JP3749279B2 - Antifungal agent for nails - Google Patents

Description

[0001]
[Industrial application fields]
The present invention relates to an antifungal agent for nails relating to the treatment of fungal infection (hereinafter referred to as onychomycosis) in the nail and the skin around the nail. More specifically, the present invention relates to an antifungal agent for treating onychomycosis for treatment by absorbing an antifungal agent through percutaneous absorption and / or nail absorption.
[0002]
[Prior art and problems to be solved by the invention]
Onychomycosis is the main symptom of nail plate opacity, and there are few cases of prominent keratinous growth of the nail plate due to infection by ringworm fungus, Candida and other fungi. . The treatment of mycosis in the dermatological field needs to be carried out patiently for a long time, and in particular, onychomycosis is currently difficult to treat.
[0003]
As treatment methods for onychomycosis, external treatment, internal use therapy, nail extraction method, X-ray irradiation method and the like have been implemented. External therapy is a method in which liquids, creams, and the like are externally applied as antifungal agents, but even if applied for a long period of time, the drug hardly permeates the nails, and thus little effect is seen. For internal therapy, griseofulvin, etc., is known, but it is said that it has a long period of internal use and has side effects such as drug eruption, hypersensitivity symptoms, renal disorder, liver disorder, etc. Yes. The nail removal method is a method of performing nail detachment operation to remove fungi existing in the nail together with the nail and applying a drug to the nail bed. However, not only is it accompanied by pain, but the nail of onychomycosis is fragile, so that there is a tendency for fragments of the affected nail to remain, and the healing is not complete. The X-ray irradiation method may be effective for eliminating chronic inflammation, but it is not effective for ringworm. As described above, it is difficult to treat onychomycosis, and the current treatment method itself has not been established.
[0004]
As an example of external therapy, there is an example of a liquid agent comprising an imidazole antifungal agent and a long chain fatty acid described in JP-A-58-32818. However, it is not easy to penetrate the fungal palliative part inside the nail sufficiently and continuously with the drug as the active ingredient. Japanese Patent Laid-Open No. 63-258814 discloses a method for increasing the solubility of a drug in an aqueous solution by using urea as a solubilizing agent, and the bioavailability is disclosed in Japanese Patent Laid-Open No. 5-85929. There is a description of a method of using a hydrophilic penetrant so that the penetrability into water becomes advantageous. As a method of using a film-forming agent, JP-A-6-216511 discloses a preparation composition comprising a hydrophobic film-forming agent and a solvent in order to obtain a preparation excellent in adhesion to nails of the nail, permeability and storage. Japanese Patent Application Laid-Open No. 6-9342 discloses a method of using a film-forming nail enamel containing urea.
[0005]
However, in any method, since the nail works as a strong barrier, the antifungal agent does not reach the fungal distribution site and a therapeutic effect cannot be obtained. That is, the nail plate is composed of three layers, and the physicochemical properties of these three layers are different when the nail bed is divided into the C layer, the B layer, and the A layer from the nail bed side. Layer A and layer B are layers with low drug diffusivity, and in addition, layer B is a layer with low dispersibility to fat-soluble drugs, so the hydrophilic-hydrophobic balance of the pharmaceutical composition is taken into account. Even so, it was not easy for the antifungal agent to penetrate the nails.
[0006]
[Means for Solving the Problems]
As a result of intensive studies on an effective therapeutic agent for onychomycosis, the present inventors have found that an antifungal agent for nail containing a sulfur atom-containing compound having a reducing ability increases the local concentration of an antifungal agent on the nail plate and nail bed. Thus, the present inventors have found that the treatment for onychomycosis can be effectively performed and completed the present invention.
[0007]
That is, the nail which becomes a barrier in the external therapy consists of keratin, and keratin is a protein containing many cystine residues, and this cystine residue forms a bridge composed of SS bonds between peptide chains. It has been found that by blending a sulfur atom-containing compound having a reducing ability, it can be cleaved to promote permeation of the antifungal agent.
[0008]
The sulfur atom-containing compound having the reducing ability is not particularly limited, but sodium sulfide, sodium hydrosulfide, thioacetic acid, dithioacetic acid, dithiophosphoric acid, dithiocarbamic acid derivative, alkylsulfinic acid derivative, arylsulfinic acid derivative and cysteine derivative (N -Acetylcysteine, etc.), 4-t-butylbenzyl mercaptan, thiosalicylic acid, cysteamine hydrochloride, thioglycolic acid and its derivatives (ammonium thioglycolate, 2-ethylhexyl thioglycolate, butyl thioglycolate, methoxybutyl thioglycolate) , Trimethylolpropane tris (thioglycolate, etc.), 1-thioglycerol, 2-mercaptoethanol, β-mercaptopropionic acid and its derivatives (2-ethylhexyl β-mercaptopropionic acid, β-mercaptopropionate 3-methoxybutyl, trimethylolpropane tris (β-thiopropionate, etc.), benzyl mercaptan, 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof (sodium salt, zinc salt, etc.), Mercaptans such as 2-mercaptobenzimidazole and its salts (such as zinc salt), 2-mercaptomethylbenzimidazole, 6-mercaptopurine, 6-methylmercaptopurine, 5-mercaptouracil, thiomalic acid and its derivatives (such as sodium salt) And the like.
[0009]
Preferred are mercaptans, and more preferred are the following mercaptans, 4-t-butylbenzyl mercaptan, thiosalicylic acid, cysteamine hydrochloride, thioglycolic acid and its derivatives (ammonium thioglycolate, 2-ethylhexyl thioglycolate, Butyl thioglycolate, methoxybutyl thioglycolate, trimethylolpropane tris (thioglycolate, etc.), 1-thioglycerol, β-mercaptopropionic acid and its derivatives (β-mercaptopropionic acid 2-ethylhexyl, β-mercaptopropion) Acid 3-methoxybutyl, trimethylolpropane tris (β-thiopropionate), 2-mercaptoimidazoline, 2-mercaptobenzothiazole and salts thereof (sodium salt, zinc salt, etc.), 2- Le mercaptobenzimidazole and its salts (zinc salt), 2-mercaptomethyl benzimidazole, thiomalic acid and its derivatives (sodium salt, etc.).
[0010]
More preferably, mercaptans having less irritation, such as 4-t-butylbenzyl mercaptan, thioglycolic acid and derivatives thereof (ammonium thioglycolate, 2-ethylhexyl thioglycolate, butyl thioglycolate, methoxybutyl thioglycolate, Trimethylolpropane tris (thioglycolate, etc.), 1-thioglycerol, 2-mercaptobenzimidazole and salts thereof (zinc salt, etc.), thiomalic acid and derivatives thereof (sodium salt, etc.).
[0011]
There is no restriction | limiting about the compounding quantity of the sulfur atom containing compound which has a reducing ability, It determines according to a formulation dosage form.
[0012]
The antifungal agent of the present invention is not particularly limited, but tolnaftate, ciclopirox olamine, tolsiclate, pyrrolnitrin, haloprozin, undecylenic acid, salicylic acid, thianthol, pyrrolnitrin, exeramide, amorolfine hydrochloride, terbinafine hydrochloride, hydrochloric acid Examples include imidazole antifungal agents such as butenafine, clotrimazole, miconazole nitrate, econazole nitrate, isoconazole nitrate, sulconazole nitrate, oxyconazole nitrate, bifonazole, croconazole hydrochloride, thioconazole, neticoconazole hydrochloride, ketoconazole and the like.
[0013]
There is no restriction | limiting about the compounding quantity of an antifungal agent, and it determines according to a formulation dosage form and the minimum effective inhibitory concentration of an antifungal agent.
[0014]
The dosage form of the composition of the present invention is not limited as long as it is an external preparation, and any suspension, emulsion, liquid, cream, ointment, plaster, patch, patch, tape, etc. can be applied.
In addition, various kinds of additives such as stabilizers, surfactants, plasticizers, solubilizers, bases, suspending agents, antioxidants, wetting agents, softeners, emollients, absorptions as pharmaceutical ingredients Accelerators, pressure-sensitive adhesives, thickeners, pH adjusters, preservatives, solvents, solubilizers and the like can be added as necessary.
[0015]
Test method [0016]
1. Drug nail permeation test 2-Pinch nail in chamber diffusion cell and examine permeability of antifungal agent through nail from donor side to receiver side (nail effective area 0.049 cm ² , donor and receiver volume 2 ml) . The receiver side of the diffusion cell is filled with PEG400 aqueous solution or physiological saline, and the nail antifungal agent-containing composition is applied to the donor side and fixed. The time is zero, 200 μl is sampled from the receiver side every fixed time, and the amount of the antifungal agent in the receiver side solution is quantified by high performance liquid chromatography. After sampling, 200 μl of fresh drug-free saline is added to the receiver side of the cell.
[0017]
2. Drug release test The release of an antifungal agent from a patch containing an antifungal agent into physiological saline is examined using a Franz-type cell. The Franz-type cell is maintained at a temperature of 37 ° C., and the light-shielding cell is colored brown. The cell volume on the receiver side is 20 ml, and the effective area in contact with physiological saline is 3.8 cm ² .
The receiver side of the cell is filled with physiological saline, and the antifungal agent for nails is fixed on the donor side so as to be in contact with the physiological saline. This time is set to time zero. 500 μl is sampled from the receiver side at regular intervals, and the amount of the antifungal agent in physiological saline is quantified by high performance liquid chromatography. After sampling, 500 μl of fresh saline without drug is added to the receiver side of the cell.
[0018]
3. Drug penetration into nail An antifungal agent for nail is applied or applied to a nail of a healthy person in a certain area after weighing, and left in a thermostat at 35 ° C. and 50% RH for 24 hours. Remove the antifungal agent for nail from the nail, measure the weight, and then wipe the nail with paper soaked with methanol. Shave up to about 0.5 mm below the application surface, put in a beaker, add 14 ml of 50% methanol water, and leave it in a 35 ° C. incubator for 24 hours.
After filtering this, the filtrate is measured by liquid chromatography, the amount of antifungal agent that has penetrated into the nail is determined, and what percentage of the amount of antifungal agent in the initially applied composition has penetrated into the nail .
[0019]
4. Physical property change test method of nail A normal person's nail is immersed in an antifungal agent for nail at 37 ° C., stress measurement with a rheometer is measured over time, and the measurement date for stress before immersion is measured. It is expressed as a stress ratio (SR). The stress measurement uses as an index the force when the nail piece is pushed into the guide by 1 mm.
[0020]
【Example】
Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.
[0021]
Example 1
2 g of econazole nitrate was dissolved in 95 g of a 10% ethanol-isopropyl myristate solution, and 3 g of mercaptoethanol was added to obtain a liquid antifungal agent for nails. The permeation coefficient of econazole nitrate determined from Test Method 1 was 2 × 10 ⁻⁶ (cm / s), indicating a high permeability not seen in the past.
[0022]
Comparative Example 1
An antifungal solution was obtained in exactly the same manner as in Example 1, except that mercaptoethanol was replaced with isopropyl myristate. The permeation coefficient of econazole nitrate determined from Test Method 1 was 3 × 10 ⁻⁷ (cm / s).
[0023]
Example 2
3 g of tolnaftate was suspended and dissolved in 80 g of 40% ethanol water, 14 g of propylene glycol, and 3 g of 4-t-butylbenzyl mercaptan to obtain a liquid agent for an antifungal agent for nails. SR2 on the second day in Test Method 4 was 0.08, a significant reduction in nail hardness was observed, and the permeability coefficient of tolnaftate determined from Test Method 1 was 5 × 10 ⁻⁷ (cm / s). It showed high permeability not seen in the past.
[0024]
Comparative Example 2
In Example 2, an antifungal solution was obtained in exactly the same manner, except that 4-t-butylbenzyl mercaptan was replaced with water. SR2 on the second day in Test Method 4 was 0.3, and the permeability coefficient of tolnaftate obtained from Test Method 1 was 2 × 10 ⁻⁸ (cm / s).
[0025]
Example 3
In a four-necked flask equipped with a stirrer and a reflux condenser thermometer under N ₂ gas atmosphere, 96 parts of isononyl acrylate ester, 4 parts of acrylic acid, 200 parts of ethyl acetate, 0.2 part of azoisobutyronitrile Charged, polymerized at an internal temperature of 65 ° C. for 6 hours, then heated to 80 ° C. and aged for 3 hours to obtain a polymer substance A-containing solution having adhesiveness at room temperature.
5 parts by weight of propylene glycol, 2 parts by weight of thioglycolic acid, and 3 parts by weight of econazole nitrate were added to 100 parts by weight of the solid content of the polymer substance A, mixed thoroughly and dissolved, and then subjected to corona discharge treatment. It was applied and dried on a 25 μm-thick PET film so that the thickness after drying was 25 μm to obtain a tape preparation of an antifungal agent for nails. According to Test Methods 2 and 3, the drug release properties of this tape preparation and the drug penetration into the nail were determined. The cumulative release amount of econazole nitrate was 20 and 48 μg / cm ² at 4 and 12 hours, respectively, and it was confirmed that the drug was released from the tape preparation at an almost constant rate. Further, the amount of penetration into the nail was 5% of the total amount of econazole nitrate, and it was confirmed that it penetrated into dense healthy nails.
[0026]
Comparative Example 3
A tape preparation of an antifungal agent was obtained in exactly the same manner except that the polymer substance A of Example 3 was used and only the thioglycolic acid of Example 3 was removed. The cumulative release of econazole nitrate showed almost the same value, but no penetration of econazole nitrate into the nail was observed.
[0027]
Example 1 and Comparative Example 1, Example 2 and Comparative Example 2, Example 3 and Comparative Example 3 show that the antifungal agent for nail of the present invention is effective for treating onychomycosis.
[0028]
【The invention's effect】
It is possible to increase the local concentration of antifungal agents on the nail plate and nail bed and to effectively treat onychomycosis when a nail antifungal agent is applied by adding a sulfur atom-containing compound having reducing ability. I found it.

Claims (2)

An antifungal composition for nails, comprising a sulfur atom-containing compound having a reducing ability and an antifungal agent . However, an amino acid having a sulfur atom is excluded from a sulfur atom-containing compound having a reducing ability. The antifungal composition for nails according to claim 1, wherein the sulfur atom-containing compound having reducing ability is a mercaptan.