WO2020013179A1 - Percutaneous absorption composition with controlled release of minoxidil - Google Patents
Percutaneous absorption composition with controlled release of minoxidil Download PDFInfo
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- WO2020013179A1 WO2020013179A1 PCT/JP2019/027141 JP2019027141W WO2020013179A1 WO 2020013179 A1 WO2020013179 A1 WO 2020013179A1 JP 2019027141 W JP2019027141 W JP 2019027141W WO 2020013179 A1 WO2020013179 A1 WO 2020013179A1
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- minoxidil
- ketone group
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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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
- 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
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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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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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
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
Definitions
- the present invention relates to a percutaneous absorption composition in which the release of minoxidil into the skin is controlled, and a method for controlling minoxidil in the skin.
- the bond between the water-soluble drug and the fat-soluble site is broken 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 encapsulated in liposomes, dissolved and dispersed in an oily base material, and applied to the skin. After permeation of the stratum corneum, the interface of the liposome is disrupted inside the skin by enzymes or the like, and the water-soluble drug is released.
- Patent Documents 1 to 5 Recently, it has been reported that a permeation enhancer (transdermal absorption enhancer) such as terpene or higher alcohol is used to enhance transdermal absorption of a drug.
- a permeation enhancer transdermal absorption enhancer
- terpene or higher alcohol is used to enhance transdermal absorption of a drug.
- JP 2013-241449 A International Publication No. WO2012 / 043701 JP 2010-100650 A Japanese Patent No. 5680197 JP 2010-6771 A
- Prodrug conversion is an excellent method for imparting lipophilicity to water-soluble drugs to enhance transdermal absorption, but it is a complicated process for the production process of organic synthesis and complicated procedures for obtaining approval for the manufacture and sale of drugs and quasi-drugs. Is required.
- tranexamic acid an artificial amino acid, inhibits activation by binding to plasmin, a proteolytic enzyme, in the epidermis, thereby suppressing melanin production. It is known to. Utilizing this effect, in recent years, whitening effects have come to be claimed and have attracted attention as a raw material for cosmetics. However, there is a problem that the skin permeability of tranexamic acid is low.
- An object of the present invention is to provide a method for easily increasing the transdermal absorbability of minoxidil without using a prodrug by organic synthesis.
- the present inventors have conducted intensive studies and found that minoxidil forms a complex with a fat-soluble compound having a ketone group through an interaction, thereby easily giving the minoxidil a fat-solubility to promote the process.
- the present inventors have found that minoxidil can be easily released into the skin while improving skin absorbability, and completed the present invention.
- the present invention (1) a complex formed by interaction between minoxidil and a fat-soluble compound having a ketone group; (2)
- the fat-soluble compound having a ketone group is at least one selected from the group consisting of a terpene having a ketone group, a lignoid having a ketone group, a vanilloid having a ketone group, a curcuminoid having a ketone group, chromone, and coumarin.
- a composition comprising minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption controlling agent; (13) The composition according to the above (12), further comprising a fat-soluble medium; (14) The composition according to any of (8) to (13), wherein the transdermal absorption controlling agent is an alcohol; (15) The composition according to (14), wherein the alcohol is at least one selected from the group consisting of ethanol, geraniol, citronellol, and 1,2-hexanediol. (16) controlling the release of the minoxidil from the complex into the skin, comprising a step of dissolving the complex according to any one of the above (1) to (7) in a transdermal absorption controlling agent.
- a method for releasing the minoxidil from the complex into the skin comprising a step of dissolving the complex according to any one of (1) to (7) in a transdermal absorption controlling agent; (18) a method of releasing minoxidil into the skin from a composition comprising minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption controlling agent; (19) a method for producing a complex formed by interaction between the minoxidil and the fat-soluble compound having a ketone group, comprising a step of mixing a powder of minoxidil and a fat-soluble compound having a ketone group; (20) a composition comprising the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption controlling agent, comprising a step of mixing a powder of minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption controlling agent.
- Method of manufacturing a product (21) The complex according to (1), wherein the essential
- the complex of the present invention since minoxidil and the fat-soluble compound having a ketone group are complexed through an interaction, the complex can be uniformly dissolved (fat-solubilized or oil-solubilized) in the fat-soluble medium. As a result, the percutaneous absorbability of the minoxidil can be improved, and after permeation of the stratum corneum, the minoxidil can be released to exert a medicinal effect. In the present invention, the release of minoxidil from the complex in the skin can be controlled by appropriately using a transdermal absorption controlling agent.
- the complex of the present invention minoxidil and the fat-soluble compound having a ketone group are complexed through an interaction. Therefore, the complex of the present invention can be in a chemical equilibrium relationship with minoxidil and the fat-soluble compound having the ketone group. As a result, in the fat-soluble medium, the complex is fat-solubilized by solvation or cluster formation. While it can exist stably, it dissociates and releases minoxidil inside the skin, so that it can exert its medicinal effect.
- the complex of the present invention may be complexed through an interaction that can dissociate in water.
- minoxidil may be used alone, or may be used in combination with one or more optional water-soluble active ingredients.
- a water-soluble active ingredient of the present invention is not particularly limited as long as it is an active ingredient such as a water-soluble drug or cosmetic that can form a complex through interaction with a fat-soluble compound having a ketone group.
- Any water-soluble pharmaceutical or cosmetic active ingredient for example, amino acids, hydrophilic vitamins, sugars, peptides and other hydrophilic drugs can be used.
- Examples of such a water-soluble active ingredient of the present invention include those having an amino group, a hydroxyl group, or a thiol group.
- ketone groups respectively have various interactions with the ketone group of the fat-soluble compound having a ketone group, for example, ionic bond, hydrogen bond, dipole interaction, van der Waals force, charge transfer interaction, ⁇ - It can form ⁇ interaction, hydrophobic interaction, solvation, reversible chemical bond, etc.
- amino acid 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. , Tyrosine, and natural amino acids such as 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.
- peptides examples include known peptides and peptides having specific effects (for example, since they are recognized by human T cells, they are expected to have a therapeutic effect on hay fever). Specific examples include peptide A (amino acid sequence: QFAKLTGFTLMG) and peptide B (amino acid sequence: SMKVTVAFNQFGP).
- hydrophilic drug examples include zanamivir (relenza), acyclovir, cytarabine ocphosphate, and fludarabine phosphate.
- the fat-soluble compound having a ketone group of the present invention is not particularly limited as long as it is a fat-soluble compound containing at least one ketone group, and any compound containing an aliphatic ketone or an aromatic ketone can be used. . Above all, a fat-soluble compound having 4 or more carbon atoms, for example, 4 to 50 and having a ketone group is preferable. Further, from the viewpoints of natural origin and safety, terpene having a ketone group, lignoid having a ketone group, vanilloid having a ketone group, curcuminoid having a ketone group, chromone and coumarin having a ketone group are more preferable.
- the tautomeric enol type: CC (OH)-can also be included in the ketone group in the present invention.
- both ends of-(C O)-are bonded to carbon atoms.
- Examples of the terpene having a ketone group include geranylacetone, camphor such as ( ⁇ ) -camphor, (+)-camphor, and ( ⁇ )-camphor, and carvone and capsanthin.
- camphor such as ( ⁇ ) -camphor, (+)-camphor, and ( ⁇ )-camphor
- carvone and capsanthin examples of the terpene having a ketone group
- camphor is preferable, and a natural product such as an essential oil containing the above compound may be used.
- camphor is used from the viewpoint of satisfactorily solubilizing minoxidil.
- Essential oil is a general term for volatile organic matter produced by plants, and is generally a mixture of many compounds. There is no particular limitation, and the present invention can be implemented as long as the terpene having a ketone group of the present invention is contained.
- camphor is a mixture of camphor as a main component (50 to 60%) and limonene (5 to 10%), ⁇ -pinene, myrcene and the like.
- the sage is, for example, a mixture of camphor as a main component (20 to 30%), Cis-Thujong (15 to 20%), eucalyptol (10 to 15%), and the like.
- lignoid having a ketone group examples include flavone.
- Examples of the vanilloid having a ketone group include gingerol and shogaol.
- curcuminoid having a ketone group for example, curcumin, demethoxycurcumin, bisdemethoxycurcumin and the like can be mentioned, and curcumin is preferable from the viewpoint of satisfactorily solubilizing minoxidil.
- Examples of the aliphatic ketone and the aromatic ketone include methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin, and vitamin K.
- the above-mentioned fat-soluble compounds having a ketone group may be used alone or in combination of two or more.
- the lipophilic compound having a ketone group of the present invention is particularly preferably geranylacetone or (+)-camphor, from the viewpoint of satisfactorily solubilizing minoxidil.
- the transdermal absorption controlling agent of the present invention is not particularly limited as long as it is commonly used for controlling transdermal absorption of active ingredients of water-soluble medicines or cosmetics in the field of medicines and cosmetics, especially skin external preparations.
- a transdermal absorption controller having a hydroxyl group is preferable, and a monohydric or polyhydric alcohol is particularly preferably used.
- a transdermal absorption controlling agent may be further complexed through an interaction. In such a conjugate, the release of minoxidil 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; nerolidol, geraniol, menthol, borneol, isoborneol, nerol, citronellol, and fentyl.
- Examples thereof include terpenes having a hydroxyl group such as alcohol, carveol, and neomenthol, and preferably include methanol, ethanol, citronellol, and geraniol.
- Examples of the above higher alcohol include octanol, nonanol, decanol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, and fine oxocol 180 (FO180).
- And C8-18 saturated alcohols such as oleyl alcohol, linoleyl alcohol, and linolenyl alcohol.
- octanol, decanol, lauryl alcohol, myristyl alcohol, and oleyl alcohol are used, and more preferably, oleyl alcohol is used.
- polyhydric alcohol examples include ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol,
- examples include 1,5-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diethylene glycol, triethylene glycol, and polyethylene glycol 400, and preferably include propylene glycol and 1,2-hexanediol. .
- the complex of the present invention can be easily prepared by mixing the minoxidil and the fat-soluble compound having a ketone group, and heating and cooling for a certain period of time as necessary. From the viewpoint that a complex can be obtained favorably, it is preferable to add and mix the transdermal absorption control agent of the present invention, particularly the liquid transdermal absorption control agent. Further, the transdermal absorption controlling agent of the present invention is preferably in a liquid form in that the obtained complex can be stably dissolved. In this case, the solution of the obtained transdermal absorption control agent in which the complex is dissolved can be used for preparing the transdermal absorption composition of the present invention.
- minoxidil When minoxidil is a solid (preferably a crystal), it is preferable to mix it in a powder form in order to obtain the composite of the present invention well.
- a method for forming a powder include a method based on dry pulverization.
- the conditions of the dry pulverization are not particularly limited as long as minoxidil can be pulverized into small pieces, but it is preferable to use a pulverizer such as a mortar, a ball mill, a homogenizer, a cutter mill, and a hammer mill.
- the pulverizing time and the processing pressure are appropriately adjusted according to the hardness of the minoxidil to be pulverized.
- the powder obtained by the above method is desirably further sieved to make the particle size 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 between the minoxidil and the fat-soluble compound having a ketone group varies depending on the type of these substances used, but is 1: 1 to 100, preferably 1:10 to 50.
- the mixing ratio of the minoxidil, the fat-soluble compound having a ketone group, and the percutaneous absorption controlling agent varies depending on the type of these substances used, but is 1: 1. 100100: 1 to 100, preferably 1: 1 to 100: 10 to 50, more preferably 1:10 to 50:10 to 50.
- the composition ratio (molar ratio) of the minoxidil and the fat-soluble compound having a ketone group that constitutes the complex of the present invention is 1 to 100: 100 to 1, more preferably 1 to 10:10 to 1. is there.
- the present invention by appropriately using the above-mentioned transdermal absorption controlling agent, particularly a monohydric or polyhydric alcohol, for example, depending on the type and the amount of these transdermal absorption controlling agents, in the skin after percutaneous absorption.
- the release of minoxidil from the conjugate of the invention can be controlled.
- the lipophilicity of the transdermal absorption controlling agent for example, by increasing the carbon number
- the release of minoxidil of the present invention can be delayed, and the lipophilicity of the transdermal absorption controlling agent can be reduced.
- the lipophilicity of the transdermal absorption controlling agent can enhance the release of minoxidil of the present invention.
- the present invention also relates to a method of controlling the release of minoxidil from the complex in the skin, comprising the step of dissolving the complex of the present invention in a transdermal absorption controlling agent.
- the present invention also relates to the use of a transdermal absorption control agent to control the release of minoxidil from the complex of the present invention in the skin.
- the above-mentioned percutaneous absorption controlling agents may be used alone or in combination of two or more.
- the fat-soluble medium of the present invention is not particularly limited as long as it is a fat-soluble medium commonly used as a base material in the field of medicines and cosmetics, especially skin external preparations, and is preferably a transdermal absorption promoting fat-soluble medium. Can be used.
- the transdermal absorption-promoting fat-soluble medium is particularly limited as long as it is commonly used for promoting transdermal absorption of a water-soluble drug or an active ingredient of a cosmetic in the field of medicines and cosmetics, especially skin external preparations.
- limonene eg, d-limonene
- cyclopentasiloxane KF995: Isopropyl myristate (IPM), squalane, squalane, squalene, silicone oil, jojoba oil, almond oil, olive oil, horse oil, mineral oil, etc.
- IPM isopropyl myristate
- IPM isopropyl myristate
- Cyclopentasiloxane squalane, limonene
- the above-mentioned fat-soluble medium may be used alone or in combination of two or more.
- the percutaneous absorption composition of the present invention can be prepared by mixing a solution of the percutaneous absorption control agent in which the complex obtained above is dissolved and the fat-soluble medium.
- the complex of the present invention can exhibit good solubility in fat-soluble media by using an appropriate transdermal absorption control agent.
- the fat-soluble medium is squalane, geraniol or citronellol is preferable as the transdermal absorption control agent, and when the fat-soluble medium is IPM, ethanol or 1,2-hexanediol is preferable as the transdermal absorption control agent.
- the fat-soluble medium is KF995, geraniol or citronellol is preferred as the transdermal absorption control agent.
- the transdermal absorption composition of the present invention may be used as such, but may be used as a conventional pharmaceutical preparation, particularly as a skin external preparation or cosmetic.
- the pharmaceutical preparations or cosmetics are acceptable in the field of pharmaceuticals and cosmetics such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, etc., so long as the effects of the present invention are not impaired. May be included.
- the external preparation for skin of the present invention can contain components that can be usually blended in 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 surfactants, amphoteric surfactants, nonionic surfactants, powders, pigments, dyes, preservatives and fungicides, resins, pH adjusters, antioxidants, ultraviolet absorbers, chelating agents, thickeners, Examples include humectants, alcohol, water, and fragrances.
- the present invention also relates to a method for transdermally administering minoxidil, comprising applying the transdermal composition of the present invention to the skin.
- the present invention also relates to the use of the transdermal absorption composition of the present invention for transdermal administration of the above-mentioned minoxidil.
- the composition of the present invention may be a composition containing the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption controlling 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 said minoxidil, comprising applying the composition of the present invention to the skin.
- the invention also relates to the use of the composition of the invention for transdermal administration of said minoxidil.
- percutaneous absorption test of minoxidil oil solubilized solution (1) The stratum corneum is hydrophobic and becomes more hydrophilic as it goes deeper. In other words, oil solubilization is an effective means for breaking through the stratum corneum barrier. Therefore, after permeating the skin barrier using an oil solubilized solution of minoxidil, a transdermal absorption test was performed to determine whether or not to release minoxidil in an aqueous PBS solution.
- the transdermal absorption compositions used in this experiment are Comparative Example 1, Example 1, and Example 2 shown in Table 1 above.
- the transdermal absorption test was performed as follows. As a transdermal absorption test, pig skin (Yucatan Micro Pig (Charles River Japan)) was used.
- a stir bar and 5 mL of an aqueous PBS solution were added to the receiver phase of the Franz cell, the pig skin was sandwiched between the upper portions of the aqueous PBS solution, and water at 37 ° C. was flowed through the water jacket of the Franz cell.
- the receiver phase was agitated and 200 ⁇ L of Comparative Example 1, Example 1, and Example 2 were placed on pig skin. Twenty-four hours later, a methanol extract of pig skin and a PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC-MS.
- the conditions of LC-MS are as follows.
- Example of Preparation of Percutaneous Absorption Composition Containing Minoxidil Using IPM and Olive Oil as Oil Base Material In a 6 mL screw-neck sample tube, 42.5 mg of minoxidil, 42.5 mg of (+)-camphor, and 2000 mg of ethanol were placed. The mixture was stirred at room temperature for 30 minutes. Thirty minutes later, 1850 mg of IPM and 200 mg of olive oil were added to the obtained homogeneous ethanol solution to prepare a percutaneous absorption composition of Example 3 (minoxidil (1%) oil-solubilized solution).
- the percutaneous absorption composition used in this experiment is a commercially available product 1 containing Minoxidil at a concentration of 5% (Reup ⁇ 5 Plus, Taisho Pharmaceutical), and Example 3.
- the transdermal absorption test was performed as follows. As a transdermal absorption test, pig skin (Yucatan Micro Pig (Charles River Japan)) was used. A stir bar and 5 mL of an aqueous PBS solution were added to the receiver phase of the Franz cell, the pig skin was sandwiched between the upper portions of the aqueous PBS solution, and water at 37 ° C. was flowed through the water jacket of the Franz cell.
- the receiver phase was agitated and 200 ⁇ L of Commercial Product 1 and Example 3 were placed on pig skin. Twenty-four hours later, a methanol extract of pig skin and a PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC-MS.
- the conditions of LC-MS are as follows. Column temperature: 30 ° C, detection mass (m / z): 210, eluent: 10 mM ammonium formate / acetonitrile (10/90, vol / vol), flow rate: 0.2 mL The results are shown in FIGS.
- Example 3 the amount of minoxidil in porcine skin was detected about 9.7 times higher in Example 3 as compared with the commercial product 1. Further, the amount of minoxidil in the receiver solution was detected to be about 27.9 times larger in Example 3. Since the commercially available product 1 contains 5% minoxidil, the transdermal absorption composition of Example 3 (minoxidil (1%) oil-solubilized solution) used in this experiment promotes transdermal absorption, Promising as a transdermal drug delivery system (DDS) material.
- DDS transdermal drug delivery system
- the complex of the present invention can improve the transdermal absorbability of minoxidil, increase the content in the skin, and release minoxidil inside the skin to exert a medicinal effect.
- the percutaneous absorption composition of the present invention containing the compound can be used as an external preparation for skin, for example, a drug or cosmetic used for external skin treatment.
- a transdermal absorption control agent by appropriately using a transdermal absorption control agent, the release of minoxidil from the complex of the present invention inside the skin is controlled, so that it can be used for a drug delivery system.
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Abstract
Description
本発明は、ミノキシジルの皮膚中での放出が制御された経皮吸収組成物、及びミノキシジル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 percutaneous absorption composition in which the release of minoxidil into the skin is controlled, and a method for controlling minoxidil 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 percutaneous absorption technology for inducing an active ingredient to be absorbed from the skin so as to directly act on the skin has been advanced.
In particular, water-soluble drugs are difficult to penetrate into the stratum corneum, which has high fat solubility, and one of the methods for increasing the transdermal absorbability is fat solubilization (oil solubilization) of water-soluble drugs. Have been. For example, a fat-solubilized site is introduced into a water-soluble drug by organic synthesis (prodrug formation), dissolved and dispersed in an oily base material, and applied to the skin. After penetrating the stratum corneum, the bond between the water-soluble drug and the fat-soluble site is broken 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 encapsulated in liposomes, dissolved and dispersed in an oily base material, and applied to the skin. After permeation of the stratum corneum, the interface of the liposome is disrupted inside the skin by enzymes or the like, 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 permeation enhancer (transdermal absorption enhancer) such as terpene or higher alcohol is used to enhance transdermal 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 conversion is an excellent method for imparting lipophilicity to water-soluble drugs to enhance transdermal absorption, but it is a complicated process for the production process of organic synthesis and complicated procedures for obtaining 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 an agent to be made into a prodrug or encapsulated in a liposome, for example, tranexamic acid, an artificial amino acid, inhibits activation by binding to plasmin, a proteolytic enzyme, in the epidermis, thereby suppressing melanin production. It is known to. Utilizing this effect, in recent years, whitening effects have come to be claimed and have attracted attention as a raw material for cosmetics. However, there is a problem that the skin permeability of tranexamic acid is low.
本発明は、有機合成によるプロドラッグ化によらずにミノキシジル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 minoxidil without using a prodrug by organic synthesis.
本発明者らは、鋭意研究の結果、ミノキシジルが、相互作用を介して、ケトン基を有する脂溶性化合物と複合体を形成することで、簡便に、当該ミノキシジルに脂溶性を付与してその経皮吸収性が高められる一方、皮膚中では容易にミノキシジルが放出され得ることを見出し、本発明を完成させた。 The present inventors have conducted intensive studies and found that minoxidil forms a complex with a fat-soluble compound having a ketone group through an interaction, thereby easily giving the minoxidil a fat-solubility to promote the process. The present inventors have found that minoxidil can be easily released into the skin while improving skin absorbability, and completed the present invention.
すなわち、本発明は、
(1) ミノキシジルとケトン基を有する脂溶性化合物とにより、相互作用を介して形成された、複合体；
(2) 前記ケトン基を有する脂溶性化合物が、ケトン基を有するテルペン、ケトン基を有するリグノイド、ケトン基を有するバニロイド、ケトン基を有するクルクミノイド、クロモン、及びクマリンからなる群より一つ以上選ばれる、前記(1)記載の複合体；
(3) 前記ケトン基を有するテルペンが（＋）－カンファー又はゲラニルアセトンである、前記(2)記載の複合体；
(4) 前記ケトン基を有するリグノイドがフラボンである、前記(2)記載の複合体；
(5) 前記ケトン基を有するバニロイドがギンゲロール又はショウガオールである、前記(2)記載の複合体；
(6) 前記ケトン基を有するクルクミノイドがクルクミンである、前記(2)記載の複合体；
(7) 前記ケトン基を有する脂溶性化合物が、メチルエチルケトン、メチルイソブチルケトン、アセトフェノン、クルクミン又はビタミンＫである、前記(1)記載の複合体；
(8) 前記(1)～(7)のいずれか一つ記載の複合体、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) 前記複合体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、オリーブオイル、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)記載の組成物；
(12) ミノキシジル、ケトン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) さらに脂溶性媒体を含む、前記(12)記載の組成物；
(14) 前記経皮吸収制御剤がアルコールである、前記(8)～(13)記載の組成物；
(15) 前記アルコールがエタノール、ゲラニオール、シトロネロール、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(14)記載の組成物；
(16) 前記(1)～(7)のいずれか一つ記載の複合体を、経皮吸収制御剤に溶解させる工程を含む、前記複合体からの前記ミノキシジルの皮膚中での放出を制御する方法；
(17) 前記(1)～(7)のいずれか一つ記載の複合体を、経皮吸収制御剤に溶解させる工程を含む、前記複合体からの前記ミノキシジルを皮膚中で放出させる方法；
(18) ミノキシジル、ケトン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、前記ミノキシジルを皮膚中で放出させる方法；
(19) ミノキシジルの粉末とケトン基を有する脂溶性化合物とを混合する工程を含む、前記ミノキシジルと前記ケトン基を有する脂溶性化合物とにより相互作用を介して形成された複合体の製造方法；
(20) ミノキシジルの粉末とケトン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、前記ミノキシジル、前記ケトン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の製造方法；
(21) 精油中に、前記ケトン基を有する脂溶性化合物を含む、前記(1)記載の複合体；
(22) 前記精油が、クスノキ又はセージである、前記(21)記載の複合体；
に関する。
That is, the present invention
(1) a complex formed by interaction between minoxidil and a fat-soluble compound having a ketone group;
(2) The fat-soluble compound having a ketone group is at least one selected from the group consisting of a terpene having a ketone group, a lignoid having a ketone group, a vanilloid having a ketone group, a curcuminoid having a ketone group, chromone, and coumarin. A complex according to (1) above;
(3) The complex according to (2), wherein the terpene having a ketone group is (+)-camphor or geranylacetone;
(4) The complex according to (2), wherein the lignoid having a ketone group is a flavone;
(5) the complex according to (2), wherein the vanilloid having a ketone group is gingerol or shogaol;
(6) The complex according to (2), wherein the curcuminoid having a ketone group is curcumin;
(7) The complex according to (1), wherein the fat-soluble compound having a ketone group is methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin, or vitamin K;
(8) A transdermal absorption composition comprising the complex according to any one of the above (1) to (7), a transdermal absorption controlling agent, and a fat-soluble medium;
(9) The transdermal absorption composition according to (8), wherein the complex is dissolved in the fat-soluble medium;
(10) The composition according to (8) or (9), wherein the fat-soluble medium is a transdermal absorption promoting fat-soluble medium;
(11) The composition according to (10), wherein the transdermal absorption-promoting fat-soluble medium is at least one selected from the group consisting of isopropyl myristate, olive oil, cyclopentasiloxane, squalane, and limonene.
(12) a composition comprising minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption controlling agent;
(13) The composition according to the above (12), further comprising a fat-soluble medium;
(14) The composition according to any of (8) to (13), wherein the transdermal absorption controlling agent is an alcohol;
(15) The composition according to (14), wherein the alcohol is at least one selected from the group consisting of ethanol, geraniol, citronellol, and 1,2-hexanediol.
(16) controlling the release of the minoxidil from the complex into the skin, comprising a step of dissolving the complex according to any one of the above (1) to (7) in a transdermal absorption controlling agent. Method;
(17) A method for releasing the minoxidil from the complex into the skin, comprising a step of dissolving the complex according to any one of (1) to (7) in a transdermal absorption controlling agent;
(18) a method of releasing minoxidil into the skin from a composition comprising minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption controlling agent;
(19) a method for producing a complex formed by interaction between the minoxidil and the fat-soluble compound having a ketone group, comprising a step of mixing a powder of minoxidil and a fat-soluble compound having a ketone group;
(20) a composition comprising the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption controlling agent, comprising a step of mixing a powder of minoxidil, a fat-soluble compound having a ketone group, and a transdermal absorption controlling agent. Method of manufacturing a product;
(21) The complex according to (1), wherein the essential oil comprises the fat-soluble compound having the ketone group;
(22) The complex according to (21), wherein the essential oil is camphor tree or sage;
About.
本発明の複合体は、ミノキシジルと、ケトン基を有する脂溶性化合物とが、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、当該ミノキシジル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、ミノキシジルを放出して薬効を奏することもできる。
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ミノキシジルの放出を制御することもできる。
In the complex of the present invention, since minoxidil and the fat-soluble compound having a ketone group are complexed through an interaction, the complex can be uniformly dissolved (fat-solubilized or oil-solubilized) in the fat-soluble medium. As a result, the percutaneous absorbability of the minoxidil can be improved, and after permeation of the stratum corneum, the minoxidil can be released to exert a medicinal effect.
In the present invention, the release of minoxidil from the complex in the skin can be controlled by appropriately using a transdermal absorption controlling agent.
本発明の複合体では、ミノキシジルと、ケトン基を有する脂溶性化合物とが、相互作用を介して複合化している。そのため、本発明の複合体は、ミノキシジル及び該ケトン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、解離してミノキシジルを放出するので薬効を発揮させ得る。
本発明の複合体は、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。
In the complex of the present invention, minoxidil and the fat-soluble compound having a ketone group are complexed through an interaction. Therefore, the complex of the present invention can be in a chemical equilibrium relationship with minoxidil and the fat-soluble compound having the ketone group. As a result, in the fat-soluble medium, the complex is fat-solubilized by solvation or cluster formation. While it can exist stably, it dissociates and releases minoxidil inside the skin, so that it can exert its medicinal effect.
The complex of the present invention may be complexed through an interaction that can dissociate in water.
本発明では、ミノキシジルを単独で使用してもよいが、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。
このような本発明の水溶性有効成分は、ケトン基を有する脂溶性化合物と、相互作用を介して複合体を形成し得る、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。
このような本発明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、ケトン基を有する脂溶性化合物の当該ケトン基と、種々の相互作用、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得る。
In the present invention, minoxidil may be used alone, or may be used in combination with one or more optional water-soluble active ingredients.
Such a water-soluble active ingredient of the present invention is not particularly limited as long as it is an active ingredient such as a water-soluble drug or cosmetic that can form a complex through interaction with a fat-soluble compound having a ketone group. Any water-soluble pharmaceutical or cosmetic active ingredient, for example, amino acids, hydrophilic vitamins, sugars, peptides and other hydrophilic drugs can be used.
Examples of such a water-soluble active ingredient of the present invention include those having an amino group, a hydroxyl group, or a thiol group. These groups respectively have various interactions with the ketone group of the fat-soluble compound having a ketone group, for example, ionic bond, hydrogen bond, dipole interaction, van der Waals force, charge transfer interaction, π- It can form π interaction, hydrophobic interaction, solvation, reversible chemical bond, etc.
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 acid 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. , Tyrosine, and natural amino acids such as 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 peptides include known peptides and peptides having specific effects (for example, since they are recognized by human T cells, they are expected to have a therapeutic effect on hay fever). Specific examples include peptide A (amino acid sequence: QFAKLTGFTLMG) and peptide B (amino acid sequence: SMKVTVAFNQFGP).
前記親水性薬剤として、例えば、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 zanamivir (relenza), acyclovir, cytarabine ocphosphate, and fludarabine phosphate.
本発明のケトン基を有する脂溶性化合物は、ケトン基を少なくとも１個含む脂溶性の化合物であれば、特に制限されず、脂肪族ケトンや芳香族ケトンを含む任意の化合物が使用することができる。中でも、炭素数が４以上、例えば４～５０の、ケトン基を有する脂溶性化合物が好ましい。更に、天然由来かつ安全性の観点から、ケトン基を有するテルペン、ケトン基を有するリグノイド、ケトン基を有するバニロイド、ケトン基を有するクルクミノイド、ケトン基を有するクロモンやクマリンなどがより好ましい。
なお、本発明においてケトン基とは、－（Ｃ＝Ｏ）－（両端はいずれも水素原子とは結合していない）で表される基を意味する。また、その互変異性型であるエノール型：＝Ｃ（ＯＨ）－も本発明においてケトン基に包含され得る。
好ましくは、本発明のケトン基は、－（Ｃ＝Ｏ）－の両端がいずれも炭素原子と結合している。
The fat-soluble compound having a ketone group of the present invention is not particularly limited as long as it is a fat-soluble compound containing at least one ketone group, and any compound containing an aliphatic ketone or an aromatic ketone can be used. . Above all, a fat-soluble compound having 4 or more carbon atoms, for example, 4 to 50 and having a ketone group is preferable. Further, from the viewpoints of natural origin and safety, terpene having a ketone group, lignoid having a ketone group, vanilloid having a ketone group, curcuminoid having a ketone group, chromone and coumarin having a ketone group are more preferable.
In the present invention, the ketone group means a group represented by-(C = O)-(both ends are not bonded to a hydrogen atom). In the present invention, the tautomeric enol type: ＣC (OH)-can also be included in the ketone group in the present invention.
Preferably, in the ketone group of the present invention, both ends of-(C = O)-are bonded to carbon atoms.
前記ケトン基を有するテルペンとして、例えば、ゲラニルアセトン、カンファー、例えば（±）－カンファー、（＋）－カンファー、及び（－）－カンファー、ならびにカルボン及びカプサンチンなどが挙げられ、ミノキシジルを良好に脂溶化させる点から、ゲラニルアセトン又は（＋）－カンファーが好ましく、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、ミノキシジルを良好に脂溶化させる点から、クスノキである。
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、本発明のケトン基を有するテルペンが含まれていれば実施可能である。
クスノキは、一例としては、カンファーが主な成分(５０～６０％)であり、リモネン(５～１０％)、α-ピネン、ミルセン等の混合物である。
セージは、一例としては、カンファーが主な成分（２０～３０％）であり、Ｃｉｓ－ツジョン(１５～２０％)、ユーカリプトール(１０～１５％)等の混合物である。
Examples of the terpene having a ketone group include geranylacetone, camphor such as (±) -camphor, (+)-camphor, and (−)-camphor, and carvone and capsanthin. In view of this, geranylacetone or (+)-camphor is preferable, and a natural product such as an essential oil containing the above compound may be used. Preferably, camphor is used from the viewpoint of satisfactorily solubilizing minoxidil.
Essential oil is a general term for volatile organic matter produced by plants, and is generally a mixture of many compounds. There is no particular limitation, and the present invention can be implemented as long as the terpene having a ketone group of the present invention is contained.
As an example, camphor is a mixture of camphor as a main component (50 to 60%) and limonene (5 to 10%), α-pinene, myrcene and the like.
The sage is, for example, a mixture of camphor as a main component (20 to 30%), Cis-Thujong (15 to 20%), eucalyptol (10 to 15%), and the like.
前記ケトン基を有するリグノイドとして、例えば、フラボンなどが挙げられる。 {Examples of the lignoid having a ketone group include flavone.
前記ケトン基を有するバニロイドとして、例えば、ギンゲロール又はショウガオールなどが挙げられる。 バ Examples of the vanilloid having a ketone group include gingerol and shogaol.
前記ケトン基を有するクルクミノイドとして、例えば、クルクミン、デメトキシクルクミン、ビスデメトキシクルクミンなどが挙げられ、ミノキシジルを良好に脂溶化させる点から、クルクミンが好ましい。 ク ル As the curcuminoid having a ketone group, for example, curcumin, demethoxycurcumin, bisdemethoxycurcumin and the like can be mentioned, and curcumin is preferable from the viewpoint of satisfactorily solubilizing minoxidil.
前記脂肪族ケトンや芳香族ケトンとしては、例えば、メチルエチルケトン、メチルイソブチルケトン、アセトフェノン、クルクミン又はビタミンＫなどが挙げられる。 Examples of the aliphatic ketone and the aromatic ketone include methyl ethyl ketone, methyl isobutyl ketone, acetophenone, curcumin, and vitamin K.
本発明では、前記のケトン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。
本発明のケトン基を有する脂溶性化合物は、ミノキシジルを良好に脂溶化させる点から、とりわけゲラニルアセトン又は（＋）－カンファーが好ましい。
In the present invention, the above-mentioned fat-soluble compounds having a ketone group may be used alone or in combination of two or more.
The lipophilic compound having a ketone group of the present invention is particularly preferably geranylacetone or (+)-camphor, from the viewpoint of satisfactorily solubilizing minoxidil.
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。本発明の複合体を脂溶性媒体中で良好に安定化し得る点から、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。
本発明の複合体は、ミノキシジルと、ケトン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、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、皮膚中でのミノキシジルの放出がより良好に制御される。
The transdermal absorption controlling agent of the present invention is not particularly limited as long as it is commonly used for controlling transdermal absorption of active ingredients of water-soluble medicines or cosmetics in the field of medicines and cosmetics, especially skin external preparations. From the viewpoint that the complex of the present invention can be favorably stabilized in a fat-soluble medium, a transdermal absorption controller having a hydroxyl group is preferable, and a monohydric or polyhydric alcohol is particularly preferably used.
In the complex of the present invention, in addition to minoxidil and the fat-soluble compound having a ketone group, a transdermal absorption controlling agent may be further complexed through an interaction. In such a conjugate, the release of minoxidil 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、シトロネロール、及びゲラニオールが挙げられる。 Examples of the monohydric alcohol include lower alcohols such as methanol, ethanol, 1-propanol, and 2-propanol; higher alcohols; nerolidol, geraniol, menthol, borneol, isoborneol, nerol, citronellol, and fentyl. Examples thereof include terpenes having a hydroxyl group such as alcohol, carveol, and neomenthol, and preferably include methanol, ethanol, citronellol, and geraniol.
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、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、ラウリルアルコール、ミリスチルアルコール、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が挙げられる。
Examples of the above higher alcohol include octanol, nonanol, decanol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, and fine oxocol 180 (FO180). :
And C8-18 saturated alcohols such as oleyl alcohol, linoleyl alcohol, and linolenyl alcohol. Preferably, octanol, decanol, lauryl alcohol, myristyl alcohol, and oleyl alcohol are used, and more preferably, oleyl alcohol is used.
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、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、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、プロピ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, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, Examples include 1,5-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diethylene glycol, triethylene glycol, and
本発明の複合体は、前記ミノキシジルと、前記ケトン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。複合体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、得られた複合体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、得られた複合体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。
ミノキシジルが固体（好ましくは結晶）の場合、本発明の複合体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、ミノキシジル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、粉砕されるミノキシジルの硬さに応じて、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。
前記ミノキシジルと前記ケトン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、１：１～１００、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、前記ミノキシジル、前記ケトン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、１：１～１００：１～１００、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。
本発明の複合体を構成する、前記ミノキシジル及び前記ケトン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 complex of the present invention can be easily prepared by mixing the minoxidil and the fat-soluble compound having a ketone group, and heating and cooling for a certain period of time as necessary. From the viewpoint that a complex can be obtained favorably, it is preferable to add and mix the transdermal absorption control agent of the present invention, particularly the liquid transdermal absorption control agent. Further, the transdermal absorption controlling agent of the present invention is preferably in a liquid form in that the obtained complex can be stably dissolved. In this case, the solution of the obtained transdermal absorption control agent in which the complex is dissolved can be used for preparing the transdermal absorption composition of the present invention.
When minoxidil is a solid (preferably a crystal), it is preferable to mix it in a powder form in order to obtain the composite of the present invention well. Examples of a method for forming a powder include a method based on dry pulverization. The conditions of the dry pulverization are not particularly limited as long as minoxidil can be pulverized into small pieces, but it is preferable to use a pulverizer such as a mortar, a ball mill, a homogenizer, a cutter mill, and a hammer mill. In addition, the pulverizing time and the processing pressure are appropriately adjusted according to the hardness of the minoxidil to be pulverized.
The powder obtained by the above method is desirably further sieved to make the particle size 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 between the minoxidil and the fat-soluble compound having a ketone group varies depending on the type of these substances used, but is 1: 1 to 100, preferably 1:10 to 50.
When the percutaneous absorption controlling agent is also mixed, the mixing ratio of the minoxidil, the fat-soluble compound having a ketone group, and the percutaneous absorption controlling agent varies depending on the type of these substances used, but is 1: 1. １００100: 1 to 100, preferably 1: 1 to 100: 10 to 50, more preferably 1:10 to 50:10 to 50.
The composition ratio (molar ratio) of the minoxidil and the fat-soluble compound having a ketone group that constitutes the complex of the present invention is 1 to 100: 100 to 1, more preferably 1 to 10:10 to 1. is there.
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複合体からのミノキシジル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）、本発明のミノキシジル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）、本発明のミノキシジルの放出を促進させることができる。本発明は、本発明の複合体を、経皮吸収制御剤に溶解させる工程を含む、当該複合体からのミノキシジル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、本発明の複合体からのミノキシジル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 transdermal absorption controlling agent, particularly a monohydric or polyhydric alcohol, for example, depending on the type and the amount of these transdermal absorption controlling agents, in the skin after percutaneous absorption. The release of minoxidil from the conjugate of the invention can be controlled. For example, by increasing the lipophilicity of the transdermal absorption controlling agent (for example, by increasing the carbon number), the release of minoxidil of the present invention can be delayed, and the lipophilicity of the transdermal absorption controlling agent can be reduced. (Eg, by reducing the number of carbon atoms) can enhance the release of minoxidil of the present invention. The present invention also relates to a method of controlling the release of minoxidil from the complex in the skin, comprising the step of dissolving the complex of the present invention in a transdermal absorption controlling agent. The present invention also relates to the use of a transdermal absorption control agent to control the release of minoxidil from the complex of the present invention in the skin.
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 controlling agents may be used alone or in combination of two or more.
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）、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、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）、オリーブオイル、シクロペンタシロキサン、スクアラン、リモネン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 commonly used as a base material in the field of medicines and cosmetics, especially skin external preparations, and is preferably a transdermal absorption promoting fat-soluble medium. Can be used.
The transdermal absorption-promoting fat-soluble medium is particularly limited as long as it is commonly used for promoting transdermal absorption of a water-soluble drug or an active ingredient of a cosmetic in the field of medicines and cosmetics, especially skin external preparations. For example, limonene (eg, d-limonene), cyclopentasiloxane (KF995):
Isopropyl myristate (IPM), squalane, squalane, squalene, silicone oil, jojoba oil, almond oil, olive oil, horse oil, mineral oil, etc. can be used, and preferably isopropyl myristate (IPM), olive oil , Cyclopentasiloxane, squalane, limonene can be used.
In the present invention, the above-mentioned fat-soluble medium may be used alone or in combination of two or more.
本発明の経皮吸収組成物は、前記で得られた複合体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 percutaneous absorption composition of the present invention can be prepared by mixing a solution of the percutaneous absorption control agent in which the complex obtained above is dissolved and the fat-soluble medium.
本発明の複合体は、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。 複合 The complex of the present invention can exhibit good solubility in fat-soluble media by using an appropriate transdermal absorption control agent. From this viewpoint, for example, when the fat-soluble medium is squalane, geraniol or citronellol is preferable as the transdermal absorption control agent, and when the fat-soluble medium is IPM, ethanol or 1,2-hexanediol is preferable as the transdermal absorption control agent. When the fat-soluble medium is KF995, geraniol or citronellol is preferred as the transdermal absorption control agent.
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、前記ミノキシジルを経皮投与するための方法にも関する。また、本発明は、前記ミノキシジル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 used as a medicine or cosmetics, the transdermal absorption composition of the present invention may be used as such, but may be used as a conventional pharmaceutical preparation, particularly as a skin external preparation or cosmetic. The pharmaceutical preparations or cosmetics are acceptable in the field of pharmaceuticals and cosmetics such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, diluents, etc., so long as the effects of the present invention are not impaired. May be included.
The external preparation for skin of the present invention can contain components that can be usually blended in 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 surfactants, amphoteric surfactants, nonionic surfactants, powders, pigments, dyes, preservatives and fungicides, resins, pH adjusters, antioxidants, ultraviolet absorbers, chelating agents, thickeners, Examples include humectants, alcohol, water, and fragrances.
The present invention also relates to a method for transdermally administering minoxidil, comprising applying the transdermal composition of the present invention to the skin. The present invention also relates to the use of the transdermal absorption composition of the present invention for transdermal administration of the above-mentioned minoxidil.
また、本発明の組成物は、前記ミノキシジル、前記ケトン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、前記ミノキシジルを経皮投与するための方法にも関する。また、本発明は、前記ミノキシジル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 the minoxidil, the fat-soluble compound having a ketone group, and the transdermal absorption controlling 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 said minoxidil, comprising applying the composition of the present invention to the skin. The invention also relates to the use of the composition of the invention for transdermal administration of said minoxidil.
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）、ミリスチン酸イソプロピル（ＩＰＭ）（特級）、ギ酸アンモニウム（特級）、オリーブオイル、１×ＰＢＳは和光純薬工業（株）より入手した。ミノキシジル、ゲラニルアセトン、（＋）－カンファーは東京化成工業（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
カラム：Shodex Asahipak NH2P-40 2D (2.0 mm I.D. x 150 mm)
1. Reagents and Equipment Reagents used in the examples are shown below.
Ethanol (special grade), isopropyl myristate (IPM) (special grade), ammonium formate (special grade), olive oil, 1 × PBS were obtained from Wako Pure Chemical Industries, Ltd. Minoxidil, geranylacetone, and (+)-camphor were obtained from Tokyo Chemical Industry Co., Ltd. Acetonitrile (for high performance liquid chromatography) was obtained from Kanto Chemical Co., Ltd.
The equipment used for the analysis is shown below.
Liquid chromatograph mass spectrometer (LC / MS)
Apparatus: e2695 (LC unit), 2489 (UV-Vis detector), 3100 Mass Detector, manufactured by Nippon Waters Co., Ltd. Column: Shodex Asahipak NH2P-40 2D (2.0 mm ID x 150 mm)
２．脂肪族ケトンを添加したミノキシジルを含む経皮収吸収組成物の調製例
６ｍＬのねじ口サンプル管に、ミノキシジル４０ｍｇ、表１に示した脂肪族ケトン２００ｍｇ、及びエタノール２ｍＬを加え、室温で１時間撹拌した。１時間後、得られた均一になったエタノール溶液にミリスチン酸イソプロピル（ＩＰＭ）を２ｍＬ加え、比較例１ならびに実施例１及び２の経皮吸収組成物を調製した。
調製条件を表１に示す。
Table 1 shows the preparation conditions.
３．ミノキシジル油溶化溶液の経皮吸収性試験（１）
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、ミノキシジルの油溶化溶液を用いて、皮膚バリアを突破した後、ＰＢＳ水溶液中でミノキシジルを放出するか否かの経皮吸収性試験を行った。
本実験で用いた経皮吸収組成物は、前記表１にある比較例１、実施例１、及び実施例２である。
経皮吸収性試験は次のとおりに行った。経皮吸収性試験としてはブタ皮膚（Yucatan Micro Pig（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。レシーバー相を攪拌し、比較例１、実施例１、及び実施例２の２００μＬをブタ皮膚の上に載せた。２４時間後に豚皮膚のメタノール抽出液及びレシーバー相のＰＢＳ水溶液をサンプリングし、ＬＣ－ＭＳによりミノキシジル量を定量した。ＬＣ－ＭＳの条件は以下のとおりである。
カラム温度：３０℃、検出質量（ｍ／ｚ）：２１０、溶離液：１０ｍＭギ酸アンモニウム／アセトニトリル（１０／９０，ｖоl／ｖоl）、流速：０．２ｍＬ
結果を図１及び図２に示す。
3. Percutaneous absorption test of minoxidil oil solubilized solution (1)
The stratum corneum is hydrophobic and becomes more hydrophilic as it goes deeper. In other words, oil solubilization is an effective means for breaking through the stratum corneum barrier. Therefore, after permeating the skin barrier using an oil solubilized solution of minoxidil, a transdermal absorption test was performed to determine whether or not to release minoxidil in an aqueous PBS solution.
The transdermal absorption compositions used in this experiment are Comparative Example 1, Example 1, and Example 2 shown in Table 1 above.
The transdermal absorption test was performed as follows. As a transdermal absorption test, pig skin (Yucatan Micro Pig (Charles River Japan)) was used. A stir bar and 5 mL of an aqueous PBS solution were added to the receiver phase of the Franz cell, the pig skin was sandwiched between the upper portions of the aqueous PBS solution, and water at 37 ° C. was flowed through the water jacket of the Franz cell. The receiver phase was agitated and 200 μL of Comparative Example 1, Example 1, and Example 2 were placed on pig skin. Twenty-four hours later, a methanol extract of pig skin and a PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC-MS. The conditions of LC-MS are as follows.
Column temperature: 30 ° C, detection mass (m / z): 210, eluent: 10 mM ammonium formate / acetonitrile (10/90, vol / vol), flow rate: 0.2 mL
The results are shown in FIGS.
結果として、比較例１と比較して、ブタ皮膚中のミノキシジル量は、ゲラニルアセトン添加（実施例１）では約５４倍、（＋）－カンファー添加（実施例２）では約３０倍、多く検出された。また、レシーバー液中では、比較例１が検出限界以下であったのに対して、ゲラニルアセトン添加（実施例１）及び（＋）－カンファー添加（実施例２）とも、経皮吸収性を示す結果となった。
これらの結果から、脂肪族ケトンを添加したミノキシジル油溶化溶液は、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。
As a result, as compared with Comparative Example 1, the amount of minoxidil in pig skin was detected to be about 54 times more when geranylacetone was added (Example 1) and about 30 times more when (+)-camphor was added (Example 2). Was done. Further, in the receiver solution, Comparative Example 1 was below the detection limit, whereas geranylacetone addition (Example 1) and (+)-camphor addition (Example 2) showed transdermal absorption. The result was.
These results indicate that the minoxidil oil solubilizing solution with the aliphatic ketone promotes transdermal absorption and is promising as a transdermal drug delivery system (DDS) material.
４．油脂性基材としてＩＰＭとオリーブオイルを用いたミノキシジルを含む経皮収吸収組成物の調製例
６ｍＬのねじ口サンプル管に、ミノキシジル４２．５ｍｇ、（＋）－カンファー４２．５ｍｇ、及びエタノール２０００ｍｇを加え、室温で３０分撹拌した。３０分後、得られた均一になったエタノール溶液にＩＰＭを１８５０ｍｇ、オリーブオイル２００ｍｇを加え、実施例３の経皮吸収組成物〔ミノキシジル（１％）油溶化溶液〕を調製した。
4. Example of Preparation of Percutaneous Absorption Composition Containing Minoxidil Using IPM and Olive Oil as Oil Base Material In a 6 mL screw-neck sample tube, 42.5 mg of minoxidil, 42.5 mg of (+)-camphor, and 2000 mg of ethanol were placed. The mixture was stirred at room temperature for 30 minutes. Thirty minutes later, 1850 mg of IPM and 200 mg of olive oil were added to the obtained homogeneous ethanol solution to prepare a percutaneous absorption composition of Example 3 (minoxidil (1%) oil-solubilized solution).
５．ミノキシジル油溶化溶液の経皮吸収性試験（２）
本実験で用いた経皮吸収組成物は、ミノキシジルが５％の濃度で含まれている市販品１（リアップ×５プラス、大正製薬）、及び実施例３である。
経皮吸収性試験は次のとおりに行った。経皮吸収性試験としてはブタ皮膚（Yucatan Micro Pig（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。レシーバー相を攪拌し、市販品１及び実施例３の２００μＬをブタ皮膚の上に載せた。２４時間後に豚皮膚のメタノール抽出液及びレシーバー相のＰＢＳ水溶液をサンプリングし、ＬＣ－ＭＳによりミノキシジル量を定量した。ＬＣ－ＭＳの条件は以下のとおりである。
カラム温度：３０℃、検出質量（ｍ／ｚ）：２１０、溶離液：１０ｍＭギ酸アンモニウム／アセトニトリル（１０／９０，ｖоl／ｖоl）、流速：０．２ｍＬ
結果を図３及び図４に示す。
5. Percutaneous absorption test of Minoxidil oil solubilized solution (2)
The percutaneous absorption composition used in this experiment is a commercially available product 1 containing Minoxidil at a concentration of 5% (Reup × 5 Plus, Taisho Pharmaceutical), and Example 3.
The transdermal absorption test was performed as follows. As a transdermal absorption test, pig skin (Yucatan Micro Pig (Charles River Japan)) was used. A stir bar and 5 mL of an aqueous PBS solution were added to the receiver phase of the Franz cell, the pig skin was sandwiched between the upper portions of the aqueous PBS solution, and water at 37 ° C. was flowed through the water jacket of the Franz cell. The receiver phase was agitated and 200 μL of Commercial Product 1 and Example 3 were placed on pig skin. Twenty-four hours later, a methanol extract of pig skin and a PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC-MS. The conditions of LC-MS are as follows.
Column temperature: 30 ° C, detection mass (m / z): 210, eluent: 10 mM ammonium formate / acetonitrile (10/90, vol / vol), flow rate: 0.2 mL
The results are shown in FIGS.
結果として、市販品１と比較して、ブタ皮膚中のミノキシジル量は、実施例３では約９．７倍多く検出された。また、レシーバー液中のミノキシジル量は、実施例３では約２７．９倍多く検出された。
市販品１が５％のミノキシジルを含んでいることからも本実験で使用した実施例３の経皮吸収組成物〔ミノキシジル（１％）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。
As a result, the amount of minoxidil in porcine skin was detected about 9.7 times higher in Example 3 as compared with the commercial product 1. Further, the amount of minoxidil in the receiver solution was detected to be about 27.9 times larger in Example 3.
Since the commercially available product 1 contains 5% minoxidil, the transdermal absorption composition of Example 3 (minoxidil (1%) oil-solubilized solution) used in this experiment promotes transdermal absorption, Promising as a transdermal drug delivery system (DDS) material.
本発明の複合体は、ミノキシジル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、皮膚内部でミノキシジルを放出して、薬効を奏することができるので、このような複合体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複合体からのミノキシジル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。
The complex of the present invention can improve the transdermal absorbability of minoxidil, increase the content in the skin, and release minoxidil inside the skin to exert a medicinal effect. The percutaneous absorption composition of the present invention containing the compound can be used as an external preparation for skin, for example, a drug or cosmetic used for external skin treatment.
In addition, by appropriately using a transdermal absorption control agent, the release of minoxidil from the complex of the present invention inside the skin is controlled, so that it can be used for a drug delivery system.
Claims (22)
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10218737A (en) * | 1997-02-10 | 1998-08-18 | Taisho Pharmaceut Co Ltd | Hair restorer |
| JPH1112136A (en) * | 1997-06-27 | 1999-01-19 | Taisho Pharmaceut Co Ltd | Minoxidil-containing aerosol |
| JP2004091354A (en) * | 2002-08-30 | 2004-03-25 | Kanebo Ltd | Hair tonic |
| JP2005145900A (en) * | 2003-11-17 | 2005-06-09 | Tsumura & Co | Hair restorer composition and itching inhibitor |
| JP2010100561A (en) * | 2008-10-23 | 2010-05-06 | Mitsukan Group Honsha:Kk | Ciliary muscle relaxant |
| JP2010517938A (en) * | 2006-10-27 | 2010-05-27 | ジュセッペ・トリジャンテ | Compounds and methods for preventing hair loss |
| WO2017094905A1 (en) * | 2015-12-02 | 2017-06-08 | 金印株式会社 | Hair restoration/growth stimulating agent |
-
2019
- 2019-07-09 WO PCT/JP2019/027141 patent/WO2020013179A1/en not_active Ceased
- 2019-07-09 JP JP2020530197A patent/JPWO2020013179A1/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10218737A (en) * | 1997-02-10 | 1998-08-18 | Taisho Pharmaceut Co Ltd | Hair restorer |
| JPH1112136A (en) * | 1997-06-27 | 1999-01-19 | Taisho Pharmaceut Co Ltd | Minoxidil-containing aerosol |
| JP2004091354A (en) * | 2002-08-30 | 2004-03-25 | Kanebo Ltd | Hair tonic |
| JP2005145900A (en) * | 2003-11-17 | 2005-06-09 | Tsumura & Co | Hair restorer composition and itching inhibitor |
| JP2010517938A (en) * | 2006-10-27 | 2010-05-27 | ジュセッペ・トリジャンテ | Compounds and methods for preventing hair loss |
| JP2010100561A (en) * | 2008-10-23 | 2010-05-06 | Mitsukan Group Honsha:Kk | Ciliary muscle relaxant |
| WO2017094905A1 (en) * | 2015-12-02 | 2017-06-08 | 金印株式会社 | Hair restoration/growth stimulating agent |
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| BENN, S. ET AL.: "Potent Odorants in Peppermint and Cornmint Oils Characterized by GC-0 and AEDA", PERFUMER & FLAVORIST, vol. 23, no. 5, 1998, pages 5 - 16 * |
| ELAISSI, A. ET AL.: "Variation in Volatile Leaf Oils of Seven Eucalyptus Spiecies Harvested from Zerniza Arboreta( Tunisia)", CHEMISTRY & BIODIVERSITY, vol. 8, no. 2, 2011, pages 362 - 372, XP055675070 * |
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