JP7344451B2 - Transdermal absorption inhibitor and insect repellent composition - Google Patents

Description

The present invention provides a novel hydrophobic substance transdermal absorption inhibitor that suppresses transdermal absorption of insect repellent ingredients even when the skin surface temperature is high and improves the odor derived from insect repellent ingredients when applied, and a novel hydrophobic substance transdermal absorption inhibitor containing the same. The present invention relates to pest repellent compositions.

Originally, the skin is an important organ that covers the surface of the body, protects the interior of the body and various organs, and protects the body from invasion of foreign substances and stimulation from the outside. However, some drugs easily penetrate into the skin. The conditions for a substance that easily permeates are that the molecular weight is 500 or less (Non-Patent Document 1), the octanol/water partition coefficient (LogKO/W, LogPO/W) is 1 to 3, and it is moderately fat-soluble. (Non-Patent Document 2) etc. are known. Substances that penetrate the skin include nitroglycerin, estradiol, N,N-diethyl-m-toluamide, and the like.

For example, pest repellents that protect the human body from pests use ingredients such as N,N-diethyl-m-toluamide (DEET), pyrethroid agents, and plant-derived essential oils. DEET, which is highly effective, is solubilized with a solvent such as ethanol and is most commonly used. However, since these insect repellent ingredients are easily absorbed through the skin and are volatile, there is a problem that they disappear from the skin surface and are difficult to maintain their effects. In addition, when increasing the amount of repellent ingredients blended in order to improve sustainability, there is a problem in that irritation may occur due to the repellent ingredients absorbed transdermally.

As a method for alleviating irritation caused by pest repellents, Patent Document 1 discloses a product containing a specific alkylene oxide derivative, which has an excellent long-lasting pest repellent effect, causes little skin irritation (tingling sensation), and has a smooth feel after application. A pest repellent composition with excellent stability over time has been proposed.

In addition, Patent Document 2 proposes a method of containing a specific alkylene oxide derivative to suppress the penetration of insect repellents into the skin, reduce irritation caused by the agents, and improve the sustainability of the insect repellent effect. has been done.
Pest repellents are often used in the summer, especially outdoors, due to the increase in mosquitoes, but human skin surface temperatures can exceed 40 degrees Celsius outdoors in the summer and under sunlight. In such a state where the surface temperature is high, there is a problem in that the penetration of hydrophobic substances into the skin is promoted, making skin irritation more likely.

On the other hand, there is a problem with pest repellent components such as DEET in that the repellent component itself has a unique odor. Therefore, for example, Patent Document 3 discloses that by blending an insect repellent ingredient, a water-soluble solvent such as ethanol, and water, and specifying that the mass ratio of the water-soluble solvent to water is 1.2 to 3.0, Techniques have been proposed to improve feel and odor. However, water-soluble solvents could promote the absorption of insect repellent ingredients.

Against this background, there has been a need for a transdermal absorption inhibitor and a composition thereof that exhibits a high absorption inhibitory effect even when the skin surface temperature is high and improves the odor derived from insect repellent ingredients during application.

Japanese Patent Application Publication No. 2019-70049 WO 2018/030532 pamphlet Japanese Patent Application Publication No. 2003-192503

R.C. Wester et. al.; Percutaneous absorption. Mechanisms-Methodology-Drug-Delivery, New York, 107-23, 1983 T. Yano et al.; Life Sci., 39, 1043-50, 1986

The object of the present invention is to provide a novel transdermal absorption inhibitor of a hydrophobic substance that suppresses transdermal absorption of insect repellent ingredients even when the skin surface temperature is high and improves the odor derived from insect repellent ingredients when applied. An object of the present invention is to provide a pest repellent composition comprising:

The present inventors conducted intensive studies to solve the above problems, and found that the molecular weight pattern determined by gel permeation chromatography was asymmetric, and a new alkyl oxide derivative with a molecular weight distribution biased toward the high molecular weight side was found. We have found that the above problems can be solved.

That is, the present invention is as follows.
(1) A transdermal absorption inhibitor that suppresses transdermal absorption of pest repellent ingredients having an octanol/water partition coefficient LogPO/W of 0 to 8,
The ratio Mz/Mw of the weight average molecular weight (Mw) and the z-average molecular weight (Mz), which is expressed by formula (1) and calculated from the chromatogram determined by gel permeation chromatography measurement, satisfies the relationship of formula (2). A transdermal absorption inhibitor characterized by:

Z-[O-(PO)a-[(PO)b/(EO)c]-H]n...(1)

(In formula (1),
Z represents a residue obtained by removing all hydroxyl groups from a compound having 1 to 6 carbon atoms and 1 to 3 hydroxyl groups,
n indicates a number from 1 to 3 ,
PO represents an oxypropylene group,
EO represents an oxyethylene group,
a and b each indicate the average number of added moles of the oxypropylene group PO,
c indicates the average number of added moles of the oxyethylene group EO,
100≧ a+b+c≧ 15 and b/c= 1/3 to 5/1,
(PO)b/(EO)c indicates that the oxypropylene group PO and the oxyethylene group EO are randomly added, and the random ratio x of the oxypropylene group PO and the oxyethylene group EO is 0.80. ≦x≦ 0.97 . )

5≦Mz/Mw≦60... (2)

(2) (A) 0.1 to 20% by mass of the transdermal absorption inhibitor according to claim 1;
A pest repellent that suppresses transdermal absorption of the pest repellent component, characterized by containing (B) 0.1 to 50% by mass of a pest repellent component, and (C) 99.8 to 30% by mass of a solvent. Composition.

According to the novel alkyl oxide derivative of the present invention, the transdermal absorption of pest repellent ingredients is suppressed even when the skin surface temperature is high, and the transdermal absorption of a novel hydrophobic substance improves the odor derived from pest repellent ingredients when applied. Suppressants and pest repellent compositions containing the same can be obtained.

FIG. 1 is a model chromatogram diagram for explaining Mz/Mw defined in the present invention.

In this specification, the numerical range defined using the symbol "~" shall include the numerical values at both ends (upper limit and lower limit) of "~". For example, "2-5" represents 2 or more and 5 or less.

(Component (A): alkylene oxide derivative)
The alkyl oxide derivative of the present invention is a compound represented by formula (1).

Z-[O-(PO)a-[ (PO)b/(EO)c]-H]n...(1)

Z is a residue obtained by removing all hydroxyl groups from a compound (Z(OH)n) having 1 to 6 carbon atoms and 1 to 3 hydroxyl groups, and n is the residue of the compound (Z(OH)n) The number of hydroxyl groups is 1 to 3 . Compounds having 1 to 3 hydroxyl groups (Z(OH)n) include methanol, ethanol, butanol if n=1; ethylene glycol, propylene glycol, hexylene glycol if n=2; If it is 3, examples include glycerin and trimethylolpropane. Furthermore, a mixture of these may be used as the compound having 1 to 3 hydroxyl groups. Most preferably, n=1 to 3, and particularly preferably n=1.

When n=1, Z is R ¹ in formula (1). R ¹ is a hydrocarbon group having 1 to 6 carbon atoms. The hydrocarbon group having 1 to 6 carbon atoms represented by R ¹ is a functional group consisting of carbon and hydrogen, and is one type selected from an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, or an aralkyl group, An alkyl group or an alkenyl group is preferred, an alkyl group or an alkenyl group having 1 to 6 carbon atoms is more preferred, and an alkyl group having 1 to 6 carbon atoms is most preferred. The alkyl group having 1 to 6 carbon atoms may be linear or branched, but a linear one is more preferable. Examples of the linear alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, propyl group, butyl group, and hexyl group. The number of hydrocarbon groups having 1 to 6 carbon atoms represented by R ¹ may be one or more.

PO represents an oxypropylene group, EO represents an oxyethylene group, and a and b represent the average number of moles of PO and EO added, respectively. a represents a number from 0 to 100, b represents a number from 1 to 100, c represents a number from 1 to 200, and a+b+c≧10.

(PO)b/(EO)c indicates a polyoxyalkylene group formed by randomly adding PO and EO, and the molar ratio (b/c) of PO and EO is 1/3 to 5/1, and the PO and EO The random rate x is 0.80 ≦x≦ 0.97 .
If a+b+c is less than 15 , the percutaneous absorption suppressing effect may become insufficient. From this viewpoint, a+b+c is more preferably 15 or more, and most preferably 25 or more.
Furthermore, as a+b+c increases, the viscosity increases. From the viewpoint of ease of dispersion and blending, a+b+c is particularly preferably 100 or less.
Further, the total average number of added moles n×(a+b+c) of PO and EO is preferably 30 or more, more preferably 40 or more, and most preferably 50 or more. Further, it is preferably 100 or less, and most preferably 80 or less.

When b/c is less than 1/3 , stickiness may occur when the pest repellent composition is prepared. When the ratio is 5/1 or more, the stability of the formulation may deteriorate. b/c is preferably 1/3 to 3/1, more preferably 1/3 to 2/1.

The random rate x of PO and EO is obtained from equation (3).

x=(b+c)/(a+b+c)...(3)
The random rate x is set to 0.80 ≦x≦ 0.97 . If the random ratio x is less than 0.80 , the effect of suppressing percutaneous absorption may become insufficient. It is particularly preferably 0.8 or more, and most preferably 0.85 or more.
Moreover, it is most preferable that the random rate x is 0.97 or less.

(GPC characteristics of alkylene oxide derivative)
The alkylene oxide derivative of the present invention is defined by the molecular weight obtained by a chromatogram obtained using a differential refractometer in gel permeation chromatography (GPC). This chromatogram is a graph representing the relationship between refractive index intensity and elution time.

In the derivative of the present invention, the ratio Mz/Mw of the weight average molecular weight (Mw) and the z average molecular weight (Mz) obtained from the chromatogram is 5≦Mz/Mw≦60.

The method for calculating Mz/Mw will be further described with reference to the chromatogram model diagram of FIG. 1. The horizontal axis shows the elution time, and the vertical axis shows the refractive index intensity obtained using a differential refractometer. When a sample solution is injected into a gel permeation chromatograph and developed, the molecules with the highest molecular weight begin to elute, and the elution curve rises as the refractive index intensity increases. Thereafter, after passing the local maximum point where the refractive index intensity is maximum, the elution curve begins to descend.

Here, Mw and Mz are obtained from GPC using the following formulas.

However, N is the number of polymer molecules, M is the molecular weight, and C is the sample concentration.
Mw is a weighted average using the molecular weight as a weight, and Mz is a weighted average using the square of the molecular weight as a weight. Mw is influenced by the presence of high molecular weight, and Mz is influenced even more than Mw by the presence of high molecular weight. Therefore, the alkylene oxide derivative of the present invention has Mw and Mz as shown in the chromatogram shown in FIG.

When Mz/Mw is less than 5, the effect of suppressing percutaneous absorption may become insufficient. If Mz/Mw is greater than 60, the molecular weight distribution will be biased toward higher molecular weights, and viscosity will increase, making it difficult to disperse and mix into various formulations. From this viewpoint, Mz/Mw is preferably 60 or less, more preferably 40 or more, and particularly preferably 50 or more.

In the present invention, gel permeation chromatography (GPC) for determining Mz/Mw is performed using a SHODEX (registered trademark) GPC101GPC dedicated system, a SHODEX RI-71s differential refractometer, and a SHODEX KF-G column as a guard column. Three HODEX KF804L columns were installed in succession at a column temperature of 40°C, and tetrahydrofuran was flowed as a developing solvent at a flow rate of 1 ml/min. 0.1 ml of a 0.1 wt% tetrahydrofuran solution of the obtained reaction product was injected, and the BORWIN GPC Obtain a chromatogram expressed by refractive index intensity and elution time using a calculation program.

When producing the alkylene oxide derivative of the present invention, preferably, an alkylene oxide having 3 carbon atoms, that is, oxypropylene, is used as an initiator in the presence of a composite metal cyanide catalyst (hereinafter abbreviated as DMC catalyst). Ring-opening addition. An initiator having at least one hydroxyl group in the molecule and a DMC catalyst are added to a reaction vessel, and oxypropylene is continuously or intermittently added to carry out addition polymerization under stirring in an inert gas atmosphere. Oxypropylene may be added under pressure or under atmospheric pressure.

At this time, there is no limit to the average feed rate of oxypropylene, but it is desirable to change it depending on the amount of oxypropylene charged. Specifically, V1 is the speed at which 5 to 20 wt% of the total supply of oxypropylene is supplied (supply amount per unit time), and V1 is the speed at which 20 to 50 wt% of the total supply of oxypropylene is supplied. V2, when the speed during which 50 to 100 wt% of the total supply of oxypropylene is supplied is V3, V1/V2 = 1.1 to 2.0, V2/V3 = 1.1 to 1.5. It is preferable to control the average feed rate of oxypropylene so that:

Further, the reaction temperature is preferably 50°C to 150°C, more preferably 70°C to 110°C. If the reaction temperature is higher than 150°C, the catalyst may be deactivated. When the reaction temperature is lower than 50°C, the reaction rate is slow and productivity is poor.

As the initiator in the present invention, in formula (1), as Z(OH)n, a compound having 1 to 24 carbon atoms and 1 to 6 hydroxyl groups, or a compound obtained by adding oxypropylene to these compounds may be used. I can do it. Examples of the initiator include butanol, butylpropylene glycol, polyoxypropylene glycol, polyoxypropylene glyceryl ether, ethylene glycol, propylene glycol, hexylene glycol, glycerin, trimethylolpropane, erythritol, pentaerythritol, sorbitan, diglycerin, Examples include alkyl glycosides, xylitol, dipentaerythritol, sorbitol, inositol, and the like. When Z is R ¹ , a monohydric alcohol (R ¹ OH) having a hydrocarbon group having 1 to 24 carbon atoms and represented by R ¹ can be used as the initiator.

There is no particular restriction on the trace amount of water contained in the initiator and oxypropylene, but it is desirable that the amount of water contained in the initiator is 0.5 wt% or less, and for oxypropylene it is preferably 0.01 wt% or less. .

The amount of the DMC catalyst used is not particularly limited, but is preferably 0.0001 to 0.1 wt%, more preferably 0.001 to 0.05 wt%, based on the alkylene oxide derivative produced. The DMC catalyst may be introduced all at once into the reaction system, or may be introduced in portions in sequence. After the polymerization reaction is completed, the composite metal complex catalyst is removed. The catalyst can be removed by known methods such as filtration, centrifugation, and treatment with a synthetic adsorbent.
Although a known DMC catalyst can be used in the present invention, it can be represented by formula (6), for example.

Md[M'y(CN)z]e( _H2O )f・(R)g...(6)

In formula (6), M and M' are metals, R is an organic ligand, d, e, y, and z are positive integers that vary depending on the valence and coordination number of the metal, and f and g are metals. is a positive integer that changes depending on the coordination number.
Examples of the metal M include Zn(II), Fe(II), Fe(III), Co(II), Ni(II), Al(III), Sr(II), Mn(II), Cr(III), Examples include Cu(II), Sn(II), Pb(II), Mo(IV), Mo(VI), W(IV), W(VI), and among them, Zn(II) is preferably used.
Metal M' includes Fe(II), Fe(III), Co(II), Co(III), Cr(II), Cr(III), Mn(II), Mn(III), Ni(II). , V(IV), and V(V), among which Fe(II), Fe(III), Co(II), and Co(III) are preferably used.

As the organic ligand R, alcohol, ether, ketone, ester, etc. can be used, and alcohol is more preferable. Preferred organic ligands are water-soluble, and specific examples include tert-butyl alcohol, n-butyl alcohol, iso-butyl alcohol, N,N-dimethylacetamide, ethylene glycol dimethyl ether (glyme), diethylene glycol dimethyl ether ( Diglyme), etc. Particularly preferred is Zn ₃ [Co(CN) ₆ ] ₂ coordinated with tert-butyl alcohol.

When the total amount of component (A), component (B) and component (C) is 100% by mass, the content of component (A) is preferably 0.1 to 20% by mass, and It is preferably 0.5 to 15% by weight, particularly preferably 0.5 to 10% by weight. If the content of component (A) is too low, the effect of suppressing percutaneous absorption may be insufficient, and if the content is too high, the pest repellent composition may become sticky.

(Component (B): Pest repellent component)
The pest repellent component (B) used in the present invention is a drug that has the effect of repelling pests, such as pyrethrin, jasmolin, allethrin, resmethrin, furamethrin, phenothrin, permethrin, cyphenothrin, etofenprox, cyfluthrin, bifenthrin, cilafluofen. pyrethroid agents such as propoxur, carbamate agents such as fenobucarb, organic phosphorus agents such as dichlorvos, fenthion, fenitrothion, pest control ingredients such as neonicotinoids such as imidacloprid, acetamiprid, dinotefuran, and N,N-diethyl. -m-toluamide (DEET), icaridin, 2,3,4,5-bis-(δ-butylene)-tetrahydrofurfural (MGK-11), di-n-propyl isocincomelonate (MGK-326), etc. Chemically synthesized repellent ingredients, insect repellents for clothing such as naphthalene, ginger, and paradichlorobenzene, essential oils such as eucalyptus oil, citronella oil, lemongrass oil, peppermint oil, geranium oil, rosemary oil, and thyme oil, p-menthane. Examples include insect repellent components derived from essential oils such as 3,8-diol, L-menthol, cineole, α-pinene, citronellal, camphor, and linalool.

Among them, from the viewpoint of safety and pest repellent effect, N,N-diethyl-m-toluamide (DEET), icaridin, phenothrin, and essential oil are preferable, and N,N-diethyl-m-toluamide (DEET) is more preferable. .

The pest repellent component (B) used in the present invention has an octanol/water partition coefficient LogPO/W of 0 to 8. These insect repellent ingredients are easily absorbed into the skin, and therefore the effects of the present invention are particularly significant. From this point of view, the octanol/water partition coefficient LogPO/W of the pest repellent component (B) is set to 0 to 8, more preferably 0 to 5, and particularly preferably 0 to 3.

In the present invention, when the total amount of component (A), component (B) and component (C) is 100% by mass, the content of pest repellent component (B) is preferably 0.1 to 50% by mass. be. When the amount of the pest repellent component (B) added is less than 0.1% by mass, it is difficult to obtain a sufficient pest repellent effect. Therefore, the amount of pest repellent component (B) added is preferably 0.1% by mass or more, preferably 1% by mass or more, and even more preferably 3% by mass or more. Furthermore, if the amount of the pest repellent component (B) exceeds 50% by mass, the feel during application may deteriorate or skin irritation may occur. Therefore, the amount of pest repellent component (B) added is 50% by mass or less, preferably 20% by mass or less, and more preferably 15% by mass or less.

(Component (C): solvent)
As the solvent (C), water, a water-soluble organic solvent, and a mixed solvent of water and a water-soluble organic solvent are preferable, and a mixed solvent with a mass ratio of water and a water-soluble organic solvent of 3:1 to 1:1 is more preferable. preferable. Examples of water-soluble organic solvents include methanol, ethanol, n-propanol, isopropanol, 2-methyl-2-propanol, n-butanol, ethylene glycol, propylene glycol, 1,3-butylene glycol, 1,2-pentanediol, , 2-hexanediol, hexylene glycol, acetone, diethyl ether, and tetrahydrofuran. Among the water-soluble organic solvents, methanol, ethanol, n-propanol, and isopropanol are preferred, and ethanol is more preferred.
The content of the solvent (C) is 99.8 to 30% by mass since it is the remainder of component (A) and component (B).

(Additive)
The pest repellent composition of the present invention may further contain additives that can be added normally. These additives include surfactants, hydrocarbon oils, ester oils, higher fatty acids, higher alcohols, oils such as silicone oils, humectants such as glycerin, sorbitol, and polyethylene glycol, paraoxybenzoic acid esters, sodium benzoate, and phenoxyethanol. preservatives such as ethylenediaminetetraacetate, chelating agents such as edetate, pearlizing agents such as ethylene glycol distearate, ultraviolet absorbers such as paramethoxycinnamate, methoxydibenzoylmethane, thickeners, antioxidants. Agents, pH adjusters, plant extracts, amino acids, vitamins, pigments, and fragrances can be added as appropriate.

The pest repellent composition of the present invention can be manufactured according to conventional methods. Further, the dosage form is arbitrary, and it can be used as a transparent liquid, a pearl liquid, a paste, a cream, a gel, a solid, an aerosol spray, or a non-aerosol spray.

The present invention will be explained in detail below by giving Examples and Comparative Examples.
(Synthesis of multi-metal cyanide complex catalyst)
Into 2.0 ml of an aqueous solution containing 2.1 g of zinc chloride, 15 ml of an aqueous solution containing 0.84 g of potassium hexacyanocobaltate K ₃ Co(CN)6 was added dropwise over 15 minutes at 40° C. with stirring. After the dropwise addition was completed, 16 ml of water and 16 g of tert-butyl alcohol were added, the temperature was raised to 70° C., and the mixture was stirred for 1 hour. After cooling to room temperature, a filtration operation (first filtration) was performed to obtain a solid. To this solid were added 14 ml of water and 8.0 g of tert-butyl alcohol, and after stirring for 30 minutes, a filtration operation (second filtration) was performed to obtain a solid.

Furthermore, 18.6 g of tert-butyl alcohol and 1.2 g of methanol were added to this solid again, and after stirring for 30 minutes, a filtration operation (third filtration) was performed, and the obtained solid was dried at 40°C under reduced pressure for 3 hours. Then, 0.7 g of a composite metal cyanide complex catalyst was obtained.

(Synthesis Example 1: Synthesis of Example Compound A1)
A 5L autoclave equipped with a thermometer, pressure gauge, safety valve, nitrogen gas blowing pipe, stirrer, vacuum exhaust pipe, cooling coil, and steam jacket was charged with 56 g of butanol and 0.03 g of a composite metal cyanide complex catalyst, and after purging with nitrogen. The temperature was raised to 110°C, and 176 g of oxypropylene was added dropwise from a nitrogen gas blowing tube under conditions of 0.3 MPa or less. Changes in pressure and temperature inside the reaction tank over time were measured. After 1 hour, The pressure inside the reactor decreased rapidly. Thereafter, a mixture of 1054 g of oxypropylene and 1164 g of oxyethylene was gradually added dropwise through a nitrogen gas blowing tube while maintaining the inside of the reaction tank at 90° C. under conditions of 0.5 MPa or less. After the addition was completed, the mixture was reacted at 90°C for 1 hour, treated under reduced pressure at 75-85°C for 1 hour, and then filtered. The obtained Compound 1 was measured by gel permeation chromatography.

However, butanol was used from KH Neochem, oxypropylene from Sumitomo Chemical, and oxyethylene from Nippon Shokubai.

(Synthesis Examples 2 and 3: Synthesis of Example Compounds A2 and A3)
A compound was synthesized in the same manner as in Synthesis Example 1 except for the starting materials, the average number of added moles of oxypropylene and oxyethylene, and the random ratio. The obtained Example Compounds A2 and A3 were measured by gel permeation chromatography.

(Synthesis Example 4: Synthesis of Comparative Example Compound A'1)
A 5L autoclave equipped with a thermometer, pressure gauge, safety valve, nitrogen gas blowing pipe, stirrer, vacuum exhaust pipe, cooling coil, and steam jacket was charged with 56 g of butanol and 6.0 g of potassium hydroxide as a catalyst, and after purging with nitrogen. The temperature was raised to 110° C., and a mixture of 1230 g of oxypropylene and 1164 g of oxyethylene was gradually added dropwise through a nitrogen gas blowing tube under conditions of 0.5 MPa or less. After the addition was completed, the reaction was carried out at 110°C for 1.5 hours, and after being treated under reduced pressure at 75-85°C for 1 hour, the reaction product was transferred to a 5L eggplant flask, immediately neutralized with 1N hydrochloric acid, and dehydrated under a nitrogen gas atmosphere. , filtration was performed.

Table 1 shows the Mz/Mw and compound properties determined from the chromatograms of Synthesis Examples 1 to 4. However, the hydroxyl value was measured in accordance with JIS K-1557-1, and the molecular weight was calculated from the hydroxyl value.

Further, as a comparative example compound, a commercially available product, SY-DP9 (polyoxypropylene (9) diglyceryl ether, manufactured by Sakamoto Pharmaceutical Co., Ltd.) was used.

(Preparation of Examples 1 to 7 and Comparative Examples 1 to 5)
Each Example and Comparative Example composition was prepared. A liquid pest repellent composition was obtained by blending raw materials with the compositions shown in Tables 2 to 5 and mixing them at room temperature until uniform.

(Percutaneous absorption inhibition test)
Using the obtained pest repellent composition, the transdermal absorption rate of the pest repellent component was measured according to the following method. Note that a vertical diffusion cell was used as the test device.
1. A skin permeability test membrane (Strat-M, manufactured by Merck Millipore) was attached to a vertical diffusion cell so that the dermal structure side of the membrane was located on the receptor cell side.
2. Approximately 1 mL of the above-prepared insect repellent composition was dropped onto the stratum corneum structure side of the membrane, and was covered and fixed with aluminum foil.
3. The receptor cell was filled with 5 mL of pure water.
4. During the experiment, the purity inside the receptor cell was stirred by a stirrer, and the temperature inside the receptor cell was kept at 45℃ by circulating hot water at 45℃ using a heater/circulator in the water jacket covering the receptor cell. The temperature was kept constant at ℃.
5. One hour after the temperature inside the receptor cell reached 45° C., 400 μL of physiological saline was sampled from the sampling port of receptor cell 2, and then the same amount of pure water was returned to keep the liquid volume constant.
6. The amount of pest repellent components in the sampled liquid was measured by HPLC. From the measurement results of the pest repellent component amount, the relative transdermal absorption rate (%) to the blank was calculated using the following formula.

Transdermal absorption rate for blank after 1 hour =
(Transdermal absorption amount of Examples and Comparative Examples after 1 hour) / (Transdermal absorption amount of blank after 1 hour) x 100

The relative transdermal absorption rate with respect to the obtained blank was determined according to the following criteria, and the test results are listed in Tables 2 and 3.

◎: The relative percutaneous absorption rate to the blank is less than 30% ○: The relative percutaneous absorption rate to the blank is 30% or more and less than 40% △: The relative percutaneous absorption rate to the blank is 40% or more , less than 60% ×: Relative percutaneous absorption rate to blank is 60% or more

(Improvement effect on odor during application)
DEET, an insect repellent, was evaluated for its odor improvement effect when applied. Examples 1 and 4 to 7 and Comparative Examples 1, 4, and 5 were sprayed onto the arms of 10 monitors in an amount of 2 ml, and a sensory evaluation was performed. Regarding the odor during application, relative evaluation was made in 3 stages according to the following scoring criteria in comparison with a blank. A total score of 10 people was calculated and evaluated based on the following evaluation criteria. The test results are listed in Tables 4 and 5.

Scoring criteria

3 points: Odors derived from pest repellent ingredients have been improved.

2 points: The odor derived from pest repellent ingredients has been slightly improved.

1 point: Odors derived from insect repellent ingredients have not been improved.

Evaluation criteria ◎: 25 points or more ○: 20 points or more, less than 25 △: less than 20 points

From Examples 1 to 7, all pest repellent compositions of the present invention were tested at 45°C, which is higher than body temperature, and were excellent in suppressing transdermal absorption and improving odor derived from pest repellent ingredients. .

On the other hand, as is clear from Comparative Examples 1 to 5, Comparative Example Compound 1 and Comparative Example Substances, which do not correspond to the alkylene oxide derivatives of the present invention, suppress transdermal absorption and reduce odor derived from pest repellent ingredients. The improvement effect was not met.

Claims (2)

A transdermal absorption inhibitor that suppresses transdermal absorption of an insect repellent ingredient having an octanol/water partition coefficient LogPO/W of 0 to 8,
The ratio Mz/Mw of the weight average molecular weight (Mw) and the z-average molecular weight (Mz), which is expressed by formula (1) and calculated from the chromatogram determined by gel permeation chromatography measurement, satisfies the relationship of formula (2). A transdermal absorption inhibitor characterized by:

Z-[O-(PO)a-[(PO)b/(EO)c]-H]n...(1)

(In formula (1),
Z represents a residue obtained by removing all hydroxyl groups from a compound having 1 to 6 carbon atoms and 1 to 3 hydroxyl groups,
n indicates a number from 1 to 3 ,
PO represents an oxypropylene group,
EO represents an oxyethylene group,
a and b each indicate the average number of added moles of the oxypropylene group PO,
c indicates the average number of added moles of the oxyethylene group EO,
100≧ a+b+c≧ 15 and b/c= 1/3 to 5/1,
(PO)b/(EO)c indicates that the oxypropylene group PO and the oxyethylene group EO are randomly added, and the random ratio x of the oxypropylene group PO and the oxyethylene group EO is 0.80. ≦x≦ 0.97 . )

5≦Mz/Mw≦60... (2)
(A) 0.1 to 20% by mass of the percutaneous absorption inhibitor according to claim 1;
(B) A pest repellent that suppresses transdermal absorption of the pest repellent component, characterized by containing 0.1 to 50% by mass of the pest repellent component, and (C) 99.8 to 30% by mass of a solvent. agent composition.

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