JP7045467B2 - External gel composition and its usage - Google Patents

Description

The present invention relates to an external gel composition and a method for using the same.

In cancer patients, cancer treatment affects the mucous membranes of the mouth and is prone to stomatitis. For example, in anti-cancer drug treatment, when a drug that easily causes mouth ulcer is administered, and in radiation therapy for head and neck cancer (cancer in the range from head to neck), when radiation directly hits the mucous membrane of the mouth. Mouth ulcer is inevitable. The pain of mouth ulcer is so strong that it is impossible to eat.

As a symptomatic treatment for stomatitis, a patch to be directly applied to the affected area (for example, Afterseal ^(R) 25 μg, manufactured by Taisho Tomiyama Pharmaceutical Co., Ltd .; active ingredient triamcinolone acetonide), an ointment to be applied to the affected area (for example, dexartin oral ointment, Nippon Kayaku Co., Ltd .; active ingredient dexamethasone), and a spray agent sprayed on the affected area (for example, 50 μg for external use of Salcote ^(R) capsule, Teijin Pharma Co., Ltd .; active ingredient beclomethasone propionate) and the like.

However, these therapeutic agents contain steroids, which are immunosuppressive agents, as active ingredients, and are therefore not desirable for cancer patients.

In addition, when eating a meal from the mouth, the patch attached to the affected area may come off, or the ointment or spray applied to the affected area may be lost, and the pain of mouth ulcer cannot be suppressed.

An agent or material capable of suppressing such pain of mouth ulcer is desired.

For example, Patent Document 1 states that "an aqueous solution of alginic acid intended for application on the surface in the form of skin or mucous membrane and dissolved in a 70-90% by weight aqueous phase and a 1-7% by weight aqueous phase. The first component in the form of an ointment containing a salt and hydrophilic lipid crystals dispersed in an aqueous phase of 8-25% by weight, and is intended to be applied over the ointment on the surface and soluble alginic acid. An agent for producing a protective layer on a surface in the form of skin or mucous membrane, characterized by comprising a second component containing a calcium salt for converting the salt into an insoluble calcium salt "(claimed). Item 1).

Further, Patent Document 2 is a drug having good adhesion on a mucous membrane, which is characterized by containing at least two kinds of mutually gel-forming components physically separated from each other. Contains at least one calcium salt and at least one polysaccharide as components that can form a gel, contains calcium chloride or organic calcium salt as the calcium salt, and alginic acid, polyglulonic acid, polymannuronic acid, and propylene glycol as polysaccharides. Agents containing alginic acid, polysaccharideuronic acid, salts or esters thereof, pectin or mixtures thereof have been described (claims 8-10).

Special Publication No. 63-018566 Japanese Patent Publication No. 63-502186

However, the agent described in Patent Document 1 and the agent described in Patent Document 2 do not have sufficient retention (difficulty in peeling from the oral mucosa) and are easily peeled from the affected area.

Therefore, it is an object of the present invention to provide an external gel composition capable of forming a gel having excellent retention.
Another object of the present invention is to provide a method for using this external gel composition.

As a result of diligent studies to solve the above problems, the present inventors have made a two-component structure containing a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more and a second aqueous solution containing an aluminum compound. By doing so, it was found that an external gel composition having excellent retention and a method of using the same could be provided, and the present invention was completed.

That is, the present invention is the following [1] to [19].
[1] A two-component external gel composition containing a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more and a second aqueous solution containing an aluminum compound.
[2] The external gel composition according to the above [1], wherein the aluminum compound is an aluminum carboxylate.
[3] The external gel composition according to the above [1] or [2], wherein the aluminum compound is a hydroxycarboxylate of aluminum.
[4] The external gel composition according to any one of the above [1] to [3], wherein the aluminum compound is aluminum lactate.
[5] The external gel composition according to any one of the above [1] to [4], wherein the alginate is at least one selected from the group consisting of sodium alginate, potassium alginate and ammonium alginate.
[6] The external gel composition according to any one of the above [1] to [5], wherein the weight average molecular weight of the alginate is 2 million or more.
[7] The external gel composition according to any one of the above [1] to [6], wherein the weight average molecular weight of the alginate is 3 million or more.
[8] One of the above [1] to [7], wherein the concentration of the aluminum compound is in the range of 0.1% by mass to 10% by mass with respect to the total mass of the second aqueous solution. The above-mentioned external gel composition.
[9] One of the above [1] to [8], wherein the concentration of the alginate is in the range of 0.1% by mass to 3% by mass with respect to the total mass of the first aqueous solution. The above-mentioned external gel composition.
[10] The above-mentioned one of [1] to [8], wherein the concentration of the alginate is in the range of 2% by mass to 10% by mass with respect to the total mass of the first aqueous solution. External gel composition.
[11] The external gel composition according to any one of the above [1] to [10], which is for a bioprotective material.
[12] The external gel composition according to any one of the above [1] to [10], which is used as a protective material for mucous membranes.
[13] The external gel composition according to the above [12], wherein the mucous membrane is an oral mucosa.
[14] The external gel composition according to any one of the above [1] to [10], which is for an oral mucosa protective material.
[15] The external gel composition according to any one of the above [1] to [10], which is used for a wound dressing.
[16] A spray containing a main agent containing a first spray container and a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more contained in the first spray container, and
A kit comprising a spray containing a gelling agent containing a second spray container and a second aqueous solution containing an aluminum compound contained in the second spray container.
[17] A tube containing a tube container and a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more contained in the tube container, and a tube containing a main agent, and
A kit comprising a spray container and a spray containing a gelling agent containing a second aqueous solution containing an aluminum compound contained in the spray container.
[18] The first aqueous solution is sprayed on the oral mucosa,
The method for using the external gel composition according to the above [9], wherein the second aqueous solution is sprayed onto the first aqueous solution sprayed on the oral mucosa.
[19] The first aqueous solution is applied to the oral mucosa and
The method for using the external gel composition according to the above [10], wherein the second aqueous solution is sprayed onto the first aqueous solution applied to the oral mucosa.

According to the present invention, it is possible to provide an external gel composition capable of forming a gel having excellent retention.
The present invention can also provide a method of using this external gel composition.

In the present invention, the range represented by using "-" shall include both ends of "-". For example, the range represented by "A to B" includes A and B.

[External gel composition]
The external gel composition of the present invention is a two-component external gel composition containing a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more and a second aqueous solution containing an aluminum compound.
As a two-component type of a first aqueous solution and a second aqueous solution, the first aqueous solution is attached to, for example, the oral mucosa, and the second aqueous solution is attached thereto, so that the aluminum ions in the second aqueous solution become the whole of the first aqueous solution. Aqueous solution is mixed with the first aqueous solution and the second aqueous solution to form an alginate gel.

The alginate gel with the external gel composition of the present invention has excellent retention on the oral mucosa (difficulty of peeling from the oral mucosa), and an aqueous solution of alginate is gelled with aluminum ions and then attached to the oral mucosa. It cannot be achieved by itself.
The details of the mechanism by which the excellent retention of the external gel composition of the present invention is exhibited are unknown, but one reason is considered to be the anchoring effect of the alginate gel on the oral mucosa.

When the aqueous solution before gelation by aluminum ions is attached to the oral mucosa, mucin, which is an oral mucosal component, and Na alginate are bonded by hydrogen bonds. When an aqueous solution of an aluminum compound is attached on top of an aqueous solution of alginate attached to the oral mucosa, gelation proceeds from the opposite side of the aqueous solution of alginate to the oral mucosa, and Na alginate as a sol remains at the adhesive interface. Maintains adhesiveness by remaining. On the other hand, if the pre-gelled alginate gel is attached to the oral mucosa, hydrogen bonds with the oral mucosa are not formed, so that adhesiveness cannot be obtained.

<First aqueous solution>
The first aqueous solution is an aqueous solution containing alginate having a weight average molecular weight of 1 million or more.

《Alginate》
(kinds)
The alginate is not particularly limited as long as it is a salt of alginate, but is preferably a monovalent cation salt of alginate, more preferably a monovalent metal salt or an ammonium salt of alginate, and further preferably an alkali metal salt or ammonium of alginate. It is a salt, more preferably a sodium alginate salt (sodium alginate), a potassium salt (potassium alginate) or an ammonium salt (ammonium alginate), and even more preferably a sodium alginate salt (sodium alginate).

Here, the alkali metal contains lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs), and does not contain francium (Fr).

Quantitative and qualitative analysis of monovalent cations constituting alginate can be performed by ion chromatography.
-Measurement condition column: Ion exchange resin (inner diameter 4.0 mm, length 25 cm)
Mobile phase: Methanesulfonic acid solution (20 mmol / L)
Flow rate: 1.0 mL / min
Sample injection volume: 25 μL
Column temperature: 40 ° C
Suppressor: Electrodialysis type detector: Electrical conductivity detector (30 ° C)

(Weight average molecular weight)
The weight average molecular weight of the alginate is not particularly limited as long as it is 1 million or more, but is preferably 2 million or more, more preferably 3 million or more, still more preferably 3.5 million or more, still more preferably 4 million. That is all.
When the weight average molecular weight of the alginate is less than 1 million, the holding power of the alginate gel obtained by gelling the first aqueous solution with the second aqueous solution to the oral mucosa is weak, and the alginate is easily peeled off from the oral mucosa.

The upper limit of the weight average molecular weight of the alginate is not particularly limited, but is preferably 10 million or less, more preferably 5 million or less, and further preferably 4.5 million or less. When the weight average molecular weight of alginate is 10 million or less, the viscosity of the aqueous solution of alginate does not become too high and handling becomes easier.

The weight average molecular weight of the alginate can be measured using size exclusion chromatography (SEC).
The GPC (Gel Permeation Chromatography) measurement conditions for measuring the weight average molecular weight of alginate are described below.
-GPC measurement conditions-Column: TSKgel G6000 + G4000 + G2500 PWXL
・ Eluent: 0.2 mol / L sodium nitrate ・ Flow rate: 0.7 mL / min
・ Injection amount: 50 μL
-Sample concentration: 0.1%
・ Analysis time: 60 minutes ・ Detection: RI (Refractive Index: differential refractometer)

(concentration)
The concentration of the alginate (content of alginate) in the first aqueous solution is not particularly limited. When the first aqueous solution is sprayed on the oral mucosa, it is preferably in the range of 0.1% by mass to 3% by mass, more preferably in the range of 1% by mass to 3% by mass, based on the total mass of the first aqueous solution. , More preferably in the range of 1.5% by mass to 3% by mass, and even more preferably in the range of 1.5% by mass to 2.5% by mass. When the first aqueous solution is applied to the oral mucosa, it is preferably in the range of 2% by mass to 10% by mass, more preferably in the range of 3% by mass to 10% by mass, and further preferably in the range of 4% by mass. It is in the range of ~ 10% by mass.
When the concentration of the alginate is within this range, the viscosity of the aqueous solution becomes easier to handle, and it becomes easier to adhere to the oral mucosa. In addition, the scratch resistance after gelation becomes more excellent.

The concentration of the alginate can be measured by the size exclusion chromatography described above.

"water"
The water that dissolves the arginate in the first aqueous solution is not particularly limited, and deionized water, distilled water, milliQ water, RO (reverse osmosis) water, or the like can be used. Purified water, sterile purified water, or water for injection may also be used among those specified in the 17th revised Japanese Pharmacopoeia.

<< Ingredients other than alginate and water >>
The first aqueous solution may contain components other than alginate and water, such as preservatives, as long as the effects of the present invention are not impaired.
Here, examples of preservatives include, for example, benzoic acid, sodium benzoate, propionic acid, sodium propionate, sorbic acid, potassium sorbate, and methylparaben, ethylparaben, propylparaben, isopropylparaben, butylparaben, isobutyl. Examples thereof include paraoxybenzoic acid esters such as paraben and benzylparaben.

<< How to use the first aqueous solution >>
The method of using the first aqueous solution is not particularly limited and may be adhered to the oral mucosa, especially the affected area of mouth ulcer, but when the concentration is adjusted to be relatively low, the oral mucosa, especially the oral mucosa, is treated like a spray. It is preferable to spray it on the affected area of stomatitis, and when the concentration is adjusted to be relatively high, it is preferable to apply it to the oral mucosa, particularly the affected area of stomatitis, like an ointment.

<Second aqueous solution>
The second aqueous solution is an aqueous solution containing an aluminum compound.

《Aluminum compound》
(kinds)
The aluminum compound is not particularly limited as long as it is a compound containing aluminum, but is preferably a water-soluble aluminum compound, more preferably an aluminum carboxylate, still more preferably an aluminum hydroxycarboxylate, and even more preferably. Is aluminum lactate.

Examples of the above water-soluble aluminum compounds are aluminum chloride (AlCl ₃ ), aluminum sulfate (Al ₂ (SO ₄ ) ₃ ), aluminum nitrate (Al (NO ₃ ) ₃ ), ammonium myoban (AlNH ₄ (SO ₄ ) ₂ ).・ 12H ₂ O), potassium myoban (AlK (SO ₄ ) ₂・ 12H ₂ O), aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate And aluminum isocitrate, but are not limited to these.

Examples of the above aluminum carboxylates are, but are limited to, aluminum acetate, aluminum propionate, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartrate, aluminum citrate and aluminum isocitrate. It is not something that will be done.

Examples of the hydroxycarboxylic acid of aluminum are, but are not limited to, aluminum glycolate (aluminum hydroxyacetate), aluminum lactate, aluminum malate, aluminum tartarate, aluminum citrate and aluminum isocitric acid.

(concentration)
The concentration of the aluminum compound is not particularly limited, but is preferably in the range of 0.1% by mass to 10% by mass, more preferably in the range of 1% by mass to 8% by mass, based on the total mass of the second aqueous solution. It is in the range of 2% by mass to 5% by mass, more preferably.
When the concentration of the aluminum compound is within this range, the first aqueous solution can be gelled more quickly, and the scratch resistance becomes more excellent.

"water"
The water that dissolves the aluminum compound in the second aqueous solution is not particularly limited, but the water that dissolves alginate in the first aqueous solution can be used. The first aqueous solution and the second aqueous solution may use the same type of water or different types of water.

<< Ingredients other than aluminum compounds and water >>
The second aqueous solution may contain components other than aluminum compounds and water, such as preservatives, as long as the effects of the present invention are not impaired.
Examples of the preservative include preservatives that may be contained in the first aqueous solution.

<< How to use the second aqueous solution >>
The method of using the second aqueous solution is not particularly limited, and the first aqueous solution may be attached to the oral mucosa, particularly the affected area of stomatitis, and then adhered onto the first aqueous solution attached to the oral mucosa, but it may be sprayed. It is preferable to spray it on the first aqueous solution attached to the oral mucosa like an agent. In addition, "above the first aqueous solution" means the surface of the first aqueous solution adhering to the oral mucosa on the side opposite to the oral mucosa side.

[Use of external gel composition]
The use of the external gel composition of the present invention is not particularly limited, and examples thereof include a bioprotective material.
Examples of the bioprotective material include a skin protective material, a mucous membrane protective material, a wound protective material, and the like. The mucous membrane is not particularly limited, and examples thereof include an oral mucosa, a nasal mucosa, and an airway mucosa. The protective material for the oral mucosa may be referred to as the protective material for the oral mucosa, the protective material for the nasal mucosa may be referred to as the protective material for the nasal mucosa, and the protective material for the airway mucosa may be referred to as the protective material for the airway mucosa.
The external gel composition of the present invention can also be used as a wound dressing.
In addition, other uses of the external gel composition of the present invention include, for example, a drug sustained-release base material, a moisturizing material, and a hemostatic material (particularly, a local hemostatic material).

[kit]
<First aspect>
As a first aspect of the kit of the present invention, a spray containing a main agent containing a first spray container and a first aqueous solution containing an arginate having a weight average molecular weight of 1 million or more contained in the first spray container, and Examples thereof include a kit containing a spray containing a gelling agent containing a second spray container and a second aqueous solution containing an aluminum compound contained in the second spray container.

《Spray with main agent》
The first aqueous solution is the one described above.

The first spray container is not particularly limited as long as it can spray a liquid, and a conventionally known spray container for spraying can be used.

《Spray with gelling agent》
The second aqueous solution is the one described above.

The second spray container is not particularly limited as long as it can spray a liquid, and a conventionally known spray container for spraying can be used.

《Other components》
The first aspect of the kit of the present invention may include an instruction manual in addition to the spray containing the main agent and the spray containing the gelling agent.

<Second aspect>
As a second aspect of the kit of the present invention, a tube container and a tube containing a first aqueous solution containing arginate having a weight average molecular weight of 1 million or more contained in the tube container, and a spray container and a spray container may be used. Examples thereof include a kit containing a spray containing a gelling agent containing a second aqueous solution containing the contained aluminum compound.

《Tube with main agent》
The first aqueous solution is the one described above.

The tube container is not particularly limited as long as it can squeeze a semi-solid, and a conventionally known tube container can be used.

《Spray with gelling agent》
The second aqueous solution is the one described above.

The spray container is not particularly limited as long as it can spray a liquid, and a conventionally known spray container for spraying can be used.

《Other components》
A second aspect of the kit of the present invention may include an instruction manual in addition to the tube containing the main agent and the spray containing the gelling agent.

[How to use the gel composition for external use]
<First aspect>
The first aspect of the method of using the external gel composition of the present invention is characterized in that the first aqueous solution is sprayed on the oral mucosa, and then the second aqueous solution is sprayed on the first aqueous solution sprayed on the oral mucosa. That is, the first aqueous solution and the second aqueous solution are used as a spraying agent.

The first aqueous solution is the one described above.
The method of spraying the first aqueous solution onto the oral mucosa is not particularly limited, but it is preferable to spray the first aqueous solution onto the oral mucosa by spraying.

The second aqueous solution is the one described above.
The method of spraying the second aqueous solution onto the oral mucosa is not particularly limited, but it is preferable to spray the second aqueous solution onto the oral mucosa by spraying.

<Second aspect>
A second aspect of the method of using the external gel composition of the present invention is characterized in that the first aqueous solution is applied to the oral mucosa, and then the second aqueous solution is sprayed onto the first aqueous solution applied to the oral mucosa. That is, the first aqueous solution is used as an ointment and the second aqueous solution is used as a spray.

The first aqueous solution is the one described above.
The method of applying the first aqueous solution to the oral mucosa is not particularly limited, but it is preferable to take the first aqueous solution on a cotton swab or the like and apply it to the oral mucosa.

The second aqueous solution is the one described above.
The method of spraying the second aqueous solution onto the oral mucosa is not particularly limited, but it is preferable to spray the second aqueous solution onto the oral mucosa by spraying.

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

[Examples 1 to 10, Comparative Examples 1 to 6]
<Preparation of liquid A>
As shown in Table 1, an aqueous solution of sodium alginate (solution A) was prepared by mixing sodium alginate and water.

<Preparation of liquid B>
As shown in Table 1, aluminum lactate, ammonium alum [AlNH ₄ (SO ₄ ) 2.12H ₂ O], potassium alum [ _AlK (SO ₄ ) _{2.12H 2} O], calcium lactate, calcium acetate, calcium carbonate or lactate. Iron (II) and water were mixed to prepare an aqueous solution (solution B) containing aluminum ion, calcium ion or iron (II) ion.

<Performance evaluation>
<< Fabrication of pseudo-biological membrane >>
TDAB (Tetradodecyl ammonium bromide, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 50 mg), polyvinyl chloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd .; 800 mg), and DOPP (di-n-octylphosphonate, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) (Manufactured by; 0.6 mL) was dissolved in THF (tetratetra, manufactured by Wako Pure Chemical Industries, Ltd .; 10 mL) and dried at room temperature with a chalet to obtain a lipid film (about 200 μm thick).
Next, agar (Calicolican (registered trademark), manufactured by Ina Food Industry Co., Ltd .; 0.5 g) and gellan gum (Kelcogel (registered trademark), manufactured by CP Kelco Co.; 0.1 g) are mixed with distilled water (49.4 g). The prepared lipid film was attached to the gel.
Subsequently, the surface of the lipid membrane was coated with an MPC (2-methacryloyloxyethyl phosphorylcholine) polymer (LICIDURE (registered trademark) -CM5206, manufactured by NOF CORPORATION) to obtain a pseudo biological membrane.

<< Evaluation of retention >>
Liquid A was sprayed on the prepared pseudo-biological membrane (1 cmΦ, 500 μm thickness), liquid B was sprayed, and then the mixture was allowed to stand for 1 minute and gelled on the pseudo-biological membrane to prepare an evaluation sample.
The prepared evaluation sample was placed in a petri dish and filled with artificial saliva (Salibate (registered trademark), manufactured by Teijin Pharma Limited) until the evaluation sample was immersed. This petri dish was placed in a constant temperature shaker (AS ONE Small Shaking Incubator 1-6142-01) (37 ° C.) and shaken at medium speed (scale 6). In this test, the time required for the evaluation sample to disappear from the pseudo-biological membrane due to exfoliation or dissolution was measured, and the retention was evaluated according to the following criteria.
(Evaluation criteria for retention)
Held for 1 hour or more ... A
Peeled or dissolved in less than 1 hour ... C
The evaluation results are shown in Table 1.

<< Evaluation of scratch resistance >>
Liquid A was sprayed on the prepared pseudo-biological membrane (1 cmΦ, 500 μm thickness), liquid B was sprayed, and then the mixture was allowed to stand for 1 minute and gelled on the pseudo-biological membrane to prepare an evaluation sample.
The prepared sample is repeatedly worn with a wear tester (surface quality measuring machine Tribogear TYPE: 14 FW, manufactured by Shinto Kagaku Co., Ltd.), and the number of times (reciprocating) until the evaluation sample is peeled off or dissolved from the pseudo biological membrane is measured. , Scratch resistance was evaluated according to the following criteria. A hemispherical human skin gel (hardness 7) (manufactured by EXCEL) was set on the head of the wear tester, and the test was conducted under the conditions of a load of 10 g, an amplitude of 20 mm, and a speed of 6000 mm / min.
(Evaluation criteria for scratch resistance)
Endured more than 50 times ... A
Peeled or melted 10 times or more and less than 50 times ... B
Peeled or dissolved less than 10 times ... C
The evaluation results are shown in Table 1.

<Evaluation of sprayability>
The viscosity (cP, 25 ° C.) at high shear (3000 1 / s) was measured using a rheometer (Anton Pearl Co., Ltd.), and the sprayability was evaluated according to the following criteria.
The viscosity was 200 cP or less ... A
The viscosity was more than 200 cP and less than 300 cP ... B
The viscosity was 300 cP or more ... C
The evaluation results are shown in Table 1.

In Table 1, sodium alginate is as follows (both manufactured by Kimika). In addition, Mw represents a weight average molecular weight.
Sodium alginate (IS) ... Kimika algin IS Mw = 4.05 million Sodium alginate (I-8) ... Kimika algin I-8 Mw = 3.9 million sodium alginate (I-5) ... Kimika algin I-5 Mw = 3.04 million sodium alginate (I-3) ... Kimika algin I-3 Mw = 2.75 million sodium alginate (I-1) ... Kimika algin I-1 Mw = 780,000 sodium alginate (ULV-L3) ... Kimika Algin ULV-L3 Mw = 50,000

[Examples 11 to 20, Comparative Examples 7 to 12]
<Preparation of liquid A>
As shown in Table 2, an aqueous solution of sodium alginate (solution A) was prepared by mixing sodium alginate and water.

<Preparation of liquid B>
As shown in Table 2, aluminum lactate, ammonium alum [AlNH ₄ (SO ₄ ) 2.12H ₂ O], potassium alum [ _AlK (SO ₄ ) _{2.12H 2} O], calcium lactate, calcium acetate, calcium carbonate or lactate. Iron (II) and water were mixed to prepare an aqueous solution (solution B) containing aluminum ion, calcium ion or iron (II) ion.

<Performance evaluation>
<< Fabrication of pseudo-biological membrane >>
Pseudobiological membranes were prepared in the same manner as in Examples 1 to 11 and Comparative Examples 1 to 6.

<< Evaluation of retention >>
Liquid A was applied to the prepared pseudo-biological membrane (1 cmΦ, 500 μm thickness), liquid B was sprayed, and then the mixture was allowed to stand for 1 minute to be gelled on the pseudo-biological membrane to prepare an evaluation sample.
The prepared evaluation sample was placed in a petri dish and filled with artificial saliva (Salibate (registered trademark), manufactured by Teijin Pharma Limited) until the evaluation sample was immersed. This petri dish was placed in a constant temperature shaker (AS ONE Small Shaking Incubator 1-6142-01) (37 ° C.) and shaken at medium speed (scale 6). In this test, the time required for the evaluation sample to disappear from the pseudo-biological membrane due to exfoliation or dissolution was measured, and the retention was evaluated according to the following criteria.
Held for 1 hour or more ... A
Peeled or dissolved in less than 1 hour ... C
The evaluation results are shown in Table 2.

<Evaluation of scratch resistance>
Liquid A was applied to the prepared pseudo-biological membrane (1 cmΦ, 500 μm thickness), liquid B was sprayed, and then the mixture was allowed to stand for 1 minute to be gelled on the pseudo-biological membrane to prepare an evaluation sample.
The prepared evaluation sample is repeatedly worn with a wear tester (surface quality measuring machine Tribogear TYPE: 14 FW, manufactured by Shinto Kagaku Co., Ltd.), and the number of times (reciprocating) until the sample is peeled off or dissolved from the pseudo biological membrane is measured. , Scratch resistance was evaluated according to the following criteria. A hemispherical human skin gel (hardness 7) (manufactured by EXCEL) was set on the head of the wear tester, and the test was conducted under the conditions of a load of 10 g, an amplitude of 20 mm, and a speed of 6000 mm / min.
Endured more than 50 times ... A
Peeled or melted 10 times or more and less than 50 times ... B
Peeled or dissolved less than 10 times ... C
The evaluation results are shown in Table 2.

In Table 2, sodium alginate is as follows (both manufactured by Kimika). In addition, Mw represents a weight average molecular weight.
Sodium alginate (IS) ... Kimika algin IS Mw = 4.05 million Sodium alginate (I-8) ... Kimika algin I-8 Mw = 3.9 million sodium alginate (I-5) ... Kimika algin I-5 Mw = 3.04 million sodium alginate (I-3) ... Kimika algin I-3 Mw = 2.75 million sodium alginate (I-1) ... Kimika algin I-1 Mw = 780,000 sodium alginate (ULV-L3) ... Kimika Algin ULV-L3 Mw = 50,000

[Explanation of results]
<Examples 1 to 10, Comparative Examples 1 to 6>
Examples 1 to 10 were superior in both retention and scratch resistance as compared with Comparative Examples 1 to 6.

<< Examples 1 to 3 >>
Examples 2 and 3 in which the concentration of sodium alginate in the liquid A was 2% by mass or more were more excellent in scratch resistance as compared with Example 1 in which the concentration of sodium alginate was less than 2% by mass.

<< Examples 2, 4, 5 >>
Examples 2 and 5 in which the concentration of aluminum lactate in the liquid B was 2% by mass or more were more excellent in scratch resistance as compared with Example 4 in which the concentration of aluminum lactate was less than 2% by mass.

<< Examples 2, 6 to 8, Comparative Examples 1 and 2 >>
Examples 2 and 6 in which the weight average molecular weight of sodium alginate in the liquid A was 3.5 million or more had better scratch resistance than Examples 7 and 8 in which the weight average molecular weight was less than 3.5 million. Further, Comparative Example 1 and Comparative Example 2 in which the weight average molecular weight of sodium alginate in the liquid A was less than 1 million were inferior in both retention and scratch resistance.

<< Examples 2, 9, and 10 >>
Example 2 in which aluminum sulfate was used as the aluminum compound in the liquid B had better scratch resistance than Example 9 in which ammonium alum was used and Example 10 in which potassium alum was used.

<Examples 11 to 20, Comparative Examples 7 to 12>
Examples 11 to 20 were superior in both retention and scratch resistance as compared with Comparative Examples 7 to 12.

<< Examples 11 to 13 >>
Examples 12 and 13 in which the concentration of sodium alginate in the liquid A was 2% by mass or more were more excellent in scratch resistance as compared with Example 11 in which the concentration of sodium alginate was less than 2% by mass.

<< Examples 12, 14, 15 >>
Examples 12 and 15 in which the concentration of aluminum lactate in the liquid B was 2% by mass or more were more excellent in scratch resistance as compared with Example 14 in which the concentration of aluminum lactate was less than 2% by mass.

<< Examples 12, 16-18, Comparative Examples 7, 8 >>
Examples 12 and 16 in which the weight average molecular weight of sodium alginate in the liquid A was 3.5 million or more were more excellent in scratch resistance as compared with Examples 17 and 18 in which the weight average molecular weight was less than 3.5 million. Further, Comparative Example 7 and Comparative Example 8 in which the weight average molecular weight of sodium alginate in the liquid A was less than 1 million were inferior in both retention and scratch resistance.

<< Examples 12, 19, 20 >>
Example 12 in which aluminum sulfate was used as the aluminum compound in the liquid B had better scratch resistance than Example 19 in which ammonium alum was used and Example 20 in which potassium alum was used.

Claims (17)

A two-component external gel composition containing a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more and a second aqueous solution containing an aluminum compound. The external gel composition according to claim 1, wherein the aluminum compound is a carboxylate of aluminum. The external gel composition according to claim 1 or 2, wherein the aluminum compound is a hydroxycarboxylate of aluminum. The external gel composition according to any one of claims 1 to 3, wherein the aluminum compound is aluminum lactate. The external gel composition according to any one of claims 1 to 4, wherein the alginate is at least one selected from the group consisting of sodium alginate, potassium alginate and ammonium alginate. The external gel composition according to any one of claims 1 to 5, wherein the alginate has a weight average molecular weight of 2 million or more. The external gel composition according to any one of claims 1 to 6, wherein the alginate has a weight average molecular weight of 3 million or more. The external gel composition according to any one of claims 1 to 7, wherein the concentration of the aluminum compound is in the range of 0.1% by mass to 10% by mass with respect to the total mass of the second aqueous solution. .. The external gel composition according to any one of claims 1 to 8, wherein the concentration of the alginate is in the range of 0.1% by mass to 3% by mass with respect to the total mass of the first aqueous solution. .. The external gel composition according to any one of claims 1 to 8, wherein the concentration of the alginate is in the range of 2% by mass to 10% by mass with respect to the total mass of the first aqueous solution. The external gel composition according to any one of claims 1 to 10, which is for a bioprotective material. The external gel composition according to any one of claims 1 to 10, which is used as a protective material for mucous membranes. The external gel composition according to claim 12, wherein the mucous membrane is an oral mucosa. The external gel composition according to any one of claims 1 to 10, which is for an oral mucosa protective material. The external gel composition according to any one of claims 1 to 10, which is for a wound dressing. A spray containing a main agent containing a first spray container and a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more contained in the first spray container, and
An external kit comprising a spray containing a gelling agent containing a second spray container and a second aqueous solution containing an aluminum compound contained in the second spray container. A tube containing a tube container and a first aqueous solution containing alginate having a weight average molecular weight of 1 million or more contained in the tube container, and a tube containing a main agent, and
An external kit comprising a spray container and a spray containing a gelling agent containing a second aqueous solution containing an aluminum compound contained in the spray container.