WO2020116587A1 - ポリマーミセル担体組成物及び薬物含有ポリマーミセル組成物 - Google Patents

ポリマーミセル担体組成物及び薬物含有ポリマーミセル組成物 Download PDF

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WO2020116587A1
WO2020116587A1 PCT/JP2019/047712 JP2019047712W WO2020116587A1 WO 2020116587 A1 WO2020116587 A1 WO 2020116587A1 JP 2019047712 W JP2019047712 W JP 2019047712W WO 2020116587 A1 WO2020116587 A1 WO 2020116587A1
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drug
polymer micelle
composition
skin
less
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PCT/JP2019/047712
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English (en)
French (fr)
Japanese (ja)
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健介 四本
美穂 小久保
佐季子 安岡
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ナノキャリア株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/30—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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/90—Block copolymers
    • 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
    • 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
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to a polymer micelle carrier composition applicable as a carrier or the like of a cosmetic composition, and a drug-containing polymer micelle composition in which a drug is contained in the carrier composition.
  • a block copolymer having a hydrophilic segment derived from polyethylene glycol (PEG) and a hydrophobic segment derived from a polyamino acid has a polymer micelle structure having a hydrophobic region in an inner shell portion due to hydrophobic interaction between polymers.
  • the polymer micelle technology using the block copolymer is a poorly water-soluble drug by holding a poorly water-soluble anticancer drug in the micelle in a state where it can be slowly released to the outside of the micelle by utilizing the micelle formation mechanism by hydrophobic interaction. It has been studied as a technique capable of increasing the drug retention in blood while allowing intravenous administration by solubilization (Patent Document 1: Patent No. 2777530; Patent Document 2: International Publication No.
  • the polymer micelle technology is a technology aimed at continuously delivering the contained components such as drugs to the target object (living tissue) by improving the retention property in blood, and therefore a certain amount or more is required to exert the action. Since it has a particle size of 2 and the early release of the contained components outside the micelles is suppressed, the short-term diffusion that enhances the penetration efficiency of the contained drug itself into the skin is prioritized. It has been thought that it is difficult to be compatible with the technological orientation. Further, among the penetration enhancers commonly used in external preparations for skin (for example, fatty acids such as oleic acid, monoterpenes such as urea and menthol), particularly poorly water-soluble ones are used as a solvent for polymer micelles.
  • Patent Document 4 International Publication No. 2016/137006
  • One of the main objects of the present invention is to provide a polymer micelle carrier composition and a drug-containing polymer micelle composition that can improve the efficiency of drug penetration into the skin.
  • the present inventors have included a penetration enhancer in a polymer micelle composition for percutaneous absorption by containing a drug at a concentration at which a contact angle ratio described below is a predetermined value or less. It was found that the drug has a non-linear increase in the permeability of the drug, and the present invention has been completed.
  • a drug containing an aqueous medium and a block copolymer having a hydrophilic polymer chain segment and a hydrophobic polymer chain segment that forms a polymer micelle structure in the aqueous medium is contained.
  • a carrier composition is provided.
  • a drug-containing polymer micelle composition containing the polymer micelle carrier composition and a drug.
  • a method for promoting the penetration of a drug into the skin which comprises forming an aqueous medium and a polymer micelle structure in the aqueous medium, and a hydrophilic polymer chain segment and A polymer micelle composition comprising a block copolymer having a hydrophobic polymer chain segment and a drug is used to permeate the drug into the skin, and a penetration enhancer is added to the polymer micelle composition according to Formula A above.
  • a method including the inclusion at a concentration a such that the calculated contact angle ratio is 0.82 or less.
  • a hydrophilic polymer that is a penetration enhancer for promoting the penetration of a drug into the skin and forms a polymer micelle structure in the aqueous medium.
  • a polymer micelle composition containing a block copolymer having a chain segment and a hydrophobic polymer chain segment, and the drug at a contact angle ratio calculated by the formula A of 0.82 or less contained at a concentration a An agent is provided.
  • the efficiency of drug penetration into the skin can be improved.
  • FIG. 1 is a graph showing the relationship between the contact angle ratio of an aqueous solution of a test compound and the amount of drug in the skin transdermally absorbed by the drug-containing polymer micelle composition of the external phase addition mode containing the test compound.
  • FIG. 2 is a graph showing the amount of the drug transdermally absorbed by the drug-containing polymer micelle composition of the example of the complex/integration mode containing the test compound in the skin in comparison with the comparative example.
  • the polymer micelle carrier composition of the present invention (which may be appropriately referred to as the “carrier composition of the present invention”) contains an aqueous medium and a block copolymer that forms a polymer micelle structure in the aqueous medium, and further, Contains a penetration enhancer.
  • the type of penetration enhancer is not limited, and various known penetration enhancers can be used, but of these, a surfactant is preferable.
  • the surfactant include anionic surfactants, cationic surfactants, nonionic surfactants, etc. Among them, nonionic surfactants are preferable.
  • the nonionic surfactant refers to a surfactant that does not show ionicity even when dissolved in water, in other words, a hydrophilic group that does not ionize even when dissolved in water (for example, a hydroxyl group, an ether bond, an acid amide, (Eg, ester) in the molecule.
  • nonionic surfactants include propylene glycol monofatty acid ester, ethylene glycol monofatty acid ester, glycerin monofatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methyl glucoside fatty acid ester, Alkyl polyglucoside, polyoxyethylene alkyl ether (for example, POE(30) cetyl ether), polyoxyethylene alkylphenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholesterol, polyoxyethylene cholestanol, poly Oxyethylene polyoxypropylene alkyl ether, polyoxyethylene monofatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester (for example, Tween 80, Tween 60, Tween 20), polyoxyethylene Sorbitol fatty acid ester (for example, t
  • Ionic surfactants such as anionic surfactants and cationic surfactants that have been generally used as penetration enhancers in conventional skin external preparations mainly reduce the barrier ability of the stratum corneum, and Although it promotes the permeation of the skin into the skin, it may cause skin irritation.
  • nonionic surfactants having weak skin irritation are considered to have a weak effect of lowering the barrier function of the stratum corneum, and have not been used as penetration enhancers.
  • the permeability to the skin is nonlinear.
  • the penetration enhancer according to the present invention is involved in the disintegration of the polymer micelle on the skin and the subsequent promotion of the penetration of the drug between corneocytes. Conceivable.
  • the penetration enhancer may be present by being incorporated in the polymer micelle structure formed by the block copolymer, or may be present in the aqueous medium which is the outer phase of the polymer micelle. In general, it is difficult to make a precise division because a penetration enhancer molecule can move between these modes of existence, but the mode in which the penetration enhancer molecule is mainly incorporated in the polymer micelle structure is referred to.
  • the “composite/integration mode” and the mode mainly existing in the aqueous medium are called “external phase addition mode”.
  • the carrier composition of the present invention contains a penetration enhancer at a concentration a at which the contact angle ratio calculated by the following formula A is equal to or lower than a predetermined upper limit value.
  • the contact angle ratio of the penetration enhancer mainly depends on the type and the concentration of the penetration enhancer. If the kind and the concentration of the penetration enhancer are specified, the contact angle ratio corresponding to them is calculated by the above formula A. It is possible to
  • the measurement of the “contact angle of the aqueous solution containing the penetration enhancer” and the “contact angle of water” in the formula A is performed under the conditions of a temperature of 18° C., standard atmospheric pressure (101,325 Pa), and a humidity of 40%. I shall.
  • the other measurement conditions are as follows. On the surface of a blackboard (EA440DV-16 manufactured by Esco), Strat-M (SKBM02560 (25mm Disk) manufactured by Merck Millipore), which is a pseudo-skin, is used, with its corneal side facing upward, and the surface of the film is uneven In a state where the film is pulled and placed so that it cannot be visually confirmed, the outer periphery of the film is fixed at four places with adhesive tape (Nichiban: Cellotape (registered trademark) CT405AP-18, 18 mm ⁇ 35 m), and then the composition 30 ⁇ L of each sample was dropped on the surface of the horny layer of the pseudomimetic skin, allowed to stand for 5 minutes, an image of the droplet was taken, and each sample was contacted using the image analysis software cellSens (Olympus Standard: Standard) Measure the corner.
  • EA440DV-16 manufactured by Esco
  • Strat-M SKBM02560 (25mm Disk) manufactured by Merck Milli
  • the “contact angle of the aqueous solution containing the penetration enhancer” in the above formula A usually changes due to the coexistence of other components such as polymer micelles. Therefore, the measurement of the “contact angle of the aqueous solution containing the penetration enhancer” is performed using an aqueous solution substantially containing no solute other than the penetration enhancer.
  • the upper limit value of the contact angle ratio calculated by the formula A is usually 0.82 or less, preferably 0.81 or less, more preferably 0.80 or less, still more preferably 0.79 or less, and particularly preferably 0. It is 78 or less.
  • the contact angle ratio is 0.82 or less
  • the amount in the skin as an index of skin permeability reaches 5.7 ⁇ g/g or more
  • the contact angle ratio is 0.81.
  • the skin content can be up to 6.8 ⁇ g/g or more, and for example, by setting the contact angle ratio to 0.80 or less, the skin content can be up to 8.0 ⁇ g/g or more, and for example, the contact angle ratio.
  • the contact angle ratio of 0.78 or less improves the skin content to 10.2 ⁇ g/g or more. obtain.
  • the contact angle ratio is 0.72 or less
  • the amount in the skin is 11.0 ⁇ g/g or more
  • the contact angle ratio is 0.65 or less
  • the amount in the skin is 12.0 ⁇ g/g or more and the contact angle ratio is 0.59.
  • a skin content of 13.0 ⁇ g/g or more can be achieved
  • a contact angle ratio of 0.53 or less a skin content of 14.0 ⁇ g/g or more can be achieved.
  • the hydrophilic polymer chain segment may be a polyethylene glycol-derived segment and the hydrophobic polymer chain segment may be a polyamino acid-derived segment.
  • the hydrophilic polymer chain segment and the hydrophobic polymer chain segment may have covalent bonds at the ends of the main chain.
  • the number of repeating units of the hydrophilic polymer chain segment can be set to, for example, 20 or more, for example, 45 or more, for example, 1000 or less, for example 700 or less, or for example 450 or less.
  • the molecular mass of the hydrophilic polymer chain segment can be set to, for example, 1,000 Da or more, such as 2,000 Da or more, and also 5,000 Da or more, for example, 40,000 Da or less, or, for example, 30,000 Da or less, or, for example, 20, It can be set to 000 Da or less.
  • the number of repeating units of the hydrophobic polymer chain segment can be set to, for example, 10 or more, for example, 20 or more, for example, 200 or less, for example 100 or less, or for example 60 or less.
  • the molecular mass of the hydrophobic polymer chain segment can be set to, for example, 1,000 Da or more, or for example, 2,000 Da or more, for example, 30,000 Da or less, or for example, 16,000 Da or less, or, for example, 10,000 Da or less.
  • the hydrophobic polymer chain segment in the block copolymer may have, for example, a residue of an alkyl group side chain amino acid or an aralkyl group side chain amino acid in its repeating unit.
  • alkyl group side chain amino acid include glutamic acid, aspartic acid, alanine, valine, leucine and isoleucine.
  • aralkyl group side chain amino acid include phenylalanine.
  • the ratio of the number of residues of the alkyl group side chain amino acid or the aralkyl group side chain amino acid to the total number of repeating units of the hydrophobic polymer chain segment is not limited, and is, for example, 20% or more, or, for example, 35% or more, or, for example, 40%. It can be above, for example 50% or more, also for example 80% or more, for example 95% or more, for example 99% or more, for example 100%.
  • the ratio of the molecular mass of the hydrophobic polymer chain segment to the molecular mass of 100% of the hydrophilic polymer chain segment can be set to, for example, 10% or more, or 20% or more, for example, 400% or less, or, for example, 300% or less. ..
  • Examples of the structural formula of the block copolymer include the following general formulas (I) and (II).
  • R 1 and R 3 are each independently a hydrogen atom, a C 1-6 alkoxy group, an aryloxy group, an aryl C 1-3 oxy group, a cyano group or a carboxyl group.
  • R 2 is a hydrogen atom, a saturated or unsaturated C 1 To C 29 aliphatic carbonyl group or arylcarbonyl group, R 4 represents a hydroxyl group, a saturated or unsaturated C 1 to C 30 aliphatic oxy group or an aryl-lower alkyloxy group.
  • R 5 and R 6 each independently represent a side chain of an amino acid. However, 50% or more, for example 80% or more, for example 95% or more, for example 99% or more, for example 100% of the n repeating units, for example 100% is an alkyl group side chain or aralkyl group side chain having 1 to 8 carbon atoms.
  • the amino acid side chain of R 5 and R 6 which is not an alkyl group side chain having 1 to 8 carbon atoms or an aralkyl group side chain may be a hydrophilic group having an OH group or a COOH group.
  • m is, for example, an integer of 20 or more, or 45 or more, for example, 700 or less, or 450 or less.
  • n is, for example, an integer of 10 or more, or 20 or more, for example, 200 or less, or 100 or less, or 60 or less.
  • L 1 is —NH—, —Z—NH—, —Z—, and —Z—S—Z—NH— (where Z is independently C 1 to A C 6 alkylene group)
  • L 2 is —Z—, —CO—Z—CO—, —Z—CO—Z—CO—, —NH—CO—Z—CO— and It is a linking group selected from —Z—NH—CO—Z—CO— (wherein Z is independently a C 1 -C 6 alkylene group).
  • Another example of the structural formula of the block copolymer includes the following general formulas (III) and (IV).
  • R 7 is —O— or —NH—
  • R 8 is a hydrogen atom, a phenyl group, a benzyl group, a —(CH 2 ) 4 -phenyl group, an unsubstituted or A C 4 -C 16 alkyl group substituted with an amino group or a carbonyl group, or a residue of a sterol derivative
  • R 9 is a methylene group.
  • n1 is an integer in the range of 10 to 200
  • n2 is an integer in the range of 0 to 200 (provided that when n2 is 1 or more, (COCHNH) Unit and (COR 9 CHNH) unit are present at random
  • R 8 is independently selected in each amino acid unit in one block copolymer and is present at random.
  • R 8 is a hydrogen atom, it is 75% or less of the entire R 8
  • y is 1 or 2.
  • Another example of the structural formula of the block copolymer includes the following general formulas (V) and (VI).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and L 2 are the same as those in formulas (I) and (II). They are the same, and the definitions of R 7 , R 8 , R 9 , and y are the same as those in the general formulas (III) and (IV).
  • n3 is an integer in the range of 1 to 200
  • n4 is an integer in the range of 1 to 200
  • n5 is an integer in the range of 0 to 200.
  • the unit indicated by n4 and the unit indicated by n5 exist at random.
  • the unit represented by n3, the unit represented by n4, and the unit represented by n5 may exist at random, and the block formed by the unit represented by n3 and the unit represented by n4 (In the case where n5 is 1 or more), it may exist separately in a block composed of the unit indicated by n5.
  • the n3 repeating units are alkyl groups having 1 to 8 carbon atoms. It is a side chain or an aralkyl group side chain.
  • the amino acid side chain which is not an alkyl group side chain having 1 to 8 carbon atoms or an aralkyl group side chain may be a hydrophilic group having an OH group or a COOH group.
  • the ratio of the unit indicated by n3 to the total number n3+n4+n5 of the unit indicated by n3, the unit indicated by n4, and the unit indicated by n5 is, for example, 20% or more, or, for example, 35% or more, It may also be for example 40% or more, for example 50% or more, for example 80% or more, for example 90% or more.
  • the block copolymer can be formed by, for example, purifying a polymer having a hydrophilic polymer chain and a polymer having a polyamino acid chain as they are or by purifying them so as to narrow the molecular mass distribution as needed, and then coupling them by a known method.
  • anionic living polymerization is performed using an initiator capable of imparting R 1 to form a polyethylene glycol chain, and then an amino group is introduced on the growth terminal side, and the amino group is introduced. It can also be formed by polymerizing a desired amino acid containing an alkyl side chain amino acid from the end.
  • the ratio of the penetration enhancer to the block copolymer constituting the polymer micelle in the carrier composition of the present invention is not limited as long as it satisfies the requirement of the contact angle ratio described above, but in the external phase addition mode and the composite/integration mode.
  • the mass ratio with respect to 100% of the block copolymer can be, for example, 1% or more, or 5% or more, or 10% or more, and for example, 500% or less, 300% or less, or 250% or less.
  • the carrier composition of the present invention does not inhibit the skin permeation promoting effect of the permeation enhancer, in addition to the block copolymer constituting the polymer micelle, the permeation enhancer, and the aqueous medium (usually water), and is for external use on the skin.
  • Other known components may be contained within a range not hindering the use. Examples of such components include buffers, surfactants, stabilizers, adsorbents, suspending agents, gelling agents, dyes, and fragrances.
  • the carrier composition of the present invention from the viewpoint of skin permeability of the micelle-encapsulating component, the concentration of fats and oils relative to 100% by weight of polymer micelles is, for example, 14.5% by mass or less, 12% by mass or less, 10% by mass or less, It is preferably 8% by mass or less, 5% by mass or less, 3% by mass or less, or 1% by mass or less, and from the viewpoint of avoiding skin irritation, the concentration of alcohols relative to 100% by mass of the polymer micelle is, for example, It is preferably 14.5% by mass or less, 13% by mass or less, 12% by mass or less, or 11% by mass or less.
  • oil and fat means an ester of glycerin and fatty acid called triglyceride, and examples thereof include squalane, olive oil, jojoba oil and the like.
  • alcohol refers to one in which one or more hydrogen atoms of a hydrocarbon are substituted with a hydroxy group (—OH), and examples thereof include monohydric alcohols such as ethanol and cetanol, Examples include polyhydric alcohols such as butylene glycol and glycerin.
  • the polymer micelle carrier composition of the present invention can be suitably used as a drug carrier for percutaneously absorbing a drug.
  • the drug-containing polymer micelle composition of the present invention can be suitably used as both a skin external cosmetic (including a quasi drug in the present specification) and a skin external drug.
  • skin absorption means that the drug in the external preparation for skin applied to the skin surface is transferred to the epidermis to increase the amount of the drug in the skin. It does not exclude that the part further transfers to the dermis.
  • the drug-containing polymer micelle composition of the present invention By adding various drugs to the carrier composition of the present invention, the drug-containing polymer micelle composition of the present invention (this may be appropriately referred to as “the drug-containing composition of the present invention”) is prepared.
  • the “drug-containing polymer micelle composition” can also be prepared by adding a drug when preparing the polymer micelles. That is, the drug-containing composition of the present invention contains the carrier composition of the present invention and the drug contained in the carrier composition.
  • any drug that can exert a skin improving effect and a hair-growth/hair-growth effect can be used.
  • a drug may be water-soluble or poorly water-soluble.
  • Specific examples of the drug include polyphenols (for example, resveratrol), glycyrrhetinic acid and its derivatives, indomethacin, steroids, vitamin D3 derivatives, metal complexes (for example, zinc complex, cadmium complex, copper complex, gold complex, silver complex, Etc.), kojic acid, cyclosporine, sotrastaurine, apremilast and the like.
  • the position where the polymer micelle formed by the block copolymer contains the drug includes the following three regions.
  • Hydrophilic region of polymer micelle formed by hydrophilic polymer chain segment of block copolymer (2) Hydrophobic region of polymer micelle formed by hydrophobic polymer chain segment of block copolymer, and (3) Polymer micelle Is a surface region, which is the outer surface of the hydrophilic region.
  • the drug may be present only in any one of these three regions, or may be present over two or more regions.
  • the content of the drug in the polymer micelle is, for example, a physical adsorption action depending on the polarity of the drug (in the present specification, a hydrophilic interaction or a hydrophobic interaction) as long as the micelle structure having the above-mentioned three regions is formed. .) and by electrostatic interactions, for example by adding a charge opposite to that of a charged drug to at least a portion of the block copolymer, and also to, for example, side chains and free end moieties of at least a portion of the block copolymer. It may be secured by a chemical bond (eg ester bond, amide bond, hydrazide bond, coordinate bond).
  • a chemical bond eg ester bond, amide bond, hydrazide bond, coordinate bond.
  • the carrier composition of the present invention can be formed, for example, as follows. i) preparing a forming solution with the block copolymer added to an organic solvent, ii) removing the organic solvent from the forming solution, and iii) adding water to the residue (eg, solid or paste) after the removing. Can be formed by preparing a suspension containing the block copolymer and iv) dispersing the block copolymer in the suspension.
  • the drug-containing composition of the present invention can be prepared by mixing the drug with the block copolymer at the time of forming the carrier composition, specifically, at the time of preparing the forming solution of i) above.
  • the carrier composition prepared in advance can also be formed by mixing the drug and the carrier composition.
  • the drug may be mixed in the form of a drug solution containing the drug, or may be mixed by adding it to a solution containing the carrier composition (for example, the dispersion obtained in iv)).
  • the organic solvent include acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, and methanol.
  • the forming solution can contain two or more organic solvents and may further contain a small amount of water.
  • the organic solvent may be removed from the forming solution by known methods such as evaporation, extraction or membrane separation.
  • the water added to the residue after removing the organic solvent may contain an additive such as a salt or a stabilizer.
  • Dispersion of the mixture may be carried out by a known micronization means such as ultrasonic irradiation, a high pressure emulsifying machine or an extruder.
  • the procedure for incorporating the penetration enhancer into the carrier composition or the drug-containing composition is not limited.
  • a penetration enhancer may be added after manufacture of the carrier composition or drug-containing composition.
  • the penetration enhancer and the drug may be added at the same time or sequentially in any order.
  • the carrier composition or the drug-containing composition in the external phase addition mode can be obtained.
  • a permeation enhancer may coexist during the production of the carrier composition to be integrated/complexed with the polymer micelle structure. According to this method, a carrier composition or a drug-containing composition in a composite/integrated form can be obtained.
  • the integration/complexation of the penetration enhancer can be performed, for example, by mixing the block copolymer, the penetration enhancer and the drug in an organic solvent, removing the organic solvent, and then adding water to disperse the mixture.
  • the resulting dispersion can be further subjected to a high-pressure dispersion treatment (for example, using a high-pressure disperser Nanoveider under ice bath cooling, at a pressure of 150 Mpa, 10 times).
  • the penetration enhancer when the drug is transdermally absorbed by the polymer micelle composition containing the drug, the penetration enhancer coexists in the composition at a concentration that provides the predetermined contact angle ratio.
  • a method of promoting skin penetration of such a drug as well as a penetration enhancer used in such a method.
  • a skin permeation promoting method and permeation promoting agent details such as the block copolymer constituting the polymer micelle composition, the drug, the respective components such as the permeation promoting agent, and the contact angle ratio for obtaining the desired permeation promoting action are described. , As described in detail above in relation to the carrier composition and the drug-containing composition of the present invention.
  • the contact angle ratio of each sample was calculated according to the following formula A′ when the contact angle of the sample consisting of only water (corresponding to Comparative Example A1 in Table 1 below) was set to 1. However, the third digit after the decimal point in the calculation was rounded down.
  • Block copolymer As a block copolymer, a polyethylene glycol-poly( ⁇ -benzyl-L-glutamate)-block copolymer prepared by the following procedure (hereinafter referred to as “PEG-PBLG”) (PEG molecular weight 10,000, ⁇ -benzyl The degree of polymerization of -L-glutamate 40) was used.
  • PEG-PBLG polyethylene glycol-poly( ⁇ -benzyl-L-glutamate)-block copolymer prepared by the following procedure (hereinafter referred to as “PEG-PBLG”) (PEG molecular weight 10,000, ⁇ -benzyl The degree of polymerization of -L-glutamate 40) was used.
  • BLG-NCA which is ⁇ -amino acid-N-carboxyanhydride (NCA) for polymerizing PBLG segment
  • PEG-NH 2 molecular mass 10000 Da
  • PEG-NH 2 2 to 42 after addition eq
  • the reaction solution was reprecipitated with a mixed solvent of hexane/ethyl acetate (1/1) and washed with the same solvent. After drying, PEG-PBLG powder was obtained. From the analysis by 1 H-NMR, the polymerization degree of the PEG segment in PEG-PBLG was 227, and the polymerization degree of the PBLG segment was 40.
  • the structural formula of PEG-PBLG is shown as the following formula (1).
  • composition samples As a drug, 5 mg of resveratrol (Cat.180-02773 manufactured by Wako Pure Chemical Industries, Ltd.) was weighed and dissolved in methanol. Further, 0.5 g of PEG-PBLG prepared by the above procedure was weighed and completely dissolved with acetone. After mixing both solutions, the solvent was distilled off with an evaporator. Then, 49.5 g of water was added and stirred, and a high-pressure dispersion treatment (Nano Vader, 150 Mpa, 10 pass, ice bath cooling) was performed to obtain a resveratrol-containing PEG-PBLG micelle (drug-containing polymer micelle) solution.
  • resveratrol Cat.180-02773 manufactured by Wako Pure Chemical Industries, Ltd.
  • the concentration of the test compound in each of the compositions of Examples A1 to A6 and Comparative Examples A1 to A3 thus obtained is the concentration shown in each column of Table 1 below.
  • the mass ratio of the test compound when the block copolymer (PEG-PBLG) constituting the micelles was 100% was the same as that of Example A1 and Comparative Examples.
  • A2 is 222%
  • Examples A2, A4, and A5 are 111% each
  • Example A3 is 55.5%
  • Example A6 and Comparative Example A3 are 11.1%
  • Comparative Example A1 is 0% (test compound). None).
  • compositions of Examples A1 to A6 and Comparative Examples A1 to A3 take a mode in which the test compound is mainly present in the external phase of the drug-containing polymer micelle (external phase addition mode).
  • ⁇ Measurement of skin content Frozen pig ear skin (KAC Co., Ltd.: product number BSS005) stored at ⁇ 20° C. or lower was thawed in a water bath at 32° C. After thawing, the water on the skin was removed, and the mixture was allowed to stand for 30 minutes and returned to room temperature. A site having no scratch and measuring less than 20 g/cm 2 ⁇ h was selected and cut out with a water evaporation (TEWL) measurement (Delfin: VapoMeter, Franz cell adapter for 9 mm SWL2040-09), and used as a sample.
  • TEWL water evaporation
  • This skin sample was set in an in-line cell (PermeGear's ILC07 in-line cell automatic transdermal absorption test system), and PBS was immersed in the donor and receiver sides for 1 hour to equilibrate, and then the PBS on the donor side was removed. Then, 30 ⁇ L of each of the compositions of Examples A1 to A6 and Comparative Examples A1 to A3 (drug-containing polymer micelle composition containing a test compound) was added. Six hours after the addition, the skin sample was collected, the tape strip was carried out twice to remove the sample that had not penetrated into the skin, and the remaining skin was stored at -20°C or lower.
  • a skin sample stored at -20°C or lower was thawed at room temperature. After cutting so that only the effective permeation area remained, the mass of the skin was measured, and then the skin was crushed under the following conditions.
  • a homogenizer (equipment: Polytron homogenizer PT-3500 manufactured by KINEMATICA, shaft (20 mm): PT-DA20/2EC-B193 manufactured by KINEMATICA) was used for crushing while cooling with ice without applying heat. The rotation speed during crushing was 12,000 to 13,000 rpm. The crushing time was set to 30 seconds or less in principle, but if it was not sufficiently crushed, it was cooled in ice and then re-executed for 30 seconds.
  • Example 3 Examination of amount of permeation enhancer in composite/integrated embodiment composition in skin] -Preparation of composition samples: 0.5 g of PEG-PBLG and 0.5 g of Tween 80 were weighed and acetone was added. After complete dissolution, the solution was added to 5 mg of resveratrol weighed in advance. After distilling off acetone with a centrifugal evaporator, 49 g of water was added. The dispersion was subjected to high-pressure dispersion treatment (Nano Vader, 150 Mpa, 10 pass, ice bath cooling) to obtain a composition of Example B, which is a resveratrol-containing PEG-PBLG/Tween80 composite micelle solution.
  • test compound (Tween 80) in the obtained composition of Example B was 1% by mass, and the test compound (Tween 80) when the block copolymer (PEG-PBLG) constituting the micelle was 100%. Is 100% (100 parts by weight of Tween 80 to 100 parts by weight of PEG-PBLG).
  • composition of this Example B1 takes a mode in which the test compound is mainly compounded and integrated in the polymer micelle (composite/unified mode).
  • Example B1 The amount of drug in the skin determined for the composition of Example B1 is shown in Table 2 below along with the contact angle ratio of the corresponding aqueous test compound solution.
  • the composition of Example B1 contained 1% by mass of Tween 80 as a test compound, and the contact angle ratio was 0.68 as in Example A2 of Experiment 2.
  • the contact angle ratio and the amount in the skin of Comparative Example A1 of Experiment 2 containing no test compound are also shown.
  • FIG. 2 shows the amount of drug percutaneously absorbed by the drug-containing polymer micelle composition of Example B1 in the combined/integrated form in a bar graph in comparison with Comparative Example A1.

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AMEEN, DINA ET AL.: "Transdermal delivery of dimethyl fumarate for Alzheimer's disease: Effect of penetration enhancers", INT J PHARM, vol. 529, no. 1-2, 2017, pages 465 - 473, XP085156654, DOI: 10.1016/j.ijpharm.2017.07.031 *
LAAKSO, RAIJA ET AL.: "Bi-exponential first-order release kinetics of indomethacin from tablets containing polysorbate 80", INT J PHARM, vol. 19, no. 1, 1984, pages 35 - 42, XP023844467, DOI: 10.1016/0378-5173(84)90130-3 *
SOM, ITI ET AL.: "Status of surfactants as penetration enhancers in transdermal drug delivery", J PHARM BIOALLIED SCI, vol. 4, no. 1, 2012, pages 2 - 9, XP002217325 *
YOTSUMOTO, KENSUKE ET AL.: "Skin penetration of connotation components in PEG-PBLG micelles", ABSTRACTS OF THE 138TH ANNUAL MEETING OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 25 March 2018 (2018-03-25) *

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