JP2006257029A - Antifungal agent and skin lotion containing the same - Google Patents

Antifungal agent and skin lotion containing the same Download PDF

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JP2006257029A
JP2006257029A JP2005077289A JP2005077289A JP2006257029A JP 2006257029 A JP2006257029 A JP 2006257029A JP 2005077289 A JP2005077289 A JP 2005077289A JP 2005077289 A JP2005077289 A JP 2005077289A JP 2006257029 A JP2006257029 A JP 2006257029A
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heteropolyacid
antifungal agent
antifungal
skin
acid
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JP2005077289A
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Japanese (ja)
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Keiko Miyashita
景子 宮下
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Paratex Japan:Kk
株式会社パラテックスジャパン
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Abstract

An object of the present invention is to propose a novel antifungal agent which has excellent antifungal properties and can be used as an active ingredient for treating trichomycosis.
As an antifungal agent containing a heteropolyacid and / or a salt thereof, this antifungal agent is contained in an external preparation for skin as an antifungal component, and as an external skin pharmaceutical composition for trichomycosis, It is contained as an active ingredient of the therapeutic agent for ringworm. As the heteropolyacid and / or a salt thereof, a Keggin type or a Dawson type is mainly used, and a defect type or a substitution type is used.

Description

  The present invention relates to an antifungal agent, and more particularly, to an antifungal agent for treating athlete's foot, which is one of skin diseases.

  Athlete's foot is a skin disease caused by the infestation of athlete's foot in the stratum corneum of the skin, where it proliferates there. In addition to hand and leg ringworm between the toes and fingers, body ringworm and crotch Ringworm, head tinea and the like are included. Commonly referred to as athlete's foot refers to yeasts that are unicellular fungi and fungi that are multicellular fungi, the former representative is Candida and the latter representative is ringworm. It is well known that these athlete's foot bacteria still plague many people with symptoms such as infiltration, redness and itching.

  Those widely used in clinical settings as antifungal agents are broadly classified into antifungal agents such as polyene macrolides, nucleic acid analogs, and azoles, and many drugs relating to these have been proposed. Furthermore, in recent years, in place of azole fungicides, for example, a combination of allylamine antifungal agent terbinafine in addition to microbial fungi (see Patent Document 1) and morpholine antifungal agent amorolfine. Several new antifungal agents have been proposed, such as those (see Patent Document 2).

  However, for example, even the azole antifungal agent described above is considered to have antibacterial activity over all fungi, but it has a low antibacterial activity against trichomycetes and is an antibacterial action. Treatment takes a long time, and even if it seems to have been completely cured, recurrence may be repeated, and a satisfactory effect has not been obtained. That is, as described above, despite the fact that various antifungal agents have been developed, no definitive drugs have been obtained, and new antifungal agents including new skeletons have not been obtained. Development is desired.

On the other hand, heteropolyacids, which are a kind of metal oxide molecule, have been conventionally known mainly as organic synthesis catalysts. Yes. And as a formulation using this heteropoly acid, for example, Patent Document 3 and Patent Document 4 include a mold remover composition or a washing machine comprising a heteropoly acid mixed with a peroxy compound and an alkaline substance. A cleaning composition has been proposed.
JP 2003-306437 A JP 2004-203895 A Japanese Patent Laid-Open No. 11-21207 Japanese Patent Laid-Open No. 11-71597

  However, the mold remover composition and the washing machine detergent composition disclosed in Patent Document 3 and Patent Document 4 each contain a peroxyacid and an alkaline substance in addition to the heteropolyacid, The heteropolyacid in such a composition acts on a peroxyacid in an alkaline environment and does not exhibit antibacterial properties by the heteropolyacid alone. To date, the antifungal properties of heteropolyacids and their use as antifungal agents for treating ringworm mycosis are not known at all.

  Therefore, the problem to be solved by the present invention relates to an antifungal agent and an external preparation for skin containing the same, which solves the above-mentioned conventional problems, and is a novel drug having excellent antifungal properties. It is an object of the present invention to propose an antifungal agent that can be used to treat ringworm mycosis.

  As a result of diligent studies focusing on colorless heteropolyacids that are stable in a wide pH range and easy to molecularly design, the inventors have conducted extensive studies on polyacids. The present inventors have found that it can exhibit antifungal properties alone and can be applied as an antifungal agent for athlete's foot treatment, and has completed the present invention. Since this heteropolyacid can molecularly design a stable complex in a wide range from alkali to acidic range, development of various antifungal agents can be expected.

  According to the present invention, first, an antifungal agent containing a heteropolyacid and / or a salt thereof is provided. Heteropoly acids have an infinite number of possible structures depending on the type of metal, how polyhedrons are connected, the type of heteroatoms, etc., so various structures can be realized by selecting various elements and ligands and designing their molecules. And the intended antifungal properties can be exhibited.

  Second, the heteropolyacid salt is one or two selected from the group consisting of alkali metal ions, alkaline earth metal ions, ammonium ions, and alkylammonium ions, with some or all of the hydrogen ions of the heteropolyacid. An antifungal agent obtained by substituting with ions of more than one species is provided.

Third, the heteropolyacid is a Keggin structure represented by the general formula [XM 12 O 40 ] n- (wherein X is a heteroatom, M is a polyatom, and n is a valence), or The heteropolyacid has a Dawson structure represented by the general formula [X 2 M 18 O 62 ] n- (wherein X is a heteroatom, M is a polyatom, and n is a valence). An antifungal agent is provided.

  Fourthly, an antifungal agent characterized in that at least one or more of the polyatoms of the heteropolyacid are missing or substituted with another atom is provided. A heteropolyacid having a structure in which a polyatom is missing or a substituted structure is expected to exhibit a new antifungal property due to a different skeleton structure compared to a heteropolyacid in which a polyatom is not missing.

  Fifth, an external preparation for skin containing the antifungal agent of the present invention as an antifungal component is provided, and further an external preparation for skin characterized by being a therapeutic agent for trichomycosis.

  According to the present invention, since the heteropolyacid and / or salt thereof exhibits antifungal properties, an antifungal agent that exhibits the desired antifungal properties by using various molecular designs of the heteropolyacid is used. become able to. Moreover, it is useful especially as a therapeutic agent for ringworm mycosis by using the skin external preparation containing this antifungal agent.

First, the heteropolyacid that is the antifungal agent of the present invention will be described below.
Heteropoly acids are included in a broad sense of polyacids, and are based on tetrahedral or octahedral units in which oxygen atoms are coordinated 4 or 6 to metal atoms (polyatoms), and other metals and elements (heteroatoms). At the center, this unit is a metal oxide molecule constructed by sharing vertices and edges.

The atoms constituting the heteropolyacid (including both polyatoms and heteroatoms) broadly include transition metal elements and some typical elements, and the polyatoms include Ti, V, Cr, Mo, W, V, among others. 4A to 7A transition metal elements such as Nb, Ta and the like are used. When the heteropolyacid is composed of an octahedral unit in which 6 oxygen atoms are coordinated to one poly atom, the poly atom is located at the center of the octahedral unit, and the oxygen atom is at the apex of the octahedron. Be positioned. The general formula of the octahedral unit is represented by MO 6 (M is a poly atom).

  As a hetero atom, a transition metal element of group 4A to 7A is used as well as a poly atom, and further, typical metal elements such as P, Si, B, Ge, S, Al, As, Ga, Se, Te, etc. -Typical nonmetallic elements can be used. This heteroatom is located in the center of the above-described octahedral unit composed of a polyatom and an oxygen atom in the heteropolyacid. In particular, those using Si, P, and B as heteroatoms are preferable in terms of ease of molecular design.

The heteropolyacid has, as a basic skeleton, a Keggin structure represented by a general formula [XM 12 O 40 ] n- (where X is a heteroatom, M is a polyatom, and n is a valence). Dawson structure represented by the formula [X 2 M 18 O 62 ] n- (wherein X is a heteroatom, M is a polyatom, and n is a valence), weekly structure, and Anderson type A structure, a silverstone structure, a strandberg structure, a Lindvist structure, or the like can be used. Preferably, it constitutes a Keggin type structure and a Dawson type structure, but is not limited thereto.

Specifically, the Keggin structure is a structure in which four sets of M 3 O 13 units are condensed around one heteroatom. The Keggin-type heteropolyacid can have a structure in which M 3 O 13 units are rotated by 60 °, and any one of isomers from α to ε is used depending on the rotation state of four M 3 O 13 units. be able to. The valence n depends on the heteroatom. For example, if the heteroatom is P, n = 3, if Si, n = 4, and if B, n = 5.

As the heteropolyacid, a defect type structure in which several octahedral units (MO 6 ) are removed from the Keggin type structure described above can be used. The defect type structure includes a primary defect type (general formula [XM 11 O 39 ] n− ) in which one octahedral unit (that is, one poly atom) is lost, or three octahedral units (that is, three). A tertiary defect type (general formula [XM 9 O 34 ] n− ) in which a poly atom of the compound is deficient. The Dawson structure described above is a condensate of two polyacids lacking the M3O13 unit from the Keggin structure. The deficient Dawson structure is represented by [X 2 M 17 O 61 ] n- .

  In addition, a heteropolyacid having a structure in which another atom is incorporated into a deficient part of the deficient structure to form a basic skeleton, that is, a structure in which the polyatom of the heteropolyacid is substituted with another atom may be used. Good. The substituted atom occupies approximately the same position as the original polyatom and is bonded in a way that shares the oxygen atom with the polyatom unit. Examples of other atoms to be substituted include transition metal elements such as Ti, Rh, and Mn.

In the heteropolyacid used as the antifungal agent of the present invention, at least one kind or two or more kinds of polyatoms and heteroatoms are variously combined, and the skeleton structure is not particularly limited. That is, the antifungal agent of the present invention can appropriately combine the types of heteroatoms, the rotational state of M 3 O 13 units, the number of missing MO 6 units and their positions, and the type and number of mixed polyatoms. A vast number of heteropolyacids can be used. Since such heteropolyacids form one molecule unlike ordinary metal oxides, they are excellent in that the structure can be accurately measured by X-ray structural analysis or the like and the molecular design is easy.

  The heteropolyacid is composed of heteropolyacid ions, hydrogen ions, other water molecules or solvent molecules in the lattice, or a part or all of the hydrogen ions are alkali metal ions such as Na and K, It is configured as a salt substituted with one or more ions selected from the group consisting of alkaline earth metal ions such as Ca and Sr, ammonium ions, and alkylammonium ions such as tetraalkylammonium ions. In particular, a salt in which all the hydrogen ions of the heteropolyacid are substituted is preferably used.

  Examples of the heteropolyacid used as the antifungal agent of the present invention include 12-tungstosilicic acid, 11-tungstosilicic acid, 9-tungstosilicic acid, 12-tungstoboric acid, 12-tungstoboric acid, 11-tungstovanadate, 11-tungsten Strinic acid, 9-tungstophosphoric acid, 18-tungstophosphoric acid, 17-tungstotitanium phosphoric acid, 12-tungstosulfuric acid, 12-molybdosulfuric acid, 18-tungstosulfuric acid, 12-molybdosilicic acid, 11-molybdosilicic acid, 9- Examples thereof include molybdosilicic acid, 18-molybdophosphoric acid, and potassium, sodium and tetrabutylammonium salts thereof. Of these, 12-tungstosilicic acid, 11-tungstosilicic acid, 9-tungstosilicic acid, 18-tungstophosphoric acid, and potassium and sodium salts thereof are preferable.

  The heteropolyacids shown above can be produced by conventional or known techniques, and the method is not limited. In general, it can be obtained by heating an acidic salt solution (about pH 1 to about pH 2) containing an oxide salt containing the target poly atom and a simple oxygen acid of hetero atom or a salt thereof. As an example, when 12-tungsto potassium silicate is produced, sodium tungstate is dissolved in hot water, and hydrochloric acid, a sodium metasilicate aqueous solution, and hydrochloric acid are sequentially added. After heating, further add sodium tungstate and hydrochloric acid and cool. Finally, an alkali is added to adjust the pH to about 2, and the target product can be obtained by recrystallization. The structure of the produced heteropolyacid can be confirmed by X-ray diffraction, UV spectrum, IR spectrum, etc. in addition to chemical analysis.

Next, the skin external preparation of the present invention will be described below.
The antifungal agent of the present invention can be used by being added to an external preparation for skin as an antifungal component (active ingredient) for the treatment of dermatomycosis. Especially as this skin external preparation, it is useful to make it a medicine for treating ringworm bacteriomyopathy, and the treatment and alleviation of such symptoms can be expected due to excellent antifungal properties.

  The dosage form of the external preparation for skin of the present invention is not particularly limited, and examples thereof include liquids, aerosols, gels, creams, powders, ointments, poultices, sols, aqueous solutions, alcohols, and glycerin / glycols. Oil agents, suspension lotions, emulsion lotions, varnishes, sprays, and the like. In these preparations, the content of the antifungal agent of this example is at least 0.001% by weight or more, preferably 0.05 to 10% by weight, more preferably 0.1 to 5.0% by weight. Is done.

  The external preparation for skin of the present invention can contain an optional component that is usually used as an external preparation for skin, in addition to the antifungal agent described above, which is an active ingredient. Such optional components include, for example, other antifungal agents, antihistamines, anti-inflammatory agents, antipruritic agents, keratin macerators, astringent / skin protective agents, local anesthetics, moisturizing aids, pH adjusters, bactericides, etc. Of these, one or two or more of them can be used in combination.

  The antifungal agent other than the heteropolyacid is not particularly limited as long as it can be used for external use. And organic acid salts, inorganic acid salts or metal salts thereof. The antifungal agent containing the heteropolyacid of the present Example and these antifungal agents can be mixed to prepare a skin external preparation having excellent antifungal properties.

  Examples of the antihistamine include diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorpheniramine maleate and the like.

  Examples of the anti-inflammatory agent include glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, allantoin, hinokitiol, paeoniflorin, cordyceps, plant extracts having anti-inflammatory activity, or mixtures thereof.

  As an antipruritic agent, crotamiton etc. are mentioned, for example.

  Examples of keratolytic agents include salicylic acid and urea.

  Examples of the astringent / skin protective agent include guaiaazulene, popidone iodine, heparin-like substances and the like.

  Examples of local anesthetics include aminobenzoic acid ester, oxybuprocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate, bupivacaine hydrochloride, procaine hydrochloride, mebivacaine hydrochloride, ropivacaine hydrochloride hydrate, oxesazein , Ethyl piperidinoacetylaminobenzoate, lidocaine and the like.

  Examples of moisturizing aids include urea, heparin analogs, pyrrolidone carboxylic acid, collagen, γ-oryzanol, γ-linolenic acid, linoleic acid, vitamin E, vitamin D, vitamin A, vitamin A, squalene, squalane, glycerin, polyethylene glycol, Examples include cholesterol, triglyceride, ceramide and the like.

  Examples of the pH adjuster include citric acid, sodium citrate, potassium hydroxide, sodium hydroxide, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, phosphorus Examples thereof include sodium dihydrogen acid, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and mixtures thereof.

  Examples of the disinfectant include benzalkonium chloride, chlorhexidine, decalinium chloride, resorcin, phenyl, chlorobutanol, iodo, boric acid, triacetylammonium pentachlorophenate, or salts thereof.

  The external preparation for skin of the present invention can be formulated into various dosage forms as described above by blending various bases and carriers by a conventional method. Examples of the liquid carrier include water, lower alcohol, ethylene glycol, glycerin, and other various solvents.

  As an aerosol carrier, for example, the above-mentioned liquid carrier and Freon gas, liquefied propane gas, or the like can be blended and used.

  As the gel base, for example, a combination of the above-mentioned liquid carrier and a gel generating agent can be used. As the gel generating agent, for example, a carboxyvinyl polymer and a base such as an organic amine or an aqueous sodium hydroxide solution can be used. Or cellulose ethers such as hydroxypropylcellulose, sodium alginate, propylene glycol alginate and the like.

  As the cream base, for example, an emulsifier such as a nonionic surfactant and a gel base, an ointment base and / or an aqueous base can be used in combination.

  Examples of powder bases include, for example, calcium carbonate, calcium phosphate, lactose, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium stearate, aluminum stearate, talc, silicon, and other inert diluents and granulating agents. , Dispersants, binders and the like can be used alone or in combination.

  Ointment bases include peanut oil, olive oil, sesame oil, coconut oil, paraffin oil, lanolin, petrolatum, zinc oxide, beeswax, macrogol, stearyl alcohol, cetanol, propylene glycol, fatty acids, fatty acid esters, etc. alone or in combination Can be used.

  As the base of the poultice, for example, a plasticizer, a dispersant, a solvent and the like suitable for silicone-based, acrylic-based, rubber-based and the like adhesives can be used alone or in combination.

  Furthermore, the external preparation for skin of the present invention can be formulated by combining conventional solubilizers, stabilizers, preservatives and the like in addition to the above-mentioned base. These various preparations can be prepared by conventional methods, and can be produced, for example, in the same manner as described in the 14th revised Japanese Pharmacopoeia.

  Examples of the present invention will be described below. In addition, this invention is not restrict | limited by the Example shown below.

  The antifungal agent of this example has a heteropolyacid salt having a Keggin type structure and a Dawson type structure as a heteropolyacid, a defective structure lacking a poly atom, and a substituted structure in which the poly atom is substituted with another atom. Heteropolyacid salts and the like were synthesized and manufactured (see Table 1).

<Antifungal evaluation (1)>
Various heteropolyacids were selected as antifungal agents, which were dissolved in an aqueous solvent to prepare a predetermined concentration (40 mg / 10 ml) to obtain test bodies (Examples 1 to 13). Each test specimen was added to a Sabouraud agar medium (manufactured by Nippon Pharmaceutical Co., Ltd.) in an amount of about 1/9 of the medium, mixed well, then dispensed into a petri dish and solidified to obtain a measurement plate. Moreover, a Sabouraud agar medium (manufactured by Nippon Pharmaceutical Co., Ltd.) without heteropoly acid was prepared (Comparative Example 1). 5 μl of a bacterial solution of trichophyton (Trichophyton mentagrophytes) was dropped on these measurement plates and cultured at 28 ° C. for 7 days.

  After culturing, the presence / absence, size, and shape of ringworm fungus colonies are visually observed, and when the degree of antifungal activity is compared with Comparative Example 1, the growth of ringworm fungi is hardly recognized. The growth / proliferation of ringworm fungi was compared in terms of area ratio, and was evaluated in three stages according to increase / decrease in “+”. The results are shown in Table 1.

<Antifungal evaluation (2)>
Using a heteropolyacid (18-tungstophosphoric acid ammonium salt), a liquid preparation was prepared by blending 5 wt% heteropolyacid, 75 wt% water, and 20 wt% ethanol. This solution is filled in a spray container and sprayed directly onto the affected area of subjects (2 persons) suffering from intercostal foot tinea bacteriomyopathy to prevent symptoms from mitigating symptoms (skin condition, itching, etc.) Sex was evaluated.

  As a result, prior to the use of this example, white maceration was observed in the intercostal space, and the skin was cracked or peeled, scales were seen around the affected area, and there was strong itching. On the second day after using the liquid preparation of this example, white maceration disappeared in one subject and itching / pain resolved, and in any subject, about 2 weeks, Improved to normal skin condition.

<Antifungal evaluation (3)>
A heteropolyacid (12-tungstosilicate potassium salt) was used to prepare an ointment by blending 3 parts by weight of heteropolyacid with 100 parts by weight of Japanese Pharmacopoeia Macrogol Ointment (manufactured by Maruishi Pharmaceutical Co., Ltd.). Specifically, the heteropolyacid was added to the macrogol ointment dissolved at 70 ° C., mixed uniformly, and then cooled to obtain an ointment. An ointment was applied to the affected area of 2 subjects with intercostal foot tinea bacteriomycosis, and antifungal properties were evaluated from the symptom-relieving effect (skin condition, itching, etc.).

  As a result, itching and pain were improved about 1 week after the start of use, and the skin began to regenerate in about 3 weeks in all subjects.

Claims (8)

  1.   An antifungal agent containing a heteropolyacid and / or a salt thereof.
  2.   The heteropolyacid salt is one or more ions selected from the group consisting of alkali metal ions, alkaline earth metal ions, ammonium ions, and alkylammonium ions, with some or all of the hydrogen ions of the heteropolyacid. The antifungal agent according to claim 1, wherein the antifungal agent is substituted with
  3. The heteropolyacid has a Keggin structure represented by the general formula [XM 12 O 40 ] n- (wherein X is a heteroatom, M is a polyatom, and n is a valence). The antifungal agent according to claim 1 or 2.
  4. The heteropolyacid has a Dawson structure represented by the general formula [X 2 M 18 O 62 ] n- (wherein X is a heteroatom, M is a polyatom, and n is a valence). The antifungal agent according to claim 1 or 2, wherein
  5.   The antifungal agent according to any one of claims 1 to 4, wherein at least one poly atom of the heteropolyacid is missing.
  6.   The antifungal agent according to any one of claims 1 to 5, wherein a polyatom of the heteropolyacid is substituted with another atom.
  7.   A skin external preparation comprising the antifungal agent according to any one of claims 1 to 6 as an antifungal component.
  8.   The external preparation for skin according to claim 7, wherein the external preparation for skin is a therapeutic agent for trichomycosis.
JP2005077289A 2005-03-17 2005-03-17 Antifungal agent and skin lotion containing the same Pending JP2006257029A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016511241A (en) * 2013-02-06 2016-04-14 ペーオーエム パテントフェルヴァルトゥングス ゲゼルシャフト ビュルゲルリッフェン レヒツPom Patentverwaltungs Gbr Heteropolyoxometalates

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016511241A (en) * 2013-02-06 2016-04-14 ペーオーエム パテントフェルヴァルトゥングス ゲゼルシャフト ビュルゲルリッフェン レヒツPom Patentverwaltungs Gbr Heteropolyoxometalates
US10531665B2 (en) 2013-02-06 2020-01-14 Pom Patentverwaltungs Gbr Heteropolyoxometalates

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