Topical skin products containing aniline derivatives

Abstract

The purpose of this invention is to provide a topical skin preparation containing an aniline derivative as the active ingredient, with high stability and transdermal absorption. This invention provides a topical skin preparation containing a compound selected from the group consisting of an aniline derivative represented by formula (I) [where W represents S or O] or a pharmacologically acceptable salt thereof, or their hydrates, as the active ingredient, and further containing a higher monohydric alcohol or synthetic squalane having 16 to 20 carbon atoms.

Description

Technical Field

[0001] This invention relates to topical skin preparations containing aniline derivatives or salts thereof. Additionally, this invention relates to transdermal delivery systems for delivering aniline derivatives topically to the skin. Background Technology

[0002] Human papillomavirus (HPV) belongs to the Papillomaviridae family and is a DNA virus with a circular double-stranded DNA genome. HPV is transmitted through contact infection. HPV infects epithelial cells and mucous membranes, expressing HPV proteins in infected host cells to replicate the virus. In particular, the E6 and E7 proteins, as non-structural proteins, are known to cause abnormal cell proliferation by breaking down tumor suppressor genes such as the p53 and pRB genes in host cells, leading to various diseases such as warts (common warts, flat warts, plantar warts, etc.), cervical cancer, condyloma acuminata, and pharyngeal papillomas. To date, more than 100 types of HPV have been identified, and based on their carcinogenicity, they are classified into low-risk types that cause benign tumors such as warts, condyloma acuminata, and papillomas, and high-risk types that cause malignant tumors such as cervical cancer.

[0003] Treatment for human papillomavirus (HPV) genital warts primarily involves laser therapy (laser vaporization), cryotherapy using liquid nitrogen, electrocautery, and surgical excision. However, HPV viral genes tend to remain in the basal cells of the epidermis, leading to frequent recurrences and thus becoming a significant burden on patients. Additionally, the treatment of HPV-induced genital warts utilizes BESELNA cream (registered trademark) (manufactured by Mochida Pharmaceutical Co., Ltd.), with imiquimod as the active ingredient, but this sometimes causes severe inflammatory reactions, resulting in side effects such as erosion, ulceration, epidermal detachment, and fever. Therefore, caution should be exercised to avoid overdose.

[0004] N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide (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) is known to exert its antiviral effect by targeting host cell phosphorylases, inhibiting the expression of the E6 and E7 genes of human papillomavirus (HPV), and stabilizing the p53 gene. Topical treatments for HPV-related warts and condyloma acuminata using such thioamide derivatives are anticipated.

[0005] As a treatment for human papillomavirus (HPV) warts, a patch for HPV warts has been reported, characterized in that each unit area (1 cm²) contains [amount missing]. 2 It contains 50 to 500 μg of N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide, which is repeatedly applied once a day (Patent Document 3: Japanese Patent Application Publication No. 2021-059500).

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

[0007] However, the aforementioned thioamide derivatives are poorly soluble in water and exhibit poor stability after dissolution. Furthermore, topical skin preparations are not preferably formulated with irritating substances such as organic solvents, making it difficult to manufacture topical formulations containing these thioamide derivatives as active ingredients. Moreover, even when they can be manufactured as topical preparations, the active ingredients cannot adequately penetrate the skin, sometimes failing to achieve sufficient absorption into the epidermis. Therefore, no topical skin preparations containing thioamide derivatives with high drug stability and transdermal absorption suitable for human papillomavirus (HPV) warts or condyloma acuminata have been reported.

[0008] Existing technical documents

[0009] Patent documents

[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 literature 1: Yamamoto M et al., J Clin Invest, 2014, 124(8), 3479-3488 Summary of the Invention

[0017] The problem the invention aims to solve

[0018] The purpose of this invention is to provide a topical skin preparation with aniline derivatives as the active ingredient, high drug stability, and high transdermal absorption.

[0019] Solution for solving the problem

[0020] The inventors have conducted in-depth research on a topical skin formulation using N-[5-fluoro-2-(1-piperidinyl)phenyl]-4-pyridinethioamide, an aniline derivative, which exhibits high stability of the active pharmaceutical ingredient, high transdermal absorption, and low irritation. The results showed that by using the aniline derivative in conjunction with a specific absorption enhancer, a combination of components in a topical skin formulation can maintain the stability of the active pharmaceutical ingredient while achieving good transdermal absorption, thus completing the present invention. Furthermore, in a preferred embodiment, the topical skin formulation of the present invention is considered to have low skin irritation.

[0021] The topical skin agent of the present invention comprises the following methods.

[0022] [1] A topical skin preparation containing, 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 hydrates thereof, and also containing a higher monohydric alcohol or synthetic squalane having 16 to 20 carbon atoms.

[0023]

[0024] [In the formula, W represents S or O.]

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

[0026]

[0027] [3] In the skin topical agent described in [1] or [2] above, the aforementioned higher monohydric alcohol with 16 to 20 carbon atoms is a higher monohydric alcohol with a branched structure.

[0028] [4] In the skin topical agent described above [3], the aforementioned branched-chain higher monohydric alcohol is 2-octyldodecanool, hexyldecanool or isostearyl alcohol.

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

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

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

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

[0033] [9] The skin topical agent according to [8] above is characterized in that the crystals of the aforementioned active ingredient of the aforementioned oily ointment are dispersed in the ointment matrix.

[0034]

[10] The topical skin preparation according to any one of [1] to [9] above is characterized in that it is used for the treatment, improvement and / or inhibition of the progression of DNA viral diseases.

[0035]

[11] According to the skin topical agent described above

[10] , wherein the aforementioned DNA viral diseases are selected from the group consisting of warts, condyloma acuminata, 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, varicella and herpes zoster caused by varicella-zoster virus, Kaposi's sarcoma caused by human herpesvirus type 8, bovine papillomavirus (BPV) caused by bovine papillomavirus (BPV), bovine infectious pustular vulvovaginitis and bovine infectious 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 dispersed (preferably in crystalline form) in the matrix from the group consisting of aniline derivatives represented by formula (I) or (Ia) above, or their pharmacologically acceptable salts, or their hydrates; and

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

[0040]

[13] According to the transdermal delivery system described above

[12] , the aforementioned higher monohydric alcohol with 16 to 20 carbon atoms is 2-octyldodecanool, hexyldecanool or isostearyl alcohol.

[0041]

[14] According to the transdermal delivery system described in

[12] or

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

[0042] The effects of the invention

[0043] According to the present invention, a topical skin preparation with high drug stability and transdermal absorption is provided. In a preferred embodiment, the topical skin preparation has low irritation. Attached Figure Description

[0044] Figure 1 This is a diagram illustrating the outline of the manufacturing process of the topical skin agent (ointment) of the present invention.

[0045] Figure 2 The results confirmed the tissue transferability to the epidermis by administering (applying) the topical skin preparation (ointment) of the present invention to rats.

[0046] Figure 3 The results confirmed the tissue transferability to the epidermis by administering (applying) the topical skin preparation (ointment) of the present invention to rats.

[0047] Figure 4 The results confirmed the tissue transferability to the epidermis by administering (applying) the topical skin preparation (ointment) of the present invention to rats. Detailed Implementation

[0048] The following description, using exemplary embodiments as examples, illustrates the preferred methods and materials that can be used in the implementation of the present invention. However, the present invention is not limited to the embodiments described below. It should be noted that, unless otherwise specified, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, any materials and methods equivalent or identical to those described in this specification can be used in the implementation of the present invention. Additionally, all publications and patents cited in connection with the present invention, such as documents illustrating methods, materials, etc., that can be used in the present invention, are cited in this specification and constitute a part of this specification.

[0049] In this specification, the designation "A~B" indicating a numerical range refers to a range including the endpoints A and B. The same applies to "A to B". Additionally, in this specification, "about" is used to imply an allowance of ±10%. It should be noted that the weight percentage of each component described in this specification refers to the proportion of each component's weight when the weight of the topical preparation (i.e., the total amount of the formulation) is set to 100.

[0050] The topical skin preparation of the present invention contains an aniline derivative of formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof, as an active ingredient (pharmaceutical ingredient).

[0051]

[0052] [In the formula, W represents S or O.]

[0053] The topical skin preparation 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 the active ingredient (principal ingredient).

[0054]

[0055] The term "pharmacologically acceptable salt" in this specification is not particularly limited to any salt that forms a salt with the compounds of the present invention represented by formula (I) or (Ia) above and is pharmacologically acceptable. Examples include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts, etc. Furthermore, their hydrates refer to compounds or salts thereof that also contain stoichiometric or non-stoichiometric amounts of water bonded by non-covalent intermolecular forces.

[0056] The topical skin preparation of the present invention (hereinafter, sometimes simply referred to as the topical preparation) contains a therapeutically effective amount of a compound represented by formula (I) or formula (Ia) as an aniline derivative or a pharmacologically acceptable salt thereof, or a hydrate thereof (hereinafter, sometimes simply referred to as the active ingredient, compound, or main drug of the present invention, all of which have the same meaning). A therapeutically effective amount means an amount sufficient to produce at least one effect of treating, improving, or inhibiting the progression of the disease when the topical preparation of the present invention is applied to the affected area of ​​a person with a disease. Alternatively, a therapeutically effective amount means an amount capable of inhibiting the proliferation of DNA viruses in the affected area when the topical preparation of the present invention is applied to the affected area of ​​a person with a disease. Not limited thereto, for example, the active ingredient of the present invention may be contained in an amount of about 0.5% by weight (lower limit), preferably about 1.0% by weight, more preferably about 2% by weight, further preferably about 3% by weight, and an amount of about 20% by weight (upper limit), preferably about 15% by weight, more preferably about 10% by weight, relative to the total weight of the topical preparation. If the amount is less than 0.5% by weight, it lacks effectiveness; on the other hand, if the amount is more than 20% by weight, the properties of the formulation may not be suitable as a coating agent.

[0057] In addition to the active ingredient of the present invention, the topical application of the present invention also contains a higher monohydric alcohol or synthetic squalane with 16 to 20 carbon atoms. By containing a higher monohydric alcohol or synthetic squalane with 16 to 20 carbon atoms, the topical application of the present invention can promote the transdermal transfer of the active ingredient of the present invention into the epidermis when applied to the skin. That is, the higher monohydric alcohol or synthetic squalane with 16 to 20 carbon atoms in the topical application of the present invention acts as a transdermal absorption enhancer for the active ingredient of the present invention.

[0058] The higher monohydric alcohol or synthetic squalane containing 16 to 20 carbon atoms in the topical agent of the present invention may be only a higher alcohol or synthetic squalane, or may be a combination of a higher alcohol and synthetic squalane. Furthermore, there may be only one higher alcohol, or a combination of two or more.

[0059] The hydrocarbon chain (aliphatic) in higher monohydric alcohols having 16 to 20 carbon atoms can be a saturated hydrocarbon or an unsaturated hydrocarbon. Higher monohydric alcohols having 16 to 20 carbon atoms preferably have a branched structure. Examples are not limited thereto, such as cetaneol, heptadecanol, stearyl alcohol, nonadecanol, arachidonicol (eicosyl alcohol), palmitoyl alcohol, oleyl alcohol, 2-octyldodecaneol, hexyldecaneol, and isostearyl alcohol, preferably cetaneol, stearyl alcohol, oleyl alcohol, 2-octyldodecaneol, hexyldecaneol, or isostearyl alcohol, and more preferably 2-octyldodecaneol, hexyldecaneol, or isostearyl alcohol.

[0060] 2-Octylidene alcohol is a branched monohydric alcohol with 20 carbon atoms and a molecular weight of 298.5.

[0061]

[0062] Hexyldecyl alcohol is a branched monohydric alcohol with 16 carbon atoms and a molecular weight of 242.44.

[0063]

[0064] Isostearyl alcohol is a branched monohydric alcohol with 18 carbon atoms and a molecular weight of 270.49.

[0065]

[0066] Synthetic squalane is a higher fatty acid with 30 carbon atoms and a molecular weight of 410.73.

[0067]

[0068] The topical formulation of the present invention contains, for example, a higher monohydric alcohol or synthetic squalane having 16 to 20 carbon atoms in an amount of about 2% by weight (lower limit), preferably about 3% by weight, more preferably about 5% by weight, and an amount of about 40% by weight (upper limit), preferably about 30% by weight, more preferably about 20% by weight, relative to the total amount of the topical formulation. If the content is less than about 2% by weight, the transdermal absorption of the active ingredient becomes insufficient; on the other hand, if the content is more than about 40% by weight, crystal precipitation becomes significant, and formulation becomes difficult.

[0069] The topical formulation of the present invention is characterized in that, in addition to being an active ingredient that is an aniline derivative, it also contains a higher monohydric alcohol with 16 to 20 carbon atoms or synthetic squalane (hereinafter sometimes simply referred to as the absorption enhancer of the present invention). The 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 these ratio ranges, good transdermal absorption of the active ingredient can be achieved, and formulation as a topical skin formulation becomes easier.

[0070] The topical formulation of the present invention is not particularly limited as long as it can be applied (covered) to the skin. It is preferably an oily ointment using an oily base, and more preferably a dispersion ointment in which the active ingredient is substantially uniformly dispersed in the ointment base. In addition to being poorly soluble, the aniline derivative, the active ingredient of the present invention, is unstable when dissolved in water. Therefore, an oily base is preferred. Furthermore, if it is a crystalline dispersion ointment, the active ingredient becomes more stable, which is even more preferable. Crystalline dispersion ointments have the advantage of being easy to prepare, but have the disadvantage of poor drug absorption. In the present invention, by combining the aniline derivative, the active ingredient, with a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane, it is possible to provide a topical skin formulation, particularly an ointment, that overcomes these disadvantages, has good drug stability, and good transdermal absorption.

[0071] The following describes the ointment-based topical application of the present invention for skin use. However, the present invention is not limited thereto.

[0072] When manufacturing the topical application of the present invention using an oily ointment, it is preferable to contain 30% by weight or more of an oily matrix. More preferably, the content of the oily matrix in the oily ointment is 40-90% by weight, further preferably 50-90% by weight, and even more preferably 60-90% by weight. The oily matrix content referred to herein means the total content obtained by summing the petrolatum and other oily matrices exemplified below, but in the present invention, it refers to the content excluding higher monohydric alcohols with 16-20 carbon atoms that function as absorption enhancers and synthetic squalane.

[0073] The oily matrix used in this invention can be an oily matrix that adheres to the skin, allows the active ingredient to remain on the skin for a long time, is easy to apply, is non-irritating to the skin, and does not affect the stability of the active ingredient. In this invention, a known oily matrix (ointment matrix) can be used, and petrolatum is a preferred example. The petrolatum in this invention can be either yellow petrolatum or white petrolatum as listed in the Japanese Pharmacopoeia, with white petrolatum being preferred. Other examples of oily matrices include, for example, natural waxes, petroleum waxes, and other hydrocarbons. Examples of natural waxes include beeswax (unbleached beeswax, non-chemically bleached white beeswax, chemically bleached white beeswax, etc.) and carnauba wax. Examples of petroleum waxes include paraffin wax and microcrystalline wax. Examples of other hydrocarbons include fatty acids, fatty acid esters, polyol fatty acid esters, higher alcohols, hydrocarbons, silicone oils, and liquid paraffin. Hydrocarbons selected from the group consisting of paraffin wax, waxes, and beeswax are preferred examples.

[0074] The ointment base of this invention can be used alone or in combination of two or more. For example, a mixture of petrolatum and other oils can be used. Other oils that can be used can be solid, semi-solid, or liquid. Higher monohydric alcohols with 16 to 20 carbon atoms contained in the topical agents of this invention can also be used as other oils mentioned herein.

[0075] The topical skin preparation of the present invention can be prepared by mixing with one or more additives, in addition to aniline derivatives. Examples of additives that can be added as needed include water (purified water, hot spring water, deep water, etc.), alcohols, oils, surfactants, metal soaps, gelling agents, powders, alcohols, water-soluble polymers, film-forming agents, resins, UV protectants, inclusion complexes, antibacterial agents, fragrances, deodorants, salts, pH adjusters, antioxidants (stabilizers), cooling agents, extracts derived from animals / microorganisms, plant extracts, blood circulation promoters, astringents, anti-seborrheic agents, whitening agents, anti-inflammatory agents, reactive oxygen species scavengers, cell activators, moisturizers, chelating agents, keratolytic agents, enzymes, hormones, vitamins, and absorption enhancers other than those mentioned above, such as higher olefinic acids (e.g., oleic acid). The ointment can be prepared using conventional methods, and the amounts of the aforementioned additives can be determined using conventional methods without impairing the effects of the present invention.

[0076] The ointment of the present invention may also contain other agents effective for skin diseases. Examples include anti-inflammatory agents such as glycyrrhetinic acid, antihistamines such as chlorpheniramine maleate, and medicinal ingredients such as arnica tincture. Other agents effective for skin diseases may be combined with the ointment without compromising the effectiveness 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 together with the absorption enhancer of the present invention in an ointment matrix, preferably the aniline derivative having a structure in which it is dispersed as crystals in the ointment matrix. The ointment of the present invention having such a structure can also be manufactured according to the general method for manufacturing ointments. For example, (1) the matrix components (white petrolatum, white beeswax, higher alcohols), desired surfactants, separation inhibitors such as fatty acid esters, and the matrix components are uniformly mixed under heating and stirring to prepare an oil phase. Then (2) a mixture of the drug, desired matrix components (liquid paraffin, white petrolatum), and the drug agent, which are uniformly mixed under heating and stirring, is added to the oil phase and mixed to obtain the desired ointment. Other additives (pH adjusters, etc.) may be added together with the drug agent as needed. Stirring and mixing can be performed using, for example, a homogeneous mixer, a paddle mixer, or a combination thereof. In the case of using multiple ointment matrices, they may also be pre-mixed.

[0078] The ointment of the present invention can be used not only in all available tubes (e.g., aluminum tubes, aluminum laminated tubes, resin (e.g., polyethylene) tubes), but also in plastic bottle containers, glass containers, etc.

[0079] The aniline derivative, as an active ingredient of the present invention, exhibits antiviral activity against DNA viruses. Therefore, the topical skin preparations (particularly ointments) of the present invention can be used to treat, improve, and / or inhibit the progression of DNA viral diseases. Viruses exhibiting antiviral activity as active ingredients of the present invention include, but are not limited to, human adenovirus, hepatitis B virus, human herpesviruses (e.g., herpes simplex virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 8, varicella-zoster virus), smallpox virus, polyomavirus, bovine herpesvirus (e.g., bovine herpesvirus 1), human papillomavirus (HPV), bovine papillomavirus, canine papillomavirus, and feline papillomavirus. Preferably, HPV, herpes simplex virus, human herpesvirus 8, bovine papillomavirus, and varicella-zoster virus are preferred, and HPV is more preferred.

[0080] The topical skin agents (particularly ointments) of the present invention can be used for, but are not limited to, diseases caused by human papillomavirus (HPV), human herpesvirus, bovine papillomavirus, canine papillomavirus, or feline papillomavirus. For human diseases, the topical skin agents of the present invention are preferably used for diseases caused by HPV, such as warts, condyloma acuminata, vulvar intraepithelial tumors, anal intraepithelial tumors or vaginal intraepithelial tumors, herpes labialis caused by herpes simplex virus, genital herpes, Kaposi's varicelliform eruption, Kaposi's sarcoma caused by human herpesvirus 8, varicella and shingles caused by varicella-zoster virus, and more preferably for diseases caused by HPV. The topical skin agents of the present invention are particularly preferred for warts or condyloma acuminata caused by HPV. For bovine diseases, the topical skin agent 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 canine diseases, the topical skin agent of the present invention is preferably used for papillomas, inverted papillomas, and multicentric intraepithelial squamous cell carcinomas caused by canine papillomavirus. For feline diseases, the topical skin agent of the present invention is preferably used for papillomas, inverted papillomas, and multicentric intraepithelial squamous cell carcinomas caused by feline papillomavirus.

[0081] The application of the topical skin agents (especially ointments) of the present invention can be limited to any mammal suffering from diseases caused by DNA viruses. The target species are not limited to this; examples include, for instance, humans, monkeys, mice, rats, dogs, cattle, horses, pigs, sheep, goats, cats, rabbits, hamsters, and guinea pigs. Humans, dogs, cattle, cats, and rabbits are preferred examples, and humans or cattle are even more preferred, with humans being particularly preferred. Furthermore, the target species are preferably mammals suffering from diseases caused by the aforementioned viruses, more preferably mammals suffering from diseases caused by human papillomavirus (HPV) or human herpesvirus (HHV), and particularly preferably mammals suffering from diseases caused by human papillomavirus (HPV).

[0082] The topical skin preparations (especially ointments) of the present invention can be used as antiviral agents on affected areas of the target skin. The topical skin preparations of the present invention are applied to the affected area in appropriate amounts once to several times a day.

[0083] Furthermore, the topical skin preparations (especially ointments) of the present invention can be used to prevent recurrence when applied to affected areas of skin that have undergone treatments including laser therapy (laser vaporization), cryotherapy using liquid nitrogen, electrocautery, surgical excision, etc.

[0084] Example

[0085] The present invention will be specifically described below through embodiments, but the present invention is not limited to the following embodiments.

[0086] (Example 1) Manufacturing of Ointment

[0087] The manufacturing process of the ointment is outlined below. Figure 1 RKP00156 is the main drug, with 2-octyldodecanool (a higher monohydric alcohol) and synthetic squalane as additives.

[0088] (1) Preparation of matrix phase

[0089] The weighed white petrolatum, white beeswax, glyceryl monostearate, and higher monohydric alcohols or synthetic squalane are used in an emulsifier, with a paddle and homogenizer, to heat and stir simultaneously to prepare the matrix phase.

[0090] (2) Preparation of the active pharmaceutical ingredient dispersion

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

[0092]

[0093] (Hereinafter, the above compound is sometimes referred to as RKP00156). The active pharmaceutical ingredient (API), liquid paraffin, and white petrolatum were mixed uniformly while heating to prepare the API dispersion. The dispersion of the API was confirmed visually.

[0094] (3) Preparation of ointments

[0095] The active pharmaceutical ingredient dispersion is added to the matrix phase, and the contents are slowly cooled as they become homogeneous to prepare an ointment that is not filled into a container.

[0096] Through the above processes, an ointment containing 5% of the active pharmaceutical ingredient (compound Ia) with the composition shown in Table 1 below was manufactured (Examples 1 to 7). The higher monohydric alcohols used in Examples 1 to 6 are as described below. The higher monohydric alcohols with 16 to 20 carbon atoms are those used in Examples 2 to 4.

[0097] Example 1: Butyloctanol (12 carbons, molecular weight 186.3)

[0098] Example 2: 2-Octyldodecanol (20 carbons, molecular weight 298.5)

[0099] Example 3: Hexyldecyl alcohol (16 carbons, molecular weight 242.44)

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

[0101] Example 5: Decyltetradecanool (24 carbons, molecular weight 354.66)

[0102] Example 6: Dodecyl hexadecyl alcohol (28 carbons, molecular weight 410.76)

[0103] [Table 1]

[0104]

[0105] As comparative examples, ointments containing 5% of the active pharmaceutical ingredient, as shown in Table 2 below, were similarly manufactured (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] (Experimental Example 1) Confirmation of tissue transfer to the epidermis

[0109] The following confirms the tissue transferability of the active ingredient in the ointment to the rat epidermis.

[0110] Using male SD rats (7 weeks old), the back hair of the rats was shaved the day before the ointment was applied. For the animals, under anesthesia, 50 μL (approximately 5 mg / cm³) was administered. 2The ointment was evenly applied to a 3cm x 3cm area of ​​the shaved back skin. Application was performed by pre-spreading and adhering a covering film to the rat's back skin. Immediately after application, the treatment site was covered with the film and then secured with an adhesive elastic bandage (using the so-called sealing bandage method). At 0, 3, and 6 hours post-administration, blood was drawn from the posterior vena cava under isoflurane anesthesia, and the animals were euthanized by exsanguination. The adhesive elastic bandage and film were then removed. The area where the film was removed was wiped with dry, absorbent cotton, then wiped twice with absorbent cotton moistened with hot water, and further wiped four times with cotton soaked in 70% alcohol. The treated area was then shaved with a razor, and after three tape removals, the skin was collected. The collected skin was divided into epidermis and dermis, and compound Ia, the active ingredient, was extracted from each tissue. The concentration was determined by LC / MS / MS to confirm tissue translocation to each tissue. The results are presented below. Figure 2 .

[0111] In the transdermal absorption of the active ingredient (compound Ia) of the present invention, medium-chain fatty acid triglycerides (Comparative Example 2) had no effect, and isopropyl myristate (Comparative Example 3) slightly promoted transdermal absorption, but not sufficiently. In contrast, the ointments of the present invention (Examples 1 to 7) containing higher monohydric alcohols or synthetic squalane predominantly promoted the transdermal absorption of the active ingredient of the present invention, especially the ointments containing 2-octyldodecanool, hexyldecanool, isostearyl alcohol, or synthetic squalane, which showed a significant effect in promoting transdermal absorption.

[0112] (Example 2) Study on the dosage of transdermal absorption enhancer (1)

[0113] The effect of the amount of absorption enhancer added on the transdermal absorption of the active ingredient was confirmed as follows. As the absorption enhancer, 2-octyldodecanool, hexyldecanool, or synthetic squalane were used, with the addition amounts 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] The tissue metastasis of the active ingredient in rats was studied using the manufactured ointment, in the same manner as in Experimental Example 1. The results are presented below. Figure 3 The effect of promoting transdermal absorption was confirmed, depending on the concentration of the absorption enhancer.

[0117] (Example 3) Study on the dosage of transdermal absorption enhancer (2)

[0118] The amount of higher monohydric alcohols added in the manufacture of ointments was investigated. Ointments were manufactured using 2-octyldodecanool as an absorption enhancer at proportions ranging from 20% to 50%, and the viscosity of the manufactured ointments was measured. The proportions and viscosities of the various ointments are shown in Table 4 below.

[0119] [Table 4]

[0120]

[0121] The ointment's viscosity decreased depending on the amount of 2-octyldodecanool added. Ointments with a formulation up to 40% were semi-solid, while those with 50% were highly viscous liquids. This confirmed that the absorption enhancer could be formulated up to 40%. Furthermore, the ointment was applied to the skin to assess its feel. Based on the evaluation of the physical properties of the manufactured formulation (appearance, viscosity, crystal growth, and spreadability), the optimal amount of 2-octyldodecanool added was 20% or less.

[0122] (Experimental Example 2) Study on Skin Irritation

[0123] In rats, ointments containing 3%, 5%, and 10% of the active pharmaceutical ingredient (dosage: 15, 25, and 50 mg / body per day) and a placebo ointment of 0.5 g, prepared in the same manner as in Example 1 and comprising the components shown in Table 5 below (Examples 17-19), were transdermally administered to the back skin once daily for 90 days. No changes were observed at the administration site for either ointment, and no skin irritation was observed. Additionally, ointments (containing 5% and 10% of the active pharmaceutical ingredient in two dosages) (Examples 18 and 19) and a placebo ointment of 0.5 g were repeatedly transdermally administered to the back skin of healthy individuals twice daily at 12-hour intervals for 7 days. No skin irritation was observed at the administration site for either ointment.

[0124] [Table 5]

[0125]

[0126] Furthermore, an ointment containing 5% of the active pharmaceutical ingredient as shown in Examples 3 and 7 of Table 1 was applied to the normal skin of healthy individuals, and no irritation was observed at the application site after 3 hours and 6 hours.

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

[0128] Ointments containing 5% of the active ingredient, consisting of the composition shown in Table 6 below, were prepared in the same manner as in Example 1 (Examples 20 and 21).

[0129] [Table 6]

[0130]

[0131] The procedure was performed in the same manner as in Experiment 1 to confirm the transfer of the active ingredient from the manufactured ointment to the rat epidermis. The results are presented in... Figure 4 The effects of this invention have also been confirmed when used in combination with higher monohydric alcohols and synthetic squalane as absorption enhancers.

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

[0133] The detailed description above is merely illustrative of the purpose and object of the invention and does not limit the appended claims. Based on the teachings set forth in this specification, various modifications and substitutions to the described embodiments will be apparent to those skilled in the art without departing from the appended claims.

[0134] Industrial availability

[0135] According to the present invention, a topical skin medication with an aniline derivative as the main active ingredient is provided. The topical skin medication of the present invention maintains the stability of the main active ingredient and exhibits good transdermal absorption.

Claims

1. An oily ointment containing, as an active ingredient, a compound selected from the group consisting of an aniline derivative represented by formula (I) or a pharmacologically acceptable salt thereof, or hydrates thereof, and further containing a higher monohydric alcohol having 16 to 20 carbon atoms or synthetic squalane. in, The active ingredient crystals are dispersed in the ointment base, and The oily ointment contains more than 30% by weight of an oily base, and The hydrocarbon chains in the higher monohydric alcohols having 16-20 carbon atoms are saturated hydrocarbons, and the higher monohydric alcohols having 16-20 carbon atoms are higher monohydric alcohols with branched structures. Here, the term "oily ointment containing more than 30% by weight of oily matrix" refers to the total amount of oily matrix components other than higher monohydric alcohols with 16-20 carbon atoms and synthetic squalane, which is more than 30% by weight relative to the total amount of the oily ointment. In the formula, W represents S or O.

2. The oily ointment 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 their pharmacologically acceptable salts, or their hydrates. 。 3. The oily ointment according to claim 2, wherein, The branched-chain higher monohydric alcohol is 2-octyldodecanool, hexyldecanool, or isostearyl alcohol.

4. The oleotropic ointment according to any one of claims 1 to 3, wherein the active ingredient is contained in 0.5% to 20% by weight.

5. The oleolate according to any one of claims 1 to 3, wherein it contains, at 1% to 40% by weight, a higher monohydric alcohol or synthetic squalane having 16 to 20 carbon atoms.

6. The oleolate according to claim 5, wherein it contains, at 1% to 20% by weight, a higher monohydric alcohol or synthetic squalane having 16 to 20 carbon atoms.

7. The grease-based ointment according to any one of claims 1 to 3, wherein, The weight ratio of the active ingredient to a higher monohydric alcohol or synthetic squalane with 16 to 20 carbon atoms is 1:80 to 20:

1.

8. The grease-based ointment according to any one of claims 1 to 3, characterized in that, It is used for the treatment, improvement, and / or inhibition of the progression of DNA viral diseases.

9. The grease-based ointment according to claim 8, wherein, The DNA viral diseases are selected from the group consisting of warts, vulvar intraepithelial neoplasia, anal intraepithelial neoplasia, and vaginal intraepithelial neoplasia caused by human papillomavirus; herpes labialis, genital herpes, and Kaposi's varicelliform eruption caused by herpes simplex virus; Kaposi's sarcoma caused by human herpesvirus type 8; varicella and herpes zoster caused by varicella-zoster virus; and bovine papillomatosis caused by bovine papillomavirus, wherein the warts include condyloma acuminata.

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