JP7464243B2 - Treatment for dry, itchy skin - Google Patents

Description

The present invention relates to a topical skin application preparation containing an acid mucopolysaccharide and an antihistamine, and in particular to a topical skin application preparation used to improve dry skin accompanied by itching.

When the skin becomes dry due to various reasons such as dry air or lack of sebum, it can become sensitive to irritation and develop itching and inflammation.

To improve dry skin symptoms accompanied by itching, it is effective to apply a moisturizer and use an antihistamine as an antipruritic drug at the same time.

Heparinoids, a type of mucopolysaccharide polysulfate ester, can retain a large amount of water because they have many hydrophilic groups such as sulfate, carboxyl, and hydroxyl groups, and have high moisturizing properties, so they are used as moisturizers to improve dry skin symptoms (Patent Document 1). Meanwhile, diphenhydramine is a type of antihistamine and is used as an antipruritic drug (Patent Document 2). Using these in combination is effective in improving dry skin symptoms accompanied by itching.

However, when heparinoids, which have a negative charge due to sulfate or hydroxyl groups, are mixed with diphenhydramine, which has a positive charge in water, the ionic bonds between them cause cloudiness or precipitation, resulting in problems with the quality of the drug, such as unevenness and a foreign body sensation.

Patent 5876962 Tokkou 5-74152

The objective of the present invention is to suppress the clouding or precipitation that occurs when an acidic mucopolysaccharide and an antihistamine are mixed into a topical composition.

It was found that the addition of a monovalent anion to a composition containing an acidic mucopolysaccharide and an antihistamine can suppress the clouding and precipitation of an external skin application agent containing an acidic mucopolysaccharide and an antihistamine. Furthermore, it was found that the use of glycyrrhizinic acid or a salt thereof in combination exhibits an even more effective effect in suppressing clouding and precipitation.

More specifically, in order to solve the above-mentioned problems, the present application provides the following aspects:
[1]: A composition for external use containing an acid mucopolysaccharide, an antihistamine, and a monovalent anion;
[2]: The topical composition according to claim 1, wherein the acid mucopolysaccharide is a heparinoid;
[3]: The composition for external use according to claim 1 or 2, wherein the concentration of the heparinoid is 0.1 to 0.5% (w/w);
[4]: The composition for external use according to any one of claims 1 to 3, wherein the antihistamine is an antihistamine having an amino group;
[5]: The composition for external use according to claim 4, wherein the antihistamine is diphenhydramine or a salt thereof, or chlorpheniramine or a salt thereof;
[6]: The composition for external use according to claim 5, wherein the concentration of diphenhydramine or a salt thereof is 0.2 to 2% (w/w);
[7]: The composition for external use according to claim 5, wherein the concentration of chlorpheniramine or a salt thereof is 0.1 to 1% (w/w);
[8]: The composition for external use according to any one of claims 1 to 7, wherein the monovalent anion is a chloride ion;
[9]: The composition for external use according to any one of claims 1 to 8, wherein the monovalent anion is added as a salt with a monovalent cation;
[10]: The composition for external use according to claim 9, wherein the monovalent cation is a sodium ion, a potassium ion, or an ammonium ion;
[11]: The composition for external use according to claim 10, wherein the salt composed of a monovalent anion and a monovalent cation is sodium chloride;
[12]: The topical composition described in claim 11, wherein the concentration of sodium chloride is 2 to 10% (w/w).

As disclosed in the present invention, it has been found that the addition of monovalent anions to acid mucopolysaccharides and antihistamines can suppress the clouding and precipitation that occurs in topical skin applications that contain acid mucopolysaccharides and antihistamines. Furthermore, it has been found that the use of glycyrrhizinic acid or a salt thereof in combination with the above composition provides an even more effective clouding and precipitation suppression effect.

The inventors have discovered that the addition of a monovalent anion when incorporating an acidic mucopolysaccharide and an antihistamine into a topical composition can prevent the clouding and precipitation that occurs in the topical composition, and have thus completed the present invention.

Based on this finding, the present invention provides a composition for external use that contains an acid mucopolysaccharide, an antihistamine, and a monovalent anion.

Acidic mucopolysaccharides The topical composition of the present invention is characterized by containing acidic mucopolysaccharides as the first component. The acidic mucopolysaccharides used in the present invention refer to a group of substances that have hydrophilic groups such as sulfate groups, carboxyl groups, and hydroxyl groups and are characterized by being strongly negatively charged, and have the common function of retaining a large amount of water within the molecule. Such acidic mucopolysaccharides include sodium chondroitin sulfate, sodium hyaluronate, and heparin-like substances, any of which can be used in the present invention. In the present invention, it is preferable to use heparin-like substances as acidic mucopolysaccharides, from the viewpoint of having many sulfate groups and being easily negatively charged.

Heparinoids in the present invention refer to substances that have a similar structure or action to "heparin," which has a blood coagulation inhibitory effect, and are physically called polysulfated chondroitin sulfates. In the present invention, mucopolysaccharide polysulfate esters that meet the criteria for "heparinoids" listed in the Japanese Pharmacopoeia can be used. The content of heparinoids in the topical composition of the present invention can be, for example, 0.01-5% (w/w) of the total, preferably 0.05-1% (w/w), and more preferably 0.1-0.5% (w/w).

In the present invention, other acidic mucopolysaccharides such as those mentioned above (sodium chondroitin sulfate, sodium hyaluronate, etc.) can also be used in the topical composition at the same content as the heparinoids.

Antihistamines The topical composition of the present invention is characterized by including an antihistamine as a second component. Histamine is one of the neurotransmitters that cause allergies in the body, and causes allergic symptoms by acting on _H1 receptors (histamine _H1 receptors). Antihistamines are generally characterized by their functional ability to suppress the action of histamine by inhibiting (antagonizing) the _H1 receptor (i.e., exhibiting antihistamine action).

The antihistamines used in the present invention include diphenylpyraline, diphenhydramine, cyproheptadine, triprolidine hydrochloride, hydroxyzine, promethazine, homochlorcyclizine, alimemazine, chlorpheniramine, d-chlorpheniramine, diphenylpyraline, hydroxyzine, clemastine, ebastine, azelastine, epinastine, olopatadine, cetirizine, fexofenadine, oxatomide, emedastine fumarate, ketotifen, Non-limiting examples of drugs that may be used include bepotastine, mequitazine, loratadine, brompheniramine, cyproheptadine, terfenadine, triprolidine, carbinoxamine, phenindamine, azatadine, tripelennamine, dexchlorpheniramine, methdilazine, desloratadine, dimenhydrinate, doxylamine, and the like, and alternative forms of these drugs, such as alternative salt forms, free acid forms, free base forms, and hydrates.

The antihistamine used in the present invention may be characterized as an antihistamine having an amino group among the antihistamines exemplified above, because it is positively charged. As antihistamines having such characteristics, it is preferable to use diphenhydramine, chlorpheniramine, isothipendyl, and alternative forms of these drugs, such as alternative salt forms, free acid forms, free base forms, and hydrates. In the present invention, the antihistamine can generally be used in the topical composition at a concentration of 0.1 to 2% (w/w).

In the present invention, when diphenhydramine is used as a specific embodiment of the antihistamine, diphenhydramine or a salt thereof can be used in the topical composition at a concentration of, for example, 0.2 to 2% (w/w).

In the present invention, other antihistamines such as those mentioned above can also be used. In that case, when chlorpheniramine or a salt thereof is used as a specific embodiment of the antihistamine, it can be used in a concentration of 0.1 to 1% (w/w) in the topical composition, and when isothipendyl hydrochloride is used as a specific embodiment of the antihistamine, it can be used in a concentration of 0.15 to 0.75% (w/w).

Monovalent anion The topical composition of the present invention is characterized by including a monovalent anion as a third component. When a heparinoid, which has a negative charge due to sulfate or hydroxyl groups, and an antihistamine, which has a positive charge in water, are mixed together, they become cloudy or precipitate. This is thought to be because the dissolved heparinoid and the antihistamine form ionic bonds to generate colloidal particles, causing the mixture to become cloudy, and the particles then become too large to maintain a dispersed state, causing precipitation. It is thought that adding a monovalent anion to the mixture can prevent ionic bonds between the heparinoid and the antihistamine, and as a result, it is possible to prevent cloudiness and precipitation.

Examples of monovalent anions that can be used in the topical composition of the present invention include, but are not limited to, chloride ions, bromide ions, and iodide ions. Of these, it is particularly preferable to use chloride ions in the present invention.

The monovalent anion in the present invention can also be added to the topical composition as a salt with a monovalent cation. By adding the monovalent anion to the topical composition as a salt with a monovalent cation, the monovalent anion can exert a solubilizing effect.

In this case, the monovalent cation used in combination with the monovalent anion may be any monovalent cation, but examples include sodium ions, potassium ions, and ammonium ions.

The monovalent anions and monovalent cations thus prepared are prepared in the form of salts and dissolved in a composition for external use, thereby forming monovalent anions and monovalent cations in the composition for external use. Specifically, in the present invention, examples of salts that form monovalent anions and monovalent cations in the composition for external use include sodium chloride, ammonium chloride, and potassium chloride.

These salts may be added at concentrations at which the respective components are permitted for use in topical compositions, e.g., sodium chloride at a concentration of 2-10% (w/w), ammonium chloride at a concentration of 2-10% (w/w), and potassium chloride at a concentration of 2-10% (w/w).

When referring to a topical composition in the present invention, the form is not particularly limited, and examples include liquid topical compositions (e.g., solutions, gels, emulsions, suspensions, extracts, tinctures, aerosols, liposomes, etc.), semi-solid topical compositions (e.g., ointments, plasters, creams, etc.), etc. In the present invention, it is preferable to apply a liquid topical composition.

The topical composition of the present invention may contain any component (e.g., carrier, base, additive, etc.) that is generally acceptable for addition, depending on the form of the topical composition described above. Specific optional components are not particularly limited, and may include, for example, oils and fats, mineral oils, waxes, fatty acids, silicone oils, jojoba oil, sterols, esters, metal soaps, alcohol, sugar, polymer compounds, surfactants, pH adjusters, powder components, chelating agents, colorants (coloring agents), water, etc. These optional components may be used in appropriate combinations according to the form of the topical composition to be used. The topical composition of the present invention may further contain a transdermal absorption enhancer.

Other active ingredients The topical composition of the present invention may further contain active ingredients that are commonly used in topical compositions. Such active ingredients include glycyrrhizic acid or its salts, allantoin, panthenol, etc. These other active ingredients may be added at concentrations that are acceptable for use in topical compositions, such as 0.1-1% (w/w) for glycyrrhizic acid or its salts, 0.2-1% (w/w) for allantoin, and 1-5% (w/w) for panthenol.

The salts of other active ingredients used in the present invention are not particularly limited as long as they are pharma- ceutically acceptable, and examples thereof include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and amine salts such as tri(n-butyl)amine salts, triethylamine salts, pyridine salts, and amino acid salts.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these.

Example 1: Examination of additives that do not cause turbidity or precipitation In Example 1, the objective was to search for additives that do not cause turbidity or precipitation when diphenhydramine, an antihistamine, and a heparinoid, an acid mucopolysaccharide, are mixed.

The components used in this example were prepared as shown in Table 1 for components A, B, and C, and were dissolved. Then, component B was added to component A, and the mixture was stirred and mixed for 1 minute at room temperature (15-25°C) using a stirring rod. Then, component C was added and the mixture was stirred for 1 minute at room temperature (15-25°C) using a stirring rod, to obtain the respective liquid compositions.

The liquid properties of the obtained liquid composition were visually confirmed and evaluated. Specifically, the liquid properties of the liquid composition were evaluated visually at room temperature (15-25°C) by placing approximately 50 mL of the above composition in a cylindrical transparent glass container with a diameter of 35 mm. The liquid properties of the liquid composition were evaluated at two points in time: immediately after preparation and after storage in a refrigerator at 5°C for 3 days.

The evaluation criteria were as follows: a transparent glass container containing the liquid composition was observed from the side at room temperature (15 to 25° C.) and the liquid composition was evaluated according to the following criteria:
◎: completely clear;
○: Slightly whitish but almost clear, and the other side of the container can be seen completely;
△: Cloudy but semi-transparent, allowing the container to be seen through;
×: The container is cloudy and the other side cannot be seen, or precipitated particles are visible;
The results are shown at the bottom of Table 1.

As shown in Comparative Examples 1 and 2, the liquid compositions in which either a heparinoid or diphenhydramine was dissolved alone were clear both immediately after preparation and after storage in a refrigerator at 5°C for three days. However, as shown in Comparative Example 3, when a heparinoid and diphenhydramine were combined, the liquid composition became cloudy and precipitation was observed both immediately after preparation and after storage in a refrigerator at 5°C for three days.

On the other hand, when sodium chloride was added to the aqueous solution as in Example 1, the liquid composition containing a heparinoid and diphenhydramine became clear.

Example 2: Verification of Optimal Concentration In Example 2, the objective was to explore the optimal concentration of sodium chloride, which was shown in Example 1 to be an additive substance for preventing cloudiness or precipitation.

The components used in Example 2 were prepared as shown in component A, component B, and component C in Table 2, and were dissolved as described in Example 1. Component A was added to component B and mixed with stirring, and then component C was added and stirred to obtain each liquid composition. In Example 2, since the objective was to find the optimal concentration of sodium chloride, the composition of all components in component A, including diphenhydramine, and the composition of all components in component C, including a heparinoid, were left unchanged, and only the amount of sodium chloride in component B was changed to confirm the optimal concentration of sodium chloride.

The liquid properties of the obtained liquid composition were evaluated using the same method as described in Example 1. The results are shown at the bottom of Table 2.

As shown in Comparative Examples 3 and 4, when sodium chloride was added at 1% or less, the solution became cloudy and precipitates were observed both immediately after preparation and after storage in a refrigerator at 5°C for 3 days.

In contrast, as shown in Production Examples 2 to 6, when the amount of sodium chloride was increased from 2% to 10%, a clear liquid composition was obtained both immediately after preparation and after storage in a refrigerator at 5°C for 3 days.

However, as shown in Comparative Example 5, when the sodium chloride content exceeded 10%, a clear liquid composition was obtained immediately after preparation, but after storage in a refrigerator at 5°C for 3 days, the liquid composition became cloudy and precipitation was observed.

Example 3: Combined effect of glycyrrhizinic acid In Example 3, the purpose was to confirm what effect glycyrrhizinic acid, which is commonly used as one of the active ingredients in topical medications, exhibits in the topical composition of the present invention.

The ingredients used in Example 3 were prepared as shown in the A, B, and C components in Table 3, and were dissolved as described in Example 1. Component A was added to component B and mixed with stirring, and then component C was added and stirred to obtain the respective liquid compositions. In Example 3, dipotassium glycyrrhizinate, which is commonly used as one of the active ingredients in topical drugs, was added at a certain concentration (1% by weight) to confirm its effect on the liquid properties of the topical composition of the present invention.

The liquid properties of the obtained liquid composition were evaluated using the same method as described in Example 1. The results are shown at the bottom of Table 3.

Comparative Example 6 corresponds to the composition of Comparative Example 3 mixed with 1% by weight of dipotassium glycyrrhizinate, but as shown in Comparative Example 6, dipotassium glycyrrhizinate alone was unable to suppress clouding and precipitation of the liquid composition. On the other hand, in Comparative Example 7, which is the composition of Comparative Example 4 mixed with 1% by weight of dipotassium glycyrrhizinate, the liquid properties immediately after preparation were significantly improved, and a clear liquid composition was obtained. However, even in the case of Comparative Example 7, the liquid properties did not improve after storage in a refrigerator at 5°C for 3 days, and clouding and precipitation were observed.

In Production Examples 7 and 8, which correspond to the compositions of Production Examples 2 and 1 mixed with 1% by weight of dipotassium glycyrrhizinate, the liquid properties were improved over those of Production Examples 2 and 1 by using sodium chloride and dipotassium glycyrrhizinate in combination. Specifically, the liquid properties immediately after preparation, which were translucent (△) in Production Example 2, were improved to clear (◎) in Production Example 7, and the liquid properties after storage in a refrigerator at 5°C for 3 days, which were translucent (△) in Production Example 1, were improved to clear (◎) in Production Example 8. Thus, it was revealed that dipotassium glycyrrhizinate improves the liquid properties of liquid compositions when low concentrations of sodium chloride are used.

Example 4: Selection of optimal salt In Example 4, the purpose was to search for an additive substance that could replace sodium chloride, which was shown in Example 1 to be an additive substance that would not cause turbidity or precipitation.

The components used in Example 4 were prepared as shown in the A, B, and C components in Table 4, and were dissolved as described in Example 1. Component A was added to component B and mixed with stirring, and then component C was added and stirred to obtain the respective liquid compositions. In Example 4, the purpose was to search for an additive that could replace sodium chloride, so the composition of all the components in component A, including diphenhydramine, and the composition of all the components in component C, including a heparinoid, were left unchanged, and the 3 wt% sodium chloride in component B was changed to various additives, and the effects of mixing 3 wt% of various additives were confirmed.

The liquid properties of the obtained liquid composition were evaluated using the same method as described in Example 1. The results are shown at the bottom of Table 4.

As shown in Production Examples 1, 9, and 10, the monovalent anion chloride ion ( ^Cl- ) was the most effective in preventing cloudiness or precipitation, and in particular, when it was added as a salt with monovalent cations sodium ion (Na ⁺ ), potassium ion (K ⁺ ), or ammonium ion ( _NH4 ⁺ ), the liquid composition became clear immediately after preparation. Furthermore, it was revealed that the liquid properties after storage in a refrigerator at 5°C for 3 days were also clear or almost clear when these three components were added.

On the other hand, even when chloride ions ( ^Cl- ) were added, as shown in Comparative Examples 8 and 9, when chloride ions and divalent cations barium ions (Ba2 ⁺ ) and calcium ions (Ca2 ⁺ ) were added, it was found that in Comparative Example 8, the product became cloudy and precipitated both immediately after production and after storage in a refrigerator at 5°C for three days, and in Comparative Example 9, the product became cloudy and precipitated after storage in a refrigerator at 5°C for three days.

Furthermore, as shown in Comparative Examples 10 to 12, when the divalent anion carbonate ion (CO ₃ ^2- ) (Comparative Example 10), sulfate ion (SO ₄ ^2- ) (Comparative Example 11), or trivalent anion phosphate ion (PO ₄ ^3- ) (Comparative Example 12) was added, a certain degree of clouding prevention effect was observed immediately after production, but in all Comparative Examples, it was found that clouding and precipitation occurred after storage in a refrigerator at 5°C for three days.

Example 5: Study of antihistamines In Example 5, the purpose was to study antihistamines other than diphenhydramine, and to confirm whether the use of chlorpheniramine would enable prevention of the clouding and precipitation similar to that in the case of diphenhydramine.

The components used in Example 5 were prepared as shown in the A, B, and C components in Table 5, and were dissolved as described in Example 1. Component A was added to component B and mixed with stirring, and then component C was added and stirred to obtain the respective liquid compositions. In Example 5, in order to explore whether there are combinations that can prevent clouding and precipitation with antihistamines other than diphenhydramine, first, in comparison with Production Example 1, the composition of all components in component B, including sodium chloride, and the composition of all components in component C, including a heparinoid, were kept the same, and only diphenhydramine in component A was changed to chlorpheniramine (Production Example 11), and combinations with antihistamines other than diphenhydramine were examined.

On the other hand, as a comparison with Production Example 11, it was confirmed whether the liquid properties of the liquid composition would change by not adding sodium chloride (Component B) (Comparative Example 13).

The liquid properties of the obtained liquid composition were evaluated using the same method as described in Example 1. The results are shown at the bottom of Table 5.

As shown in Production Examples 1 and 11, the effect of preventing cloudiness and precipitation was the same whether diphenhydramine was used as the antihistamine (Production Example 1) or chlorpheniramine maleate was used. It was also revealed that the liquid properties after storage in a refrigerator at 5°C for three days became clear or almost clear when these three ingredients were added.

On the other hand, when chlorpheniramine maleate was used as component A and sodium chloride was not added (Comparative Example 13), it was found that the liquid became cloudy and precipitated both immediately after production and after storage in a refrigerator at 5°C for three days. This was the same liquid property as in Comparative Example 3, where sodium chloride was not added to Example 1.

According to the present invention, by further adding a monovalent anion to a topical skin preparation containing an acidic mucopolysaccharide and an antihistamine, it is possible to provide a topical skin preparation that suppresses clouding and precipitation. Furthermore, it has been found that by further using glycyrrhizinic acid or a salt thereof in combination with the above composition, an even more excellent effect of suppressing clouding and precipitation can be achieved.

Products containing a combination of heparinoids and diphenhydramine are already on the market, but they are all cream or milky white emulsion compositions, and cloudiness and precipitation are difficult to notice. This time, the technology was developed to commercialize a uniform, clear water-soluble liquid, but the reaction between these two components is a phenomenon that occurs in the aqueous phase of the emulsion composition, and it is believed that this technology can be used in other applications. Therefore, according to the present invention, even in the case of a cream or milky white emulsion composition containing an acid mucopolysaccharide and an antihistamine, it is possible to provide a cream or milky white emulsion composition that suppresses cloudiness and precipitation by further adding a monovalent anion.

Claims (5)

A liquid composition for external use that contains sodium chloride to suppress the clouding or precipitation that occurs due to heparinoids and diphenhydramine or its salts, or chlorpheniramine or its salts. The composition for external use according to claim 1, wherein the concentration of the heparinoid is 0.1-0.5% (w/w). The composition for external use according to claim 1 or 2, wherein the concentration of diphenhydramine or its salt is 0.2 to 2% (w/w). The composition for external use according to claim 1 or 2, wherein the concentration of chlorpheniramine or its salt is 0.1 to 1% (w/w). The composition for external use according to any one of claims 1 to 4, wherein the concentration of sodium chloride is 2 to 10% (w/w).