a lotion, a cosmetic gel, an emulsion. It can also be carried out as an oral composition such as a mouthwash and a refreshing agent in the mouth.

[0025]

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

First, Table 1 shows the cyclodextrin polymer tubes containing oil-soluble substances and the like incorporated in the compositions for skin and oral cavity in the examples of the present invention. These are prepared by adding a substance to be encapsulated or a solution thereof to an aqueous solution of a cyclodextrin polymer tube while agitating and dispersing the substance, and incorporating the substance into the cyclodextrin polymer tube.

[Table 1]

Next, as Examples 1 to 3 of the present invention, Table 2 shows prescriptions of skin lotions. They are,
After mixing (1), (2) and (4) in Table 2 to make them uniform, (3) is sequentially added and dispersed to prepare.

[Table 2]

Next, Table 3 shows the formulations of skin emulsions as Examples 4 to 6 of the present invention. These are prepared as follows. The oil phase components (1) to (5) in Table 3 are mixed, heated to dissolve uniformly, and kept at 70 ° C. On the other hand, the water phase components (6) to (8) and (10) are mixed and heated to homogenize them to 70 ° C. The oil phase component is gradually added to this aqueous phase component while stirring to emulsify, and the mixture is cooled and (9) is added and dispersed at room temperature.

[Table 3]

Table 4 shows the formulations of gel skin preparations as Examples 7 to 9 of the present invention. These are prepared as follows. After (2) is uniformly dissolved in (6) in Table 4, (4) is dissolved in (1) and added, and then (3) is added to increase the viscosity and (5) is dispersed.

[Table 4]

Table 5 shows Examples 10 to 1 of the present invention.
2 shows the formulation of moisturizing lotion. The method for preparing these is as follows. In Table 5, (1) to (3) and (5) are mixed and dissolved, and (4) and (6) are added and mixed.

[Table 5]

Table 6 shows the formulation of the sunscreen emulsion which is Example 13 of the present invention. It is prepared as follows. The oil phase components (1) to (5) in Table 6 were mixed and heated to 70
° C. On the other hand, the water phase components (6), (9), and (12) 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, (8) is added to neutralize, uniformly emulsified with a homomixer and cooled.
After cooling, add (10) and (11) at 40 ℃, mix evenly,
Disperse.

[Table 6]

Table 7 shows the formulation of the mouth cooling agent of Example 14 of the present invention. This is (1), (2), (4) in Table 7.
Are mixed and homogenized, and (3) is dispersed therein to prepare.

[Table 7]

Table 8 shows the formulations of the aqueous bath salts as Example 15 and Example 16 of the present invention. These are prepared by mixing and homogenizing (1), (2) and (4) in Table 8 and dispersing (3).

[Table 8]

Among the above-mentioned examples, first of all, the skin preparations of Examples 1 to 9 were evaluated for stability and therapeutic effect on dermatitis. At this time, instead of the cyclodextrin polymer tube encapsulating the oil-soluble substance or the like in each example, each oil-soluble substance or the like was blended without enclosing in the cyclodextrin polymer tube, and the total amount was 100.0 with purified water.
What was adjusted to weight% was made into the comparative example. In addition, the blending amount of the oil-soluble substance or the like in each comparative example is such that the oil-soluble substance-containing cyclodextrin polymer tube in each example is included so as to be contained in the same degree as the calculated value of these components contained in each example. 1/10 amount of the compounding amount of.

Regarding the stability, after storage at 25 ° C. for 3 months, the appearance and condition and the presence or absence of activity reduction of oil-soluble substances and the like were observed and evaluated. Etc. "is not observed", "△; Appearance and state change or a slight decrease in activity of oil-soluble substances, etc.", "x;
The appearance and state changes or the activity of oil-soluble substances, etc. is significantly reduced. " Regarding the therapeutic effect on dermatitis, 20 dermatitis patients were set as one group, and each group was allowed to use each of the Example and Comparative Example once a day for one week in a blind,
The improvement situation of skin inflammation was observed. The result is "improvement",
The evaluation was made in three grades of "slightly improved" and "no change", and the number of panelists who accepted each evaluation was shown. The above results are summarized in Table 9.

[0036]

[Table 9] From Table 9, in all of the examples of the present invention, good stability was observed. Further, in the group used in the Examples, a tendency of improving dermatitis was observed in all panelists. This is because, in the present invention, an oily component having an emollient effect on the skin and a component having a cell activating effect, an anti-inflammatory effect, a wound healing effect, etc. are well retained on the skin and gradually released from the cyclodextrin polymer tube. It is thought that this is due to the release. On the other hand, in each of the comparative examples, the oil-soluble substance was not stably dispersed, and retinol,
As for prostaglandin E ₁ and epidermal growth factor, the activity was remarkably decreased. Moreover, the therapeutic effect on dermatitis was also insufficient.

Next, with respect to Examples 10 to 12,
The stability was evaluated in the same manner as described above, and the use test was conducted for the 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 blindly used, respectively, and a sensory evaluation was performed on the moisturizing feeling, refreshing feeling, and sticky feeling of the lotion. . The result is "There is a moist feeling and a refreshing feeling;
"Point", "Somewhat; 4 points", "Neither can be said; 3
"Point", "Slightly; 2 points", "No; 1 point", "No; 5 points", "Slightly No; 4 points" for stickiness
"I can't say either; 3 points", "Somewhat; 2 points",
"Yes; 1 point" was scored and the average value of 20 persons was calculated and shown. The results are summarized in Table 10.
Comparative Examples 10 to 12 were prepared in the same manner as above.

[0038]

[Table 10] From Table 10, good stability was observed in all of the examples of the present invention, but separation and precipitation of oil-soluble substances and alteration of collagen-derived peptides were observed in comparative examples. Also in the use test results, in each of the use groups of the examples, in addition to a sufficient moist feeling, a refreshing feeling and almost no sticky feeling were recognized. On the other hand, in the group using the comparative examples, a few panelists felt a refreshing feeling, and a sticky feeling was considerably observed.

Next, with respect to Example 13 of the present invention, a sun protection factor (Sun Protection Factor)
r, 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 closure patch test was conducted for 48 hours using 30 male panelists for each sample,
The results were evaluated according to the criteria shown in Table 11, and the average value of the skin irritation index of 30 persons was obtained. Comparative Example 13 was prepared in the same manner as above.

[Table 11]

[0042]

[Table 12] The above results are summarized in Table 12. From Table 12, in Example 13 of the present invention, a moderate SPF value is shown, and skin irritation is not recognized. On the other hand, in Comparative Example 13, some skin irritation was recognized even though the SPF value was considerably lower than in Example 13.
Thus, in the case of incorporating the ultraviolet absorber in the cyclodextrin polymer tube, the dispersibility of the ultraviolet absorber is improved and the skin absorption of these is suppressed, and the ultraviolet absorption effect and the safety to the skin are improved. It is thought that both can be improved.

In Example 14 of the present invention, the stability was evaluated in the same manner as described above, and the use test was performed on the strength and the durability of the refreshing feeling. In the use test, 20 male and female 20-year-old panelists were used as one group, and each of Example 14 and Comparative Example 14 was blindly used, and the refreshing feeling was "strong; 5 points", "somewhat strong; 4". Point ","normal;
“3 points”, “Slightly weak; 2 points”, “Weak; 1 point”, and “Persistent; 5 points”, “Slightly persistent; 4 points”, “Normal; 3 points”, “Not very persistent; 2 The results were scored by sensory evaluation of "point" and "does not last; 1 point". Comparative Example 14 was prepared in the same manner as above.

[0044]

[Table 13] The results are summarized in Table 13. From Table 13, it is shown that in Example 14 of the present invention, good stability was observed, an appropriate cooling sensation was obtained, and that it lasted well. On the other hand, in Comparative Example 14, the dispersibility of l-menthol was poor, and the evaluation of the sustainability of the refreshing feeling was also poor.

Finally, with respect to Examples 15 and 16, the storage stability and the persistence of color tone and aroma when added to bath water were evaluated. Storage stability is evaluated in the same manner as above,
Regarding the persistence of color tone and scent in the bath water, 40 ml of the bath water at 42 ° C. was poured with 10 ml of each of the Examples and Comparative Examples, and the stability of the color tone and the persistence of the scent after 3 hours were evaluated. Both are “good; ○” and “somewhat bad;
It was expressed as “Δ” and “poor; ×”. In addition, Comparative Examples 15 and 16 were prepared in the same manner as above. The results are summarized in Table 14.

[0046]

[Table 14] From Table 14, in Example 15 and Example 16 of the present invention,
It is clear that the dispersion stability of the fragrance component and the dye during storage, the stability of the color tone when the bath water is added, and the persistence of the fragrance are good. Further, in Comparative Examples 15 and 16, the dispersion stability of the fragrance components and the like was poor, and the stability of the color tone and the persistence of the scent were also poor.

[0047]

INDUSTRIAL APPLICABILITY As described in detail above, according to the present invention, an oil-soluble substance or peptide can be stably incorporated in an aqueous base, and it is highly biocompatible and safe for skin and oral mucosa. A skin and oral composition could be obtained. Further, in the present invention, various effects such as stabilization of unstable physiologically active ingredient, drug or peptide, improvement of sustainability due to sustained release of active ingredient, etc. could be obtained.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 9/50 A61K 9/50 V 31/01 ADA 31/01 ADA 31/045 ACK 31/045 ACK 31/07 31/07 31/20 31/20 31/355 31/355 31/557 31/557 31/575 31/575 31/685 31/685 38/22 47/40 J 47/40 D 37/24

Claims (14)

[Claims] 1. A composition for skin and oral cavity, which comprises one or more cyclodextrin polymer tubes containing an oil-soluble substance. 2. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is a chain hydrocarbon. 3. The skin and oral composition according to claim 1, wherein the oil-soluble substance is a higher aliphatic alcohol. 4. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is a higher fatty acid. 5. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is a terpenoid. 6. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is a steroid. 7. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is an oil-soluble vitamin. 8. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is prostaglandin. 9. The skin and oral composition according to claim 1, wherein the oil-soluble substance is a phospholipid. 10. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is a sphingolipid. 11. The skin and oral composition according to claim 1, wherein the oil-soluble substance is an oil-soluble pigment. 12. The composition for skin and oral cavity according to claim 1, wherein the oil-soluble substance is an ultraviolet absorber. 13. A composition for skin and oral cavity, which comprises a cyclodextrin polymer tube encapsulating a peptide. 14. The composition according to claim 1, wherein the composition for skin and oral cavity is a cosmetic for skin and oral cavity.