JP2000103722A - Promotion of percutaneous absorption - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently permeate a pharmacodynamic component through an application part by forming a gel having a card-house or net-work structure with an oil solution or an oil gelling agent and suppressing the lateral diffusion of the oil solution or the pharmacodynamic component mixed with the oil solution on skin. SOLUTION: A gel having a card-house or a net-work structure is formed with (A) an oil solution (e.g. a fatty acid ester, a polyfunctional carboxylic acid ester, or the like) and (B) an oil gelling agent (e.g. wax, metal soap, a dextrin fatty acid ester, or the like) and lateral diffusion of the oil solution or a pharmacodynamic component (e.g. a ceramide, a ceramide analog structural substance, a humectant, or the like) mixed with the oil solution on skin is suppressed to promote the percutaneous absorption at the application part. Preferably, a percutaneous absorption promoter comprises 1-99 wt.%, especially 5-90 wt.% of the component A and 0.001-60 wt.%, especially 0.01-50 wt.% of the component B.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for suppressing the lateral diffusion of a medicinal ingredient on the skin and promoting percutaneous absorption at an application portion, and a percutaneous absorption enhancer having such a function.

[0002]

2. Description of the Related Art As a method of efficiently penetrating a medicinal ingredient into skin, there are a method of using a transdermal absorption enhancer and a method of using an oil agent having a high affinity for a stratum corneum component as a penetration medium. However, the conventional percutaneous absorption enhancers did not provide sufficient effects and were not satisfactory in terms of safety, feeling of use, and the like. As an oil agent having a high affinity for the stratum corneum component, liquid oil is advantageous, but on the skin, the diffusion on the skin surface (lateral direction) is large due to the effect of the sebum oil film secreted from the sebaceous glands, which is effective The components could not be efficiently and locally penetrated only into the application part.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for efficiently penetrating a medicinal component into a site to be applied.

[0004]

That is, the present invention provides a method for forming a gel having a card house or a network structure by using an oil agent and an oil gelling agent, and applying a medicinal ingredient incorporated in the oil agent or the oil agent onto the skin. The present invention provides a method for suppressing the lateral diffusion of liposomes and promoting percutaneous absorption in the application section.

Further, the present invention relates to (a) an oil agent, and (b)
It contains an oil gelling agent that makes the NMR spectrum longitudinal relaxation time of the oil agent when mixed with the oil agent longer than that of the oil agent alone, and forms a gel having a card house or network structure when dissolved in the oil agent. It is intended to provide a transdermal absorption enhancer and a cosmetic containing the same.

[0006]

DETAILED DESCRIPTION OF THE INVENTION The oil agent used in the present invention is not particularly limited as long as it is blended in cosmetics and the like and is transdermally absorbed. For example, fatty acid esters, polycarboxylic acid esters, and fatty acid polyvalent oils are used. Examples thereof include alcohol esters, hydroxy acid esters, octyl methoxycinnamate, octyl paradimethylaminobenzoate, dl-α-tocopherol, and dl-α-tocopherol nicotinate.

The medicinal component used with the oil is not particularly limited as long as it can be dissolved in the oil and absorbed from the skin. For example, ceramides, ceramide-like structural substances, humectants, amino acids, whitening agents , An anti-inflammatory agent, a singlet oxygen scavenger, an antioxidant, an alcohol, a sterol, a blood circulation promoter and the like.

[0008] The oil gelling agent used in the present invention is not particularly limited as long as it can form a gel having a card house or network structure when dissolved in the oil agent. Representative examples include the following (i) to (iv). (I) A polymer substance having an oil-soluble property or a property of swelling remarkably in oil. For example, rubber is one example. (Ii) Oil-soluble resins such as carnauba wax and paraffin wax. (Iii) those which form an emulsion and harden the oil. For example, detergents and certain protein derivatives. (Iv) Low molecular weight organic compounds that form a unique molecular arrangement in oil that is different from that of the oil itself and solidify the oil.

[0009] Such oil gelling agents include wax, metal soap, dextrin fatty acid ester, 1,2-
Hydroxystearic acid and dibenzylidene sorbitol are preferred.

[0010] In the present invention, the card house structure formed of an oil agent and an oil gelling agent has a structure in which cards of playing cards are overlapped, and a network structure is a three-dimensionally mesh-like structure. Having the structure described above. These structures can be confirmed by a scanning electron microscope.

As the oil gelling agent, those which make the NMR spectrum longitudinal relaxation time of the oil agent when mixed with the oil agent longer than that of the oil agent alone are preferable. In the present invention, N
The relaxation time of the MR spectrum is measured by an inversion recovery method (inversion recovery). This is 180 °, -90 ° and-
This is a method using a 180 ° pulse sequence. First, when the first 180 ° pulse is given, the magnetization M ₀ becomes −Z
Defeated in the direction. This magnetization recovers in the Z-axis direction over time. The magnetization M (t) at time t is given by the following equation (1).

[0012]

[Equation 1] M (t) = M ₀ {1-2 EXP (−t / T ₁ )}

(Where M₀Is the magnetization at time 0 and M is
Magnetization at time t, where t is time and T ₁Is the vertical relaxation time
Show. ). Then after t hours a second 90 °
When a pulse is applied, the magnetization of the Z axis is tilted on the Y axis. This
, Sample the FID and set its size to time t.
Plotted on the other hand, the vertical
Interval T₁Can be calculated. In the present invention, NMR-EX
270 (manufactured by JEOL),¹³Vertical relaxation of C spectrum
The sum time was measured.

The oil gelling agent is such that when mixed with the oil agent used in this manner, the longitudinal relaxation time of the NMR spectrum of the oil agent is longer than the longitudinal relaxation time of the oil agent alone (the difference ΔT in the longitudinal relaxation time). ₍₁ is positive), and more preferably ΔT ₁ is more than 0 second and 1 second or less. When two or more types of oils are used, the longitudinal relaxation time of the NMR spectrum of the mixture of the oils when mixed with the mixture of the oils may be longer than the longitudinal relaxation time of the mixture of the oils alone. I just need.

In the present invention, such a gel having a card house or a network structure is formed by the oil agent and the oil gelling agent, whereby the oil agent or a medicinal ingredient incorporated in the oil agent is laterally diffused on the skin. Can be suppressed, and percutaneous absorption in the application part can be promoted, but in such a card house or network structure, having a powder can further promote absorption from the skin, preferable. The powder used here is not particularly limited as long as it is generally used for cosmetics, and examples thereof include dimethylsiloxane, methylhydrogensiloxane, and homo- or copolymers thereof, spherical resin powder (eg, spherical nylon and the like), Fine particle zinc oxide, polymethylsilsesquioxane, silica, mica, dialkyl phosphate, sericite, kaolin, talc, titanium oxide, iron oxide, alumina, zirconia and the like can be mentioned. These powders may be subjected to hydrophobic treatment such as silicone treatment, fluorine treatment, metal soap treatment, and fatty acid treatment.

[0016] These powders, as well as the oil gelling agent, the NMR spectrum longitudinal relaxation time of the oil agent when mixed with oil, is preferably intended to be longer than the case of the oil agent alone, [Delta] T ₁ is More preferably, there is more than 0 second and not more than 1 second. The powder has an average particle size of 0.001 to 100μ.
m is preferred. The powder is 0.001 to 50 with respect to the oil agent.
It is preferably used in the range of weight%.

The transdermal absorption enhancer of the present invention contains the above-mentioned (a) oil agent and (b) oil gelling agent. (A) One or more oil agents can be used, and it is preferable to mix 1 to 99% by weight, particularly 5 to 90% by weight in the whole composition. Further, one or more kinds of the oil gelling agent (b) can be used, and 0.001 to 60% by weight in the total composition,
In particular, it is preferable to add 0.01 to 50% by weight. Further, the ratio of the oil gelling agent to the oil agent is not particularly limited as long as the above-mentioned gel is formed,
It is preferably 1 to 60% by weight, particularly preferably 0.01 to 50% by weight.

It is preferable that the above-mentioned powder is further added to the transdermal absorption enhancer of the present invention because the absorption of oils and the like into the skin can be further promoted. One or more powders can be used, and 0.1 to 60% by weight, particularly 0.1 to
It is preferable to mix 50% by weight.

The transdermal absorption enhancer of the present invention may contain, in addition to the above-mentioned components, components commonly used in cosmetics and the like, for example, surfactants, polyhydric alcohols, organic acids, water and the like to impair the effects of the present invention. It can be appropriately compounded within a range not known.

The cosmetic of the present invention contains the above-mentioned percutaneous absorption enhancer, and its amount is preferably 0.001 to 60% by weight, particularly preferably 0.1 to 50% by weight.

In the cosmetic of the present invention, in addition to the above-mentioned components, components usually used in cosmetics, for example, the above-mentioned medicinal components, surfactants, water, fragrances, dyes, preservatives, etc. Can be appropriately compounded within a range that does not impair the effect of the above, and can be produced according to a usual method.

The cosmetic of the present invention can be applied to any dosage form such as emulsification type, dispersion type, two-layer type, solubilizing type, gel, etc., and lotion, emulsion, cream, pack, foundation, lipstick, lip It can be applied to cosmetics such as sticks.

[0023]

According to the present invention, it is possible to suppress the lateral diffusion of the oil agent or the medicinal ingredient blended in the oil agent on the skin surface and to promote the absorption at the application part. The active ingredient can efficiently penetrate only into the application site.

[0024]

EXAMPLES Example 1 Cosmetics having the compositions shown in Tables 1 to 4 were produced by a conventional method.
With respect to the obtained cosmetic, the percutaneous absorption of a spiro ether compound (a compound described in JP-A-7-206657) as a medicinal component was evaluated. Further, the structure of the gel was confirmed by a scanning electron microscope. The results are shown in Tables 1 to 4.

(Evaluation Method) Each cosmetic (50 mg) was applied to the skin surface (2 cm ² ) of Yucatan micropig and left in a thermo-hygrostat at 37 ° C. and saturated humidity for 18 hours. Thereafter, the unpermeated components remaining on the skin surface were removed, and the permeated components were extracted and recovered, and the amount of transdermal absorption of the spiroether compound was measured by HPLC. The sample application site was designated as area 1, and the site (3.3 cm ² ) 0.5 cm away from the application site was designated as area 2,
A region (4.8 cm ² ) separated by 1.0 cm was defined as area 3, and the amount of transdermal absorption in each area was measured. The results are shown in Tables 1 to 4. The numerical values are shown as relative values when the numerical value when all the coating amounts permeate is set to 100.

[0026]

[Table 1]

[0027]

[Table 2]

Example 2 An emulsion having the following composition was produced by a conventional method. The resulting emulsion had a network structure.

(Components) (% by weight) Palmitic acid 1.0 Stearic acid 1.0 Cetanol 1.0 Monohexadecyl phosphate sodium salt 2.0 Sorbitan monostearate 0.5 Glycerin 10.0 Ethanol 5.0 Spiroether compound 0.5 Isotridecyl isononanoate 3.0 1,3-dimethylbutylhexadecyl ether 1.0 Lactic acid 2.0 Polymethylsilsesquioxane (Tospearl 145A, manufactured by Toshiba Silicone Co., Ltd.) 5.0 Purified water balance

Example 3 A cream having the following composition was produced by a conventional method. The resulting cream had a network structure.

(Components) (% by weight) Stearic acid 2.0 Cetanol 1.0 Cholesterol 3.0 2-Hexadecylphosphate arginine salt 2.0 Polyoxyethylene hydrogenated castor oil (50EO) 0.5 α-mono Isostearyl glyceryl ether 0.2 Succinic acid 1.0 Kojic acid 1.0 Sodium hyaluronate 0.05 Polyacrylic acid 0.5 Sodium hydroxide 0.2 Dextrin fatty acid ester (Leopearl KL, manufactured by Chiba Milling Co., Ltd.) 3.0 Glycerin 5.0 Spiroether compound 0.5 Isotridecyl isononanoate 7.0 1,3-dimethylbutylhexadecyl ether 1.0 Polymethylsilsesquioxane (Tospearl 145A, manufactured by Toshiba Silicone Co., Ltd.) 5.0 Purified water balance

Example 4 A creamy foundation having the following composition was produced by a conventional method. The obtained foundation had a network structure.

(Ingredients) (% by weight) Titanium oxide 6.0 Sericite 8.0 Iron oxide 1.0 Sorbitan fatty acid ester (Reodol MO-6, manufactured by Kao Corporation) 5.0 Isotridecyl isononanoate 12.0 1, 3-dimethylbutylhexadecyl ether 3.0 sorbitan monostearate 0.5 dimethylpolysiloxane (KF90A 6cs, manufactured by Shin-Etsu Chemical Co., Ltd.) 30.0 spiroether compound 0.01 glycerin 2.0 silica (Sildex H-122, (Asahi Glass Co., Ltd.) 10.0 Dialkyl phosphate 2.0 Purified water Remainder

Example 5 A stick having the following composition was produced by a conventional method. The resulting stick had a card house structure.

Table 6 (Components) (% by weight) Liquid paraffin 5.0 Squalane 10.0 1,3-dimethylbutylhexadecyl ether 10.0 Dextrin fatty acid ester (Leopearl KL, manufactured by Chiba Milling Co., Ltd.) 3.0 Celesin 5.0 0 Silicone oil (SH244, manufactured by Toray Industries) 40.0 Titanium oxide 10.0 Spiroether compound 0.01 Microcrystalline wax (W-445, manufactured by Witco) Remainder

In each of the cosmetics obtained in Examples 2 to 5, the lateral diffusion of the oil agent and the medicinal ingredient on the skin was suppressed, and the absorption in the application part was promoted.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Yamagata Saki Seiji 2-1-3 Bunka, Sumida-ku, Tokyo F-term in Kao Corporation Research Laboratories 4C076 AA09 AA17 AA51 BB31 DD27 DD29 DD30 DD34 DD37 DD38 DD39 DD41 DD42 DD45 DD59 EE03 EE09 EE26 EE27 EE30 EE38 EE55 FF34 4C083 AB032 AB172 AB212 AB242 AB432 AC012 AC022 AC072 AC102 AC122 AC172 AC182 AC242 AC302 AC342 AC432 AC442 AC842 DD902 EE11

Claims (5)

[Claims] An oil agent and an oil gelling agent form a gel having a card house or a network structure, suppress lateral diffusion of the oil agent or a drug compound incorporated in the oil agent on the skin, and To promote percutaneous absorption of skin. 2. The method of claim 1, wherein the powder is in a card house or network structure. 3. The longitudinal relaxation time of an NMR spectrum of the oil agent when the oil gelling agent and / or powder is mixed with the oil agent,
3. The method according to claim 2, wherein the length is longer than that of the oil agent alone. 4. The longitudinal relaxation time of the NMR spectrum of (a) the oil agent and (b) the oil agent when mixed with the oil agent is made longer than that of the oil agent alone, and the card house or the network is dissolved when dissolved in the oil agent. A transdermal absorption enhancer containing an oil gelling agent for forming a gel having a structure. 5. A cosmetic comprising the percutaneous absorption enhancer according to claim 4.