JP7587928B2 - Blocking agent for metal allergy-causing substances - Google Patents

Description

The present invention relates to a novel agent for blocking substances that cause metal allergies.

Metal products are one of the causes of skin troubles. Metal products such as accessories, watches, belts, underwear hooks, glasses, dental metal, doorknobs, stationery, and stainless steel products often come into direct contact with the skin, causing adverse effects such as pain, itching, rashes, swelling, redness, and rashes. Metals are also found in air pollutants such as PM2.5 and yellow sand, which are known to cause rough skin and chapped lips. Such adverse effects are serious not only for those with metal allergies, but also for those who are negative for the condition. Many people who are negative still feel irritation from metals, and even those who do not have any symptoms may continue to come into contact with metals because they are unaware of the symptoms, and the allergens may accumulate in the body without realizing it, putting them at risk of developing a metal allergy.

Therefore, there is a need to take measures to prevent the skin, lips, etc. from coming into contact with metal allergy-causing substances. For example, Patent Document 1 discloses a liquid preparation for preventing metal allergies that contains polyvinyl alcohol. Patent Document 2 discloses a composition for protecting the skin that contains at least one metal capture agent having a carboxyl, sulfonyl, or sulfate moiety. Patent Document 3 discloses a method for reducing contact between metal cations and the skin and reducing or preventing skin troubles caused by sweat. Patent Document 4 discloses an allergen adsorption composition that contains at least one of powders consisting of kaolin, talc, sericite, mica, silica, silicic acid and/or its salt, silicic anhydride, titanium oxide, and activated carbon. Under these circumstances, there has been a demand for further substances that are highly effective in preventing contact between the skin, lips, etc. and metal allergy-causing substances.

Special Publication No. 06-55665 Special table 2017-523246 publication JP 2006-321773 A JP 2002-167332 A JP 2017-61548 A International Publication No. 2019/176265

The objective of the present invention is to provide a novel agent for blocking substances that cause metal allergies.

As a result of extensive research into various substances, the present inventors have discovered a component that is highly effective as a blocking agent for substances that cause metal allergies, and have completed the following invention.
(1) A blocking agent for metal allergy causative substances, comprising one or more polymers selected from the group consisting of hydrophobized hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.
(2) The metal allergy-causing substance blocking agent according to (1), which blocks metal allergy-causing substances by trapping the metal allergy-causing substances with the polymer and protecting the skin and/or lips from the metal allergy-causing substances.

By applying the metal allergy-causing substance blocking agent of the present invention, it is possible to block contact between the skin, lips, etc. and metal allergy-causing substances.

FIG. 1 shows the results of the artificial membrane permeability test in Example 2. FIG. 2 shows the results of the hydrophobic film function test using various materials of Example 3. FIG. 3 shows the results of the hydrophobic film function test using hydrophobized HPMC at various concentrations in Example 4.

The present invention provides a blocking agent for metal allergy-causing substances, which contains one or more polymers selected from the group consisting of hydrophobized hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose (hereinafter, sometimes referred to as the polymer of the present invention).

The present invention also includes hydrophobized hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose for use in a blocking agent for metal allergy-causing substances; a method for blocking metal allergy-causing substances, comprising applying a blocking agent for metal allergy-causing substances containing one or more polymers selected from the group consisting of hydrophobized hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose to a subject in need of blocking metal allergy-causing substances; and the use of one or more polymers selected from the group consisting of hydrophobized hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose for producing a blocking agent for metal allergy-causing substances.

The metal allergy-causing substance blocking agent of the present invention blocks metal allergy-causing substances by trapping the metal allergy-causing substances with the polymer of the present invention and protecting the skin and/or lips from the metal allergy-causing substances. Blocking metal allergy-causing substances has the following advantages: it is possible to prevent or reduce metal allergies, it is possible to wear metal products such as accessories without worrying about the discomfort caused by metal, it is possible to avoid contact with harmful substances that contain metal, and it is possible to prevent the onset of metal allergies even in those who have no subjective symptoms.

Metal allergies are caused by allergens formed when metal ions eluted from metals come into contact with skin and bind to proteins, such as skin proteins. In this specification, "substances causing metal allergies" refers to metal ions that can elute from metals as ions to form allergens and cause metal allergies, and examples include ions of metals such as nickel, cobalt, and chromium. However, this does not exclude metal ions such as stainless steel, titanium, zirconium, gold, and silver, which are less likely to elute as ions and cause allergies.

"Blocking metal allergy-causing substances" refers to reducing or preventing contact between the skin and/or lips and metal allergy-causing substances, and the metal allergy-causing substance blocking agent of the present invention (hereinafter sometimes referred to as the agent of the present invention) blocks metal allergy-causing substances by trapping metal allergy-causing substances with the polymer contained in the agent of the present invention and protecting the skin and/or lips from metal allergy-causing substances.

"Capturing a metal allergy-causing substance" refers to the binding of the polymer molecule of the present invention to a metal allergy-causing substance, for example, capturing the metal allergy-causing substance by forming a complex or electrostatic capture. The ability to capture a metal allergy-causing substance can be determined, for example, as described in the Examples, by adding a test substance to a solution containing the metal allergy-causing substance and then measuring the reduction in the metal ion that is the metal allergy-causing substance by a color reaction, but is not limited to this. For example, it can be determined by adding a test substance to a solution of nickel, the metal allergy-causing substance, and measuring the reduction in the metal ion by a color reaction. In addition, transition metals other than nickel, such as chromium, manganese, iron, cobalt, and copper, also behave in a similar manner, so it is also possible to measure the reduction in such transition metal ions.

"Protecting the skin and/or lips from metal allergy-causing substances" refers to protecting the skin and/or lips from contact by forming a film on the surface of the skin and/or lips and/or inhibiting the permeation of metal allergy-causing substances. "Forming a film" refers to the agent of the present invention covering the skin. "Permeation of metal allergy-causing substances" refers to the metal allergy-causing substances passing through the film formed by the agent of the present invention to reach the skin and/or lips. The ability to protect against metal allergy-causing substances can be determined, for example, as described in the Examples, by measuring the permeability of metal allergy-causing substances using an artificial membrane permeability test or measuring the film function using a film function test, but is not limited thereto.

"Prevention of metal allergies" refers to reducing or preventing contact between the skin and/or lips and substances that cause metal allergies, thereby suppressing the production of allergens and/or their accumulation in the body, and suppressing metal allergies and/or their precursor symptoms or discomfort, such as irritation, pain, itchiness, rash, swelling, redness, and rash, caused by wearing metal or coming into contact with substances that contain metal.

The agent of the present invention contains one or more polymers selected from the group consisting of hydrophobized hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose (i.e., the polymer of the present invention) as an active ingredient.

Hydroxypropyl cellulose (also known as HPC, CAS number: 9004-64-2) may be produced by known methods, or a commercially available product may be used. Commercially available products include, but are not limited to, the HPC series manufactured by Nippon Soda, such as HPC-M, HPC-H, and HPC-VH, which have a viscosity of 150 to 6000 mPa·s and a weight average molecular weight of about 700,000 to 2,500,000, or a mixture of these may be used. As the polymer of the present invention, preferably, HPC-H, which has a viscosity of 1,000 to 4,000 mPa·s and a molecular weight of about 1,000,000, can be used.

Hydroxypropyl methylcellulose (also known as HPMC, hypromellose, CAS number: 9004-65-3) may be produced by a known method, or a commercially available product may be used. Commercially available products include, but are not limited to, the Metrose (registered trademark) 60SH, 65H, and 90SH series manufactured by Shin-Etsu Chemical Co., Ltd., which have a degree of substitution of 1.4 to 0.9 (average number of hydroxyl groups substituted with methoxy groups per glucose ring unit of cellulose) and a molar substitution of 0.15 to 0.25 (average number of moles of hydroxypropoxy groups or hydroxyethoxy groups added per glucose ring unit of cellulose), a viscosity of 1,000 to 100,000 mPa·s, and a weight average molecular weight of 100,000 to 1,000,000, or a mixture of these may be used. As the polymer of the present invention, a Metrose such as Metrose 90SH-4000 having a viscosity of 4,000 mPa·s may preferably be used.

Hydrophobized hydroxypropyl methylcellulose (also known as stearoxy hydroxypropyl methylcellulose, hydroxypropyl methylcellulose stearoxy ether, CAS number: 141615-27-2) may be produced by known methods, such as those described in Patent Documents 5 and 6, or a commercially available product may be used. Examples of commercially available products include, but are not limited to, Sangelose (registered trademark) manufactured by Daido Kasei Kogyo Co., Ltd., which has 20% to 30% methoxy groups, 5.0 to 15.0% hydroxypropoxy groups, 0.1 to 2.0% stearyloxyhydroxypropoxy groups, and a viscosity of 60 to 300 mPa·S. Hydrophobically modified alkyl cellulose (Sangelose (registered trademark) 60 series) has a weight average molecular weight of about 300,000 to 500,000, and hydrophobically modified alkyl cellulose (Sangelose (registered trademark) 90 series) has a weight average molecular weight of about 700,000 to 900,000. The L type is water-soluble, and the M and H types are water-insoluble. These can be used alone or in combination. As the polymer of the present invention, Sangelose (registered trademark) 60L or 90L can be preferably used.

本発明のポリマーは、１種を単独で用いてもよく、２種以上組み合わせて用いてもよい。 The polymer that is the active ingredient in the agent of the present invention, i.e.

The polymers of the present invention may be used alone or in combination of two or more.

The content of the polymer, which is the active ingredient in the agent of the present invention, is not limited as long as it can block metal allergy-causing substances, but can be arbitrarily selected depending on conditions such as form, application site, and use, for example, 0.05 to 2.0% by weight, 0.1 to 1.0% by weight, 0.1 to 0.8% by weight, 0.4 to 0.6% by weight, 0.4 to 0.5% by weight, 0.5 to 0.6% by weight, etc.

The agent of the present invention can be used as an anti-allergy or antibacterial ointment, spray, gel, skin lotion, or various cosmetics such as moisturizing cream, skin lotion, foundation, hair cream, makeup base, sunscreen, pharmaceuticals, quasi-drugs, or a composition or base thereof (hereinafter, sometimes referred to as the composition of the present invention, etc.). The composition of the present invention can be produced by a conventional method in a formulation in which an excipient, carrier and/or diluent, etc., and other ingredients are appropriately combined depending on the dosage form. For example, if the agent of the present invention is used in a composition in the form of an ointment that is applied directly to the skin or lips, the effect of blocking metal allergy-causing substances on the skin and/or lips can be directly exerted. In addition, since it is possible that metal allergy-causing substances attached to hair, etc. unknowingly come into contact with the skin and/or lips and cause allergies, for example, if the agent of the present invention is used in a composition in the form of a hair cream that is applied to the hair, the effect of blocking metal allergy-causing substances can be indirectly exerted.

The form of the agent and composition of the present invention can be selected arbitrarily according to the active ingredient, application site, use, and other conditions, such as gel, paste, liquid, cream, balm, etc., as long as it can exert an effect of blocking substances that cause metal allergies.

Additives may be selected and used in combination with the agent and composition of the present invention as necessary, provided that the effects of the present invention are not impaired. Examples of additives include colorants, preservatives, thickeners, binders, disintegrants, dispersants, stabilizers, gelling agents, antioxidants, preservatives, pH adjusters, oils, powders, water, alcohols, chelating agents, fragrances, various medicinal ingredients, preservatives, neutralizing agents, and other known additives that can be appropriately selected and used. In order to further enhance the effects of the present invention, one or more other ingredients, such as other metal allergy-causing substance blocking agents, allergy countermeasure drugs, coating agents, protective agents, adsorbents, etc., may be used in combination.

The amount of the agent and composition of the present invention to be applied can be, for example, 0.1 mg/ ^cm2 to 10.0 mg/ ^cm2 , 0.5 mg/ ^cm2 to 5.0 mg/ ^cm2 , 1.0 mg/ ^cm2 to 5.0 mg/ ^cm2 , ^2.0 mg/cm2 to 4.0 mg/ ^cm2 , 2.0 mg/ ^cm2 to 3.0 mg/ ^cm2 , 1.0 mg/ ^cm2 to 2.0 mg/ ^cm2, etc. per skin, but is not particularly limited and can be changed appropriately depending on conditions such as the type or concentration of the active ingredient, the form of the agent or composition, the application site, and the purpose.

In addition, the route of administration of the agent and composition of the present invention can be a mode that can exert a blocking effect on the skin or lips against substances that cause metal allergies, such as application to the skin, lips, hair, etc.

Next, the present invention will be described in more detail with reference to examples. Note that the present invention is not limited to these examples.

Example 1: Test of metal allergen causative substance capture ability The metal allergen causative substance capture ability was examined by examining the capture ability of nickel ions, which are representative substances that cause metal allergens. As candidate substances for the agent of the present invention, each sample shown in Table 1 below was dissolved in purified water to prepare a concentration of 0.5% by weight. Water was used as a control.

5 g of a 10 ppm nickel nitrate aqueous solution (atomic absorption reagent (Kanto Chemical) diluted with purified water) was mixed with 1 g of a 0.5% aqueous solution of the above test substance and 4 g of purified water that had been adjusted with 0.1% NaOH if the pH of the test water was low so that the test water was within the pH range of 5 to 9, and stirred. A measurement method using the 1,2-cyclohexanedionedioxime (nioxime) method as the color development principle (Kyoritsu Rikagaku Kenkyusho Pack Test Nickel (DPM) (Model WAK-Ni (D))) was used, and according to the attached instructions, the test water was placed in the attached test tube, gently shaken 5 to 6 times, and after 2 minutes, centrifuged (3000 rpm, 1 min) and the color reaction was visually confirmed. When compared with the attached standard color sheet, the nickel concentration of the control was shown to be 5 ppm. Candidate substances that showed a nickel concentration of 2 ppm or less were judged to have nickel ion capture ability. If the test substance was water-insoluble, the powder was filtered with the above-mentioned nickel aqueous solution, and the filtrate was tested and judged in the same way.

The candidate substances used and the results are shown in Table 1 below. The substances with nickel ion-trapping ability are indicated by ◯, and those without nickel ion-trapping ability are indicated by ×.

Among the many polymers and polysaccharides, HPC, HPMC, and hydrophobized HPMC are found to be highly effective, and are found to have the same nickel ion trapping effect as PVA, bentonite, and EDTA.

Example 2: Artificial membrane permeability test Among the candidate substances in Example 1, polysaccharide cellulose-based polymers (HPC, HPMC, hydrophobized HPMC, HEC, CMC), and, among the substances that showed nickel ion capture effect in Example 1, synthetic polymer PVA, clay mineral bentonite, and chelating agent EDTA were used to prepare 0.5% aqueous solution samples in the same manner as in Example 1, and water was used as a control.

In a Franz cell in which an artificial membrane (durapore (PVDF) 25 mm, 0.22 μm/millipore) was sandwiched between silicon membranes with a diameter of 1.5 cm, 32°C PBS buffer (pH 7.5/Takara) was circulated, and 200 μL of each sample was spread over the artificial membrane. After 5 minutes, 200 μL of 125 ppm nickel chloride aqueous solution (nickel chloride (II) hexahydrate (Fujifilm) prepared with purified water) was applied and gently blended. After 2 hours, the receiver liquid was taken into a test tube (Kyoritsu Rika) as in Example 1, and after centrifugation (3000 rpm, 1 min), the nickel concentration was quantified by absorbance measurement (554 nm). If a statistically significant decrease in nickel concentration was observed compared to the control, it was determined that there was an effect of suppressing nickel ion permeation.

The results are shown in Figure 1. Nickel ion permeability was significantly reduced in HPC, HPMC, and hydrophobized HPMC, and it can be seen that, like bentonite and EDTA, they do not allow nickel ions to pass through and are effective in protecting the skin from substances that cause metal allergies. On the other hand, although they are also polysaccharide cellulose-based polymers, no significant reduction in permeability was observed in HEC and CMC, and no significant reduction in permeability was observed even with PVA, which is known to have metal allergy prevention effects in Patent Document 1.

Example 3: Hydrophobic film function test of various substances A 0.5% aqueous solution of the candidate substance used in Example 2, water as a control substance without film function, and silicone oil (dimethylpolysiloxane (6 mPa·s)) as a control substance with film function were used. 0.1 g of each sample was spread and applied in a circle with a diameter of 2.5 cm on a filter paper (70 mm/ADVANTEC) placed on a beaker, and after 10 minutes, another filter paper was placed underneath and two drops of purified water were dropped from the top. After 1 minute, the weight of the purified water that had permeated the lower filter paper was measured. If the weight of the purified water was significantly reduced compared to water, it was determined that there was a hydrophobic film function.

The results are shown in Figure 2. Figure 2 shows that, among the candidate substances, hydrophobized HPMC has the same hydrophobic film-forming effect as silicone oil (dimethylpolysiloxane (6 mPa·s)), and is effective in protecting the skin from substances that cause metal allergies. On the other hand, although they are also polysaccharide cellulose-based polymers, HEC and CMC did not show a significant hydrophobic film-forming effect, and PVA, which is known to have metal allergy prevention effects in Patent Document 1, showed a weak hydrophobic film-forming effect.

Example 4: Hydrophobic film function test using hydrophobized HPMC at various concentrations The concentration dependency of the hydrophobized HPMC, which showed excellent effects in Example 3, was confirmed. A hydrophobic film function test was performed using the same method as in Example 3, except that hydrophobized HPMC at various concentrations (0.1%, 0.3%, 0.5%) was used.

The results are shown in Figure 3. Figure 3 shows that the protective effect of hydrophobized HPMC against metal allergy-causing substances increases in a concentration-dependent manner.

The results of Examples 1 to 4 show that there are differences in effectiveness among cellulose compounds, with no effect observed for CMC and HEC, but high blocking effects for metal allergy-causing substances were observed for HPC, HPMC, and hydrophobized HPMC. It is expected that the polymer of the present invention can be applied to skin, lips, hair, etc. to block allergy-causing substances. The polymer of the present invention can be used to manufacture a metal allergy-causing substance blocking agent as described in the following formulation example.

Formulation example 1: Lotion

Formulation example 2: Lotion

Formulation example 3: Moisture gel

Formulation example 4: Lotion

Formulation example 5: Lotion

Formulation example 6: Moisture gel

Formulation Example 7: Lotion

Formulation example 8: Lotion

Formulation example 9: Moisture gel

(Preparation of Formulation Examples 1 to 9)
Moisturizers, various drugs, citric acid, and buffering agents are dissolved in purified water. Fragrances, surfactants, and preservatives are dissolved in ethanol, and the ethanol phase is solubilized in the water phase to obtain the lotion.

（製法）精製水に保湿剤、薬剤、緩衝剤を溶解して水相とする。エタノールに防腐剤、香料、オレイルアルコール、界面活性剤を溶解し、先の水相に可溶化し、透明化粧水を得る。 Formulation example 10: Lotion

(Production method) Dissolve moisturizers, medicinal agents, and buffering agents in purified water to make the aqueous phase. Dissolve preservatives, fragrances, oleyl alcohol, and surfactants in ethanol and solubilize them in the aqueous phase to obtain a transparent lotion.

（製法）
精製水に保湿剤、薬剤、緩衝剤を溶解して水相とする。防腐剤、香料、界面活性剤を溶解し、先の水相に可溶化し、透明化粧水を得る。 Formulation Example 11: Lotion

(Production method)
Moisturizers, drugs, and buffers are dissolved in purified water to form the aqueous phase. Preservatives, fragrances, and surfactants are dissolved and solubilized in the aqueous phase to obtain a transparent lotion.

（製法）
精製水に保湿剤、アルカリを加えた後、緩衝剤を加える。油溶性成分を油分に溶解し、水相とホモミキサーで乳化し、エモリエントローション（Ｏ／Ｗ）を得る。 Formulation Example 12: Emollient Lotion (O/W)

(Production method)
A moisturizing agent and an alkali are added to purified water, followed by the addition of a buffer. Oil-soluble ingredients are dissolved in oil, and emulsified with the water phase using a homomixer to obtain an emollient lotion (O/W).

（製法）
精製水に水溶性高分子を均一溶解させた後、残りの成分を添加し、均一溶解させ、モイスチャージェルを得る。 Formulation example 13: Moisture gel

(Production method)
After the water-soluble polymer is uniformly dissolved in purified water, the remaining ingredients are added and uniformly dissolved to obtain a moisture gel.

（製法）
精製水に保湿剤、アルカリを加え、７０℃に加熱。油分に界面活性剤、防腐剤、酸化防止剤、香料を加え、７０℃に加熱し、先の水相に添加、ホモミキサーを用いて乳化し、クリーム（Ｏ／Ｗ）を得る。 Formulation Example 14: Cream (O/W)

(Production method)
Moisturizer and alkali are added to purified water and heated to 70° C. Surfactant, preservative, antioxidant and fragrance are added to oil, heated to 70° C., added to the previous water phase and emulsified using a homomixer to obtain a cream (O/W).

（製法）
原液はエタノールに他の成分を加え溶解し、ろ過する。充填は缶に原液を入れ、バルブ装着、ガスを注入し、ヘアスプレーを得る。 Formulation Example 15: Hairspray

(Production method)
The concentrate is dissolved in ethanol with the other ingredients and then filtered. To fill the can, the concentrate is poured into a can, a valve is attached, and gas is injected to obtain the hairspray.

（製法）
精製水に水溶性高分子を均一溶解させた後、残りの成分を添加し、均一溶解させ、モイスチャージェルを得る。 Formulation example 16: Moisture gel

(Production method)
After the water-soluble polymer is uniformly dissolved in purified water, the remaining ingredients are added and uniformly dissolved to obtain a moisture gel.

（製法）
精製水に保湿剤、増粘剤を加え、７０℃に加熱した油分に界面活性剤、防腐剤、酸化防止剤、香料を加え、ディスパーを用いて乳化し、クリーム（Ｏ／Ｗ）を得る。 Formulation Example 17: Cream (O/W)

(Production method)
A moisturizer and a thickener are added to purified water, and a surfactant, a preservative, an antioxidant and a fragrance are added to oil heated to 70°C, and the mixture is emulsified using a disper to obtain a cream (O/W).

（製法）
精製水に保湿剤、増粘剤を加え、７０℃に加熱した油分に界面活性剤、防腐剤、酸化防止剤、香料を加え、ディスパーを用いて乳化し、冷却してバーム（Ｗ／Ｏ）を得る。 Formulation Example 18: Solid Balm (W/O)

(Production method)
Moisturizers and thickeners are added to purified water, and surfactants, preservatives, antioxidants, and fragrances are added to oil heated to 70°C, emulsified using a disper, and cooled to obtain a balm (W/O).

（製法）油性成分を加熱し溶解させ、粉末を配合し、ホモミキサーで分散させた後、別途調製した水相成分を徐々に添加しながら、ホモミキサーを用いて乳化させ、化粧下地を得る。 Formulation Example 19: Sunscreen (W/O)

(Production method) The oily component is heated and dissolved, the powder is mixed in, and the mixture is dispersed using a homomixer. A separately prepared aqueous phase component is gradually added while emulsifying using a homomixer to obtain a makeup base.

Claims (2)

A blocking agent for metal allergy causative substances, comprising one or more polymers selected from the group consisting of hydrophobized hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose. The metal allergy-causing substance blocking agent according to claim 1, wherein the polymer blocks the metal allergy-causing substance by capturing the metal allergy-causing substance and protecting the skin and/or lips from the metal allergy-causing substance.

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