WO1995015152A1

WO1995015152A1 - External preparation

Info

Publication number: WO1995015152A1
Application number: PCT/JP1994/002015
Authority: WO
Inventors: Zenichi Ogita
Original assignee: Zenichi Ogita
Priority date: 1993-11-30
Filing date: 1994-11-30
Publication date: 1995-06-08
Also published as: AU1119895A

Abstract

An external preparation which is excellent in the adhesion to and residence in the living organism and can be improved in suspension stability. The preparation comprises an aqueous solution of a temperature-sensitive polymer and a water-soluble or insoluble drug for external use. It is sol at a temperature below that of the living organism but turns into gel at the surface temperature of the same. The gel is water-insoluble and the sol-gel conversion is reversible.

Description

Membrane External preparation technology

The present invention relates to an external preparation for external use such as injection, gargle, compress, spray, application, wiping, disinfection, eye drops, ear drops, nasal drops, etc.More specifically, adhesion and retention during use An external preparation capable of significantly improving the use of the composition.

Background art

Conventionally, the drug is dissolved in a solvent such as water, ethanol or oil (including water or ethanol extraction and dissolution) or suspended and used for external use. Known liquid preparations, for example, injection, gargle, poultice, spray, application, wiping, disinfection, eye drops, ear drops, nasal drops, etc. are known.

These conventional external preparations are used for the purpose of increasing the viscosity and improving the adhesion and retention on the surface of a living body, for example, honey, glycerin, a Rubber rubber, tragacanth rubber sodium alginate, methanol resin, canola box methylcell mouth mouth sodium (CMC sodium rubber) ), Gelatin, chondroitin sulfate, and other high molecular compounds were also added.

However, in the case of a conventional external preparation, the above-mentioned high concentration is required in order to improve the adhesion to the surface of the living body or the retention. If too much of the parent compound is added, the viscosity of the external preparation will increase significantly with it, depending on the prescription of injection, gargle, compress, spray, application, wiping, disinfection, eye drops, ear drops, nasal drops, etc. There was a serious problem that was extremely difficult to use.

Thus, the present invention solves the problems of conventional external preparations, such as difficulty in use, reduction in adhesion to living body surfaces and reduction in retention, and can be used easily. The purpose of the present invention is to provide a new external preparation which can improve the adhesiveness and retention property on the surface of a living body.

Disclosure of the invention

The present invention solves the above-mentioned problems, and comprises an aqueous solution of a temperature-sensitive polymer in which the sol-gel transition of the aqueous solution is reversible, and a water-soluble or water-insoluble external drug. It is an external preparation that is formulated and is in a sol state at a temperature lower than the body temperature, becomes a gel state at the temperature of the living body surface, does not dissolve in water in a gel state, and is a sol-gel. An external preparation characterized by being reversible in transition is provided.

BEST MODE FOR CARRYING OUT THE INVENTION

In the case of the above-mentioned external preparation of the present invention, the external preparation itself may be arbitrary, and may be any of the conventionally known ones, that is, suitable. Various types of water-soluble, water-insoluble, and oil-soluble are used. These topical drugs are used as liquids (sols) dissolved or dispersed in the above-mentioned aqueous polymer solution, or used as gel-like ointments, etc. thing You can do it.

When water-insoluble external drugs are used, they may be mixed in a water-insoluble medium. In this case, a minimum amount of a dispersing agent may be added. As a matter of course, the external preparation of the present invention may further optionally contain additional components as long as the purpose of the invention is met.

Examples of topical drugs include, for example, aspirin, sulfenamic acid, mefenamic acid, indomethacin, tolmetin ibuprofen, ketoprofen Non-steroidal anti-inflammatory agents such as benzoquinone, vinyl chloride, and steroloid anti-inflammatory agents such as coltizon and dexamethasone; nitrate; gentamicin; Antibacterial agents such as pyromidic acid and ofloxacin, various vitamins and antihistamines, and naphazolin and tetrahydrozole For external use such as vasoconstrictors such as benzoquinone, chloramnicol, benzalconium chloride, tetracycline, and various other transdermally absorbable formulations Drugs are used.

As described above, the external preparation of the present invention is in a sol state at a temperature lower than the biological temperature, becomes a gel state at the temperature of the biological surface, does not dissolve in water in the gel state, and has a sol-gel It is characterized by the reversibility of metastasis, and in this case, it improves adhesion and retention to living organisms during use.

In other words, when dropped or applied to the surface of a living body, the external preparation of the present invention instantaneously changes to a gel state due to the sol-gel transition and stably adheres to and stays on the living body surface. And the body temperature If the temperature is lowered to less than 10 ° C., the sol becomes low in viscosity again, so that the external preparation of the present invention can be easily removed.

For such external preparations having such characteristics, an aqueous solution of a sensitive polymer whose sol-gel transition is reversible in an aqueous solution is blended as an essential component.

More specifically, this sensitive polymer can be presented as a combination of multiple blocks with cloud points and a hydrophilic block. it can.

Blocks with a cloud point of n. &. susceptible polymer become insoluble in water at ha. J¾ above the cloud point and become water soluble at temperatures below the cloud point. Part.

The thermoreversible sol-gel transition of a susceptible polymer-aqueous solution is due to the nature of the hydrophobic bonds between the blocks, which increases immediately with the increase of the hydrophobic bonds inn¾, and the change increases with temperature. On the other hand, it is irreversible.

The presence of a plurality of blocks having a cloud point in a molecule means that an aqueous solution of an imi-sensitive polymer forms a water-insoluble gel at or above the sol-gel transition temperature. Required for

A block having an fc point is preferably a polymer compound having a negative temperature coefficient of solubility in water, and more specifically, a polymer having a fc point. Lenoxide, copolymer of propylene oxide with other alkylene oxides, poly N-substituted (meth) acrylamide derivative, N-substituted ) The difference between the acrylamide derivative and other hydrophilic or hydrophobic monomers A polymer compound selected from the group consisting of a copolymer, polyvinyl methyl ether, and polyvinyl alcohol partially acetylated is preferred, and its cloud point is below 0 ° C. Preferably as high as 37 and less o

In the above copolymer of N-substituted (meta) acrylamide and another hydrophilic or hydrophobic monomer, the copolymerization with the hydrophilic monomer results in the formation of the product. The cloud point increases, and when copolymerized with hydrophobic monomers, the cloud point of the product decreases.

Therefore, by selecting these monomers to be copolymerized, the desired cloud point (for example, a cloud point higher than 0 and less than or equal to 37 ° C.) can be obtained. High molecular compounds can be obtained.

For example, after measuring about 1 wt% aqueous solution of the above-mentioned polymer compound (block having a cloud point), it is cooled to a transparent homogeneous solution, and then gradually heated (temperature rise about l ° C). The point at which the solution first becomes cloudy at first (CZ min) can be taken as the cloud point.

& a 'The hydrophilic block that constitutes the sensitive polymer is necessary because the aqueous solution of the temperature-sensitive polymer is in a liquid (sol) state below the sol-gel transition temperature. In addition, it prevents the temperature-sensitive polymer from agglomerating and precipitating due to too strong a hydrophobic bond between blocks having a cloud point above the sol-gel transition temperature. Required to maintain state.

Examples of the hydrophilic block include methylcellulose, dextran, polyethylene oxide, and polyvinyl alcohol. , Poly N-vinyl pi-Ridone, Poly-vinyl pyridine, Polyacrylamide, Polymethylamide, Polyamide, PolyN-methyl Lua acrylamide, polyhydroxymethyl acrylate, polyacrylic acid, polyacrylic acid, polyvinyl sulfonic acid, polyvinyl sulfonate, polyacrylic acid Styrene sulfonate and salts thereof are preferred, but poly UN, N-dimethylamino thiazole methacrylate, poly N, N -N-methyl phenylamine N, N-dimethylaminopropyl mouth Pirua crylamide, and salts thereof may be used.

There is no particular limitation on the method of bonding the block having a hydrophilic block to the block having a polymerizable group, for example, a polymerizable functional group (for example, a block) in any of the blocks. (Reroll group), and the other block can be combined by a simple solid body to give the other block. This is achieved by introducing functional groups (for example, a hydroxyl group, a carboxylic acid group, or an isopropyl group) and linking the two by a chemical reaction. I can do it. At that time, usually, a plurality of reactive functional groups are introduced into the hydrophilic block. Combination of block with cloud point and hydrophilic block Monomer giving block with point and monomer giving hydrophilic block It is also possible to obtain by book polymerization

For example, the bond between the cloud-opening polypyrene oxide and hydrophilic block is formed by anion polymerization or cation polymerization.

D pyrenoxide and the moieties that make up “other water-soluble polymers” Nomer (eg, ethylene oxide) can be repeated and polymerized repeatedly, and polypropylene oxide and “other water-soluble polymers” (eg, It is possible to obtain a block copolymer to which ethylene oxide is bonded.

Such a block copolymer is obtained by introducing a polymerizable group (for example, an acryloyl group) into the terminal of polypropylene oxide and forming a water-soluble polymer. It can also be obtained by copolymerizing nomads.

7 The ¾α-sensitive polymer introduces a functional group capable of binding and reacting with a functional group (for example, a hydroxyl group) at the terminal of poly (propylene oxide) in a water-soluble polymer and reacts the two. You can also get it by using the product, and Polypropylene oxide and Polyethylene oxide ί, the brand name `` Bluronic F

-127 J can also be obtained by connecting materials such as J (manufactured by Asahi Denka Kogyo Co., Ltd.).

By adjusting the composition of the blocks with cloud point and hydrophilic blocks, the degree of water supply and hydrophilicity of both blocks, and the molecular weight of Z or their The sol-gel transition temperature of the temperature-sensitive polymer aqueous solution, that is, the sol-gel transition temperature of the agent for external use of the present invention can be controlled.o Depending on the component added to the agent for external application. The sol-gel transition temperature can also be controlled, and preferably the sol-gel transition temperature is controlled to be higher than 0 and lower than 37 ° C.

The temperature-sensitive polymer as described above is used in the present invention. It is formulated as an aqueous solution, and the aqueous solution in this case is an aqueous solution containing the temperature-sensitive polymer, and further contains a solvent or a water-soluble substance that is compatible with water. It is good. For example, solvents that are compatible with water include alcohols such as ethanol, glycerin, propylene glycol, and acetone. Illustrated.

Examples of the water-soluble substance include various salts and water-soluble polymers.

Further, the water-insoluble medium that can be used in the compounding of the above-mentioned water-insoluble topical drug means a solvent that is incompatible with water. Examples include hydrocarbons such as hexane and liquid paraffin, vegetable oils, waxes, petrolatum, polyesters, and the like.

In addition, the suspending aid is a substance having an effect of enhancing the suspendability of a water-insoluble drug or a water-insoluble solvent containing the drug in a temperature-sensitive polymer aqueous solution. For example, various surfactants described below are used, but nonionic surfactants are particularly preferably used.

For example, examples of anionic surfactants include alkyl sulfates such as sodium dodecyl sulfate, and polyoxyethylene alkyl ether sulfate. Salts, poloxyshethylene alkylphenyl ether sulfates, fatty acid salts, alkylsulfonates, alkylbenzensulfonates, alkyls Lunafurethren sulfonate, alkyl linoleate, polyoxyethylene alkenyl monoterinate, polyoxyethylene alkyne two Examples of cationic surfactants include ruthel phosphate and quaternary anions such as dodecinoletrimethinoleanmonium chloride. Examples of amphoteric surfactants include, for example, N, N—dimethyl-N—dodecyl-N—kammonium salt, primary to tertiary fatty amine salts, and the like. Examples of non-ionic surfactants include betaines such as ruboxime methyl ammonium betaine, and polyoxythienyl nonylphenyl.ポ Polyoxyethylenyl ether, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene Roxyshethylene Polyhydric alcohol fatty acid partial ester etc. can be listed.o

There is no particular limitation on the mixing ratio of the external preparation of the present invention, but a range in which the characteristics of the external preparation of the present invention are not impaired by the use of the above-mentioned temperature-sensitive polymer. Needless to say, the amount of prescription drug used as an external preparation should be appropriately adjusted.

The amount of the topical drug is, for example, generally in the range of about 0.01 to 30 parts by weight based on 100 parts by weight of the temperature-sensitive polymer of the present invention. .

When a suspending aid is added, the amount of addition depends on the type, but is generally based on 100 parts by weight of the external preparation.

0.01 to 5 parts by weight, preferably about 0.05 to 1 part by weight.

In addition, the above-mentioned external preparations are applied in a liquid form by dropping or coating. In addition to the above-mentioned effects, it has an excellent effect of greatly improving the adhesion and retention properties of the water-insoluble topical drug due to the change to a gel state. The effect of remarkably improving the suspension stability of an external preparation containing a water-insoluble medium containing it is particularly noteworthy. This is because the temperature-sensitive polymer aqueous solution effectively blocks the mutual aggregation of a water-insoluble drug or a water-insoluble medium containing the same, which gels and suspends on the surface of a living body. It is.

This effect of iSm./Sensitivity Polymer has a detrimental effect on living organisms, and may also be a suspension of surfactants that may adversely affect the efficacy of pharmaceuticals. O A significant reduction in the amount of auxiliaries used o

Hereinafter, examples will be shown, and the external preparation of the invention will be described in more detail.

Reference example 1

Polypropylene oxide triamino compound (Propylene oxide; molecular weight: about 300,000, manufactured by Digifaron Chemical Co., USA): Difarmi T — 300 000) 10 g and polyaminopolyamide at both ends (a molecular weight of about 600,000, manufactured by Kawaken Fine Chemical Co., Ltd.) ) Dissolve 30 g in 900 ml of the mouth opening solution, and use tri-isolate (colonet T-1).

65, manufactured by Nippon Polyurethane Industry Co., Ltd.) and reacted at room temperature for 3 hours. Next, add 10 g of isopropylamine, leave for 3 hours, concentrate, and precipitate in n-hexane. I let you. After filtration, the precipitate was dried under vacuum to obtain 30 g of a polymer compound (P).

This polymer compound was dissolved in distilled water at a concentration of 8 wt% under ice cooling. Further, when the aqueous solution of the polymer compound was gradually heated, the viscosity gradually increased from 10 and solidified at about 14 ° C. to form a gel.

Further, when the gel was cooled, it was returned to an aqueous solution at 10 ° C. However, the gel was poured into a large amount of distilled water at 25 ° C, but did not dissolve.

These changes were repeatedly observed reversibly.

Reference example 2

h <) For each mole of one mouth, one mole of mouth and one mole of ethylene oxide by addition of 160 moles by cationic polymerization. After obtaining the toluene solution, 0.02 mol of the polyethylenoxyside triol was dissolved in 100 ml of distilled water, and the permanganate solution was dissolved in 100 ml of distilled water. Add 1 mol and carry out oxidation reaction at 25 ° C for 60 minutes to obtain a polyoxyethylene triboxyl compound, which is a polyoxyethylene trioxide. 10 g of a boxyl form and a pyrene oxide diamino compound having a lip mouth (an average degree of polymerization of propylene oxide of about 65, manufactured by Difon Chemical Co., USA): D-min (D-400)

0 g was dissolved in 100 ml of carbon tetrachloride, and 1.2 g of hexinole carbodiimide was added thereto, followed by a reaction for 6 hours under reflux at the boiling point. After cooling and filtering the reaction solution, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain a polymer compound to be used in the present invention.

The polymer compound was dissolved in distilled water at a concentration of 8 wt% under ice-cooling. When the aqueous solution of the polymer compound was slowly heated, the viscosity gradually increased from 5 ° C, and solidified at about 10 ° C to form a gel.

When the gel was further cooled, it returned to an aqueous solution at 5 ° C, but was poured into a large amount of distilled water at 25 ° C, but these changes without dissolution were reversible. It was repeatedly observed.

Example 1

Dissolve 10 g of boric acid in 100 ml of hot water, cool to room temperature, add 25 ml of hot water, and simultaneously add the temperature-sensitive polymer obtained in Reference Example 1 above. After adding 25 g of (P), purified water was added to bring the total amount to 50 O ml.

Next, the polymer mixture was completely dissolved under ice-cooling and stirring with the above mixture to prepare a mouthwash and a mouthwash.

The sol-gel transition temperature of the mouthwash and mouthwash was measured by a change in fluidity, and as a result, it was about 13 ° C.

Example 2

Purified water was added to 100 ml of Isosinger Garnole, 25 ml of nodulating water, and 25 g of the polymer compound (P) obtained in Reference Example 1 to make a total volume of 500 ml. The polymer compound was completely dissolved under ice-cooling and stirring to prepare a mouthwash and a mouthwash. The sol-gel transition temperature of the gargle and mouthwash was measured by a change in fluidity, and was found to be about 10 ° C.

Example 3

Dissolve 10 g of lead acetate in 100 m1 of purified water from which dissolved carbon dioxide has been removed by boiling beforehand.After cooling, add basic lead carbonate that has precipitated and an appropriate amount of acetic acid. Then, 50 g of the polymer compound (P) obtained in Reference Example 1 was added to the solution, and completely dissolved under ice-cooling and stirring to prepare a poultice (tail) agent. .

The sol-gel transition temperature of the poultice was measured by a change in fluidity, and was found to be about 14 ° C.

Example 4

1.0 g of epidrin hydrochloride, 0.5 g of clobutano mono-ole and 5 g of the polymer compound (P) obtained in Reference Example 1 were added to 100 ml of 100 ml of the polymer compound (P). Nasal solution was prepared by completely dissolving in physiological saline with ice cooling and stirring.

The sol-gel transition temperature of the nasal solution was measured by a change in fluidity, and as a result, it was about 12 ° C.

Example 5

1.0 g of sodium bicarbonate, 500 mg (potency) of chloramphenic alcohol, 1.5 g of boric acid, and 0.023 g of phenol ,. Methyl laoxybenzoate, 5 g of the polymer compound (P) obtained in Reference Example 1 was added to sterile purified water so that the total volume would be 100 ml, and cooled with ice. Dissolve completely with stirring to produce ear drops Made.

The sol-gel transition temperature of the eardrop was measured by a change in fluidity, and was found to be about 12 ° C.

Example 6

1.0 g of sodium sulfate pin, 0.56 g of sodium dihydrogen phosphate, 0.28 g of sodium hydrogen phosphate 0.36 g of sodium chloride and 5 g of the polymer compound (P) obtained in Reference Example 1 were diluted 500 fold so that the total amount was 100 ml. An aqueous solution of benzalconium was added and completely dissolved under ice-cooling and stirring to prepare an ophthalmic solution.

The sol-gel transition temperature of the eye drop was measured by a change in fluidity, and as a result, it was about 11 ° C.

Example 7

19.1 g of boric acid was dissolved in 100 ml of purified water to prepare solution A.

12.4 g of boric acid and 100 g of the molecular compound (P) obtained in Reference Example 1 were added to 100 ml of purified water under ice-cooling and stirring. The solution was completely dissolved in to prepare a solution B.

Next, Solution A and Solution B were thoroughly mixed with ice cooling and stirring to prepare an eyewash (PH 8.2) for contact lenses.

As a result of measuring the sol-gel transition temperature of the eyewash for concret lens by change in fluidity, it was found to be about 13 ° C. Example 8

70 m in 3.5 g of the polymer compound (P) obtained in Reference Example The purified water was added, and the polymer (P) was completely dissolved in a refrigerator at 4 ° C to prepare a 5% polymer (P) solution. (USP unit) 30 m 1 flow rate. Rinse with Rafin (Moleco Pit P-70, manufactured by Muramatsu Oil Research Laboratories) and 4. Cooled sufficiently in refrigerator C. This fluid paraffin is slowly dropped into the above 5% polymer compound (P) solution, and the solution is stirred with a stirrer to reduce the fluid paraffin to the P solution. The suspension was dispersed in the oil to prepare an oil-in-water type suspension. These operations were performed in the refrigerator in Step 4. The sol-gel transition temperature of this suspension was about 14. Also, when the gelled suspension was observed with a microscope, the particle size distribution of the dispersed liquid paraffin was from 100 m to 100 m Was about 500 m. The liquid paraffin particles in the suspension are stable for a long time without any agglomeration, without agglomeration, even without the use of surfactants. The effect of gelling was confirmed. The resulting suspension could be used as an ointment to prevent purulent dermatitis, burns and trauma. If the suspension is cooled to about 14 ° C or less when applied, the suspension becomes a sol and is very easy to apply, and when it adheres to the skin, it becomes a gel at body temperature. Therefore, the adhesiveness was very good, and it could be used comfortably without any discomfort. Example 9

800 g of purified water was added to 40 g of the polymer compound (P) obtained in Reference Example, and the polymer compound was placed in a refrigerator at 4 ° C. (P) was completely dissolved to prepare a 5% solution. On the other hand, 30 g of tetracycline was polished with 200 m1 of liquid paraffin (Molecon Conoless U-8, manufactured by Muramatsu Oil Research Institute). Then, the o-flowing paraffin sufficiently cooled in a 4 ° C refrigerator is slowly dropped into the above 5% 问 molecular compound (P) solution, and the solution is stirred with a stirrer. Then, the liquid paraffin was dispersed in the P solution to prepare an oi 1 inwater type suspension. These operations were carried out in a refrigerator at 4 ° C. 7 The sol-gel transfer temperature of this suspension was about 14 ° C. The suspension was observed under a microscope. It has been observed that the particle size distribution of the dispersed fluid paraffin is

The average was about 100 m from 100 m, and the average was about 500 m. The liquid paraffin particles in the suspension do not clump or coagulate without the use of surfactants, and do not agglomerate for a long period of time. The effect of gelling the suspension was observed. The suspension thus obtained could be used as an oral ointment. If the suspension is cooled to about 14 C or less when applied to the oral cavity, the suspension becomes a sol, so it can be applied to the oral cavity using Jet No.5. In addition, when the suspension adheres to the oral cavity, the suspension turns into a gel at body temperature, and has excellent adhesion or retention in the oral cavity, and is comfortable without feeling uncomfortable. It could be used.

Comparative Example 1

5% of the polymer compound (P) in the suspension shown in Example 8 was replaced with 2% of carboxymethylphenol (CMC), The same operation was performed to obtain a similar suspension. When the suspension was observed with a microscope, the particle size distribution of the dispersed fluid paraffin was 100 mm! It ranged from 11 to 1000 m, with an average of about 500 m. The liquid paraffin particles in the suspension do not use surfactants, so if left undisturbed, they will gradually aggregate in 10 minutes and eventually complete Separated into two phases. In addition, since this suspension had a relatively high viscosity and had fluidity, when applied to the skin, the suspension flowed down and had poor retention.

Potential for industrial use

Since the topical preparation of the present invention contains a temperature-sensitive polymer aqueous solution having a property of sol-gel transfer above the surface temperature of the living body, it forms a solution (sol-like) in a cool and dark place, When heated at (25 to 35 ° C), it immediately changes to a gel and accumulates. As a result, the use of external preparations becomes remarkably easy, the adhesion and retention on the surface of the living body are remarkably improved, and the sustainability of the drug can be remarkably enhanced. Furthermore, since the sol-gel transition temperature is higher than 0 ° C and lower than 37 ° C, there is no thermal damage to the living body surface.

Furthermore, the suspension stability of a water-insoluble drug or a water-insoluble solvent containing the drug is remarkably improved.

Claims

The scope of the claims

1. An external preparation in which an aqueous solution of a temperature-sensitive polymer whose sol-gel transition is reversible and a water-soluble or water-insoluble external drug are combined. It is characterized by being in a sol state at a lower temperature, becoming a gel state at the temperature of a living body surface, being insoluble in water in a gel state, and having a reversible sol-gel transition. External preparation.

2. The external preparation according to claim 1, wherein the external preparation is dissolved or dispersed.

3. The external preparation according to claim 1 or 2, wherein the water-insoluble external drug is contained in and mixed with a water-insoluble medium.

4. The external preparation according to any one of claims 1 to 3, further comprising a dispersion aid.

5. The external preparation according to claim 1 or 4, wherein the 5 degree sensitive polymer comprises a conjugate of a plurality of blocks having a cloud point and a hydrophilic block.

6. The external preparation according to claim 5, wherein the block having the cloud point of the IDE degree sensitive polymer is a polymer having a negative solution temperature coefficient for water.

7. The external preparation according to claim 3, wherein the water-insoluble medium is a hydrocarbon, a vegetable oil, a wax, a cellulose, or an ether.

8 Mouthwash consisting of any of the external preparations of claim 1 or 7

• Mouthwash

9. A poultice comprising the external preparation according to any one of claims 1 to 7

10. A nasal solution comprising the external preparation according to any one of claims 1 to 7.

11. An eardrop solution comprising the external preparation according to any one of claims 1 to 7.

12. An ophthalmic solution comprising the external preparation of any one of claims 1 to 7 o

13. An eyewash solution comprising the external preparation according to any one of claims 1 to 7.

14. An anti-suppuration ointment comprising the external preparation according to any one of claims 1 to 7.

15. An oral ointment comprising the external preparation according to any one of claims 1 to 7.