JP2000198783A - Absorption promoting composition of pantothenic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an absorption promoting composition of a pantothenic acid derivative capable of improving digestibility in organisms and carrying out long-term storage and useful as a medicine by adding a neutral ester, or the like, and a nonionic surfactant to a specific pantothenic acid derivative. SOLUTION: This absorption promoting composition comprises a pantothenic acid derivative of the formula [R1 and R2 are each H or a protecting group of OH; R3 is a 5-25C monovalent aliphatic hydrocarbon or the like which is substitutable with an aromatic group; A is a divalent aliphatic hydrocarbon which is substitutable with an aromatic group; either one of X and Y is the group N(R6) and the other is O or the like; R6 is H or the like; (n) is 1-4] preferably (1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido] cyclohexan-1-yl 3-[(4R)-N (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate), a neutral or alcoholic ester (preferably triethyl citrate) and a nonionic surfactant.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the general formula

[0002]

Embedded image

(Wherein R ¹ and R ² are the same or different and are a hydrogen atom or a hydroxyl-protecting group, and R ¹ and R ² may be combined to form a hydroxyl-protecting group;
R ³ is a C ₅ -C ₂₅ which is saturated or unsaturated and which may be substituted by a linear, branched or cyclic aromatic group;
A monovalent aliphatic hydrocarbon group or an amino group represented by the formula —N (R ⁴ ) R ⁵ , wherein R ⁴ is a saturated or unsaturated and linear, branched or cyclic C ₃ -C ₂₅ A monovalent aliphatic hydrocarbon group, wherein R ⁵ is a hydrogen atom or a monovalent aliphatic hydrocarbon group which may be substituted with a saturated or unsaturated and linear, branched or cyclic aromatic group; A is a C ₂ -C ₁₆ divalent aliphatic hydrocarbon group which is saturated or unsaturated and may be substituted with a linear, branched or cyclic aromatic group, hydrogen group or a divalent aromatic heterocyclic group, either the formula -N X and Y (R ⁶⁾ - is an amino group represented by and the other is -O -, - S- or formula -N ( R ⁷ ) —an amino group represented by R ⁶ and R
⁷ is a hydrogen atom or a lower alkyl group, and n is 1 to
4 is an integer. ) To the pantothenic acid derivative
The present invention relates to a composition for promoting the absorption of pantothenic acid derivatives, which comprises a neutral or alcoholic ester and a nonionic surfactant.

[0004]

2. Description of the Related Art The pantothenic acid derivative represented by the general formula (I) is an acyl CoA-cholesterol-acyl transferase (Acyl CoA-Cholesterol-).
Acyltransferase (ACAT)) has been found as a compound having an inhibitory action (Japanese Unexamined Patent Publication No. 3-218).
No. 340). ACAT is abundant in intracellular microsomes of the liver and small intestine, and is known to be involved in the absorption of cholesterol in the intestine and the accumulation as cholesterol ester in cells. Therefore, a compound that inhibits ACAT is expected as a drug having both a blood lipid-lowering action based on inhibition of cholesterol absorption and an anti-atherosclerotic action.

[0005]

The pantothenic acid derivative represented by the above general formula (I) was confirmed to be a compound having an excellent ACAT enzyme inhibitory action, but was administered orally to a living body. Since the compound was hardly absorbed from the digestive tract, a satisfactory effect could not be obtained. Thus, there is a need for a pantothenic acid derivative represented by the above general formula (I), which has a higher absorption rate of an orally administered compound into a living body and a higher bioavailability. Furthermore,
In the manufactured composition, it is required that the compound to be contained is stabilized and the preparation can be stored for a long period of time.

[0006]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, a neutral or alcoholic ester and a non-ionic compound have been added to the pantothenic acid derivative represented by the general formula (I). It has been found that by preparing a composition containing a surfactant, the absorption rate in the living body can be improved and long-term storage can be achieved, and the present invention has been completed.

That is, the present invention is to dissolve a pantothenic acid derivative represented by the above general formula (I) in a neutral or alcoholic ester or a mixed solvent thereof, ie, a diester carbonate, an oxyacid ester or a mixed solvent thereof. The present invention provides a composition for promoting the absorption of a pantothenic acid derivative represented by the general formula (I), which contains a nonionic surfactant or a mixture thereof, and expands the application range of this compound as a pharmaceutical.

The neutral or alcoholic ester of the present invention includes, for example, carbonic acid diester, oxyacid ester and the like. The neutral or alcoholic ester is a pantothenic acid derivative represented by the above general formula (I)
0.05 part by weight or more, preferably 0.1 part by weight, per 1 part by weight.
1 to 40.0 parts by weight, more preferably 0.5 to 10.
0 parts by weight can be used. These neutral or alcoholic esters can be used alone, or a plurality of them can be used in combination.

The above-mentioned carbonic acid diester is an ester used as a component of cosmetics, as a solvent, a plasticizer and a gelling agent in oral preparations, general external preparations and preparations for oral administration in the field of medicine. It can be classified into linear diester or cyclic diester, dimethyl carbonate, diethyl carbonate, diisopropyl carbonate as linear diester, ethylene carbonate (ethylene carbonate) as cyclic diester,
Propylene carbonate (propylene carbonate) and the like can be mentioned. These esters can be used alone or as a mixture of two or more. Carbonate or its cyclic diester is a compound that is commercially available or easily available.

The oxyacid ester of the present invention is an ester used as a plasticizer in a film coating composition for an oral preparation in the field of medicine. Examples of the ester include triethyl citrate, tributyl citrate and the like. These esters can be used alone or as a mixture of two or more.

The nonionic surfactant of the present invention is generally widely used as an emulsifier, a dispersant and the like in the field of medicine, and is classified into ether type, ether ester type, ester type and nitrogen-containing type. Can be. These nonionic surfactants can be used in an amount of 0.5 to 50 parts by weight, preferably 1 to 25 parts by weight, per 1 part by weight of the pantothenic acid derivative represented by the general formula (I). These nonionic surfactants can be used alone or in combination of two or more.

The ether type nonionic surfactant is, for example, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, etc., and the ether ester type nonionic surfactant is, for example, polyoxyethylene sorbitan fatty acid ester. Non-ionic surfactants of the ester type, such as polyoxyethylene glycerin fatty acid esters, etc., include, for example, nitrogen-containing non-ionic surfactants such as sorbitan fatty acid esters, propylene glycol fatty acid esters, ethylene glycol fatty acid esters, ester glycerin fatty acid esters, etc. Surfactants can be classified, for example, into polyoxyethylene fatty acid amides, polyoxyethylene alkylamines, and the like.

Examples of the polyoxyethylene alkyl ether include polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, and polyoxyethylene stearyl ether. Examples of the polyoxyethylene alkyl allyl ether include polyoxyethylene nonyl. Examples of the polyoxyethylene sorbitan fatty acid ester include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, and polyoxyethylene sorbitan monooleate. Examples of the polyoxyethylene glycerin fatty acid ester include polyoxyethylene glycerin monostearate Polyoxyethylene glycerin triisostearate and the like can be mentioned. Examples of the hydrogenated castor oil derivatives include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60. Examples of the sorbitan fatty acid ester include polyoxyethylene fatty acid ester, sorbitan trioleate, sorbitan monooleate, sorbitan monostearate, and sorbitan monocaprylate.Examples of the propylene glycol fatty acid ester include sorbitan fatty acid ester. Propylene glycol caprylate, propylene glycol dicaprylate, propylene glycol monoisooctanoate, propylene glycol diisooctanoate, propylene glycol dicaprate, etc. Can be mentioned, as the ethylene glycol fatty acid esters,
For example, ethylene glycol monocaprylate, ethylene glycol dicaprylate, ethylene glycol monoisooctanoate, ethylene glycol diisooctanoate, and the like, and as the glycerin fatty acid ester,
Glycerin monooleate, glyceryl monostearate, glyceryl monocaprylate, tetraglycerin monocaprylate, tetraglycerin hexacaprylate and the like can be mentioned.As the polyoxyethylene fatty acid amide, for example, polyoxyethylene stearamide,
Palm oil fatty acid diethanolamide and the like can be mentioned, and as polyoxyethylene alkylamine, for example, polyoxyethylene oleylamine and the like can be mentioned.

In a further preferred embodiment of the absorption promoting composition of the present invention, triethyl citrate 1.4 to 2.9 is added to 1 part by weight of the pantothenic acid derivative represented by the above general formula (I).
6.8 to 14.1 parts by weight of polyoxyethylene hydrogenated castor oil, which is a nonionic surfactant, and 4.4 to 9.2 parts by weight of propylene glycol monocaprylate can be used.

The pantothenic acid derivative of the present invention represented by the general formula (I) is described in, for example, the above-mentioned JP-A-3-218340.
Compounds produced by the method described in Japanese Patent Application Laid-Open (JP-A) No. H10-26095 can be mentioned. In the pantothenic acid derivative represented by the general formula (I), examples of the lower alkyl group include a linear or branched C _{1 to} C ₅ aliphatic hydrocarbon group. In the present invention, the pantothenic acid derivative represented by the general formula (I) is a compound represented by the general formula:

Embedded image(Where R⁸Is C_Three~ C_TenLinear or branched hydrocarbons of
A radical, R⁹May be substituted with a phenyl group
C₁~ C_TenIs a linear or branched hydrocarbon group. )
Can also be used.
The pantothenic acid derivative represented by the general formula (II)
And C₁~ C_TenA linear or branched hydrocarbon group of
For example, methyl, ethyl, propyl, butyl
Group, isopropyl group, isobutyl group, s-butyl group, t
-Butyl group, isopentyl group, neopentyl group (2,2
-Dimethylpropyl group), pentyl group, hexyl group,
Butyl, octyl, nonyl, decyl, etc.
I can do it. Also, C_Three~ C _TenStraight or branched coal
As the hydride group, for example, propyl group, butyl group, iso-
Propyl group, isobutyl group, s-butyl group, t-butyl
Group, isopentyl group, neopentyl group (2,2-dimethyl
Propyl), pentyl, hexyl, heptyl
Group, octyl group, nonyl group, decyl group, etc.
Wear. Further, C-substituted phenyl₁~ C_TenStraight chain
Examples of the branched or branched hydrocarbon group include benzyl
Group, 2-phenylethyl group, 3-phenylethyl group, etc.
Can be mentioned. Bread represented by the general formula (I)
As the tothenic acid derivative, for example, (1S, 2S) -2-
[3- (2,2-dimethylpropyl) -3-nonyluree
Id] cyclohexane-1-yl 3-[(4R) -N
-(2,2,5,5-tetramethyl-1,3-dioxa
-4-carbonyl) amino] propionate and the like
Can be

The absorption promoting composition of the present invention can be produced according to a conventional method for producing each dosage form. For example, in the case of a hard capsule, a pantothenic acid derivative represented by the above general formula (I) is added to a neutral or alcoholic ester and dissolved at room temperature, and then a nonionic surfactant is added and the mixture is heated to 40 to 60 ° C. Then, the mixture is mixed with stirring, and the resulting solution is filled into hard capsules by a conventional method to produce a solution. In the case of granules or tablets, it can be produced by adsorbing the above solution onto a porous inorganic powder such as silicic anhydride, and then forming the solution into granules or tablets.

Preferred dosage forms of the absorption promoting composition of the present invention include soft capsules filled with the composition,
Examples include hard capsules, oral preparations such as granules and tablets adsorbed on porous powder and solidified, nasal drops, eye drops, lotions, injections, suppositories and the like. When the pantothenic acid derivative represented by the general formula (I) is orally administered, the dose is 1 to 1000 mg per day.

[0018]

EXAMPLES The present invention will be further described below with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited thereto.

Reference Example 1 (1S, 2S) -2- [3- (2,2-dimethylpropyl) -3-nonylureido] cyclohexane-1-yl 3-[(4R) -N- (2,2,5 , 5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionate (hereinafter referred to as a propionate compound) as a preparation for oral administration, into granules produced by wet granulation into hard capsules using a capsule filling machine. Filled. The filling amount is 2
No. Capsule was 375 mg.

Reference Example 2 As another preparation for promoting absorption of a propionate compound by a conventional method, 5 parts of oleic acid was added to 1 part of the propionate compound and dissolved at room temperature. Add this solution to polyoxyethylene hydrogenated castor oil (Nikkor HCO60:
Nikko Chemicals, hereinafter abbreviated as HC)
The mixture was heated and melted at 40 ° C., and filled into hard capsules using an oil-viscous filling machine. The filling amount was 150 mg per No. 4 capsule.

Reference Example 3 The capsule obtained in Reference Example 2 was further coated with an enteric coating agent (methacrylic acid copolymer LD Reme, manufactured by
Eudragit) to give an enteric capsule.

Test Example 1 The rhesus monkey 3 was forcibly fasted from the day before the test using the propionate compound preparations of Reference Examples 1, 2 and 3.
The head was orally administered at 90 mg / body. After administration,
Blood was collected over time, and the blood concentration was measured by the following method. Table 1 shows the results. (Measurement of propionate compound in blood) 100 μL of plasma
1% aqueous 30% acetonitrile solution and propionate compound-d6 (50 ng / mL) as an internal standard
Add 100 μL and stir. Next, about 2 mL of methanol, acetonitrile and purified water are passed in this order in order and added to Bond Elut C18 which has been equilibrated. 30%
After washing with 2 mL of acetonitrile aqueous solution and 2 mL of 50% acetonitrile aqueous solution, 90% acetonitrile aqueous solution was added.
Add 8 mL to elute. To this, 30 μL of a 2.5% aqueous ammonia solution was added, and after stirring, 25 μL of the aqueous solution was measured by high performance liquid chromatography under the following conditions.

(High-performance liquid chromatograph operating conditions) Detector: tandem mass spectrometer Ionization method; Electrospray ionization method Spray voltage: 4.5 KV Capillary temperature; 240 ° C Monitoring ion; Propionate compound and propionate compound-d6 Column: Shiseido CAPCELL PAK C18
UG-120 Column temperature: 40 ° C. Mobile phase: purified water (solution A) / methanol (solution B) = 1/9 solution A and solution B were mixed at a ratio of 1/9 by HPLC and sent.

[0024]

[Table 1]

From the results shown in Table 1, the Cmax of the normal preparation in which the wet granules were filled into capsules was 6.0 ng / mL. This value was not a satisfactory value for a preparation for oral administration and was judged to be extremely difficult to be absorbed. Therefore, as a result of examining other absorption promoting composition preparations according to the conventional method, as shown in Table 1, both gastric and enteric capsules were Cmax.
It was confirmed that the absorbency was improved by about 6 times relative to Reference Example 1. In addition, the AUC showed that the enteric capsules had about twice as much improvement in absorbency as the gastric capsules.

Test Example 2 The propionate compound preparations of Reference Examples 2 and 3 were placed in a glass bottle and stored in a sealed state at 60 ° C. for one week, and properties and purity tests (decomposition product production, liquid chromatography) were measured. Table 2 shows the results. (Measurement of Decomposition Product) Dissolve 0.075 g of the contents of the capsule in 50 mL of the mobile phase to prepare a sample solution. 1 mL of this liquid
, And add the mobile phase to make exactly 100 mL,
Use as standard solution. 20 μL of the sample solution and the standard solution were measured by high performance liquid chromatography under the following conditions. (High-performance liquid chromatograph operating conditions) Detector: UV absorption spectrophotometer (measurement wavelength: 205 nm) Column: AM-312 manufactured by YMC Column temperature: 40 ° C Mobile phase: acetonitrile / water mixture (3: 1)

[0027]

[Table 2]

From the results shown in Table 2, the other preparations for absorption enhancing composition according to the conventional method of Reference Example 2 were very unstable.

REFERENCE EXAMPLE 4 20 parts of propylene carbonate (manufactured by Showa Denko KK, hereinafter abbreviated as PC) and triethyl citrate (manufactured by Carter Food Science, hereinafter referred to as T) were added to 1 part of the propionate compound.
C) and dissolved at room temperature. This liquid was filled into hard capsules using an oil-viscous filling machine. The filling amount is 2
No. capsule was 350 mg.

Reference Example 5 A propionate compound preparation composition was obtained in the same manner as in Reference Example 4, except that 0.1 part of HC was added.

Example 1 To 1 part of the propionate compound, 0.05 part of PC was added, 5 parts of HC was further added, and the mixture was heated and dissolved at 40 ° C., and filled into hard capsules using an oil-viscosity filling machine. The filling amount was 350 mg for the No. 2 capsule.

Example 2 1.6 parts of PC and propylene glycol monocaprylate (Cefsol 2
18: Nikko Chemicals Co., Ltd .; hereinafter abbreviated as MG) 4.4 parts were added and dissolved at room temperature. To this solution, 7.0 parts of HC was added, and the mixture was heated and dissolved at 40 ° C., and filled into hard capsules using an oil-viscosity filling machine. The filling amount was 350 mg for the No. 2 capsule.

Example 3 A propionate compound preparation composition was obtained in the same manner as in Example 2 except that 2.9 parts of PC, 14.1 parts of HC, and 9.2 parts of MG were used.

Example 4 A propionate compound preparation composition was obtained in the same manner as in Example 1 except that 8 parts of PC and 50.0 parts of HC were used.

Example 5 A propionate compound preparation composition was obtained in the same manner as in Example 4 except that 3.0 parts of HC was used.

Example 6 A propionate compound preparation composition was obtained in the same manner as in Example 5 except that HC was replaced with 5.0 parts.

Example 7 A propionate compound preparation composition obtained in the same manner as in Example 6 except that PC was changed to 40.0 parts, was allowed to cool to room temperature, and filled in a bottle to obtain an internal solution of the propionate compound. .

Example 8 A propionate compound preparation composition was obtained in the same manner as in Example 1 except that TC was used instead of PC.

Example 9 A propionate compound preparation composition was obtained in the same manner as in Example 8, except that TC was changed to 1.4 parts, HC was changed to 6.8 parts, and MG was changed to 4.4 parts.

Example 10 A propionate compound preparation composition was obtained in the same manner as in Example 2 except that TC was used instead of PC.

Example 11 A propionate compound preparation composition was obtained in the same manner as in Example 3 except that PC was replaced with TC.

Example 12 In Example 10, 6.8 parts of TC, 29.5 parts of HC, and MG were used.
Was replaced with 19.3 parts to obtain a propionate compound preparation composition.

Example 13 A propionate compound preparation composition was obtained in the same manner as in Example 6 except that PC was replaced with TC.

Example 14 A propionate compound formulation was prepared in the same manner as in Example 2 except that HC60 of Example 2 was changed to polyoxyethylene sorbitan monooleate (Nikkor TO-10M: manufactured by Nikko Chemicals Co., Ltd .; hereinafter abbreviated as TW). Dissolve by heating at ℃
The soft capsules were filled by a liner type automatic soft capsule filling machine according to a conventional method. Filling amount is 350 for No.5 Oblong
mg. The coating component used was composed of 100 g of gelatin, 400 g of concentrated glycerin, 30 g of ethyl paraben, and 10 g of propyl paraben.

Test Example 3 As a result of examining an absorption-promoting composition preparation by a conventional method, improvement in gastrointestinal absorption was confirmed by increasing solubility. Therefore, the solubility of the compositions of Examples 1 to 14 and Reference Examples 1 to 5 was examined. Table 3 shows the results.

[0046]

[Table 3]

From the results in Table 3, it was confirmed that the solubility was improved.

Test Example 4 Reference Example 1, Examples 2 and 1 provided with enteric coating
0 propionate compound formulation, 75 mg / b in three rhesus monkeys fasted forcibly from the day before the test.
It was orally administered at ody. After the administration, blood was collected over time, and the blood concentration was measured in the same manner as in Test Example 1. Table 4 shows the results
Shown in

[0049]

[Table 4]

From the results shown in Table 4, the Cmax of the normal preparation in which the wet granules were filled into capsules was 3.7 ng / mL, but the absorption-enhancing composition preparation coated with the enteric coating had a Cmax relative to that of Reference Example 1. As a result, an improvement of about 5 times in the absorbency was confirmed.

Test Example 5 The propionate compound preparations of Reference Example 2, Examples 2 and 10 were placed in a glass bottle, stored in a sealed state at 60 ° C. for one week, and subjected to a property and purity test (amount of decomposed product, liquid chromatography). The measurement was performed in the same manner as in Test Example 2. Table 5 shows the results.

[0052]

[Table 5]

From the results shown in Table 5, the preparation of the composition for promoting absorption of the present invention was stable.

[0054]

The composition of the present invention prepared by dissolving the pantothenic acid derivative represented by the general formula (I) in a neutral or alcoholic ester and adding a nonionic surfactant or a mixture thereof. Showed increased solubility in water and an effect of promoting absorption. In addition, this composition is stable and improves the bioavailability of the pantothenic acid derivative represented by the general formula (I), thereby expanding the range of application as a pharmaceutical.

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Claims (8)

[Claims] 1. A compound of the general formulaNeutral or alcohol to pantothenic acid derivative represented by
Mixed with a non-ionic surfactant and a non-ionic surfactant
Composition for promoting absorption of pantothenic acid derivative characterized by the following:
(Where R¹And R^TwoAre the same or different,
And a protecting group for a hydroxyl group or a hydroxyl group.¹And R^TwoIs one
And a protecting group for a hydroxyl group may be formed. ^ThreeIs also saturated
Or unsaturated and linear, branched or cyclic
C optionally substituted with an aromatic group_Five~ C_{twenty five}Monovalent aliphatic coal
A hydride group or a formula -N (R^Four) R^FiveAn amino group represented by
This R^FourIs saturated or unsaturated and is linear or branched
Or annular C_Three~ C_{twenty five}A monovalent aliphatic hydrocarbon group
R^FiveIs a hydrogen atom or a saturated or unsaturated and linear
Substituted by an aromatic, branched or cyclic aromatic group
A is a monovalent aliphatic hydrocarbon group, A is saturated or
Unsaturated, linear, branched or cyclic aromatic groups
C optionally substituted with_Two~ C₁₆Divalent aliphatic hydrocarbon
Group, divalent aromatic hydrocarbon group or divalent aromatic heterocyclic group, X
And Y are of the formula -N (R⁶)-
A amino group and the other is -O-, -S- or a formula -N (R
⁷)-An amino group represented by⁶And R⁷Is water
And n is an integer of 1-4.
is there. ) 2. A pantothenic acid derivative represented by the general formula: _{3. The} composition according to claim 1, which is a pantothenic acid derivative represented by the formula: wherein R ⁸ is a C ₃ -C ₁₀ linear or branched hydrocarbon group, and R ⁹ is substituted with a phenyl group. A C ₁ -C ₁₀ linear or branched hydrocarbon group which may be substituted.) 3. The method according to claim 1, wherein the pantothenic acid derivative is (1S, 2S)-
2- [3- (2,2-dimethylpropyl) -3-nonylureido] cyclohexane-1-yl 3-[(4R)
The composition according to claim 1 or 2, which is -N- (2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl) amino] propionate. 4. The composition according to claim 1, wherein the neutral or alcoholic ester is a carbonic acid diester or an oxyacid ester. 5. The nonionic surfactant is an ether type surfactant.
The composition according to any one of claims 1 to 4, which is a nonionic surfactant of an ether ester type, an ester type or a nitrogen-containing type. 6. A pantothenic acid derivative based on 1 part by weight,
The composition according to claim 4 or 5, wherein the neutral or alcoholic ester is 0.5 to 10 parts by weight and the nonionic surfactant is 1 to 25 parts by weight. 7. The composition according to claim 6, wherein the neutral or alcoholic ester is triethyl citrate and the nonionic surfactant is polyoxyethylene hydrogenated castor oil and / or propylene glycol monocaprylate. . 8. An amount of the pantothenic acid derivative per 1 part by weight,
Triethyl citrate is 1.4 to 2.9 parts by weight, polyoxyethylene hydrogenated castor oil is 6.8 to 14.1 parts by weight, and propylene glycol monocaprylate is 4.4 to 2.9 parts by weight.
The composition according to claim 7, wherein the amount is 9.2 parts by weight.