External preparation for skin containing aniline derivative

Abstract

The purpose of the present invention is to provide an external preparation for the skin, which contains an aniline derivative as a main drug and has high main drug stability and transdermal absorbability. The present invention provides an external preparation for the skin, which contains, as an active ingredient, a compound selected from the group consisting of an aniline derivative represented by formula (I) [in the formula, W represents S or O], a pharmacologically acceptable salt thereof, or a hydrate of the aniline derivative or the pharmacologically acceptable salt, and which further contains a C16-20 higher monohydric alcohol or synthetic squalane. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an external preparation for skin containing an aniline derivative or a salt thereof. In addition, the present invention relates to a transdermal delivery system for delivering an aniline derivative to a local part of the skin. Background Art

[0002] Human papillomavirus (HPV) belongs to the family Papillomaviridae and is a DNA virus with circular double-stranded DNA as genome. HPV is spread by contact infection. HPV infects epithelium and mucous membranes, and expresses HPV protein in infected host cells to replicate the virus. In particular, it is known that E6 protein and E7 protein, which are non-structural proteins, cause abnormal cell proliferation by decomposing tumor suppressor genes such as p53 gene and pRB gene of host cells, and become the cause of various diseases such as warts such as common warts, flat warts, and plantar warts, cervical cancer, condyloma acuminatum, and papilloma of the pharynx. HPV is known to have more than 100 types so far, and according to its carcinogenicity, it is classified into low-risk types that are the cause of benign tumors such as warts, condyloma acuminatum, and papilloma, and high-risk types that are the cause of malignant tumors such as cervical cancer.

[0003] The treatment of human papillomavirus (HPV) warts mainly involves surgical treatments such as laser therapy (laser vaporization), cryotherapy using liquid nitrogen, electrocautery, and surgical excision. However, the viral genes of HPV are easily retained in the epidermal basal cells, and relapse frequently, thus becoming a great burden on the patient. In addition, the treatment of condyloma acuminatum similarly produced by HPV uses BESELNA (registered trademark) cream (manufactured by Mochida Pharmaceutical Co., Ltd.) with imiquimod as the active ingredient, but sometimes causes severe inflammatory reactions, and side effects such as erosion, ulcer, epidermolysis, and fever occur. Therefore, attention should be paid to avoid overdose.

[0004] As a compound that exhibits antiviral effects on papillomavirus, N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide is known (Patent Document 1: WO2005 / 063293, Patent Document 2: WO2009 / 020198, Non-Patent Document 1: Yamamoto M et al., J Clin Invest, 2014, 124(8), 3479-3488). It is known that N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide targets the phosphorylase of host cells, inhibits the expression of the E6 gene and E7 gene of human papillomavirus (HPV), and stabilizes the p53 gene, thereby exerting an antiviral effect. Skin topical therapeutic drugs for HPV warts and condyloma acuminatum using such thioamide derivatives are expected.

[0005] As a therapeutic drug for human papillomavirus (HPV) genital warts, a patch for HPV genital warts has been reported, which is characterized in that per unit area (1 cm 2 ) contains 50 to 500 μg of N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide and is repeatedly applied once a day (Patent Document 3: Japanese Patent Publication No. 2021-059500).

[0006] In addition, the above-mentioned compounds have been reported to have antiviral effects on herpes simplex virus, human herpes virus type 8 (Patent Document 2, Non-Patent Document 1, Patent Document 4: Japanese Patent Application Publication No. 2021-046360), and antiviral effects on bovine papillomavirus (Patent Document 5: WO2021 / 246332).

[0007] However, the above-mentioned thioamide derivatives are poorly soluble in water and have poor stability after dissolution. In addition, the skin external preparations are not preferably irritating substances such as organic solvents, so it is difficult to manufacture external preparations containing the above-mentioned thioamide derivatives as active ingredients. Furthermore, even if it can be manufactured in the form of an external preparation, the above-mentioned active ingredient cannot fully penetrate the skin and sometimes cannot be fully absorbed into the epidermis. Therefore, there has been no report on skin external preparations suitable for human papillomavirus (HPV) warts and condyloma acuminatum that contain thioamide derivatives and have high stability of the main drug and percutaneous absorbability.

[0008] Prior art literature

[0009] Patent Literature

[0010] Patent Document 1: WO2005 / 063293

[0011] Patent Document 2: WO2009 / 020198

[0012] Patent Document 3: Japanese Patent Application Publication No. 2021-059500

[0013] Patent Document 4: Japanese Patent Application Publication No. 2021-046360

[0014] Patent document 5: WO2021 / 246332

[0015] Non-patent literature

[0016] Non-patent document 1: Yamamoto M et al., J Clin Invest, 2014, 124(8), 3479-3488 Summary of the invention

[0017] Problem that the invention aims to solve

[0018] An object of the present invention is to provide a skin external preparation containing an aniline derivative as an active ingredient and having high stability of the main drug and high transdermal absorbability.

[0019] Solutions for solving problems

[0020] The present inventors have conducted in-depth research on a skin external preparation using N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide as an aniline derivative, with high stability of the main drug and transdermal absorbability and low irritation. As a result, they found that by using an aniline derivative together with a specific absorption accelerator, a combination of components of a skin external preparation with good transdermal absorbability while maintaining the stability of the main drug can be achieved, thereby completing the present invention. In addition, in a preferred embodiment, the skin external preparation of the present invention is also considered to have low skin irritation.

[0021] The external preparation for skin of the present invention includes the following aspects.

[0022] [1] A skin external preparation comprising as an active ingredient a compound selected from the group consisting of an aniline derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof, and further comprising a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane.

[0023]

[0024] [W] wherein W represents S or O.

[0025] [2] The external preparation for skin according to [1] above, wherein the active ingredient is a compound selected from the group consisting of aniline derivatives represented by the following formula (Ia) or pharmacologically acceptable salts thereof, or hydrates thereof.

[0026]

[0027] [3] The external preparation for skin according to [1] or [2], wherein the higher monohydric alcohol having 16 to 20 carbon atoms is a higher monohydric alcohol having a branched structure.

[0028] [4] The external preparation for skin according to [3] above, wherein the higher monohydric alcohol having a branched structure is 2-octyldodecanol, hexyldecanol or isostearyl alcohol.

[0029] [5] The external skin preparation according to any one of [1] to [4] above, which contains the active ingredient in an amount of about 0.5% to 20% by weight (preferably about 0.5% to 15% by weight, more preferably about 1% to 10% by weight).

[0030] [6] The external skin preparation according to any one of [1] to [5] above, which contains the higher monohydric alcohol having 16 to 20 carbon atoms or the synthetic squalane in an amount of about 1% to about 40% by weight (preferably about 2% to about 30% by weight, more preferably about 5% to about 20% by weight).

[0031] [7] The external preparation for skin according to any one of [1] to [6] above, wherein the weight ratio of the active ingredient to the higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane is 1:80 to 20:1 (preferably 1:40 to 15:2, more preferably 1:20 to 2:1).

[0032] [8] The external skin preparation according to any one of [1] to [7] above, wherein the dosage form is an oily ointment.

[0033] [9] The external preparation for skin according to [8] above, wherein the crystals of the active ingredient of the oily ointment are dispersed in the ointment base.

[0034]

[10] The external preparation for skin according to any one of [1] to [9] above, which is used for treating, ameliorating and / or inhibiting the progression of a DNA viral disease.

[0035]

[11] The external preparation for skin according to the above

[10] , wherein the aforementioned DNA viral disease is a disease selected from the group consisting of warts, condyloma acuminatum, vulvar intraepithelial neoplasia, anal intraepithelial neoplasia and vaginal intraepithelial neoplasia caused by human papillomavirus (HPV), herpes labialis, genital herpes and Kaposi's varicelliform eruption caused by herpes simplex virus, chickenpox and herpes zoster caused by varicella-zoster virus, Kaposi's sarcoma caused by human herpesvirus type 8, bovine papillomavirus caused by bovine papillomavirus (BPV), bovine contagious pustular vulvovaginitis and bovine contagious balanoposthitis caused by bovine herpesvirus type 1, papilloma, inverted papilloma and multicentric intraepithelial squamous cell carcinoma caused by canine papillomavirus, and papilloma, inverted papilloma and multicentric intraepithelial squamous cell carcinoma caused by feline papillomavirus.

[0036]

[12] A transdermal delivery system comprising:

[0037] (a) Oily base (ointment base);

[0038] (b) a compound selected from the group consisting of aniline derivatives represented by the above formula (I) or formula (Ia) or pharmacologically acceptable salts thereof, or hydrates thereof, dispersed (preferably dispersed in the form of crystals) in the matrix; and

[0039] (c) A higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane dispersed in the matrix.

[0040]

[13] The transdermal delivery system according to

[12] above, wherein the higher monohydric alcohol having 16 to 20 carbon atoms is 2-octyldodecanol, hexyldecanol or isostearyl alcohol.

[0041]

[14] The transdermal delivery system according to

[12] or

[13] above, wherein the weight ratio of the compound to the higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane is 1:80 to 20:1 (preferably 1:40 to 15:2, more preferably 1:20 to 2:1).

[0042] Effects of the Invention

[0043] According to the present invention, a skin external preparation having high stability of a main drug and high transdermal absorbability is provided. In a preferred embodiment, the skin external preparation has low irritation. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is a diagram showing an outline of the production process of the external preparation for skin (ointment) of the present invention.

[0045] Figure 2 These are the results of administering (applying) the external preparation for skin (ointment) of the present invention to rats and confirming the tissue transferability to the epidermis.

[0046] Figure 3 These are the results of administering (applying) the external preparation for skin (ointment) of the present invention to rats and confirming the tissue transferability to the epidermis.

[0047] Figure 4 These are the results of administering (applying) the external preparation for skin (ointment) of the present invention to rats and confirming the tissue transferability to the epidermis. DETAILED DESCRIPTION

[0048] Below, take illustrative embodiment as example, describe the preferred method and material that can be used in the implementation of the present invention while describing the present invention, but the present invention is not limited to the following mode of recording.It should be noted that, as long as there is no special description in the text, all technical terms and scientific terms used in this specification have the same meaning as those skilled in the art of the present invention are usually understood.In addition, any material and method that is equal or the same as the record in this specification can be used similarly in the implementation of the present invention.In addition, all publications and patents cited in this specification related to the present invention, for example, as the document of the method, material etc. that can be used in the present invention, are quoted in this specification and constitute a part of this specification.

[0049] In this specification, the description of "A to B" indicating a numerical range refers to a numerical range including A and B as endpoints. In addition, the same applies to "A to B". In addition, in this specification, "about" is used to allow ±10%. It should be noted that the weight % of each component recorded in this specification refers to the ratio of the weight of each component when the weight of the external preparation (i.e., the total amount of the preparation) is set to 100.

[0050] The external preparation for skin of the present invention contains an aniline derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient (main drug ingredient).

[0051]

[0052] [W] wherein W represents S or O.

[0053] The external preparation for skin of the present invention preferably contains an aniline derivative represented by the following formula (Ia) or a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient (main drug ingredient).

[0054]

[0055] In this specification, "pharmacologically acceptable salts thereof" are not particularly limited as long as they form salts with the compounds of the present invention represented by the above-mentioned formula (I) or formula (Ia) and are pharmacologically acceptable salts, and examples thereof include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, etc. In addition, their hydrates refer to compounds or salts thereof that also contain a stoichiometric or non-stoichiometric amount of water bonded by non-covalent intermolecular forces.

[0056] The skin external preparation of the present invention (hereinafter, sometimes referred to as the external preparation) contains a therapeutically effective amount of a compound represented by the above-mentioned formula (I) or formula (Ia) as an aniline derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof (hereinafter, sometimes referred to as the active ingredient, compound or main drug of the present invention, all of which have the same meaning). The therapeutically effective amount refers to an amount sufficient for producing at least one effect of treating, improving, and inhibiting the progression of the disease when the external preparation of the present invention is applied to the affected part of an object with a disease. Alternatively, the therapeutically effective amount refers to an amount that can inhibit the proliferation of DNA viruses in the affected part when the external preparation of the present invention is applied to the affected part of an object with a disease. Without being limited to this, for example, the active ingredient of the present invention is contained in an amount of about 0.5% by weight as a lower limit, preferably about 1.0% by weight, more preferably about 2% by weight, and further preferably about 3% by weight, and about 20% by weight as an upper limit, preferably about 15% by weight, and more preferably about 10% by weight, relative to the total weight of the external preparation. If the amount is less than 0.5% by weight, the effectiveness is insufficient, while if the amount exceeds 20% by weight, the properties of the preparation may be unsuitable as a coating agent.

[0057] The external preparation of the present invention contains, in addition to the active ingredient of the present invention, a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane. The external preparation of the present invention contains a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane, and when the external preparation of the present invention is applied to the skin, the transfer of the active ingredient of the present invention into the epidermis can be promoted. That is, the higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane in the external preparation of the present invention has a role as a percutaneous absorption promoter of the active ingredient of the present invention.

[0058] The higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane contained in the external preparation of the present invention may be only a higher alcohol or synthetic squalane, or a combination of a higher alcohol and synthetic squalane. In addition, the higher alcohol may be only one kind or a combination of two or more kinds.

[0059] The hydrocarbon chain (aliphatic) in the higher monohydric alcohol having 16 to 20 carbon atoms may be a saturated hydrocarbon or an unsaturated hydrocarbon. The higher monohydric alcohol having 16 to 20 carbon atoms preferably has a branched structure. It is not limited thereto, and examples thereof include cetanol, heptadecanol, stearyl alcohol, nonadecanol, arachidyl alcohol (eicosanol), palmityl alcohol, oleyl alcohol, 2-octyldodecanol, hexyldecanol, and isostearyl alcohol, preferably cetanol, stearyl alcohol, oleyl alcohol, 2-octyldodecanol, hexyldecanol, or isostearyl alcohol, and more preferably 2-octyldodecanol, hexyldecanol, or isostearyl alcohol.

[0060] 2-Octyldodecanol is a higher monohydric alcohol having a branched structure, having 20 carbon atoms and a molecular weight of 298.5 and having the following structural formula.

[0061]

[0062] Hexyldecanol is a higher monohydric alcohol having a branched structure, having 16 carbon atoms and a molecular weight of 242.44 and having the following structural formula.

[0063]

[0064] Isostearyl alcohol is a higher monohydric alcohol having a branched structure, having 18 carbon atoms and a molecular weight of 270.49 and having the following structural formula.

[0065]

[0066] Synthetic squalane is a higher fatty acid having the following structural formula and having 30 carbon atoms and a molecular weight of 410.73.

[0067]

[0068] The external preparation of the present invention contains a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane in an amount of about 2% by weight as a lower limit, preferably about 3% by weight, more preferably about 5% by weight, and about 40% by weight, preferably about 30% by weight, more preferably about 20% by weight, relative to the total amount of the external preparation. If the content is less than about 2% by weight, the transdermal absorbability of the active ingredient becomes insufficient, while if the content is more than about 40% by weight, crystal precipitation becomes significant, and it is difficult to formulate the drug.

[0069] The external preparation of the present invention is characterized in that, in addition to the active ingredient of the aniline derivative, it also contains a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane (hereinafter, sometimes referred to as the absorption enhancer of the present invention), and the mixing ratio of the active ingredient to the absorption enhancer is, for example, 1:80 to 20:1, preferably 1:40 to 15:2, more preferably 1:20 to 2:1, further preferably 1:10 to 2:1, and most preferably 1:5 to 1:1. By adjusting to the range of these mixing ratios, good transdermal absorbability of the active ingredient can be achieved, and formulation as an external preparation for skin becomes easy.

[0070] The topical preparation of the present invention is not particularly limited as long as it can be applied (coated) to the skin. It is preferably an oily ointment using an oily base, and more preferably a dispersed ointment in which the active ingredient is roughly uniformly dispersed in the ointment base. In addition to being poorly soluble, the aniline derivative as the active ingredient of the present invention is unstable if dissolved in water, so it is preferred to use an oily base, and further, if it is a crystal dispersion ointment dispersed in a crystalline state, the active ingredient becomes more stable, which is more preferred. Crystal dispersion ointments have the advantage of simple preparation, but have the disadvantage of poor drug absorption. In the present invention, by combining the aniline derivative as an active ingredient with a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane, it is possible to provide a skin topical preparation, especially an ointment, which overcomes these shortcomings and has good main drug stability and percutaneous absorption.

[0071] Hereinafter, the skin external preparation of the present invention will be described in the form of an ointment, but the present invention is not limited thereto.

[0072] When the external preparation of the present invention is manufactured with an oily ointment, it is preferred to contain an oily base of more than 30% by weight. The content of the oily base in the oily ointment is more preferably 40 to 90% by weight, further preferably 50 to 90% by weight, and further preferably 60 to 90% by weight. The content of the oily base mentioned here refers to the content obtained by summing up the vaseline and other oily bases exemplified below, but in the present invention, it refers to the content of the higher monohydric alcohol and synthetic squalane with a carbon number of 16 to 20 that do not function as an absorption promoter.

[0073] The greasy base used in the present invention can be used to adhere to the skin, keep the active ingredient on the skin for a long time, be easy to apply, have no irritation to the skin, and do not affect the stability of the active ingredient. In the present invention, a known greasy base (ointment base) can be used, and vaseline can be preferably cited. The vaseline in the present invention can be any of the yellow vaseline and white vaseline in the Japanese Pharmacopoeia, preferably white vaseline. In addition, as a greasy base, for example, natural wax, petroleum wax, other hydrocarbons, etc. can be exemplified. As natural wax, beeswax (unbleached beeswax, non-chemically bleached white beeswax, chemically bleached white beeswax, etc.), carnauba wax, etc. can be exemplified. As petroleum wax, paraffin, microcrystalline wax, etc. can be exemplified. As other hydrocarbons, fatty acids, fatty acid esters, polyol fatty acid esters, higher alcohols, hydrocarbons, silicone oils, liquid paraffin, etc. can be cited. Hydrocarbons selected from the group consisting of paraffin, wax and beeswax can be preferably exemplified.

[0074] The ointment base of the present invention can be used alone or in combination of two or more. For example, a mixture of vaseline and other oil components can be used. As other oil components that can be used, any of solid, semisolid or liquid can be used. The higher monohydric alcohol with 16 to 20 carbon atoms contained in the external preparation of the present invention can also be used as the other oil components mentioned here.

[0075] The skin external preparation of the present invention can be prepared by mixing with one or more additives in addition to the aniline derivatives. As additives added as needed, water (purified water, hot spring water, deep water, etc.), alcohol, oil, surfactant, metal soap, gelling agent, powder, alcohol, water-soluble polymer, film-forming agent, resin, ultraviolet protection agent, inclusion compound, antibacterial agent, fragrance, deodorant, salt, pH regulator, antioxidant (stabilizer), cooling agent, extract derived from animal / microorganism, plant extract, blood circulation promoter, astringent, anti-seborrheic agent, whitening agent, anti-inflammatory agent, active oxygen scavenger, cell activator, moisturizer, chelating agent, keratolytic agent, enzyme, hormone, vitamins, and absorption promoters other than the above-mentioned such as higher olefin acid (such as oleic acid, etc.) can be listed. The preparation of ointment can be carried out according to conventional methods, and the amount of the aforementioned additives can also be determined according to conventional methods within the scope of not damaging the effect of the present invention.

[0076] The ointment of the present invention may also contain other drugs effective for skin diseases. Examples thereof include anti-inflammatory agents such as glycyrrhetinic acid, antihistamines such as chlorpheniramine maleate, herbal medicinal ingredients such as arnica tincture, etc. Other drugs effective for skin diseases may be added within a range that does not impair the effects of the present invention.

[0077] The ointment of the present invention has a structure in which the aniline derivative as an active ingredient is dispersed in the ointment base together with the absorption promoter of the present invention, and preferably the aniline derivative has a structure in which the aniline derivative is dispersed in the ointment base as a crystal. The ointment of the present invention having such a structure can also be manufactured according to a general ointment manufacturing method. For example, (1) the base component (white vaseline, white beeswax, higher alcohol), the surfactant, the separation inhibitor such as fatty acid ester and the base component as needed are uniformly mixed under heating and stirring to prepare an oil phase. Then (2) a mixture in which the drug, the base component (liquid paraffin, white vaseline) as needed and the medicament are uniformly mixed under heating and stirring is added to the oil phase, and mixed to obtain the desired ointment. As needed, other additives (pH adjusters, etc.) are added together with the medicament. Stirring and mixing can use, for example, a homogenizer, a paddle mixer, a combination thereof, etc. When using a variety of ointment bases, they can also be mixed in advance.

[0078] The ointment of the present invention can be used by being sealed in any available tube (eg, aluminum tube, aluminum laminate tube, resin (eg, polyethylene) tube) and can also be used by being sealed in a plastic bottle container, a glass container, and the like.

[0079] Aniline derivatives as active ingredients of the present invention have antiviral activity against DNA viruses. Therefore, the skin topical preparations (particularly ointments) of the present invention can be used for the treatment, improvement and / or inhibition of progress of DNA viral diseases. Viruses showing antiviral activity as active ingredients of the present invention include, but are not limited to, human adenovirus, hepatitis B virus, human herpes virus (e.g., herpes simplex virus, cytomegalovirus, Epstein-Barr virus, human herpes virus type 8, varicella zoster virus), smallpox virus, polyomavirus, bovine herpes virus (e.g., bovine herpes virus type 1), human papillomavirus (HPV), bovine papillomavirus, canine papillomavirus and feline papillomavirus. Preferably, HPV, herpes simplex virus, human herpes virus type 8, bovine papillomavirus, varicella zoster virus, more preferably HPV.

[0080] The skin external preparation of the present invention (particularly ointment) can be used for diseases caused by human papillomavirus (HPV), human herpes virus, bovine papillomavirus, bovine herpes virus, canine papillomavirus or feline papillomavirus, but is not limited thereto. For human diseases, the skin external preparation of the present invention is preferably used for diseases caused by HPV, such as warts, condyloma acuminatum, vulvar intraepithelial neoplasia, anal intraepithelial neoplasia or vaginal intraepithelial neoplasia, oral herpes caused by herpes simplex virus, genital herpes, Kaposi's varicelliform eruption, Kaposi's sarcoma caused by human herpes virus type 8, chickenpox and herpes zoster caused by varicella zoster virus, and more preferably for diseases caused by HPV. The skin external preparation of the present invention is particularly preferably used for warts or condyloma acuminatum caused by HPV. For cattle diseases, the skin preparation of the present invention is preferably used for diseases caused by bovine papillomavirus, such as bovine papillomatosis, and diseases caused by bovine herpesvirus type 1, such as bovine infectious rhinotracheitis and bovine infectious pustular vulvovaginitis. For dog diseases, the skin preparation of the present invention is preferably used for papilloma, inverted papilloma, and multicentric intraepithelial squamous cell carcinoma caused by canine papillomavirus. For cat diseases, the skin preparation of the present invention is preferably used for papilloma, inverted papilloma, and multicentric intraepithelial squamous cell carcinoma caused by feline papillomavirus.

[0081] The object to which the skin external preparation (particularly ointment) of the present invention can be applied is not limited as long as it is a mammal that develops a disease caused by a DNA-type virus. The object is not limited thereto, and examples thereof include humans, monkeys, mice, rats, dogs, cattle, horses, pigs, sheep, goats, cats, rabbits, hamsters, and guinea pigs. Preferably humans, dogs, cattle, cats, and rabbits can be listed, and humans or cattle can be further preferably listed, and humans can be particularly preferably listed. In addition, the object is preferably a mammal that develops a disease caused by the above-mentioned virus, more preferably a mammal that develops a disease caused by a papillomavirus or a human herpes virus, and particularly preferably a mammal that develops a disease caused by a human papillomavirus.

[0082] The external preparation for skin of the present invention (particularly an ointment) can be used as an antiviral agent on the affected part of the subject's skin. The external preparation for skin of the present invention is applied to the affected part once to several times a day in an appropriate amount.

[0083] In addition, the external preparation for skin of the present invention (particularly ointment) can be used to prevent recurrence by applying to the affected part of the skin that has been treated with surgical treatments including laser therapy (laser vaporization), cryotherapy using liquid nitrogen, electrocautery, surgical excision, etc.

[0084] Example

[0085] Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to the following examples.

[0086] (Example 1) Preparation of ointment

[0087] The outline of the ointment production process is shown in Figure 1 . 2-Octyldodecanol and synthetic squalane as higher monohydric alcohols are used as additives, and RKP00156 is the main drug.

[0088] (1) Preparation of matrix phase

[0089] The weighed white vaseline, white beeswax, glyceryl monostearate and higher monohydric alcohol or synthetic squalane are stirred in an emulsifier with a paddle and a homogenizer while heating to prepare a matrix phase.

[0090] (2) Preparation of the main drug dispersed phase

[0091] As the main drug, a compound represented by the following formula (Ia) (Compound Ia) was used:

[0092]

[0093] (Hereinafter, the above compound may be referred to as RKP00156.) The main drug, liquid paraffin and white vaseline were uniformly mixed while heating to prepare a main drug dispersion phase. The dispersion of the main drug was confirmed visually.

[0094] (3) Preparation of ointment

[0095] The main drug dispersed phase is added to the base phase, and when the contents become uniform, the mixture is slowly cooled to prepare an ointment before being filled in a container.

[0096] By the above process, ointments (Examples 1 to 7) containing 5% of the main drug (Compound Ia) and having the composition shown in Table 1 below were prepared. The higher monohydric alcohols used in Examples 1 to 6 are as follows. The higher monohydric alcohols having 16 to 20 carbon atoms are Examples 2 to 4.

[0097] Example 1: Butyl octanol (carbon number 12, molecular weight 186.3)

[0098] Example 2: 2-octyldodecanol (carbon number 20, molecular weight 298.5)

[0099] Example 3: Hexyldecanol (carbon number 16, molecular weight 242.44)

[0100] Example 4: Isostearyl alcohol (carbon number 18, molecular weight 270.49)

[0101] Example 5: Decyltetradecanol (carbon number 24, molecular weight 354.66)

[0102] Example 6: Dodecyl hexadecanol (carbon number 28, molecular weight 410.76)

[0103] [Table 1]

[0104]

[0105] As comparative examples, ointments containing 5% of the main drug and having the composition shown in Table 2 below were similarly prepared (Comparative Examples 1 to 3). Comparative Example 1 did not contain an absorption enhancer. Comparative Examples 2 and 3 contained medium chain fatty acid triglycerides (Comparative Example 2) and isopropyl myristate (Comparative Example 3), which are absorption enhancers commonly used in ointments.

[0106] [Table 2]

[0107]

[0108] (Test Example 1) Confirmation of tissue metastasis to the epidermis

[0109] The tissue transferability of the main drug of the ointment to the rat epidermis was confirmed as follows.

[0110] SD rats (male, 7 weeks old) were used. The back of the rats was shaved one day before the ointment was applied. Under anesthesia, 50 μL (about 5 mg / cm 2) The ointment was evenly applied to the skin of the shaved back in an area of ​​3cm×3cm. The ointment was applied by spreading the covering film in advance and sticking it to the rat's back skin. After application, the administration site was immediately covered with a film, and then an adhesive stretch bandage was wrapped around it to fix it (using the so-called sealing bandage method). After 0, 3 and 6 hours after administration, blood was collected from the posterior vena cava under isoflurane anesthesia, and the animal was euthanized by bleeding, and the adhesive stretch bandage and film were peeled off. After wiping the part where the film was peeled off with dry cotton wool, wipe it twice with cotton wool moistened with hot water, and further wipe it 4 times with 70% alcohol cotton wool. Then, the applied part was shaved with a razor, and after 3 times of tape stripping, the skin of the applied part was collected. The collected skin was divided into the epidermis and dermis, and the compound Ia as the main drug was extracted from each tissue, and the concentration was measured by LC / MS / MS to confirm the tissue transfer to each tissue. The results are shown in Figure 2 .

[0111] In the percutaneous absorption of the active ingredient (Compound Ia) of the present invention, medium chain fatty acid triglyceride (Comparative Example 2) had no effect, and isopropyl myristate (Comparative Example 3) slightly promoted percutaneous absorption, but not sufficiently. In contrast, the ointments of the present invention (Examples 1 to 7) to which higher monohydric alcohols or synthetic squalane were added were dominant in promoting percutaneous absorption of the active ingredient of the present invention, and in particular, the ointments containing 2-octyldodecanol, hexyldecanol, isostearyl alcohol or synthetic squalane showed a significant percutaneous absorption promoting effect.

[0112] (Example 2) Study on the amount of percutaneous absorption enhancer added (1)

[0113] The effect of the amount of absorption enhancer added on the percutaneous absorption of the main drug was confirmed as follows. As an absorption enhancer, 2-octyldodecanol, hexyldecanol or synthetic squalane was used, and the amount added was changed to the amount shown in Table 3 below, and ointments were prepared in the same manner as in Example 1 (Examples 8 to 11).

[0114] [Table 3]

[0115]

[0116] Using the prepared ointment, the tissue metastasis of the main drug in rats was studied in the same manner as in Test Example 1. The results are shown in Figure 3 The effect of promoting percutaneous absorption was confirmed depending on the concentration of the absorption enhancer.

[0117] (Example 3) Study on the amount of percutaneous absorption enhancer added (2)

[0118] The amount of higher monohydric alcohol added in the manufacture of ointments was studied. Ointments were manufactured using 2-octyldodecanol as an absorption enhancer at a mixing ratio of 20% to 50%, and the viscosity of the manufactured ointments was measured. The mixing ratio and the viscosity of each manufactured ointment are shown in Table 4 below.

[0119] [Table 4]

[0120]

[0121] Depending on the amount of 2-octyldodecanol added, the viscosity of the ointment is reduced. The ointment with a mixing ratio of up to 40% is semisolid, but the ointment with 50% is a liquid with high viscosity. Thus, it was confirmed that the absorption promoter can be mixed up to 40%. In addition, the manufactured ointment was applied to the skin to confirm the feeling of use. The results of the physical property evaluation (properties, viscosity, crystal growth, coating feeling) of the manufactured preparation showed that the addition amount of 2-octyldodecanol is most preferably less than 20%.

[0122] (Test Example 2) Study on skin irritation

[0123] For rats, ointments containing 3%, 5%, and 10% of the main drug (dosage: 15, 25, and 50 mg / body per day) (Examples 17 to 19) and 0.5 g of placebo ointment, which were prepared in the same manner as in Example 1 and consisted of the composition shown in Table 5 below, were percutaneously administered to the back skin once a day for 90 days. As a result, no changes were confirmed at the administration site for any of the ointments, and there was no skin irritation. In addition, ointments (containing 2 dosages of 5% and 10% of the main drug) (Examples 18 and 19) and 0.5 g of placebo ointment were repeatedly percutaneously administered to the back skin of healthy people twice a day at 12-hour intervals for 7 days. As a result, no skin irritation was confirmed at the administration site for any of the ointments.

[0124] [Table 5]

[0125]

[0126] Furthermore, when an ointment containing 5% of the main drug of the composition of Example 3 and Example 7 shown in Table 1 was applied to normal skin of healthy subjects, no irritation was observed at the administration site 3 hours and 6 hours later.

[0127] (Example 4) Study on the combination of percutaneous absorption enhancers

[0128] Ointments containing 5% of the main drug and having the compositions shown in the following Table 6 were prepared in the same manner as in Example 1 (Examples 20 and 21).

[0129] [Table 6]

[0130]

[0131] The same operation as in Test Example 1 was performed to confirm the transfer of the main drug from the prepared ointment to the rat epidermis. The results are shown in Figure 4 The effects of the present invention were also confirmed when a higher monohydric alcohol and synthetic squalane were used in combination as an absorption enhancer.

[0132] This application claims priority based on Japanese Patent Application No. 2022-75963 filed in Japan on May 2, 2022, and the contents thereof are incorporated herein by reference. The contents of Japanese Patent Application No. 2022-75963 are incorporated herein by reference and constitute a part of this specification.

[0133] The above detailed description only illustrates the purpose and object of the present invention and does not limit the attached claims. According to the teachings recorded in this specification, it is obvious to those skilled in the art that various changes and substitutions are made to the described embodiments without departing from the attached claims.

[0134] Industrial Applicability

[0135] According to the present invention, a skin external medicine containing an aniline derivative as a main drug is provided. The skin external medicine of the present invention can maintain the stability of the main drug and has good percutaneous absorbability.

Claims

1. A skin external preparation comprising as an active ingredient a compound selected from the group consisting of an aniline derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof, and further comprising a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane, In the formula, W represents S or O.

2. The external preparation for skin according to claim 1, wherein The active ingredient is a compound selected from the group consisting of aniline derivatives represented by the following formula (Ia) or pharmacologically acceptable salts thereof, or hydrates thereof, 3. The external preparation for skin according to claim 2, wherein The higher monohydric alcohol having 16 to 20 carbon atoms is a higher monohydric alcohol having a branched structure.

4. The external preparation for skin according to claim 3, wherein The higher monohydric alcohol with a branched structure is 2-octyldodecanol, hexyldecanol or isostearyl alcohol. 5 . The external preparation for skin according to claim 1 , comprising the active ingredient in an amount of about 0.5% by weight to about 20% by weight. 6 . The external preparation for skin according to claim 1 , comprising about 1% by weight to about 40% by weight of the higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane.

7. The external preparation for skin according to any one of claims 1 to 4, wherein The weight ratio of the effective ingredient to the higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane is 1:80 to 20:

1.

8. The external preparation for skin according to any one of claims 1 to 4, wherein The dosage form is a greasy ointment.

9. The external preparation for skin according to claim 8, characterized in that The crystals of the active ingredient of the oily ointment are dispersed in an ointment base.

10. The external preparation for skin according to any one of claims 1 to 4, characterized in that The invention is used for treating, improving and / or inhibiting the progress of DNA viral diseases.

11. The external preparation for skin according to claim 10, wherein The DNA viral disease is a disease selected from the group consisting of warts, genital warts, vulvar intraepithelial neoplasia, anal intraepithelial neoplasia and vaginal intraepithelial neoplasia caused by human papillomavirus, oral herpes, genital herpes and Kaposi's varicelliform eruption caused by herpes simplex virus, Kaposi's sarcoma caused by human herpesvirus type 8, chickenpox and herpes zoster caused by varicella-zoster virus, and bovine papillomavirus caused by bovine papillomavirus.

Images