JP4260078B2 - Transdermal absorption enhancing skin external composition - Google Patents

Description

  The present invention relates to a skin percutaneous absorption-promoting skin external composition, and in particular, said skin external use which improves the percutaneous absorption ability of components that exhibit medicinal effects such as moisturizing effect, whitening effect, antioxidant effect, anti-chicken effect, etc. Relates to the composition.

  As for the above-mentioned composition for external use of skin, it is often preferable that its medicinal components permeate through the epidermis and act in the basal layer, such as a whitening agent, but the stratum corneum that forms the surface of human skin is barrier-like. Therefore, transdermal absorption of a water-soluble whitening component is not always effective. For this reason, in general, it has been attempted to add a so-called percutaneous absorption enhancer in order to enhance the percutaneous absorption of a medicinal component for a composition for external use on the skin.

Hirokawa Shoten, Pharmaceutical Development, Volume 13, Drug Delivery Methods, Chapter 2, Control of Absorption Process, 2.3 Improvement of Transdermal Absorption JP-A-8-67612 JP 2000-143475 A JP 2001-48781 A

  The conditions for such a transdermal absorption enhancer include: It must not be pharmacological, toxic, irritating or antigenic. 2. Has a transdermal absorption effect and is reversible. 3. It can coexist stably with various bases and can be applied to various dosage forms. 4). Do not impair the color, smell, feeling of use, etc. 5). It is said that it must be recognized as a component of an external composition for skin, such as cosmetics, quasi-drugs, and pharmaceuticals. It is known to use dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N, N-pyrrolidone or the like as a transdermal absorption accelerator for the purpose of improving the properties (Non-patent Document 1).

  However, these do not necessarily give effective transdermal absorption promoting ability, and because of strong skin irritation, they may cause rough skin and sometimes erythema on the skin. This is not always sufficient. Also, octanol, oleyl alcohol, lauric acid, etc. have a specific odor and skin irritation, are easily oxidized in the air, and often produce an acid odor. These are also not practical transdermal absorption enhancers from the viewpoint of off-flavor, usability, and the like.

  Various proposals have been made as a transdermal absorption enhancer for a whitening component and a hair-growth component in cosmetics and hair-growth compositions (JP-A-8-67612: Patent Document 1, JP-A-2000-143475: Patents). Document 2), these percutaneous absorption enhancers described in Patent Documents 1 and 2, etc. are all used selectively in combination with specific medicinal ingredients in each case, and various skin external compositions. It is not necessarily expected to be uniformly applicable to various dosage forms. Accordingly, there is a need for a versatile skin external composition that has low skin irritation, good usability, and can enhance the transdermal absorbability of various skin medicinal ingredients.

  The inventors of the present invention have a so-called amphiphilic property in which 1,2-alkanediols having 4 to 8 carbon atoms have lipophilicity and hydrophilicity, and can permeate the epidermis relatively easily. For example, since it has an affinity for water-soluble whitening components (arbutin and the like), it is predicted that these have the action of promoting percutaneous absorption of medicinal ingredients, and in particular, the degree of lipophilicity of 1,2-octanediol Focusing on the remarkable features, we studied the use of these as a percutaneous absorption enhancer of water-soluble medicinal components of the composition for external use on the skin. 1,2-octanediol and the like are not irritating and toxic to the skin and have antiseptic, antibacterial and moisturizing effects per se, and the present inventors have already proposed a composition for external use on the skin. (Japanese Patent Laid-Open No. 2001-48781: Patent Document 3). However, it is not known that these 1,2-octanediols and the like are used as a transdermal absorption enhancer.

As a result of studies and experiments by the present inventors on the effect of promoting transdermal absorption of the C ₄ -C ₈ 1,2-alkanediols to the externally applied medicinal components, these are all in comparison with the medicinal components. It has been found that when a 1,2-alkanediol is used as a mixture, it provides a significant absorption-promoting effect, and a remarkable accelerating effect is seen in the percutaneous absorption of the medicinal component.

According to the present invention, percutaneous absorption comprising a mixture of 1,2-octanediol and 1,2-pentanediol and / or 1,2-hexanediol with a specific water-soluble medicinal ingredient for external use on the skin. An accelerated skin topical composition is provided.

All of these 1,2-alkanediols have both lipophilicity and hydrophilicity, and when these mixtures are used in a water-soluble topical skin, they are transdermally absorbable. Is promoted. In particular, among the C _{4 to} C ₈ 1,2-alkanediols, 1,2-octanediol having the highest lipophilicity and high molecular weight is used in combination with 1,2-pentanediol and / or 1,2-hexanediol. As a result, it was found that the percutaneous absorbability of the external component for skin was remarkably improved.

  A preferred blending ratio of the 1,2-octanediol and 1,2-pentanediol and / or 1,2-hexanediol is 2 to 100: 100 (% by weight). A preferable transdermal absorption effect can be obtained by setting the blending ratio to 2: 100 or more. On the other hand, the effect improves as the blending ratio of 1,2-octanediol increases, but the degree of increase becomes substantially flat in the vicinity of 1: 1.

  Examples of the water-soluble medicinal ingredients used in the present invention include arbutin as a whitening agent and a plant extract containing the same, hydroquinone, 1-ascorbic acid and water-soluble salts thereof, water-soluble salts of ascorbyl phosphate, and ascorbic acid glucoside. There are alkali neutralized products. Anti-inflammatory components include glycyrrhizic acid salts and derivatives, and other low molecular collagen, peptides, water-soluble vitamins, and essential amino acids. In addition, so-called photosensitizing dyes that are attracting attention as components of compositions for external use of skin as exhibiting cell activation, macrophage activity effects and antibacterial properties in extremely small amounts, for example, 2,2 ′ [3- [2- (3-heptyl -4-methyl-2-thiazoline-2-ylidene) ethylidene] propenylene] bis [3-heptyl-4-methylthiazolinium iodide], 2- [2- (3-heptyl-4-methyl-2-thiazoline) 2-ylidene) methine] -3-heptylthiazolinium iodide, 6- [2- (5-bromo-2-pyridyl) aminovinyl] -1-ethyl-2-picolinium iodide, 2- (2 -Aminovinyl) -3,4-dimethyl-oxalolinium iodide, 2- (ρ-dimethylaminostyryl) -3-heptyl-4-methyl-thiazolinium iodide complex Examples thereof include cyclic compounds.

The composition for external use of the skin of the present invention takes forms such as whitening lotion, anti-inflammatory emulsion, skin protective emulsion, hair growth lotion, etc. as shown in each example, but is not particularly limited thereto, Various medicinal ingredients used according to the purpose and various dosage forms such as aqueous solutions, emulsions and creams can be generally applied. In each of such uses, in addition to the above-mentioned main active ingredient and C ₄ -C ₈ 1,2-alkanediol as a transdermal absorption enhancer in each case, for example, in the preparation of a normal skin external composition Fats and oils, waxes, surfactants, moisturizers, antioxidants, organic acids, alkalis, pigments, dyes, antiseptics, pH adjusters, UV absorbers, chelating agents, thickeners, Alcohol, a fragrance | flavor, water, etc. can be mix | blended. In these cases, the content of the mixture of C _{4 to} C ₈ 1,2-alkanediol is from 0.1 to 6.0% by weight based on the total formulation. If the blending ratio is 0.1% by weight or less, the desired effect of promoting percutaneous absorption cannot be obtained substantially. If the blending ratio is 6.0% by weight or more, skin irritation occurs, and the feeling during application becomes poor.

Percutaneous absorption promotion experiment In order to confirm the percutaneous absorption promotion action of the water-soluble medicinal ingredient by C ₄ -C ₈ 1,2-alkanediol in the present invention, pig skin showing physiological functions close to human skin is used as a skin sample. The experiment was carried out by the method shown below.

Experimental equipment / method Place the chemical sample phase of the water-soluble medicinal ingredient on the receptor phase placed in the thermostatic chamber (37 ^° C) through the pig skin fixed to the bottom, and pass through the pig skin to transfer to the receptor phase. A horizontal membrane cell configured to take out the chemical sample from the sampling port with stirring was used as an experimental apparatus. The receptor phase was stirred for 30 minutes while injecting standard gas (CO ₂ ), a sample was taken, and the concentration of β-arbutin permeated through the pig skin was measured by HPLC to determine the transdermal absorption rate.

Test condition temperature: 24 ± 1 ^o C
Water-soluble medicinal ingredients: β-Arbutin (1 g / L aqueous solution)
Transdermal absorption enhancer: 1,2-pentanediol (hereinafter PD), 1,2-hexanediol (hereinafter HD), 1,2-octanediol (hereinafter OD)
Phosphate buffer (PBS): pH 7.1

The C _{4 to} C ₈ 1,2-alkanediols were used as 300 cc of 1 g / L aqueous solution of each alkanediol or a mixture thereof with respect to 100 cc of 1 g / L aqueous solution of arbutin, and PBS + arbutin as a control group Only an aqueous solution was used.

  The PBS + arbutin transdermal absorption rate as a control group was 9.39 ± 9.45 (mg / cc). On the other hand, when PD and HD were added alone to arbutin, the absorption rate was not different from the control group or showed a lower value, and the OD was a very high value of 10.70 ± 4.26. showed that. On the other hand, when OD was mixed with PD or HD, the absorption rate of arbutin was as high as 303.07 ± 97.19 or 72.76 ± 46.60. In the above test, the mixing ratio of OD / PD and HD was first set to 1: 1. However, it was confirmed that the mixing ratio was 1:50 or more and the absorption rate of arbutin was significantly improved.

  Based on the above test results, 1,2-octanediol and 1,2-pentanediol and / or 1,2-hexanediol in order to enhance the transdermal absorption effect of various medicinal components of the water-soluble external composition composition for skin And various skin external compositions were prepared.

Example 1. Whitening lotion
PD 1.5% by weight
OD 0.5
1,3-butanediol 10.0
Ethanol 4.0
Glycerin 3.0
Xanthan gum 0.3
Arbutin 2.5
1-sodium ascorbate 3.0
Sodium citrate 0.3
Fragrance Adjust the total amount to 100.0 g with purified water.

Example 2 Anti-inflammatory latex HD 2.0% by weight
PD 1.0
OD 0.5
Propylene glycol 5.0
Glycerin 3.0
Pionine 0.002
Pyridoxine hydrochloride 0.5
Palmitic acid 3.0
Glyceryl stearate 2.0
Cetyl octanoate 5.0
Polysorbate 40 0.4
Fine particle titanium oxide 2.0
Dimethicone 0.2
Perfume appropriate amount xanthan gum 0.2
The total amount is made 100.0 g with purified water.

Example 3 FIG. Skin protection emulsion Palmitic acid 4.5% by weight
Cetanol 2.5
Glyceryl stearate 2.3
Polysorbate 40 0.6
Ultrapurified lanolin 3.8
Jojoba oil 2.0
Cetyl octanoate 5.0
HD: OD = 10: 3 2.0
1,3-butanediol 6.0
Glycerin 3.0
Luminekis 0.002
Hinokitiol 0.02
The total amount is made 100.0 g with purified water.

Example 4 Hair growth lotion PD: OD = 5: 1 4.0% by weight
Takanal 0.004
1,2-butylene glycol 1.0
Pantothenic acid Ca 0.2
Hinokitiol 0.05
Lactic acid menthyl 0.3
Assembly extract 4.0
Ethanol 20.0
Decaglycerin oleate 1.5
Fragrance Adjust the total amount to 100.0 g with purified water.

In each example:
PD = 1,2-pentanediol.
HD = 1,2-hexanediol.
OD = 1,2-octanediol.
Pin demon down = 2- [2- (3-heptyl-4-methyl-2-thiazoline-2-ylidene) methine] -3-heptyl-thiazolyl iodide (No. photosensitive dye 201).
Ruminekisu = 2- (2-amino-vinyl) -3,4-dimethyl - O key Zaroriniumuyou product (No. photosensitive dye 401).
Takanal = 6- [2- (5-bromo-2-pyridyl) aminovinyl] -1-ethyl-2-picolinium iodide (photosensitive dye 301).

In each of the above examples, various external compositions for skin using a mixture of C _{5 to} C ₈ alkanediols as a percutaneous absorption enhancer are stable regardless of their blending components and dosage forms. There was no skin irritation, and in particular, the effect of promoting transdermal absorption of medicinal components could be improved significantly.

Claims (3)

To a mixture of 1,2-octanediol and 1,2-pentanediol and / or 1,2-hexanediol, the following water-soluble external skin medicinal components (a), (b), (c), (d) A skin percutaneous absorption promoting skin external composition comprising at least one of the following :
(A) a whitening component comprising at least one of arbutin and sodium ascorbate,
(B) an antibacterial and anti-inflammatory component comprising at least one of pyridoxine hydrochloride and hinokitiol,
(C) a moisturizing component comprising at least one of glycerin and propylene glycol;
(D) 2- [2- (3-Heptyl-4-methyl-2-thiazoline-2-ylidene) methine] -3-heptylthiazolinium iodide, 2- (2-aminovinyl) -3, 4- A cell activation component comprising dimethyl-oxalolinium iodide and at least one photosensitive dye in 6- [2- (5-bromo-2-pyridyl) aminovinyl] -1-ethyl-2-picolinium iodide . The ratio of 1,2-octanediol and 1,2-pentanediol and / or 1,2-mixture of hexane diol 2-100: 100 by weight% claim 1 transdermal absorption promoting skin external composition according object.   2. The transdermal system according to claim 1, wherein the ratio of the mixture of 1,2-octanediol and 1,2-pentanediol and / or 1,2-hexanediol to the composition is 0.1 to 6.0% by weight. Absorption-promoting external composition for skin.