Oil-in-water type emulsion composition

Abstract

To provide a pharmaceutical formulation of an oil-in-water type emulsion composition comprising zinc chloride as an active ingredient having excellent separation inhibiting properties and medicine release properties.SOLUTION: There is provided an oil-in-water type emulsion composition which comprises (A) 30 mass% or more of zinc chloride, (B) an oily base selected from the group consisting of a hydrocarbon oil and a higher alcohol, (C) a nonionic surfactant and (D) an aqueous base selected from the group consisting of water and a polyhydric alcohol, wherein an oil-in-water type emulsion composition in which the content of the component (B) is 52 pts.wt. or more based on 100 pts.wt. of the total of the component (B) and the component (C), and the content of the component (B) is 11.7 pts.wt. or more based on 100 pts.wt. of the total of the component (B) and the component (D), has excellent separation inhibiting properties and an oil-in-water type emulsion composition in which the component (D) is water and a polyethylene glycol has excellent medicine release properties.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an oil-in-water emulsion composition having excellent separation inhibitory properties and / or drug release properties.

Background Art

[0002] Some external preparations are used for the treatment of skin malignancies and skin lesions of breast cancer, and their effectiveness and necessity are widely recognized. For example, as Mohs ointment, an external preparation containing zinc chloride as an active ingredient and having the efficacy of stopping bleeding or exudate at cancerous skin ulcer sites that cannot be controlled by ordinary hemostatic agents is known.

[0003] This preparation has been continuously improved from the original formulation studied by Mohs (Frederic Edward Mohs) in terms of availability of raw materials, applicability to the affected area, and prevention of viscosity increase over time. As improved formulations, so-called starch formulations (Non-Patent Document 1), sorbitol formulations (Non-Patent Document 2), and macrogol formulations (Non-Patent Document 3) are known. The starch formulation is composed of easily available raw materials such as zinc chloride, zinc oxide, glycerin, water, and starch, and is actually used as an in-hospital preparation. The sorbitol formulation has improved applicability by adding sorbitol to the starch formulation. The macrogol formulation is obtained by replacing the starch and sorbitol in the sorbitol formulation with macrogol and crystalline cellulose, and the viscosity increase over time is relatively suppressed.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0005] Because topical preparations containing zinc chloride as the active ingredient are highly acidic, there is a very high risk of damaging normal skin if the applied preparation drips onto areas other than the affected area. While the above-mentioned improved formulations have been improved in terms of applicability and inhibition of viscosity increase, there is still room for improvement in terms of adhesion to moist areas such as cancerous skin ulcer sites.

[0006] To improve adhesion to biological tissues, it is considered effective to further incorporate an oily base. In order to further incorporate an oily base, it must be in the form of an emulsion composition, but the formulation characteristics when zinc chloride is used as an emulsion composition in conventional topical preparations have not been sufficiently studied. Therefore, when the present inventors formulated a topical preparation with zinc chloride as the active ingredient in the form of an oil-in-water emulsion composition, they encountered the problem that it was extremely easy to separate due to the unique characteristic of this topical preparation that the active ingredient is highly acidic.

[0007] On the other hand, formulation design to improve the efficacy of topical preparations containing zinc chloride as the active ingredient has not been sufficiently considered, and there is room for improvement.

[0008] In view of the above, the object of the present invention is to provide a formulation of an oil-in-water emulsion composition containing zinc chloride as an active ingredient that exhibits excellent separation inhibition and / or drug release properties. [Means for solving the problem]

[0009] As a result of diligent research, the inventors have found that in an oil-in-water emulsion composition using zinc chloride as an active ingredient, excellent separation inhibition is achieved by adjusting the ratio of the oily base to a predetermined range. Furthermore, they have found that excellent drug release is achieved when polyethylene glycol is added. In addition to adjusting the ratio of the oily base or adding polyethylene glycol, they have also found that excellent discoloration inhibition is achieved when the HLB value and / or content of the nonionic surfactant is adjusted to a predetermined range, that adhesion is further improved when a silicate compound is added, and that drug release is further improved by adjusting the amount of silicate compound to a predetermined amount. The present invention was completed by further research based on these findings.

[0010] In other words, the present invention provides inventions in the following embodiments. Item 1. (A) 30% by weight or more of zinc chloride, (B) an oily base selected from the group consisting of hydrocarbon oils and higher alcohols, (C) a nonionic surfactant, and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols. The content of (B) is 52 parts by weight or more per 100 parts by weight of the total amount of component (B) and component (C), and An oil-in-water emulsion composition in which the content of (B) is 11.7 parts by weight or more per 100 parts by weight of the total amount of component (B) and component (D). Item 2. (A) 30% by weight or more of zinc chloride, (B) an oily base selected from the group consisting of hydrocarbon oils and higher alcohols, (C) a nonionic surfactant, and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols, An oil-in-water emulsion composition wherein component (D) is water and polyethylene glycol. Item 3. The oil-in-water emulsion composition according to item 1 or 2, wherein the content of component (D) is 42 parts by weight or more per 100 parts by weight of the total amount of component (B), component (C), and component (D). Item 4. An oil-in-water emulsion composition according to any one of items 1 to 3, wherein the content of component (C) is 12.7% by weight or less. Item 5. An oil-in-water emulsion composition according to any one of items 1 to 4, wherein the content of component (C) is 1 to 7.5% by weight. Item 6. The above (C) component is one or more nonionic surfactants, The oil-in-water emulsion composition according to any one of claims 1 to 5, wherein the HLB value of component (C), expressed as a weighted average of the HLB values ​​of each nonionic surfactant by content, is 8 to 17. Item 7. The oil-in-water emulsion composition according to any one of items 1 to 6, wherein the component (D) comprises a polyhydric alcohol, and the polyhydric alcohol comprises a solid polyalkylene glycol. Item 8. The oil-in-water emulsion composition according to any one of items 1 to 9, wherein the component (B) comprises both a hydrocarbon oil and a higher alcohol. Item 9. The oil-in-water emulsion composition according to any one of items 1 to 8, wherein the higher alcohol is a linear alcohol. Item 10. An oil-in-water emulsion composition according to any one of items 1 to 11, further comprising a silicate compound. Item 11. The oil-in-water emulsion composition according to Item 10, wherein the content of the silicic acid compound is 0.7% by weight or less. Item 12. The oil-in-water emulsion composition according to any one of items 1 to 11, wherein the (C) component is selected from the group consisting of polyoxyalkylene alkyl ethers and polyoxyalkylene arachidyl ethers. Item 13. The oil-in-water emulsion composition according to Item 12, wherein the (C) component is two or more polyoxyalkylene alkyl ethers, and the hydrophobic alkyl groups of each polyoxyalkylene alkyl ether are the same as those of each other. Item 14. The content of (B) is 52 parts by weight or more per 100 parts by weight of the total amount of component (B) and component (C), and An oil-in-water emulsion composition according to any one of claims 2 to 13, wherein the content of (B) is 11.7 parts by weight or more per 100 parts by weight of the total amount of component (B) and component (D). Item 15. An oil-in-water emulsion composition according to any one of items 1 to 14, used as an inhibitor of bleeding or exudate in cancerous skin ulcer sites, or as an agent for reducing cancerous skin ulcers. Item 16. Use of any of the oil-in-water emulsion compositions described in items 1 to 14 for the suppression of bleeding or exudation in cancerous skin ulcer sites, or for the reduction of cancerous skin ulcers. Item 17. A method for suppressing bleeding or exudation at a site of a cancerous skin ulcer, or a method for reducing a cancerous skin ulcer, comprising the step of applying an oil-in-water emulsion composition described in any of Items 1 to 14 to a patient with a cancerous skin ulcer. [Effects of the Invention]

[0011] According to the present invention, a formulation of an oil-in-water emulsion composition containing zinc chloride as an active ingredient is provided, which exhibits excellent separation inhibition and / or drug release properties. [Modes for carrying out the invention]

[0012] The first oil-in-water emulsion composition of the present invention comprises (A) 30 to 60% by weight of zinc chloride (hereinafter also referred to as "component (A)"), (B) an oily base selected from the group consisting of hydrocarbons and higher alcohols (hereinafter also referred to as "component (B)"), (C) a nonionic surfactant (hereinafter also referred to as "component (C)"), and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols (hereinafter also referred to as "component (D)"); the content of (B) per 100 parts by weight of the total amount of component (B) and component (C) (hereinafter also referred to as "ratio 1") is 52 parts by weight or more; and the content of (B) per 100 parts by weight of the total amount of component (B) and component (D) (hereinafter also referred to as "ratio 2") is 11.7 parts by weight or more.

[0013] The second oil-in-water emulsion composition of the present invention contains (A) 30 to 60% by weight of zinc chloride (hereinafter also referred to as the “(A) component”), (B) an oil-based base selected from the group consisting of hydrocarbons and higher alcohols (hereinafter also referred to as the “(B) component”), (C) a nonionic surfactant (hereinafter also referred to as the “(C) component”), and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols (hereinafter also referred to as the “(D) component”), and is characterized in that the (D) component is water and polyethylene glycol.

[0014] The first oil-in-water emulsion composition and the second oil-in-water emulsion composition are collectively referred to as the “oil-in-water emulsion composition”. Hereinafter, the oil-in-water emulsion composition of the present invention will be described in detail.

[0015] (A) Zinc chloride The oil-in-water emulsion composition of the present invention contains zinc chloride at a specific concentration as the (A) component. Zinc chloride is a component known as a component of moxa ointment.

[0016] Zinc chloride has an astringent and corrosive action on tissues and a bactericidal action based on its protein denaturing action. Therefore, zinc chloride exhibits effects such as fixation of tumors, accompanying hemostasis and suppression of exudate, and reduction of bad odor due to secondary infection. Zinc chloride used in the present invention can be used without particular limitation as long as it can be used as an external composition. For example, zinc chloride described in the seventeenth revised Japanese Pharmacopoeia can be mentioned.

[0017] The content of zinc chloride in the oil-in-water emulsion composition of the present invention is 30% by weight or more. The lower limit of the preferred content of zinc chloride is 40% by weight or more, more preferably 43% by weight or more. The upper limit of the content of zinc chloride is not particularly limited, but from the viewpoint of more preferably obtaining separation inhibitory properties, for example, it is 60% by weight or less, preferably 55% by weight or less, more preferably 50% by weight or less, and still more preferably 46% by weight or less.

[0018] (B) Oily base The oil-in-water emulsion composition of the present invention contains, as component (B), a specific oily base selected from the group consisting of hydrocarbon oils and higher alcohols in a predetermined ratio.

[0019] The hydrocarbon oil used in this invention may be any of the following, as long as it is pharmaceutically acceptable: a solid hydrocarbon oil, a semi-solid (paste-like) hydrocarbon oil, or a liquid hydrocarbon oil. Examples of solid hydrocarbon oils include paraffin wax (solid paraffin), ceresin, petrolatum, and microcrystalline wax. Examples of semi-solid (paste-like) hydrocarbon oils include petrolatum and gelling hydrocarbons. Examples of liquid hydrocarbon oils include liquid paraffin, squalene, and squalane.

[0020] These polyhydric hydrogen oils may be used individually or in combination of multiple types.

[0021] Among these hydrocarbons, solid hydrocarbon oils are preferred, and paraffin wax (solid paraffin) is preferred.

[0022] The higher alcohol can be any pharmaceutically acceptable monohydric alcohol with 6 or more carbon atoms. For example, monohydric alcohols with 8 to 24 carbon atoms are preferred, preferably monohydric alcohols with 10 to 22 carbon atoms, more preferably monohydric alcohols with 14 to 20 carbon atoms, and even more preferably monohydric alcohols with 16 to 18 carbon atoms.

[0023] The carbon chain of the higher alcohol used in this invention may be linear or branched. Furthermore, the carbon chain of the higher alcohol used in this invention may be saturated or unsaturated, but saturated is preferred.

[0024] Examples of higher alcohols used in the present invention include linear higher alcohols such as caprylic alcohol, lauryl alcohol, myristyl alcohol, cetanol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, arachidyl alcohol, behenyl alcohol, and linoglyceryl alcohol; and branched higher alcohols such as isostearyl alcohol and 2-octyldodecanol. These higher alcohols may be used individually or in combination of two or more.

[0025] From the viewpoint of further improving separation inhibition, the higher alcohols used in the present invention are preferably linear higher alcohols (i.e., not containing branched alcohols as higher alcohols), more preferably linear monohydric alcohols having 10 to 22 carbon atoms, even more preferably linear monohydric alcohols having 14 to 20 carbon atoms, even more preferably linear monohydric alcohols having 16 to 18 carbon atoms, and particularly preferably cetanol and stearyl alcohol.

[0026] In the present invention, component (B) may be either a hydrocarbon oil or a higher alcohol, or both may be used, but it is preferable to use both a hydrocarbon oil and a higher alcohol from the viewpoint of improving separation inhibition and / or discoloration inhibition.

[0027] In the first oil-in-water emulsion composition of the present invention, the content of (B) (ratio 1) relative to 100 parts by weight of the total amount of component (B) and component (C) is 52 parts by weight or more. In the second oil-in-water emulsion composition of the present invention, the content of (B) (ratio 1) relative to 100 parts by weight of the total amount of component (B) and component (C) is preferably 52 parts by weight or more. From the viewpoint of further improving separation suppression, the ratio 1 is preferably 60 parts by weight or more, more preferably 65 parts by weight or more, and even more preferably 70 parts by weight or more. There is no particular upper limit to the ratio 1, but for example, it is less than 100 parts by weight, preferably 95 parts by weight or less, more preferably 90 parts by weight or less, and even more preferably 80 parts by weight or less.

[0028] In the first oil-in-water emulsion composition of the present invention, the content of (B) (ratio 2) relative to 100 parts by weight of the total amount of component (B) and component (D) is 11.7 parts by weight or more. In the second oil-in-water emulsion composition of the present invention, the content of (B) (ratio 2) relative to 100 parts by weight of the total amount of component (B) and component (D) is preferably 11.7 parts by weight or more. From the viewpoint of further improving separation suppression, the ratio 2 is preferably 15.5 parts by weight or more, more preferably 25 parts by weight or more, and even more preferably 30 parts by weight or more. There is no particular upper limit to the ratio 2, but for example, it is 63 parts by weight or less, preferably 50 parts by weight or less, more preferably 45 parts by weight or less, even more preferably 40 parts by weight or less, and even more preferably 35 parts by weight or less.

[0029] The specific content (total amount) of component (B) in the oil-in-water emulsion composition of the present invention is, for example, 6 to 46.5% by weight, preferably 11.5 to 46.5% by weight, more preferably 13 to 35% by weight, and preferably 15 to 32% by weight.

[0030] In the oil-in-water emulsion composition of the present invention, the content of component (B) per 1 part by weight of component (A) is preferably 0.34 to 0.73 parts by weight.

[0031] In the oil-in-water emulsion composition of the present invention, when component (B) contains a hydrocarbon oil, the specific content of the hydrocarbon oil is, for example, 0.8 to 16% by weight, preferably 9 to 14% by weight.

[0032] In the oil-in-water emulsion composition of the present invention, when component (B) contains a higher alcohol, the specific content of the higher alcohol can be, for example, 3 to 16% by weight, preferably 4 to 8% by weight.

[0033] In the oil-in-water emulsion composition of the present invention, when component (B) contains a hydrocarbon oil and a higher alcohol, the content of the higher alcohol per 1 part by weight of the hydrocarbon oil is, for example, 0.2 to 8.2 parts by weight, preferably 0.35 to 1 part by weight.

[0034] (C) Nonionic surfactant The oil-in-water emulsion composition of the present invention contains a nonionic surfactant as component (C).

[0035] Examples of nonionic surfactants used in the present invention include polyoxyalkylene alkyl ethers, polyoxyalkylene arachidyl ethers, polymers of ethylene oxide and / or propylene oxide, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. These nonionic surfactants may be used individually or in combination.

[0036] Among these nonionic surfactants, polyoxyalkylene alkyl ethers and polyoxyalkylene arachil ethers are preferred from the viewpoint of further improving separation inhibition and / or discoloration inhibition.

[0037] Polyoxyalkylene alkyl ethers are ethers of polyalkylene glycol and higher alcohols. Examples of higher alcohols include monohydric alcohols with 8 to 24 carbon atoms, specifically linear higher alcohols such as caprylic alcohol, lauryl alcohol, myristyl alcohol, cetanol, stearyl alcohol, oleyl alcohol, linoleyl alcohol, arachidyl alcohol, behenyl alcohol, and linoglyceryl alcohol, with stearyl alcohol and behenyl alcohol being preferred. The alkylene group of the polyalkylene glycol has 2 to 3 carbon atoms, and specific examples of polyalkylene glycols include polyethylene glycol, polypropylene glycol, and combinations thereof, with polyethylene glycol being preferred. The number of alkylene oxide additions in the polyoxyalkylene alkyl ether is, for example, 2 to 35, preferably 2 to 20. These polyoxyalkylene alkyl ethers may be used individually or in combination.

[0038] Polyoxyalkylene arachidyl ethers are ethers of polyalkylene glycol and arachidyl alcohol. Examples of arachidyl alcohols include benzyl alcohol and phenethyl alcohol. The alkylene group of the polyalkylene glycol has 2 to 3 carbon atoms, and specific examples of polyalkylene glycols include polyethylene glycol, polypropylene glycol, and combinations thereof, with polyethylene glycol being preferred. The number of alkylene oxides added to the polyoxyalkylene arachidyl ether is, for example, 2 to 35, preferably 2 to 20. These polyoxyalkylene arachidyl ethers may be used individually or in combination of multiple types.

[0039] In the present invention, either polyoxyalkylene alkyl ether or polyoxyalkylene arachyl ether may be used, or both may be used in combination. However, from the viewpoint of further improving separation inhibition, polyoxyalkylene alkyl ether is preferably used.

[0040] Furthermore, in the present invention, when multiple types of polyoxyalkylene alkyl ethers (i.e., two or more types) are used, the hydrophobic alkyl groups of each polyoxyalkylene alkyl ether (i.e., alkyl groups derived from the above-mentioned higher alcohols) may be the same or different, but from the viewpoint of further improving separation inhibition, they are preferably the same.

[0041] The HLB values ​​of each nonionic surfactant used as component (C) are not particularly limited, and examples include 7 to 19. Similarly, the HLB value expressed by weighting the HLB of one or more nonionic surfactants used as component (C) by their content (hereinafter also referred to as "HLB value of component (C)") is not particularly limited, but examples include 8 to 17. Furthermore, from the viewpoint of improving discoloration suppression, the HLB value of component (C) is preferably 11.5 to 15, 11.5 to 13, or 11.5 to 12. Regarding the method for calculating the HLB value of component (C), for example, when using a combination of 3% by weight of a nonionic surfactant with an HLB of 8 and 2% by weight of a nonionic surfactant with an HLB of 17 as component (C), the weighted average of each HLB based on their content is calculated as {8 × 3 / (3 + 2)} + {17 × 2 / (3 + 2)} = 11.6.

[0042] The amount of component (C) in the oil-in-water emulsion composition of the present invention is not particularly limited, as long as its relationship to the amount of component (B) is as described above (i.e., the content of (B) is 52 parts by weight or more per 100 parts by weight of the total amount of components (B) and (C)). A specific content of component (C) in the oil-in-water emulsion composition of the present invention is, for example, 12.7% by weight or less. From the viewpoint of improving discoloration suppression, a specific content of component (C) is preferably 1 to 7.5% by weight, more preferably 1.5 to 7.5% by weight, 3 to 7% by weight, or 4 to 6% by weight.

[0043] In the oil-in-water emulsion composition of the present invention, the content of component (C) per 1 part by weight of component (A) is preferably 0.09 to 0.14 parts by weight.

[0044] (D) Aqueous base The oil-in-water emulsion composition of the present invention contains an aqueous base selected from the group consisting of water and polyhydric alcohols as component (D). The first oil-in-water emulsion composition of the present invention usually contains water as component (D), preferably both water and polyhydric alcohols. In the second oil-in-water emulsion composition of the present invention, component (D) is water and polyethylene glycol.

[0045] The polyhydric alcohol used in the first oil-in-water emulsion composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Specific examples of polyhydric alcohols used in the present invention include, for example, dihydric alcohols such as propylene glycol, 1,3-butylene glycol, ethylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, and polyethylene glycol; and trihydric alcohols such as glycerin.

[0046] In the first oil-in-water emulsion composition and the second oil-in-water emulsion composition of the present invention, the molecular weight of polyethylene glycol is not particularly limited, and for example, the number average molecular weight calculated based on the hydroxyl value measured in accordance with JIS K 1557 can range from 3600 to 22000. In other words, the polyethylene glycol may be a liquid polyethylene glycol at 25°C, a semi-solid (paste-like) polyethylene glycol at 25°C, or a solid polyethylene glycol at 25°C. These polyhydric alcohols may be used individually or in combination. Specific examples of polyethylene glycol include macrogol 400 (number average molecular weight 400), macrogol 1500 (number average molecular weight 550), macrogol 4000 (number average molecular weight 3100), macrogol 6000 (number average molecular weight 8600), and macrogol 20000 (number average molecular weight 20000), as described in the 17th edition of the Japanese Pharmacopoeia.

[0047] In the first oil-in-water emulsion composition of the present invention, these polyhydric alcohols may be used individually or in combination of two or more.

[0048] In the first oil-in-water emulsion composition of the present invention, among these polyhydric alcohols, dihydric alcohols are preferred. Furthermore, from the viewpoint of improving discoloration suppression, component (D) preferably comprises semi-solid or solid polyethylene glycol, more preferably solid polyethylene glycol, more preferably polyethylene glycol with a number average molecular weight of 2500 to 10000, and even more preferably polyethylene glycol with a number average molecular weight of 2800 to 4500. In the second oil-in-water emulsion composition of the present invention, from the viewpoint of further improving drug release, polyethylene glycol preferably comprises solid polyethylene glycol, more preferably polyethylene glycol with a number average molecular weight of 2500 to 10000, and even more preferably polyethylene glycol with a number average molecular weight of 2800 to 4500.

[0049] The amount of component (D) in the first oil-in-water emulsion composition of the present invention is not particularly limited, as long as its relationship to the amount of component (B) is as described above (i.e., the content of (B) is 11.7 parts by weight or more per 100 parts by weight of the total amount of components (B) and (D)). The amount of component (D) in the second oil-in-water emulsion composition of the present invention is preferably set to an amount such that its relationship to the amount of component (B) is as described above (i.e., the content of (B) is 11.7 parts by weight or more per 100 parts by weight of the total amount of components (B) and (D)). Specific content (total amount) of component (D) in the oil-in-water emulsion composition of the present invention includes, for example, 16 to 50% by weight, preferably 25 to 40% by weight, and more preferably 30 to 36% by weight.

[0050] In the oil-in-water emulsion composition of the present invention, the content of component (D) per 1 part by weight of component (A) is preferably 0.56 to 0.91 parts by weight.

[0051] The amount of component (D) in the oil-in-water emulsion composition of the present invention is, from the viewpoint of improving the applicability of the oil-in-water emulsion composition, preferably 42 parts by weight or more, 48 parts by weight or more, or 52 parts by weight or more, as the content of component (D) relative to 100 parts by weight of the total amount of components (B), (C), and (D) (hereinafter also referred to as "ratio 3"). There is no particular upper limit to ratio 3, but examples include 76 parts by weight or less, 70 parts by weight or less, or 60 parts by weight or less.

[0052] The water content in the oil-in-water emulsion composition of the present invention can be, for example, 10 to 50% by weight, preferably 14 to 42% by weight, more preferably 20 to 34% by weight, and even more preferably 25 to 30% by weight.

[0053] When the first oil-in-water emulsion composition of the present invention contains a polyhydric alcohol, the polyhydric alcohol content is, for example, 0.5 to 22% by weight, preferably 1 to 20% by weight, more preferably 2.5 to 10% by weight, and even more preferably 3 to 7% by weight. The polyethylene glycol content in the second oil-in-water emulsion composition of the present invention is, for example, 0.5 to 22% by weight, preferably 1 to 20% by weight, more preferably 2.5 to 10% by weight, and even more preferably 3 to 7% by weight.

[0054] In the first oil-in-water emulsion composition of the present invention, when component (D) contains water and a polyhydric alcohol, the content of the polyhydric alcohol per 1 part by weight of water is, for example, 0.02 to 0.85 parts by weight, preferably 0.05 to 0.5 parts by weight, and more preferably 0.1 to 0.3 parts by weight. In the second oil-in-water emulsion composition of the present invention, the content of polyethylene glycol per 1 part by weight of water is, for example, 0.02 to 0.85 parts by weight, preferably 0.05 to 0.5 parts by weight, and more preferably 0.1 to 0.3 parts by weight.

[0055] Silicate compounds The oil-in-water emulsion composition of the present invention may further contain a silicate compound. The silicate compound may be added for the purpose of improving the adhesion and / or drug release properties of the oil-in-water emulsion composition.

[0056] Silicate compounds are compounds that contain silicon dioxide (SiO2) as a component, and specific examples include silicon dioxide, aluminum silicate, magnesium silicate, magnesium aluminum silicate, sodium magnesium silicate, and calcium silicate. These silicate compounds may be used individually or in combination. Among these silicate compounds, silicon dioxide is preferred.

[0057] When the oil-in-water emulsion composition of the present invention contains a silicate compound, the silicate compound content can be, for example, 0.1 to 3% by weight, preferably 0.3 to 2% by weight, and more preferably 0.4 to 0.8% by weight.

[0058] Furthermore, when the oil-in-water emulsion composition of the present invention contains a silicate compound, the silicate compound content is preferably 0.7% by weight or less, more preferably 0.6% by weight or less, and even more preferably 0.55% by weight or less, from the viewpoint of further improving drug release properties. The lower limit of the silicate compound content is not particularly limited, but examples include 0.1% by weight or more, 0.3% by weight or more, or 0.4% by weight or more.

[0059] Other ingredients The oil-in-water emulsion composition of the present invention may, in addition to the above components, optionally contain other bases and / or additives commonly used in topical skin preparations, etc. Such bases are not particularly limited to the extent that they are pharmaceutically acceptable, but examples include oily bases other than component (B) above, such as ester oils, fatty acid triglycerides, higher fatty acids, and silicone oils; aqueous bases other than component (D) above, such as monovalent lower (C1-C5) alcohols; and surfactants other than component (C) above, such as anionic surfactants, cationic surfactants, and amphoteric surfactants. In addition, additives include cellulose derivatives (methylcellulose, ethylcellulose, hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, methylhydroxyethylcellulose, and their esters, etc.), polyvinyl alcohol, colorants (titanium dioxide, etc.), flavoring agents, pH adjusters, humectants (dl-sodium pyrrolidone carboxylate solution, D-sorbitol solution, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, UV absorbers, chelating agents, buffering agents, solubilizers, preservatives, and the like.

[0060] In addition to the above-mentioned components, the oil-in-water emulsion composition of the present invention may optionally contain agents used to treat skin malignancies and skin lesions of breast cancer. Examples of such agents include zinc oxide, zinc oxide preparations (zinc oxide starch, zinc oxide ointment, and phenol-zinc oxide liniment, etc.).

[0061] Characteristics, Formulation, etc. The formulation form of the oil-in-water emulsion composition of the present invention is not particularly limited, but from the viewpoint of applicability and retention on the skin, it is usually a cream. Furthermore, a specific embodiment of the topical composition of the present invention is usually a topical pharmaceutical.

[0062] The pH (at 25°C) of the oil-in-water emulsion composition of the present invention can be, for example, 0.6 to 2.6. The consistency of the oil-in-water emulsion composition of the present invention can be, for example, 80 to 130 (1 / 10 mm), preferably 85 to 125 (1 / 10 mm), more preferably 95 to 120 (1 / 10 mm), and more preferably 100 to 110 (1 / 10 mm), as measured at 25°C in accordance with JIS K2220.

[0063] Furthermore, the oil-in-water emulsion composition of the present invention may be either a preparation for use or a commercially available formulation, but it is particularly preferable that the oil-in-water emulsion composition of the present invention be a commercially available formulation because it has excellent separation inhibition properties.

[0064] Purpose The oil-in-water emulsion composition of the present invention is used by applying it to the affected area where bleeding or exudate is observed in cancerous skin ulcer sites. Such affected areas have developed extensive cancerous skin ulcers due to advanced skin cancer or cancers other than skin cancer exposed on the body surface (e.g., breast cancer, head and neck cancer, etc.), and bleeding or exudate is observed. The oil-in-water emulsion composition of the present invention can be used to improve the quality of life (QOL) in such cancerous skin ulcer sites by reducing bleeding or exudate, or by preventing infection or odor caused by these. Furthermore, the oil-in-water emulsion composition of the present invention may also be used for the purpose of reducing cancerous skin ulcers. The oil-in-water emulsion composition of the present invention can be used, for example, in a similar manner to the application of the Moses procedure. Specifically, the topical composition of the present invention is applied to the surface of a cancerous skin ulcer to fix the tumor tissue. In fixing the tumor tissue, the tumor blood vessels are hardened, causing degeneration and necrosis of the tumor tissue, and the necrotic tissue can be fixed and dried. After confirming the fixation of the tumor tissue, the applied oil-in-water emulsion composition can be removed as needed.

[0065] Usage / Dosage The oil-in-water emulsion composition of the present invention can be used in a manner and dosage appropriate to the size of the affected area where bleeding or exudation is observed in cancerous skin ulcer sites, and the degree of bleeding or exudation. For example, it can be used in a manner and dosage based on the Moses method. For example, it can be applied to the affected area once every 7 to 10 days for a period of time appropriate to the symptoms of the affected area.

[0066] Manufacturing method The oil-in-water emulsion composition of the present invention can be manufactured according to known methods for manufacturing emulsions. For example, the following method can be used to manufacture the emulsion composition of the present invention. First, an oil phase composition is prepared by mixing component (B) and other oily components added as needed. Separately, an aqueous phase composition is prepared by mixing component (A) and component (D) and other water-soluble components added as needed. Component (C) may be incorporated into either the aqueous phase composition or the oil phase composition, or both, but it is preferable to incorporate it into the oil phase composition. Next, the obtained aqueous phase composition and oil phase composition are mixed and emulsified using an emulsification method such as a homogenizer to obtain the oil-in-water emulsion composition of the present invention. [Examples]

[0067] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0068] Test Example 1 The oil-in-water emulsion compositions shown in Tables 1 to 10 were prepared by the following procedure. First, the oil phase composition was prepared by mixing components (B) and (C) shown in Tables 1 to 10 and heating and dissolving them. Separately, the aqueous phase composition was prepared by mixing components (A) and (D) and light anhydrous silicic acid shown in Tables 1 to 10. The aqueous phase composition was gradually added to the temperature-controlled oil phase composition, and the particles (oil droplets) were refined using a homomixer. The mixture was then cooled while stirring to obtain the oil-in-water emulsion composition. The obtained oil-in-water emulsion composition is described below. <1> We evaluated the separation inhibition properties. Furthermore, for several compositions, the following was done: <2> from <8> The following evaluations or measurements were performed. The results are shown in Tables 1 to 10.

[0069] <1> Separation suppression The separation inhibition properties were evaluated for all oil-in-water emulsion compositions. Specifically, 20-30 g of each oil-in-water emulsion composition was placed in a glass bottle (inner diameter approximately 30 mm) and stored at 50°C for 4 weeks. The appearance of the oil-in-water emulsion compositions after storage was visually evaluated according to the following criteria. ○: No separation observed △: The aqueous phase is slightly separated (aqueous phase thickness is less than 5% of the total). ×: The aqueous phase is slightly separated (aqueous phase thickness is between 5% and 10% of the total). ××: The aqueous phase was significantly separated (more than 10% of the total aqueous phase thickness).

[0070] <2> Lack of liquidity The oil-in-water emulsion compositions of Examples 1 to 25 were evaluated for their fluidity. Specifically, approximately 5.5 g of the oil-in-water emulsion composition was spread evenly in a circular area with an inner diameter of 30 mm and a height of 5 mm on a horizontal plastic plate. The plastic plate was then tilted 90° from the horizontal plane, and it was evaluated whether the oil-in-water emulsion composition spilled out of the circular area within 15 minutes. A circle (○) was used if the oil-in-water emulsion composition did not spill out, and a cross (×) was used if the oil-in-water emulsion composition spilled out.

[0071] <3> Spreadability The oil-in-water emulsion compositions of Examples 1-25, 57-66, 73, 74, 76, 81, 83-85, 87-90, 92-95, 97, 99, 101, 104, 105, 107, 114, and 125 were evaluated for their applicability (overall evaluation of softness and spreadability). Specifically, wearing gloves, the compositions were scooped up with the first joint of the index finger and applied to chicken breast meat, and evaluated according to the following criteria. ◎: Excellent softness and spreadability, making it easy to apply. ○: Can be applied due to its good softness and spreadability. △: It is somewhat hard and has poor spreadability, making application difficult (application itself is possible). ×: It is hard and difficult to spread, making it unsuitable for application.

[0072] <4> Discoloration suppression The discoloration inhibition properties of the oil-in-water emulsion compositions of Examples 1, 3 to 53 were evaluated. Specifically, 20 to 30 g of the oil-in-water emulsion composition was placed in a glass bottle (inner diameter approximately 30 mm) and stored at 50°C for 4 weeks. The appearance of the oil-in-water emulsion composition after storage was visually evaluated according to the following criteria. ○: Same as before storage △: Slightly discolored compared to before storage. ×: Obvious discoloration compared to before storage.

[0073] <5> Gluing time The adhesion time of the oil-in-water emulsion compositions in Examples 10, 59, 64-66, 73, 74, 76, 81, 83-90, 92, 94, 95, 97, 99, 101, 104, 105, and 107 was evaluated. Specifically, approximately 5.5 g of the oil-in-water emulsion composition was spread evenly in a circular area with an inner diameter of 30 mm and a height of 0.5 mm on a horizontal chicken breast. The chicken breast was then tilted 90° from the horizontal plane, and the time (minutes) required for the oil-in-water emulsion composition to fall was measured. The measurement time was evaluated up to a maximum of 60 minutes. The closer the adhesion time is to 60 minutes, the better the adhesion is considered to be.

[0074] <6> pH For the oil-in-water emulsion compositions of Examples 10, 83, 84, 89, 90, 95, 99, 100, 103-105, and 107, the pH was measured at 20-25°C using a pH meter.

[0075] <7> Drug release amount The drug release properties of oil-in-water emulsion compositions in Examples 10, 57-61, 64-65, 70, 71, 73-75, 81, 83, 85, 87-90, 92-94, 97, 101, 104, 107, 118, and 126 were evaluated. Specifically, a stirring bar was placed in a glass bottle with an inner diameter of approximately 30 mm and a height of 64 mm, and the inside of the glass bottle was filled with approximately 30 g of purified water. Separately, an oil-in-water emulsion composition was evenly filled into a circular ring with an inner diameter of 15 mm and a height of 5 mm, which was placed on the top surface of a filter with a pore size of 0.22 μm, and the bottom surface of the filter was placed in contact with the water surface in the glass bottle. The stirring bar was set to rotate at 300 rpm and stirred for 15 minutes. The purified water in the glass bottle was collected, and the amount of zinc chloride (mg) released from the oil-in-water emulsion composition in the circular ring into the purified water via the filter was measured.

[0076] <8> consistency The consistency (1 / 10 mm) was measured for the oil-in-water emulsion compositions of Examples 10, 57-61, 64-66, 73, 74, 76, 81, 83-85, 87-90, 92-95, 97, 99-101, 103-105, and 107. Specifically, the oil-in-water emulsion composition was used as the sample, adjusted to 25°C, filled into a measuring container, and after removing excess sample and leveling the sample surface, measurement was performed according to JIS K2220. For the measurement, a micro-cone, suitable container, and shaft as described in EUROPEAN PHARMACOPEIA 9.0, 2.9.9 MEASUREMENT OF CONSISTENCY BY PENETROMETRY Figure 2.9.9.-3 were used.

[0077] [Table 1]

[0078] [Table 2]

[0079] [Table 3]

[0080] [Table 4]

[0081] [Table 5]

[0082] [Table 6]

[0083] [Table 7]

[0084] [Table 8]

[0085] [Table 9]

[0086] [Table 10]

[0087] As shown in the comparison between Examples 1 to 127 and Comparative Examples 1 to 9, it was confirmed that excellent separation inhibition can be obtained in an oil-in-water emulsion composition comprising (A) 30% by weight or more of zinc chloride, (B) an oily base selected from the group consisting of hydrocarbon oils and higher alcohols, (C) a nonionic surfactant, and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols, when the content of (B) (ratio 1) relative to 100 parts by weight of the total amount of component (B) and component (C) is 52 parts by weight or more, and the content of (B) (ratio 2) relative to 100 parts by weight of the total amount of component (B) and component (D) is 11.7 parts by weight or more (Examples 1 to 127).

[0088] Furthermore, in cases where component (B) contains only higher alcohols and no hydrocarbons (Examples 26-29, 54-56, 122-127), it was confirmed that better separation inhibition was obtained when ratio 1 was 52-90 parts by weight and / or ratio 2 was 15.7 parts by weight or more (Examples 26-29, 122-127). In contrast, when component (B) contains both hydrocarbons and higher alcohols (Examples 1-25, 30-53, 57-121), it was confirmed that it was even more preferable in that excellent separation inhibition was obtained over a wider range, with ratio 1 being 52 parts by weight or more and ratio 2 being 11.7 parts by weight or more.

[0089] Furthermore, as shown in the comparison between Example 46 and Example 47, it was observed that separation inhibition improved when the higher alcohol contained in component (B) was a linear alcohol and did not contain a branched alcohol (Example 46).

[0090] Among the oil-in-water emulsion compositions tested for applicability in Examples 1-25, 57-66, 73, 74, 76, 81, 83-85, 87-90, 92-95, 97, 99, 101, 104, 105, 107, 114, and 125, applicability was further improved when the content of component (D) (ratio 3) relative to 100 parts by weight of the total amount of component (B), component (C), and component (D) was 42 parts by weight or more (Examples 4-6, 9-25, 57-66, 73, 74, 76, 81, 83-85, 87-90, 92-95, 97, 99, 101, 104, 105, 107, 114, and 125).

[0091] Among the oil-in-water emulsion compositions of Examples 1, 3 to 53, which were tested for discoloration inhibition, when component (B) contained both hydrocarbon oil and higher alcohol (Examples 1, 3 to 53), excellent discoloration inhibition was obtained when the content of component (C) was 1 to 7.5% by weight and the HLB value (weighted average) of component (C) was 8 to 15 (Examples 1, 4 to 6, 9 to 11, 13, 14 to 22, 30 to 53). Even better discoloration inhibition was obtained when the content of component (C) was 1.5 to 7.5% by weight and the HLB value (weighted average) of component (C) was 11.5 to 15 (Examples 1, 4 to 6, 9 to 11, 14 to 17, 19 to 22, 32 to 42).

[0092] Furthermore, among the oil-in-water emulsion compositions of Examples 1, 3 to 53, which were tested for discoloration inhibition, when component (B) contained only higher alcohols without hydrocarbons (Examples 26 to 29), excellent discoloration inhibition was obtained when component (D) contained solid polyalkylene glycol (Examples 28, 29).

[0093] A comparison between Example 86 and Example 87, and between Example 104 and Example 105, revealed that adhesion was further improved when a silicate compound was included (Examples 87 and 105).

[0094] Test Example 2 The oil-in-water emulsion compositions shown in Table 11 were prepared by the following procedure. First, the oil phase composition was prepared by mixing components (B) and (C) shown in Table 11 and heating and dissolving them. Separately, the aqueous phase composition was prepared by mixing components (A) and (D) and light anhydrous silicic acid shown in Table 11. The aqueous phase composition was gradually added to the temperature-controlled oil phase composition, and the particles (oil droplets) were refined using a homomixer. The mixture was then cooled while stirring to obtain the oil-in-water emulsion composition. The obtained oil-in-water emulsion composition was then used in Test Example 1. <1> and <7> Separation inhibition and drug release properties were evaluated in the same manner. The results are shown in Table 11. Table 11 also shows the results for Examples 10, 74, and 75 of Test Example 1.

[0095] [Table 11]

[0096] As shown in Examples 10, 74, 75, and 128-144, it was confirmed that excellent separation inhibition can be obtained in an oil-in-water emulsion composition comprising (A) 30% by weight or more of zinc chloride, (B) an oily base selected from the group consisting of hydrocarbon oils and higher alcohols, (C) a nonionic surfactant, and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols, provided that the content of (B) (ratio 1) relative to 100 parts by weight of the total amount of component (B) and component (C) is 52 parts by weight or more, and the content of (B) (ratio 2) relative to 100 parts by weight of the total amount of component (B) and component (D) is 11.7 parts by weight or more.

[0097] Furthermore, as shown in the comparison between Examples 10, 74, 75, 128-138 and Examples 139-144, in an oil-in-water emulsion composition comprising (A) 30% by weight or more of zinc chloride, (B) an oily base selected from the group consisting of hydrocarbon oils and higher alcohols, (C) a nonionic surfactant, and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols, it was confirmed that when component (D) is water and polyethylene glycol (Examples 10, 74, 75, 128-138), the drug release is also improved. Moreover, as shown in the comparison between Examples 10, 74, 128-138 and Example 75, it was confirmed that the drug release is further improved when the amount of light anhydrous silicic acid is 0.7% by weight or less (Examples 10, 74, 128-138). This also coincided with the finding that, when comparing Examples 10, 57-61, 64-65, 70-71, 73-74, 81, 83, 85, 87-90, 92-94, 97, 101, and 107 of Test Example 1 with Examples 75, 118, and 126, the drug release was further improved when the amount of light anhydrous silicic acid was 0.7% by weight or less (Examples 10, 57-61, 64-65, 70-71, 73-74, 81, 83, 85, 87-90, 92-94, 97, 101, and 107).

Claims

1. (A) 30% by weight or more of zinc chloride, (B) an oily base selected from the group consisting of hydrocarbon oils and higher alcohols, (C) a nonionic surfactant, and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols, the component (C) is selected from the group consisting of polyoxyalkylene alkyl ethers and polyoxyalkylene aralkyl ethers, The content of (B) is 52 parts by weight or more relative to 100 parts by weight of the total amount of the (B) component and the (C) component, and An oil-in-water emulsion composition, wherein the content of (B) is 11.7 parts by weight or more relative to 100 parts by weight of the total amount of the components (B) and (D).

2. (A) 30% by weight or more of zinc chloride, (B) an oily base selected from the group consisting of hydrocarbon oils and higher alcohols, (C) a nonionic surfactant, and (D) an aqueous base selected from the group consisting of water and polyhydric alcohols, The oil-in-water emulsion composition, wherein the component (D) is water and polyethylene glycol.

3. 3. The oil-in-water emulsion composition according to claim 1, wherein the content of the component (D) is 42 parts by weight or more relative to 100 parts by weight of the total amount of the component (B), the component (C), and the component (D).

4. 3. The oil-in-water emulsion composition according to claim 1, wherein the content of the component (C) is 12.7% by weight or less.

5. 3. The oil-in-water emulsion composition according to claim 1, wherein the content of component (C) is 1 to 7.5% by weight.

6. the component (C) is one or more nonionic surfactants, 3. The oil-in-water emulsion composition according to claim 1, wherein the HLB value of component (C), expressed as a weighted average of the HLB values ​​of the nonionic surfactants in terms of their content, is 8 to 17.

7. 2. The oil-in-water emulsion composition according to claim 1, wherein the component (D) comprises a polyhydric alcohol, and the polyhydric alcohol comprises a solid polyalkylene glycol.

8. 3. The oil-in-water emulsion composition according to claim 1, wherein the component (B) comprises both a hydrocarbon oil and a higher alcohol.

9. 3. The oil-in-water emulsion composition according to claim 1, wherein the higher alcohol is a linear alcohol.

10. The oil-in-water emulsion composition according to claim 1 or 2, further comprising a silicic acid compound.

11. 11. The oil-in-water emulsion composition according to claim 10, wherein the content of the silicate compound is 0.7% by weight or less.

12. 3. The oil-in-water emulsion composition according to claim 1, wherein the component (C) is two or more types of polyoxyalkylene alkyl ethers, and the hydrophobic alkyl groups of the respective polyoxyalkylene alkyl ethers are the same as each other.

13. The content of (B) is 52 parts by weight or more relative to 100 parts by weight of the total amount of the (B) component and the (C) component, and 3. The oil-in-water emulsion composition according to claim 2, wherein the content of the component (B) is 11.7 parts by weight or more relative to 100 parts by weight of the total amount of the component (B) and the component (D).