HK40076552B - Oil-based composition - Google Patents
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- HK40076552B HK40076552B HK42022065502.1A HK42022065502A HK40076552B HK 40076552 B HK40076552 B HK 40076552B HK 42022065502 A HK42022065502 A HK 42022065502A HK 40076552 B HK40076552 B HK 40076552B
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Description
This application is a divisional application of the invention patent application with application number 201880071202.1 entitled "Oil-based Composition". The aforementioned invention patent application is the Chinese national phase application of the PCT international application with application number PCT/JP2018/040287 filed on October 30, 2018.
Technical Field
This invention relates to an oil-based composition that stably contains the active ingredients of an anti-aging cosmetic.
Background Technology
Wrinkles are a representative symptom of skin aging caused by increasing age. Wrinkles are broadly classified into superficial wrinkles that can be improved through moisturizing and deep wrinkles caused by the accumulation of UV exposure and physical irritants; the latter, deep wrinkles, are very difficult to prevent or improve. Furthermore, various wrinkle-improving agents are currently under development (see, for example, Non-Patent Literature 1). Among such wrinkle-improving agents, those with retinoic acid as the active ingredient are well-known. In the United States, retinoic acid is licensed as a treatment for wrinkles and acne, but it is not licensed in Japan due to safety concerns, such as skin irritation. In addition, other wrinkle-improving agents have been reported, such as collagen production promoters (see, for example, Patent Literature 1) and hyaluronic acid production promoters (see, for example, Patent Literature 2). However, it is difficult to say that all of the aforementioned wrinkle-improving agents have sufficient efficacy, and an effective method has not yet been established.
Elastase inhibitors are wrinkle improvers with a different mechanism of action than the aforementioned wrinkle improvers. Elastin, a structural protein present in skin tissue, forms cross-linked structures and maintains tissue elasticity. It is well known that skin stimuli such as ultraviolet radiation overexpress and activate elastase, an enzyme that degrades elastin, causing elastin denaturation and breakdown, leading to decreased skin tension and elasticity, and promoting wrinkle formation. Elastase inhibitors exert their effect of preventing or improving wrinkle formation by inhibiting this elastin-degrading enzyme. On the other hand, although structural analysis of elastin-degrading enzymes and matrices, as well as research on their structure-activity relationships, are constantly developing, it is difficult to achieve high enzyme inhibitory activity and selectivity using low-molecular-weight organic molecules. Ingredients with high enzyme inhibitory activity contain a large number of peptides and their derivatives (e.g., see Patent Document 3).
As elastase inhibitors of such peptide derivatives, peptide derivatives represented by WS7622A monosulfate or disulfate are known (e.g., see Patent Document 4), and attempts have been made to apply them to ischemic diseases through this pharmacological action. In addition, compounds represented by the following general formula (1) are known to have leukocyte elastase inhibitory activity similar to WS7622A, and their preventive or therapeutic effects on skin aging have been reported (e.g., see Patent Document 5).
In the formula, R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms.
Existing technical documents
Patent Document 1: Japanese Patent Application Publication No. 2002-255847
Patent Document 2: Japanese Patent Application Publication No. 2004-123637
Patent Document 3: International Publication No. 2001/40263
Patent Document 4: International Publication No. 1998/27998
Patent Document 5: International Publication No. 1999/43352
Non-Patent Literature 1: Development Technology of Anti-aging, Whitening and Moisturizing Cosmetics, CMC Publishing, supervised by Masato Suzuki, Chapter 2 (Anti-aging and Anti-wrinkle) Functional Cosmetics
Summary of the Invention
The problem to be solved by the present invention
The inventors have discovered that, since the compound represented by the general formula (1) is easily decomposed, there is a stability problem when the compound is contained in a skin anti-aging composition.
The present invention was made under the following circumstances, and the problem to be solved is to provide a method for chemically stable formulation in a composition of a compound of the above general formula (1), its isomers and/or their pharmaceutically acceptable salts.
Problem-solving methods
In view of the above, the inventors, after in-depth research, discovered that by dispersing the compound represented by the general formula (1), its isomers and/or their pharmaceutically acceptable salts into a specific oiling agent to form an oily composition, the decomposition of the compound can be suppressed.
Furthermore, in dispersion compositions, the dispersed components typically settle over time. The inventors have discovered that by further containing powders, solid lipids, and/or semi-solid lipids in the composition, the compounds represented by the general formula (1), their isomers, and/or pharmaceutically acceptable salts can be uniformly dispersed, thereby achieving dispersion stability over time, thus completing the present invention.
That is, the present invention is as follows.
[1] An oily composition comprising: a compound of the following general formula (1), its isomers and/or their pharmaceutically acceptable salts, and an oil having 0 to 2 hydroxyl groups.
In the formula, R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms.
[2][1] In the composition described, the oil having 0 to 2 hydroxyl groups is selected from the group consisting of hydrocarbon oil, silicone oil and ester oil.
In the compositions described in [3][1] or [2], the content of the oil having 0 to 2 hydroxyl groups is 50% or more by mass of the whole composition.
The compositions described in any one of [4][1] to [3] further contain an oily gelling agent.
The composition described in any one of [5][1] to [4] further contains powder.
[6][5] In the composition described, the content of the powder is 0.5 to 20% by mass of the whole composition.
The composition described in any one of [7][1] to [6] is an oleogel formulation.
[8][7] The composition contains more than 5% by mass of solid grease and/or semi-solid grease as a whole composition.
The composition described in any one of [9][1] to [8] is substantially free of water.
The composition described in any one of [10][1] to [9] is a topical skin agent.
Effects of the present invention
According to the present invention, it is possible to provide chemically stable compositions in which the decomposition of the compounds represented by the general formula (1), their isomers, and/or their pharmaceutically acceptable salts is inhibited. Furthermore, it is possible to provide compositions in which the compounds remain uniformly dispersed after a period of time.
Detailed Implementation
The compositions of the present invention are characterized in that they contain: a compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts, and an oil having 0 to 2 hydroxyl groups.
The compounds represented by general formula (1), their isomers and/or their pharmaceutically acceptable salts can be manufactured by, for example, the method described in Japanese Patent Application Publication No. 04-297446.
The compound represented by general formula (1) is an optically active compound having multiple asymmetric carbon atoms in its molecular structure. Therefore, as its isomers, there exist enantiomers and diastereomers. Furthermore, as the compound represented by general formula (1) of the present invention, there exist racemic mixtures, enantiomers, diastereomers, and compounds in which the above isomers are mixed in any proportion.
Regarding the compound represented by the general formula (1) of the present invention, R1 represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylic acid ester group having 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
The R1 may preferably include: carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl, propoxycarbonylmethyl, propoxycarbonylethyl, propoxycarbonylpropyl, propoxycarbonylbutyl, butoxycarbonylmethyl, butoxycarbonylethyl, butoxycarbonylpropyl, butoxycarbonylbutyl, etc., and more preferably, carboxymethyl.
The R2 and R3 can preferably be listed independently as follows: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and more preferably isopropyl.
The compound represented by general formula (1) exhibits human leukocyte elastase inhibitory activity, and is expected to have a therapeutic effect on ischemic cerebral diseases, such as cerebral infarction. Furthermore, for example, as described in International Publication No. 1999/43352, it has preventive or therapeutic effects on skin aging. In addition, the compound represented by general formula (1) of this invention promotes the regeneration of elastic fibers in the dermal papillae, the regeneration of fine collagen fibers in the dermis directly beneath the epidermis, and increases epidermal thickness, thereby exerting a preventive or improving effect on wrinkle formation.
The compound represented by general formula (1) is preferably the compound represented by general formula (2) below.
Regarding the compound represented by the general formula (2) of the present invention, R4 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms substituted by a carboxyl group, and R5 and R6 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms. Specifically, R4 can be represented by carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 3-carboxybutyl, 4-carboxybutyl, etc., and more preferably, carboxymethyl.
R5 and R6 each independently represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms. R5 and R6 can preferably be specifically listed as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and more preferably isobutyl. Furthermore, suitable examples of compounds represented by the general formula (2) include 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-isopentanoyl-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyl ... [Propyl]amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N- [3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl] [4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[ ...[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ -[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl] -L-Isopentyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro- 1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide (3(RS)-N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2- [Oxypropyl]-L-proline amide), N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide.
Among the compounds represented by the general formula (2) above, 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane is more preferably listed, and 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane represented by the formula (3) below is even more preferred. In addition, as the compound contained in the composition of the present invention, the sodium salt of the 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (hereinafter also referred to as "KSK32") is particularly preferred.
It should be noted that KSK32, according to other nomenclature, can also be expressed as N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[(RS)-3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, which is the same compound.
In this invention, the compound represented by general formula (1) can be directly included in the composition, or it can be treated with a pharmaceutically acceptable acid or base to convert it into a salt form and used as a salt. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and carbonate can be listed; organic acid salts such as maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, p-toluenesulfonate, and benzenesulfonate can be listed; alkali metal salts such as sodium and potassium salts can be listed; alkaline earth metal salts such as calcium and magnesium salts can be listed; organic amine salts such as triethylamine, triethanolamine, ammonium, monoethanolamine, and piperidine salts can be listed; and basic amino acid salts such as lysine and arginine salts can be listed.
Furthermore, the compositions of the present invention may also contain one or more of the compounds represented by the general formula (1), their isomers and/or their pharmaceutically acceptable salts.
The content of the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts in the composition of the present invention is not particularly limited, but is preferably 0.01 to 10% by mass relative to the whole composition, more preferably 0.1 to 5% by mass. By containing it within this range, the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts can easily exert their effect of preventing or improving the formation of wrinkles.
It can be fully utilized.
The compositions of the present invention are obtained by dispersing the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts in an oil having 0 to 2 hydroxyl groups.
The oil is not particularly limited and is selected from the group consisting of hydrocarbon oils, silicone oils, and ester oils. Furthermore, the number of hydroxyl groups is more preferably 0 to 1, and even more preferably 0, i.e., no hydroxyl groups.
Here, the number of hydroxyl groups refers to the number in a single molecule.
Examples of suitable hydrocarbon oils include, for example, paraffin, isoparaffin, liquid paraffin, α-olefin oligomers, polyethylene, squalane, isododecane, isohexadecane, etc.
As a silicone oil, it may or may not have side chains, and it may or may not be cross-linked. Preferred examples include polysiloxane, dimethyl polysiloxane, decamethylcyclopentasiloxane, methyl polysiloxane, diphenyl dimethyl silicone oil, etc.
Preferred ester oils include, for example, glyceryl tri-2-ethylhexanoate, glyceryl triisostearate, hexadecyl 2-ethylhexanoate, tri(caprylic/capric) glyceryl tristearate, ethylene glycol distearate, N-lauroyl sarcosinate, glyceryl triisostearate, diisostearate malate, and ethylene glycol monostearate.
The oil in the composition of the present invention is capable of dispersing the compound represented by general formula (1), its isomers and/or their pharmaceutically acceptable salts.
Furthermore, since the compounds represented by the general formula (1), their isomers, and/or their pharmaceutically acceptable salts are prone to decomposition, there is a problem that the content of the compound decreases over time in compositions containing them. To address this problem, the present invention enables the chemically stable formulation of the compound in the composition by using an oil having 0 to 2 hydroxyl groups as a dispersion medium.
The oil having 0 to 2 hydroxyl groups in the composition of the present invention comprises 50% by mass or more, more preferably 80% by mass, and even more preferably 90% by mass or more, relative to the total composition. Within this range, the compound represented by the general formula (1), its isomers, and/or their pharmaceutically acceptable salts are readily dispersed.
Furthermore, the total content of oils in the compositions of the present invention is generally 50% by mass or more relative to the whole composition, preferably 60% by mass or more.
Furthermore, the content of the oil having three or more hydroxyl groups is preferably 50% by mass or less relative to the total composition, more preferably 25% by mass or less, and even more preferably 5% by mass or less. This is because when oils having three or more hydroxyl groups coexist in a certain amount or more, the compound represented by the general formula (1), its isomers, and/or their pharmaceutically acceptable salts are easily decomposed, and there is a situation where the residual amount of the compound in the composition decreases over time.
Here, examples of oils containing hydroxyl groups include, but are not limited to, monoesters or diesters formed from fatty acids and polyglycerols, esters formed from fatty acids and sugar alcohols, and esters formed from fatty acids and polysaccharide alcohols.
Furthermore, the oil in the composition of the present invention preferably contains solid grease and/or semi-solid grease, more preferably solid grease and/or semi-solid grease having 0 to 2 hydroxyl groups, and even more preferably solid grease and/or semi-solid grease without hydroxyl groups.
By containing solid or semi-solid lipids, the viscosity of the composition increases, thus the compounds, isomers, and/or pharmaceutically acceptable salts of the general formula (1) dispersed in the composition are less likely to settle over time, resulting in a composition with excellent dispersion stability over time. This embodiment is applicable to oleogel formulations, etc., described later.
The content of solid fats and/or semi-solid fats is preferably 5% by mass or more of the total composition, more preferably 10% by mass or more, and even more preferably 20% by mass or more. Furthermore, it is preferably 50% by mass or less of the total composition, more preferably 40% by mass or less, and even more preferably 30% by mass or less.
Here, solid grease includes semi-solid grease. It should be noted that solid grease refers to grease that does not flow at 25°C, while semi-solid grease refers to grease that does not deform significantly in an environment without stress at 1 atmosphere and 20°C, but deforms when subjected to a small amount of stress (approximately 10–100 g/ cm² ). Furthermore, a melting point of 50°C or higher is preferred.
Examples of plant-derived solid and/or semi-solid lipids include carnauba wax, wood wax, candelilla wax, rice bran wax, shea butter, and African wood resin. Examples of animal-derived solid and/or semi-solid lipids include beeswax, shellac wax, and insect wax. Examples of petroleum-derived substances include refined waxes such as paraffin wax and microcrystalline wax. Examples of mineral-derived solid and/or semi-solid lipids include refined waxes such as ceresin, serotonin, and montan wax. Solid or semi-solid lipids from plant and animal sources often contain hydroxyl groups; therefore, refined waxes from petroleum or mineral sources are preferred. It should be noted that these solid and/or semi-solid lipids can be used alone or in combination of two or more.
The compositions of the present invention preferably further contain an oily gelling agent. By containing an oily gelling agent, the viscosity of the composition increases, and therefore the compounds, isomers and/or pharmaceutically acceptable salts of the general formula (1) dispersed in the composition are less likely to settle over time, resulting in a composition with excellent dispersion stability over time.
Here, "oil-based gelling agent" refers to a gelling agent that is compatible with oily components such as oils. There is no particular limitation, and examples include 12-hydroxystearic acid, palmitic dextrin, (palmitic acid/octanoic acid) dextrin, dibutyllauroyl glutamine, and dimethylsiloxane cross-linked polymers.
The content of the oily gelling agent is preferably 0.5% by mass or more of the total composition, more preferably 2% by mass or more, and even more preferably 5% by mass or more. Furthermore, it is preferably 20% by mass or less of the total composition, more preferably 15% by mass or less, and even more preferably 10% by mass or less.
When the composition of the present invention is an oleogel formulation as described later, it is preferable to further contain an oily gelling agent in the solid or semi-solid grease, or to replace the solid or semi-solid grease with an oily gelling agent. In this case, the content is preferably 5% by mass or more of the total composition, including the solid or semi-solid grease.
The compositions of the present invention preferably further contain powder. By containing powder, the viscosity of the composition increases, and therefore the compounds, isomers thereof, and/or pharmaceutically acceptable salts thereof dispersed in the composition according to the general formula (1) are less likely to settle over time, resulting in a composition with excellent dispersion stability over time. This embodiment is suitable for oleogel formulations, etc., as described later.
The powder content is preferably 0.5 to 20% by mass of the whole composition, more preferably 1 to 5% by mass.
As for powders, examples include: surface-treated powders such as silica (anhydrous silica), mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, alumina, and barium sulfate; surface-treated inorganic pigments such as iron oxide red, iron oxide yellow, iron oxide black, cobalt oxide, ultramarine, cyan violet, titanium oxide, and zinc oxide; surface-treated pearlescent agents such as mica titanium, fish scale foil, and bismuth oxychloride; and laked pigments such as Red 202 and Red 22. Organic dyes such as No. 8, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, etc., and organic powders such as polyester powder, polyamide powder, polyethylene powder, polymethyl methacrylate, nylon powder, and organopolysiloxane elastomers.
Furthermore, there are no particular limitations on the shape; examples include spherical, hemispherical, and sheet-like shapes commonly used in cosmetics and other topical skin agents, as well as porous shapes.
In addition, the particle size should be the same as that used in typical cosmetics and other topical skin agents.
In this invention, porous silica is particularly preferred from the viewpoint of the dispersion stability of the composition.
The compositions of the present invention are oily and generally substantially free of water. Here, "substantially free of water" means that its content relative to the whole composition is preferably 0.1% by mass or less, more preferably 0.01% by mass or less, and even more preferably 0.001% by mass or less.
This is because, when water is present in the composition, the compound represented by the general formula (1), its isomers and/or their pharmaceutically acceptable salts become readily decomposed, and there is a situation where the residual amount of the compound in the composition decreases over time.
Regardless of whether it has fluidity, the oily composition of the present invention can be any dosage form such as emulsion, ointment, or oleogel, preferably an oleogel.
The oleogel formulation of this invention typically has a high viscosity and low flowability. For example, it is preferably non-flowable at 25°C, i.e., solid. Furthermore, the viscosity at 25°C is preferably 20,000 Pa·s or higher. By using this formulation, the compound represented by general formula (1), its isomers, and/or their pharmaceutically acceptable salts are less likely to precipitate over time, resulting in a composition with excellent dispersion stability over time.
In the compositions of the present invention, the compound represented by general formula (1), its isomers, and/or their pharmaceutically acceptable salts have a high residual amount in the composition over time. Specifically, for example, the content of the compound after storage at 60°C for 2 weeks is preferably 60% or more, more preferably 80% or more, and even more preferably 95% or more, relative to the content of the compound after storage at 5°C for 2 weeks.
The compositions of the present invention are compositions in which the compounds of the general formula (1), their isomers, and/or their pharmaceutically acceptable salts exhibit high dispersion stability over time. Specifically, for example, this means that no sedimentation of the compound is visually observed after standing at 40°C for 1 day. Alternatively, after standing at 40°C for 1 day, the concentration difference of the compound in the upper 95 v/v% and the lower 95 v/v% of the composition is preferably within 10%, more preferably within 5%, and even more preferably within 0.5%.
In the compositions of the present invention, as previously described, the compounds represented by general formula (1), their isomers, and/or their pharmaceutically acceptable salts are capable of preventing or improving wrinkle formation. Furthermore, the compounds in the compositions of the present invention exhibit excellent decomposition and dispersion stability over time. Therefore, the compositions of the present invention are suitable for use as topical skin agents, more preferably in cosmetics, and particularly preferably in anti-aging cosmetics. It should be noted that cosmetics here include quasi-pharmaceuticals.
In addition to the above-mentioned components, the compositions of the present invention may optionally contain any components commonly used in topical skin preparations, provided that the technical effects of the present invention are not impaired. Examples of such optional components include various active ingredients, oily components, surfactants, polyols, thickeners, ultraviolet absorbers, etc.
As active ingredients, examples include whitening ingredients, wrinkle-improving ingredients, anti-inflammatory ingredients, and extracts from plants and animals.
As a whitening ingredient, any substance commonly used in cosmetics is acceptable; there are no specific limitations. Examples include 4-n-butylresorcinol, ascorbic acid glycoside, 3-O-ethyl ascorbic acid, tranexamic acid, arbutin, ellagic acid, kojic acid, linoleic acid, niacinamide, 5,5'-dipropyldiphenyl-2,2'-diol, disodium 5'-adenosine, hexadecyl tranexamic acid, potassium 4-methoxysalicylate, hydroquinone, and pantothenic acid.
As other wrinkle-improving ingredients, any substance commonly used in cosmetics is acceptable, without specific limitations. Examples include niacinamide, vitamin A or its derivatives (retinol, retinaldehyde, retinoic acid, tretinoin, isotretinoin, tocopherol retinoate, retinyl palmitate, retinol acetate, etc.), benzyl ursolic acid, ursolic acid phosphate, benzyl betulinate, and benzoic acid phosphate.
Extracts derived from plants and animals are acceptable as long as they are substances commonly used in cosmetics; there are no particular limitations. Examples of preferred extracts include: Akebia quinata extract, Phellodendron chinense extract, Asparagus cochinchinensis extract, Avocado extract, Hydrangea macrophylla extract, Almond extract, Arnica extract, Aloe vera extract, Prunus armeniaca extract, Apricot kernel extract, Ginkgo biloba extract, Dalbergia odorifera extract, Fennel extract, Angelica sinensis extract, Rosa rugosa extract, Eleutherococcus senticosus extract, Coptis chinensis extract, Scutellaria baicalensis extract, Phellodendron chinense extract, Coptis chinensis extract, Ginseng extract, Forsythia suspensa extract, Sesamum indicum extract, Sweet orange extract, Pyracantha fortuneana extract, Pueraria lobata extract, Chamomile extract, Carrot extract, Artemisia capillaris extract, Licorice extract, Actinidia chinensis extract, Cucumber extract, Guava extract, Sophora flavescens extract, Gardenia jasminoides extract, Pteris vittata extract, Sophora flavescens root extract, and Walnut extract. Extracts of various herbs, including grapefruit extract, black rice extract, chlorella extract, mulberry extract, white-flowered sesame vine extract, alpinia leaf extract, gentian extract, geranium extract, black tea extract, burdock extract, rice extract, fermented rice extract, fermented rice bran extract, rice germ oil, blueberry extract, salvia extract, soapwort extract, soapberry extract, wild hawthorn extract, silkworm excrement extract, Sichuan pepper extract, shiitake mushroom extract, rehmannia extract, lithospermum extract, perilla extract, Japanese linden extract, mosquito grass extract, peony extract, ginger extract, calamus root extract, birch extract, schizonepeta extract, stevia extract, stevia ferment, ivy extract, hawthorn thorn extract, elderberry extract, and yarrow. Herb extracts, peppermint extract, medicinal sage extract, mallow extract, chuanxiong extract, Japanese swert extract, mulberry bark extract, rhubarb extract, soybean extract, jujube extract, thyme extract, dandelion extract, tea extract, clove extract, sweet tea extract, capsicum extract, angelica extract, calendula extract, peach kernel extract, spruce extract, houttuynia cordata extract, tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, ophiopogon japonicus extract, lotus extract, parsley extract, birch extract, witch hazel extract, sage extract, Japanese cypress extract, loquat extract, coltsfoot extract, senna stem extract, poria cocos extract, butcher's broom extract. Extracts include grape extract, grape seed extract, loofah extract, safflower extract, peppermint extract, European linden extract, peony extract, hops extract, Korean pine extract, oregano leaf extract, European horse chestnut extract, banana extract, sago palm extract, lemon balm extract, seaweed extract, peach extract, cornflower extract, eucalyptus extract, strawberry saxifrage extract, grapefruit extract, lily extract, coix seed extract, artemisia extract, lavender extract, green tea extract, apple extract, rooibos tea extract, ganoderma lucidum extract, lettuce extract, lemon extract, forsythia extract, astragalus extract, rose extract, rosemary extract, white chamomile extract, royal jelly extract, and burnet root extract.
As anti-inflammatory components, examples include matrine, glycyrrhizin, glycyrrhizic acid, glycyrrhetinic acid, and panthenol, with glycyrrhizic acid and its salts, alkyl esters of glycyrrhetinic acid and their salts, and glycyrrhetinic acid and its salts being preferred.
Examples of surfactants include anionic surfactants such as fatty acid soaps (sodium lauryl salt, sodium palmitate, etc.), potassium lauryl sulfate, and triethanolamine alkyl sulfate; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, and laurylamine oxide; betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.); imidazoline amphoteric surfactants (2-cocoyl-2-imidazolium hydroxide-1-carboxyethoxy disodium salt, etc.); and acylmethyl taurine.
Polyglycerol sesquiisostearate, sorbitol fatty acid esters (sorbitol monostearate, sorbitol sesquioleate, etc.), glycerol fatty acid esters (glycerol monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivatives, glyceryl alkyl ethers, POE sorbitol fatty acid esters (POE sorbitol monooleate, polyoxyethylene sorbitol monostearate, etc.), POE sorbitol fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerol fatty acid esters (POE... - Glyceryl monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic, POE/POP alkyl ethers (POE/POP2-decyltetradecyl ether, etc.), Tetronic, POE castor oil and hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), sucrose fatty acid esters, alkyl glycosides and other nonionic surfactants, etc.
Examples of polyols include polyethylene glycol, glycerol, 1,3-butanediol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerol, isoprenediol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, and 1,2-octanediol.
Examples of thickeners include guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, guar gum, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methyl hydroxypropylcellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratin sulfate, chondroitin, mucin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratin sulfate, locust bean gum, succinosaccharide, carboxylic acid, chitosan, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, alkyl-modified carboxyvinyl polymers, sodium polyacrylate, polyethylene glycol, and bentonite.
Examples of UV absorbers include p-aminobenzoic acid UV absorbers, o-aminobenzoic acid UV absorbers, salicylic acid UV absorbers, cinnamic acid UV absorbers, benzophenone UV absorbers, sugar-based UV absorbers, 2-(2’-hydroxy-5’-tert-octylphenyl)benzotriazole, and 4-methoxy-4’-tert-butyldibenzoylmethane, among others.
The compositions of the present invention can be manufactured by processing the essential components, preferred components, optional components, etc., according to conventional methods.
Example
The present invention will now be described in more detail by providing examples. However, the present invention is obviously not limited to these examples.
<Manufacturing Example 1>
According to the formulations shown in Tables 1 and 2 below, an oil gel-type topical skin agent was manufactured. Specifically, component A was heated and dissolved at 95°C and mixed. Then, using a disperser, the mixture was stirred at 3000 rpm for 1 minute at 95°C while component B was added to the mixture. After defoaming, the mixture was filled into a container and cooled to solidify, yielding an oily solid cosmetic.
<Experimental Example>
(1) Evaluation of the decomposition stability of KSK32
The KSK32 content of each prepared oil-based solid cosmetic was measured after storage at 60℃ for 2 weeks. The proportion (residual rate) with the KSK32 content after storage at 5℃ for 2 weeks as 100 was calculated. A residual rate of 95% or higher was rated as ◎ for decomposition stability, less than 95% but more than 80% as ○, less than 80% but more than 60% as △, and less than 60% as ×. The results are shown in Tables 1 and 2.
It should be noted that approximately 0.5g of cosmetic product was weighed, diluted to 50mL, and used as a sample solution for high-performance liquid chromatography (HPLC) in the mobile phase to determine the content of KSK32.
HPLC conditions: Column: reversed-phase column (3.0 × 100 mm); Column temperature: room temperature; Mobile phase: aqueous solution of anionic sulfonic acid surfactant/THF 25%; pH: 3; Flow rate: 0.4 mL/min; Detection: 240 nm.
(2) Evaluation of dispersion stability
After each prepared oily solid cosmetic was allowed to stand at 40℃ for 1 day, KSK32 was visually observed for sedimentation. The dispersion stability was rated as ○ when uniformly dispersed and × when sedimentation was observed. The results are shown in Tables 1 and 2.
<Manufacturing Example 2>
Prepare ointment-type topical skin agents according to the formulations shown in Table 3 below, and prepare emulsion-type topical skin agents according to the formulations shown in Table 4. Specifically, dissolve component A by heating at 95°C and mix. Then, stir at 3000 rpm for 1 minute at 95°C using a disperser, while simultaneously adding component B to the mixture to obtain the respective oily cosmetics.
For the oily cosmetics of Examples 20 and 21, the decomposition stability and dispersion stability of KSK32 were confirmed to be good by the methods of the above test examples.
Table 3 (mass%)
※The number in parentheses in the oil name indicates the number of hydroxyl groups.
Table 4 (mass%)
※The number in parentheses in the oil name indicates the number of hydroxyl groups.
Industrial applicability
This invention can be applied to cosmetics and other topical skin agents.
This application is a divisional application of the invention patent application with application number 201880071202.1 entitled "Oil-based Composition". The aforementioned invention patent application is the Chinese national phase application of the PCT international application with application number PCT/JP2018/040287 filed on October 30, 2018.
Technical Field
This invention relates to an oil-based composition that stably contains the active ingredients of an anti-aging cosmetic.
Background Technology
Wrinkles are a representative symptom of skin aging caused by increasing age. Wrinkles are broadly classified into superficial wrinkles that can be improved through moisturizing and deep wrinkles caused by the accumulation of UV exposure and physical irritants; the latter, deep wrinkles, are very difficult to prevent or improve. Furthermore, various wrinkle-improving agents are currently under development (see, for example, Non-Patent Literature 1). Among such wrinkle-improving agents, those with retinoic acid as the active ingredient are well-known. In the United States, retinoic acid is licensed as a treatment for wrinkles and acne, but it is not licensed in Japan due to safety concerns, such as skin irritation. In addition, other wrinkle-improving agents have been reported, such as collagen production promoters (see, for example, Patent Literature 1) and hyaluronic acid production promoters (see, for example, Patent Literature 2). However, it is difficult to say that all of the aforementioned wrinkle-improving agents have sufficient efficacy, and an effective method has not yet been established.
Elastase inhibitors are wrinkle improvers with a different mechanism of action than the aforementioned wrinkle improvers. Elastin, a structural protein present in skin tissue, forms cross-linked structures and maintains tissue elasticity. It is well known that skin stimuli such as ultraviolet radiation overexpress and activate elastase, an enzyme that degrades elastin, causing elastin denaturation and breakdown, leading to decreased skin tension and elasticity, and promoting wrinkle formation. Elastase inhibitors exert their effect of preventing or improving wrinkle formation by inhibiting this elastin-degrading enzyme. On the other hand, although structural analysis of elastin-degrading enzymes and matrices, as well as research on their structure-activity relationships, are constantly developing, it is difficult to achieve high enzyme inhibitory activity and selectivity using low-molecular-weight organic molecules. Ingredients with high enzyme inhibitory activity contain a large number of peptides and their derivatives (e.g., see Patent Document 3).
As elastase inhibitors of such peptide derivatives, peptide derivatives represented by WS7622A monosulfate or disulfate are known (e.g., see Patent Document 4), and attempts have been made to apply them to ischemic diseases through this pharmacological action. In addition, compounds represented by the following general formula (1) are known to have leukocyte elastase inhibitory activity similar to WS7622A, and their preventive or therapeutic effects on skin aging have been reported (e.g., see Patent Document 5).
In the formula, R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms.
Existing technical documents
Patent Document 1: Japanese Patent Application Publication No. 2002-255847
Patent Document 2: Japanese Patent Application Publication No. 2004-123637
Patent Document 3: International Publication No. 2001/40263
Patent Document 4: International Publication No. 1998/27998
Patent Document 5: International Publication No. 1999/43352
Non-Patent Literature 1: Development Technology of Anti-aging, Whitening and Moisturizing Cosmetics, CMC Publishing, supervised by Masato Suzuki, Chapter 2 (Anti-aging and Anti-wrinkle) Functional Cosmetics
Summary of the Invention
The problem to be solved by the present invention
The inventors have discovered that, since the compound represented by the general formula (1) is easily decomposed, there is a stability problem when the compound is contained in a skin anti-aging composition.
The present invention was made under the following circumstances, and the problem to be solved is to provide a method for chemically stable formulation in a composition of a compound of the above general formula (1), its isomers and/or their pharmaceutically acceptable salts.
Problem-solving methods
In view of the above, the inventors, after in-depth research, discovered that by dispersing the compound represented by the general formula (1), its isomers and/or their pharmaceutically acceptable salts into a specific oiling agent to form an oily composition, the decomposition of the compound can be suppressed.
Furthermore, in dispersion compositions, the dispersed components typically settle over time. The inventors have discovered that by further containing powders, solid lipids, and/or semi-solid lipids in the composition, the compounds represented by the general formula (1), their isomers, and/or pharmaceutically acceptable salts can be uniformly dispersed, thereby achieving dispersion stability over time, thus completing the present invention.
That is, the present invention is as follows.
[1] An oily composition comprising: a compound of the following general formula (1), its isomers and/or their pharmaceutically acceptable salts, and an oil having 0 to 2 hydroxyl groups.
In the formula, R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms.
[2][1] In the composition described, the oil having 0 to 2 hydroxyl groups is selected from the group consisting of hydrocarbon oil, silicone oil and ester oil.
In the compositions described in [3][1] or [2], the content of the oil having 0 to 2 hydroxyl groups is 50% or more by mass of the whole composition.
The compositions described in any one of [4][1] to [3] further contain an oily gelling agent.
The composition described in any one of [5][1] to [4] further contains powder.
[6][5] In the composition described, the content of the powder is 0.5 to 20% by mass of the whole composition.
The composition described in any one of [7][1] to [6] is an oleogel formulation.
[8][7] The composition contains more than 5% by mass of solid grease and/or semi-solid grease as a whole composition.
The composition described in any one of [9][1] to [8] is substantially free of water.
The composition described in any one of [10][1] to [9] is a topical skin agent.
Effects of the present invention
According to the present invention, it is possible to provide chemically stable compositions in which the decomposition of the compounds represented by the general formula (1), their isomers, and/or their pharmaceutically acceptable salts is inhibited. Furthermore, it is possible to provide compositions in which the compounds remain uniformly dispersed after a period of time.
Detailed Implementation
The compositions of the present invention are characterized in that they contain: a compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts, and an oil having 0 to 2 hydroxyl groups.
The compounds represented by general formula (1), their isomers and/or their pharmaceutically acceptable salts can be manufactured by, for example, the method described in Japanese Patent Application Publication No. 04-297446.
The compound represented by general formula (1) is an optically active compound having multiple asymmetric carbon atoms in its molecular structure. Therefore, as its isomers, there exist enantiomers and diastereomers. Furthermore, as the compound represented by general formula (1) of the present invention, there exist racemic mixtures, enantiomers, diastereomers, and compounds in which the above isomers are mixed in any proportion.
Regarding the compound represented by the general formula (1) of the present invention, R1 represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylic acid ester group having 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
The R1 may preferably include: carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl, propoxycarbonylmethyl, propoxycarbonylethyl, propoxycarbonylpropyl, propoxycarbonylbutyl, butoxycarbonylmethyl, butoxycarbonylethyl, butoxycarbonylpropyl, butoxycarbonylbutyl, etc., and more preferably, carboxymethyl.
The R2 and R3 can preferably be listed independently as follows: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and more preferably isopropyl.
The compound represented by general formula (1) exhibits human leukocyte elastase inhibitory activity, and is expected to have a therapeutic effect on ischemic cerebral diseases, such as cerebral infarction. Furthermore, for example, as described in International Publication No. 1999/43352, it has preventive or therapeutic effects on skin aging. In addition, the compound represented by general formula (1) of this invention promotes the regeneration of elastic fibers in the dermal papillae, the regeneration of fine collagen fibers in the dermis directly beneath the epidermis, and increases epidermal thickness, thereby exerting a preventive or improving effect on wrinkle formation.
The compound represented by general formula (1) is preferably the compound represented by general formula (2) below.
Regarding the compound represented by the general formula (2) of the present invention, R4 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms substituted by a carboxyl group, and R5 and R6 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms. Specifically, R4 can be represented by carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 3-carboxybutyl, 4-carboxybutyl, etc., and more preferably, carboxymethyl.
R5 and R6 each independently represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms. R5 and R6 can preferably be specifically listed as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and more preferably isobutyl. Furthermore, suitable examples of compounds represented by the general formula (2) include 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-isopentanoyl-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyl ... [Propyl]amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N- [3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl] [4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[ ...[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ -[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl] -L-Isopentyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro- 1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide (3(RS)-N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2- [Oxypropyl]-L-proline amide), N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide.
Among the compounds represented by the general formula (2) above, 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane is more preferably listed, and 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane represented by the formula (3) below is even more preferred. In addition, as the compound contained in the composition of the present invention, the sodium salt of the 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (hereinafter also referred to as "KSK32") is particularly preferred.
It should be noted that KSK32, according to other nomenclature, can also be expressed as N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[(RS)-3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, which is the same compound.
In this invention, the compound represented by general formula (1) can be directly included in the composition, or it can be treated with a pharmaceutically acceptable acid or base to convert it into a salt form and used as a salt. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and carbonate can be listed; organic acid salts such as maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, p-toluenesulfonate, and benzenesulfonate can be listed; alkali metal salts such as sodium and potassium salts can be listed; alkaline earth metal salts such as calcium and magnesium salts can be listed; organic amine salts such as triethylamine, triethanolamine, ammonium, monoethanolamine, and piperidine salts can be listed; and basic amino acid salts such as lysine and arginine salts can be listed.
Furthermore, the compositions of the present invention may also contain one or more of the compounds represented by the general formula (1), their isomers and/or their pharmaceutically acceptable salts.
The content of the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts in the composition of the present invention is not particularly limited, but is preferably 0.01 to 10% by mass relative to the whole composition, more preferably 0.1 to 5% by mass. By containing it within this range, the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts can easily exert their effect of preventing or improving the formation of wrinkles.
It can be fully utilized.
The compositions of the present invention are obtained by dispersing the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts in an oil having 0 to 2 hydroxyl groups.
The oil is not particularly limited and is selected from the group consisting of hydrocarbon oils, silicone oils, and ester oils. Furthermore, the number of hydroxyl groups is more preferably 0 to 1, and even more preferably 0, i.e., no hydroxyl groups.
Here, the number of hydroxyl groups refers to the number in a single molecule.
Examples of suitable hydrocarbon oils include, for example, paraffin, isoparaffin, liquid paraffin, α-olefin oligomers, polyethylene, squalane, isododecane, isohexadecane, etc.
As a silicone oil, it may or may not have side chains, and it may or may not be cross-linked. Preferred examples include polysiloxane, dimethyl polysiloxane, decamethylcyclopentasiloxane, methyl polysiloxane, diphenyl dimethyl silicone oil, etc.
Preferred ester oils include, for example, glyceryl tri-2-ethylhexanoate, glyceryl triisostearate, hexadecyl 2-ethylhexanoate, tri(caprylic/capric) glyceryl tristearate, ethylene glycol distearate, N-lauroyl sarcosinate, glyceryl triisostearate, diisostearate malate, and ethylene glycol monostearate.
The oil in the composition of the present invention is capable of dispersing the compound represented by general formula (1), its isomers and/or their pharmaceutically acceptable salts.
Furthermore, since the compounds represented by the general formula (1), their isomers, and/or their pharmaceutically acceptable salts are prone to decomposition, there is a problem that the content of the compound decreases over time in compositions containing them. To address this problem, the present invention enables the chemically stable formulation of the compound in the composition by using an oil having 0 to 2 hydroxyl groups as a dispersion medium.
The oil having 0 to 2 hydroxyl groups in the composition of the present invention comprises 50% by mass or more, more preferably 80% by mass, and even more preferably 90% by mass or more, relative to the total composition. Within this range, the compound represented by the general formula (1), its isomers, and/or their pharmaceutically acceptable salts are readily dispersed.
Furthermore, the total content of oils in the compositions of the present invention is generally 50% by mass or more relative to the whole composition, preferably 60% by mass or more.
Furthermore, the content of the oil having three or more hydroxyl groups is preferably 50% by mass or less relative to the total composition, more preferably 25% by mass or less, and even more preferably 5% by mass or less. This is because when oils having three or more hydroxyl groups coexist in a certain amount or more, the compound represented by the general formula (1), its isomers, and/or their pharmaceutically acceptable salts are easily decomposed, and there is a situation where the residual amount of the compound in the composition decreases over time.
Here, examples of oils containing hydroxyl groups include, but are not limited to, monoesters or diesters formed from fatty acids and polyglycerols, esters formed from fatty acids and sugar alcohols, and esters formed from fatty acids and polysaccharide alcohols.
Furthermore, the oil in the composition of the present invention preferably contains solid grease and/or semi-solid grease, more preferably solid grease and/or semi-solid grease having 0 to 2 hydroxyl groups, and even more preferably solid grease and/or semi-solid grease without hydroxyl groups.
By containing solid or semi-solid lipids, the viscosity of the composition increases, thus the compounds, isomers, and/or pharmaceutically acceptable salts of the general formula (1) dispersed in the composition are less likely to settle over time, resulting in a composition with excellent dispersion stability over time. This embodiment is applicable to oleogel formulations, etc., described later.
The content of solid fats and/or semi-solid fats is preferably 5% by mass or more of the total composition, more preferably 10% by mass or more, and even more preferably 20% by mass or more. Furthermore, it is preferably 50% by mass or less of the total composition, more preferably 40% by mass or less, and even more preferably 30% by mass or less.
Here, solid grease includes semi-solid grease. It should be noted that solid grease refers to grease that does not flow at 25°C, while semi-solid grease refers to grease that does not deform significantly in an environment without stress at 1 atmosphere and 20°C, but deforms when subjected to a small amount of stress (approximately 10–100 g/ cm² ). Furthermore, a melting point of 50°C or higher is preferred.
Examples of plant-derived solid and/or semi-solid lipids include carnauba wax, wood wax, candelilla wax, rice bran wax, shea butter, and African wood resin. Examples of animal-derived solid and/or semi-solid lipids include beeswax, shellac wax, and insect wax. Examples of petroleum-derived substances include refined waxes such as paraffin wax and microcrystalline wax. Examples of mineral-derived solid and/or semi-solid lipids include refined waxes such as ceresin, serotonin, and montan wax. Solid or semi-solid lipids from plant and animal sources often contain hydroxyl groups; therefore, refined waxes from petroleum or mineral sources are preferred. It should be noted that these solid and/or semi-solid lipids can be used alone or in combination of two or more.
The compositions of the present invention preferably further contain an oily gelling agent. By containing an oily gelling agent, the viscosity of the composition increases, and therefore the compounds, isomers and/or pharmaceutically acceptable salts of the general formula (1) dispersed in the composition are less likely to settle over time, resulting in a composition with excellent dispersion stability over time.
Here, "oil-based gelling agent" refers to a gelling agent that is compatible with oily components such as oils. There is no particular limitation, and examples include 12-hydroxystearic acid, palmitic dextrin, (palmitic acid/octanoic acid) dextrin, dibutyllauroyl glutamine, and dimethylsiloxane cross-linked polymers.
The content of the oily gelling agent is preferably 0.5% by mass or more of the total composition, more preferably 2% by mass or more, and even more preferably 5% by mass or more. Furthermore, it is preferably 20% by mass or less of the total composition, more preferably 15% by mass or less, and even more preferably 10% by mass or less.
When the composition of the present invention is an oleogel formulation as described later, it is preferable to further contain an oily gelling agent in the solid or semi-solid grease, or to replace the solid or semi-solid grease with an oily gelling agent. In this case, the content is preferably 5% by mass or more of the total composition, including the solid or semi-solid grease.
The compositions of the present invention preferably further contain powder. By containing powder, the viscosity of the composition increases, and therefore the compounds, isomers thereof, and/or pharmaceutically acceptable salts thereof dispersed in the composition according to the general formula (1) are less likely to settle over time, resulting in a composition with excellent dispersion stability over time. This embodiment is suitable for oleogel formulations, etc., as described later.
The powder content is preferably 0.5 to 20% by mass of the whole composition, more preferably 1 to 5% by mass.
As for powders, examples include: surface-treated powders such as silica (anhydrous silica), mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, alumina, and barium sulfate; surface-treated inorganic pigments such as iron oxide red, iron oxide yellow, iron oxide black, cobalt oxide, ultramarine, cyan violet, titanium oxide, and zinc oxide; surface-treated pearlescent agents such as mica titanium, fish scale foil, and bismuth oxychloride; and laked pigments such as Red 202 and Red 22. Organic dyes such as No. 8, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, etc., and organic powders such as polyester powder, polyamide powder, polyethylene powder, polymethyl methacrylate, nylon powder, and organopolysiloxane elastomers.
Furthermore, there are no particular limitations on the shape; examples include spherical, hemispherical, and sheet-like shapes commonly used in cosmetics and other topical skin agents, as well as porous shapes.
In addition, the particle size should be the same as that used in typical cosmetics and other topical skin agents.
In this invention, porous silica is particularly preferred from the viewpoint of the dispersion stability of the composition.
The compositions of the present invention are oily and generally substantially free of water. Here, "substantially free of water" means that its content relative to the whole composition is preferably 0.1% by mass or less, more preferably 0.01% by mass or less, and even more preferably 0.001% by mass or less.
This is because, when water is present in the composition, the compound represented by the general formula (1), its isomers and/or their pharmaceutically acceptable salts become readily decomposed, and there is a situation where the residual amount of the compound in the composition decreases over time.
Regardless of whether it has fluidity, the oily composition of the present invention can be any dosage form such as emulsion, ointment, or oleogel, preferably an oleogel.
The oleogel formulation of this invention typically has a high viscosity and low flowability. For example, it is preferably non-flowable at 25°C, i.e., solid. Furthermore, the viscosity at 25°C is preferably 20,000 Pa·s or higher. By using this formulation, the compound represented by general formula (1), its isomers, and/or their pharmaceutically acceptable salts are less likely to precipitate over time, resulting in a composition with excellent dispersion stability over time.
In the compositions of the present invention, the compound represented by general formula (1), its isomers, and/or their pharmaceutically acceptable salts have a high residual amount in the composition over time. Specifically, for example, the content of the compound after storage at 60°C for 2 weeks is preferably 60% or more, more preferably 80% or more, and even more preferably 95% or more, relative to the content of the compound after storage at 5°C for 2 weeks.
The compositions of the present invention are compositions in which the compounds of the general formula (1), their isomers, and/or their pharmaceutically acceptable salts exhibit high dispersion stability over time. Specifically, for example, this means that no sedimentation of the compound is visually observed after standing at 40°C for 1 day. Alternatively, after standing at 40°C for 1 day, the concentration difference of the compound in the upper 95 v/v% and the lower 95 v/v% of the composition is preferably within 10%, more preferably within 5%, and even more preferably within 0.5%.
In the compositions of the present invention, as previously described, the compounds represented by general formula (1), their isomers, and/or their pharmaceutically acceptable salts are capable of preventing or improving wrinkle formation. Furthermore, the compounds in the compositions of the present invention exhibit excellent decomposition and dispersion stability over time. Therefore, the compositions of the present invention are suitable for use as topical skin agents, more preferably in cosmetics, and particularly preferably in anti-aging cosmetics. It should be noted that cosmetics here include quasi-pharmaceuticals.
In addition to the above-mentioned components, the compositions of the present invention may optionally contain any components commonly used in topical skin preparations, provided that the technical effects of the present invention are not impaired. Examples of such optional components include various active ingredients, oily components, surfactants, polyols, thickeners, ultraviolet absorbers, etc.
As active ingredients, examples include whitening ingredients, wrinkle-improving ingredients, anti-inflammatory ingredients, and extracts from plants and animals.
As a whitening ingredient, any substance commonly used in cosmetics is acceptable; there are no specific limitations. Examples include 4-n-butylresorcinol, ascorbic acid glycoside, 3-O-ethyl ascorbic acid, tranexamic acid, arbutin, ellagic acid, kojic acid, linoleic acid, niacinamide, 5,5'-dipropyldiphenyl-2,2'-diol, disodium 5'-adenosine, hexadecyl tranexamic acid, potassium 4-methoxysalicylate, hydroquinone, and pantothenic acid.
As other wrinkle-improving ingredients, any substance commonly used in cosmetics is acceptable, without specific limitations. Examples include niacinamide, vitamin A or its derivatives (retinol, retinaldehyde, retinoic acid, tretinoin, isotretinoin, tocopherol retinoate, retinyl palmitate, retinol acetate, etc.), benzyl ursolic acid, ursolic acid phosphate, benzyl betulinate, and benzoic acid phosphate.
Extracts derived from plants and animals are acceptable as long as they are substances commonly used in cosmetics; there are no particular limitations. Examples of preferred extracts include: Akebia quinata extract, Phellodendron chinense extract, Asparagus cochinchinensis extract, Avocado extract, Hydrangea macrophylla extract, Almond extract, Arnica extract, Aloe vera extract, Prunus armeniaca extract, Apricot kernel extract, Ginkgo biloba extract, Dalbergia odorifera extract, Fennel extract, Angelica sinensis extract, Rosa rugosa extract, Eleutherococcus senticosus extract, Coptis chinensis extract, Scutellaria baicalensis extract, Phellodendron chinense extract, Coptis chinensis extract, Ginseng extract, Forsythia suspensa extract, Sesamum indicum extract, Sweet orange extract, Pyracantha fortuneana extract, Pueraria lobata extract, Chamomile extract, Carrot extract, Artemisia capillaris extract, Licorice extract, Actinidia chinensis extract, Cucumber extract, Guava extract, Sophora flavescens extract, Gardenia jasminoides extract, Pteris vittata extract, Sophora flavescens root extract, and Walnut extract. Extracts of various herbs, including grapefruit extract, black rice extract, chlorella extract, mulberry extract, white-flowered sesame vine extract, alpinia leaf extract, gentian extract, geranium extract, black tea extract, burdock extract, rice extract, fermented rice extract, fermented rice bran extract, rice germ oil, blueberry extract, salvia extract, soapwort extract, soapberry extract, wild hawthorn extract, silkworm excrement extract, Sichuan pepper extract, shiitake mushroom extract, rehmannia extract, lithospermum extract, perilla extract, Japanese linden extract, mosquito grass extract, peony extract, ginger extract, calamus root extract, birch extract, schizonepeta extract, stevia extract, stevia ferment, ivy extract, hawthorn thorn extract, elderberry extract, and yarrow. Herb extracts, peppermint extract, medicinal sage extract, mallow extract, chuanxiong extract, Japanese swert extract, mulberry bark extract, rhubarb extract, soybean extract, jujube extract, thyme extract, dandelion extract, tea extract, clove extract, sweet tea extract, capsicum extract, angelica extract, calendula extract, peach kernel extract, spruce extract, houttuynia cordata extract, tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, ophiopogon japonicus extract, lotus extract, parsley extract, birch extract, witch hazel extract, sage extract, Japanese cypress extract, loquat extract, coltsfoot extract, senna stem extract, poria cocos extract, butcher's broom extract. Extracts include grape extract, grape seed extract, loofah extract, safflower extract, peppermint extract, European linden extract, peony extract, hops extract, Korean pine extract, oregano leaf extract, European horse chestnut extract, banana extract, sago palm extract, lemon balm extract, seaweed extract, peach extract, cornflower extract, eucalyptus extract, strawberry saxifrage extract, grapefruit extract, lily extract, coix seed extract, artemisia extract, lavender extract, green tea extract, apple extract, rooibos tea extract, ganoderma lucidum extract, lettuce extract, lemon extract, forsythia extract, astragalus extract, rose extract, rosemary extract, white chamomile extract, royal jelly extract, and burnet root extract.
As anti-inflammatory components, examples include matrine, glycyrrhizin, glycyrrhizic acid, glycyrrhetinic acid, and panthenol, with glycyrrhizic acid and its salts, alkyl esters of glycyrrhetinic acid and their salts, and glycyrrhetinic acid and its salts being preferred.
Examples of surfactants include anionic surfactants such as fatty acid soaps (sodium lauryl salt, sodium palmitate, etc.), potassium lauryl sulfate, and triethanolamine alkyl sulfate; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, and laurylamine oxide; betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.); imidazoline amphoteric surfactants (2-cocoyl-2-imidazolium hydroxide-1-carboxyethoxy disodium salt, etc.); and acylmethyl taurine.
Polyglycerol sesquiisostearate, sorbitol fatty acid esters (sorbitol monostearate, sorbitol sesquioleate, etc.), glycerol fatty acid esters (glycerol monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivatives, glyceryl alkyl ethers, POE sorbitol fatty acid esters (POE sorbitol monooleate, polyoxyethylene sorbitol monostearate, etc.), POE sorbitol fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerol fatty acid esters (POE... - Glyceryl monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic, POE/POP alkyl ethers (POE/POP2-decyltetradecyl ether, etc.), Tetronic, POE castor oil and hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), sucrose fatty acid esters, alkyl glycosides and other nonionic surfactants, etc.
Examples of polyols include polyethylene glycol, glycerol, 1,3-butanediol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerol, isoprenediol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, and 1,2-octanediol.
Examples of thickeners include guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, guar gum, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methyl hydroxypropylcellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratin sulfate, chondroitin, mucin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratin sulfate, locust bean gum, succinosaccharide, carboxylic acid, chitosan, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, alkyl-modified carboxyvinyl polymers, sodium polyacrylate, polyethylene glycol, and bentonite.
Examples of UV absorbers include p-aminobenzoic acid UV absorbers, o-aminobenzoic acid UV absorbers, salicylic acid UV absorbers, cinnamic acid UV absorbers, benzophenone UV absorbers, sugar-based UV absorbers, 2-(2’-hydroxy-5’-tert-octylphenyl)benzotriazole, and 4-methoxy-4’-tert-butyldibenzoylmethane, among others.
The compositions of the present invention can be manufactured by processing the essential components, preferred components, optional components, etc., according to conventional methods.
Example
The present invention will now be described in more detail by providing examples. However, the present invention is obviously not limited to these examples.
<Manufacturing Example 1>
According to the formulations shown in Tables 1 and 2 below, an oil gel-type topical skin agent was manufactured. Specifically, component A was heated and dissolved at 95°C and mixed. Then, using a disperser, the mixture was stirred at 3000 rpm for 1 minute at 95°C while component B was added to the mixture. After defoaming, the mixture was filled into a container and cooled to solidify, yielding an oily solid cosmetic.
<Experimental Example>
(1) Evaluation of the decomposition stability of KSK32
The KSK32 content of each prepared oil-based solid cosmetic was measured after storage at 60℃ for 2 weeks. The proportion (residual rate) with the KSK32 content after storage at 5℃ for 2 weeks as 100 was calculated. A residual rate of 95% or higher was rated as ◎ for decomposition stability, less than 95% but more than 80% as ○, less than 80% but more than 60% as △, and less than 60% as ×. The results are shown in Tables 1 and 2.
It should be noted that approximately 0.5g of cosmetic product was weighed, diluted to 50mL, and used as a sample solution for high-performance liquid chromatography (HPLC) in the mobile phase to determine the content of KSK32.
HPLC conditions: Column: reversed-phase column (3.0 × 100 mm); Column temperature: room temperature; Mobile phase: aqueous solution of anionic sulfonic acid surfactant/THF 25%; pH: 3; Flow rate: 0.4 mL/min; Detection: 240 nm.
(2) Evaluation of dispersion stability
After each prepared oily solid cosmetic was allowed to stand at 40℃ for 1 day, KSK32 was visually observed for sedimentation. The dispersion stability was rated as ○ when uniformly dispersed and × when sedimentation was observed. The results are shown in Tables 1 and 2.
<Manufacturing Example 2>
Prepare ointment-type topical skin agents according to the formulations shown in Table 3 below, and prepare emulsion-type topical skin agents according to the formulations shown in Table 4. Specifically, dissolve component A by heating at 95°C and mix. Then, stir at 3000 rpm for 1 minute at 95°C using a disperser, while simultaneously adding component B to the mixture to obtain the respective oily cosmetics.
For the oily cosmetics of Examples 20 and 21, the decomposition stability and dispersion stability of KSK32 were confirmed to be good by the methods of the above test examples.
Table 3 (mass%)
※The number in parentheses in the oil name indicates the number of hydroxyl groups.
Table 4 (mass%)
※The number in parentheses in the oil name indicates the number of hydroxyl groups.
Industrial applicability
This invention can be applied to cosmetics and other topical skin agents.
This application is a divisional application of the invention patent application with application number 201880071202.1 entitled "Oil-based Composition". The aforementioned invention patent application is the Chinese national phase application of the PCT international application with application number PCT/JP2018/040287 filed on October 30, 2018.
Technical Field
This invention relates to an oil-based composition that stably contains the active ingredients of an anti-aging cosmetic.
Background Technology
Wrinkles are a representative symptom of skin aging caused by increasing age. Wrinkles are broadly classified into superficial wrinkles that can be improved through moisturizing and deep wrinkles caused by the accumulation of UV exposure and physical irritants; the latter, deep wrinkles, are very difficult to prevent or improve. Furthermore, various wrinkle-improving agents are currently under development (see, for example, Non-Patent Literature 1). Among such wrinkle-improving agents, those with retinoic acid as the active ingredient are well-known. In the United States, retinoic acid is licensed as a treatment for wrinkles and acne, but it is not licensed in Japan due to safety concerns, such as skin irritation. In addition, other wrinkle-improving agents have been reported, such as collagen production promoters (see, for example, Patent Literature 1) and hyaluronic acid production promoters (see, for example, Patent Literature 2). However, it is difficult to say that all of the aforementioned wrinkle-improving agents have sufficient efficacy, and an effective method has not yet been established.
Elastase inhibitors are wrinkle improvers with a different mechanism of action than the aforementioned wrinkle improvers. Elastin, a structural protein present in skin tissue, forms cross-linked structures and maintains tissue elasticity. It is well known that skin stimuli such as ultraviolet radiation overexpress and activate elastase, an enzyme that degrades elastin, causing elastin denaturation and breakdown, leading to decreased skin tension and elasticity, and promoting wrinkle formation. Elastase inhibitors exert their effect of preventing or improving wrinkle formation by inhibiting this elastin-degrading enzyme. On the other hand, although structural analysis of elastin-degrading enzymes and matrices, as well as research on their structure-activity relationships, are constantly developing, it is difficult to achieve high enzyme inhibitory activity and selectivity using low-molecular-weight organic molecules. Ingredients with high enzyme inhibitory activity contain a large number of peptides and their derivatives (e.g., see Patent Document 3).
As elastase inhibitors of such peptide derivatives, peptide derivatives represented by WS7622A monosulfate or disulfate are known (e.g., see Patent Document 4), and attempts have been made to apply them to ischemic diseases through this pharmacological action. In addition, compounds represented by the following general formula (1) are known to have leukocyte elastase inhibitory activity similar to WS7622A, and their preventive or therapeutic effects on skin aging have been reported (e.g., see Patent Document 5).
In the formula, R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms.
Existing technical documents
Patent Document 1: Japanese Patent Application Publication No. 2002-255847
Patent Document 2: Japanese Patent Application Publication No. 2004-123637
Patent Document 3: International Publication No. 2001/40263
Patent Document 4: International Publication No. 1998/27998
Patent Document 5: International Publication No. 1999/43352
Non-Patent Literature 1: Development Technology of Anti-aging, Whitening and Moisturizing Cosmetics, CMC Publishing, supervised by Masato Suzuki, Chapter 2 (Anti-aging and Anti-wrinkle) Functional Cosmetics
Summary of the Invention
The problem to be solved by the present invention
The inventors have discovered that, since the compound represented by the general formula (1) is easily decomposed, there is a stability problem when the compound is contained in a skin anti-aging composition.
The present invention was made under the following circumstances, and the problem to be solved is to provide a method for chemically stable formulation in a composition of a compound of the above general formula (1), its isomers and/or their pharmaceutically acceptable salts.
Problem-solving methods
In view of the above, the inventors, after in-depth research, discovered that by dispersing the compound represented by the general formula (1), its isomers and/or their pharmaceutically acceptable salts into a specific oiling agent to form an oily composition, the decomposition of the compound can be suppressed.
Furthermore, in dispersion compositions, the dispersed components typically settle over time. The inventors have discovered that by further containing powders, solid lipids, and/or semi-solid lipids in the composition, the compounds represented by the general formula (1), their isomers, and/or pharmaceutically acceptable salts can be uniformly dispersed, thereby achieving dispersion stability over time, thus completing the present invention.
That is, the present invention is as follows.
[1] An oily composition comprising: a compound of the following general formula (1), its isomers and/or their pharmaceutically acceptable salts, and an oil having 0 to 2 hydroxyl groups.
In the formula, R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms.
[2][1] In the composition described, the oil having 0 to 2 hydroxyl groups is selected from the group consisting of hydrocarbon oil, silicone oil and ester oil.
In the compositions described in [3][1] or [2], the content of the oil having 0 to 2 hydroxyl groups is 50% or more by mass of the whole composition.
The compositions described in any one of [4][1] to [3] further contain an oily gelling agent.
The composition described in any one of [5][1] to [4] further contains powder.
[6][5] In the composition described, the content of the powder is 0.5 to 20% by mass of the whole composition.
The composition described in any one of [7][1] to [6] is an oleogel formulation.
[8][7] The composition contains more than 5% by mass of solid grease and/or semi-solid grease as a whole composition.
The composition described in any one of [9][1] to [8] is substantially free of water.
The composition described in any one of [10][1] to [9] is a topical skin agent.
Effects of the present invention
According to the present invention, it is possible to provide chemically stable compositions in which the decomposition of the compounds represented by the general formula (1), their isomers, and/or their pharmaceutically acceptable salts is inhibited. Furthermore, it is possible to provide compositions in which the compounds remain uniformly dispersed after a period of time.
Detailed Implementation
The compositions of the present invention are characterized in that they contain: a compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts, and an oil having 0 to 2 hydroxyl groups.
The compounds represented by general formula (1), their isomers and/or their pharmaceutically acceptable salts can be manufactured by, for example, the method described in Japanese Patent Application Publication No. 04-297446.
The compound represented by general formula (1) is an optically active compound having multiple asymmetric carbon atoms in its molecular structure. Therefore, as its isomers, there exist enantiomers and diastereomers. Furthermore, as the compound represented by general formula (1) of the present invention, there exist racemic mixtures, enantiomers, diastereomers, and compounds in which the above isomers are mixed in any proportion.
Regarding the compound represented by the general formula (1) of the present invention, R1 represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a straight-chain or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylic acid ester group having 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
The R1 may preferably include: carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl, propoxycarbonylmethyl, propoxycarbonylethyl, propoxycarbonylpropyl, propoxycarbonylbutyl, butoxycarbonylmethyl, butoxycarbonylethyl, butoxycarbonylpropyl, butoxycarbonylbutyl, etc., and more preferably, carboxymethyl.
The R2 and R3 can preferably be listed independently as follows: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and more preferably isopropyl.
The compound represented by general formula (1) exhibits human leukocyte elastase inhibitory activity, and is expected to have a therapeutic effect on ischemic cerebral diseases, such as cerebral infarction. Furthermore, for example, as described in International Publication No. 1999/43352, it has preventive or therapeutic effects on skin aging. In addition, the compound represented by general formula (1) of this invention promotes the regeneration of elastic fibers in the dermal papillae, the regeneration of fine collagen fibers in the dermis directly beneath the epidermis, and increases epidermal thickness, thereby exerting a preventive or improving effect on wrinkle formation.
The compound represented by general formula (1) is preferably the compound represented by general formula (2) below.
Regarding the compound represented by the general formula (2) of the present invention, R4 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms substituted by a carboxyl group, and R5 and R6 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms. Specifically, R4 can be represented by carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 3-carboxybutyl, 4-carboxybutyl, etc., and more preferably, carboxymethyl.
R5 and R6 each independently represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms. R5 and R6 can preferably be specifically listed as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and more preferably isobutyl. Furthermore, suitable examples of compounds represented by the general formula (2) include 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-isopentanoyl-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyl ... [Propyl]amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N- [3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl] [4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[ ...[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ -[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl] -L-Isopentyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentyl-N-[3,3,3-trifluoro- 1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide (3(RS)-N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2- [Oxypropyl]-L-proline amide), N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide.
Among the compounds represented by the general formula (2) above, 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane is more preferably listed, and 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane represented by the formula (3) below is even more preferred. In addition, as the compound contained in the composition of the present invention, the sodium salt of the 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-isopentanoyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (hereinafter also referred to as "KSK32") is particularly preferred.
It should be noted that KSK32, according to other nomenclature, can also be expressed as N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-isopentanyl-N-[(RS)-3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-proline amide, which is the same compound.
In this invention, the compound represented by general formula (1) can be directly included in the composition, or it can be treated with a pharmaceutically acceptable acid or base to convert it into a salt form and used as a salt. For example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and carbonate can be listed; organic acid salts such as maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, p-toluenesulfonate, and benzenesulfonate can be listed; alkali metal salts such as sodium and potassium salts can be listed; alkaline earth metal salts such as calcium and magnesium salts can be listed; organic amine salts such as triethylamine, triethanolamine, ammonium, monoethanolamine, and piperidine salts can be listed; and basic amino acid salts such as lysine and arginine salts can be listed.
Furthermore, the compositions of the present invention may also contain one or more of the compounds represented by the general formula (1), their isomers and/or their pharmaceutically acceptable salts.
The content of the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts in the composition of the present invention is not particularly limited, but is preferably 0.01 to 10% by mass relative to the whole composition, more preferably 0.1 to 5% by mass. By containing it within this range, the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts can easily exert their effect of preventing or improving the formation of wrinkles.
It can be fully utilized.
The compositions of the present invention are obtained by dispersing the compound of general formula (1), its isomers and/or their pharmaceutically acceptable salts in an oil having 0 to 2 hydroxyl groups.
The oil is not particularly limited and is selected from the group consisting of hydrocarbon oils, silicone oils, and ester oils. Furthermore, the number of hydroxyl groups is more preferably 0 to 1, and even more preferably 0, i.e., no hydroxyl groups.
Here, the number of hydroxyl groups refers to the number in a single molecule.
Examples of suitable hydrocarbon oils include, for example, paraffin, isoparaffin, liquid paraffin, α-olefin oligomers, polyethylene, squalane, isododecane, isohexadecane, etc.
As a silicone oil, it may or may not have side chains, and it may or may not be cross-linked. Preferred examples include polysiloxane, dimethyl polysiloxane, decamethylcyclopentasiloxane, methyl polysiloxane, diphenyl dimethyl silicone oil, etc.
Preferred ester oils include, for example, glyceryl tri-2-ethylhexanoate, glyceryl triisostearate, hexadecyl 2-ethylhexanoate, tri(caprylic/capric) glyceryl tristearate, ethylene glycol distearate, N-lauroyl sarcosinate, glyceryl triisostearate, diisostearate malate, and ethylene glycol monostearate.
The oil in the composition of the present invention is capable of dispersing the compound represented by general formula (1), its isomers and/or their pharmaceutically acceptable salts.
Furthermore, since the compounds represented by the general formula (1), their isomers, and/or their pharmaceutically acceptable salts are prone to decomposition, there is a problem that the content of the compound decreases over time in compositions containing them. To address this problem, the present invention enables the chemically stable formulation of the compound in the composition by using an oil having 0 to 2 hydroxyl groups as a dispersion medium.
The oil having 0 to 2 hydroxyl groups in the composition of the present invention comprises 50% by mass or more, more preferably 80% by mass, and even more preferably 90% by mass or more, relative to the total composition. Within this range, the compound represented by the general formula (1), its isomers, and/or their pharmaceutically acceptable salts are readily dispersed.
Furthermore, the total content of oils in the compositions of the present invention is generally 50% by mass or more relative to the whole composition, preferably 60% by mass or more.
Furthermore, the content of the oil having three or more hydroxyl groups is preferably 50% by mass or less relative to the total composition, more preferably 25% by mass or less, and even more preferably 5% by mass or less. This is because when oils having three or more hydroxyl groups coexist in a certain amount or more, the compound represented by the general formula (1), its isomers, and/or their pharmaceutically acceptable salts are easily decomposed, and there is a situation where the residual amount of the compound in the composition decreases over time.
Here, examples of oils containing hydroxyl groups include, but are not limited to, monoesters or diesters formed from fatty acids and polyglycerols, esters formed from fatty acids and sugar alcohols, and esters formed from fatty acids and polysaccharide alcohols.
Furthermore, the oil in the composition of the present invention preferably contains solid grease and/or semi-solid grease, more preferably solid grease and/or semi-solid grease having 0 to 2 hydroxyl groups, and even more preferably solid grease and/or semi-solid grease without hydroxyl groups.
By containing solid or semi-solid lipids, the viscosity of the composition increases, thus the compounds, isomers, and/or pharmaceutically acceptable salts of the general formula (1) dispersed in the composition are less likely to settle over time, resulting in a composition with excellent dispersion stability over time. This embodiment is applicable to oleogel formulations, etc., described later.
The content of solid fats and/or semi-solid fats is preferably 5% by mass or more of the total composition, more preferably 10% by mass or more, and even more preferably 20% by mass or more. Furthermore, it is preferably 50% by mass or less of the total composition, more preferably 40% by mass or less, and even more preferably 30% by mass or less.
Here, solid grease includes semi-solid grease. It should be noted that solid grease refers to grease that does not flow at 25°C, while semi-solid grease refers to grease that does not deform significantly in an environment without stress at 1 atmosphere and 20°C, but deforms when subjected to a small amount of stress (approximately 10–100 g/ cm² ). Furthermore, a melting point of 50°C or higher is preferred.
Examples of plant-derived solid and/or semi-solid lipids include carnauba wax, wood wax, candelilla wax, rice bran wax, shea butter, and African wood resin. Examples of animal-derived solid and/or semi-solid lipids include beeswax, shellac wax, and insect wax. Examples of petroleum-derived substances include refined waxes such as paraffin wax and microcrystalline wax. Examples of mineral-derived solid and/or semi-solid lipids include refined waxes such as ceresin, serotonin, and montan wax. Solid or semi-solid lipids from plant and animal sources often contain hydroxyl groups; therefore, refined waxes from petroleum or mineral sources are preferred. It should be noted that these solid and/or semi-solid lipids can be used alone or in combination of two or more.
The compositions of the present invention preferably further contain an oily gelling agent. By containing an oily gelling agent, the viscosity of the composition increases, and therefore the compounds, isomers and/or pharmaceutically acceptable salts of the general formula (1) dispersed in the composition are less likely to settle over time, resulting in a composition with excellent dispersion stability over time.
Here, "oil-based gelling agent" refers to a gelling agent that is compatible with oily components such as oils. There is no particular limitation, and examples include 12-hydroxystearic acid, palmitic dextrin, (palmitic acid/octanoic acid) dextrin, dibutyllauroyl glutamine, and dimethylsiloxane cross-linked polymers.
The content of the oily gelling agent is preferably 0.5% by mass or more of the total composition, more preferably 2% by mass or more, and even more preferably 5% by mass or more. Furthermore, it is preferably 20% by mass or less of the total composition, more preferably 15% by mass or less, and even more preferably 10% by mass or less.
When the composition of the present invention is an oleogel formulation as described later, it is preferable to further contain an oily gelling agent in the solid or semi-solid grease, or to replace the solid or semi-solid grease with an oily gelling agent. In this case, the content is preferably 5% by mass or more of the total composition, including the solid or semi-solid grease.
The compositions of the present invention preferably further contain powder. By containing powder, the viscosity of the composition increases, and therefore the compounds, isomers thereof, and/or pharmaceutically acceptable salts thereof dispersed in the composition according to the general formula (1) are less likely to settle over time, resulting in a composition with excellent dispersion stability over time. This embodiment is suitable for oleogel formulations, etc., as described later.
The powder content is preferably 0.5 to 20% by mass of the whole composition, more preferably 1 to 5% by mass.
As for powders, examples include: surface-treated powders such as silica (anhydrous silica), mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, alumina, and barium sulfate; surface-treated inorganic pigments such as iron oxide red, iron oxide yellow, iron oxide black, cobalt oxide, ultramarine, cyan violet, titanium oxide, and zinc oxide; surface-treated pearlescent agents such as mica titanium, fish scale foil, and bismuth oxychloride; and laked pigments such as Red 202 and Red 22. Organic dyes such as No. 8, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, etc., and organic powders such as polyester powder, polyamide powder, polyethylene powder, polymethyl methacrylate, nylon powder, and organopolysiloxane elastomers.
Furthermore, there are no particular limitations on the shape; examples include spherical, hemispherical, and sheet-like shapes commonly used in cosmetics and other topical skin agents, as well as porous shapes.
In addition, the particle size should be the same as that used in typical cosmetics and other topical skin agents.
In this invention, porous silica is particularly preferred from the viewpoint of the dispersion stability of the composition.
The compositions of the present invention are oily and generally substantially free of water. Here, "substantially free of water" means that its content relative to the whole composition is preferably 0.1% by mass or less, more preferably 0.01% by mass or less, and even more preferably 0.001% by mass or less.
This is because, when water is present in the composition, the compound represented by the general formula (1), its isomers and/or their pharmaceutically acceptable salts become readily decomposed, and there is a situation where the residual amount of the compound in the composition decreases over time.
Regardless of whether it has fluidity, the oily composition of the present invention can be any dosage form such as emulsion, ointment, or oleogel, preferably an oleogel.
The oleogel formulation of this invention typically has a high viscosity and low flowability. For example, it is preferably non-flowable at 25°C, i.e., solid. Furthermore, the viscosity at 25°C is preferably 20,000 Pa·s or higher. By using this formulation, the compound represented by general formula (1), its isomers, and/or their pharmaceutically acceptable salts are less likely to precipitate over time, resulting in a composition with excellent dispersion stability over time.
In the compositions of the present invention, the compound represented by general formula (1), its isomers, and/or their pharmaceutically acceptable salts have a high residual amount in the composition over time. Specifically, for example, the content of the compound after storage at 60°C for 2 weeks is preferably 60% or more, more preferably 80% or more, and even more preferably 95% or more, relative to the content of the compound after storage at 5°C for 2 weeks.
The compositions of the present invention are compositions in which the compounds of the general formula (1), their isomers, and/or their pharmaceutically acceptable salts exhibit high dispersion stability over time. Specifically, for example, this means that no sedimentation of the compound is visually observed after standing at 40°C for 1 day. Alternatively, after standing at 40°C for 1 day, the concentration difference of the compound in the upper 95 v/v% and the lower 95 v/v% of the composition is preferably within 10%, more preferably within 5%, and even more preferably within 0.5%.
In the compositions of the present invention, as previously described, the compounds represented by general formula (1), their isomers, and/or their pharmaceutically acceptable salts are capable of preventing or improving wrinkle formation. Furthermore, the compounds in the compositions of the present invention exhibit excellent decomposition and dispersion stability over time. Therefore, the compositions of the present invention are suitable for use as topical skin agents, more preferably in cosmetics, and particularly preferably in anti-aging cosmetics. It should be noted that cosmetics here include quasi-pharmaceuticals.
In addition to the above-mentioned components, the compositions of the present invention may optionally contain any components commonly used in topical skin preparations, provided that the technical effects of the present invention are not impaired. Examples of such optional components include various active ingredients, oily components, surfactants, polyols, thickeners, ultraviolet absorbers, etc.
As active ingredients, examples include whitening ingredients, wrinkle-improving ingredients, anti-inflammatory ingredients, and extracts from plants and animals.
As a whitening ingredient, any substance commonly used in cosmetics is acceptable; there are no specific limitations. Examples include 4-n-butylresorcinol, ascorbic acid glycoside, 3-O-ethyl ascorbic acid, tranexamic acid, arbutin, ellagic acid, kojic acid, linoleic acid, niacinamide, 5,5'-dipropyldiphenyl-2,2'-diol, disodium 5'-adenosine, hexadecyl tranexamic acid, potassium 4-methoxysalicylate, hydroquinone, and pantothenic acid.
As other wrinkle-improving ingredients, any substance commonly used in cosmetics is acceptable, without specific limitations. Examples include niacinamide, vitamin A or its derivatives (retinol, retinaldehyde, retinoic acid, tretinoin, isotretinoin, tocopherol retinoate, retinyl palmitate, retinol acetate, etc.), benzyl ursolic acid, ursolic acid phosphate, benzyl betulinate, and benzoic acid phosphate.
Extracts derived from plants and animals are acceptable as long as they are substances commonly used in cosmetics; there are no particular limitations. Examples of preferred extracts include: Akebia quinata extract, Phellodendron chinense extract, Asparagus cochinchinensis extract, Avocado extract, Hydrangea macrophylla extract, Almond extract, Arnica extract, Aloe vera extract, Prunus armeniaca extract, Apricot kernel extract, Ginkgo biloba extract, Dalbergia odorifera extract, Fennel extract, Angelica sinensis extract, Rosa rugosa extract, Eleutherococcus senticosus extract, Coptis chinensis extract, Scutellaria baicalensis extract, Phellodendron chinense extract, Coptis chinensis extract, Ginseng extract, Forsythia suspensa extract, Sesamum indicum extract, Sweet orange extract, Pyracantha fortuneana extract, Pueraria lobata extract, Chamomile extract, Carrot extract, Artemisia capillaris extract, Licorice extract, Actinidia chinensis extract, Cucumber extract, Guava extract, Sophora flavescens extract, Gardenia jasminoides extract, Pteris vittata extract, Sophora flavescens root extract, and Walnut extract. Extracts of various herbs, including grapefruit extract, black rice extract, chlorella extract, mulberry extract, white-flowered sesame vine extract, alpinia leaf extract, gentian extract, geranium extract, black tea extract, burdock extract, rice extract, fermented rice extract, fermented rice bran extract, rice germ oil, blueberry extract, salvia extract, soapwort extract, soapberry extract, wild hawthorn extract, silkworm excrement extract, Sichuan pepper extract, shiitake mushroom extract, rehmannia extract, lithospermum extract, perilla extract, Japanese linden extract, mosquito grass extract, peony extract, ginger extract, calamus root extract, birch extract, schizonepeta extract, stevia extract, stevia ferment, ivy extract, hawthorn thorn extract, elderberry extract, and yarrow. Herb extracts, peppermint extract, medicinal sage extract, mallow extract, chuanxiong extract, Japanese swert extract, mulberry bark extract, rhubarb extract, soybean extract, jujube extract, thyme extract, dandelion extract, tea extract, clove extract, sweet tea extract, capsicum extract, angelica extract, calendula extract, peach kernel extract, spruce extract, houttuynia cordata extract, tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, ophiopogon japonicus extract, lotus extract, parsley extract, birch extract, witch hazel extract, sage extract, Japanese cypress extract, loquat extract, coltsfoot extract, senna stem extract, poria cocos extract, butcher's broom extract. Extracts include grape extract, grape seed extract, loofah extract, safflower extract, peppermint extract, European linden extract, peony extract, hops extract, Korean pine extract, oregano leaf extract, European horse chestnut extract, banana extract, sago palm extract, lemon balm extract, seaweed extract, peach extract, cornflower extract, eucalyptus extract, strawberry saxifrage extract, grapefruit extract, lily extract, coix seed extract, artemisia extract, lavender extract, green tea extract, apple extract, rooibos tea extract, ganoderma lucidum extract, lettuce extract, lemon extract, forsythia extract, astragalus extract, rose extract, rosemary extract, white chamomile extract, royal jelly extract, and burnet root extract.
As anti-inflammatory components, examples include matrine, glycyrrhizin, glycyrrhizic acid, glycyrrhetinic acid, and panthenol, with glycyrrhizic acid and its salts, alkyl esters of glycyrrhetinic acid and their salts, and glycyrrhetinic acid and its salts being preferred.
Examples of surfactants include anionic surfactants such as fatty acid soaps (sodium lauryl salt, sodium palmitate, etc.), potassium lauryl sulfate, and triethanolamine alkyl sulfate; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, and laurylamine oxide; betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.); imidazoline amphoteric surfactants (2-cocoyl-2-imidazolium hydroxide-1-carboxyethoxy disodium salt, etc.); and acylmethyl taurine.
Polyglycerol sesquiisostearate, sorbitol fatty acid esters (sorbitol monostearate, sorbitol sesquioleate, etc.), glycerol fatty acid esters (glycerol monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivatives, glyceryl alkyl ethers, POE sorbitol fatty acid esters (POE sorbitol monooleate, polyoxyethylene sorbitol monostearate, etc.), POE sorbitol fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerol fatty acid esters (POE... - Glyceryl monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic, POE/POP alkyl ethers (POE/POP2-decyltetradecyl ether, etc.), Tetronic, POE castor oil and hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), sucrose fatty acid esters, alkyl glycosides and other nonionic surfactants, etc.
Examples of polyols include polyethylene glycol, glycerol, 1,3-butanediol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerol, isoprenediol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, and 1,2-octanediol.
Examples of thickeners include guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum, guar gum, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methyl hydroxypropylcellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratin sulfate, chondroitin, mucin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratin sulfate, locust bean gum, succinosaccharide, carboxylic acid, chitosan, chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, alkyl-modified carboxyvinyl polymers, sodium polyacrylate, polyethylene glycol, and bentonite.
Examples of UV absorbers include p-aminobenzoic acid UV absorbers, o-aminobenzoic acid UV absorbers, salicylic acid UV absorbers, cinnamic acid UV absorbers, benzophenone UV absorbers, sugar-based UV absorbers, 2-(2’-hydroxy-5’-tert-octylphenyl)benzotriazole, and 4-methoxy-4’-tert-butyldibenzoylmethane, among others.
The compositions of the present invention can be manufactured by processing the essential components, preferred components, optional components, etc., according to conventional methods.
Example
The present invention will now be described in more detail by providing examples. However, the present invention is obviously not limited to these examples.
<Manufacturing Example 1>
According to the formulations shown in Tables 1 and 2 below, an oil gel-type topical skin agent was manufactured. Specifically, component A was heated and dissolved at 95°C and mixed. Then, using a disperser, the mixture was stirred at 3000 rpm for 1 minute at 95°C while component B was added to the mixture. After defoaming, the mixture was filled into a container and cooled to solidify, yielding an oily solid cosmetic.
<Experimental Example>
(1) Evaluation of the decomposition stability of KSK32
The KSK32 content of each prepared oil-based solid cosmetic was measured after storage at 60℃ for 2 weeks. The proportion (residual rate) with the KSK32 content after storage at 5℃ for 2 weeks as 100 was calculated. A residual rate of 95% or higher was rated as ◎ for decomposition stability, less than 95% but more than 80% as ○, less than 80% but more than 60% as △, and less than 60% as ×. The results are shown in Tables 1 and 2.
It should be noted that approximately 0.5g of cosmetic product was weighed, diluted to 50mL, and used as a sample solution for high-performance liquid chromatography (HPLC) in the mobile phase to determine the content of KSK32.
HPLC conditions: Column: reversed-phase column (3.0 × 100 mm); Column temperature: room temperature; Mobile phase: aqueous solution of anionic sulfonic acid surfactant/THF 25%; pH: 3; Flow rate: 0.4 mL/min; Detection: 240 nm.
(2) Evaluation of dispersion stability
After each prepared oily solid cosmetic was allowed to stand at 40℃ for 1 day, KSK32 was visually observed for sedimentation. The dispersion stability was rated as ○ when uniformly dispersed and × when sedimentation was observed. The results are shown in Tables 1 and 2.
<Manufacturing Example 2>
Prepare ointment-type topical skin agents according to the formulations shown in Table 3 below, and prepare emulsion-type topical skin agents according to the formulations shown in Table 4. Specifically, dissolve component A by heating at 95°C and mix. Then, stir at 3000 rpm for 1 minute at 95°C using a disperser, while simultaneously adding component B to the mixture to obtain the respective oily cosmetics.
For the oily cosmetics of Examples 20 and 21, the decomposition stability and dispersion stability of KSK32 were confirmed to be good by the methods of the above test examples.
Table 3 (mass%)
※The number in parentheses in the oil name indicates the number of hydroxyl groups.
Table 4 (mass%)
※The number in parentheses in the oil name indicates the number of hydroxyl groups.
Industrial applicability
This invention can be applied to cosmetics and other topical skin agents.
Claims (9)
1. An oily composition comprising: a compound of the following general formula (1), its isomers and/or their pharmaceutically acceptable salts, and an oil having 0 hydroxyl groups, wherein the oil having 0 hydroxyl groups is present in an amount of more than 50% by mass of the whole composition;
In the formula, R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and R2 and R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms.
2. The composition according to claim 1, wherein the oil having 0 hydroxyl groups is selected from the group consisting of hydrocarbon oils, silicone oils, and ester oils.
3. The composition according to claim 1 or 2, characterized in that the composition further contains an oily gelling agent.
4. The composition according to claim 1 or 2, wherein the composition further comprises powder.
5. The composition according to claim 4, wherein the content of the powder is 0.5 to 20% by mass of the whole composition.
6. The composition according to claim 1 or 2, wherein the composition is an oleogel formulation.
7. The composition according to claim 6, characterized in that it contains more than 5% by mass of solid grease and/or semi-solid grease as a whole composition.
8. The composition according to claim 1 or 2, characterized in that the composition contains less than 0.1% by mass of water as a whole composition.
9. The composition according to claim 1 or 2, wherein the composition is a topical skin agent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2017-220078 | 2017-11-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK40076552A HK40076552A (en) | 2023-02-17 |
| HK40076552B true HK40076552B (en) | 2024-08-02 |
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