JPH06128148A - Skin external preparation - Google Patents

Abstract

PURPOSE:To provide a skin external preparation excellent in the percutaneous absorbability of the physiologically active substance therein, also producible at a low cost. CONSTITUTION:The objective skin external preparation is characterized by essentially containing (1) a physiologically active substance, (2) a hardly volatile aliphatic dicarboxylic diester, (3) an oily substance, and (4) a surfactant.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a skin external preparation having excellent skin absorbability of a physiologically active substance contained therein.

[0002]

2. Description of the Related Art Conventionally, a mixture of a fatty acid ester or a fatty acid triglyceride (fat) with a surfactant has been widely used as a base for an external preparation for skin. Further, in Japanese Patent Publication No. 2-44815, 3 g of α-monomethyl branched isostearyl glyceryl ether is added.
A mixture of 25 g of petrolatum, 5 g of isopropyl myristate and 66 g of purified water is described. By the way, in the external preparation for skin, the skin absorbability of the physiologically active substance contained therein largely differs depending on the component composition of the base. The base disclosed in Japanese Patent Publication No. 2-44815 described above uses α-monomethyl-branched isostearyl glyceryl ether as its component,
It enhances the skin absorbability of physiologically active substances. However, this α-monomethyl-branched isostearyl glyceryl ether has a drawback that it is inferior in mixing solubility because it is high in production cost and is solid at room temperature.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a skin external preparation which is excellent in skin absorbability of a physiologically active substance contained therein and can be manufactured at low cost.

[0004]

As a result of earnest studies to solve the above-mentioned problems, the present inventor has surprisingly found that it is difficult to volatilize in a liquid state at room temperature, which is used as a plasticizer for low temperature in the plastic field. It was found that an external preparation excellent in skin absorbability (skin permeability) of a physiologically active substance can be produced at low cost by using a divalent aliphatic dicarboxylic acid diester, and thus completed the present invention. That is, according to the present invention, (i) a physiologically active substance, (ii) a non-volatile aliphatic dicarboxylic acid diester which is liquid at room temperature, (ii)
There is provided a skin external preparation characterized by containing i) an oily substance and (iv) a surfactant as essential components.

In the present invention, the aliphatic dicarboxylic acid diester used as a skin external preparation component is at room temperature (30 ° C.).
It is sufficient that it is a non-volatile substance that exhibits a liquid state, and that having a boiling point of 180 ° C. or higher is generally used. Such an aliphatic dicarboxylic acid diester is represented by the following general formula. R ¹ OOC- (CH ₂ ) n-COOR ² (1) In the above formula, R ¹ and R ² represent an aliphatic group, and n is 2 to 10.
Indicates an integer. The aliphatic group includes an alkyl group and an alkenyl group, the carbon number of which is 1 or more, and usually 1 to 12
Is. Specific examples of the aliphatic dicarboxylic acid diester include diethyl succinate, diisopropyl succinate,
Diethyl adipate, diisopropyl adipate, diisooctyl adipate, dioctyl adipate, didecyl adipate, decyl isooctyl adipate, diethyl azelate, diisopropyl azelate, diisooctyl azelate, diethyl sebacate, diisopropyl sebacate, dibutyl sebacate, Dioctyl sebacate and the like can be mentioned.

The oily substance used in the present invention is a substance which is liquid or solid at room temperature, and includes fatty acid ester, higher fatty acid triglyceride, higher aliphatic alcohol, higher fatty acid, petrolatum, lanolin, liquid paraffin, squalane, beeswax and them. A mixture of

The fatty acid ester used may be liquid or solid at room temperature. This fatty acid ester generally has 4 to 22 carbon atoms, preferably 8 to 8 carbon atoms.
It can be C ₂ -C ₁₈ lower and higher alcohol esters of saturated or unsaturated linear or branched fatty acids of the order of ₁₈ . Examples of the fatty acid component include butyric acid, octanoic acid, nonanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and oleic acid. Examples of alcohol components include ethanol, propanol, isopropanol, butanol, hexanol, decanol, myristyl alcohol, dodecanol, cetyl alcohol, and hexadecyl alcohol. Suitable fatty acid esters include, for example, isopropyl myristate, isopropyl laurate, isopropyl caprylate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, dodecyl oleate, 2-octyl dodecyl myristate, hexyl decyl. Examples thereof include dimethyl octanoate, cetyl lactate, myristyl lactate, propylene glycol monocaprylate, glycerol monocaprylate, and propylene glycol dicaprylate. Particularly preferred is isopropyl myristate.

As the higher fatty acid triglyceride, various liquid or semi-solid fatty acids at room temperature, and naturally occurring animal and vegetable substances can be used. These are generally called fats and oils and are widely available industrially. There are many kinds of vegetable oils, beef tallow, liver oil, lanolin, lard and the like, but preferably vegetable oils, especially olives,
Camellia oil, soybean oil, rapeseed oil, corn oil, castor oil, safflower oil and the like can be used. In addition, deodorized fish oil containing abundant eicosapentadecanoic acid, which has recently attracted attention for its effects on allergies and malignant tumors, can also be used.

Examples of higher alcohols include cetanol, stearyl alcohol, behenyl alcohol and lanolin alcohol. Examples of the higher fatty acid include octanoic acid, nonanoic acid, capric acid, lauric acid, misostinic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and behenylic acid.

The surfactant used in the present invention is HLB.
4-18, preferably 10-16, various conventionally known compounds can be used, but a nonionic surfactant is preferably used. As a preferred nonionic surfactant,
Polyoxyethylene glyceryl monostearate, polyoxyethylene glyceryl monooleate, polyoxyethylene glyceryl monomyristate, polyoxyethylene glyceryl mono higher fatty acid ester such as polyoxyethylene glyceryl monopalmitate, and polyoxypropylene monofatty acid ester, Examples thereof include polyoxyethylene aliphatic alcohol ether.

In the external preparation for skin of the present invention, an alcohol compound may be added, if necessary, in order to further promote the skin absorbability of the physiologically active substance. As the alcohol compound, ethanol, isopropanol,
In addition to lower monohydric alcohols such as n-propanol and isobutanol, alkylene glycols such as ethylene glycol, propylene glycol and isoprene glycol,
Examples thereof include polyethylene glycol recall, polyalkylene glycol such as polypropylene glycol, and polyhydric alcohol such as glycerin, diethanolamine, triethanolamine, and diisopropanolamine.

Examples of the physiologically active substance in the present invention include corticosteroids, non-steroids, antibiotics, bactericides, antifungal agents, vitamins, antihistamines, local anesthetics, coronary antihypertensive agents, and antineoplastic agents. , Narcotic analgesics, prostaglandins, hypnotics, psychotropic agents, hormonal agents and the like.

In the external preparation for skin of the present invention, the proportion of the aliphatic dicarboxylic acid ester used is 1 to 15 parts by weight, preferably 2 to 8 parts by weight, per 1 part by weight of the physiologically active substance. The oily substance is 1 to 10 parts by weight, preferably 3 to 8 parts by weight, based on 1 part by weight of the aliphatic diester. The ratio of use of the surfactant is 5 to 50 wt%, preferably 10 to 45 wt%, based on the whole skin external preparation.
The physiologically active substance is 0.05 to 1 with respect to the whole external preparation for skin
It is 0 wt%, preferably 1 to 7 wt%. When an alcohol compound is used, the proportion of the alcohol compound used is 0 to 15 parts by weight, preferably 2 to 10 parts by weight, relative to 1 part by weight of the physiologically active substance. In the present invention, it is preferable to use ethanol as the alcohol compound, but this ethanol is 2 to 1 with respect to the whole skin external preparation.
It is preferable to use 5 parts by weight, preferably 3 to 10 parts by weight.

The external preparation for skin of the present invention has a high molecular weight (molecular weight: about 1000 or more) physiologically active substance which has been conventionally treated as having poor skin absorbability, a water-insoluble physiologically active substance, water and an organic substance. It is possible to absorb a physiologically active substance such as a poorly soluble physiologically active substance in a solvent into the skin at a high absorption rate. In this case, examples of the large-molecular-weight physiologically active substance, the water-insoluble physiologically active substance, and the physiologically active substance which is poorly soluble in water and an organic solvent include those shown below. (Large molecular weight physiologically active substance) cyclosporine, azatricyclooctacocene derivative, rapamycin and the like. (Non-water-soluble physiologically active substance) Mycophenolic acid, fusidic acid, free base of macrolide antibiotics, taxol, terpene anticancer agents of plant origin, etc. (Physiologically active substance that is sparingly soluble in water and organic solvents) 15-deoxysupergarin, β-carotene and its derivatives, folic acid and its derivatives, and the like.

The external preparation for skin of the present invention is applied in various forms such as ointments and creams, and its composition is adjusted appropriately according to the form of the product. When the external preparation for skin of the present invention is applied in the form of an ointment, it is preferable that it has the following component composition. (1) Physiologically active substance: 0.1 to 10 wt%, preferably 1 to 5 wt% (2) Aliphatic dicarboxylic acid diester: 1 to 15 wt%, preferably 2 to 8 wt%. (3) Oily substance: 1 to 10 wt%, preferably 3 to 8 wt%. (4) Surfactant: 5 to 50 wt%, preferably 10 to 45 wt%. (5) Lower monohydric alcohol: 0 to 15 wt%, preferably 2 to 10 wt%. (6) Polyhydric alcohol: 0-10 wt%, preferably 2-8 wt% (7) Filler: 0-10 wt%, preferably 5-8 wt%. (8) Purified water: 0 to 10 wt%, preferably 1 to 5 wt%. As the filler, organic and inorganic fine powders are used. The particle size of this filler is usually 0.2 to 20 μm.
m, preferably 0.5 to 10 μm. Preferable examples of the filler include fine silica such as Aerosil, alumina, resin powder, silicate powder, clay powder, sepiolite powder, montmorillonite powder, fluorine-containing mica powder, hydroxypropylcellulose powder and the like. .

When the external preparation for skin of the present invention is applied in the form of a cream, it is preferable that it has the following component composition. (1) Physiologically active substance: 0.1-10 wt%, preferably 1-5 wt% (2) Aliphatic dicarboxylic acid diester: 1-15 wt%, preferably 2-8 wt% (3) Oily substance: 1-15 wt% , Preferably 2 to 10 wt% (4) surfactant: 1 to 20 wt%, preferably 3 to 10 wt% (5) lower monohydric alcohol: 0 to 10 wt%, preferably 2 to 8 wt% (6) polyhydric alcohol : 0-10 wt%, preferably 2-8 wt% (7) Filler 0-10 wt%, preferably 0.1-5 wt% (8) Purified water 0-60 wt%, preferably 10-40 wt%

If desired, the external preparation for skin of the present invention may contain an appropriate amount of auxiliary components such as a thickener (polymer) colorant, a fragrance and an anti-piping agent such as para-aminobenzoic acid esters. The external skin preparation of the present invention can be prepared according to a conventionally used formulation method. For example, first, required amounts of an aliphatic dicarboxylic acid diester, an oily substance and a surfactant are stirred under heating to form a homogeneous solution, and after cooling,
It can be prepared by adding and mixing a solution in which a desired amount of the physiologically active substance is dissolved in water or a lower alcohol, further adding auxiliary components, and stirring well to obtain a homogeneous mixture.

[0018]

The external preparation for skin of the present invention has the excellent solubility of the aliphatic dicarboxylic acid diester contained therein and the action of the surfactant to uniformly mix the physiologically active substance, the aliphatic dicarboxylic acid diester and the oily substance. They are compatible with each other and have a high therapeutic effect on the skin absorbability of physiologically active substances. In addition, it is excellent in stability and coatability, has no skin irritation, and is of high quality as an external preparation for skin.

[0019]

EXAMPLES Next, prescription examples of the external preparation for skin of the present invention will be explained. Example 1 (Cyclosporin cream A) (1) Physiologically active substance cyclosporin 5 wt% (2) Aliphatic dicarboxylic acid diester diethyl sebacate 4 wt% (3) Oily substance isopropyl myristate 3 wt% Isotridecyl myristate 2 wt% cetanol 3 wt% (4 ) Alcohol compound Isopropylene glycol 3 wt% Diisopropanolamine 2 wt% (5) Surfactant POE (20) sorbitan monooleate 1 wt% sorbitan monostearate 1 wt% POE (5) glyceryl 5 wt% (6) Filler Carboxyvinyl polymer 0.2 wt% (7) Bactericide P-paraben 0.1 wt% M-paraben 0.1 wt% (8) Purified water balance

Example 2 (Cyclosporin cream B) (1) Physiologically active substance cyclosporin 5 wt% (2) Aliphatic dicarboxylic acid diester diethyl sebacate 3 wt% (3) Oily substance isopropyl myristate 5 wt% Isotridecyl myristate 2 wt% Behenyl alcohol 3 wt % Olive oil 8 wt% (4) Alcohol compound Ethanol 5 wt% Polyethylene glycol (molecular weight: 400) 5 wt% Triethanolamine 2 wt% (5) Surfactant POE (20) sorbitan monooleate 2 wt% POE (40) monostearate 3 wt % POE (5) glyceryl monostearate 3 wt% (6) Filler carboxyvinyl polymer 1 wt% (7) Bactericide P-paraben 0.1 wt% M-paraben 0.1 wt% ( ) Purified water balance

Example 3 (Cyclosporin cream C) (1) Physiologically active substance cyclosporin 5 wt% (2) Aliphatic dicarboxylic acid diester diethyl sebacate 4 wt% (3) Oily substance isopropyl palmitate 3 wt% Isotridecyl myristate 2.5 wt% Cetanol 3wt% Lanolin 10wt% Olive oil 5wt% Stearic acid 2.5wt% (4) Alcohol compound Isopropylene glycol 2wt% Diisopropanolamine 2wt% (5) Surfactant Monooleic acid POE (20) Sorbitan 2wt% Monostearate POE (5) Glyceryl 5 wt% sorbitan monostearate 2 wt% (6) Filler carboxyvinyl polymer 0.2 wt% (7) Bactericide P-paraben 0.1 wt% M-paraben 0.1 wt% (8) Purified water balance

Example 4 (Cyclosporin cream D) (1) Physiologically active substance Cyclosporin 5 wt% (2) Aliphatic dicarboxylic acid diester diethyl sebacate 4 wt% (3) Oily substance Beeswax 5 wt% Whale wax 5 wt% Isopropyl myristate 3 wt% Isotridecyl myristate 2wt% Cetanol 3wt% Olive oil 5wt% Stearic acid 3wt% (4) Alcohol compound Isopropylene glycol 3wt% Diisopropanolamine 2wt% (5) Surfactant Monooleic acid POE (20) sorbitan 2wt% Monostearate POE (5) Glyceryl 6 wt% sorbitan monostearate 2 wt% (6) Filler carboxyvinyl polymer 0.2 wt% (7) Bactericide P-paraben 0.1 wt% M-paraben .1wt% (8) Liquid paraffin balance

Example 5 (Cyclosporine ointment A) (1) Physiologically active substance cyclosporin 5 wt% (2) Aliphatic dicarboxylic acid diester diethyl sebacate 3 wt% (3) Oily substance squalene 3 wt% Isotridecyl myristate 3 wt% Safflower oil 36 wt % White petrolatum 39.8 wt% (4) Alcohol compound Ethanol 5 wt% (5) Surfactant POE (9) Lauryl ether 0.2 wt% POE (60) Hydrogenated castor oil 5 wt%

Example 6 (Cyclosporine ointment B) (1) Physiologically active substance cyclosporin 5 wt% (2) Aliphatic dicarboxylic acid diester diethyl sebacate 3 wt% (3) Oily substance Robehip oil 37 wt% Glyceryl monostearate 37 wt% Linole Isopropyl acid 3 wt% (4) Alcohol compound Isoprene glycol 3 wt% (5) Surfactant POE (6) sorbitan monostearate 6 wt% (6) Filler Silicon dioxide powder (aerial) 6 wt%

Example 7 The effect of cyclosporin cream A was confirmed by skin transplantation of mice. The skin of a 5-week-old male CBA mouse was transplanted to a male C3H / HeN mouse of the same age, and the ointment prepared according to Example 1 from the 3rd day after transplantation, about 0.1
g was applied to the skin twice a day at and around the transplanted area until the graft fell off. The results are shown in Table 1.

[0026]

[Table 1]

In the control group to which the cream without addition of cyclosporine was applied, the graft fell off on average in 12.7 days.
In the group to which the cream containing 5% cyclosporine was applied, all the grafts grew for 60 days or longer. In the group to which the cream containing 1% cyclosporine was applied, the graft survival time was significantly prolonged, and the average survival time was 31.3 days.

Claims (2)

[Claims] 1. A method comprising: (i) a physiologically active substance, (ii) a non-volatile aliphatic dicarboxylic acid diester which is liquid at room temperature, (iii) an oily substance, and (iv) a surfactant as essential components. Characteristic external preparation for skin. 2. The external preparation for skin according to claim 1, which contains an alcohol compound.