Heparinoid-containing gel composition and method for inhibiting viscosity decrease thereof

Abstract

To increase an initial viscosity of a heparinoid-containing gel composition that contains a heparinoid, water, and a thickening agent to become a certain level or higher while sufficiently suppressing the decrease in viscosity during storage.SOLUTION: There is provided a gel composition containing a heparinoid, water, and a thickening agent, the content of the heparinoid being 0.05 to 3 mass% based on the total amount of the gel composition, the content of hydrophobized hydroxypropylmethylcellulose being 0.5 to 1 mass% based on the total amount of the gel composition as the thickening agent, the content of the carboxyvinyl polymer being 0.1 to 0.5 mass% based on the total amount of the gel composition, and the heparinoid-containing gel composition further containing 0.3 to 7 mass% of tocopherol acetate based on the total amount of the gel composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a heparinoid-containing gel composition containing a heparinoid, water, and a thickener, and a method for inhibiting a decrease in viscosity of a heparinoid-containing gel composition. [Background technology]

[0002] Heparinoids have moisturizing, blood circulation promoting, and anti-inflammatory effects on the skin, and are therefore known to have excellent effects in improving skin diseases and skin conditions such as xerosis, cold skin, and keratosis, as well as so-called dry skin.Many topical preparations for administering such effective heparinoids to the skin have been investigated.

[0003] For example, Japanese Patent Application Laid-Open No. 2011-231128 (Patent Document 1) describes an external pharmaceutical composition containing a heparinoid, allantoin and / or an allantoin derivative, and panthenol and / or a panthenol-related substance.

[0004] Furthermore, Japanese Patent Application Laid-Open Publication No. 2017-171643 (Patent Document 2) describes an external composition containing (A) a carboxyvinyl polymer, (B) a heparinoid, (C) at least one selected from the group consisting of glycyrrhizinic acid, glycyrrhetinic acid, derivatives thereof, and salts thereof, and (D) a polyhydric alcohol, wherein the content of component (D) is 3% by weight or more and the pH is 4.0 to 6.0, and further describes that the composition may contain (E) hydroxypropyl methylcellulose.

[0005] Furthermore, Japanese Patent Application Laid-Open Publication No. 2019-119690 (Patent Document 3) describes an oil-in-water emulsion composition containing 0.05 to 0.6% by mass of a heparin-like substance, 0.01 to 0.5% by mass of hydrophobic hydroxypropyl methylcellulose, an oil, a surfactant, and water, and having a pH of 4.5 to 7.0 at 30°C. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Laid-Open No. 2011-231128 [Patent Document 2] Japanese Patent Application Laid-Open No. 2017-171643 [Patent Document 3] Japanese Patent Application Publication No. 2019-119690 Summary of the Invention [Problem to be solved by the invention]

[0007] However, as a result of studies by the present inventors, when a gel preparation, i.e., a heparinoid-containing gel composition, is used as a topical preparation for administering a heparinoid to the skin, the present inventors have found that, as will be explained below, it is important that the initial viscosity is relatively high and that viscosity loss during storage is sufficiently suppressed. That is, in order to sufficiently prevent dripping upon application to the skin, to provide a good feel during and after application, and to stably exert the intended efficacy of the heparinoid, it is effective for the viscosity of the heparinoid-containing gel composition to be higher than a predetermined level. On the other hand, the present inventors have found that because gel preparations applied to the skin as needed are often carried by users and are subject to diverse storage and use environments, viscosity loss during storage can be a problem for heparinoid-containing gel compositions.

[0008] The present invention has been made in consideration of the above-mentioned problems, and aims to increase the initial viscosity of a heparin-like substance-containing gel composition containing a heparin-like substance, water, and a thickener to a predetermined level or higher, while sufficiently suppressing viscosity reduction during storage. [Means for solving the problem]

[0009] As a result of extensive research to achieve the above-mentioned object, the inventors have discovered that in a gel composition containing a heparin-like substance, water and a thickener, by setting the content of the heparin-like substance within a predetermined range, containing a combination of a predetermined amount of hydrophobic hydroxypropyl methylcellulose and a predetermined amount of carboxyvinyl polymer as the thickener, and further containing a predetermined amount of tocopherol acetate, a heparin-like substance-containing gel composition having an initial viscosity higher than a predetermined level can be obtained without phase separation, and that the viscosity decrease of the obtained heparin-like substance-containing gel composition during storage can be sufficiently suppressed, thereby completing the present invention.

[0010] That is, the present invention provides the following aspects.

[0011] [1] Heparinoid, water 、 thickener , nonionic surfactant, ester oil and solubilizing agent a gel composition comprising the above, wherein the content of the heparinoid is 0.05 to 3% by mass based on the total amount of the gel composition, and the gel composition contains, as the thickener, 0.5 to 1% by mass based on the total amount of the gel composition of hydrophobized hydroxypropyl methylcellulose and 0.1 to 0.5% by mass based on the total amount of the gel composition of carboxyvinyl polymer; The nonionic surfactant is at least one selected from the group consisting of glyceryl monostearate, glyceryl monooleate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tetrastearate, polyoxyethylene sorbit tetraoleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyethylene glycol monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene oleyl ether, in an amount of 0.01 g based on the total amount of the gel composition.The ester oil contains 1 to 10% by mass of diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, isostearyl isostearate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, neopentyl glycol di-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, oleyl oleate, octyldodecyl oleate, decyl oleate, neopentyl glycol dicaprate, 2-ethylhexyl succinate, isocetyl stearate, butyl stearate, diisopropyl sebacate, cetyl lactate, tetradecyl lactate, isopropyl myristate, octyldodecyl myristate, myristyl The gel composition contains at least one selected from the group consisting of cetyl palmitate, myristyl myristate, octyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearate, phytosteryl oleate, diisostearyl malate, para-methoxycinnamate, and pentaerythritol tetrarosinate in an amount of 1 to 30% by mass based on the total mass of the gel composition, and as the solubilizing agent, the gel composition contains at least one selected from the group consisting of propylene glycol, polyethylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate in an amount of 0.5 to 20% by mass based on the total mass of the gel composition. The heparinoid-containing gel composition further contains 0.3 to 7 mass % of tocopherol acetate based on the total mass of the gel composition.

[0012] [2] The heparinoid-containing gel composition according to [1], further comprising 0.2 to 0.9% by mass of diphenhydramine based on the total amount of the gel composition.

[0013] [3] The heparinoid-containing gel composition according to [1] or [2], further containing 2 to 10% by mass of crotamiton based on the total amount of the gel composition.

[0014] [4] The nonionic surfactant is at least one selected from the group consisting of polyoxyethylene sorbitan monostearate, polyethylene glycol monostearate, and polyoxyethylene cetyl ether. Based on the total amount of gel composition 0.3~5% by mass The heparinoid-containing gel composition according to any one of [1] to [3], comprising:

[0015] [5] The ester oil is at least one selected from the group consisting of cetyl 2-ethylhexanoate and isopropyl myristate. Based on the total amount of gel composition 5~20% by mass, and and propylene glycol as the solubilizing agent. Based on the total amount of gel composition 1~10% by mass The heparinoid-containing gel composition according to any one of [1] to [4], comprising:

[0016] [6] A heparinoid-containing gel composition according to any one of [1] to [5], which has an initial viscosity of 30,000 to 60,000 mPa·s as measured using a Brookfield viscometer at a temperature of 25°C and a rotation speed of 10 rpm, and a viscosity retention rate {((viscosity after storage at 60°C for 1 week) / (initial viscosity)) × 100} of 95% or more after sealed storage at 60°C for 1 week.

[0017] [7] Heparinoid, water 、 thickener , nonionic surfactant, ester oil and solubilizing agent a gel composition containing the above-mentioned heparinoid in an amount of 0.05 to 3% by mass based on the total amount of the gel composition, and containing, as the thickener, 0.5 to 1% by mass of hydrophobic hydroxypropyl methylcellulose based on the total amount of the gel composition and 0.1 to 0.5% by mass of a carboxyvinyl polymer based on the total amount of the gel composition; The nonionic surfactant is at least one selected from the group consisting of glyceryl monostearate, glyceryl monooleate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tetrastearate, polyoxyethylene sorbit tetraoleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyethylene glycol monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene oleyl ether, in an amount of 0.01 g based on the total amount of the gel composition.The ester oil may be diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, isostearyl isostearate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, neopentyl glycol di-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, oleyl oleate, octyldodecyl oleate, decyl oleate, neopentyl glycol dicaprate, 2-ethylhexyl succinate, isocetyl stearate, butyl stearate, diisopropyl sebacate, cetyl lactate, tetradecyl lactate, isopropyl myristate, octyldodecyl myristate, myristyl The gel composition contains at least one member selected from the group consisting of cetyl phosphate, myristyl myristate, octyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearate, phytosteryl oleate, diisostearyl malate, para-methoxycinnamate, and pentaerythritol tetrarosinate in an amount of 1 to 30% by mass based on the total mass of the gel composition, and as the solubilizing agent, the gel composition contains at least one member selected from the group consisting of propylene glycol, polyethylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate in an amount of 0.5 to 20% by mass based on the total mass of the gel composition. The method for suppressing a decrease in viscosity of a heparinoid-containing gel composition further comprises containing 0.3 to 7% by mass of tocopherol acetate based on the total amount of the gel composition, thereby suppressing a decrease in viscosity of the gel composition.

[0018] [8] A method for inhibiting a decrease in viscosity of a heparinoid-containing gel composition according to [7], wherein the initial viscosity measured using a Brookfield viscometer at a temperature of 25°C and a rotation speed of 10 rpm is 30,000 to 60,000 mPa·s, and the viscosity retention rate after sealed storage at 60°C for one week {((viscosity after storage at 60°C for one week) / (initial viscosity)) × 100} is 95% or more. [Effects of the Invention]

[0019] According to the present invention, in a heparinoid-containing gel composition containing a heparinoid, water, and a thickener, it is possible to increase the initial viscosity to a predetermined level or higher and sufficiently suppress viscosity reduction during storage. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will be described in detail below based on preferred embodiments thereof.

[0021] The heparin-like substance-containing gel composition of the present invention is a gel composition containing a heparin-like substance, water, and a thickener, wherein the content of the heparin-like substance is 0.05 to 3 mass% based on the total amount of the gel composition, and the thickeners include 0.5 to 1 mass% hydrophobic hydroxypropyl methylcellulose based on the total amount of the gel composition and 0.1 to 0.5 mass% carboxyvinyl polymer based on the total amount of the gel composition, and further contains 0.3 to 7 mass% tocopherol acetate based on the total amount of the gel composition.

[0022] In addition, the method of the present invention for inhibiting a decrease in viscosity of a gel composition containing a heparin-like substance is a method characterized by inhibiting a decrease in viscosity of the gel composition by comprising a gel composition containing a heparin-like substance, water, and a thickener, wherein the content of the heparin-like substance is 0.05 to 3 mass% based on the total amount of the gel composition, and the gel composition contains, as the thickener, 0.5 to 1 mass% of hydrophobic hydroxypropyl methylcellulose based on the total amount of the gel composition and 0.1 to 0.5 mass% of carboxyvinyl polymer based on the total amount of the gel composition, and further containing 0.3 to 7 mass% of tocopherol acetate based on the total amount of the gel composition.

[0023] The heparinoid used in the present invention is a substance also known as mucopolysaccharide polysulfate or heparinoid, which is a sulfated mucopolysaccharide having a repeating disaccharide structure of D-glucuronic acid and N-acetyl-D-galactosamine. Heparinoids have many hydrophilic groups, such as sulfate, carboxyl, and hydroxyl groups, in their structure, and have high moisturizing properties, resulting in effects such as moisturizing the skin, promoting blood circulation, and anti-inflammatory effects. Heparinoids listed in the Japanese Pharmacopoeia (JP) Non-Drug Standards are preferably used. Commercially available heparinoids can be used, including those manufactured by API Corporation, Yantai Dongcheng Biochemicals Co., Ltd., and LABORATORI DERIVATI ORGANICI SpA.

[0024] The content of the heparinoid in the gel composition of the present invention must be 0.05 to 3% by mass based on the total amount of the gel composition. If the content of the heparinoid is below the lower limit, the aforementioned efficacy is difficult to obtain, while if the content of the heparinoid is above the upper limit, the viscosity of the resulting gel composition is low, and phase separation is likely to occur during storage. Since a low content of the heparinoid tends to make it difficult to obtain the aforementioned efficacy, while a high content of the heparinoid tends to lower the viscosity of the resulting gel composition, the content of the heparinoid is more preferably 0.1 to 2% by mass, even more preferably 0.1 to 1% by mass, and particularly preferably 0.2 to 0.5% by mass based on the total amount of the gel composition.

[0025] In the gel composition of the present invention, a combination of a carboxyvinyl polymer and hydrophobized hydroxypropyl methylcellulose is used as a thickener. Using either a carboxyvinyl polymer or hydrophobized hydroxypropyl methylcellulose alone cannot produce a heparinoid-containing gel composition having an initial viscosity higher than a predetermined level without causing phase separation. Furthermore, using a carboxyvinyl polymer in combination with a water-soluble polymer other than hydrophobized hydroxypropyl methylcellulose (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), or sodium carboxymethylcellulose (CMC-Na)) cannot produce a heparinoid-containing gel composition having an initial viscosity higher than a predetermined level without causing phase separation. By using a combination of a carboxyvinyl polymer and hydrophobized hydroxypropyl methylcellulose as a thickener in a heparinoid-containing gel composition, a heparinoid-containing gel composition having an initial viscosity higher than a predetermined level can be produced without causing phase separation.

[0026] The hydrophobized hydroxypropyl methylcellulose (hydrophobized HPMC) used in the present invention is a compound in which a long-chain alkyl group, which is a hydrophobic group, is introduced into hydroxypropyl methylcellulose (HPMC), which is a cellulose ether derivative. The long-chain alkyl group introduced into HPMC is a C8 to C 24 Alkyl groups are preferred, and C 10 ~C 20 Alkyl groups are more preferred, lauryl groups, myristyl groups, palmityl groups, and stearyl groups are even more preferred, and stearyl groups are particularly preferred. As the hydrophobized HPMC, one type may be used alone, or two or more types may be used in combination. As such hydrophobized HPMC, commercially available products can be used, such as Sangelose 60L, Sangelose 60M, Sangelose 90L, and Sangelose 90M (all manufactured by Daido Chemical Industry Co., Ltd.).

[0027] The hydrophobized HPMC may contain, based on its mass, 0 to 33% by mass of methoxy groups, preferably 10 to 30% by mass, more preferably 21.5 to 30% by mass, and even more preferably 21.5 to 24% by mass or 27 to 30% by mass of methoxy groups. The hydrophobized HPMC may also contain, based on its mass, 0 to 20% by mass of hydroxypropyloxy groups, preferably 4 to 15% by mass, and more preferably 7 to 11% by mass of hydroxypropyloxy groups. Furthermore, the hydrophobized HPMC may be HPMC containing stearyloxy groups (stearyloxy HPMC). The stearyloxy HPMC may contain 0.3 to 4.5% by mass of stearyloxy hydroxypropyloxy groups, preferably 0.3 to 2% by mass of stearyloxy hydroxypropyloxy groups, and more preferably 0.3 to 0.6% by mass or 1 to 2% by mass of stearyloxy hydroxypropyloxy groups, based on the mass of the stearyloxy HPMC.

[0028] The content of hydrophobized HPMC in the gel composition of the present invention must be 0.5 to 1% by mass based on the total amount of the gel composition. If the content of the hydrophobized HPMC is less than the lower limit, it becomes difficult to obtain a heparinoid-containing gel composition having an initial viscosity higher than a predetermined level, even when used in combination with a carboxyvinyl polymer. On the other hand, if the content of the hydrophobized HPMC is greater than the upper limit, the viscosity becomes excessively high, making it difficult to spread during application, and the occurrence of scum-like lumps (smearing) after application, which tends to result in a poor usability. From the same perspective, the content of the hydrophobized HPMC is more preferably 0.6 to 0.9% by mass based on the total amount of the gel composition.

[0029] The carboxyvinyl polymer used in the present invention is a polymer having a crosslinked structure partially crosslinked with polyacrylic acid as the main chain. The degree of polymerization of the carboxyvinyl polymer used in the present invention is not particularly limited, and one type may be used alone, or two or more types may be used in combination. Commercially available carboxyvinyl polymers can be used, such as Carbopol 980, Carbopol 981, Carbopol 2984, Carbopol 5984, Carbopol ETD2050, and Carbopol Ultrez 10 (all manufactured by Lubrizol); Hiviswako 103, Hiviswako 104, Hiviswako 105, Sintaren K, Sintaren L, and Sintaren M (all manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.); and Junron PW-120, Junron PW-121, and Junron PW-312S (all manufactured by Toagosei Co., Ltd.). Furthermore, the carboxyvinyl polymer according to the present invention preferably has a viscosity (measured with a Brookfield viscometer) of 500 to 8000 mPa·s, more preferably 1000 to 6000 mPa·s, of a 0.2% by mass aqueous solution at 25°C.

[0030] The content of the carboxyvinyl polymer in the gel composition of the present invention must be 0.1 to 0.5% by mass based on the total amount of the gel composition. If the content of the carboxyvinyl polymer is less than the lower limit, it becomes difficult to obtain a heparinoid-containing gel composition having an initial viscosity higher than a predetermined level, even when used in combination with hydrophobized hydroxypropyl methylcellulose. On the other hand, if the content of the carboxyvinyl polymer exceeds the upper limit, phase separation is likely to occur. From the same perspective, the content of the carboxyvinyl polymer is more preferably 0.2 to 0.4% by mass based on the total amount of the gel composition.

[0031] The heparinoid-containing gel composition of the present invention further contains a predetermined amount of tocopherol acetate in addition to the hydrophobized hydroxypropyl methylcellulose and the carboxyvinyl polymer as thickeners.

[0032] Tocopherol acetate is an ester of tocopherol (vitamin E) and acetic acid. It is an oil-soluble vitamin E derivative obtained by acetylating the hydroxyl group at the 6th position of dl-α-tocopherol. It is known to have antioxidant and blood circulation promoting effects.

[0033] The tocopherol acetate content in the gel composition of the present invention must be 0.3 to 7% by mass based on the total amount of the gel composition. If the tocopherol acetate content is less than the lower limit, the viscosity decrease of the resulting gel composition during storage is not sufficiently suppressed. On the other hand, if the tocopherol acetate content exceeds the upper limit, not only is the viscosity decrease of the resulting gel composition during storage not sufficiently suppressed, but phase separation is also likely to occur. From the same perspective, the tocopherol acetate content is more preferably 0.5 to 5% by mass based on the total amount of the gel composition.

[0034] The present inventors have discovered that by further adding a predetermined amount of tocopherol acetate to a heparinoid-containing gel composition containing a predetermined amount of hydrophobized hydroxypropyl methylcellulose and a predetermined amount of carboxyvinyl polymer as thickeners, a heparinoid-containing gel composition having an initial viscosity higher than a predetermined level can be obtained without phase separation, and the viscosity loss of the resulting heparinoid-containing gel composition during storage is sufficiently suppressed. On the other hand, even if the heparinoid-containing gel composition contains a blood circulation-promoting component other than tocopherol acetate (e.g., vanillyl nonylate, dl-camphor, capsaicin, methyl salicylate), the viscosity loss of the resulting heparinoid-containing gel composition during storage is not sufficiently suppressed. The fact that tocopherol acetate has the effect of significantly suppressing the viscosity loss of a heparinoid-containing gel composition during storage is a surprising effect that would not have been easily predicted by anyone skilled in the art.

[0035] As described above, the present invention provides a heparinoid-containing gel composition having an initial viscosity higher than a predetermined level without causing phase separation. Such an initial viscosity higher than a predetermined level is preferably 30,000 to 60,000 mPa·s as measured using a Brookfield viscometer at 25°C and 10 rpm. If the initial viscosity of the heparinoid-containing gel composition is below the lower limit, dripping upon application to the skin tends to be difficult to prevent. On the other hand, if the initial viscosity exceeds the upper limit, spreading of the composition onto the skin tends to be difficult. Furthermore, the present invention sufficiently prevents viscosity loss during storage in heparinoid-containing gel compositions having an initial viscosity higher than a predetermined level. The level at which such viscosity loss is prevented is preferably a viscosity retention rate {((viscosity after storage at 60°C for 1 week) / (initial viscosity)) × 100} of 95% or more, more preferably 96% or more, after sealed storage at 60°C for 1 week.

[0036] In the present invention, the viscosity measured using a Brookfield viscometer at a temperature of 25° C. and a rotation speed of 10 rpm is a viscosity measured using the following device and under the following measurement conditions. Device name: BROOKFIELD DIGITAL VISCOMETER (manufactured by Brookfield, USA) Spindle speed: 10 rpm Measurement temperature: 25℃ Measurement time: 330sec Spindle: SC4-14 Chamber: SC4-6RP.

[0037] The gel composition of the present invention contains water in addition to the heparinoid, thickeners (hydrophobized HPMC and carboxyvinyl polymer), and tocopherol acetate. The water content in the gel composition of the present invention is not particularly limited and may be appropriately determined depending on the composition of the other components, but is preferably 50 to 90% by mass, more preferably 60 to 80% by mass, based on the total amount of the gel composition.

[0038] From the viewpoint of preventing phase separation, it is preferable that the gel composition of the present invention does not contain lower alcohols, and it is particularly preferable that it does not contain ethanol.

[0039] In addition to the heparinoid, water, thickeners (hydrophobized HPMC and carboxyvinyl polymer), and tocopherol acetate, the gel composition of the present invention may contain active ingredients used in pharmaceuticals, quasi-drugs, cosmetics, etc., as needed, within the scope of not impairing the effects of the present invention. Examples of such active ingredients include antihistamine ingredients, antipruritic ingredients, tissue-protecting ingredients, anti-inflammatory ingredients, antifungal ingredients, whitening ingredients, herbal ingredients, and local anesthetic ingredients.

[0040] Examples of antihistamine components include diphenhydramine, chlorpheniramine, mequitazine, azelastine, emedastine, ketotifen, or derivatives thereof, with diphenhydramine being preferred. When an antihistamine component (preferably diphenhydramine) is incorporated into the gel composition of the present invention, its content is preferably 0.2 to 0.9% by mass, and more preferably 0.3 to 0.7% by mass, based on the total mass of the gel composition. If the content of the antihistamine component (preferably diphenhydramine) is less than the lower limit, the efficacy of the antihistamine component tends to be difficult to obtain. On the other hand, if the content exceeds the upper limit, the viscosity retention rate of the resulting gel composition during storage tends to decrease.

[0041] Examples of antipruritic ingredients include crotamiton and steroids, with crotamiton being preferred. When an antipruritic ingredient (preferably crotamiton) is incorporated into the gel composition of the present invention, its content is preferably 2 to 10% by mass, and more preferably 4 to 6% by mass, based on the total mass of the gel composition. If the content of the antipruritic ingredient (preferably crotamiton) is less than the lower limit, the efficacy of the antipruritic ingredient tends to be difficult to obtain. On the other hand, if the content exceeds the upper limit, the resulting gel composition tends to be prone to phase separation during storage.

[0042] Examples of tissue protective ingredients include panthenol, allantoin, zinc oxide, etc. When a tissue protective ingredient is blended into the gel composition of the present invention, the content thereof is preferably 0.01 to 5% by mass based on the total amount of the gel composition.

[0043] Examples of anti-inflammatory ingredients include glycyrrhetinic acid, glycyrrhizinic acid or derivatives thereof, licorice extract, steroid compounds (hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, cortisone, flumethasone, beclomethasone, fluticasone or derivatives thereof), indomethacin, ibuprofen, ibuprofen piconol, bufexamac, ufenamate, piroxicam, ketoprofen, salicylic acid or derivatives thereof, dimethylisopropylazulene, Angelica acutiloba extract, Lithospermum root extract, etc. When an anti-inflammatory ingredient is incorporated into the gel composition of the present invention, the content thereof is preferably 0.01 to 1% by mass based on the total amount of the gel composition.

[0044] Examples of antifungal drug components include butenafine hydrochloride, terbinafine hydrochloride, neticonazole hydrochloride, luliconazole, efinaconazole, bifonazole, ketoconazole, lanoconazole, etc. When an antifungal drug component is incorporated into the gel composition of the present invention, the content thereof is preferably 0.01 to 1% by mass based on the total amount of the gel composition.

[0045] Examples of whitening ingredients include L-cysteine, hydroquinone, glucosamine, L-ascorbic acid, glutathione, kojic acid, ellagic acid, placenta extract, ubiquinones, and derivatives thereof. When a whitening ingredient is blended into the gel composition of the present invention, the content thereof is preferably 0.01 to 1% by mass based on the total amount of the gel composition.

[0046] Examples of herbal ingredients include Bupleurum Root, Poria Cocos Root, Cinnamon Bark, Licorice Root, Scutellaria Root, Phellodendron Bark, Coptis Rhizome, Sanshichi Blossom, Rehmannia Root, Peony Root, Cnidium Rhizome, Angelica Root, Glehnia Root, Safflower Root, Platycodon Grandiflorum, Ginger Root, Poria Root, Scutellaria Baicalensis, Mokutsu Root, Burdock Fruit, Zingiber Officinale, Siberian Root, Sophora Root, Atractylodes Rhizome, and Inchinko Root, etc. When a herbal ingredient is incorporated into the gel composition of the present invention, the content thereof is preferably 0.01 to 1% by mass based on the total amount of the gel composition.

[0047] Examples of local anesthetic ingredients include lidocaine, dibucaine, procaine, tetracaine, aminobenzoic acid, or derivatives thereof. When a local anesthetic ingredient is incorporated into the gel composition of the present invention, the content thereof is preferably 0.01 to 2% by mass based on the total amount of the gel composition.

[0048] In the heparin-like substance-containing gel composition of the present invention, in addition to the active ingredient, surfactants, oils, solubilizers, pH adjusters, higher fatty acids, preservatives, cooling agents, etc. may be blended as ingredients to constitute the gel composition.

[0049] As surfactant, from the viewpoint of skin irritation, nonionic surfactant is preferred.As nonionic surfactant, glyceryl monostearate, glyceryl monooleate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tetrastearate, polyoxyethylene sorbitan tetraoleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyethylene glycol monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether etc. are enumerated, among which, from the viewpoint of more suppressing the phase separation of the obtained gel composition, polyoxyethylene sorbitan monostearate, polyethylene glycol monostearate, polyoxyethylene cetyl ether are preferred, and the combination of polyoxyethylene sorbitan monostearate and polyethylene glycol monostearate, the combination of polyoxyethylene sorbitan monostearate and polyoxyethylene cetyl ether are particularly preferred. When a surfactant (preferably a nonionic surfactant) is blended in the gel composition of the present invention, the content thereof is preferably 0.1 to 10 mass %, more preferably 0.3 to 5 mass %, and particularly preferably 0.5 to 3 mass %, based on the total amount of the gel composition. If the content of the surfactant (preferably a nonionic surfactant) is less than the lower limit, phase separation of the resulting gel composition tends to occur easily, while if the content exceeds the upper limit, the viscosity of the resulting gel composition tends to decrease and the composition tends to become sticky when applied.

[0050] Examples of oils include natural animal and vegetable oils, hydrocarbon oils, ester oils, silicone oils, etc., and ester oils are preferred because they make the resulting gel composition easier to spread and tend to be less sticky after application. Examples of ester oils include diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, isostearyl isostearate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, neopentyl glycol di-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, oleyl oleate, octyldodecyl oleate, decyl oleate, neopentyl glycol dicaprate, 2-ethylhexyl succinate, isocetyl stearate, butyl stearate, diisopropyl sebacate, cetyl lactate, tetradecyl lactate, and isopropyl myristate. Examples of suitable oils include octyldodecyl myristate, cetyl myristate, myristyl myristate, octyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearate, phytosteryl oleate, diisostearyl malate, para-methoxycinnamate, and pentaerythritol tetrarosinate. Among these, cetyl 2-ethylhexanoate and isopropyl myristate are preferred, and a combination of cetyl 2-ethylhexanoate and isopropyl myristate is particularly preferred, as they tend to make the resulting gel composition easier to spread and less sticky after application. When an oil (preferably an ester oil) is incorporated into the gel composition of the present invention, the content thereof is preferably 1 to 30% by mass, more preferably 5 to 20% by mass, and particularly preferably 10 to 15% by mass, based on the total mass of the gel composition. If the oil (preferably ester oil) content is less than the lower limit, the moisturizing properties of the resulting gel composition tend to decrease, while if it exceeds the upper limit, the resulting gel composition tends to dry more slowly when applied.

[0051] Examples of solubilizing agents include propylene glycol, polyethylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate, with propylene glycol being preferred due to its low skin irritation. When a solubilizing agent is incorporated into the gel composition of the present invention, its content is preferably 0.5 to 20% by mass, more preferably 1 to 10% by mass, and particularly preferably 3 to 7% by mass, based on the total mass of the gel composition. If the content of the solubilizing agent is less than the lower limit, a sufficient solubilizing effect tends to be insufficient. On the other hand, if the content exceeds the upper limit, the resulting gel composition tends to be sticky after application.

[0052] Examples of pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.), and organic bases (diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, etc.), of which diethanolamine is preferred because it is liquid at room temperature, does not deliquesce, and is easy to handle. When a pH adjuster is incorporated into the gel composition of the present invention, the content thereof is preferably 0.01 to 0.5% by mass based on the total amount of the gel composition.

[0053] Examples of higher fatty acids include isostearic acid, oxystearic acid, oleic acid, stearic acid, palmitic acid, behenic acid, myristic acid, lauric acid, lanolinic acid, linoleic acid, linolenic acid, etc., of which oleic acid is preferred. When a higher fatty acid is blended into the gel composition of the present invention, the content thereof is preferably 0.1 to 5% by mass based on the total amount of the gel composition.

[0054] Examples of preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl parahydroxybenzoate, methyl parahydroxybenzoate, phenoxyethanol, etc., of which methyl parahydroxybenzoate is preferred from the viewpoints of excellent solubility in water and low skin irritation. When a preservative is incorporated into the gel composition of the present invention, the content thereof is preferably 0.01 to 1% by mass based on the total amount of the gel composition.

[0055] Examples of the refreshing agent include menthol (l-menthol, dl-menthol, etc.), camphor (d-camphor, dl-camphor, etc.), terpenoids such as borneol, essential oils containing terpenoids (mentha oil), or pharmacologically acceptable salts thereof. When a refreshing agent is blended in the gel composition of the present invention, the content thereof is preferably 0.01 to 7% by mass based on the total amount of the gel composition.

[0056] The pH of the heparin-like substance-containing gel composition of the present invention is not particularly limited as long as it is within a physiologically or pharmaceutically acceptable range, but from the viewpoint of skin irritation, the pH is preferably 2 to 11.5, more preferably 3 to 10, and particularly preferably 5 to 8.

[0057] Furthermore, the dynamic viscoelasticity of the heparin-like substance-containing gel composition of the present invention is not particularly limited, but from the viewpoint of more adequately preventing dripping when applied to the skin and providing a more pleasant feel during and after application, it is preferable that the maximum load measured under the following conditions using a rheometer be 0.3 to 0.7 N, the elastic modulus be 2.5 to 6.0 N, and the yield stress be 0.9 to 2.0 Pa.

[0058] The maximum load, modulus of elasticity, and yield stress are parameters (physical properties) related to dynamic viscoelasticity, measured using a rheometer to measure the repulsive force, etc., when a test probe is pressed into the gel composition under the following conditions, and are physical properties that indicate the elasticity of the gel composition. Device name: SUN RHEO METER (manufactured by Sun Scientific Co., Ltd.) Test probe (adapter): 20mm diameter disc Test stand speed (probe pushing speed): 600mm / min Probe pushed in: 10 mm Sample part: UM sample bottle 100 mL (manufactured by AS ONE Corporation) Sample amount: 80g ± 0.5g Measurement temperature: 25℃.

[0059] The heparin-like substance-containing gel composition of the present invention is in the form of a gel, and its preparation method is not particularly limited. It can be prepared by weighing out the above-mentioned heparin-like substance, water, thickener (hydrophobized HPMC and carboxyvinyl polymer) and tocopherol acetate, and, if necessary, the above-mentioned active ingredient and ingredients for constituting the gel composition to the desired mixing ratio, and mixing them by conventional methods. [Example]

[0060] The present invention will be described in more detail below based on examples and comparative examples, but the present invention is not limited to the following examples.

[0061] (Examples 1 to 5 and Comparative Examples 1 to 15) The components shown in Tables 1 to 4 were weighed out to the desired blend ratio and mixed in a conventional manner to prepare heparinoid-containing gel compositions. The numerical values ​​for the composition in the tables indicate the content (% by mass) of each component based on the total amount of the resulting gel composition.

[0062] Carbopol 981 NF POLYMER, a trade name of Lubrizol, is used as a carboxyvinyl polymer; Sangelose 90L, a trade name of Daido Chemical Industry Co., Ltd. is used as a hydrophobized hydroxypropyl methylcellulose (hydrophobized HPMC); METOLOSE 90SH-15000SR, a trade name of Shin-Etsu Chemical Co., Ltd. is used as a hydroxypropyl cellulose (HPC); Klucel HF PHARM Hydroxypropylcellulose, a trade name of Ashland; Natrosol 250 HHX PHARM Hydroxyethylcellulose, a trade name of Ashland; and Cellogen, a trade name of sodium carboxymethylcellulose (CMC-Na), a trade name of Dai-ichi Kogyo Seiyaku Co., Ltd. are used as hydroxypropyl cellulose (HPC). P-815C, polyoxyethylene sorbitan monostearate manufactured by Nippon Surfactant Kogyo Co., Ltd. under the trade name TS-10MV, polyoxyethylene cetyl ether manufactured by Nippon Surfactant Kogyo Co., Ltd. under the trade name BC-40, and polyethylene glycol monostearate manufactured by Nippon Surfactant Kogyo Co., Ltd. under the trade name MYS-55MV were used.

[0063] <Viscosity measurement of gel composition> For the heparinoid-containing gel compositions obtained in the Examples and Comparative Examples, the initial viscosity immediately after production was measured using the B-type viscometer under the measurement conditions described above. Next, each heparinoid-containing gel composition was sealed in a resin container and stored at 60°C for 1 week, after which the viscosity was measured in the same manner, and the viscosity retention rate {((viscosity after storage at 60°C for 1 week) / (initial viscosity)) × 100} was calculated. The results are shown in Tables 1 to 4.

[0064] [Table 1]

[0065] [Table 2]

[0066] [Table 3]

[0067] [Table 4]

[0068] As is clear from the results shown in Tables 1 to 4, it was confirmed that even when a carboxyvinyl polymer was used as a thickener in combination with a water-soluble polymer other than hydrophobized hydroxypropyl methylcellulose {HPMC (Comparative Example 6), HPC (Comparative Example 7), HEC (Comparative Example 8), CMC-Na (Comparative Example 9)}, it was not possible to obtain a heparin-like substance-containing gel composition with an initial viscosity of 30,000 mPa·s or more without phase separation occurring.

[0069] In contrast, it was confirmed that by using a combination of carboxyvinyl polymer and hydrophobized hydroxypropyl methylcellulose (hydrophobized HPMC) as a thickener (Examples 1 to 5), a heparinoid-containing gel composition with an initial viscosity of 30,000 mPa·s or more could be obtained without phase separation.

[0070] Furthermore, even when a heparin-like substance-containing gel composition containing carboxyvinyl polymer and hydrophobized hydroxypropyl methylcellulose (hydrophobized HPMC) as thickeners was supplemented with a blood circulation-promoting component other than tocopherol acetate {vanillylamide nonylate (Comparative Example 2), dl-camphor (Comparative Example 3), capsaicin (Comparative Example 4), methyl salicylate (Comparative Example 5)}, the viscosity retention rate of the resulting heparin-like substance-containing gel composition during storage was less than 95%, and it was confirmed that the decrease in viscosity during storage was not sufficiently suppressed.

[0071] In contrast, by adding a predetermined amount of tocopherol acetate to a heparin-like substance-containing gel composition containing carboxyvinyl polymer and hydrophobized hydroxypropyl methylcellulose (hydrophobized HPMC) as thickeners (Examples 1 to 5), a heparin-like substance-containing gel composition having an initial viscosity higher than a predetermined level was obtained without phase separation, and it was confirmed that the viscosity retention rate of the obtained heparin-like substance-containing gel composition during storage was 95% or more, and that viscosity decrease during storage was sufficiently suppressed.

[0072] On the other hand, even when tocopherol acetate was added to a heparin-like substance-containing gel composition containing carboxyvinyl polymer and hydrophobized hydroxypropyl methylcellulose (hydrophobized HPMC) as thickeners, if the content was outside the range of the present invention (Comparative Examples 10 to 13), the viscosity retention rate of the resulting heparin-like substance-containing gel composition during storage was less than 95%, and it was confirmed that the decrease in viscosity during storage was not sufficiently suppressed.

[0073] Furthermore, even when a predetermined amount of tocopherol acetate was added to a heparin-like substance-containing gel composition containing carboxyvinyl polymer and hydrophobized hydroxypropyl methylcellulose (hydrophobized HPMC) as thickeners, it was confirmed that when the heparin-like substance content was outside the range of the present invention (Comparative Example 14), the initial viscosity was low and phase separation occurred during storage.

[0074] Furthermore, when a predetermined amount of tocopherol acetate was added to a heparinoid-containing gel composition containing only hydrophobized hydroxypropylmethylcellulose (hydrophobized HPMC) as a thickener (no carboxyvinyl polymer) (Comparative Example 15), it was confirmed that the initial viscosity was low and the viscosity retention rate during storage was also low. [Industrial Applicability]

[0075] As described above, according to the present invention, in a heparin-like substance-containing gel composition containing a heparin-like substance, water, and a thickener, it is possible to increase the initial viscosity to a predetermined level or higher and sufficiently suppress viscosity reduction during storage.

[0076] Therefore, according to the heparin-like substance-containing gel composition and its method for inhibiting viscosity decrease of the present invention, dripping when applied to the skin is sufficiently prevented even under various storage and usage environments, the feeling of use during and after application is good, and the desired efficacy of the heparin-like substance is stably exerted.

Claims

1. A gel composition containing a heparinoid, water, a thickener, a nonionic surfactant, an ester oil, and a solubilizing agent, wherein the content of the heparinoid is 0.05 to 3% by mass based on the total amount of the gel composition, the gel composition contains as the thickener 0.5 to 1% by mass based on the total amount of the gel composition of hydrophobized hydroxypropyl methylcellulose and 0.1 to 0.5% by mass based on the total amount of the gel composition of a carboxyvinyl polymer, and the nonionic surfactant is selected from the group consisting of glyceryl monostearate, glyceryl monooleate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tetrastearate, polyoxyethylene sorbit tetraoleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyethylene glycol monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, and polyoxyethylene oleyl ether. The gel composition contains 0.1 to 10% by mass of at least one selected from the group consisting of diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, isostearyl isostearate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, neopentyl glycol di-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, oleyl oleate, oleic acid ... octyldodecyl myristate, decyl oleate, neopentyl glycol dicaprate, 2-ethylhexyl succinate, isocetyl stearate, butyl stearate, diisopropyl sebacate, cetyl lactate, tetradecyl lactate, isopropyl myristate, octyldodecyl myristate, cetyl myristate, myristyl myristate, octyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearate, phytosteryl oleate,A heparinoid-containing gel composition comprising at least one selected from the group consisting of diisostearyl malate, paramethoxycinnamate esters, and pentaerythritol tetrarosinate in an amount of 1 to 30% by mass, based on the total mass of the gel composition; at least one solubilizing agent selected from the group consisting of propylene glycol, polyethylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate in an amount of 0.5 to 20% by mass, based on the total mass of the gel composition; and further comprising tocopherol acetate in an amount of 0.3 to 7% by mass, based on the total mass of the gel composition.

2. 2. The heparinoid-containing gel composition according to claim 1, further comprising 0.2 to 0.9% by mass of diphenhydramine based on the total mass of the gel composition.

3. 2. The heparinoid-containing gel composition according to claim 1, further comprising 2 to 10% by mass of crotamiton based on the total mass of the gel composition.

4. A heparin-like substance-containing gel composition as described in claim 1, characterized in that the nonionic surfactant contains at least one selected from the group consisting of polyoxyethylene sorbitan monostearate, polyethylene glycol monostearate, and polyoxyethylene cetyl ether in an amount of 0.3 to 5 mass% based on the total amount of the gel composition.

5. A heparin-like substance-containing gel composition as described in claim 1, characterized in that the ester oil is at least one selected from the group consisting of cetyl 2-ethylhexanoate and isopropyl myristate in an amount of 5 to 20 mass% based on the total amount of the gel composition, and the solubilizing agent is propylene glycol in an amount of 1 to 10 mass% based on the total amount of the gel composition.

6. A heparin-like substance-containing gel composition according to any one of claims 1 to 5, characterized in that the initial viscosity measured using a B-type viscometer at a temperature of 25°C and a rotation speed of 10 rpm is 30,000 to 60,000 mPa·s, and the viscosity retention rate after sealed storage at 60°C for one week {((viscosity after storage at 60°C for one week) / (initial viscosity)) x 100} is 95% or more.

7. A gel composition containing a heparinoid, water, a thickener, a nonionic surfactant, an ester oil, and a solubilizing agent, the content of the heparinoid is 0.05 to 3% by mass based on the total amount of the gel composition, the gel composition contains as the thickener 0.5 to 1% by mass based on the total amount of the gel composition of hydrophobic hydroxypropyl methylcellulose and 0.1 to 0.5% by mass based on the total amount of the gel composition of a carboxyvinyl polymer, and the nonionic surfactants include glyceryl monostearate, glyceryl monooleate, sorbitan monostearate, monooleate, sorbitan monostearate, sorbitan monooleate ... selected from the group consisting of sorbitan leate, sorbitan sesquioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tetrastearate, polyoxyethylene sorbit tetraoleate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, polyethylene glycol monooleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether and polyoxyethylene oleyl ether At least one of the ester oils is contained in an amount of 0.1 to 10% by mass based on the total amount of the gel composition, and examples of the ester oil include diisobutyl adipate, 2-hexyldecyl adipate, di-2-heptylundecyl adipate, isostearyl isostearate, trimethylolpropane triisostearate, cetyl 2-ethylhexanoate, neopentyl glycol di-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, pentaerythritol tetra-2-ethylhexanoate, cetyl octanoate, oleyl oleate, and octyldodecyl oleate. , decyl oleate, neopentyl glycol dicaprate, 2-ethylhexyl succinate, isocetyl stearate, butyl stearate, diisopropyl sebacate, cetyl lactate, tetradecyl lactate, isopropyl myristate, octyldodecyl myristate, cetyl myristate, myristyl myristate, octyl palmitate, 2-ethylhexyl palmitate, 2-hexyldecyl palmitate, 2-heptylundecyl palmitate, cholesteryl 12-hydroxystearate, phytosteryl oleate, diisostearyl malate,A method for inhibiting a decrease in viscosity of a heparinoid-containing gel composition, characterized in that the gel composition contains at least one member selected from the group consisting of paramethoxycinnamate esters and pentaerythritol tetrarosinate in an amount of 1 to 30% by mass, based on the total mass of the gel composition, and contains at least one member selected from the group consisting of propylene glycol, polyethylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate as the solubilizing agent in an amount of 0.5 to 20% by mass, based on the total mass of the gel composition, and further contains tocopherol acetate in an amount of 0.3 to 7% by mass, based on the total mass of the gel composition, thereby inhibiting a decrease in viscosity of the gel composition.

8. A method for inhibiting a decrease in viscosity of a heparin-like substance-containing gel composition according to claim 7, characterized in that the initial viscosity measured using a B-type viscometer under conditions of a temperature of 25°C and a rotation speed of 10 rpm is 30,000 to 60,000 mPa·s, and the viscosity retention rate after sealed storage at 60°C for one week {((viscosity after storage at 60°C for one week) / (initial viscosity)) x 100} is 95% or more.

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