WO2019022249A1 - Composition d'absorption transdermique à libération contrôlée de minoxidil - Google Patents

Composition d'absorption transdermique à libération contrôlée de minoxidil Download PDF

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WO2019022249A1
WO2019022249A1 PCT/JP2018/028335 JP2018028335W WO2019022249A1 WO 2019022249 A1 WO2019022249 A1 WO 2019022249A1 JP 2018028335 W JP2018028335 W JP 2018028335W WO 2019022249 A1 WO2019022249 A1 WO 2019022249A1
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minoxidil
aldehyde group
lipid
complex
soluble
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PCT/JP2018/028335
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English (en)
Japanese (ja)
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文靖 小野
後藤　雅宏
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国立大学法人九州大学
日産化学株式会社
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Priority to JP2019532891A priority Critical patent/JPWO2019022249A1/ja
Publication of WO2019022249A1 publication Critical patent/WO2019022249A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Definitions

  • the present invention relates to a transdermal absorption composition in which the release of minoxidil in the skin is controlled, and a method of controlling minoxidil in the skin.
  • water-soluble drugs are difficult to penetrate into the highly lipid-soluble stratum corneum, and one of the methods for enhancing the percutaneous absorbability thereof is oil-solubilization (water-solubilization) of water-soluble drugs. It is done.
  • a lipid solubilization site is introduced into a water-soluble drug by organic synthesis (prodrugation), and it is dissolved and dispersed in an oleaginous substrate and applied to the skin.
  • the bond between the water-soluble drug and the lipid-soluble site is broken inside the skin by an enzyme or the like, and the water-soluble drug is released.
  • an aqueous solution of a water-soluble drug is enclosed in a liposome, dissolved and dispersed in an oleaginous substrate, and applied to the skin.
  • the interface of the liposome is broken by enzymes and the like inside the skin, and the water-soluble drug is released.
  • permeability enhancers skin absorption enhancers
  • terpenes and higher alcohols in order to enhance the percutaneous absorbability of drugs
  • Pro-drugization is an excellent method of imparting lipophilicity to water-soluble drugs and enhancing transdermal absorption, but it is a complicated procedure for manufacturing process of organic synthesis and approval of manufacturing and marketing of pharmaceuticals and quasi-drugs. Is required.
  • tranexamic acid which is an artificial amino acid
  • plasmin which is a proteolytic enzyme in the epidermis to inhibit activation. It is known to do.
  • the whitening effect has come to be realized using this action, and has been attracting attention as a raw material for cosmetics.
  • the skin permeability of tranexamic acid is low.
  • An object of the present invention is to provide a method for simply enhancing the percutaneous absorbability of minoxidil without making it into a prodrug by organic synthesis.
  • minoxidil can form a complex with a lipid-soluble compound having an aldehyde group through a reversible interaction that can be dissociated in water, thereby easily providing While providing lipid solubility and enhancing its percutaneous absorbability, it has been found that minoxidil can be easily released in the skin, thus completing the present invention.
  • the present invention (1) A complex formed through an interaction that can be dissociated in water with minoxidil and a lipid-soluble compound having an aldehyde group; (2) The complex according to the above (1), wherein the at least one lipid-soluble compound having an aldehyde group is selected from the group consisting of terpene having an aldehyde group, lignin having an aldehyde group, and vanilloid having an aldehyde group; (3) The complex according to the above (2), wherein the terpene having an aldehyde group is citral or citronellal; (4) The complex according to the above (2), wherein the lignin having an aldehyde group is cinnamaldehyde; (5) The complex according to the above (2), wherein the vanilloid having an aldehyde group is vanillin.
  • the complex of the present invention is complexed with minoxidil and a lipid-soluble compound having an aldehyde group through an interaction capable of dissociating in water, it is uniformly dissolved in oil-soluble medium (lipid solubilization or oil solubilization) As a result, the percutaneous absorbability of the minoxidil can be improved, and after penetrating the stratum corneum, minoxidil can be released by water inside the skin to exert medicinal effects.
  • the release of minoxidil from the above complex in the skin can also be controlled by appropriately using a percutaneous absorption regulator.
  • FIG. 5 shows the amount of minoxidil in pig skin when the fat-soluble medium is changed. It is a figure which shows the amount of minoxidil in a receiver liquid when changing a fat-soluble medium. It is a figure which shows the amount of minoxidil in pig skin when the amount of citral is changed. It is a figure which shows the amount of minoxidil in a receiver liquid when the amount of citral is changed. It is a figure which shows the amount of minoxidil in pig skin when the amount of minoxidil is changed. It is a figure which shows the amount of minoxidil in a receiver liquid when the amount of minoxidil is changed. It is a figure which shows the amount of minoxidil in pig skin per tape. FIG.
  • FIG. 5 shows the amount of minoxidil in pig skin and in receiver fluid. It is a figure which shows the amount of various aldehydes in the pig skin per tape. It is a figure which shows the amount of various aldehydes in pig skin and in a receiver liquid.
  • the complex of the present invention minoxidil and a lipid-soluble compound having an aldehyde group are complexed through an interaction that can be dissociated in water. Therefore, the complex of the present invention can be in chemical equilibrium with minoxidil and the lipid-soluble compound having the aldehyde group, and as a result, in the lipid-soluble medium, it becomes lipid-soluble by solvation, cluster formation, etc. While it can be stably present, it can be efficacious because it is easily dissociated by the water contained therein to release minoxidil inside the skin.
  • 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 may be an active ingredient such as a water-soluble medicine or cosmetic which can form a complex with a lipid-soluble compound having an aldehyde group through an interaction capable of dissociating in water.
  • any water-soluble pharmaceutical or cosmetic active ingredient such as amino acids, hydrophilic vitamins, sugars, peptides and other hydrophilic drugs can be used.
  • those having an amino group, a hydroxyl group or a thiol group can be mentioned.
  • aldehyde group of the lipid-soluble compound having an aldehyde group which can be dissociated in water, such as ionic bonds, hydrogen bonds, dipolar interactions, van der Waals forces, charge transfer interactions. , ⁇ - ⁇ interaction, hydrophobic interaction, solvation, reversible chemical bond, etc.
  • 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 And natural amino acids such as tyrosine and valine.
  • 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.
  • hydrophilic vitamin examples include ascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl glucoside, ethyl ascorbic acid, vitamins B1, B2, B4, B5, B6, B7 and B12.
  • sugar examples include glucose, trehalose, dextran, pullulan, cyclodextrin, mannitol, glucosamine, galactosamine, raffinose, mannan and pectin.
  • the peptide which has a specific effect (For example, since it is recognized by the human T cell, a pollen allergy therapeutic effect is anticipated etc.) other than a well-known peptide is mentioned.
  • Specific examples are peptide A (amino acid sequence: QFAKLTGFTLMG), and peptide B (amino acid sequence: SMKVTVAFNQFGP).
  • hydrophilic agent examples include zanamivir (Lelenza), acyclovir, cytarabine octophosphate, fludarabine phosphate and the like.
  • the lipid-soluble compound having an aldehyde group of the present invention is not particularly limited as long as it is a lipid-soluble compound containing at least one aldehyde group, and any compound containing aliphatic aldehyde or aromatic aldehyde can be used. .
  • terpene having an aldehyde group, lignin having an aldehyde group, vanilloid having an aldehyde group and the like are preferable from the viewpoint of natural origin and safety.
  • terpene having an aldehyde group examples include citral, citronellal, cyclocitolar, safranal, ferandral, perylaldehyde, tagetone, retinal and the like, and citral and citronellal are preferable in that minoxidil is well lipidated,
  • natural products such as essential oils (essential oils) containing the above-mentioned compounds may be used.
  • lemongrass or citronella is preferred in terms of good lipid solubilization of minoxidil.
  • Essential oil is a generic term for volatile organic substances produced by plants, and is generally a mixture of many compounds.
  • lemongrass is mainly composed of citral (50 to 80%), and a mixture of geraniol (3 to 10%), farnesol, nerol, citronellol, myrcene and the like.
  • citronella is a main component (10 to 60%) of geraniol, a mixture of citronellol (3 to 10%), citronellal (1 to 30%) and the like.
  • Cinnamaldehyde is preferred as a lignin having an aldehyde group from the viewpoint of good lipid solubilization of minoxidil.
  • Vanillin is preferred as a vanilloid having an aldehyde group, from the viewpoint of good fat solubilization of minoxidil.
  • dodecanal or 4-butoxybenzaldehyde is also preferable, from the viewpoint of satisfactorily lipidifying minoxidil.
  • the above-mentioned lipid-soluble compounds having an aldehyde group may be used alone or in combination of two or more.
  • the lipid-soluble compounds having an aldehyde group of the present invention citral and citronellal are particularly preferable in terms of good lipid solubilization of minoxidil.
  • the transdermal absorption control agent of the present invention is not particularly limited as long as it is commonly used to control transdermal absorption of an active ingredient of a water-soluble drug or cosmetic in the fields of medicine and cosmetics, particularly external preparations for skin.
  • a percutaneous absorption controlling agent having a hydroxyl group is preferred, and in particular, a monohydric or polyhydric alcohol is preferably used.
  • the complex of the present invention may be complexed with minoxidil and a lipid-soluble compound having an aldehyde group, and further with a percutaneous absorption controlling agent through an interaction that can be dissociated in water. In such complexes, 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; and nerolidol, geraniol, menthol, borneol, isoborneol, nerol, citronellol, fentyl Alcohol, carveol, terpene having a hydroxyl group such as neomenthol, and the like can be mentioned, and methanol, ethanol, citronellol, and geraniol can preferably be mentioned.
  • Examples of the above-mentioned higher alcohols include octanol, nonanol, decanol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, and fine oxo call 180 (FO 180). : 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, lauryl alcohol, myristyl alcohol, and oleyl alcohol are mentioned, More preferably, oleyl alcohol is mentioned.
  • polyhydric alcohol examples include ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol and 2,3-butanediol. 1,5-pentanediol, 1,2-hexanediol, glycerin, dipropylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol 400 and the like, preferably propylene glycol and 1,2-hexanediol .
  • the complex of the present invention can be conveniently prepared by mixing the minoxidil and a lipid-soluble compound having an aldehyde group, heating and cooling as required for a certain period of time. It is preferable to add and mix the percutaneous absorption control agent of the present invention, particularly a liquid transdermal absorption control agent, from the viewpoint of obtaining a complex well. Moreover, it is preferable that the percutaneous absorption controlling agent of the present invention is liquid in that the obtained complex can be dissolved stably. In this case, the solution of the percutaneous absorption controlling agent in which the obtained complex is dissolved can be subjected to the preparation of the transdermal absorption composition of the present invention.
  • minoxidil When minoxidil is solid (preferably crystals), it is preferable to mix in powder in order to obtain the complex of the present invention well.
  • a method of making it into powder there is a method by dry grinding.
  • the conditions for dry pulverization are not particularly limited as long as minoxidil can be pulverized into small pieces, but it is desirable to use a pulverizer such as a mortar, a ball mill, a homogenizer, a cutter mill or a hammer mill. Further, the grinding time, the treatment pressure and the like are appropriately adjusted in accordance with the hardness of minoxidil to be ground.
  • the powder obtained by the above method is preferably further sieved to make the particle size uniform.
  • the mixing ratio of the minoxidil to the lipid-soluble compound having an aldehyde group varies depending on the type of the substance used, but is 1: 1 to 100, preferably 1:10 to 50.
  • the mixing ratio of the minoxidil, the lipid-soluble compound having the aldehyde group, and the transdermal absorption controlling agent varies depending on the types of these substances used, but 1: 1 It is -100: 1 to 100, preferably 1: 1 to 100: 10 to 50, more preferably 1:10 to 50:10 to 50.
  • the compositional ratio (molar ratio) of the minoxidil and the lipid-soluble compound having an aldehyde group constituting 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 percutaneous absorption controlling agent, particularly a monohydric or polyhydric alcohol, for example, depending on the type and amount of use of these transdermal absorption controlling agents, in the skin after percutaneous absorption.
  • the release of minoxidil from the complexes of the invention can be controlled.
  • the release of minoxidil of the present invention can be delayed by increasing the lipid solubility of the percutaneous absorption controlling agent (for example, by increasing the carbon number), and the lipid solubility of the transdermal absorption controlling agent decreases.
  • the release of minoxidil of the present invention can be promoted by (for example, reducing the carbon number).
  • the present invention also relates to a method of controlling the release of minoxidil from the complex in the skin, which comprises the steps of dissolving the complex of the present invention in a percutaneous absorption controlling agent.
  • the invention also relates to the use of a transdermal control agent for controlling the release of minoxidil from the complex of the invention in the skin.
  • the above-mentioned percutaneous absorption controlling agent 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 substrate in the field of medicines and cosmetics, particularly external preparations for skin, preferably a percutaneous absorption-promoting fat-soluble medium. It can be used.
  • the above-mentioned percutaneous absorption-promoting fat-soluble medium is not particularly limited as long as it is commonly used to promote the percutaneous absorption of active ingredients of water-soluble drugs or cosmetics in the field of medicines and cosmetics, in particular external preparations for skin.
  • limonene eg, d-limonene ((+)-limonene), in particular R-(+)-limonene
  • cyclopentasiloxane KF995: Isopropyl myristate (IPM), squalane, squalane, squalene, silicone oil, jojoba oil, almond oil, olive oil, horse oil, mineral oil and the like can be used, preferably isopropyl myristate (IPM), cyclopenta Siloxane, squalane, limonene (especially R-(+)-limonene) can be used.
  • the above-mentioned fat-soluble media may be used alone or in combination of two or more.
  • the percutaneous absorption composition of the present invention can be prepared by mixing the solution of the percutaneous absorption controlling agent in which the complex obtained above is dissolved, and the above-mentioned fat-soluble medium.
  • the complex of the present invention can exhibit good solubility in a lipid-soluble medium by using an appropriate percutaneous absorption controlling agent.
  • an appropriate percutaneous absorption controlling agent for example, when the lipid-soluble medium is squalane, geraniol or citronellol is preferable as the percutaneous absorption controlling agent, and when the lipid-soluble medium is IPM, ethanol or 1,2-hexanediol is preferable as the transdermal absorption controlling agent.
  • the fat-soluble medium is KF995
  • geraniol or citronellol is preferred as the percutaneous absorption controlling agent.
  • the percutaneously absorbable composition of the present invention may be used as it is when used as a medicine or a cosmetic, but may be used as a conventional pharmaceutical preparation, particularly as an external preparation for skin or cosmetics.
  • the pharmaceutical preparation or cosmetic is acceptable in the fields of pharmaceuticals and cosmetics such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents, and diluents as long as the effects of the present invention are not impaired. Additives 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, oils such as higher fatty acids and higher alcohols, organic acids such as citric acid and lactic acid, alkalis such as caustic soda and triethanolamine, Cationic surfactants, amphoteric surfactants, nonionic surfactants, powders, pigments, dyes, preservatives, fungicides, resins, pH adjusters, antioxidants, ultraviolet absorbers, chelating agents, thickeners, A moisturizer, alcohol, water, a perfume etc. are illustrated.
  • the present invention also relates to a method for transdermally administering the minoxidil, comprising applying to the skin the transdermally absorbable composition of the present invention.
  • the present invention also relates to the use of the transdermally absorbable composition of the present invention for transdermally administering the minoxidil.
  • the composition of the present invention may be a composition containing the minoxidil, a lipid-soluble compound having the aldehyde group, and the percutaneous absorption controlling agent, and is preferably a transdermal absorption composition.
  • the composition of the present invention may further contain the above-mentioned fat-soluble medium.
  • the present invention also relates to a method for transdermally administering the minoxidil, comprising 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 said minoxidil.
  • Reagents and Equipment The reagents used in the examples are shown below. Squalane (primary), citronellol (primary), ethanol (special grade), isopropyl myristate (IPM) (special grade), 1 ⁇ PBS, 1-dodecanal, cinnamaldehyde (special grade), (R)-(+)-limonene (primary grade) And ammonium formate (special grade) were obtained from Wako Pure Chemical Industries, Ltd. Minoxidil, vanillin, ( ⁇ )-citronellal, cis-and trans-mixture, geraniol, 4-butoxybenzaldehyde, and minoxidil were obtained from Tokyo Chemical Industry Co., Ltd.
  • the stratum corneum is hydrophobic and becomes hydrophilic as it goes deeper. That is, oil solubilization is an effective means to break through the stratum corneum barrier. Therefore, after penetrating the skin barrier using an oil solubilization solution of minoxidil, a percutaneous absorption test was performed to determine whether or not to release minoxidil in a PBS aqueous solution.
  • the percutaneously absorbable composition used in this experiment was a solution of minoxidil in a 50% aqueous ethanol solution (comparative example 2) in which ethanol (2 mL) and water (2 mL) were added to minoxidil (40 mg) as a control and citral (40 mg) to minoxidil.
  • Example 11 An oil solubilization solution (Example 10) consisting of 200 mg), ethanol (2 mL), and IPM (2 mL), and an oil solubilization solution consisting of vanillin (200 mg), ethanol (2 mL), and IPM (2 mL) in Minoxidil (40 mg) (Example 11) was prepared and their transdermal absorbability was evaluated in the following transdermal absorption test.
  • the percutaneous absorption test was performed as follows. Pig skin (Yucatan Micro Pig (manufactured by Nippon Charles River Co., Ltd.)) was used as a percutaneous absorption test.
  • a stirrer and 5 mL of PBS aqueous solution were added to the receiver phase of Franz cell, the pig skin was placed on top of the PBS aqueous solution, and water at 37 ° C. was allowed to flow through the water jacket portion of Franz cell.
  • 200 ⁇ L of a 50% aqueous solution of Minoxidil in ethanol (Comparative Example 2) or an ethanol IPM solution (Examples 10 and 11) prepared by adding citral or vanillin to Minoxidil (Examples 10 and 11) was placed on pig skin and the receiver phase was stirred. After 24 hours, a pig skin methanol extract and a receiver aqueous PBS solution were sampled, and the amount of minoxidil was quantified by LC / MS.
  • the measurement conditions of LC / MS are as follows.
  • the column temperature was set to 30 ° C. using Shodex Asahipak NH2P-40 2D (2.0 mm ID ⁇ 150 mm) for the column.
  • the eluent used 10 mM ammonium formate / acetonitrile (10/90, vol / vol), and the flow rate was set to 0.2 mL / min.
  • the detection mass number was 210. The results are shown in Table 3.
  • the amount of minoxidil in pig skin is about 22 times with citral addition (Example 10) and about 19 times with vanillin addition (Example 11) as compared to a 50% ethanol aqueous solution of Minoxidil (Comparative Example 2) In the receiver solution, it was about 51 times for citral addition (Example 10) and about 53 times for vanillin addition (Example 11). From these results, it is shown that the minoxidil oil solubilization solution added with aldehyde promotes transdermal absorbability and is promising as a transdermal drug delivery system (DDS) material.
  • DDS transdermal drug delivery system
  • the percutaneous absorption composition used in this experiment was prepared as follows. In a sample tube, 40 mg of minoxidil, 200 mg of citral and 2 mL of ethanol were added and stirred at room temperature for 1 hour. After 1 hour, 2 mL of the solvent shown in Table 4 was added to the prepared ethanol solution, and shaken with a vortex mixer to prepare the transdermal absorption compositions of Comparative Example 3 and Examples 12-14.
  • the percutaneous absorption test was performed as follows. Pig skin (Yucatan Micro Pig (manufactured by Nippon Charles River Co., Ltd.)) was used as a percutaneous absorption test. A stirrer and 5 mL of PBS aqueous solution were added to the receiver phase of Franz cell, the pig skin was placed on top of the PBS aqueous solution, and water at 37 ° C. was allowed to flow through the water jacket portion of Franz cell. Comparative Example 3 and Examples 12 to 14 (200 ⁇ L) shown in Table 4 were placed on pig skin and the receiver phase was agitated.
  • LC / MS a pig skin methanol extract and a receiver aqueous PBS solution were sampled, and the amount of minoxidil was quantified by LC / MS.
  • the measurement conditions of LC / MS are as follows. The column temperature was set to 30 ° C. using Shodex Asahipak NH 2 P-40 2D (2.0 mm ID ⁇ 150 mm) for the column. The eluent used 10 mM ammonium formate / acetonitrile (10/90, vol / vol), and the flow rate was set to 0.2 mL / min. The detection mass number was 210. The results are shown in FIGS. 1 and 2.
  • the solutions to which the fat-soluble media IPM (Example 12), KF 995 (Example 13), and limonene (Example 14) are added are Transdermal absorbability improved in pig skin and in receiver fluid. From this, it was found that the solution using a fat-soluble medium improves the percutaneous absorbability.
  • the percutaneous absorbability when changing the amount of citral used as a lipid-soluble compound having an aldehyde group was evaluated.
  • the percutaneous absorption composition used in this experiment was prepared as follows. In a sample tube, 40 mg of minoxidil, citral in an amount shown in Table 5, and 2 mL of ethanol were added and stirred at room temperature for 1 hour. After 1 hour, 2 mL of IPM was added to the prepared ethanol solution and shaken with a vortex mixer to prepare the transdermal absorption compositions of Examples 15 and 16.
  • the percutaneous absorption test was performed as follows. Pig skin (Yucatan Micro Pig (manufactured by Nippon Charles River Co., Ltd.)) was used as a percutaneous absorption test. A stirrer and 5 mL of PBS aqueous solution were added to the receiver phase of Franz cell, the pig skin was sandwiched on the PBS aqueous solution, and water of 37 ° C. was flowed in the water jacket of Franz cell. Comparative Example 4 shown in Table 5 and Examples 15 and 16 (200 ⁇ L) were placed on pig skin and the receiver phase was agitated.
  • LC / MS The measurement conditions of LC / MS are as follows.
  • the column temperature was set to 30 ° C. using Shodex Asahipak NH 2 P-40 2D (2.0 mm ID ⁇ 150 mm) for the column.
  • the eluent used 10 mM ammonium formate / acetonitrile (10/90, vol / vol), and the flow rate was set to 0.2 mL / min.
  • the detection mass number was 210. The results are shown in FIGS. 3 and 4.
  • the percutaneous absorbability when changing the amount of minoxidil was evaluated.
  • the percutaneous absorption composition used in this experiment was prepared as follows. To the sample tube, the amounts of Minoxidil, 200 mg of citral and 2 mL of ethanol shown in Table 6 were added, and stirred at room temperature for 1 hour. After 1 hour, 2 mL of IPM was added to the prepared ethanol solution, and shaken with a vortex mixer to prepare the percutaneous absorption compositions of Examples 17-19.
  • the percutaneous absorption test was performed as follows. Pig skin (Yucatan Micro Pig (manufactured by Nippon Charles River Co., Ltd.)) was used as a percutaneous absorption test. A stirrer and 5 mL of PBS aqueous solution were added to the receiver phase of Franz cell, the pig skin was sandwiched on the PBS aqueous solution, and water of 37 ° C. was flowed in the water jacket of Franz cell. Examples 17-19 (200 ⁇ L) shown in Table 6 were placed on pig skin and the receiver phase was agitated. After 24 hours, the methanol extract of pig skin and the PBS aqueous solution of the receiver phase were sampled, and the amount of minoxidil was quantified by LC / MS.
  • the measurement conditions of LC / MS are as follows.
  • the column temperature was set to 30 ° C. using Shodex Asahipak NH 2 P-40 2D (2.0 mm ID ⁇ 150 mm) for the column.
  • the eluent used 10 mM ammonium formate / acetonitrile (10/90, vol / vol), and the flow rate was set to 0.2 mL / min.
  • the detection mass number was 210. The results are shown in FIGS. 5 and 6.
  • the transdermal absorbability is also improved in proportion to the amount of minoxidil in pig skin and in the receiver fluid.
  • the tape stripping method was used to evaluate where various aldehydes used as minoxidil and a lipid-soluble compound having an aldehyde group were scattered.
  • the percutaneous absorption composition used in this experiment was prepared as follows. Into a sample tube, 40 mg of minoxidil, 200 mg of various aldehydes shown in Table 7, and 2 mL of ethanol were added, and stirred at room temperature for 1 hour. After 1 hour, 2 mL of IPM was added to the prepared ethanol solution, and shaken with a vortex mixer to prepare the transdermal absorption compositions of Examples 20 and 21.
  • the percutaneous absorption test was performed as follows. Pig skin (Yucatan Micro Pig (manufactured by Nippon Charles River Co., Ltd.)) was used as a percutaneous absorption test. A stirrer and 5 mL of PBS aqueous solution were added to the receiver phase of Franz cell, the pig skin was sandwiched on the PBS aqueous solution, and water of 37 ° C. was flowed in the water jacket of Franz cell. Comparative Example 5 shown in Table 7 and Examples 20 and 21 (200 ⁇ L) were placed on pig skin and the receiver phase was agitated. After washing the surface of pig skin with 80% ethanol after 24 hours, tape stripping was carried out from the skin surface (the tape used Nichiban Co., Ltd.
  • the eluent used 10 mM ammonium formate / acetonitrile (10/90, vol / vol), and the flow rate was set to 0.2 mL / min.
  • the detection mass number was 210.
  • the HPLC measurement conditions are as follows. The column temperature was set to 40 ° C. using GL Sciences Intersil ODS-4 5 mm (4.6 ⁇ 250 mm) for the column. Methanol / water (60/40, vol / vol) was used as an eluent and the flow rate was set to 1 mL / min.
  • the detection wavelength was 240 nm for citral and 310 nm for vanillin. The results are shown in FIGS.
  • the complex of the present invention can improve the transdermal absorbability of Minoxidil, increase the content in the skin, and release Minoxidil by water and acidic conditions inside the skin to exert medicinal effects.
  • the percutaneously absorbable composition of the present invention containing such a complex can be used for external skin preparations such as pharmaceuticals and cosmetics used for external skin therapy.
  • the release of minoxidil from the complex of the present invention inside the skin is controlled by appropriately using the percutaneous absorption controlling agent, it can be used for a drug delivery system.

Abstract

L'objet de la présente invention est de fournir un procédé permettant d'augmenter facilement les propriétés d'absorption transdermique du minoxidil sans former de promédicament par synthèse organique. La présente invention concerne : un complexe formé à partir du minoxidil et d'un composé liposoluble comprenant un groupe aldéhyde par une interaction qui peut être dissociée dans l'eau ; une composition d'absorption transdermique qui comprend le complexe, un agent de régulation de l'absorption transdermique, et un milieu liposoluble ; et un procédé de régulation de la libération du minoxidil dans la peau à partir du complexe.
PCT/JP2018/028335 2017-07-28 2018-07-27 Composition d'absorption transdermique à libération contrôlée de minoxidil WO2019022249A1 (fr)

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JP2009519940A (ja) * 2005-12-14 2009-05-21 ザーズ， インコーポレイテッド 皮膚科学的状態を処置するための組成物および方法
KR20090088275A (ko) * 2008-02-14 2009-08-19 동아제약주식회사 개선된 피부 저류 및 발모 효과를 갖는 미녹시딜 함유조성물
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