JP4799957B2 - Pharmaceutical composition for the treatment of stomatitis - Google Patents

Description

  The present invention relates to a pharmaceutical composition for the prevention and / or treatment of stomatitis. More specifically, a pharmaceutical composition for the prevention and / or treatment of stomatitis, comprising vitamin Bs and adenosine 5′-triphosphate or a physiologically acceptable salt thereof, and applied to the oral cavity It is related with the pharmaceutical composition of the form suitable for.

  Stomatitis is a general term for inflammation of the oral mucosa in which mucositis generated in the oral mucosa spreads diffusely or diffusely, and is classified into cheilitis, buccal mucositis, gingivitis, or glossitis depending on the affected site. Clinical morphologies may be classified as aphthous, catarrhal, erosive, or ulcerative. Stomatitis often encountered in daily practice is aphthous, often recurs, and is also called recurrent aphthous stomatitis. In this recurrent aphthous stomatitis, mucosal ulcers are formed, and patients suffer from eating disorders and swallowing / speech disorders due to pain, particularly contact pain.

  For recurrent aphthous stomatitis, if the cause of the onset is clear, treatment for the underlying disease is performed. However, there are various causes of recurrent aphthous stomatitis such as radiation, mechanical and chemical stimulation such as contact of dental caries and dentures, infection by bacteria, fungi, viruses, etc., Behcet's disease, or vitamin deficiency. There are also many unclear causes. Therefore, it is difficult to completely cure only with conventional treatments for the underlying disease. In addition, it is well known that many anticancer drugs have side effects of frequently causing intractable stomatitis, and intractable stomatitis in anticancer drug-treated patients induces severe pain at the time of eating a meal and greatly reduces appetite. Stomatitis caused by anticancer drugs has become a major obstacle in anticancer drug treatment because it cannot be cured unless administration of anticancer drugs is stopped.

  As therapeutic agents for stomatitis, steroidal anti-inflammatory agents such as dexamethasone and triamcinolone acetonide are used in the form of ointments, topical tablets, topical sprays, and the like. However, since the therapeutic effect of these steroidal anti-inflammatory drug-containing stomatitis drugs is insufficient, a drug using a combination of a steroidal anti-inflammatory drug and prostaglandins (see Patent Document 1), sulfodehydroabietic acid ( Chemical name: (+)-(1R, 4aS, 10aR) -1,2,3,4,4a, 9,10,10a-octahydro-1,4a-dimethyl-7- (1-methylethyl) -6 Drugs containing sulfo-1-phenanthrenecarboxylic acid) as active ingredients (see Patent Document 2), L-carnosine zinc salt, or drugs containing L-carnosine zinc salt and sodium alginate as active ingredients (see Patent Document 3) A medicine containing a bactericidal agent and an anti-inflammatory agent, and further containing a mucosal absorbable local anesthetic (see Patent Document 4), a medicine containing an analgesic and a thickener such as lysine acetylsalicylate (See Patent Document 5) and the like have been proposed.

In addition, for oral stomatitis, treatment with a medicine for internal use containing vitamin B such as vitamin B ₁ , B ₂ , B ₆ , or B ₁₂ is also generally performed. This medicine treatment is performed mainly to supplement vitamins for the purpose of improving basic diseases against stomatitis caused by vitamin deficiency (Non-patent Document 1), and direct action by local administration on stomatitis. Is not what I expected.

On the other hand, adenosine 5'-triphosphate is a compound having a high-energy phosphate bond, and has a property of releasing a large amount of energy when hydrolyzed to adenosine 5'-diphosphate and phosphoric acid. Yes. Adenosine 5'-triphosphate is also used as a medicine, and is effective for head trauma sequelae, heart failure, regulatory eye strain, chronic gastritis with gastric appendix, Meniere's disease, and vertigo based on middle ear disorders (See Non-Patent Documents 2 to 5). However, it has not been known that adenosine 5′-triphosphate has a preventive and / or therapeutic effect on stomatitis. In addition, the onset of stomatitis has been reported as a side effect of oral administration of adenosine 5'-triphosphate (see Non-Patent Document 6).
JP 2003-226644 A JP 2003-2828 A Japanese Patent Laid-Open No. 10-17490 Japanese Patent Laid-Open No. 9-95456 JP-A-8-295537 Tamai Hiroshi et al., Pediatric Internal Medicine, 36 (5), 832 (2004) Takasaki Hiroshi et al., Clinical and Research, 55. 207 (1978) Hori, et al., Pharmacology and Treatment, 3. 923 (1975) Miyoshi Akima et al., Pharmacology and Treatment, 3. 950 (1975) Akihiro Suzumura et al., Pharmacology and Treatment, 3. 933 (1975) Watanabe et al., Otolaryngology, 75. 393 (1982)

  An object of the present invention is to provide a pharmaceutical composition for preventing and / or treating stomatitis. More specifically, it is an object of the present invention to provide a pharmaceutical composition that is applied to the oral cavity and has a significantly enhanced preventive and / or therapeutic effect on stomatitis.

  As a result of intensive studies to solve the above problems, the present inventors have surprisingly surprisingly found that adenosine 5'-triphosphate, which is considered to develop stomatitis as a side effect, is combined with vitamin Bs in the oral cavity. It has been found that when it is administered locally, a remarkable preventive and therapeutic effect can be achieved for stomatitis, and the preventive and therapeutic effect is confirmed to be a synergistic effect that cannot be expected when these ingredients are used alone. did. The present invention has been completed based on the above findings.

That is, according to the present invention, a pharmaceutical composition in an oral application form for preventing and / or treating stomatitis, comprising vitamin Bs and adenosine 5′-triphosphate or a physiologically acceptable salt thereof. A pharmaceutical composition comprising an active ingredient is provided.
According to a preferred embodiment of the present invention, the above-mentioned pharmaceutical composition comprising one or more selected from the group consisting of vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , and vitamin B _{12 as} vitamin Bs; The above pharmaceutical composition comprising a combination of vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , and vitamin B ₁₂ as B; the above pharmaceutical composition in a topical administration form for the oral mucosa; ointment, cream, liquid, Or the said pharmaceutical composition of the form of an adhesive tablet is provided.

According to a further preferred embodiment of the invention, the vitamin B ₁ is thiamine disulfide, thiamine hydrochloride, thiamine nitrate, bistiamine nitrate, thiamine dicetyl nitrate ester, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisibutamine , One or more vitamin B ₁ selected from the group consisting of bisbenchamine, fursultiamine, and prosultiamine, and / or vitamin B ₂ from riboflavin, riboflavin phosphate, and riboflavin mononucleotide is one or more of vitamin B ₂ is selected from the group consisting and / or vitamin B ₆ is pyridoxine hydrochloride, one or more B vitamins selected from phosphate pyridoxal and the group consisting of pyridoxamine ₆ And / or vitamins ₁₂ cyanocobalamin, methylcobalamin, hydroxocobalamin, and one or the pharmaceutical compositions described above is a two or more vitamin B ₁₂ is selected from the group consisting of adenosyl cobalamin; and adenosine 5'-triphosphate or a physiologically 0.0003-20 parts by weight of vitamin B ₁ , 0.0005-8 parts by weight of vitamin B ₂ , 0.001-20 parts by weight of vitamin B ₆ , and vitamins per 1 part by weight of the acceptable salt The above-mentioned pharmaceutical composition containing B ₁₂ in a proportion of 0.0000003 to 0.3 parts by weight is provided.

  From another point of view, according to the present invention, the use of vitamin Bs and / or adenosine 5'-triphosphate or a physiologically acceptable salt thereof for the manufacture of the above pharmaceutical composition; and prevention of stomatitis And / or a method of treatment comprising applying a composition comprising vitamin Bs and adenosine 5′-triphosphate or a physiologically acceptable salt thereof in the oral cavity.

  The pharmaceutical composition of the present invention exhibits a prophylactic and / or therapeutic effect that is remarkably enhanced against stomatitis by the synergistic action of vitamin Bs and adenosine 5′-triphosphate or a physiologically acceptable salt thereof. it can.

  Adenosine 5′-triphosphate or a physiologically acceptable salt thereof used in the pharmaceutical composition of the present invention is a known substance and can be easily obtained by those skilled in the art. The type of physiologically acceptable salt of adenosine 5′-triphosphate is not particularly limited, and examples thereof include alkali metal salts such as sodium salt or potassium salt, or alkaline earth metal salts such as magnesium salt or calcium salt. Can be mentioned. Of these, adenosine 5′-triphosphate disodium is particularly preferred.

Examples of vitamin Bs used in the pharmaceutical composition of the present invention include, but are not limited to, vitamin B ₁ , vitamin B ₂ , vitamin B ₅ , vitamin B ₆ , vitamin B _{12 and the} like. The embodiment of B vitamins in the present invention, vitamin B _1, vitamin B _2, preferably if it contains one or more kinds selected from the group consisting of vitamins of B ₆ and vitamin B _12, vitamin B _1, vitamin Particularly preferred is the case containing all of B ₂ , vitamin B ₆ , and vitamin B ₁₂ .

Vitamin The B _1, in addition to vitamin B _1, it may be used acceptable salts thereof derivatized or physiological vitamin B _1. For example, thiamine disulfide, thiamine hydrochloride, thiamine nitrate, bistamine amine, thiamine dicetyl nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, fullsultiamine, or prosulphate Thiamine and the like can be mentioned. It may be used as a vitamin B ₁ in combination of two or more of these. Of these, thiamine disulfide is particularly preferred.

Vitamin The B _2, in addition to vitamin B _2, it may be used those salts acceptable derivative or physiologically vitamin B ₂ manner. For example, riboflavin, riboflavin phosphate, riboflavin mononucleotide and the like can be mentioned. These may be used as vitamin B ₂ in combination of two or more. Of these, riboflavin is particularly preferred.
The vitamin B _6, in addition to vitamin B _6, may be used derivatives and physiologically acceptable salts thereof of vitamin B _6. Examples thereof include pyridoxine hydrochloride, pyridoxal phosphate, and pyridoxamine. These may be used as the vitamin B ₆ in combination of two or more. Of these, pyridoxine hydrochloride is particularly preferred.
The vitamin B _12, in addition to vitamin B _12, may be used derivatives and physiologically acceptable salts thereof of vitamin B _12. Examples thereof include cyanocobalamin, methylcobalamin, hydroxocobalamin, and adenosylcobalamin. These may be used as the vitamin B ₁₂ in combination of two or more. Of these, cyanocobalamin is particularly preferred.

The combination ratio of adenosine 5′-triphosphate and vitamin B in the pharmaceutical composition of the present invention is not particularly limited. The ratio of these two components can be appropriately selected by those skilled in the art while confirming the desired effect by the test method specifically shown in the examples described in the present specification. For example, vitamin B can be selected from a range of about 0.001 to 50 parts by weight with respect to 1 part by weight of adenosine 5′-triphosphate, but is not limited to this range. Preferably, about 0.0003 to 20 parts by weight of vitamin B ₁ , about 0.0005 to 8 parts by weight of vitamin B ₂ , and 0.001 of vitamin B ₆ with respect to 1 part by weight of adenosine 5′-triphosphate. It is preferable to use about ˜20 parts by weight and / or vitamin B ₁₂ in the range of about 0.0000003 to about 0.3 parts by weight, and particularly preferable as vitamins B are vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , And all four types of vitamin B ₁₂ , vitamin B ₁ is about 0.003 to ₂ parts by weight and vitamin B ₂ is 0.005 to 0.005 parts _{per 1} part by weight of adenosine 5′-triphosphate. This is a case where about 8 parts by weight, vitamin B ₆ is about 0.01 to 2 parts by weight, and vitamin B ₁₂ is about 0.000003 to 0.03 parts by weight.

  The blending amount of adenosine 5′-triphosphate in the pharmaceutical composition of the present invention is not particularly limited, and a person skilled in the art can confirm the desired effect by the test method specifically shown in the examples described in the present specification. It can be selected as appropriate. For example, it is preferably about 0.01 to 10% by weight with respect to the total weight of the pharmaceutical composition, and in the oral cavity composition of vitamin B according to the proportion described above according to the blending amount of the above adenosine 5′-triphosphate. The amount can be determined.

  The pharmaceutical composition of the present invention can be used for the prevention and / or treatment of stomatitis. Stomatitis is a general term for inflammation of the oral mucosa in which mucositis that has occurred in the oral mucosa has spread diffusely or diffusely ("Otolaryngology Treatment Handbook", pp.373-377, published by Nanzandou Co., Ltd., 1986) JOHNS, Vol.16, No.9, pp.1410-1411, 2000; otolaryngeal neck, 75, pp.548-551, 2003). Depending on the affected area, it may be classified into cheilitis, buccal mucositis, gingivitis, or glossitis.

  Causes of stomatitis include, for example, viral (herpes simplex, herpes zoster, hand-foot-and-mouth disease, herpangina, etc.), fungal (candidiasis, rhomboid rhinitis, etc.), allergies (drug eruption, dental metal allergy, etc.) , Addictive (drug poisoning, heavy metal poisoning, etc.), metabolic (vitamin deficiency, etc.), syphilis, traumatic (denture wound, topical irritation, etc.), bacterial, hematological disease (agranulocytosis, leukemia, etc.) , Autoimmunity (such as systemic lupus erythematosis (SLE), pemphigus), symptomatic (such as Behcet's disease, Hunter glossitis, Stevens Johnson syndrome, fever), radiation (such as by radiation therapy in the head and neck region), And drug properties (such as those caused by administration of anticancer agents), and those with unknown causes (such as recurrent after, lichen planus). The classification by visual inspection is classified into, for example, catarrhal, erythematous, blister, erosion, ulcer, gangrene, pseudomembranous, dry, and aphthous. The pharmaceutical composition of the present invention is applicable to any of these stomatitis.

  A particularly preferred application target of the pharmaceutical composition of the present invention is aphthous stomatitis, and aphthah (a circular or similar circular ulcer in the mucous membrane, the ulcer surface is pseudomembranous, and red blood cells are observed around it) Recurrent after which recurs in the oral mucosa is a particularly preferred application (recurrent after is sometimes referred to as recurrent aphthous ulcer or recurrent oral ulcer: the Quintessence, Vol. 20, No, 12, pp. 128-132, 2001). The pharmaceutical composition of the present invention can also be administered prophylactically for the purpose of preventing recurrence of aphthous stomatitis and the like and suppressing the progression of oral ulcer formation.

  The pharmaceutical composition of the present invention is prepared as a pharmaceutical composition in a form suitable for oral application, and is administered to the entire oral cavity or to the area of stomatitis. Preferably, it is provided as a pharmaceutical composition in a form suitable for topical administration in the oral cavity. As described above, stomatitis may be formed in the lip, and the medicament of the present invention can also be applied to the lip. Therefore, the term “intraoral” as used herein should not be interpreted as excluding the lip. The form of the pharmaceutical composition of the present invention is not particularly limited as long as it is suitable for intraoral application. For example, it can be prepared as an ointment, cream, liquid, patch, patch, etc. An agent, cream, liquid, or adhesive tablet is particularly preferred.

  For the preparation of the pharmaceutical composition of the present invention, one or more additives for preparations usually used for formulation in the art may be used as necessary. As additives for such preparations, for example, base components such as water, thickeners, emulsifiers, neutralizing agents, preservatives, stabilizers, wetting agents, fragrances, and fats and oils may be blended. Although it is possible, it does not necessarily need to be blended and what can be blended is not limited thereto.

Examples of the thickener include sodium carboxymethylcellulose, hydroxyethylcellulose, carrageenan, sodium alginate, xanthan gum, sodium polyacrylate, polyvinyl alcohol, locust bean gum, guar gum, gelatin, hydroxypropylmethylcellulose and the like.
As an emulsifier, polyoxyethylene hydrogenated castor oil, sorbitan monostearate, glycerin fatty acid ester, propylene glycol fatty acid ester, alkyl glyceryl ether, polyoxyethylene sorbitol fatty acid ester, polysorbate, polyoxyethylene, lauromacrogol, sodium alkyl sulfate, Examples thereof include alkyl phosphates, sodium alkylbenzene sulfonate, sodium N-acyl sarcosine, N-acyl glutamate, sucrose fatty acid esters, alkyl glycosides, alkyl dimethylamine oxide, and alkyl betaines.

Examples of the neutralizing agent include inorganic acids such as hydrochloric acid, alkali hydroxides such as sodium hydroxide and potassium hydroxide, and amines such as triethanolamine, diethanolamine and diisopropanolamine.
Examples of preservatives include p-hydroxybenzoates.
Examples of the stabilizer include sodium sulfite, sodium hydrogen sulfite, dibutylhydroxytoluene, butylhydroxyanisole, edetic acid or salts thereof.
Examples of the wetting agent include polyhydric alcohols such as glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, isopropylene glycol, and polyethylene glycol.

Perfumes include spearmint oil, peppermint oil, linalool, winder green oil, sassafras oil, clove oil, peppermint oil, thyme oil, sage oil, eucalyptus oil, mayonnaise oil, cinnamon oil, lime oil, lemon oil and orange oil, etc. Natural fragrances and l-menthol, dl-camphor and the like.
Oils and fats include waxes such as lanolin, whale wax, carnauba wax, fatty acids, ester compounds such as octyldodecyl myristate, diisopropyl adipate, hexadecyl isostearate, decyl oleate, squalane, squalene, medium chain fatty acid triglycerides, liquid paraffin And silicon.

  The dosage and administration frequency of the pharmaceutical composition of the present invention are not particularly limited, and can be appropriately selected according to various conditions such as the form of the pharmaceutical composition, the cause and clinical picture of stomatitis, and the age of the patient. In general, when administered in the form of an ointment or the like, about 10 to 500 mg as a composition weight per administration can be locally administered several times a day. It is not limited to.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples.
Example 1
Add plastibase to 100g of adenosine 5'-triphosphate disodium 1.2g, thiamine disulfide 0.48g, riboflavin 0.03g, pyridoxine hydrochloride 0.48g, cyanocobalamin 1.2mg and mix at room temperature. Thus, an ointment in the oral application form was obtained.

Example 2
Purified water containing 1.2 g adenosine 5'-triphosphate disodium, 0.48 g thiamine disulfide, 0.03 g riboflavin, 0.48 g pyridoxine hydrochloride, 1.2 mg cyanocobalamin, 25 g concentrated glycerin and 0.1 g macrogol 6000 Added to 45 g and dissolved at room temperature. To this solution, 0.7 g of carboxyvinyl polymer was added and thoroughly stirred and mixed at room temperature (preparation solution A).
On the other hand, polyoxyethylene hydrogenated castor oil 60 (Nikkor HCO-60: Nikko Chemicals) 1.4 g, sorbitan monostearate (Nikkor SS-10M: Nikko Chemicals) 0.6 g, cetanol (Kao) 2 g, petrolatum (white petrolatum: (Crompon) 3 g, ethyl parahydroxybenzoate 0.1 g and propyl paraoxybenzoate 0.05 g were added to 13 g of light liquid paraffin and dissolved at 80 ° C. (Preparation solution B).
Add Preparation B to Preparation A, stir and mix well at 80 ° C., emulsify, cool to 60 ° C. or lower, add sodium hydroxide as neutralizing agent to pH 5.5, and then add purified water. In addition, a total amount of 100 g was well stirred and mixed to obtain a cream for oral application.

Example 3
12 g of adenosine 5′-triphosphate 12 g, thiamine disulfide 4.8 g, riboflavin 0.3 g, pyridoxine hydrochloride 4.8 g, cyanocobalamin 12 mg, sodium polyacrylate 973 g, magnesium stearate 5 g are mixed and compressed by a tableting method. A tablet with a weight of 50 mg per tablet was molded with a flat punch having a diameter of 7 mm to obtain a patch in an oral application form.
Example 4
Adenosine 5′-triphosphate disodium 1.2 g, thiamine disulfide 0.48 g, riboflavin 0.03 g, pyridoxine hydrochloride 0.48 g, and cyanocobalamin 1.2 mg, concentrated glycerin 25 g, paraoxybenzoic acid methyl 0.1 g and paraoxy 0.05 g of propyl benzoate was added to 60 g of purified water and dissolved at room temperature. After adjusting the pH to 5.5 with a citrate buffer, purified water was added to make a total amount of 100 g and well dissolved by stirring to obtain a liquid preparation for oral application.

Example 5
Eight week old Syrian female hamsters were used. For oral ulcers, the animal is anesthetized by intraperitoneal administration of pentobarbital, then the left cheek bag is pulled out, a cylinder with a diameter of 4 mm is pressed against the mucosal surface, 0.1 mL of 100% acetic acid is injected, and contacted for 30 seconds It was produced by. In addition, the ulcer area was calculated by measuring the major axis and minor axis (mm) of the ulcer on the second, third and fifth days from the day when the ulcer was produced. The test preparation was prepared by dissolving 60 mg adenosine 5′-triphosphate disodium, 24 mg thiamine disulfide, 1.5 mg riboflavin, 24 mg pyridoxine hydrochloride, and 60 μg cyanocobalamin in 5 mL purified water (hereinafter, “ATP”). + VBs ”), thiamine disulfide 24 mg, riboflavin 1.5 mg, pyridoxine hydrochloride 24 mg, and cyanocobalamin 60 μg dissolved in 5 mL of purified water (hereinafter referred to as“ VBs ”), and adenosine 5′-triphosphate Using preparations prepared by dissolving 60 mg of disodium acid in 5 mL of purified water (hereinafter referred to as “ATP”), 50 μL of these were applied to the ulcer site once a day from the date of ulcer preparation.

The results are shown in FIG. In the figure, white circles (◯) indicate control (untreated), black triangles (▲) indicate ATP + VBs of the present invention, black circles (●) indicate ATP, and white triangles (Δ) indicate VBs, * Indicates that there was a significant difference at p <0.05 (Multiple comparison of Tukey Type). The ulcer area was almost the same in each group on the day of ulcer creation, and the healing effect was confirmed by administration of the test preparation, and it was found that the healing effect of ATP + VBs was synergistically superior to that of ATP alone and VBs alone.
Table 1 shows the results of calculating the ratio of the ulcer area of the drug administration group when the ulcer area of the control on each measurement day was 1.000. * Mark in a table | surface shows the product of the ulcer area ratio of ATP and VBs. The ulcer area ratio of ATP + VBs was smaller than the product of the ulcer area ratio of ATP alone and VBs alone on any measurement day, and was determined to have a synergistic effect by the bulge method.

  From the above results, the pharmaceutical composition of the present invention containing a combination of adenosine 5′-triphosphate and vitamin Bs has a synergistic therapeutic effect on ulcers in the oral cavity compared to the case of each component alone. It became clear to have. Therefore, it was shown that the pharmaceutical composition of the present invention has a preventive and / or therapeutic effect on stomatitis including aphthous stomatitis, catarrhal stomatitis, erosive stomatitis, ulcerative stomatitis and the like.

FIG. 1 is a diagram showing the therapeutic effect of oral ulcers by the pharmaceutical composition of the present invention.

Claims (5)

A pharmaceutical composition of a topical oral dosage form for the prevention and / or treatment of stomatitis, which contains vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , and a combination of vitamin B ₁₂ as vitamin B And adenosine 5'-triphosphate or a physiologically acceptable salt thereof as an active ingredient. Vitamin B ₁ is thiamine disulfide, thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, thiamine dicetyl nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, fursultiamine, and a professional sul one or more vitamins B ₁ selected from the group consisting of thiamine, vitamin B ₂ riboflavin, riboflavin phosphate, and one or more vitamins selected from the group consisting of riboflavin mononucleotide a B _2, vitamin B ₆ is pyridoxine hydrochloride, pyridoxal phosphate, and a one or more vitamins B ₆ is selected from the group consisting of pyridoxamine, vitamin B ₁₂ is cyanocobalamin, methylcobalamin, hydroxocobalamin and, One or pharmaceutical composition according to claim 1 2 or more vitamin B ₁₂ is selected from the group consisting of de Bruno cobalamin. Vitamin B ₁ is 0.0003-20 parts by weight, vitamin B ₂ is 0.0005-8 parts by weight, vitamin B ₆ with respect to 1 part by weight of adenosine 5′-triphosphate or a physiologically acceptable salt thereof. the 0.001 parts by weight, and pharmaceutical composition according to claim 1 or 2 comprising vitamin B ₁₂ in an amount of from 0.0000003 to 0.3 parts by weight. The pharmaceutical composition according to any one of claims 1 to 3 , which is a topical administration form for the oral mucosa. The pharmaceutical composition according to claim 4 in the form of an ointment, cream, liquid, or patch.

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