WO2020158831A1 - Transdermal absorption composition with controlled release of water-soluble hydrochloride - Google Patents
Transdermal absorption composition with controlled release of water-soluble hydrochloride Download PDFInfo
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- WO2020158831A1 WO2020158831A1 PCT/JP2020/003282 JP2020003282W WO2020158831A1 WO 2020158831 A1 WO2020158831 A1 WO 2020158831A1 JP 2020003282 W JP2020003282 W JP 2020003282W WO 2020158831 A1 WO2020158831 A1 WO 2020158831A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a transdermal absorption composition with controlled release of a water-soluble hydrochloride in the skin, and a method for controlling a water-soluble hydrochloride in the skin, and in particular, propranolol hydrochloride and aminolevulinic acid hydrochloride.
- the bond between the water-soluble drug and the fat-soluble site is cleaved by an enzyme or the like inside the skin, and the water-soluble drug is released.
- an aqueous solution of a water-soluble drug is enclosed in liposomes, dissolved/dispersed in an oil/fat base material and applied to the skin. After permeating the stratum corneum, the liposome interface is disrupted by enzymes and the like inside the skin, and the water-soluble drug is released.
- a permeability enhancer transdermal absorption enhancer
- terpene or higher alcohol is used to enhance the percutaneous absorption of a drug.
- Prodrug formation is an excellent method for imparting lipophilicity to water-soluble drugs and increasing percutaneous absorption, but it is a complicated process for obtaining a manufacturing process for organic synthesis and approval for the manufacture and sale of drugs and quasi drugs. Is required.
- tranexamic acid As a drug that is converted into a prodrug or encapsulated in liposomes, for example, an artificial amino acid, tranexamic acid, inhibits melanin production by binding to the proteolytic enzyme plasmin and inhibiting activation in the epidermis. Is known to do. Utilizing this action, the whitening effect has recently been proclaimed, and has attracted attention as a raw material for cosmetics. However, there is a problem that tranexamic acid has low skin permeability.
- An object of the present invention is to provide a method for easily increasing the transdermal absorbability of a water-soluble hydrochloride without using a prodrug by organic synthesis.
- the present inventors have combined a water-soluble hydrochloride and a fat-soluble compound having an aldehyde group to easily impart fat-solubility to the water-soluble hydrochloride to improve its transdermal absorbability. While being enhanced, they have found that the water-soluble hydrochloride can be easily released in the skin, and completed the present invention.
- the present invention is (1) A composition containing a water-soluble hydrochloride and a fat-soluble compound having an aldehyde group; (2) The composition according to (1) above, wherein the water-soluble hydrochloride is one or more selected from the group consisting of propranolol hydrochloride, aminolevulinic acid hydrochloride, and donepezil hydrochloride. (3) The (1) or (2) above, wherein the fat-soluble compound having an aldehyde group is selected from the group consisting of a terpene having an aldehyde group, a lignoid having an aldehyde group, and a vanilloid having an aldehyde group.
- composition according to (1) or (2) above wherein the vanilloid having an aldehyde group is vanillin; (7) The composition according to (1) or (2), wherein the fat-soluble compound having an aldehyde group is dodecanal or 4-butoxybenzaldehyde; (8) A percutaneous absorption composition comprising the composition according to any one of (1) to (7) above, a percutaneous absorption control agent, and a fat-soluble medium; (9) The transdermal absorption composition according to (8) above, wherein the composition according to any one of (1) to (7) is dissolved in the fat-soluble medium; (10) The percutaneous absorption composition according to the above (8) or (9), wherein the fat-soluble medium is a percutaneous absorption-promoting fat-soluble medium; (11) The percutaneous absorption composition according to (10) above, wherein the percutaneous absorption-promoting fat-soluble medium is one or more selected from the group consisting of isopropyl myristate, cyclopentasiloxane, squalane, and limon
- the percutaneous absorption control agent is alcohol;
- the alcohol comprises methanol, ethanol, 2-propanol, geraniol, citronellol, glycerin, propylene glycol, butylene glycol, oleyl alcohol, cetanol, lauryl alcohol, stearyl alcohol, 2-hexyldecanol, and 1,2-hexanediol.
- composition according to (15) above which is selected from one or more groups; (17) Release of the water-soluble hydrochloride from the composition into the skin, comprising the step of dissolving the composition according to any one of (1) to (7) in a transdermal absorption controller. To control the; (18) Releasing the water-soluble hydrochloride from the composition into the skin, which comprises the step of dissolving the composition according to any one of (1) to (7) in a transdermal absorption controller.
- a composition containing a water-soluble hydrochloride salt and a fat-soluble compound having an aldehyde group according to the present invention has a structure in which the water-soluble hydrochloride salt and the fat-soluble compound having an aldehyde group are uniformly dissolved in a fat-soluble medium (lipophilic or oil-solubilized). It is also possible to improve the percutaneous absorbability of the water-soluble hydrochloride, and further to release the water-soluble hydrochloride inside the skin after permeation of the stratum corneum to exert a medicinal effect. it can.
- the water-soluble hydrochloride and the fat-soluble compound having the aldehyde group may form a complex through a reversible interaction capable of dissociating in water.
- the complex thus formed, the water-soluble hydrochloride and the fat-soluble compound having the aldehyde group are complexed through an interaction capable of dissociating in water, so that the fat-soluble medium is uniformly dispersed. It can be dissolved (fat-solubilized or oil-solubilized), and as a result, the percutaneous absorption of the water-soluble hydrochloride can be improved, and the water-soluble hydrochloric acid can be absorbed by the water inside the skin after permeating the stratum corneum. It can be expected that the salt can be released to exert a medicinal effect. Further, in the present invention, the release of the water-soluble hydrochloride from the complex in the skin can be controlled by appropriately using a transdermal absorption controller.
- composition (1) of the present invention the water-soluble hydrochloride salt and the fat-soluble compound having an aldehyde group
- the compound may form a complex.
- the complex the water-soluble hydrochloride salt and the fat-soluble compound having the aldehyde group are complexed via an interaction capable of dissociating in water. Therefore, the complex can be in a chemical equilibrium relationship with the water-soluble hydrochloride salt and the fat-soluble compound having the aldehyde group, and as a result, in the fat-soluble medium, it is fat-solubilized by solvation or cluster formation.
- it can be expected to be able to exert its medicinal effect because inside the skin, it is easily dissociated by the water contained therein to release the water-soluble hydrochloride.
- the water-soluble hydrochloric acid salt of the present invention may or may not form a complex with a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water, such as a pharmaceutical or cosmetic product.
- a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water, such as a pharmaceutical or cosmetic product.
- any water-soluble hydrochloride salt of the active ingredient of pharmaceuticals or cosmetics can be used.
- one or more water-soluble hydrochlorides may be used, but they may be used in combination with any one or more other water-soluble active ingredients.
- Such other water-soluble active ingredient may or may not form a complex with a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water,
- any water-soluble active ingredient for medicines or cosmetics for example, amino acids, hydrophilic vitamins, sugars, peptides and other hydrophilic drugs can be used. ..
- examples of such other water-soluble active ingredients include those having an amino group, a hydroxyl group, or a thiol group.
- These groups are, respectively, an interaction capable of dissociating in water with the aldehyde group of the fat-soluble compound having an aldehyde group, such as an ionic bond, a hydrogen bond, a dipole interaction, a Van der Waals force, a charge transfer interaction. , ⁇ - ⁇ interaction, hydrophobic interaction, solvation, and reversible chemical bond may be formed.
- amino acids examples include artificial amino acids such as tranexamic acid; and alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan.
- Artificial amino acids such as tyrosine, and valine.
- hydrophilic vitamin examples include ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl glucoside, ethyl ascorbic acid, and vitamins B1, B2, B4, B5, B6, B7, and B12.
- sugar examples include glucose, trehalose, dextran, pullulan, cyclodextrin, mannitol, glucosamine, galactosamine, raffinose, mannan, and pectin.
- peptide examples include known peptides as well as peptides having a specific efficacy (for example, a therapeutic effect on hay fever is expected because it is recognized by human T cells).
- Specific examples are peptide A (amino acid sequence: QFAKLGTGFTLMG) and peptide B (amino acid sequence: SMKVTVAFNQFGP).
- hydrophilic drug examples include minoxidil, zanamivir (relenza), acyclovir, cytarabine ocfosfate, and fludarabine phosphate.
- the fat-soluble compound having an aldehyde group of the present invention is not particularly limited as long as it is a fat-soluble compound containing at least one aldehyde group, and any compound containing an aliphatic aldehyde or an aromatic aldehyde can be used. .. Among them, terpenes having an aldehyde group, lignoides having an aldehyde group, and vanilloids having an aldehyde group are preferable from the viewpoint of natural origin and safety.
- Examples of the terpene having an aldehyde group include citral, citronellal, cyclocitral, safranal, ferrandral, perylaldehyde, tagetone, and retinal, and from the viewpoint of satisfactorily fat-solubilizing the water-soluble hydrochloride, citral and citronellal.
- citral is preferable, and natural products such as essential oils (essential oils) containing the above compounds may be used.
- Lemongrass or citronella is preferable from the viewpoint of satisfactorily fat-solubilizing the water-soluble hydrochloride.
- Essential oil is a general term for volatile organic substances produced by plants and is generally a mixture of many compounds.
- lemongrass is a mixture of citral (50 to 80%) as a main component and geraniol (3 to 10%), farnesol, nerol, citronellol and myrcene.
- citronella is a mixture of geraniol as a main component (10 to 60%), citronellol (3 to 10%), citronellal (1 to 30%) and the like.
- Cinnamic aldehyde is preferable as the lignoide having the aldehyde group, from the viewpoint of favorably fat-solubilizing the water-soluble hydrochloride.
- vanillin is preferable from the viewpoint of favorably fat-solubilizing the water-soluble hydrochloride.
- dodecanal or 4-butoxybenzaldehyde is also preferable from the viewpoint of favorably fat-solubilizing the water-soluble hydrochloride.
- the fat-soluble compound having an aldehyde group may be used alone or in combination of two or more kinds.
- the fat-soluble compound having an aldehyde group of the present invention is particularly preferably citral, citronellal, and vanillin, and particularly preferably citral, from the viewpoints of favorably fat-solubilizing the water-soluble hydrochloride or enhancing transdermal absorbability.
- the percutaneous absorption control agent of the present invention is not particularly limited as long as it is conventionally used for controlling percutaneous absorption of an active ingredient of a water-soluble drug or cosmetic in the field of medicines and cosmetics, particularly external skin preparations. From the point that the composition (1) of the present invention can be well stabilized in a fat-soluble medium, or the release of the water-soluble hydrochloride in the skin can be better controlled, a transdermal absorption control having a hydroxyl group Agents are preferable, and monohydric or polyhydric alcohols are particularly preferably used.
- the complex of the present invention may be a complex of a water-soluble hydrochloride, a lipid-soluble compound having an aldehyde group, and a transdermal absorption controller through a dissociable interaction in water. .. With such a complex, the release of the water-soluble hydrochloride salt in the skin is better controlled.
- Examples of the monohydric alcohol include lower alcohols such as methanol, ethanol, 1-propanol, and 2-propanol; higher alcohols; and nerolidol, geraniol, menthol, borneol, isoborneol, nerol, citronellol, fentyl.
- Examples thereof include terpenes having a hydroxyl group such as alcohol, carveol, and neomenthol, preferably methanol, ethanol, 2-propanol, citronellol, and geraniol, more preferably ethanol and 2-propanol.
- Examples of the higher alcohols include octanol, nonanol, decanol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol (cetanol), 2-hexyldecanol, heptadecyl alcohol, stearyl alcohol, and Fine Oxo Call 180 (FO180): And saturated alcohols having 8 to 18 carbon atoms; and unsaturated alcohols having 8 to 18 carbon atoms such as oleyl alcohol, linoleyl alcohol, and linolenyl alcohol.
- octanol decanol, cetanol, lauryl alcohol, myristyl alcohol, stearyl alcohol, 2-hexyldecanol, and oleyl alcohol
- oleyl alcohol cetanol, lauryl alcohol, stearyl alcohol, and 2-hexyldecanol.
- polyhydric alcohol examples include ethylene glycol, propylene glycol, 1,3-propanediol, butylene glycol (eg, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, or 2 , 3-butanediol), 1,5-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 400, and the like, preferably glycerin, propylene glycol, Examples include butylene glycol and 1,2-hexanediol.
- the composition (1) of the present invention can be simply prepared by mixing the water-soluble hydrochloride with the fat-soluble compound having an aldehyde group, and heating and cooling for a certain period of time if necessary. From the viewpoint that the composition (1) of the present invention can be satisfactorily obtained, it is preferable to add and mix the percutaneous absorption control agent of the present invention, particularly a liquid percutaneous absorption control agent. In addition, it is preferable that the percutaneous absorption control agent of the present invention is in a liquid state also in that the obtained composition (1) can be stably dissolved. In this case, the solution of the percutaneous absorption control agent in which the obtained composition (1) is dissolved can be used for the preparation of the percutaneous absorption composition of the present invention.
- the water-soluble hydrochloride salt is solid (preferably crystalline), it is preferable to mix it in powder form in order to obtain the composition (1) of the present invention well.
- the method for making powder include a method by dry pulverization.
- the conditions for dry crushing are not particularly limited as long as the water-soluble hydrochloride can be crushed into small pieces, but it is preferable to use a crusher such as a mortar, a ball mill, a homogenizer, a cutter mill, and a hammer mill. Further, the crushing time, the processing pressure, etc. are appropriately adjusted according to the hardness of the water-soluble hydrochloride salt to be crushed. It is desirable that the powder obtained by the above method is further sieved in order to make the particle diameter uniform.
- the sieve is preferably 500 ⁇ m or less, more preferably 200 ⁇ m or less, and particularly preferably 100 ⁇ m or less.
- the mixing ratio of the water-soluble hydrochloride and the fat-soluble compound having an aldehyde group varies depending on the type of these substances used, but is 1:0.1 to 100, preferably 1:10 to 50.
- the percutaneous absorption control agent is also mixed, the water-soluble hydrochloride salt, the lipophilic compound having an aldehyde group, the mixing ratio of the percutaneous absorption control agent, depending on the type of these substances to be used, It is 1:0.1 to 100:1 to 100, preferably 1:1 to 100:10 to 50, and more preferably 1:10 to 50:10 to 50.
- composition ratio (molar ratio) of the water-soluble hydrochloric acid salt and the fat-soluble compound having an aldehyde group, which constitutes the composition (1) of the present invention is 1 to 100:100 to 1, and more preferably 1 to It is 10:10 to 1.
- the release of the water-soluble hydrochloride salt from the composition (1) of the present invention can be controlled.
- the release of the water-soluble hydrochloride salt can be delayed, thereby increasing the lipophilicity of the percutaneous absorption control agent.
- decreasing for example, decreasing the number of carbon atoms
- the release of the water-soluble hydrochloride can be promoted.
- the present invention comprises a step of dissolving the composition (1) of the present invention in a percutaneous absorption control agent, which is selected from propranolol hydrochloride, aminolevulinic acid hydrochloride, and donepezil hydrochloride from the composition (1). It also relates to a method for controlling the release of water-soluble hydrochlorides in the skin. The present invention also relates to the use of a percutaneous absorption control agent for controlling in the skin the release of a water-soluble hydrochloride salt from the composition (1) of the present invention.
- a percutaneous absorption control agent which is selected from propranolol hydrochloride, aminolevulinic acid hydrochloride, and donepezil hydrochloride from the composition (1).
- the above-mentioned percutaneous absorption control agent may be used alone or in combination of two or more kinds.
- the fat-soluble medium of the present invention is not particularly limited as long as it is a fat-soluble medium that is commonly used as a base material in the field of pharmaceuticals and cosmetics, particularly skin external preparations, and preferably a transdermal absorption-promoting fat-soluble medium. Can be used.
- the percutaneous absorption-promoting fat-soluble medium is not particularly limited as long as it is conventionally used for promoting percutaneous absorption of an active ingredient of a water-soluble drug or cosmetic in the field of medicines and cosmetics, particularly skin external preparations.
- limonene eg, d-limonene ((+)-limonene), especially R-(+)-limonene
- cyclopentasiloxane KF995: Isopropyl myristate (IPM), squalane, squalane, squalene, silicone oil, jojoba oil, almond oil, olive oil, horse oil, diethyl sebacate, and mineral oil can be used, and preferably isopropyl myristate (IPM) ), cyclopentasiloxane, squalane, limonene (particularly R-(+)-limonene), and diethyl sebacate can be used, more preferably isopropyl myristate (IPM).
- the fat-soluble medium may be used alone or in combination of two or more kinds.
- the transdermal absorption composition of the present invention can be prepared by mixing the solution of the transdermal absorption control agent in which the composition (1) of the present invention obtained above is dissolved, and the fat-soluble medium. ..
- the composition (1) of the present invention can exhibit good solubility in a fat-soluble medium by using an appropriate transdermal absorption controller.
- the fat-soluble medium is squalane, geraniol or citronellol is preferable as the percutaneous absorption control agent, and when the fat-soluble medium is IPM, ethanol or 1,2-hexanediol is preferable as the percutaneous absorption control agent.
- the fat-soluble medium is KF995, geraniol or citronellol is preferable as the transdermal absorption controller.
- the percutaneous absorption composition of the present invention When used as a medicine or a cosmetic, it may be used as such, but it may also be used as a conventional pharmaceutical preparation, especially as a skin external preparation or a cosmetic.
- the pharmaceutical preparation or cosmetic is acceptable in the field of pharmaceuticals and cosmetics such as excipients, lubricants, binders, disintegrators, emulsifiers, stabilizers, flavors, diluents, etc. as long as the effects of the present invention are not impaired.
- the additive may be included.
- the external preparation for skin of the present invention may contain components that can be usually added to the external preparation for skin, as long as the effects of the present invention are not impaired.
- Such components include glycerin, polyhydric alcohols such as propylene glycol, liquid paraffin, squalane, higher fatty acids, oils such as higher alcohols, citric acid, organic acids such as lactic acid, caustic soda, alkalis such as triethanolamine, Cationic surfactant, amphoteric surfactant, nonionic surfactant, powder, pigment, dye, antiseptic and antifungal agent, resin, pH adjusting agent, antioxidant, ultraviolet absorber, chelating agent, thickener, Moisturizers, alcohol, water, fragrances, etc. are exemplified.
- the present invention also relates to a method for transdermal administration of a water-soluble hydrochloride salt, which comprises applying to the skin the transdermal absorption composition of the present invention.
- the present invention also relates to the use of the transdermal absorption composition of the present invention for transdermal administration of a water-soluble hydrochloride selected from propranolol hydrochloride, aminolevulinic acid hydrochloride and donepezil hydrochloride.
- the composition of the present invention may be a composition containing a water-soluble hydrochloride salt, a fat-soluble compound having the aldehyde group, and the transdermal absorption control agent, and is preferably a transdermal absorption composition. ..
- the composition of the present invention may further contain the fat-soluble medium.
- the present invention also relates to a method for transdermal administration of a water-soluble hydrochloride salt, which comprises applying the composition of the present invention to the skin.
- the present invention also relates to the use of the composition of the present invention for transdermal administration of a water soluble hydrochloride salt.
- the transdermal absorption composition used in this experiment was donepezil hydrochloride 10 mg, donepezil hydrochloride aqueous solution (comparative example 14) in which pure water 2.1 mL was added, and donepezil hydrochloride 10 mg, ethanol 1 mL, IPM 1 mL, ethanol/ Using the ethanol/IPM solution of donepezil hydrochloride added with 100 mg of IPM (1/1) (Comparative Example 15) as a standard for transdermal absorbability, the transdermal absorbability on pig skin of Example 1 prepared above was measured as follows. It was evaluated by a transdermal absorbability test. The transdermal absorption test was conducted as follows.
- pig Yucatan Micro Pig
- a stirring bar and 5 mL of a PBS aqueous solution were added to the receiver phase of the Franz cell, pig skin was sandwiched between the PBS aqueous solution upper portions, and water at 37° C. was poured into the water jacket of the Franz cell.
- 500 ⁇ L of the solutions of Comparative Examples 14 and 15 and Example 1 were placed on pig skin and the receiver phase was stirred.
- the swine skin extract after shaking and the PBS aqueous solution in the receiver phase were sampled, and the amount of donepezil hydrochloride was quantified by LC/MS.
- the LC/MS measurement conditions are as follows. Shodex Asahipak NH2P-40 2D (2.0 mm ID x 150 mm) was used for the column, and the column temperature was set to 30°C.
- the receiver phase was agitated to prepare a 5-aminolevulinic acid hydrochloride PBS solution (Comparative Example 16) having a concentration of 2 mg/mL, and a 5-aminolevulinic acid hydrochloride solution (Example 22) prepared in the above item “4.”. 200 ⁇ L of the above was placed on hairless mouse skin. After 24 hours, the PBS extract of hairless mouse skin and the PBS aqueous solution of the receiver were sampled, and the amount of 5-aminolevulinic acid hydrochloride was quantified by LC-MS.
- the conditions of LC-MS are as follows.
- transdermal absorbability was improved by solubilizing oil by adding citral.
- citral-added donepezil hydrochloride oil-solubilized solution and citral-added 5-aminolevulinic acid hydrochloride oil-solubilized solution promote percutaneous absorption and are used as transdermal drug delivery system (DDS) materials. It has shown promise.
- the composition (1) of the present invention improves the transdermal absorbability of a water-soluble hydrochloride to increase the content in the skin, and also releases the water-soluble hydrochloride inside the skin to exert a medicinal effect. Therefore, the percutaneous absorption composition of the present invention containing the composition (1) of the present invention can be used as a skin external preparation, for example, a drug or cosmetic used for skin external therapy.
- the release of the water-soluble hydrochloride from the composition (1) of the present invention inside the skin is controlled by appropriately using the transdermal absorption controlling agent, it can be used in a drug delivery system. That is, the composition (1) of the present invention can be used as a raw material for the production of a skin external preparation, for example, a drug, cosmetic, drug delivery system or the like used for skin external therapy.
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Abstract
Description
本発明は、水溶性塩酸塩の皮膚中での放出が制御された経皮吸収組成物、及び水溶性塩酸塩の皮膚中での制御方法に関するものであり、特に、プロプラノロール塩酸塩、アミノレブリン酸塩酸塩、及びドネペジル塩酸塩から選択される水溶性塩酸塩の皮膚中での放出が制御された経皮吸収組成物、及びプロプラノロール塩酸塩、アミノレブリン酸塩酸塩（「５－アミノレブリン酸塩酸塩」ともいう）、及びドネペジル塩酸塩から選択される水溶性塩酸塩の皮膚中での制御方法に関するものである。 The present invention relates to a transdermal absorption composition with controlled release of a water-soluble hydrochloride in the skin, and a method for controlling a water-soluble hydrochloride in the skin, and in particular, propranolol hydrochloride and aminolevulinic acid hydrochloride. Percutaneous absorption composition with controlled release in skin of water-soluble hydrochloride selected from salt and donepezil hydrochloride, and propranolol hydrochloride, aminolevulinic acid hydrochloride (also referred to as “5-aminolevulinic acid hydrochloride”) ), and a water-soluble hydrochloride selected from donepezil hydrochloride in the skin.
近年、皮膚から活性成分を吸収させて皮膚に直接的に作用するように誘導する経皮吸収技術に関する研究が進んでいる。
特に、水溶性薬剤については、脂溶性が高い角質層に浸透しにくいのが問題で、その経皮吸収性を高めるための方法の一つとして、水溶性薬剤の脂溶化（油溶化）が挙げられている。例えば、水溶性薬剤に対して脂溶化部位を有機合成により導入し（プロドラッグ化）、油脂性基材に溶解・分散させ皮膚に塗布する。角質層透過後、皮膚内部で酵素等により水溶性薬剤と脂溶性部位の結合が切断され、水溶性薬剤が放出される。あるいは、水溶性薬剤の水溶液をリポソーム内に封入し、油脂性基材に溶解・分散させ皮膚に塗布する。角質層透過後、皮膚内部で酵素等によりリポソームの界面が崩壊し、水溶性薬剤が放出される。
In recent years, research on transdermal absorption technology in which an active ingredient is absorbed from the skin to induce it to directly act on the skin has been advanced.
In particular, for water-soluble drugs, it is difficult to penetrate into the stratum corneum, which has high fat-solubility, and one of the methods for increasing its transdermal absorbability is fat-solubilization (oil-solubilization) of water-soluble drugs. Has been. For example, a fat-solubilized site is introduced into a water-soluble drug by organic synthesis (prodrug formation), dissolved and dispersed in an oil-and-fat base material, and applied to the skin. After permeating the stratum corneum, the bond between the water-soluble drug and the fat-soluble site is cleaved by an enzyme or the like inside the skin, and the water-soluble drug is released. Alternatively, an aqueous solution of a water-soluble drug is enclosed in liposomes, dissolved/dispersed in an oil/fat base material and applied to the skin. After permeating the stratum corneum, the liposome interface is disrupted by enzymes and the like inside the skin, and the water-soluble drug is released.
最近は、薬物の経皮吸収性を高めるため、テルペンや高級アルコールなどの透過性増強剤（経皮吸収促進剤）を使用することも報告されている（特許文献１～５）。 Recently, it has been reported that a permeability enhancer (transdermal absorption enhancer) such as terpene or higher alcohol is used to enhance the percutaneous absorption of a drug (Patent Documents 1 to 5).
プロドラッグ化は水溶性薬剤に親油性を付与し経皮吸収性を高める優れた方法であるが、有機合成の製造プロセスや、医薬品・医薬部外品の製造販売承認を得るための煩雑な手続きが必要となる。 Prodrug formation is an excellent method for imparting lipophilicity to water-soluble drugs and increasing percutaneous absorption, but it is a complicated process for obtaining a manufacturing process for organic synthesis and approval for the manufacture and sale of drugs and quasi drugs. Is required.
一方、プロドラッグ化又はリポソームに内包させる薬剤として、例えば、人工アミノ酸であるトラネキサム酸は、表皮中において、タンパク質分解酵素であるプラスミンに結合して活性化を阻害することにより、メラニンの産生を抑制することが知られている。この作用を利用して、近年、美白効果が謳われるようになり、化粧料の原料として注目を集めている。しかしながら、トラネキサム酸の皮膚浸透性は低いという問題があった。 On the other hand, as a drug that is converted into a prodrug or encapsulated in liposomes, for example, an artificial amino acid, tranexamic acid, inhibits melanin production by binding to the proteolytic enzyme plasmin and inhibiting activation in the epidermis. Is known to do. Utilizing this action, the whitening effect has recently been proclaimed, and has attracted attention as a raw material for cosmetics. However, there is a problem that tranexamic acid has low skin permeability.
本発明は、有機合成によるプロドラッグ化によらずに、水溶性塩酸塩の経皮吸収性を簡便に高めるための方法を提供することを目的とする。 An object of the present invention is to provide a method for easily increasing the transdermal absorbability of a water-soluble hydrochloride without using a prodrug by organic synthesis.
本発明者らは、鋭意研究の結果、水溶性塩酸塩及びアルデヒド基を有する脂溶性化合物を組み合せることで、簡便に、当該水溶性塩酸塩に脂溶性を付与してその経皮吸収性が高められる一方、皮膚中では容易に当該水溶性塩酸塩が放出され得ることを見出し、本発明を完成させた。 As a result of earnest studies, the present inventors have combined a water-soluble hydrochloride and a fat-soluble compound having an aldehyde group to easily impart fat-solubility to the water-soluble hydrochloride to improve its transdermal absorbability. While being enhanced, they have found that the water-soluble hydrochloride can be easily released in the skin, and completed the present invention.
すなわち、本発明は、
(１) 水溶性塩酸塩及びアルデヒド基を有する脂溶性化合物を含む組成物；
(２) 前記水溶性塩酸塩が、プロプラノロール塩酸塩、アミノレブリン酸塩酸塩、及びドネペジル塩酸塩からなる群より一つ以上選ばれる、前記(１)記載の組成物；
(３) 前記アルデヒド基を有する脂溶性化合物が、アルデヒド基を有するテルペン、アルデヒド基を有するリグノイド、及びアルデヒド基を有するバニロイドからなる群より一つ以上選ばれる、前記(１)又は(２)記載の組成物；
(４) 前記アルデヒド基を有するテルペンがシトラール又はシトロネラールである、前記(１)又は(２)記載の組成物；
(５) 前記アルデヒド基を有するリグノイドがシンナムアルデヒドである、前記(１)又は(２)記載の組成物；
(６) 前記アルデヒド基を有するバニロイドがバニリンである、前記(１)又は(２)記載の組成物；
(７) 前記アルデヒド基を有する脂溶性化合物が、ドデカナール又は４－ブトキシベンズアルデヒドである、前記(１)又は(２)記載の組成物；
(８) 前記(１)～(７)のいずれか一つ記載の組成物、経皮吸収制御剤、及び脂溶性媒体を含む、経皮吸収組成物；
(９) 前記(１)～(７)のいずれか一つ記載の組成物が前記脂溶性媒体に溶解していることを特徴とする、前記(８)記載の経皮吸収組成物；
(１０) 前記脂溶性媒体が経皮吸収促進性脂溶性媒体である、前記(８)又は(９)記載の経皮吸収組成物；
(１１) 前記経皮吸収促進性脂溶性媒体が、ミリスチン酸イソプロピル、シクロペンタシロキサン、スクアラン、及びリモネンからなる群より一つ以上選ばれる、前記(１０)記載の経皮吸収組成物；
(１２) 水溶性塩酸塩、アルデヒド基を有する脂溶性化合物、及び経皮吸収制御剤を含む組成物；
(１３) 水溶性塩酸塩が、プロプラノロール塩酸塩、アミノレブリン酸塩酸塩、及びドネペジル塩酸塩からなる群より一つ以上選ばれる、前記(１２)記載の組成物；
(１４) さらに脂溶性媒体を含む、前記(１２)又は(１３)記載の組成物；
(１５) 前記経皮吸収制御剤がアルコールである、前記(８)～(１４)のいずれか一つ記載の組成物；
(１６) 前記アルコールがメタノール、エタノール、２－プロパノール、ゲラニオール、シトロネロール、グリセリン、プロピレングリコール、ブチレングリコール、オレイルアルコール、セタノール、ラウリルアルコール、ステアリルアルコール、２－ヘキシルデカノール、及び１，２－ヘキサンジオールからなる群より一つ以上選ばれる、前記(１５)記載の組成物；
(１７) 前記(１)～(７)のいずれか一つ記載の組成物を、経皮吸収制御剤に溶解させる工程を含む、前記組成物からの前記水溶性塩酸塩の皮膚中での放出を制御する方法；
(１８) 前記(１)～(７)のいずれか一つ記載の組成物を、経皮吸収制御剤に溶解させる工程を含む、前記組成物からの前記水溶性塩酸塩を皮膚中で放出させる方法；
(１９) 水溶性塩酸塩、アルデヒド基を有する脂溶性化合物、及び経皮吸収制御剤を含む組成物から、前記水溶性塩酸塩を皮膚中で放出させる方法；
(２０) 水溶性塩酸塩の粉末とアルデヒド基を有する脂溶性化合物とを混合する工程を含む、前記水溶性塩酸塩及び前記アルデヒド基を有する脂溶性化合物を含む組成物の製造方法；
(２１) 水溶性塩酸塩の粉末とアルデヒド基を有する脂溶性化合物と経皮吸収制御剤とを混合する工程を含む、前記水溶性塩酸塩、前記アルデヒド基を有する脂溶性化合物、ならびに前記経皮吸収制御剤を含む組成物の製造方法；
に関する。
That is, the present invention is
(1) A composition containing a water-soluble hydrochloride and a fat-soluble compound having an aldehyde group;
(2) The composition according to (1) above, wherein the water-soluble hydrochloride is one or more selected from the group consisting of propranolol hydrochloride, aminolevulinic acid hydrochloride, and donepezil hydrochloride.
(3) The (1) or (2) above, wherein the fat-soluble compound having an aldehyde group is selected from the group consisting of a terpene having an aldehyde group, a lignoid having an aldehyde group, and a vanilloid having an aldehyde group. A composition of
(4) The composition according to (1) or (2), wherein the terpene having an aldehyde group is citral or citronellal;
(5) The composition according to (1) or (2) above, wherein the lignoid having an aldehyde group is cinnamaldehyde.
(6) The composition according to (1) or (2) above, wherein the vanilloid having an aldehyde group is vanillin;
(7) The composition according to (1) or (2), wherein the fat-soluble compound having an aldehyde group is dodecanal or 4-butoxybenzaldehyde;
(8) A percutaneous absorption composition comprising the composition according to any one of (1) to (7) above, a percutaneous absorption control agent, and a fat-soluble medium;
(9) The transdermal absorption composition according to (8) above, wherein the composition according to any one of (1) to (7) is dissolved in the fat-soluble medium;
(10) The percutaneous absorption composition according to the above (8) or (9), wherein the fat-soluble medium is a percutaneous absorption-promoting fat-soluble medium;
(11) The percutaneous absorption composition according to (10) above, wherein the percutaneous absorption-promoting fat-soluble medium is one or more selected from the group consisting of isopropyl myristate, cyclopentasiloxane, squalane, and limonene;
(12) A composition containing a water-soluble hydrochloride, a fat-soluble compound having an aldehyde group, and a percutaneous absorption control agent;
(13) The composition according to (12) above, wherein the water-soluble hydrochloride is one or more selected from the group consisting of propranolol hydrochloride, aminolevulinic acid hydrochloride, and donepezil hydrochloride.
(14) The composition according to the above (12) or (13), which further contains a fat-soluble medium;
(15) The composition according to any one of (8) to (14), wherein the percutaneous absorption control agent is alcohol;
(16) The alcohol comprises methanol, ethanol, 2-propanol, geraniol, citronellol, glycerin, propylene glycol, butylene glycol, oleyl alcohol, cetanol, lauryl alcohol, stearyl alcohol, 2-hexyldecanol, and 1,2-hexanediol. The composition according to (15) above, which is selected from one or more groups;
(17) Release of the water-soluble hydrochloride from the composition into the skin, comprising the step of dissolving the composition according to any one of (1) to (7) in a transdermal absorption controller. To control the;
(18) Releasing the water-soluble hydrochloride from the composition into the skin, which comprises the step of dissolving the composition according to any one of (1) to (7) in a transdermal absorption controller. Method;
(19) A method of releasing the water-soluble hydrochloride in the skin from a composition containing a water-soluble hydrochloride, a fat-soluble compound having an aldehyde group, and a transdermal absorption controller;
(20) A method for producing a composition containing the water-soluble hydrochloride salt and the fat-soluble compound having an aldehyde group, comprising a step of mixing powder of the water-soluble hydrochloride salt and a fat-soluble compound having an aldehyde group;
(21) The water-soluble hydrochloride salt, the fat-soluble compound having an aldehyde group, and the transdermal step, which includes a step of mixing a powder of a water-soluble hydrochloride salt, a fat-soluble compound having an aldehyde group, and a transdermal absorption controller. A method for producing a composition containing an absorption control agent;
Regarding
本発明の水溶性塩酸塩及びアルデヒド基を有する脂溶性化合物を含む組成物は、当該水溶性塩酸塩及び当該アルデヒド基を有する脂溶性化合物が脂溶性媒体に均一に溶解（脂溶化、もしくは油溶化）することができ、また、当該水溶性塩酸塩の経皮吸収性を向上させることもでき、さらに、角質層透過後、皮膚内部で、当該水溶性塩酸塩を放出して薬効を奏することもできる。
また、上記組成物中において、当該水溶性塩酸塩及び当該アルデヒド基を有する脂溶性化合物は、水中で解離し得る可逆的な相互作用を介して、複合体を形成していてもよい。このように形成された複合体は、当該水溶性塩酸塩と、当該アルデヒド基を有する脂溶性化合物とが、水中で解離し得る相互作用を介して複合化しているので、脂溶性媒体に均一に溶解（脂溶化、もしくは油溶化）することができ、その結果、当該水溶性塩酸塩の経皮吸収性を向上させることができ、また、角質層透過後、皮膚内部の水により当該水溶性塩酸塩を放出して薬効を奏し得ることが期待できる。
また、本発明では、経皮吸収制御剤を適宜使用することにより、皮膚中での上記複合体からの当該水溶性塩酸塩の放出を制御することもできる。
A composition containing a water-soluble hydrochloride salt and a fat-soluble compound having an aldehyde group according to the present invention has a structure in which the water-soluble hydrochloride salt and the fat-soluble compound having an aldehyde group are uniformly dissolved in a fat-soluble medium (lipophilic or oil-solubilized). It is also possible to improve the percutaneous absorbability of the water-soluble hydrochloride, and further to release the water-soluble hydrochloride inside the skin after permeation of the stratum corneum to exert a medicinal effect. it can.
In addition, in the above composition, the water-soluble hydrochloride and the fat-soluble compound having the aldehyde group may form a complex through a reversible interaction capable of dissociating in water. The complex thus formed, the water-soluble hydrochloride and the fat-soluble compound having the aldehyde group are complexed through an interaction capable of dissociating in water, so that the fat-soluble medium is uniformly dispersed. It can be dissolved (fat-solubilized or oil-solubilized), and as a result, the percutaneous absorption of the water-soluble hydrochloride can be improved, and the water-soluble hydrochloric acid can be absorbed by the water inside the skin after permeating the stratum corneum. It can be expected that the salt can be released to exert a medicinal effect.
Further, in the present invention, the release of the water-soluble hydrochloride from the complex in the skin can be controlled by appropriately using a transdermal absorption controller.
本発明の水溶性塩酸塩及びアルデヒド基を有する脂溶性化合物を含む組成物（以下「本発明の組成物(1)」ともいう）中では、当該水溶性塩酸塩と当該アルデヒド基を有する脂溶性化合物とが複合体を形成していてもよい。当該複合体では、当該水溶性塩酸塩と、当該アルデヒド基を有する脂溶性化合物とが、水中で解離し得る相互作用を介して複合化している。そのため、当該複合体は、当該水溶性塩酸塩及び当該アルデヒド基を有する脂溶性化合物と化学平衡の関係にあることができ、その結果、脂溶性媒体中では、溶媒和やクラスター生成などにより脂溶化して安定に存在し得る一方、皮膚内部では、そこに含まれる水分で容易に解離して当該水溶性塩酸塩を放出するので薬効を発揮させ得ることが期待できる。 In the composition containing the water-soluble hydrochloride salt and the fat-soluble compound having an aldehyde group (hereinafter also referred to as “composition (1) of the present invention”), the water-soluble hydrochloride salt and the fat-soluble compound having an aldehyde group The compound may form a complex. In the complex, the water-soluble hydrochloride salt and the fat-soluble compound having the aldehyde group are complexed via an interaction capable of dissociating in water. Therefore, the complex can be in a chemical equilibrium relationship with the water-soluble hydrochloride salt and the fat-soluble compound having the aldehyde group, and as a result, in the fat-soluble medium, it is fat-solubilized by solvation or cluster formation. On the other hand, it can be expected to be able to exert its medicinal effect because inside the skin, it is easily dissociated by the water contained therein to release the water-soluble hydrochloride.
本発明の水溶性塩酸塩は、アルデヒド基を有する脂溶性化合物と、水中で解離し得る相互作用を介して複合体を形成してもよいし又は形成しなくてもよく、医薬又は化粧品などの有効成分として使用することができるものであれば特に制限されず、任意の医薬又は化粧品の有効成分の水溶性塩酸塩を使用することができる。好ましくは、プロプラノロール塩酸塩、アミノレブリン酸塩酸塩、及びドネペジル塩酸塩、より好ましくは、アミノレブリン酸塩酸塩及びドネペジル塩酸塩が挙げられる。 The water-soluble hydrochloric acid salt of the present invention may or may not form a complex with a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water, such as a pharmaceutical or cosmetic product. There is no particular limitation as long as it can be used as the active ingredient, and any water-soluble hydrochloride salt of the active ingredient of pharmaceuticals or cosmetics can be used. Preferred are propranolol hydrochloride, aminolevulinic acid hydrochloride, and donepezil hydrochloride, and more preferred are aminolevulinic acid hydrochloride and donepezil hydrochloride.
本発明では、水溶性塩酸塩を１種又は２種以上使用してもよいが、他の任意の水溶性有効成分１種以上と組み合わせて使用してもよい。
このような他の水溶性有効成分は、アルデヒド基を有する脂溶性化合物と、水中で解離し得る相互作用を介して複合体を形成してもよいし又は形成しなくてもよく、水溶性の医薬又は化粧品などの有効成分であれば特に制限されず、任意の水溶性の医薬又は化粧品の有効成分、例えば、アミノ酸、親水性ビタミン、糖、ペプチドその他の親水性薬剤などを使用することができる。
このような他の水溶性有効成分として、例えば、アミノ基、ヒドロキシル基、又はチオール基を有するものが挙げられる。これらの基は、それぞれ、アルデヒド基を有する脂溶性化合物の当該アルデヒド基と、水中で解離し得る相互作用、例えば、イオン結合、水素結合、双極子相互作用、ファンデルワールス力、電荷移動相互作用、π－π相互作用、疎水相互作用や溶媒和、可逆的な化学結合などを形成してもよい。
In the present invention, one or more water-soluble hydrochlorides may be used, but they may be used in combination with any one or more other water-soluble active ingredients.
Such other water-soluble active ingredient may or may not form a complex with a fat-soluble compound having an aldehyde group through an interaction capable of dissociating in water, There is no particular limitation as long as it is an active ingredient for medicine or cosmetics, and any water-soluble active ingredient for medicines or cosmetics, for example, amino acids, hydrophilic vitamins, sugars, peptides and other hydrophilic drugs can be used. ..
Examples of such other water-soluble active ingredients include those having an amino group, a hydroxyl group, or a thiol group. These groups are, respectively, an interaction capable of dissociating in water with the aldehyde group of the fat-soluble compound having an aldehyde group, such as an ionic bond, a hydrogen bond, a dipole interaction, a Van der Waals force, a charge transfer interaction. , Π-π interaction, hydrophobic interaction, solvation, and reversible chemical bond may be formed.
前記アミノ酸として、例えば、トラネキサム酸などの人工アミノ酸；ならびにアラニン、アルギニン、アスパラギン、アスパラギン酸、システイン、グルタミン、グルタミン酸、グリシン、ヒスチジン、イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、プロリン、セリン、トレオニン、トリプトファン、チロシン、及びバリンなどの天然アミノ酸などが挙げられる。 Examples of the amino acids include artificial amino acids such as tranexamic acid; and alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan. , Natural amino acids such as tyrosine, and valine.
前記親水性ビタミンとして、例えば、アスコルビン酸、リン酸アスコルビルナトリウム、リン酸アスコルビルマグネシウム、アスコルビルグルコシド、エチルアスコルビン酸、ならびにビタミンＢ１、Ｂ２、Ｂ４，Ｂ５、Ｂ６、Ｂ７、及びＢ１２などが挙げられる。 Examples of the hydrophilic vitamin include ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl glucoside, ethyl ascorbic acid, and vitamins B1, B2, B4, B5, B6, B7, and B12.
前記糖として、例えば、グルコース、トレハロース、デキストラン、プルラン、シクロデキストリン、マンニトール、グルコサミン、ガラクトサミン、ラフィノース、マンナン、及びペクチンなどが挙げられる。 Examples of the sugar include glucose, trehalose, dextran, pullulan, cyclodextrin, mannitol, glucosamine, galactosamine, raffinose, mannan, and pectin.
前記ペプチドとしては、公知のペプチドの他、特定の効能（例えば、人のＴ細胞に認識されるため、花粉症治療効果が期待される等）を有するペプチドが挙げられる。具体例としては、ペプチドＡ（アミノ酸配列：ＱＦＡＫＬＴＧＦＴＬＭＧ）、及びペプチドＢ（アミノ酸配列：ＳＭＫＶＴＶＡＦＮＱＦＧＰ）である。 Examples of the peptide include known peptides as well as peptides having a specific efficacy (for example, a therapeutic effect on hay fever is expected because it is recognized by human T cells). Specific examples are peptide A (amino acid sequence: QFAKLGTGFTLMG) and peptide B (amino acid sequence: SMKVTVAFNQFGP).
前記親水性薬剤として、例えば、ミノキシジル、ザナミビル（リレンザ）、アシクロビル、シタラビンオクホスファート、及びリン酸フルダラビンなどが挙げられる。 Examples of the hydrophilic drug include minoxidil, zanamivir (relenza), acyclovir, cytarabine ocfosfate, and fludarabine phosphate.
本発明のアルデヒド基を有する脂溶性化合物は、アルデヒド基を少なくとも１個含む脂溶性の化合物であれば、特に制限されず、脂肪族アルデヒドや芳香族アルデヒドを含む任意の化合物が使用することができる。中でも、天然由来かつ安全性の観点から、アルデヒド基を有するテルペン、アルデヒド基を有するリグノイド、及びアルデヒド基を有するバニロイドなどが好ましい。 The fat-soluble compound having an aldehyde group of the present invention is not particularly limited as long as it is a fat-soluble compound containing at least one aldehyde group, and any compound containing an aliphatic aldehyde or an aromatic aldehyde can be used. .. Among them, terpenes having an aldehyde group, lignoides having an aldehyde group, and vanilloids having an aldehyde group are preferable from the viewpoint of natural origin and safety.
前記アルデヒド基を有するテルペンとして、例えば、シトラール、シトロネラール、シクロシトラール、サフラナール、フェランドラール、ペリルアルデヒド、タゲトン、及びレチナールなどが挙げられ、水溶性塩酸塩を良好に脂溶化させる点から、シトラール及びシトロネラール、特にシトラールが好ましく、また、上記化合物を含む精油（エッセンシャルオイル）等の天然物を使用してもよい。好ましくは、水溶性塩酸塩を良好に脂溶化させる点から、レモングラス又はシトロネラである。
精油とは、植物が産出する揮発性の有機物の総称であり、一般的に多くの化合物の混合物である。特に限定されるわけではなく、本発明のアルデヒド基を有するテルペンが含まれていれば実施可能である。
レモングラスは、一例としては、シトラール(50～80％)が主な成分であり、ゲラニオール(3～10％)、ファルネソール、ネロール、シトロネロール及びミルセン等の混合物である。
シトロネラは、一例としては、ゲラニオールが主な成分（10～60％）であり、シトロネロール(3～10%)、シトロネラール(1～30%) 等の混合物である。
Examples of the terpene having an aldehyde group include citral, citronellal, cyclocitral, safranal, ferrandral, perylaldehyde, tagetone, and retinal, and from the viewpoint of satisfactorily fat-solubilizing the water-soluble hydrochloride, citral and citronellal. In particular, citral is preferable, and natural products such as essential oils (essential oils) containing the above compounds may be used. Lemongrass or citronella is preferable from the viewpoint of satisfactorily fat-solubilizing the water-soluble hydrochloride.
Essential oil is a general term for volatile organic substances produced by plants and is generally a mixture of many compounds. It is not particularly limited, and it can be carried out as long as the terpene having an aldehyde group of the present invention is contained.
As an example, lemongrass is a mixture of citral (50 to 80%) as a main component and geraniol (3 to 10%), farnesol, nerol, citronellol and myrcene.
As an example, citronella is a mixture of geraniol as a main component (10 to 60%), citronellol (3 to 10%), citronellal (1 to 30%) and the like.
前記アルデヒド基を有するリグノイドとして、水溶性塩酸塩を良好に脂溶化させる点から、シンナムアルデヒドが好ましい。 Cinnamic aldehyde is preferable as the lignoide having the aldehyde group, from the viewpoint of favorably fat-solubilizing the water-soluble hydrochloride.
前記アルデヒド基を有するバニロイドとして、水溶性塩酸塩を良好に脂溶化させる点から、バニリンが好ましい。 As the vanilloid having an aldehyde group, vanillin is preferable from the viewpoint of favorably fat-solubilizing the water-soluble hydrochloride.
前記脂肪族アルデヒドや芳香族アルデヒドとしては、水溶性塩酸塩を良好に脂溶化させる点から、ドデカナール又は４－ブトキシベンズアルデヒドも好ましい。 As the above-mentioned aliphatic aldehyde and aromatic aldehyde, dodecanal or 4-butoxybenzaldehyde is also preferable from the viewpoint of favorably fat-solubilizing the water-soluble hydrochloride.
本発明では、前記のアルデヒド基を有する脂溶性化合物を、単独で使用してもよいし、２種以上を組み合わせて使用してもよい。
本発明のアルデヒド基を有する脂溶性化合物は、水溶性塩酸塩を良好に脂溶化させたり、経皮吸収性を高めたりする点から、とりわけシトラール、シトロネラール、及びバニリンが好ましく、特にシトラールが好ましい。
In the present invention, the fat-soluble compound having an aldehyde group may be used alone or in combination of two or more kinds.
The fat-soluble compound having an aldehyde group of the present invention is particularly preferably citral, citronellal, and vanillin, and particularly preferably citral, from the viewpoints of favorably fat-solubilizing the water-soluble hydrochloride or enhancing transdermal absorbability.
本発明の経皮吸収制御剤は、医薬や化粧品、特に皮膚外用剤の分野で、水溶性医薬又は化粧品の活性成分の経皮吸収の制御に慣用されるものであれば、特に制限されない。本発明の組成物(1)を脂溶性媒体中で良好に安定化したり、皮膚中での水溶性塩酸塩の放出がより良好に制御されたりし得る点から、ヒドロキシル基を有する経皮吸収制御剤が好ましく、特に１価又は多価アルコールが好ましく使用される。
なお、本発明の複合体は、水溶性塩酸塩と、アルデヒド基を有する脂溶性化合物に加え、さらに経皮吸収制御剤とが、水中で解離し得る相互作用を介して複合化していてもよい。そのような複合体では、皮膚中での当該水溶性塩酸塩の放出がより良好に制御される。
The percutaneous absorption control agent of the present invention is not particularly limited as long as it is conventionally used for controlling percutaneous absorption of an active ingredient of a water-soluble drug or cosmetic in the field of medicines and cosmetics, particularly external skin preparations. From the point that the composition (1) of the present invention can be well stabilized in a fat-soluble medium, or the release of the water-soluble hydrochloride in the skin can be better controlled, a transdermal absorption control having a hydroxyl group Agents are preferable, and monohydric or polyhydric alcohols are particularly preferably used.
In addition, the complex of the present invention may be a complex of a water-soluble hydrochloride, a lipid-soluble compound having an aldehyde group, and a transdermal absorption controller through a dissociable interaction in water. .. With such a complex, the release of the water-soluble hydrochloride salt in the skin is better controlled.
前記の１価のアルコールとしては、例えば、メタノール、エタノール、１－プロパノール、及び２－プロパノールなどの低級アルコール；高級アルコール；ならびにネロリドール、ゲラニオール、メントール、ボルネオール、イソボルネオール、ネロール、シトロネロール、フェンチルアルコール、カルベオール、及びネオメントールなどのヒドロキシル基を有するテルペンなどが挙げられ、好ましくはメタノール、エタノール、２－プロパノール、シトロネロール、及びゲラニオールが挙げられ、より好ましくはエタノール及び２－プロパノールが挙げられる。 Examples of the monohydric alcohol include lower alcohols such as methanol, ethanol, 1-propanol, and 2-propanol; higher alcohols; and nerolidol, geraniol, menthol, borneol, isoborneol, nerol, citronellol, fentyl. Examples thereof include terpenes having a hydroxyl group such as alcohol, carveol, and neomenthol, preferably methanol, ethanol, 2-propanol, citronellol, and geraniol, more preferably ethanol and 2-propanol.
前記の高級アルコールとして、例えば、オクタノール、ノナノール、デカノール、ウンデシルアルコール、ラウリルアルコール、トリデシルアルコール、ミリスチルアルコール、ペンタデシルアルコール、セチルアルコール（セタノール）、２－ヘキシルデカノール、ヘプタデシルアルコール、ステアリルアルコール、及びファインオキソコール１８０（ＦＯ１８０）：
などの炭素数８～１８の飽和アルコール；ならびにオレイルアルコール、リノレイルアルコール、及びリノレニルアルコールなどの炭素数８～１８の不飽和アルコールなどが挙げられる。好ましくは、オクタノール、デカノール、セタノール、ラウリルアルコール、ミリスチルアルコール、ステアリルアルコール、２－ヘキシルデカノール、及びオレイルアルコールが挙げられ、より好ましくは、オレイルアルコール、セタノール、ラウリルアルコール、ステアリルアルコール、及び２－ヘキシルデカノールが挙げられる。
Examples of the higher alcohols include octanol, nonanol, decanol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol (cetanol), 2-hexyldecanol, heptadecyl alcohol, stearyl alcohol, and Fine Oxo Call 180 (FO180):
And saturated alcohols having 8 to 18 carbon atoms; and unsaturated alcohols having 8 to 18 carbon atoms such as oleyl alcohol, linoleyl alcohol, and linolenyl alcohol. Preferred are octanol, decanol, cetanol, lauryl alcohol, myristyl alcohol, stearyl alcohol, 2-hexyldecanol, and oleyl alcohol, and more preferred are oleyl alcohol, cetanol, lauryl alcohol, stearyl alcohol, and 2-hexyldecanol. To be
前記の多価アルコールとして、例えば、エチレングリコール、プロピレングリコール、１，３－プロパンジオール、ブチレングリコール（例えば、１，２－ブタンジオール、１，３－ブタンジオール、１，４－ブタンジオール、又は２，３－ブタンジオール）、１，５－ペンタンジオール、１，２－ヘキサンジオール、グリセリン、ジプロピレングリコール、ジエチレングリコール、トリエチレングリコール、及びポリエチレングリコール４００などが挙げられ、好ましくは、グリセリン、プロピレングリコール、ブチレングリコール、及び１，２－ヘキサンジオールが挙げられる。 Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, 1,3-propanediol, butylene glycol (eg, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, or 2 , 3-butanediol), 1,5-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 400, and the like, preferably glycerin, propylene glycol, Examples include butylene glycol and 1,2-hexanediol.
本発明の組成物(1)は、水溶性塩酸塩と、前記アルデヒド基を有する脂溶性化合物とを混合させ、必要に応じて一定時間加熱し冷却することで、簡便に調製することができる。本発明の組成物(1)が良好に得られる点で、本発明の経皮吸収制御剤、特に液状の経皮吸収制御剤も加えて混合させるのが好ましい。また、得られた組成物(1)が安定に溶解し得る点でも本発明の経皮吸収制御剤は液状であることが好ましい。この場合、得られた組成物(1)が溶解した経皮吸収制御剤の溶液は、本発明の経皮吸収組成物の調製に供することができる。
水溶性塩酸塩が固体（好ましくは結晶）の場合、本発明の組成物(1)を良好に得るために、粉末にて混合することが好ましい。粉末にする方法としては、乾式粉砕による方法が挙げられる。乾式粉砕の条件としては、水溶性塩酸塩を小片に粉砕できる条件であれば特に制限されないが、乳鉢、ボールミル、ホモジナイザー、カッターミル、ハンマーミルなどの粉砕機を用いることが望ましい。また、粉砕時間や処理圧などは、粉砕される水溶性塩酸塩の硬さに応じて、適宜調整される。
上記方法にて得られた粉末は、粒径を均一にするためにさらにふるいにかけることが望ましい。ふるいとしては５００μｍ以下が好ましく、２００μｍ以下がより好ましく、１００μｍ以下が特に好ましい。
前記水溶性塩酸塩と前記アルデヒド基を有する脂溶性化合物との混合比は、使用するこれら物質の種類に応じて異なるが、１：０．１～１００、好ましくは１：１０～５０である。
前記経皮吸収制御剤も混合する場合は、前記水溶性塩酸塩、前記アルデヒド基を有する脂溶性化合物、前記経皮吸収制御剤の混合比は、使用するこれら物質の種類に応じて異なるが、１：０．１～１００：１～１００、好ましくは１：１～１００：１０～５０、より好ましくは１：１０～５０：１０～５０である。
本発明の組成物(1)を構成する、前記水溶性塩酸塩及び前記アルデヒド基を有する脂溶性化合物の構成比（モル比）は、１～１００：１００～１であり、より好ましくは１～１０：１０～１である。
The composition (1) of the present invention can be simply prepared by mixing the water-soluble hydrochloride with the fat-soluble compound having an aldehyde group, and heating and cooling for a certain period of time if necessary. From the viewpoint that the composition (1) of the present invention can be satisfactorily obtained, it is preferable to add and mix the percutaneous absorption control agent of the present invention, particularly a liquid percutaneous absorption control agent. In addition, it is preferable that the percutaneous absorption control agent of the present invention is in a liquid state also in that the obtained composition (1) can be stably dissolved. In this case, the solution of the percutaneous absorption control agent in which the obtained composition (1) is dissolved can be used for the preparation of the percutaneous absorption composition of the present invention.
When the water-soluble hydrochloride salt is solid (preferably crystalline), it is preferable to mix it in powder form in order to obtain the composition (1) of the present invention well. Examples of the method for making powder include a method by dry pulverization. The conditions for dry crushing are not particularly limited as long as the water-soluble hydrochloride can be crushed into small pieces, but it is preferable to use a crusher such as a mortar, a ball mill, a homogenizer, a cutter mill, and a hammer mill. Further, the crushing time, the processing pressure, etc. are appropriately adjusted according to the hardness of the water-soluble hydrochloride salt to be crushed.
It is desirable that the powder obtained by the above method is further sieved in order to make the particle diameter uniform. The sieve is preferably 500 μm or less, more preferably 200 μm or less, and particularly preferably 100 μm or less.
The mixing ratio of the water-soluble hydrochloride and the fat-soluble compound having an aldehyde group varies depending on the type of these substances used, but is 1:0.1 to 100, preferably 1:10 to 50.
When the percutaneous absorption control agent is also mixed, the water-soluble hydrochloride salt, the lipophilic compound having an aldehyde group, the mixing ratio of the percutaneous absorption control agent, depending on the type of these substances to be used, It is 1:0.1 to 100:1 to 100, preferably 1:1 to 100:10 to 50, and more preferably 1:10 to 50:10 to 50.
The composition ratio (molar ratio) of the water-soluble hydrochloric acid salt and the fat-soluble compound having an aldehyde group, which constitutes the composition (1) of the present invention, is 1 to 100:100 to 1, and more preferably 1 to It is 10:10 to 1.
本発明では、前述の経皮吸収制御剤、特に１価又は多価アルコールを適宜使用することで、例えば、これら経皮吸収制御剤の種類や使用量によって、経皮吸収後の皮膚中での本発明の組成物(1)からの水溶性塩酸塩の放出を制御することができる。例えば、経皮吸収制御剤の脂溶性を上昇させることにより（例えば、炭素数を増加させることにより）、当該水溶性塩酸塩の放出を遅延させることができ、経皮吸収制御剤の脂溶性を低下させることにより（例えば、炭素数を減少させることにより）、当該水溶性塩酸塩の放出を促進させることができる。本発明は、本発明の組成物(1)を、経皮吸収制御剤に溶解させる工程を含む、当該組成物(1)からのプロプラノロール塩酸塩、アミノレブリン酸塩酸塩、及びドネペジル塩酸塩から選択される水溶性塩酸塩の皮膚中での放出を制御する方法にも関する。本発明は、また、本発明の組成物(1)からの水溶性塩酸塩の皮膚中での放出を制御するための経皮吸収制御剤の使用にも関する。 In the present invention, by appropriately using the above-mentioned percutaneous absorption control agent, particularly monohydric or polyhydric alcohol, for example, depending on the type and amount of use of these percutaneous absorption control agents, The release of the water-soluble hydrochloride salt from the composition (1) of the present invention can be controlled. For example, by increasing the lipophilicity of the percutaneous absorption control agent (for example, by increasing the number of carbon atoms), the release of the water-soluble hydrochloride salt can be delayed, thereby increasing the lipophilicity of the percutaneous absorption control agent. By decreasing (for example, decreasing the number of carbon atoms), the release of the water-soluble hydrochloride can be promoted. The present invention comprises a step of dissolving the composition (1) of the present invention in a percutaneous absorption control agent, which is selected from propranolol hydrochloride, aminolevulinic acid hydrochloride, and donepezil hydrochloride from the composition (1). It also relates to a method for controlling the release of water-soluble hydrochlorides in the skin. The present invention also relates to the use of a percutaneous absorption control agent for controlling in the skin the release of a water-soluble hydrochloride salt from the composition (1) of the present invention.
本発明では、前記の経皮吸収制御剤を、単独で使用してもよいし、２種以上を組み合わせて使用してもよい。 In the present invention, the above-mentioned percutaneous absorption control agent may be used alone or in combination of two or more kinds.
本発明の脂溶性媒体は、医薬や化粧品、特に皮膚外用剤の分野で基材などとして慣用される脂溶性の媒体であれば、特に制限されず、好ましくは経皮吸収促進性脂溶性媒体を使用することができる。
前記の経皮吸収促進性脂溶性媒体は、医薬や化粧品、特に皮膚外用剤の分野で、水溶性医薬又は化粧品の活性成分の経皮吸収の促進に慣用されるものであれば、特に制限されず、例えば、リモネン（例えば、ｄ－リモネン（（＋）－リモネン）、特にＲ－（＋）－リモネン）、シクロペンタシロキサン（ＫＦ９９５）：
ミリスチン酸イソプロピル（ＩＰＭ）、スクアラン、スクワラン、スクワレン、シリコンオイル、ホホバオイル、アーモンドオイル、オリーブオイル、馬油、セバシン酸ジエチル、及びミネラルオイルなどを使用することができ、好ましくはミリスチン酸イソプロピル（ＩＰＭ）、シクロペンタシロキサン、スクアラン、リモネン（特にＲ－（＋）－リモネン）、及びセバシン酸ジエチルを使用することができ、より好ましくはミリスチン酸イソプロピル（ＩＰＭ）を使用することができる。
本発明では、前記の脂溶性媒体を、単独で使用してもよいし、２種以上を組み合わせて使用してもよい。
The fat-soluble medium of the present invention is not particularly limited as long as it is a fat-soluble medium that is commonly used as a base material in the field of pharmaceuticals and cosmetics, particularly skin external preparations, and preferably a transdermal absorption-promoting fat-soluble medium. Can be used.
The percutaneous absorption-promoting fat-soluble medium is not particularly limited as long as it is conventionally used for promoting percutaneous absorption of an active ingredient of a water-soluble drug or cosmetic in the field of medicines and cosmetics, particularly skin external preparations. For example, limonene (eg, d-limonene ((+)-limonene), especially R-(+)-limonene), cyclopentasiloxane (KF995):
Isopropyl myristate (IPM), squalane, squalane, squalene, silicone oil, jojoba oil, almond oil, olive oil, horse oil, diethyl sebacate, and mineral oil can be used, and preferably isopropyl myristate (IPM) ), cyclopentasiloxane, squalane, limonene (particularly R-(+)-limonene), and diethyl sebacate can be used, more preferably isopropyl myristate (IPM).
In the present invention, the fat-soluble medium may be used alone or in combination of two or more kinds.
本発明の経皮吸収組成物は、前記で得られた本発明の組成物(1)が溶解した経皮吸収制御剤の溶液と、前記脂溶性媒体とを混合することで調製することができる。 The transdermal absorption composition of the present invention can be prepared by mixing the solution of the transdermal absorption control agent in which the composition (1) of the present invention obtained above is dissolved, and the fat-soluble medium. ..
本発明の組成物(1)は、適切な経皮吸収制御剤を用いることにより、脂溶性媒体に対して良好な溶解性を示し得る。この観点から、例えば、脂溶性媒体がスクアランの場合、経皮吸収制御剤としてゲラニオール又はシトロネロールが好ましく、脂溶性媒体がＩＰＭの場合、経皮吸収制御剤としてエタノール又は１，２－ヘキサンジオールが好ましく、脂溶性媒体がＫＦ９９５の場合、経皮吸収制御剤としてゲラニオール又はシトロネロールが好ましい。 The composition (1) of the present invention can exhibit good solubility in a fat-soluble medium by using an appropriate transdermal absorption controller. From this viewpoint, for example, when the fat-soluble medium is squalane, geraniol or citronellol is preferable as the percutaneous absorption control agent, and when the fat-soluble medium is IPM, ethanol or 1,2-hexanediol is preferable as the percutaneous absorption control agent. When the fat-soluble medium is KF995, geraniol or citronellol is preferable as the transdermal absorption controller.
本発明の経皮吸収組成物は、医薬又は化粧品として使用する場合には、それ自体使用してもよいが、慣用の医薬製剤、特に皮膚外用剤、又は化粧品として使用してもよい。当該医薬製剤又は化粧品は、本発明の効果を損なわない限り、賦形剤、滑沢剤、結合剤、崩壊剤、乳化剤、安定剤、矯味矯臭剤、希釈剤等の医薬品や化粧品の分野で許容される添加剤を含んでもよい。
本発明の皮膚外用剤は、本発明の効果を損なわない限り、皮膚外用剤に通常配合され得る成分を含有することができる。そのような成分としては、グリセリン、プロピレングリコールなどの多価アルコール、流動パラフィン、スクワラン、高級脂肪酸、高級アルコールなどの油分、クエン酸、乳酸などの有機酸類、苛性ソーダ、トリエタノールアミンなどのアルカリ類、カチオン性界面活性剤、両性界面活性剤、非イオン性界面活性剤、粉末、顔料、染料、防腐防黴剤、樹脂、ｐＨ調整剤、酸化防止剤、紫外線吸収剤、キレート剤、増粘剤、保湿剤、アルコール、水、香料などが例示される。
本発明は、本発明の経皮吸収組成物を皮膚に適用することを含む、水溶性塩酸塩を経皮投与するための方法にも関する。また、本発明は、プロプラノロール塩酸塩、アミノレブリン酸塩酸塩、及びドネペジル塩酸塩から選択される水溶性塩酸塩を経皮投与するための本発明の経皮吸収組成物の使用にも関する。
When the percutaneous absorption composition of the present invention is used as a medicine or a cosmetic, it may be used as such, but it may also be used as a conventional pharmaceutical preparation, especially as a skin external preparation or a cosmetic. The pharmaceutical preparation or cosmetic is acceptable in the field of pharmaceuticals and cosmetics such as excipients, lubricants, binders, disintegrators, emulsifiers, stabilizers, flavors, diluents, etc. as long as the effects of the present invention are not impaired. The additive may be included.
The external preparation for skin of the present invention may contain components that can be usually added to the external preparation for skin, as long as the effects of the present invention are not impaired. Such components include glycerin, polyhydric alcohols such as propylene glycol, liquid paraffin, squalane, higher fatty acids, oils such as higher alcohols, citric acid, organic acids such as lactic acid, caustic soda, alkalis such as triethanolamine, Cationic surfactant, amphoteric surfactant, nonionic surfactant, powder, pigment, dye, antiseptic and antifungal agent, resin, pH adjusting agent, antioxidant, ultraviolet absorber, chelating agent, thickener, Moisturizers, alcohol, water, fragrances, etc. are exemplified.
The present invention also relates to a method for transdermal administration of a water-soluble hydrochloride salt, which comprises applying to the skin the transdermal absorption composition of the present invention. The present invention also relates to the use of the transdermal absorption composition of the present invention for transdermal administration of a water-soluble hydrochloride selected from propranolol hydrochloride, aminolevulinic acid hydrochloride and donepezil hydrochloride.
また、本発明の組成物は、水溶性塩酸塩、前記アルデヒド基を有する脂溶性化合物、及び前記経皮吸収制御剤を含む、組成物であってもよく、好ましくは経皮吸収組成物である。
本発明の組成物は、さらに前記脂溶性媒体を含んでもよい。
本発明は、本発明の組成物を皮膚に適用することを含む、水溶性塩酸塩を経皮投与するための方法にも関する。また、本発明は、水溶性塩酸塩を経皮投与するための本発明の組成物の使用にも関する。
Further, the composition of the present invention may be a composition containing a water-soluble hydrochloride salt, a fat-soluble compound having the aldehyde group, and the transdermal absorption control agent, and is preferably a transdermal absorption composition. ..
The composition of the present invention may further contain the fat-soluble medium.
The present invention also relates to a method for transdermal administration of a water-soluble hydrochloride salt, which comprises applying the composition of the present invention to the skin. The present invention also relates to the use of the composition of the present invention for transdermal administration of a water soluble hydrochloride salt.
以下、実施例を挙げて本発明をさらに詳しく具体的に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
１．試薬及び装置
実施例で使用した試薬を以下に示す。
エタノール（特級）、２－プロパノール（特級）、ミリスチン酸イソプロピル（ＩＰＭ）（特級）、１×ＰＢＳ、ギ酸アンモニウム（特級）、１ｍｏｌ／Ｌギ酸アンモニウム溶液は和光純薬工業（株）より入手した。ドネペジル塩酸塩、プロプラノロール塩酸塩、５－アミノレブリン酸塩酸塩、シトラール（ｃｉｓ－ ａｎｄ ｔｒａｎｓ－ ｍｉｘｔｕｒｅ）、バニリンは東京化成工業（株）より入手した。アセトニトリル（高速液体クロマトグラフィー用）は関東化学（株）より入手した。
分析に用いた装置を以下に示す。
液体クロマトグラフ質量分析計（ＬＣ／ＭＳ）
装置：ｅ２６９５（ＬＣ部）、２４８９（ＵＶ－Ｖｉｓ検出器）、３１００ＭａｓｓＤｅｔｅｃｔｏｒ、日本ウォーターズ（株）製
1. Reagents and Equipment The reagents used in the examples are shown below.
Ethanol (special grade), 2-propanol (special grade), isopropyl myristate (IPM) (special grade), 1×PBS, ammonium formate (special grade), 1 mol/L ammonium formate solution was obtained from Wako Pure Chemical Industries, Ltd. Donepezil hydrochloride, propranolol hydrochloride, 5-aminolevulinic acid hydrochloride, cis- and trans-mixture, and vanillin were obtained from Tokyo Chemical Industry Co., Ltd. Acetonitrile (for high performance liquid chromatography) was obtained from Kanto Chemical Co., Inc.
The apparatus used for the analysis is shown below.
Liquid chromatograph mass spectrometer (LC/MS)
Device: e2695 (LC part), 2489 (UV-Vis detector), 3100 Mass Detector, manufactured by Nippon Waters Co., Ltd.
２．シトラールもしくはバニリンによるドネペジル塩酸塩の油溶化
ねじ口サンプル管に、表１に示す量のドネペジル塩酸塩、アルデヒド基を有する脂溶性化合物１００ｍｇ、およびエタノール１ｍＬを加え、８０℃で１時間加熱した。加熱後、ミリスチン酸イソプロピル（ＩＰＭ）を１ｍＬ加え、ボルテックスミキサーで混合して室温下、１６時間後の溶液の様子を確認した。結果を表１に示す。
結果として、アルデヒド基を有する脂溶性化合物を加えないときはごくわずかに解け残りが見られたものの、シトラール及びバニリンを添加するとドネペジル塩酸塩の均一溶液が調製することができた。 As a result, when a fat-soluble compound having an aldehyde group was not added, a slight amount of undissolved residue was observed, but when citral and vanillin were added, a homogeneous solution of donepezil hydrochloride could be prepared.
３．シトラールもしくはバニリンによるプロプラノロール塩酸塩の油溶化
ねじ口サンプル管に、表１に示す量のプロプラノロール塩酸塩、アルデヒド基を有する脂溶性化合物１００ｍｇ（表１で特記する場合を除く）、および経皮吸収制御剤１ｍＬ（表１で特記する場合を除く）を加え、８０℃で１時間加熱した。加熱後、ミリスチン酸イソプロピル（ＩＰＭ）を１ｍＬ（表１で特記する場合を除く）加え、ボルテックスミキサーで混合して室温下、１時間後の溶液の様子を確認した。結果を表２に示す。
結果として、シトラールやバニリンを添加することにより、添加剤未添加溶液では達成しなかったプロプラノロール塩酸塩量の油溶化を達成することができた。 As a result, by adding citral or vanillin, it was possible to achieve oil solubilization of the amount of propranolol hydrochloride, which was not achieved with the additive-free solution.
４．シトラールによる５－アミノレブリン酸塩酸塩の油溶化
ねじ口サンプル管に、５－アミノレブリン酸塩酸塩８ｍｇ、シトラール８０ｍｇ、エタノール２ｍLを加え、室温下、３０分撹拌した。撹拌後、ミリスチン酸イソプロピル（ＩＰＭ）を２ｍＬ加え、ボルテックスミキサーで混合したところ、黄色均一溶液を得た（実施例２２）。
4. Oil Solubilization of 5-Aminolevulinic Acid Hydrochloride with Citral To a screw cap sample tube, 5-aminolevulinic acid hydrochloride 8 mg,
５．ドネペジル塩酸塩油溶化溶液の経皮吸収性試験
角質層は疎水的であり、深部に行くに従い親水的になる。すなわち、角質層のバリアを突破するために、油溶化は有効な手段となる。そこで、ドネペジル塩酸塩の油溶化溶液を用いて、皮膚バリアを突破した後、ブタ皮膚中およびレシーバー液中でドネペジル塩酸塩を放出するか否かの経皮吸収試験を行った。
本実験で用いた経皮吸収組成物は、ドネペジル塩酸塩１０ｍｇに、純水２．１ｍＬを加えたドネペジル塩酸塩水溶液（比較例１４）、およびドネペジル塩酸塩１０ｍｇに、エタノール１ｍＬ、ＩＰＭ１ｍＬ、エタノール/ＩＰＭ（１/１）１００ｍｇを加えたドネペジル塩酸塩のエタノール/ＩＰＭ溶液（比較例１５）を経皮吸収性の基準として、前記の調製した実施例１のブタ皮膚に対する経皮吸収性を以下の経皮吸収性試験で評価した。
経皮吸収試験は次のとおりに行った。経皮吸収試験としてはブタ（Yucatan Micro Pig）の皮膚（日本チャールスリバー社製）を用いた。フランツセルのレシーバー相に攪拌子とＰＢＳ水溶液を５ｍＬ加え、ブタ皮膚をＰＢＳ水溶液上部に挟み、フランツセルのウォータージャケット部に３７℃の水を流した。比較例１４及び１５ならびに実施例１の溶液５００μＬをブタ皮膚の上に載せ、レシーバー相を攪拌した。２４時間後、ブタ皮膚を８０％エタノール中で洗浄し、メンディングテープで表皮を１枚剥がした後、ブタ皮膚を約8等分に切断しマイクロチューブに入れ、PBS/MeOH/CH3CN = 2/1/1(vol/vol/vol) 1 mLを加え、1時間振とうさせた。振とう後のブタ皮膚抽出液およびレシーバー相のＰＢＳ水溶液をサンプリングし、ＬＣ／ＭＳによりドネペジル塩酸塩量を定量した。ＬＣ／ＭＳの測定条件は、以下の通りである。カラムにShodex Asahipak NH2P-40 2D (2.0 mm I.D. x 150 mm)を用い、カラム温度を３０℃に設定した。溶離液に２０ｍＭギ酸アンモニウム／アセトニトリル（１５／８５、ｖоl／ｖоl）を使用し、流速を０．２ｍＬ／ｍｉｎに設定した。検出質量数は３８０とした。結果を図１及び２に示す。
5. Percutaneous Absorption Test of Donepezil Hydrochloride Oil-solubilized Solution The stratum corneum is hydrophobic and becomes hydrophilic as it goes deeper. That is, oil solubilization is an effective means for breaking through the barrier of the stratum corneum. Therefore, a percutaneous absorption test was performed using an oil-solubilized solution of donepezil hydrochloride to determine whether or not donepezil hydrochloride is released in pig skin and in receiver solution after breaking through the skin barrier.
The transdermal absorption composition used in this experiment was
The transdermal absorption test was conducted as follows. As a transdermal absorption test, pig (Yucatan Micro Pig) skin (made by Charles River Japan) was used. A stirring bar and 5 mL of a PBS aqueous solution were added to the receiver phase of the Franz cell, pig skin was sandwiched between the PBS aqueous solution upper portions, and water at 37° C. was poured into the water jacket of the Franz cell. 500 μL of the solutions of Comparative Examples 14 and 15 and Example 1 were placed on pig skin and the receiver phase was stirred. After 24 hours, the porcine skin was washed in 80% ethanol, one epidermis was peeled off with a mending tape, the porcine skin was cut into about 8 equal parts and placed in a microtube, and PBS/MeOH/CH3CN = 2/ 1/1 (vol/vol/vol) 1 mL was added and shaken for 1 hour. The swine skin extract after shaking and the PBS aqueous solution in the receiver phase were sampled, and the amount of donepezil hydrochloride was quantified by LC/MS. The LC/MS measurement conditions are as follows. Shodex Asahipak NH2P-40 2D (2.0 mm ID x 150 mm) was used for the column, and the column temperature was set to 30°C. 20 mM ammonium formate/acetonitrile (15/85, v/l/v) was used as the eluent, and the flow rate was set to 0.2 mL/min. The detected mass number was 380. The results are shown in Figures 1 and 2.
結果として、シトラール添加時において、経皮吸収性が向上した。 As a result, transdermal absorbability was improved when citral was added.
６．５－アミノレブリン酸塩酸塩油溶化溶液の経皮吸収性試験
ドネペジル塩酸塩と同様に、５－アミノレブリン酸塩酸塩についても経皮吸収性試験を行った。
経皮吸収性試験としてはヘアレスマウス皮膚（株式会社星野試験動物飼育所製）を用いた。フランツセルのレシーバー相に攪拌子とＰＢＳ水溶液を５ｍＬ加え、ヘアレスマウス皮膚をＰＢＳ水溶液上部に挟み、フランツセルのウォータージャケット部に３２℃の水を流した。レシーバー相を攪拌し、濃度を２ｍｇ／ｍＬに調製した５－アミノレブリン酸塩酸塩ＰＢＳ溶液（比較例１６）、及び前記項目「４.」で調製した５－アミノレブリン酸塩酸塩溶液（実施例２２）の２００μＬをヘアレスマウス皮膚の上に載せた。２４時間後にヘアレスマウス皮膚のＰＢＳ抽出液及びレシーバーのＰＢＳ水溶液をサンプリングし、ＬＣ－ＭＳにより５－アミノレブリン酸塩酸塩量を定量した。ＬＣ－ＭＳの条件は以下のとおりである。
カラム温度：３０℃、使用カラム：Ｓｈｏｄｅｘ Ａｓａｈｉｐａｋ ＮＨ２Ｐ－４０ ２Ｄ （２．０ ｍｍ Ｉ．Ｄ． ｘ １５０ ｍｍ）、検出質量（ｍ／ｚ）：１３２、溶離液：２０ｍＭギ酸アンモニウム／アセトニトリル（３０／７０，ｖоl／ｖоl）、流速：０．２ｍＬ
結果を図３及び４に示す。
6.5 Transdermal Absorption Test of Oil-solubilized 5-Aminolevulinic Acid Hydrochloride Similar to donepezil hydrochloride, 5-aminolevulinic acid hydrochloride was also subjected to the transdermal absorption test.
Hairless mouse skin (Hoshino Test Animal Breeding Co., Ltd.) was used for the transdermal absorbability test. A stirrer and 5 mL of an aqueous PBS solution were added to the receiver phase of the Franz cell, the hairless mouse skin was sandwiched between the upper parts of the PBS aqueous solution, and water at 32° C. was poured into the water jacket of the Franz cell. The receiver phase was agitated to prepare a 5-aminolevulinic acid hydrochloride PBS solution (Comparative Example 16) having a concentration of 2 mg/mL, and a 5-aminolevulinic acid hydrochloride solution (Example 22) prepared in the above item “4.”. 200 μL of the above was placed on hairless mouse skin. After 24 hours, the PBS extract of hairless mouse skin and the PBS aqueous solution of the receiver were sampled, and the amount of 5-aminolevulinic acid hydrochloride was quantified by LC-MS. The conditions of LC-MS are as follows.
Column temperature: 30° C., column used: Shodex Asahipak NH2P-40 2D (2.0 mm ID×150 mm), detection mass (m/z): 132, eluent: 20 mM ammonium formate/acetonitrile (30/ 70, v/l/v), flow rate: 0.2 mL
The results are shown in Figures 3 and 4.
結果として、シトラール添加による油溶化を行うことで、経皮吸収性が向上した。 As a result, transdermal absorbability was improved by solubilizing oil by adding citral.
これらの結果から、シトラールを添加したドネペジル塩酸塩油溶化溶液、及びシトラールを添加した５－アミノレブリン酸塩酸塩油溶化溶液は、経皮吸収性を促進し、経皮薬物送達システム（ＤＤＳ）材料として有望であることが示された。 From these results, citral-added donepezil hydrochloride oil-solubilized solution and citral-added 5-aminolevulinic acid hydrochloride oil-solubilized solution promote percutaneous absorption and are used as transdermal drug delivery system (DDS) materials. It has shown promise.
本発明の組成物(1)は、水溶性塩酸塩の経皮吸収性を向上させて、皮膚中の含量を増大させ、また、皮膚内部で水溶性塩酸塩を放出して、薬効を奏することができるので、本発明の組成物(1)を含む本発明の経皮吸収組成物は、皮膚外用剤、例えば、皮膚外用療法に使用される医薬品や化粧品などに利用することができる。
また、経皮吸収制御剤を適宜使用することで、皮膚内部での本発明の組成物(1)からの水溶性塩酸塩の放出が制御されるので、薬物送達システムに利用することができる。
すなわち、本発明の組成物(1)は、皮膚外用剤、例えば、皮膚外用療法に使用される医薬品、化粧品、又は薬物送達システムなどの製造のための原料として使用することができる。
The composition (1) of the present invention improves the transdermal absorbability of a water-soluble hydrochloride to increase the content in the skin, and also releases the water-soluble hydrochloride inside the skin to exert a medicinal effect. Therefore, the percutaneous absorption composition of the present invention containing the composition (1) of the present invention can be used as a skin external preparation, for example, a drug or cosmetic used for skin external therapy.
In addition, since the release of the water-soluble hydrochloride from the composition (1) of the present invention inside the skin is controlled by appropriately using the transdermal absorption controlling agent, it can be used in a drug delivery system.
That is, the composition (1) of the present invention can be used as a raw material for the production of a skin external preparation, for example, a drug, cosmetic, drug delivery system or the like used for skin external therapy.
Claims (21)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02152921A (en) * | 1988-12-01 | 1990-06-12 | Nissan Chem Ind Ltd | External preparation of percutaneous absorption |
| JPH04217926A (en) * | 1991-03-28 | 1992-08-07 | Kazutoshi Morimoto | Percutaneous absorption composition of narcotic and non-narcotic analgesic agent composition |
| JP2006151927A (en) * | 2004-12-01 | 2006-06-15 | Toin Gakuen | Photodynamic therapy composition |
| JP2009022730A (en) * | 2007-06-18 | 2009-02-05 | Kyoritsu Yakuhin Kogyo Kk | Plaster |
| WO2017131214A1 (en) * | 2016-01-29 | 2017-08-03 | 日産化学工業株式会社 | Transdermally absorbable composition having controlled release of water-soluble active ingredient |
-
2020
- 2020-01-29 WO PCT/JP2020/003282 patent/WO2020158831A1/en not_active Ceased
- 2020-01-29 JP JP2020569702A patent/JPWO2020158831A1/en active Pending
- 2020-01-30 TW TW109102745A patent/TW202042797A/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02152921A (en) * | 1988-12-01 | 1990-06-12 | Nissan Chem Ind Ltd | External preparation of percutaneous absorption |
| JPH04217926A (en) * | 1991-03-28 | 1992-08-07 | Kazutoshi Morimoto | Percutaneous absorption composition of narcotic and non-narcotic analgesic agent composition |
| JP2006151927A (en) * | 2004-12-01 | 2006-06-15 | Toin Gakuen | Photodynamic therapy composition |
| JP2009022730A (en) * | 2007-06-18 | 2009-02-05 | Kyoritsu Yakuhin Kogyo Kk | Plaster |
| WO2017131214A1 (en) * | 2016-01-29 | 2017-08-03 | 日産化学工業株式会社 | Transdermally absorbable composition having controlled release of water-soluble active ingredient |
Also Published As
| Publication number | Publication date |
|---|---|
| TW202042797A (en) | 2020-12-01 |
| JPWO2020158831A1 (en) | 2021-11-25 |
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