JP5460766B2 - Pharmaceutical composition for external use - Google Patents

Description

  The present invention relates to an external pharmaceutical composition for improving or treating a skin condition in which damage or loss has occurred due to various factors. In detail, crack, red snapper, that, keratosis, psoriasis, shark skin, eczema, dermatitis, insect bite, athlete's foot, worm, shinkin, scratch, cut, stomatitis, cheilitis, cheilitis The present invention relates to an external pharmaceutical composition that efficiently improves or treats a skin disease as a factor by improving or treating damages and defects of skin and mucous membranes associated with salmon and the like. In particular, the present invention relates to an external pharmaceutical composition that restores a healthy skin state by enhancing the healing effect of an affected part that has been damaged or lost due to the above-described factors, and exhibits an excellent improvement effect or healing effect for each disease.

Cracks, red snapper, that, keratosis, dry skin, shark skin, eczema, dermatitis, insect bite, athlete's foot, tinea, shinkin, scratches, cuts, stomatitis, cheilitis, stomatitis, scissors In many cases, diseases such as affected areas, sores, dryness, cracks, inflammation and other damages or defects are induced.
For example, in eczema and dermatitis, a red rash with mild swelling is first caused by some kind of irritation, and if it becomes suppurated, it becomes a sore or a scab. When eczema and dermatitis are repeated, the skin becomes dry, thickened, hardened and cracked.
Skin troubles in winter, such as keratosis and xeroderma, are caused by destruction of the skin block function due to a decrease in skin moisture and keratinocyte lipids due to aging and excessive use of soap. Furthermore, especially in winter, the temperature is lowered, the moisture in the air is low and the skin becomes dry, and the moisture in the skin is easily evaporated. For this reason, the metabolic function of the skin is lowered, the turnover function does not work normally, and the old keratin that should be peeled off remains attached to the surface of the skin, resulting in a rustling or soft state. As symptoms progress further, cracking may occur, and it may cause scuffing or bleeding.
In the case of athlete's foot, there are three main symptoms. First, in the most common type of athlete's foot called the intercostal type, the toes are swollen red or peeled off. Next, white wiping and wiping, and reddish. Occasionally around the peeled and peeled skin, the remaining skin may become hard and cracked. In the case of the next most blister type, small blisters gather and the surroundings turn red and peel off. In the case of the keratinized type, the keratin becomes rough and thick and hard, and the skin is tattered and peeled off, or cracked and scratched.
In the case of cutaneous hemorrhoids, the passage of thick and hard stools cuts the anus, causing bleeding and severe pain. When this becomes chronic, the affected area becomes ulcerous, the anus becomes narrow, and defecation is caused.

Conventionally, steroid anti-inflammatory agents, non-steroidal anti-inflammatory agents, wound healing promoters, moisturizers, herbal extracts and the like have been used for the treatment of eczema, dermatitis and insect bites. However, it is known that steroidal anti-inflammatory agents exhibit sufficient effects due to their powerful anti-inflammatory effects, but also have many serious side effects. Furthermore, as an action of steroidal anti-inflammatory agents, it has been known that it has a granulation (tissue repair) inhibitory action, and in the case of long-term continuous use, it may worsen the symptoms. Non-steroidal anti-inflammatory agents, wound healing promoters, moisturizers, herbal extracts, etc. are effective for mild symptoms, but generally sufficient for improving severe symptoms. Not. In addition, it is known that many non-steroidal anti-inflammatory agents have high local irritation and sensitization irritation. As a treatment for keratosis and xeroderma, many external preparations containing a moisturizer, a non-steroidal anti-inflammatory agent and an antihistamine are used. However, moisturizers secondarily improve the deterioration of skin symptoms, but are thought to have no effect of improving the condition of skin that has deteriorated quickly. Non-steroidal anti-inflammatory agents and antihistamines are also considered to have no effect on healing skin damage or defects, and keratosis mainly suppresses inflammation and itching associated with keratosis and xeroderma. And may be included in drugs for the treatment of xeroderma.
Various antifungal agents are used for the treatment of athlete's foot. In recent years, antifungal agents having high antibacterial activity and high penetrability and retention in affected areas have been developed, and antifungal agents that exert therapeutic effects even once a day are being developed.
In addition, steroid anti-inflammatory agents are often used to treat inflammation and salmon to suppress inflammation, and local anesthetics are used to reduce pain. It is also known that (tissue repair) has a suppressive action, and local anesthetics are sensitizing stimuli and may not be suitable for damaged or missing affected areas.

  Moreover, although allantoin or allantoin-related substances, panthenol or panthenol-related substances have different detailed mechanisms of action, they are often blended in pharmaceuticals and cosmetics for the purpose of skin tissue repairing action and anti-inflammatory action. As a pharmaceutical, it is formulated as an adjuvant component such as steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, antihistamines, moisturizers, etc. and expected to improve or treat accompanying symptoms associated with eczema, dermatitis, insect bites, etc. Yes. However, the effect is not yet satisfactory. For example, in Patent No. 2720246, trehalose is added because allantoin or a derivative thereof, pantothenic acid, which is a panthenol related substance, or pantothenic acid or a derivative thereof alone or simultaneously is not satisfactory. It is described that the effect is synergistically enhanced. Furthermore, panthenol has been reported to enhance its effect when blended with farnesol and / or its derivatives (No. 3104938).

On the other hand, antifungal agents are used for diseases such as athlete's foot, worms, snails, candidiasis, starch, seborrheic dermatitis, and onychomycosis. In recent years, antifungal agents having excellent effects have been developed, and among them, antifungal agents having high keratin affinity are excellent in terms of effects, and have been widely used in recent years. Conventional antifungal agents required application 2 to 3 times a day, but antifungal agents with high keratin affinity have a high retention in the stratum corneum and are sufficient even when applied once a day The effect is recognized and helps to improve compliance. It is known that the effect is due to an action mechanism such as inhibition of cell membrane synthesis.
On the other hand, JP 2005-529875 reports that ciclopirox olamine, a pyrimidine antifungal agent, has an effect of wound healing, and examples of pharmaceutical compositions in combination with allantoin and panthenol analogs are also exemplified. However, there is no description on the effect of the combination of ciclopirox olamine and allantoin or panthenol analogues. In addition, there are already commercialized examples of combinations of tissue repair agents and antifungal agents, and JP-A 2005-104924 discloses an antifungal agent, particularly an anti-fungal compound selected from morpholine compounds, benzylamine compounds, and imidazole compounds. Examples of pharmaceutical compositions in which the fungicidal agent, vitamin A and / or vitamin E, and tocopherol and / or retinol are combined to enhance the bactericidal effect of the antifungal agent are described.

Patent No. 2720246 Patent No. 3104938 Special Table 2005-529875 JP 2005-104924 A

  One of the objects of the present invention is to provide an external pharmaceutical composition that is excellent in the effect of improving or treating the state of an affected part that has been damaged or lost due to various factors, and that efficiently improves or treats the disease causing the factor. is there. Another object of the present invention is to provide a method for enhancing the wound healing effect of a wound treatment promoter.

The present inventor has found that when an antifungal agent having a high affinity for keratin is added to the wound healing promoter, the effect of improving or treating the affected area damaged or lost due to various factors is synergistically enhanced. . Next, it has been found that by adding a moisturizing agent to these, the effect is further synergistically enhanced.
Therefore, this invention is a pharmaceutical composition for external use containing a wound healing promoter, an antifungal agent with high keratin affinity, and a moisturizer. The external pharmaceutical composition of the present invention has an enhanced effect of improving or treating the condition of the affected area.
The present invention is also a method for enhancing the wound healing effect of the wound healing promoter, comprising combining a wound healing promoter and an antifungal agent having high keratin affinity in combination. Furthermore, the present invention is also a method for enhancing the wound healing effect of the wound healing promoter, comprising combining a wound healing promoter, an antifungal agent having a high keratin affinity, and a moisturizer.

More specifically, the present invention relates to an allantoin and / or allantoin analog, panthenol and / or panthenol analog, retinol and / or retinol analog, tocopherol and / or tocopherol analog and azulene. And / or the external pharmaceutical composition selected from the group consisting of azulene-related substances.
Further, in the present invention, the antifungal agent having a high affinity for keratin is selected from the group consisting of bifonazole, ketoconazole, neticonazole hydrochloride, ranoconazole, luliconazole, terbinafine hydrochloride, butenafine hydrochloride, amorolfine hydrochloride, any one of the above external uses It is also a pharmaceutical composition.
Further, the present invention provides any one of the above selected from the group consisting of glycerin, urea, hyaluronic acid and salts thereof, hydrogenated soybean phospholipid, ceramide, lactic acid and salts thereof, pyrrolidone carboxylic acid and salts thereof as a humectant. It is also a pharmaceutical composition for external use.
Furthermore, the present invention includes a method for enhancing the wound healing effect of the wound healing promoter, and the method includes combining a wound healing promoter and an antifungal agent having high keratin affinity. Moreover, this invention is also the said method including adding a moisturizer further.

The pharmaceutical composition for external use of the present invention comprises a wound healing promoter, an antifungal agent having high keratin affinity, and a moisturizing agent.
The wound healing promoter is not particularly limited as long as it is an active ingredient having a skin tissue activating effect by various actions. Specifically, the wound healing promoter includes allantoin and / or allantoin-related substances, panthenol and / or panthenol-related substances, retinol and / or retinol-related substances, tocopherol and / or tocopherol-related substances, and azulene and azulene-related substances. Is included.
Allantoin or allantoin-related substances are active ingredients having wound healing / anti-inflammatory effects. Allantoin-related substances are active ingredients that have a hydantoin skeleton and have wound healing and anti-inflammatory effects. Specifically, allantoin-related substances include, but are not limited to, allantoin chlorohydroxyaluminum and allantoindihydroxyaluminum. . Panthenol and panthenol-related substances are active ingredients having a wound healing action. Panthenol-related substances are active ingredients having a wound healing action, and include panthenol esters and pantothenic acid salts. Specifically, panthenol related substances include, but are not limited to, pantothenyl ethyl ether, calcium pantothenate, sodium pantothenate, acetyl panthenyl ethyl ether. Azulene and azulene-related substances are active ingredients having wound healing / anti-inflammatory effects. An azulene-related substance is an active ingredient having an azulene skeleton and a wound healing / anti-inflammatory effect, and specifically includes, but is not limited to, dimethylisopropylazulene and sodium azulenesulfonate. Retinol and retinol-related substances are active ingredients that promote wound healing by promoting the maintenance and growth of epithelial tissues. Retinol-related substances include esters of retinol. Specifically, retinol-related substances include, but are not limited to, retinol acetate and retinol palmitate. Tocopherol and tocopherol-related substances are active ingredients that promote wound healing by improving peripheral circulation disorder. Tocopherol-related substances include tocopherol esters and salts thereof. Specifically, tocopherol analogues include, but are not limited to, tocopherol succinate calcium, tocopherol acetate, and tocopherol nicotinate.

An antifungal agent having a high affinity for keratin is an active ingredient that exerts an antifungal action by transdermal administration because of its high affinity with keratin. Preferably, the antifungal agent having a high affinity for keratin used in the present invention is an active ingredient that has excellent retention at the affected area and is effective when applied about once a day. Specifically, antifungal agents with high affinity for keratin include imidazole antifungal agents bifonazole, ketoconazole, neticonazole hydrochloride, lanoconazole, luliconazole, allylamine antifungal agent terbinafine hydrochloride, benzylamine antifungal agent Butenafine hydrochloride, which is an agent, and amorolfine hydrochloride, which is a morpholine antifungal agent. The affinity for keratin can be evaluated by measuring the adsorptivity of each antifungal agent to keratin in vitro according to a conventional method. For example, Uchida et al. Conducted a study on keratin affinity of terbinafine using keratin powder derived from human hair (Journal of the Mycological Society of Japan, 34 (2), 207-212, 1993). The keratin affinity of an antifungal agent can be evaluated. Antifungal keratin affinity is affected by pH and drug: keratin concentration ratio, but generally when drug: keratin concentration ratio is 1: 1,000 in the normal pH range of healthy skin around pH 5.0 An antifungal agent having an adsorption rate to keratin of 30% or more is considered to be an antifungal agent having a high affinity for keratin.
The moisturizer is not particularly limited as long as it is an active ingredient having a moisturizing action by various actions. Specifically, glycerin, urea, hyaluronic acid and their salts, hydrogenated soybean phospholipid, ceramide, lactic acid and their salts, pyrrolidone carboxylic acid and their salts are included as a humectant.

In the pharmaceutical composition for external use of the present invention, the above-mentioned wound healing promoter depends on the wound healing promoter used, but may be 0.01 to 10% by mass, preferably 0.03 to 5% by mass. Depending on the antifungal agent used, the antifungal agent having high affinity for keratin can be 0.1 to 5% by mass, preferably 0.5 to 2% by mass based on the total. The humectant may be 0.001 to 80% by mass, preferably 0.01 to 50% by mass, depending on the humectant used.
In the external pharmaceutical composition of the present invention, the wound healing promoter, the antifungal agent having high affinity for keratin and the moisturizing agent can be blended in two or more, respectively, in which case the total amount of each is within the above-mentioned range. It is preferable to blend so as to be.

As an experimental model for determining the effect on damage and defect, a defect wound that removes the skin, a burn caused by cauterization, and a wound model created by a scalpel are used. For example, Yamaura et al. Applied an incision model in accordance with the method of Ronsen et al. In the evaluation of tissue respirators, solcoseryl obtained from calf blood, mainly based on solcoseryl, and confirmed the healing promotion effect of solcoseryl. ing. (Applied pharmacology 22 (4) 565-579 (1981)). In addition, the wound resistance measuring device can be made at a low cost, and results with good reproducibility are obtained. Therefore, the therapeutic effect of the external preparation for skin of the present invention can be evaluated by any of these methods, but it is preferably performed according to the method of Yamaura et al. Using a cut model.
Specifically, the therapeutic effect of the external pharmaceutical composition of the present invention can be evaluated as follows, for example. A test composition that should be evaluated on the dorsal skin of the rat hair by using a scissors etc. to create a 15mm long symmetrical left and right symmetrically with a midline, and sewing the center of the cut with one silk suture. An appropriate amount of the object, for example, 30 to 70 mg is applied to the right or left of the cutaneous skin for several hours, for example, about 6 hours, once or twice a day immediately after suturing. After application, rats are immediately transferred to a cylindrical wire mesh to prevent ingestion of specimens. By repeating these operations for several days, for example, 4 to 6 days, removing the thread the day before the last day, euthanizing carbon dioxide the day after the last day, cutting the cut skin into strips, and measuring the wound tension The therapeutic effect can be evaluated. The tensile strength (TS) is measured by, for example, an apparatus improved from Yamaura (Applied Pharmacology 22 (4) 565-579 (1981)). That is, one side of the cut portion skin cut out in a strip shape is fixed, the weight is gradually applied to the opposite portion and pulled, and the necessary weight is obtained until opening. The evaluation of the effect can be performed by calculating according to the following formula (I). More specifically, according to the formula (I), each test composition is calculated based on the healing promotion rate. For example, when the healing promotion rate is less than 15%, “no healing promoting effect” and the healing promotion rate is 15 When the percentage is less than 25% and less than 25%, it can be judged as “somewhat has a healing promotion effect”, and when the healing promotion rate is 25% or more, it can be judged as “with a healing promotion effect”. As a control, an experimental group in which only a pseudo operation of applying the composition without actually applying anything can be used.

  Healing promotion rate = (TS of specimen−TS of control part) / TS × 100 of control part (I)

  The pharmaceutical composition for external use of the present invention can be prepared by blending the above-described wound healing promoter, antifungal agent with high keratin affinity, and humectant with various base components according to a conventional method. Any material that can be used as a base can be used for the preparation of the external pharmaceutical composition of the present invention. Examples of such bases include hydrocarbons such as white petrolatum, paraffin, liquid paraffin, gelled hydrocarbon, microcrystalline wax; higher fatty acids such as stearic acid, myristic acid and oleic acid; cetanol, stearyl alcohol and behenyl alcohol Higher fatty alcohols such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate and diisopropyl adipate; fatty acid ester oils such as glyceryl triisooctanoate and glyceryl tri (caprylate / caprate); mono Glyceryl stearate, glyceryl monooleate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, polyoxyethylene monostearate (20 Sorbitan, polyoxyethylene monooleate (20) sorbitan, polyoxyethylene tetrastearate (60) sorbit, polyoxyethylene tetraoleate (60) sorbit, polyoxyethylene (60) castor oil, polyoxyethylene (60) Hardened castor oil, polyoxyethylene glycol monostearate (4EO), polyethylene glycol monooleate (10EO), polyoxyethylene (9) lauryl ether, polyoxyethylene (10) cetyl ether and polyoxyethylene oleyl ether Ionic surfactants; ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate; polyhydric alcohols such as propylene glycol, 1,3-butylene glycol and polyethylene glycol; carboxyvinyl polymer, hydro Polymer compounds such as xylpropylcellulose, hypromellose, hydrophobized hydroxypropylmethylcellulose, acrylated starch 300 and polyvinylpyrrolidone; diisopropanolamine, triethanolamine, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, dihydrogen phosphate PH adjusting agents such as potassium and sodium hydrogen phosphate; organic solvents such as ethanol, isopropyl alcohol, acetone, methyl ethyl ketone and ethyl acetate; stabilizers such as sodium chloride, sodium thiosulfate, sodium sulfite and sodium edetate; methyl paraben, propyl Examples include, but are not limited to, preservatives such as paraben, benzalkonium chloride, and benzethonium chloride.

When preparing the pharmaceutical composition for external use of the present invention, it is prepared by mixing the above-mentioned components and a medium such as water, but the mixing ratio is not particularly limited, for example, 0 to 80% by mass of water, 0 to 0 to hydrocarbons 99% by mass, higher fatty acid 0-25% by mass, higher fatty alcohol 0-25% by mass, fatty acid ester oil 0-50% by mass, polyhydric alcohol fatty acid ester 0-30% by mass, surfactant 0-10% by mass, Polyhydric alcohol 0-90 mass%, polymer compound 0-10 mass%, pH adjuster 0-10 mass%, organic solvent 0-99 mass%, stabilizer 0-10 mass%, preservative 0-5 mass %.
In addition to a wound healing promoter, an antifungal agent having a high keratin affinity, and a moisturizer, the following drugs can be added to the external preparation for skin of the present invention, but the present invention is not limited thereto. Diphenhydramine and its salts, chlorpheniramine and its salts, isothipentyl and its salts, antihistamines such as diphenylimidazole, steroidal agents such as hydrocortisone, dexamethasone acetate, hydrocortisone butyrate and prednisolone valerate acetate, bufexamac, ufenamate, ibuprofen piconol , Indomethacin, ketoprofen, felbinac, piroxicam, diclofenac sodium, loxoprofen sodium, glycyrrhetinic acid, glycyrrhizic acid and its salts, anti-inflammatory agents such as toki extract and shikon extract, fat-soluble vitamins such as ascorbyl palmitate, ergocalciferol, and tacalcitol , Ascorbic acid, pyridoxine hydrochloride, nicotinic acid Water-soluble vitamins such as sodium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, benzethonium chloride, benzalkonium chloride, cetrimide and other fungicides, lidocaine and its salts, dibucaine and its salts, procaine and its salts, tetracaine and its salts, Local anesthetics such as ethyl aminobenzoate, cooling agents such as l-menthol, dl-camphor, mint oil and borneol, vasoconstrictors such as naphazoline hydrochloride, tetrahydrozoline hydrochloride and methylephedrine hydrochloride, benzyl nicotinate, Reding agents such as nonyl acid vanillylamide and chili tincture can be blended.

  In the following examples, the method for producing an external pharmaceutical composition of the present invention and the therapeutic effect thereof will be described in more detail. The pharmaceutical composition for external use of the present invention can be produced according to a method for producing ordinary ointments, creams, emulsions, gels, solutions for external use, lacquers, aerosols, patches, poultices, suppositories, and injections. I can do it.

  Allantoin, hydrogenated soybean phospholipid, terbinafine hydrochloride, liquid paraffin, microcrystalline wax, and white petrolatum were heated and mixed uniformly, and this was further cooled and stirred to obtain an ointment having the following composition.

  Allantoin, hydrogenated soybean phospholipid, ketoconazole, and plastibase were heated and mixed to be uniform, and this was further cooled and stirred to obtain an ointment having the following composition.

  Ranoconazole, diphenhydramine, polyoxyethylene monostearate, isopropyl myristate and diisopropanolamine are heated and dissolved to be uniform. Next, add a part of purified water and a liquid in which carboxyvinyl polymer is dispersed in glycerin, stir to emulsify, add a solution in which allantoin is heated and dissolved in a part of purified water, cool and stir, and cream with the following composition An agent was obtained.

  Panthenol, terbinafine hydrochloride, 1,3-butylene glycol and ethanol were stirred and dissolved uniformly, and a solution obtained by dissolving urea in purified water was added thereto and stirred to obtain a liquid for external use having the following composition.

  Panthenol, glycerin, neticonazole hydrochloride, polyethylene glycol 400 and ethanol were stirred and dissolved uniformly to obtain a liquid for external use having the following composition.

  Panthenol, glycerin, bifonazole and diphenhydramine were stirred and dissolved in a part of ethanol. Next, to a solution in which hypromellose was uniformly dispersed in a part of ethanol, a solution in which carboxyvinyl polymer was dispersed in purified water was added and stirred, and then diisopropanolamine was added to prepare a gel base. The above-mentioned ethanol solution was added to this, and it stirred uniformly, and obtained the gel agent of the following compositions.

  Panthenol, glycerin, lanoconazole, chlorpheniramine maleate and Toki extract were added to glycerin and stirred to make it uniform. Next, after adding the solution which disperse | distributed the carboxy vinyl polymer to the macrogol 400 and stirring, the diisopropanolamine and purified water were added and it stirred uniformly and the gel agent of the following compositions was obtained.

  Dimethylisopropylazulene, glycerin, terbinafine hydrochloride, ethyl acetate and ethanol were stirred and dissolved uniformly. Piroxylin was added to this and stirred to obtain a lacquer agent having the following composition.

Synergistic effect of wound healing promoter and anti-fungal agent with high keratin affinity Comparison of healing effect between external pharmaceutical composition containing wound healing promoter and anti-fungal agent with high keratin affinity and external pharmaceutical composition containing each independently .
1) Preparation of test composition and comparative composition The following compositions were prepared. The composition of each composition is shown in Table 1. The numerical value for each component in the table is the mass% of each component relative to the entire composition.

  Test composition 1: An external pharmaceutical composition containing allantoin as a wound healing promoter and terbinafine hydrochloride as an antifungal agent having high keratin affinity was prepared. The blending amount and other base components are shown in Table 1. In the preparation method, first, carboxyvinyl polymer was dispersed in purified water and heated. Separately, terbinafine hydrochloride, cetanol, stearyl alcohol, glycerin triisooctanoate, sorbitan monostearate, polysorbate 60, and diisopropanolamine were heated and uniformly dissolved. This was added to the previously heated carboxyvinyl polymer dispersion with stirring to prepare an emulsion. Next, allantoin was added to the remainder of the purified water, and the resulting mixture was heated and dissolved. The resulting emulsion was cooled and cooled to obtain a cream.

Test composition 2: A cream was obtained in the same manner as the preparation of test composition 1 except that panthenol was included as a wound healing promoter.
Test composition 3: A cream was obtained in the same manner as in the preparation of test composition 2, except that bifonazole was included as an antifungal agent having a high affinity for keratin.

Comparative composition 1: Except not containing terbinafine hydrochloride, the same operation as preparation of the test composition 1 was performed, and the cream agent was obtained.
Comparative composition 2: A cream was obtained in the same manner as in the preparation of test composition 2 except that terbinafine hydrochloride was not included.
Comparative composition 3: A cream was obtained in the same manner as in the preparation of the test composition 1 except that it did not contain allantoin.

2) Measurement of healing promotion rate of each composition Next, the healing effect of each prepared test composition was measured.
A 15mm long cut with a midline is symmetrically created on the dorsal skin of the rat hair with scissors, and each central part of the cut is sutured with a silk suture. Once applied to the left or right side of the cut skin for 6 hours. After application, the rats were immediately transferred to a cylindrical wire mesh to prevent oral intake of each test composition. These operations were repeated for 5 days, the yarn was removed after application on the 4th day, the carbon dioxide gas was euthanized on the 6th day, and the cut skin was cut into a strip to measure the wound tension. The tensile strength (TS) was measured with a modified device of Yamaura (Applied Pharmacology 22 (4) 565-579 (1981)). That is, one side of the cut portion skin cut out in a strip shape was fixed, the weight was gradually applied to the opposite portion and pulled, and the necessary weight was obtained until opening.
The healing effect was compared by calculating the healing acceleration rate calculated by the following formula (I) for each composition. As a control, an experimental group in which only a pseudo operation of applying the composition without actually applying anything was performed.
Healing promotion rate = (TS of specimen−TS of control part) / TS of control part × 100 (I)
When the healing promotion rate calculated according to the formula (I) is less than 15%, “no healing promotion effect”, and when the healing promotion rate is 15% or more and less than 25%, “there is some healing promotion effect”, the healing promotion rate is When it was 25% or more, it was determined that “healing promotion effect”.
The results are shown in Table 1 below. The numerical value regarding each component in a table | surface is the mass% of each component with respect to a composition.

Table 1. Healing promotion effect in a rat injury skin model (combination effect of wound healing promoter and anti-fungal agent with high keratin affinity)

  The wound healing promoter alone was judged as “no healing promoting effect” from the healing promotion rate calculated by the formula (I). Moreover, even with an antifungal agent having a high affinity for keratin, almost no healing promotion effect was observed, and it was determined that “no healing promotion effect”. However, by adding an antifungal agent having a high affinity for keratin to the wound healing promoter, the healing promotion rate was increased and a synergistic effect was confirmed.

Effect of moisturizer on healing promotion rate Addition of moisturizing agent to an external pharmaceutical composition containing a wound healing promoter and an antifungal agent with high keratin affinity, and using the method described in Example 9, the effect on healing promotion rate Examined. The ingredients of each composition are shown in Table 2 together with the healing promotion rate. The numerical value regarding each component in a table | surface is the mass% of each component with respect to the whole composition.

  Test composition 4: An external pharmaceutical composition containing panthenol as a wound healing promoter and terbinafine hydrochloride as an antifungal agent having high keratin affinity was prepared. First, terbinafine hydrochloride, cetanol, stearyl alcohol, octyldodecanol, sorbitan monostearate, polysorbate 60, polyoxyethylene (40) cetyl ether and diisopropanolamine were heated and dissolved uniformly. Separately, panthenol and citric acid were dissolved in purified water and heated. This was added to the previously heated oil phase with stirring to prepare an emulsion. Next, this emulsion was cooled to obtain a cream.

  Test composition 5: An external pharmaceutical composition containing panthenol as a wound healing promoter, terbinafine hydrochloride as an antifungal agent having high keratin affinity, and glycerin as a moisturizer was prepared. First, terbinafine hydrochloride, cetanol, stearyl alcohol, octyldodecanol, sorbitan monostearate, polysorbate 60, polyoxyethylene (40) cetyl ether and diisopropanolamine were heated and dissolved uniformly. Separately, panthenol, glycerin and citric acid were dissolved in purified water and heated. This was added to the previously heated oil phase with stirring to prepare an emulsion. Next, it was cooled to obtain a cream.

Test composition 6: A cream was obtained in the same manner as in the preparation of the test composition 5 except that lactic acid was included as a moisturizing agent.
Test composition 7: A cream was obtained in the same manner as in the preparation of the test composition 5 except that hydrogenated soybean phospholipid was included as a humectant.
Test composition 8: A cream was obtained in the same manner as in the preparation of the test composition 5 except that urea was included as a humectant.
Test composition 9: A cream was obtained in the same manner as the preparation of test composition 5 except that allantoin was included as a wound healing promoter and butenafine hydrochloride was included as an antifungal agent having high keratin affinity.
Test composition 10: A cream was obtained in the same manner as in the preparation of the test composition 9 except that ketoconazole was included as an antifungal agent having a high affinity for keratin.

Comparative composition 4: A cream was obtained in the same manner as in the preparation of the test composition 5 except that it did not contain a wound healing promoter and an antifungal agent with high keratin affinity.
Comparative composition 5: A cream was obtained in the same manner as in the preparation of the test composition 5 except that the antifungal agent having a high affinity for keratin was not included.

Table 2. Healing promotion effect in rat injury skin model (combination effect with moisturizer)

Table 2 continued

  The moisturizer alone was determined to have “no healing promoting effect” based on the healing promotion rate. However, by adding a moisturizer to the combination of a wound healing promoter and an antifungal agent having a high affinity for keratin, the healing acceleration rate was increased and a synergistic effect was confirmed.

Claims (3)

i) 0.03-5% by weight of allantoin, and
ii) 0.5-2% by weight of terbinafine hydrochloride, butenafine hydrochloride, or ketoconazole, and
iii) humectants ,
The characterized in that it contains, therapeutic topical pharmaceutical composition for diseases having wound. i) 1.0% by weight of allantoin, and
ii) 1.0-2.0% by weight of terbinafine hydrochloride, butenafine hydrochloride, or ketoconazole, and
iii) humectants ,
The characterized in that it contains, therapeutic topical pharmaceutical composition for diseases having wound.   The topical medicine according to claim 1 or 2, wherein the humectant is selected from the group consisting of glycerin, urea, hyaluronic acid and salts thereof, hydrogenated soybean phospholipid, ceramide, lactic acid and salts thereof, pyrrolidone carboxylic acid and salts thereof. Composition.