WO2008026776A1 - Composition transdermique, composition pharmaceutique transdermique et composition cosmétique transdermique comprenant un ingrédient actif encapsulant une micelle polymère - Google Patents

Composition transdermique, composition pharmaceutique transdermique et composition cosmétique transdermique comprenant un ingrédient actif encapsulant une micelle polymère Download PDF

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Publication number
WO2008026776A1
WO2008026776A1 PCT/JP2007/067357 JP2007067357W WO2008026776A1 WO 2008026776 A1 WO2008026776 A1 WO 2008026776A1 JP 2007067357 W JP2007067357 W JP 2007067357W WO 2008026776 A1 WO2008026776 A1 WO 2008026776A1
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group
transdermal
active ingredient
composition according
hinokitiol
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PCT/JP2007/067357
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English (en)
Japanese (ja)
Inventor
Takako Nishiya
Ichiro Nakatomi
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Nanocarrier Co., Ltd.
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Priority to JP2008532151A priority Critical patent/JP5183478B2/ja
Publication of WO2008026776A1 publication Critical patent/WO2008026776A1/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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0291—Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/676—Ascorbic acid, i.e. vitamin C
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to a transdermal composition containing polymer micelles containing an active ingredient to be absorbed transdermally, and a transdermal pharmaceutical composition and a transdermal cosmetic composition. More particularly, the present invention is useful as a nanometer-order carrier, where the transdermally absorbed active ingredient can be stably present in an aqueous medium and can enable delivery of the active ingredient to skin tissue.
  • a transdermal composition containing polymer micelles, a transdermal pharmaceutical composition containing polymer micelles containing a pharmaceutical active ingredient to be absorbed through the skin, and a polymer micelle containing cosmetic active ingredients to be absorbed through the skin A transdermal cosmetic composition is provided. Background art
  • the structure of human skin can be broadly classified into two layers: the highly lipophilic stratum corneum and the highly hydrophilic epidermis and dermis layers. Therefore, active ingredients with high lipophilicity in transdermal absorbents and the like are relatively easily distributed and diffused into the stratum corneum, but active ingredients with high hydrophilicity are hardly distributed or diffused into the stratum corneum. In addition, the percutaneous absorption of the active ingredient is lowered. However, active ingredients with very high lipophilicity are easily distributed in the stratum corneum, but are not distributed and diffused in the highly hydrophilic epidermis and dermis, and the active ingredient remains in the stratum corneum. The phenomenon "appears.
  • emulsification by a monolayer of surfactant is performed.
  • this emulsion is destroyed immediately when it is applied to the skin, so it is covered with a mono- or oligo-lamellar layer of fatty acid (Japanese Patent Application Laid-Open No. 7-165 530) or covered with a silicone surfactant.
  • Complicated work such as covering (Japanese Patent No. 3001001) is required.
  • nanoparticles and nanoparticles containing biodegradable polymers as constituents are used.
  • Nospheres are hydrolyzed in water and lose their ability to be transported as particles in a short period of time, so containers that can be stored as powders and mixed with emulsions immediately before use are required (Japanese Patent Laid-Open No. 2 0 0 3 — 2 7 5 In order to improve the dispersibility and the initial release of the active ingredient when re-dissolving the powdered nanospheres, 2 8 1 publication, JP 2 0 5 5 2 1 3 1 70 publication) Therefore, a protective colloid such as polyvinyl alcohol is required (Japanese Patent Laid-Open No. Hei 9 1 1 0 6 78).
  • transdermal absorbents containing nanometer-sized particles by emulsification containing physiologically active ingredients dispersed in a solvent require sodium dodecyl sulfate or dichloromethane during preparation, and ultimately these are called dialysis or evaporation. It must be removed by troublesome work (Japanese Patent Laid-Open No. 2000-0308 028). Disclosure of the invention
  • An object of the present invention is to stably exist in an aqueous medium in a state in which an active ingredient to be absorbed percutaneously is encapsulated, and to distribute, diffuse and accumulate the active ingredient in the skin, and the active ingredient in the skin tissue.
  • a transdermal pharmaceutical composition containing a polymer micelle containing a pharmaceutically active ingredient to be transdermally absorbed is to provide. It is to provide a transdermal cosmetic composition containing a polymer micelle containing a cosmetic active ingredient.
  • the present invention includes the following aspects.
  • the preferred embodiments include the following.
  • transdermal composition according to the aspect [1], wherein the hydrophilic region is made of polyethylene glycol.
  • the hydrophobic region comprises a polyamino acid and / or a derivative thereof.
  • transdermal composition according to embodiment [3], wherein the polyamino acid and the derivative thereof are those selected from the group consisting of dartamic acid, aspartic acid, lysine and derivatives thereof, or a mixture thereof. object.
  • R 3 each independently represents a hydrogen atom or a lower alkyl group substituted or unsubstituted by an optionally protected functional group
  • R 2 represents a hydrogen atom, saturated or unsaturated.
  • R 4 represents a hydroxyl group, a saturated or unsaturated C 3 , a C 3 Q aliphatic oxy group or an allyl lower group.
  • R 5 represents an alkyloxy group
  • R 5 represents a hydrophobic group selected from the group consisting of a hydrogen atom or a phenyl group, a C i Cs alkyl group, and a benzyl group (provided that R 5 represents each group in one block copolymer).
  • Any number of amino acid units can be selected. However, hydrogen atoms occupy 0% to 70% of the total number of amino acid units, and if present, they are present randomly.
  • 1 ⁇ 2 each independently represents a linking group
  • n is an integer from 1 0 to 2 5 0
  • X is an integer from 1 0 to 3 0
  • y is an integer from 1 or 2 To express. ]
  • R 3 each independently represents a hydrogen atom or a lower alkyl group substituted or unsubstituted by an optionally protected functional group
  • R 2 represents a hydrogen atom, saturated or unsaturated
  • C 4 to C 29 represents an aliphatic carbonyl group or an aryl carbonate group
  • R 4 represents a hydroxyl group, a saturated or unsaturated C 2, a C 3 D aliphatic oxy group or an aryl-lower alkyloxy group.
  • R 6 is phenyl group, a benzyl group, Benzoiru group, ( ⁇ ⁇ 8 alkyl and C ⁇ Cs alkyl Cal Means a hydrophobic group or hydrogen atom selected from the group consisting of boronic acid,
  • 1 ⁇ 2 represents each independently a linking group
  • n is an integer from 1 0 to 2 5 0
  • m is an integer from 1 0 to 2 5 0 0, provided that a hydrogen atom Occupies 0% to 70% of m, and if present, is present in the random.
  • the active ingredient is whitening raw material, hair growth agent, hair growth agent, hair nourishing agent, anti-inflammatory or analgesic agent, immunosuppressive agent, corticosteroid, vitamin C, vitamin A, vitamin D, vitamin E,
  • the transdermal composition according to any one of embodiments [1] to [6], which is selected from the group consisting of an antibacterial agent, an antifungal agent, an antihistamine, a polymer drug, an anticancer agent, an antibiotic, and an anesthetic.
  • the active ingredient is selected from the group consisting of hinokitiol, vitamin C derivative, bibutamin D derivative, azelaic acid, finasteride, and sildenafil citrate. Any transdermal composition.
  • transdermal composition according to any one of the embodiments [1] to [9], wherein the polymer micelle has an average particle size in the range of 30 to 2500 nm.
  • transdermal composition according to any one of the embodiments [1] to [10], wherein the polymer micelle is contained in a state dissolved or dispersed in an aqueous medium.
  • transdermal composition according to any one of the embodiments [1] to [11], wherein the active ingredient is in a concentration range of 0.0% to 7.5% (w t / w t).
  • the present invention further includes the following aspects.
  • a pharmaceutically active ingredient that can be absorbed through the skin A transdermal pharmaceutical composition comprising a polymer micelle encapsulated by a block copolymer having a region and a hydrophilic region.
  • the preferred embodiments include the following.
  • transdermal pharmaceutical composition according to embodiment [13], wherein the pharmaceutically active ingredient is in a concentration range of from 0.0 0 0 0 1% to 7.5% (w t / w t).
  • the present invention further includes the following aspects.
  • a transdermal cosmetic composition comprising a polymer micelle in which a cosmetic active ingredient to be absorbed percutaneously is encapsulated by a block copolymer having a hydrophobic region and a hydrophilic region as a whole.
  • the preferred embodiments include the following.
  • the transdermal composition containing the specific polymer micelle of the present invention, and the transdermal pharmaceutical composition and the transdermal cosmetic composition containing the same polymer micelle contain the active ingredient to be absorbed transdermally, in particular, transdermal absorption.
  • the active ingredient for pharmaceutical or cosmetic use is stably present in an aqueous medium in the state of being encapsulated in polymer micelle, and the active ingredient is distributed, diffused and accumulated in the skin, and its activity in the skin tissue. It enables the effects of the ingredients to be demonstrated.
  • Figure 1 shows the concentration dependence of the melanin synthesis inhibitory effect of micellized hinokitiol.
  • Figure 2 shows the effect of 2.5 ig Z skin model force on micellar hinokitiol and free hinokitiol on melanin synthesis in terms of hinokitiol content. .
  • FIG. 3 is a graph showing the effect on melanin synthesis when micellized hinokitiol and free hinokitiol in 5 ⁇ g / skin model cup are used in terms of the amount of hinokitiol.
  • FIG. 4 is a graph showing the effect on the melanin synthesis when using a micellar hinokitiol and a free hinokitiol in a 10 ag Z skin model force in terms of the amount of hinokitiol.
  • Figure 5 shows the effect on the melanin synthesis when using empty micelles.
  • the present invention provides a transdermal composition containing polymer micelles in which an active ingredient to be absorbed through the skin is encapsulated by a block copolymer having a hydrophobic region and a hydrophilic region as a whole.
  • the polymer micelle in the transdermal composition according to the present invention contains an active ingredient selected from the group consisting of hinokitiol, vitamin C derivative, vitamin D derivative, azelaic acid, finasteride, and sildenafil citrate.
  • it can be stably present in an aqueous medium, absorbed through the skin, and exert the effect of the active ingredient in the skin tissue.
  • the polymer that can be used to form the active ingredient-encapsulating polymer micelle in the transdermal composition of the present invention is a block copolymer composed of a hydrophilic region and a hydrophobic region as a whole. Any hydrophilic region and any hydrophobic region may be included as long as the object of the invention is met. “Entirely hydrophobic region” means that the entire region has the hydrophobicity necessary to form the core of the polymer micelle made of block copolymer, and the hydrophobicity exists within the region. It means a region caused by the hydrophobic group, and a group having a positive or negative charge can also exist in the region. Although it is not particularly limited as long as the block copolymer can form micelles, the hydrophobic group in the region is 30% to 100%, preferably 50% to: L 0%, more preferably 5% to 100%, more preferably 60% to 100%.
  • block copolymers useful in polymer micelles in the transdermal composition of the present invention include the following.
  • the hydrophilic region includes poly (ethylene glycol)
  • polysaccharides poly (vinyl pyrrolidone), poly (vinyl alcohol), poly (acrylamide), poly (acrylic acid), poly (methacrylamide), poly (methacrylic acid)
  • examples include regions derived from poly (methacrylic acid ester), poly (acrylic acid ester), polyamino acid or derivatives thereof.
  • polysaccharides include starch, dextran, fructan, and galactan.
  • the poly (ethylene glycol) segment is preferably provided with various functional groups at one end, and those having a controlled region size can be easily used.
  • the hydrophobic region as a whole includes poly [(meth) alkyl acrylate-co- (meth) acrylic acid], poly (aspartic acid) and / or derivatives thereof, poly (dal (Minic acid) and / or its derivatives, such as poly (/ 3 -benzyl spartate), poly (j6 -benzil spartate co Acid), poly (/ 3-alkyl spartate-cospartic acid), poly (i6-alyl spartate-co-spartic acid), poly (/ 3- saralkyl spartate tokoa) Sparagic acid), Poly (T monobenzyl glutamate), Poly (T monobenzyl glutamate-coglutamate), Poly (alkylalkyl tartrate), Poly (Faralkyl) Dartametochodal acid), poly () 6-alkylaspartamide-choaspartic acid), poly (faralkyldaltamido-co-glutamate) and poly (lysine
  • the block copolymer that can be used in the polymer micelle in the transdermal composition of the present invention comprises the above hydrophilic region and a generally hydrophobic region, and is composed of an aqueous medium (for example, water or buffered water or A water-miscible solvent, an aqueous solution containing methanol, polyethylene glycol, saccharides, etc.) can form all polymer micelles that can form polymer micelles.
  • the hydrophilic region is made of poly (ethylene glycol), and the entire hydrophobic region is made of the above poly (amino acid) and / or a derivative thereof.
  • such a poly (amino acid derivative) region is known per se, for example using poly (/ 3-benzyl-L-aspartic acid) or poly (arbenzyl mono-L monoglutamic acid) as is or
  • the benzyl group can be deprotected by hydrolysis and then exchanged with the corresponding alcohol or amine ester or amide to form a hydrophobic region with a forceful loxyl group in the side chain in the desired proportion.
  • Aspartic acid and glutamic acid may be of any optically active type or a mixture thereof.
  • Poly ( ; 6-Benzylue L-aspartic acid) is known to undergo ⁇ -transfer ilL by hydrolysis, but it goes without saying that the po-U (amino acid derivative) that caused the i8 rearrangement is also included in the present invention.
  • the above hydrophilic region and the hydrophobic region as a whole are connected via a linking group known per se, for example, an ester bond, an amide bond, ii, no, an ash mono ash bond, an ether bond, etc. Can be done.
  • the polymer cells in the transdermal composition of the present invention are easy to manufacture.
  • R 3 each independently represents a hydrogen atom or a substituted or unsubstituted lower alkyl group substituted with an optionally protected functional group
  • R 2 represents a hydrogen atom, saturated or unsaturated C , ⁇ C 2 9 aliphatic group or aryl group
  • R 4 represents a hydroxyl group, a saturated or unsaturated C, ⁇ C 3 Q aliphatic group or an aryl single lower alkyloxy group
  • R 5 represents a hydrogen atom or a phenyl group
  • ( ⁇ to (: 8 represents a hydrophobic group selected from the group consisting of an alkyl group and a benzyl group.
  • R 5 represents each group in one block copolymer
  • the hydrogen atom is 0% to 70%, preferably 0% to 50%, more preferably 0% to 45% with respect to the total number of amino acid units. More preferably, it occupies 0% to 40%, and when present, it exists randomly.
  • L 2 each independently represent a linking group, n is an integer from 1 0 to 25 50, X is an integer from 1 0 to 3 0 0, and y is an integer from 1 or 2 Represents.
  • the functional group that may be protected include a hydroxyl group, an acetal, a ketal, an aldehyde, and a sugar residue.
  • R 3 represents a lower alkyl group substituted with a functional group which may be protected, for example, W09 6 Z 3 3 2 3 3, W09 6/3 2 43 4, WO 9 7
  • Lower alkyl means a linear or branched alkyl group having, for example, 7 or less carbon atoms, preferably 4 or less carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group. Group etc. are included.
  • block copolymer according to the polymer micelle in the transdermal composition of the present invention may have the following formula (III) or (IV).
  • R, R 2 , R 3 , R or L or L 2 or n has the same meaning as the above formula (I) or (II), and m is an integer from 10 to 2500
  • R 6 represents a hydrophobic group or a hydrogen atom selected from the group consisting of a phenyl group, a benzyl group, a benzoyl group, a C 6 to C 8 alkyl group and a C 6 to C 8 alkyl carboxylic acid.
  • hydrogen atoms occupy 0% to 70% of m, preferably 0% to 50%, more preferably 0% to 45%, more preferably 0% to 40%, and If present, it exists randomly.
  • the linking group in the above formulas (I) to (IV) is not limited because it can be changed mainly by the production method of the block copolymer, but specific examples include: -NH-, — 0-,- 0 - Z - NH-, one CH 2 -, one 0- Z- S- Z- and - ⁇ CO- Z- NH - (wherein, Z is C 1 ⁇ C 4 alkylene group independently.)
  • L 2 is selected from the group consisting of: —CO—, one OCO—Z—CO— and A group selected from the group consisting of NHCO—Z—CO— (wherein Z is a C 4 , to a C 4 alkylene group ′).
  • Preferred active ingredients absorbed percutaneously in the polymer micelle in the transdermal composition of the present invention are whitening raw materials, hair growth agents, hair growth agents, hair nourishing agents, anti-inflammatory or analgesic agents, immunosuppressive agents, adrenal cortex Hormones, vitamins C, vitamins A, vitamins D, vitamins E, antibacterial agents, antifungal agents, antibiotics, antiviral agents, antihistamines, polymer drugs, anticancer agents, anesthetics.
  • Examples of whitening materials include hinokitiol and azelaic acid, and examples of hair growth agents include finasteride.
  • Examples of anti-inflammatory or analgesic agents include lidocaine, indomethacin, fenyuenyl, ketoprofen and the like.
  • Examples of immunosuppressants include evening chlorimus hydrate, cyclosporine and the like.
  • Examples of corticosteroids include diflucorzurone valerate, methazone valerate, dexamethasone valerate, and the like.
  • Examples of vitamin D include vitamin D derivatives such as evening calcitol, calcipotriol, and ergocalciferol.
  • Examples of vitamin A include vitamin A derivatives such as retinoic acid and tocopherol.
  • vitamin C examples include vitamin C derivatives.
  • vitamin E examples include vitamin E derivatives.
  • antifungal agents include oxyconazol nitrate, lilanaphthalate, bifonazole, amorolfine hydrochloride, and clotrimazole.
  • antihistamines include fexofenadine hydrochloride, oral latazine, azelastine hydrochloride, and oxatomide.
  • anticancer agents include 5-FU and bleomycin sulfate.
  • polymer drugs include nucleic acids (such as decoy oligos, antisense oligos, and siRNAs) and proteins (such as site force-in and antibodies).
  • hinokitiol As the active ingredient in the polymer micelle in the transdermal composition of the present invention, hinokitiol, vitamin C derivative, vitamin D derivative, azelaic acid, finasteride or sildenafil kenate are preferred, and hinokitiol is particularly preferred.
  • the particle size of the polymer micelle in the transdermal composition of the present invention is not particularly limited depending on the use, but is preferably 30 to 2500 nm when the effect of the active ingredient is exerted on the skin. Preferably it is 50-200 nm, Most preferably, it is 50-: L5Onm. When it is desired to transfer the compound from the capillary blood into the blood, the size is preferably smaller than 50 nm, more preferably 35 to 45 nm.
  • the amount of the active ingredient is not particularly limited, but is generally 0.1 to 50% by weight, preferably 1 based on the total weight of the block copolymer and the active ingredient. -30% by weight, more preferably 5 to 25% by weight.
  • Such a transdermal composition of the present invention preferably contains the polymer micelle dissolved or dispersed in an aqueous medium.
  • the aqueous medium may be added with saline, aqueous buffer, a small amount of lower alcohols, antioxidants, preservatives, etc. as necessary.
  • the dosage form of the skin composition is not particularly limited as long as the polymer micelle does not disintegrate, and examples thereof include an ointment, a coating agent, a spray, and the like, and a lotion is particularly preferable.
  • other components usually used as a transdermal absorbent may also be contained.
  • the transdermal composition contains the polymer micelles of the present invention preferably in a concentration range of 0.0 1% to 15% (wt / wt). Further, in the transdermal composition, preferably 0.0 0.001% to 7.5% (wt / w t), more preferably the active ingredient is contained in a concentration range of 0.0 0 0 0 5% to 3% (wt / wt).
  • the method for producing the polymer micelle in the transdermal composition of the present invention is not particularly limited. For example, after a block copolymer and a hydrophobic active component are dispersed and dissolved in a volatile organic solvent to form a solution, the organic solvent is then added. It is also possible to use a so-called dry-solid method in which an active ingredient-encapsulating polymer micelle having a controlled particle size is produced by mixing the remaining residue together with water and stirring for a sufficient time at a predetermined temperature. Japanese Patent Laid-Open No. 2 0 03-3-4 2 1 6 8).
  • a water-soluble medium containing a block copolymer and a water-immiscible organic solvent containing an active ingredient are mixed, and the organic solvent is volatilized while stirring to produce an active ingredient-containing polymer micelle.
  • a dispersion method may be used (see Japanese Patent Application Laid-Open No. 2000-306.12).
  • transdermal pharmaceutical composition comprising a polymer micelle encapsulating a pharmaceutically active ingredient to be absorbed through the skin with a block copolymer having a hydrophobic region and a hydrophilic region as a whole.
  • the polymer micelle is contained in a dissolved or dispersed state in an aqueous medium.
  • a saline solution in addition to pure water, a saline solution, an aqueous buffer solution, a small amount of a lower alcohol, an antioxidant, a preservative and the like may be added as necessary.
  • the dosage form of such a transdermal pharmaceutical composition is not particularly limited as long as the polymer micelle does not disintegrate, and examples thereof include an ointment, a coating agent, a spray, and the like, and lotion is particularly preferable.
  • other components usually used as a transdermal absorbent may also be contained.
  • the polymer micelle of the present invention is preferably contained in a concentration range of 0.01% to 15% (wt / wt). Further, in the transdermal pharmaceutical composition, preferably from 0.0.000% to 7.5%.
  • the active pharmaceutical ingredient is contained in a concentration range of (wt / wt), more preferably in the concentration range of 0.0 0 0 0 5% to 3% (wt / wt).
  • Specific examples of the active pharmaceutical ingredients include the active pharmaceutical ingredients as described above, and anticancer agents, antibacterial agents, antiviral agents, antibiotics, anesthetics, analgesics and the like are suitable.
  • azelaic acid, finasteride, vitamin D derivative, and sildenafil citrate are also suitable.
  • a transdermal cosmetic product comprising polymer micelles in which a cosmetic active ingredient to be absorbed through the skin is encapsulated by a block copolymer having a hydrophobic region and a hydrophilic region as a whole.
  • the polymer micelle is preferably contained in a state dissolved or dispersed in an aqueous medium.
  • aqueous medium In addition to pure water, saline, aqueous buffer, a small amount of lower alcohols, antioxidants, preservatives, humectants and the like can be added to the aqueous medium as needed.
  • transdermal cosmetic composition is not particularly limited as long as the polymer micelle does not disintegrate, and examples thereof include an ointment, a coating agent, a spray, and the like, and a lotion is particularly preferable.
  • other components usually used as a transdermal cosmetic can also be contained.
  • the polymer micelle of the present invention is preferably contained in a concentration range of 0.01% to 15% (wt / wt). Further, in the transdermal cosmetic composition, it is preferably from 0.000% to 7.5% (wt / wt), more preferably from 0.05% to 3% (wt / wt). ) Cosmetic active ingredients are included in the concentration range.
  • the active ingredient for cosmetic use include the active ingredients as described above, and preferable examples thereof include whitening hinokitiol, vitamin C derivatives and the like, and hinokitiol is particularly preferred.
  • the present invention will be described specifically by showing comparative examples and examples. 'In the following, polyethylene glycol-poly (/ 3-benzyl-l-aspartic acid) block copolymer is abbreviated as PEG-PBLA.
  • the average molecular weight of the polyethylene glycol (PEG) chain of the block copolymer is 12,00, the degree of polymerization of the polyamino acid is 40, and the introduction rate of the benzyl group in the polyamino acid side chain is 50%, After the copolymer, it is written as 1 2— 4 0 — 5 0.
  • Example 1 Hinocthiol micellization with block copolymer
  • block copolymer PEG—PBLA— 1 2-5 0-60 (with PEG molecular weight of 1, 2, 0 0 0, aspartic acid polymerization degree of 50, benzylation)
  • a glycol (PEG) -poly (j8-benjirou L-aspartic acid) block copolymer was used.
  • Intake rate of hinokitiol in the obtained polymer micelle (ratio of active ingredient incorporated into polymer micelle relative to starting amount, wt / wt%)
  • Encapsulation rate (amount of active ingredient incorporated into polymer micelle relative to polymer starting amount) %, Wt Zw t%) and polymer micelle size are shown in Table 1 below.
  • the active ingredient uptake rate was determined from the molar absorption coefficient of the amount of active ingredient not taken in, and the value obtained by subtracting this value from the starting amount of the active ingredient was obtained as the amount of active ingredient taken into the polymer micelle.
  • the particle size of the polymer micelle can be measured by a method well known to those skilled in the art. For example, using a dynamic light scattering photometer (DLS-7000DH, Otsuka Electronics Co., Ltd., Osaka Prefecture) It can be carried out.
  • the amount of hinokitiol used as a starting material is 3 mg (0.3 mL ethanol solution), and PEG—PB LA—1 2 0—5 0—6 0 or PEG—PB LA—5—2 0—1 0 0
  • the starting amount is 3 mg (3 mg Z3 mg of polymer hinokitiol) or 1.5 mg (1.5 mg / 3 mg of polymer hinokitiol)
  • the hinokitiol is micellized and the encapsulation rate is increased.
  • the size has grown.
  • the results are shown in Table 1. Micellarization of hinokitiol
  • micellized hinokitiol was examined according to the above.
  • micellar hinokitiols prepared in Example 1 were diluted with ultrapure water so that the amount of hinokitiol was 15 O z gZmL, and the 10 0 0 was diluted with EPI 1 2 0 0 It was added directly to the inside of the skin model cup, and the amount of hinokitiol present on the skin surface, in the skin tissue, and in the culture solution over time was quantified using the absorbance at 324 nm.
  • the polymer micelle solution in the cup is collected, and a washing solution for washing the skin surface with ultrapure water is added to make the total volume 1 mL, and the micellar hinoki before adding it to the EPI-200 skin model cup
  • the percentage of hinokitiol remaining on the skin surface was determined by comparison with the absorption intensity of oar at 3 24 nm.
  • the EP 1 — 2 0 0 skin model cup is soaked in 2 mL of DMS O for 12 h, and the extracted hinokitiol The amount of quinol thiol present in the skin tissue was measured.
  • the culture solution was directly measured, and the amount of hinokitiol contained in this was used as the amount of hinokitiol that came out in the culture solution.
  • Hinokitiol in the skin tissue and in the culture solution was quantified using the difference in absorbance at 3 24 nm from a control sample treated in the same manner using 100 L of ultrapure water as a control.
  • Table 2 shows the results of the skin permeability experiment conducted on the micellar hinokitiol used in Example 1. Distribution of hinokitiol in skin model in skin permeability assembly.
  • micellized hinokitiol After adding micellized hinokitiol directly into the skin model cup
  • micellar hinokitiol Comparing the distribution of hinokitiol in 12 hours and 40 hours, the amount of hinokitiol on the skin surface decreases with time, and the amount of hinokitiol in the culture medium increases with time. This suggests that micellar hinokitiol slowly permeates the skin, stays stable in the tissue, and gradually releases hinokitiol.
  • Example 3 Inhibition effect of micellar hinokitiol on melanin synthesis by block copolymer (in vitro)
  • micellar hinokitiol on melanin synthesis was examined according to the instructions.
  • micellar hinokitiol prepared in the same manner as in Example 1 was converted to the amount of hinokitiol with ultrapure water, and the amounts of 25 g / m L, 50 ugm L and 100 ig / Dilute to 1 mL and add 1 0 OL directly to the inside of the ME L- 3 0 0- B skin model cup to quantify the amount of melanin produced after 1 week, 2 weeks, and 3 weeks .
  • ME L— 3 0 0 — B skin model cup exposed to micellar hinokitiol for a certain period of time is stored at minus 20 ° C, thawed after all experiments, washed with ultrapure water, and skin tissue removed from the cup The tissue was degraded by incubation for 12 hours at 60 ° C. in 2550 L of Solvable TM (Packard Bioscience Co., Massachusetts, USA). After cooling the sample to room temperature, the tissue degradation product was removed by centrifugation (5, 20 Xg, 5 minutes, room temperature), and the amount of melanin in the supernatant was quantified using the absorbance at 490 nm.
  • a melanin calibration curve was prepared using a solution containing 0 g to 2 50 g of melanin (Sigma, Michigan, USA) in 25 50/2 L Solvable (trademark). 1 mg No mL block copolymer PEG— PB LA— 1 2-5 0— 60
  • micellar hinokitiol stays in the tissue, and hinokitiol released from polymer micelles acts on melanocytes, and the action of j6-fibroblast growth factor and melanocyte st imul at ion hormone contained in the medium. It is considered that melanin synthesis is suppressed.
  • Example 3 The effect of free hinokitiol on melanin synthesis was examined by the same method as described above. As shown in Fig. 2 to Fig. 4, the melanin synthesis inhibitory effect increases as the free hinokitiol concentration increases, but at any concentration. Micelleated hinokitiol shows a higher inhibitory effect on melanin synthesis. As is apparent from the results of Comparative Example 1, free hinokitiol permeates quickly into the culture solution without staying in the tissue, and thus cannot act on melanocytes in the tissue.
  • Example 3 Using the same micelles as in Comparative Example 3, the skin toxicity of the empty micelles was examined in the same manner as in Example 4. It is judged that there is no cytotoxicity of empty micelles (see Table 3).

Abstract

La présente invention concerne une composition transdermique comprenant une micelle de polymère encapsulant un ingrédient actif absorbé par voie transdermique avec un copolymère bloc présentant une région hydrophobe et une région hydrophile formant un tout. La présente invention concerne également une composition pharmaceutique transdermique comprenant une micelle polymère contenant un ingrédient actif pharmaceutiquement absorbé par voie transdermique. L'invention porte en outre sur une composition cosmétique transdermique comprenant une micelle polymère contenant un ingrédient cosmétiquement actif absorbé par voie transdermique.
PCT/JP2007/067357 2006-08-31 2007-08-30 Composition transdermique, composition pharmaceutique transdermique et composition cosmétique transdermique comprenant un ingrédient actif encapsulant une micelle polymère WO2008026776A1 (fr)

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JP2009275007A (ja) * 2008-05-16 2009-11-26 Ichimaru Pharcos Co Ltd ポリマーミセルからの疎水性物質の徐放方法
US9193672B2 (en) 2007-01-15 2015-11-24 Chongxi Yu High penetration prodrug compositions of retinoids and retinoid-related compounds
US9248109B2 (en) 2009-05-08 2016-02-02 Chongxi Yu High penetration prodrug compositions of peptides and peptide-related compounds
US9371284B2 (en) 2007-06-04 2016-06-21 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
US9376381B2 (en) 2006-11-08 2016-06-28 Techfields Pharma Co., Ltd. High penetration prodrug compositions of peptides and peptide-related compounds
WO2016137006A1 (fr) * 2015-02-27 2016-09-01 ナノキャリア株式会社 Composition support de micelle polymère et composition de micelle polymère
WO2016137007A1 (fr) * 2015-02-27 2016-09-01 ナノキャリア株式会社 Agent de traitement polymère
US9567329B2 (en) 2007-01-31 2017-02-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions of 1H-imidazo[4,5-c]quinolin-4-amines and 1H-imidazo[4,5-c]quinolin-4-amine-related compounds and uses thereof
JP2017036327A (ja) * 2008-12-04 2017-02-16 チョンシー ユー 高透過性組成物およびその用途
US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US9969751B2 (en) 2009-06-10 2018-05-15 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
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US11135153B2 (en) 2006-07-09 2021-10-05 Techfields Pharma Co., Ltd. High penetration composition and uses thereof
US11555014B2 (en) 2006-10-02 2023-01-17 Techfields Pharma Co., Ltd. High penetration prodrug compositions of prostaglandins and related compounds
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US9872846B2 (en) 2006-07-09 2018-01-23 Techfields Pharma Co., Ltd. High penetration compositions and uses thereof
US11555014B2 (en) 2006-10-02 2023-01-17 Techfields Pharma Co., Ltd. High penetration prodrug compositions of prostaglandins and related compounds
US9376381B2 (en) 2006-11-08 2016-06-28 Techfields Pharma Co., Ltd. High penetration prodrug compositions of peptides and peptide-related compounds
US10233197B2 (en) 2006-12-10 2019-03-19 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
US9193672B2 (en) 2007-01-15 2015-11-24 Chongxi Yu High penetration prodrug compositions of retinoids and retinoid-related compounds
US11786497B2 (en) 2007-01-15 2023-10-17 Techfields Pharma Co., Ltd. High penetration prodrug compositions of retinoids and retinoids-related compounds
US9567329B2 (en) 2007-01-31 2017-02-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions of 1H-imidazo[4,5-c]quinolin-4-amines and 1H-imidazo[4,5-c]quinolin-4-amine-related compounds and uses thereof
US9371284B2 (en) 2007-06-04 2016-06-21 Techfields Pharma Co., Ltd. Pro-drugs of NSAIAS with very high skin and membranes penetration rates and their new medicinal uses
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JP2009275007A (ja) * 2008-05-16 2009-11-26 Ichimaru Pharcos Co Ltd ポリマーミセルからの疎水性物質の徐放方法
JP2017036327A (ja) * 2008-12-04 2017-02-16 チョンシー ユー 高透過性組成物およびその用途
US11541029B2 (en) 2008-12-04 2023-01-03 Techfields Pharma Co., Ltd. High penetration compositions and their applications
US9248109B2 (en) 2009-05-08 2016-02-02 Chongxi Yu High penetration prodrug compositions of peptides and peptide-related compounds
US9969751B2 (en) 2009-06-10 2018-05-15 Techfields Pharma Co., Ltd. High penetration prodrug compositions of antimicrobials and antimicrobial-related compounds
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US11813256B2 (en) 2012-05-16 2023-11-14 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical compositon thereof for treatment of pulmonary conditions
US11857545B2 (en) 2012-05-16 2024-01-02 Techfields Pharma Co., Ltd. High penetration prodrug compositions and pharmaceutical composition thereof for treatment of pulmonary conditions
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JPWO2016137006A1 (ja) * 2015-02-27 2017-04-27 ナノキャリア株式会社 ポリマーミセル担体組成物およびポリマーミセル組成物
JPWO2016137007A1 (ja) * 2015-02-27 2017-04-27 ナノキャリア株式会社 高分子処理剤
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