JPH1180031A - External preparations and methods for enhancing transdermal or transmucosal absorption - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a transdermal or transmucosal agent having enhanced transdermal or transmucosal absorbability of a drug and having high safety, and a method of enhancing transdermal or transmucosal absorbability of a drug. An external preparation containing a drug (eg, salicylic acid) and a scrub (eg, ground apricot pericarp). Drugs are antifungals (eg, miconazole nitrate), local anesthetics (eg, ethyl 4-aminobenzoate), anti-inflammatory analgesics (eg,
The above external preparation which is indomethacin) or urea. Dosage forms include ointments, creams, gels, liniments,
Emulsions, powders or foams are preferred. A method for enhancing percutaneous or transmucosal absorbability of a drug by incorporating scrub into a drug-containing base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation, and more particularly, to an external preparation in which the percutaneous or transmucosal absorption of a drug is enhanced by blending a scrub, and the percutaneous or transmucosal absorption is enhanced. On how to do it.

[0002]

2. Description of the Related Art When a drug is administered transdermally, the stratum corneum acts as a barrier to hinder the transdermal absorption of the drug. Especially in diseased skin where the keratin layer is thick and keratin hyperplasia is remarkable,
Effective transdermal administration is difficult. Therefore, in many cases, a sufficient therapeutic effect cannot be obtained. For example, a parasitic skin disease such as a fungus in a footpad with a thick stratum corneum, for example, ringworm, often cannot obtain a sufficient therapeutic effect. Therefore, as a method of administering an amount sufficient for the manifestation of a drug effect, a drug concentration is increased, or a transdermal absorption enhancer such as a surfactant is added. However, when the concentration of the drug is increased, there is a risk of local accumulation of the drug and development of irritation. Also, there is known a risk of inducing skin irritation even when a transdermal absorption enhancer is used. Therefore, it is desired to develop a method for increasing the transdermal or transmucosal absorption of a drug and improving the therapeutic effect without increasing the drug concentration or using a transdermal absorption enhancer.

On the other hand, it is known to add scrub to cosmetics and external preparations (for example, see JP-A-2-85206).
JP-A-6-271427 and the like. However, the effect is expected to have a skin cleansing effect and a local massage effect, and only an emollient cream is described as an external preparation, such as a drug containing an antifungal agent, a local anesthetic or an anti-inflammatory drug. And no proposal has been made regarding the transdermal absorbability of urea.

[0004] Conventionally, preparations containing a local anesthetic have been widely used for itching and pain of the skin (Naoshi Ishida et al., Kidney and Dialysis, 36, 1135-1139).
P. 1994). However, since side effects of local anesthetics include urticaria, edema, rash, and pruritus (13th revised edition of the Japanese Pharmacopoeia, Hirokawa Shoten), these side effects are reduced and further improved in treatment. Therefore, there has been a demand for an antipruritic and analgesic external preparation having a sufficient therapeutic effect by using a low-dose local anesthetic.

Conventionally, urea-containing external preparations are known to have the effect of improving and treating skin dryness, but their high concentrations are known to cause skin irritation. I have. So, without increasing the concentration of urea,
Development of a method for improving the therapeutic effect has been desired.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above problems, and an object of the present invention is to enhance the percutaneous or transmucosal absorbability of a drug and to provide a highly safe external preparation and a drug. The aim is to provide a method for enhancing transdermal or transmucosal absorption.

[0007]

The external preparation according to claim 1 contains a drug and scrub. The external preparation according to claim 2 is the external preparation according to claim 1, wherein the drug is an antifungal agent, a local anesthetic, an anti-inflammatory analgesic, or urea. The external preparation according to claim 3 is the external preparation according to claim 1 or 2, wherein the dosage form of the external preparation is an ointment, cream, gel, liniment, emulsion, powder or foam. In the method for enhancing transdermal or transmucosal absorbability of a drug according to claim 4, scrub is blended in a base containing the drug. A method for enhancing the transdermal or transmucosal absorbability of a drug according to claim 5, wherein the drug is an antifungal agent, a local anesthetic, an anti-inflammatory analgesic or urea. It is a way to improve.

Hereinafter, the present invention will be described in detail. The external preparation of the present invention contains a drug and a scrub.

[0009] The scrub is a particulate material that exfoliates the stratum corneum or mucous membrane of the skin or causes minute scratches. For example, the endocarp of plants such as apricot endocarp, almond seed coat, and sesame seeds And synthetic resins such as nylon, polyethylene, polyester, styrene-acrylic copolymer, epoxy resin, etc., including arthropod shells, egg shells, crushed animal bones, shells and coral such as crabs Powder, silica powder, latex particles, sodium chloride crystals, fine powder of lipid solid at room temperature, and the like, but are not limited thereto, and any of those conventionally used as scrubs can be used. The particle size of the scrub is not particularly limited, but as the size becomes smaller, the effect of exfoliating the stratum corneum or mucous membrane or causing small scratches becomes smaller, so that the percutaneous absorption effect becomes insufficient, and as the size becomes larger, the uniformity of the scrub in the external preparation becomes uniform. 10 to 1000
μm is preferred. Similarly, when the amount of scrub in the external preparation is small, the effect of exfoliating the stratum corneum or mucous membrane or causing small scratches is reduced, so the percutaneous absorption effect becomes insufficient, and when the amount is large, the scrub in the external preparation is uniform. 0.1 to 25% by weight is preferable, and
-25% by weight is more preferred.

In the external preparation of the present invention, by blending the above scrub with a drug-containing base, the stratum corneum or mucous membrane which hinders percutaneous absorption of the drug during application is exfoliated or minute scratches are formed. Or as a result, the transdermal or transmucosal absorption of the drug is enhanced.

The above-mentioned drug is a compound which cures or alleviates the symptoms of a specific disease, and may be a substance which is absorbed percutaneously and acts systemically or locally.
For example, antifungal agents; central nervous agents, general anesthetics,
Hypnotic sedative, anxiolytic, antiepileptic, antipyretic analgesic, stimulant, stimulant, antiparkinson, psychiatric, general cold, etc .; local anesthetic, skeletal muscle relaxant for peripheral nervous system Agents, autonomic nervous agents, antispasmodics, publishing agents, antiperspirants, etc .; circulatory agents, cardiotonic agents, arrhythmias, vasoconstrictors, vasodilators, high-fat plasma agents, etc .; respiratory agents , Respiratory stimulants, antitussives, etc .; hormones (antihormones) include pituitary hormones, salivary hormones, thyroid hormones, parathyroid hormones, anabolic steroids, adrenal hormones, androgens,
Estrogen, progestin, etc .; urogenital and anal agents; dermatological agents, germicidal disinfectants for dermis, purulent diseases, analgesics, antipruritics, astringents, anti-inflammatory agents, parasitic skin diseases Preparations, emollients, etc .; dental oral agents, dental local anesthetics, etc .; vitamins; tumor agents, alkylating agents, antitumor antibiotics, etc .; allergic agents, antihistamines, stimulation therapy Agents, non-specific immunogen preparations, etc .; crude drugs and Kampo preparations; antibiotics; chemotherapeutic agents; drugs for parasites.

Among these drugs, the effects of the present invention are particularly exerted on antifungal agents, local anesthetics or antiphlogistic analgesics, or urea.

The above-mentioned antifungal agent is a substance that inhibits or kills the growth of fungi, such as undecylenic acid, zinc undecylenate, salicylic acid, antitol,
Moctar, Siccanin, Tricomycin, Nystatin, Pyrrolenitrin, Variotin, Sulfur, Croconazole Hydrochloride, Clotrimazole, Iconazole Nitrate, Econazole Nitrate, Oxyconazole Nitrate, Sulconazole Nitrate, Miconazole Nitrate, Thioconazole, Exalamide, Bifonazole, Phenylioounde Synoate and the like, but are not limited thereto. These drugs can also be used as salts. These can be used alone or in combination of two or more.

[0014] When the amount of the antifungal agent in the external preparation is small, the effect is weakened, and a sufficient therapeutic effect is not obtained. When the amount is large, the effect is increased to some extent, but side effects are likely to occur. Depends on
1-20% by weight is preferred, and 0.1-5% by weight is more preferred.

Examples of the above local anesthetics include ethyl aminobenzoate, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, lidocaine hydrochloride, lidocaine hydrochloride / epinephrine hydrochloride, oxybuprocaine hydrochloride, takecaine, bupivacaine hydrochloride, mepivacaine hydrochloride, propitocaine hydrochloride, Epinephrine hydrochloride epinephrine, oxesazein, ethyl piperidinoacetylaminobenzoate, pyridoxine hydrochloride, dimethisoquine hydrochloride, bromoxine hydrochloride, lidocaine, benzocaine, procaine, dibucaine, piperokine hydrochloride, hexiothiokine hydrochloride, benzyl alcohol, tecaine hydrochloride, cocaine hydrochloride, catecaine hydrochloride ,
Butanicain hydrochloride, Oxybutanican hydrochloride, Mebrylbutanican hydrochloride, Piperocaine hydrochloride, Chlorobutanol, Meprilcaine hydrochloride, Epilocaine hydrochloride, Amylokine hydrochloride, Isobucaine hydrochloride, Chloroprocaine hydrochloride,
Examples include, but are not limited to, tricaine hydrochloride, parethoxycaine hydrochloride, pirocaine hydrochloride, prilocaine hydrochloride, procaine amide hydrochloride, propalacaine hydrochloride, propoxycaine hydrochloride, hexylcaine hydrochloride, metabutetamine hydrochloride, metabutoxycaine hydrochloride, xylocaine.

When the amount of the local anesthetic in the external preparation is reduced, the effect is weakened and a sufficient therapeutic effect is not obtained, and when the amount is increased, the effect is increased to some extent, but side effects are likely to occur. Depends on
0.01-30% by weight is preferred, and 0.1-20% by weight
Is more preferred.

The above-mentioned anti-inflammatory analgesic is a substance having a local anti-inflammatory and / or analgesic action by external use, for example, indomethacin, ketoprofen, piroxicam, felbinac, flurbiprofen, salicylic acid,
Examples include, but are not limited to, methyl salicylate. These can be used alone or in combination of two or more.

When the amount of the anti-inflammatory analgesic in the external preparation is reduced, the effect is weakened, and a sufficient therapeutic effect is not obtained. When the amount is increased, the effect is increased to some extent, but side effects are likely to occur. Depends on
It is preferably 0.01 to 40% by weight, more preferably 0.01 to 20% by weight, and particularly preferably 0.1 to 10% by weight.

When the drug is urea, its medicinal effect is improvement and treatment of skin diseases caused by dry skin. When the amount of urea in the external preparation is small, the effect is weakened, a sufficient therapeutic effect is not obtained, and when the amount is large, the effect is increased, but side effects are likely to occur, so 0.1 to 50% by weight is preferable. 20% by weight is more preferred.

The dosage form of the external preparation of the present invention is not particularly limited as long as it can be applied to skin or mucous membranes.
For example, ointments, creams, gels, liniments, lotions, emulsions, powders, foams, and the like in which a scrub and a drug are dissolved or mixed and dispersed in a base, or a scrub and a drug dissolved or dissolved in a base Examples thereof include cataplasms, tapes, plasters and the like obtained by spreading and mixing and dispersing on a support, and particularly preferred are ointments, creams, gels, liniments, emulsions, powders and foams.

As the base, any pharmaceutically acceptable base may be used, and conventionally known bases such as ointments and liquid preparations may be used. For example, sodium alginate, gelatin, corn starch, tragacanth gum Polymers such as, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, xanthan gum, carrageenan, mannan, agarose, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyvinylpyrrolidone; Beeswax, olive oil, cocoa oil, sesame oil,
Fats and oils such as soybean oil, camellia oil, peanut oil, beef oil, pork oil, chicken oil, lanolin; white petrolatum, yellow petrolatum; paraffin; hydrocarbon gel (for example, trade name Plastibase, manufactured by Bristol-Myers Squibb); stearin Higher fatty acids such as acids; higher alcohols such as cetyl alcohol, octyl dodecanol, and stearyl alcohol; polyethylene glycol (eg, macrogol 400, macrogol 4000, etc.); glycerin monostearate; polyoxyethylene cetyl ether; self-emulsifying propylene Glycol monostearate, triethanolamine; monooleate;
Glyceride stearate; water, physiological saline, phosphate buffer, and the like, but are not limited thereto.

If necessary, a surfactant; a solubilizing agent such as polyvinylpyrrolidone; an inorganic filler such as kaolin, bentonite, zinc oxide and titanium oxide; a stabilizer such as methyl paraoxybenzoate and propyl paraoxybenzoate. Antioxidants; pH regulators; humectants such as glycerin and propylene glycol; preservatives such as benzalkonium chloride, benzethonium chloride, citric acid, sodium citrate, paraoxybenzoic acids, boric acid, borax, camphor; xanthan gum , Sodium chondroitin sulfate,
Viscous agents such as liquid paraffin, glycerin, polyethylene glycol and polyvinylpyrrolidone, or a viscous agent may be added.

Examples of the surfactant include polysorbate 80, lecithin derivative, propylene glycol fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, Polyoxyethylene sorbite fatty acid ester, polyoxyethylene alkylphenyl formaldehyde condensate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sterol / hydrogenated sterol, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, poly Oxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether Le, polyoxyethylene lanolin,
Examples include, but are not limited to, lanolin alcohol / beeswax derivatives, polyoxyethylene alkylamine / fatty acid amides, polyoxyethylene alkyl ether phosphoric acid / phosphate, polymer emulsifiers, and the like.

Among the above surfactants, polyoxyethylene sorbitan fatty acid esters (eg, POE (20) sorbitan monopalmitate), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, of which high safety has been confirmed Are particularly suitable for the present invention.

As the base of the above-mentioned tape preparation, any base can be used as long as it is pharmaceutically acceptable. Conventionally known bases can be used, for example, acrylic adhesives, rubber adhesives, silicone adhesives. Agents, urethane-based adhesives, etc., and acrylic-based adhesives and rubber-based adhesives are preferably used. As the properties of the pressure-sensitive adhesive when spread on the support, any one of a solvent type, an emulsion type, a hot melt type and the like can be used.

Examples of the acrylic pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of polyalkyl (meth) acrylate obtained by copolymerizing alkyl (meth) acrylate. A copolymer with a functional monomer or another vinyl monomer may be used.

Examples of the above-mentioned alkyl (meth) acrylate include 2-ethylhexyl (meth) acrylate, dodecyl (meth) acrylate and the like.
Examples of the polyfunctional monomer include 1,6-hexane glycol dimethacrylate and tetraethylene glycol diacrylate, and examples of the other vinyl monomer include N-vinyl-2-pyrrolidone and vinyl acetate. Is mentioned.

Examples of the rubber-based pressure-sensitive adhesive include pressure-sensitive adhesives mainly composed of natural rubber, styrene-isoprene-styrene block copolymer, styrene-olefin-styrene block copolymer and the like. A tackifier such as rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, cumarone resin, and cumarone-indene resin is added.

As the above-mentioned support, its dosage form (for example,
It is appropriately selected depending on the cataplasm, tape, etc., but is preferably a drug which is impermeable or hardly permeable and flexible, for example, cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride, vinyl acetate-chloride. Vinyl copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-
Resin films such as butyl acrylate-carbon monoxide copolymer, polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate, and polybutylene terephthalate; aluminum sheets, woven fabrics, nonwoven fabrics, and laminated sheets thereof.

The external preparation of the present invention can be obtained by, for example, a method in which a base, a scrub, a drug and the like are supplied to a mortar or a beaker and kneaded uniformly, and a method of kneading with a planetary mixer.

An external preparation using a local anesthetic as a drug in the present invention is an antipruritic and analgesic external preparation having a high therapeutic effect on itching, pain and inflammation of the skin. The amount of the topical antipruritic agent depends on the type of the disease, the degree of the symptom, the size of the affected area, etc., but is preferably 0.1 to 10 g per day. Apply to affected area.

The disease to be treated by the topical antipruritic and / or analgesic preparation, in which a local anesthetic is used as a drug in the present invention, is not particularly limited, and includes, for example, hot flashes, sores, insect bites, diaper rash, urticaria, Skin diseases such as eczema, allergic dermatitis, razor loss, genital pruritus, shoe slips, contact dermatitis, atopic dermatitis, palmar keratosis, senile pruritus, pruritus due to chronic renal failure, etc. Is mentioned.

In the present invention, a topical antipruritic agent using a local anesthetic as a drug enhances the percutaneous absorbability of the local anesthetic by squibbing, so that a preparation containing a low dose of a local anesthetic is sufficient. Since it has an excellent therapeutic effect, it can suppress side effects of local anesthetics such as urticaria, edema and rash, and has a safe and high therapeutic effect.

The disease to be treated by an external preparation in which an antifungal agent is used as a drug in the present invention is not particularly limited. For example, tinea pedis, vesicular tinea pedis, superficial head Tinea (shirakumo), tinea, lateral tinea / hand tinea (waterworm), tinea corporis (zenithi-mushi), tinea cruris (ringworm), cutaneous candidiasis, vaginal candidiasis, vaginal trichomoniasis, candidiasis (Finger erosion, intertrigo, infantile parasite erythema), peritonitis, verruca verruca, pityriasis glaucoma, erythroderma, axillary odor, jaundice, sweat blisters, fungal pruritus, etc. .

In the present invention, the disease to be treated by an external preparation in which an anti-inflammatory analgesic is used as a drug includes:
There is no particular limitation, and examples thereof include osteoarthritis, periarthritis of the shoulder, tendonitis, pericenditis, suprahumeral inflammation, and muscle pain.

[0036] In the present invention, the disease to be treated by an external preparation using urea as a drug is a condition in which skin dryness and keratinization are caused, and examples thereof include atopic dermatitis, dry skin, and advanced fingers. Examples include, but are not limited to, palmar keratoderma, senile xeroderma, palmoplantar keratosis, lichen pilaris, ichthyosis.

The method for enhancing the transdermal or transmucosal absorbability of the present invention is a method for enhancing the transdermal or transmucosal absorbability of a drug, which comprises mixing the above scrub with a drug-containing base. At the time of application, the stratum corneum or mucous membrane which hinders the percutaneous absorption of the drug is peeled off or slightly scratched, so that the percutaneous or transmucosal absorption of the drug is enhanced.

[0038]

Next, embodiments of the present invention will be described. (Example 1 and Comparative Examples 1 and 2) Endocarp of apricot was pulverized with a coffee mill to a particle size of 100 to 500 μm to prepare a scrub. The predetermined amounts of white petrolatum (Taisho Pharmaceutical Co., Ltd.) and salicylic acid (Wako Pure Chemical Industries, Ltd.) shown in Table 1 were kneaded using a mortar. Further, urea (manufactured by Wako Pure Chemical Industries, Ltd.) was added as the scrub or percutaneous absorption enhancer and kneaded to prepare an ointment.

[0039]

[Table 1]

Test Example 1 5 g of the ointment prepared in Example 1 and Comparative Examples 1 and 2 was applied to a shaved rabbit (Japanese white species) back skin in an area of 8 cm × 10 cm with a cotton swab. After coating with a film, it was fixed with a bandage. 0.5, 1, 2, 3 and 6 hours after administration of the ointment, heparin blood was collected and the concentration of salicylic acid in plasma was measured by high performance liquid chromatography. Table 2 shows the results. The numerical values in the table are the average value ± standard deviation of three individuals.

[0041]

[Table 2]

[Test Example 2] 5 g of the ointment prepared in Example 1 and Comparative Examples 1 and 2 was applied to a shaved rabbit (Japanese white species) back skin in an area of 8 cm × 10 cm using a cotton swab. After covering with a polyethylene film, it was fixed with a bandage. The ointment was removed 6 hours after administration. After repeating this operation for 7 days, on the 8th day, the degree of skin irritation was evaluated according to the following criteria of Dratez. Table 3 shows the results. The numerical values in the table are the average values of three individuals.

Score 0: no erythema 1: very mild erythema 2: clear erythema 3: moderate to severe erythema 4: slight eschar from severe erythema

[0044]

[Table 3]

From Tables 2 and 3, the external preparation of the present invention has a higher transdermal absorption effect than the external preparation containing urea, which is a transdermal absorption enhancer. It is also safe with low skin irritation.

(Example 2 and Comparative Examples 3 and 4) Endocarp of apricot was ground with a coffee mill to a particle size of 100 to 500 μm to prepare scrub. The prescribed amounts of miconazole nitrate (manufactured by Sigma) and macrogol ointment (Maruishi Pharmaceutical) shown in Table 1 were kneaded using a mortar. Further, urea (manufactured by Wako Pure Chemical Industries, Ltd.) was added as the scrub or percutaneous absorption enhancer and kneaded to prepare an ointment.

[0047]

[Table 4]

[Test Example 3] Therapeutic effect of guinea pig on experimental ringworm The following test was conducted using the ointment obtained above as a test agent. Egawa-Iwata method (Jpn. J. Med. Mycol: 20, 1)
0, 1979), ringworm was experimentally developed in Hartley male guinea pigs (body weight: 400 to 600 g), and the therapeutic effect was examined. After shaving the back of the guinea pig with an electric hair clipper, stick a 2 cm diameter circular tape (Venix cloth tape, manufactured by Sekisui Chemical Co., Ltd.) to two places on the back, and then peel off once. Each time, a new tape was used five times to remove the hair and exfoliate the stratum corneum. In this part, a spore suspension of 0.1 × 10 ⁸ cells / ml of an inoculum (Tricophyton mentagrophytes) was prepared.
05 ml was applied. Five days after the bacterial inoculation, 0.5 g of the test agent obtained in Example 2 or Comparative Examples 3 and 4 was continuously applied once a day for 5 days using a spatula.

The appearance of the above-mentioned site of ringworm onset was observed according to the following criteria. Wein described in the Egawa-Iwata method
According to the description of Stein et al., according to the description of Gordee and Mathews, no lesion was observed 0, a few small erythematous papules were observed, but the lesion was in the direction of healing and new hair was growing 1, erythema was seen in the form of islands, erythema was found throughout the inoculation site, and abundant scales or thick crusts were formed. With the accompanying state as 4, judgment was made 5 days after the start of application of the test agent. In addition, it performed similarly to the above except that macrogol ointment was used as a test agent as a comparative control, and performed the same judgment.

The tinea healing rate was calculated from the determination value (A) of the site to which macrogol ointment was applied and the determination value (B) of the site to which the test agent was applied in the same individual according to the following formula. Table 5 shows the results. The numerical values in the table are the average values of three individuals. Ringworm cure rate (%) = {(AB) / A} × 100

[0051]

[Table 5]

[Test Example 4] 5 g of the ointment prepared in Example 2 or Comparative Examples 3 and 4 was applied to a shaved rabbit (Japanese white species) back skin in an area of 8 cm × 10 cm using a cotton swab. After covering with a polyethylene film, it was fixed with a bandage. The ointment was removed 6 hours after administration. After repeating this operation once a day for 7 days, the degree of skin irritation was evaluated on the 8th day according to the above-mentioned criteria for Dratez. Table 6 shows the results. The numerical values in the table are the average values of three individuals.

[0053]

[Table 6]

From the results shown in Table 5, the external preparation of the present invention showed a higher activity for treating ringworm than the external preparation of Comparative Example 4 containing no scrub. The external preparation of the present invention had a stronger effect than the external preparation containing urea, which is a transdermal absorption enhancer.
Furthermore, from the results in Table 6, the external preparation of the present invention has low skin irritation and is safe.

(Example 3 and Comparative Examples 5 and 6) Apricot endocarp was ground to a particle size of 100 to 500 μm with a coffee mill to prepare scrub. A predetermined amount of ethyl 4-aminobenzoate (Sigma) and a hydrocarbon gel (Plastibase, trade name, Bristol-Myers Squibb) shown in Table 7 were kneaded using a mortar. Further, isopropyl myristate (produced by Nikko Chemicals Co., Ltd.) was added as the scrub or percutaneous absorption enhancer and kneaded to prepare an ointment.

[0056]

[Table 7]

Test Example 5 Using the ointment obtained above as a test agent, the following test was conducted. A 6-week-old male ddY strain mouse was subcutaneously injected with a compound 48/80 (manufactured by Sigma) saline solution at 100 μg / mouse on the back to induce pruritus. The test agent was applied to a compound 48/80 administration site using a spatula. The control group used only the hydrocarbon gel as a test agent. Each test agent was tested using 5 mice, the number of pruritus movements for 15 minutes was measured, and the average value of the 5 mice was shown in Table 8.

[0058]

[Table 8]

Test Example 6 Using a cotton swab, 5 g of the ointment prepared in Example 3 or Comparative Examples 5 and 6 was applied to the shaved rabbit (Japanese white species) back skin in an area of 8 cm × 10 cm. After covering with a polyethylene film, it was fixed with a bandage. The ointment was removed 6 hours after administration. After repeating this operation once a day for 7 days, the degree of skin irritation was evaluated on the 8th day according to the above-mentioned criteria for Dratez. Table 9 shows the results. The numerical values in the table are the average values of five individuals.

[0060]

[Table 9]

From the results shown in Table 8, the external preparation of the present invention exhibited a higher antipruritic effect than the external preparation of Comparative Example 6 containing no scrub. The external preparation of the present invention had a stronger effect than the external preparation containing isopropyl myristate, which is a transdermal absorption enhancer. Furthermore, from the results in Table 9, the external preparation of the present invention has low skin irritation and is safe.

Example 4 and Comparative Examples 7 and 8 Apricot endocarp was ground with a coffee mill to a particle size of 100 to 500 μm to prepare a scrub. A predetermined amount of indomethacin (manufactured by Wako Pure Chemical Industries, Ltd.) and hydrocarbon gel (trade name: Plastibase, manufactured by Bristol-Myers Squibb) shown in Table 10 were kneaded using a mortar. Further, isopropyl myristate (produced by Nikko Chemicals Co., Ltd.) was added as the scrub or percutaneous absorption enhancer and kneaded to prepare an ointment.

[0063]

[Table 10]

[Test Example 7] Inhibitory effect on rat carrageenin-induced footpad edema The following test was carried out using the ointment obtained above as a test agent. Sprague Dawley male rats (4
Carrageenan foot pad edema was induced at 〜5 weeks of age and weighing 100-140 g), and its local inhibitory effect was examined experimentally.

0.2 g of the ointment prepared in Example 4 or Comparative Examples 7 and 8 was applied to the right rear footpad of the rat using a spatula. 0.2 g of a hydrocarbon gel as a base of the ointment was applied using a spatula. Six hours later, 1 ml of a 1 (W / V)% aqueous solution of carrageenan was injected.

Two hours after the above-mentioned carrageenin injection, the foot pad edema volume was measured using a precismometer (manufactured by Ugobasil). From the right rear footpad edema capacity (A) to which the test agent was applied and the left rear footpad edema capacity (B) to which the hydrocarbon gel was applied, the footpad edema inhibition rate was calculated by the following formula. The results are shown in Table 11. The numerical values in the table are the average values of three individuals. Footpad edema suppression rate (%) = {(BA) / B} × 100

[0067]

[Table 11]

Test Example 8 5 g of the ointment prepared in Example 4 or Comparative Examples 7 and 8 was applied to a shaved rabbit (Japanese white species) back skin in an area of 8 cm × 10 cm using a cotton swab. After covering with a polyethylene film, it was fixed with a bandage. The ointment was removed 6 hours after administration. After repeating this operation once a day for 7 days, the degree of skin irritation was evaluated on the 8th day according to the above-mentioned criteria for Dratez. Table 12 shows the results. The numerical values in the table are the average values of three individuals.

[0069]

[Table 12]

From the results shown in Table 11, the external preparation of the present invention showed a higher inhibitory effect on carrageenan foot pad edema in rats than the external preparation of Comparative Example 8 containing no scrub. The external preparation of the present invention had a stronger effect than the external preparation containing isopropyl myristate, which is a transdermal absorption enhancer. Furthermore,
From the results in Table 12, the external preparation of the present invention has low skin irritation and is safe.

(Example 5 and Comparative Examples 9 and 10) Endocarp of apricot was ground with a coffee mill to a particle size of 100 to 500 μm to prepare scrub. 25 parts by weight of white petrolatum (manufactured by Maruishi Pharmaceutical Co., Ltd.), 22 parts by weight of stearyl alcohol (manufactured by Wako Pure Chemical), 12 parts by weight of propylene glycol (manufactured by Wako Pure Chemical), sodium lauryl sulfate (manufactured by Wako Pure Chemical). 5 parts by weight, 0.25 parts by weight of ethyl paraoxybenzoate (manufactured by Wako Pure Chemical Industries), 0.15 parts by weight of butyl paraoxybenzoate (manufactured by Wako Pure Chemical Industries) and 39.1 parts by weight of water are kneaded using a mortar. An ointment base was prepared.

A predetermined amount of the above-mentioned ointment base shown in Table 13,
Urea (manufactured by Wako Pure Chemical Industries) and scrub were kneaded until uniform, to prepare an ointment.

[0073]

[Table 13]

Test Example 9 Evaluation in Guinea Pig Dry Skin Model The following test was carried out using the ointment obtained above as a test agent. Hartley male guinea pig (weight: 300-40)
0 g) of the back skin was shaved with an electric clipper and a shaver, and a 3% by weight aqueous solution of sodium lauryl sulfate was applied with absorbent cotton once a day for 4 days to prepare dry skin. 0.2 g of the test agent was applied to the right back using a cotton swab, and an ointment base was applied to the left back for comparison. After continuous administration once a day for 4 days, the skin water retention was measured by Skicon-
200 (IBS).

The water retention of the right back skin to which the test agent was applied was A, the water retention of the left back skin to which the ointment base was applied was B, and the healthy skin which was not coated with the above 3% by weight aqueous solution of sodium lauryl sulfate was used. The dry skin healing rate was calculated by the following formula, where C was the water retention amount of the water. The results are shown in Table 14. The numerical values in the table are the average values of three individuals. Dry skin healing rate (%) = {(AB) / (CB)} ×
100

[0076]

[Table 14]

Test Example 10 5 g of the ointment prepared in Example 5 or Comparative Examples 9 and 10 was applied to a shaved rabbit (Japanese white species) back skin in an area of 8 cm × 10 cm using a cotton swab. After covering with a polyethylene film, it was fixed with a bandage. The ointment was removed 6 hours after administration. After repeating this operation once a day for 7 days, the degree of skin irritation was evaluated on the 8th day according to the above-mentioned criteria for Dratez.
Table 15 shows the results. The numerical values in the table are the average values of three individuals.

[0078]

[Table 15]

From the results shown in Table 14, the external preparation of the present invention showed a higher therapeutic effect on guinea pig dry skin than those of Comparative Examples 9 and 10 containing no scrub. From these results, it has been clarified that a high therapeutic effect can be obtained by adding scrub even if the amount of urea in the external preparation is reduced. Furthermore, as shown in Test Example 10, the skin irritation of the external preparation of the present invention was clearly lower than that of Comparative Example 9 containing 20% urea, which was the same as that of the commercially available preparation, and 5% urea containing no scrub was used. It was comparable to Comparative Example 10 which was a combination preparation.

[0080]

The composition of the external preparation according to the first aspect is as described above, and exfoliates the stratum corneum or mucous membrane which hinders the percutaneous absorption of the drug and makes a minute wound by adding a scrub. Therefore, it is possible to provide an external preparation having excellent transdermal or transmucosal absorbability and having a higher therapeutic effect than a conventional external preparation not containing scrub. further,
Since the exfoliation or minute scratches on the stratum corneum or mucous membrane are very slight, skin irritation is hardly recognized, and an external preparation having higher safety than an external preparation using a transdermal absorption enhancer can be provided.

The composition of the external preparation according to claim 2 is as described above, and since an antifungal agent, a local anesthetic, an antiphlogistic analgesic or urea is used as a drug, the antifungal, antipruritic and analgesic effects, antiphlogistic and antiphlogistic, respectively are used. The present invention can provide a highly safe external preparation having an analgesic action, an improvement in skin dryness, a therapeutic action, excellent transdermal or transmucosal absorbability, little skin irritation, and high safety.

The composition of the external preparation according to the third aspect is as described above, and all the effects of the external preparation according to the first or second aspect are more effectively exerted.

The constitution of the method for enhancing the transdermal or transmucosal absorbability of a drug according to claim 4 is as described above. By adding a scrub, the stratum corneum or mucous membrane which impedes the transdermal absorption of the drug is reduced. Since it exfoliates and causes a minute wound, according to this method, it has excellent transdermal or transmucosal absorbability, and therefore, an external preparation having a higher therapeutic effect than a conventional external preparation without scrub is used. Can provide. Furthermore, according to this method, since the exfoliation or minute scratches of the stratum corneum or mucous membrane are very slight, it is possible to provide a highly safe external preparation with little skin irritation.

The constitution of the method for enhancing the transdermal or transmucosal absorbability of the drug according to claim 5 is as described above, and the drug is an antifungal agent, a local anesthetic, an anti-inflammatory analgesic or urea. According to this method, it has antifungal, antipruritic and analgesic effects, anti-inflammatory and / or analgesic effects, or improvement and treatment of skin dryness, has excellent transdermal or transmucosal absorbability, and has skin irritation properties. And a highly safe external preparation can be provided.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/60 AAH A61K 31/60 AAH 45/00 45/00 // A61K 31/135 AAQ 31/135 AAQ (72) Inventor Yoshiko Abe 2-1 Hyakuyama, Shimamoto-cho, Mishima-gun, Osaka Prefecture Sekisui Chemical Co., Ltd.

Claims (5)

[Claims] 1. An external preparation containing a drug and scrub. 2. The external preparation according to claim 1, wherein the drug is an antifungal agent, a local anesthetic, an anti-inflammatory analgesic or urea. 3. The external preparation according to claim 1, wherein the dosage form of the external preparation is an ointment, cream, gel, liniment, emulsion, powder or foam. 4. A method for enhancing the transdermal or transmucosal absorbability of a drug by incorporating scrub into a drug-containing base. 5. The method for enhancing transdermal or transmucosal absorption according to claim 4, wherein the drug is an antifungal agent, a local anesthetic, an anti-inflammatory analgesic or urea.