WO2008047857A1 - METHOD OF PRODUCING COMPOSITION COMPRISING HARDLY WATER-SOLUBLE COMPOUND ENCLOSED IN HYDROPHILIC MATRIX AND PREPARATION FOR EXTERNAL USE COMPRISING ANTICANCER AGENT OR DRUG HAVING OCTANOL/WATER PARTITION COEFFICIENT (Log P) OF -3.0 OR MORE BUT NOT MORE THAN 3.0 ENCLOSED IN HYDROPHILIC BASE - Google Patents

METHOD OF PRODUCING COMPOSITION COMPRISING HARDLY WATER-SOLUBLE COMPOUND ENCLOSED IN HYDROPHILIC MATRIX AND PREPARATION FOR EXTERNAL USE COMPRISING ANTICANCER AGENT OR DRUG HAVING OCTANOL/WATER PARTITION COEFFICIENT (Log P) OF -3.0 OR MORE BUT NOT MORE THAN 3.0 ENCLOSED IN HYDROPHILIC BASE Download PDF

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Publication number
WO2008047857A1
WO2008047857A1 PCT/JP2007/070331 JP2007070331W WO2008047857A1 WO 2008047857 A1 WO2008047857 A1 WO 2008047857A1 JP 2007070331 W JP2007070331 W JP 2007070331W WO 2008047857 A1 WO2008047857 A1 WO 2008047857A1
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Prior art keywords
anticancer agent
protein
drug
agent
gelatin
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PCT/JP2007/070331
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French (fr)
Japanese (ja)
Inventor
Shouji Ooya
Tetsuo Hiratou
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Fujifilm Corporation
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Publication of WO2008047857A1 publication Critical patent/WO2008047857A1/en

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/539—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more oxygen atoms in the same ring, e.g. dioxazines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the present invention relates to a method for producing a hydrophilic matrix in which a poorly water-soluble compound is encapsulated at a high concentration. Furthermore, the present invention relates to an external preparation in which an anticancer agent or a drug having an octanol / water partition coefficient (LogP) of ⁇ 3.0 or more and 3.0 or less is encapsulated in a hydrophilic substrate.
  • an anticancer agent or a drug having an octanol / water partition coefficient (LogP) of ⁇ 3.0 or more and 3.0 or less is encapsulated in a hydrophilic substrate.
  • Biopolymers which are macromolecules derived from living organisms, have unique functions, and are therefore used as scaffold materials for tissue construction and as sustained release carriers for drugs.
  • the biopolymer is used as a sustained-release carrier for a drug
  • the biopolymer since the biopolymer is generally hydrophilic, it is used as a structure enclosing a water-soluble drug such as a growth factor of 1 or more. Effectiveness has been reported (Patent No. 3639593, Patent No. 3771510). It is desirable that the drug sustained-release carrier can hold various drugs ranging from water-soluble to poorly water-soluble.
  • the protein is insoluble in many organic solvents, it is difficult to immerse the drug in the hydrophilic matrix.
  • the drug may react with the cross-linking agent and cannot be stably encapsulated inside the matrix. .
  • HFIP 1,1,1,3,3,3-Hexafluoro-2-Propanol
  • TFE trifluoroethanol
  • Japanese translation of PCT publication No. 2003-500368 discloses a low-solubility therapeutic drug, one or more tocols, one or more co-solvents, as an emulsion vehicle for drugs with poor solubility.
  • a pharmaceutical composition comprising more than one surfactant is described.
  • Examples of external preparations for skin encapsulating an anticancer agent include, for example, JP-A 61-204125, 5-Fluorouracil (5-FU), 1-dedecylazacycloheptan-2-one, and An anti-cancer agent-containing ointment excellent in skin permeability characterized by containing Carbopol is described.
  • the topical skin preparation encapsulating an anticancer drug has hardly been promoted.
  • Examples of external preparations on the market include a 5-FU ointment (Kyowa Hakko) in which 5-fluorouracil (5-FU) is encapsulated in a base material mainly composed of petrolatum. In other words, the base material for external preparations containing anticancer agents is hardly devised.
  • the transdermal absorption efficiency of a drug is the molecular weight of the drug, the solubility of the drug in the base material, It is determined by the distribution coefficient. Therefore, the combination of drug and substrate is very important when considering the transdermal administration of drugs.
  • the examination of the transdermal absorption efficiency of the hydrophilicity / hydrophobicity of the drug and the nature of the substrate has been conducted to the extent that the investigation of the substrate for each drug has been conducted independently. Les.
  • transdermal absorption enhancer having a property of making the stratum corneum sparse
  • Ethanol and surfactants are known as typical components used in the technique, and the components are used in various transdermal preparations.
  • Transdermal absorption efficiency is not necessarily high, but water is also known to increase transdermal absorption efficiency. For example, it is also known that the percutaneous absorption efficiency of drugs after increasing the skin with warm water increases. Therefore, water is an important candidate component as a component that causes little skin damage and enhances the transdermal absorption efficiency of the drug.
  • biopolymers generally have a high affinity for water and biological tissues.
  • materials that are familiar to the skin surface such as gelatin. Therefore, it can be expected that the transdermal absorption efficiency is higher than that of an external preparation using the same level of hydrophilic base material containing the same concentration of drug with a high effective contact area at the interface between the skin and the base material.
  • biopolymers as a transdermal absorption preparation.
  • JP 2002-255931 A discloses a solid preparation of at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the field of food and animal feed or for use in pharmaceuticals and cosmetics.
  • A) a step of dissolving or dispersing at least one of the above active compounds in an aqueous molecular dispersion or aqueous colloidal dispersion of a proteinaceous protective colloid; and b) together with the active compound
  • a method comprising the step of coagulating and precipitating the proteinaceous protective colloid, and c) separating the agglomerated solid from water and any additional solvent used and subsequently converting it to a dry powder. Is described.
  • Patent Document 1 Japanese Patent No. 3639593
  • Patent Document 2 Japanese Patent No. 3771510
  • Patent Document 3 Japanese Translation of Special Publication 2002-531182
  • Patent Document 4 Japanese Translation of Special Publication 2004-532802
  • Patent Document 5 Japanese Patent Application Laid-Open No. 2004-321484
  • Patent Document 6 Special Table 2003-500368
  • Patent Document 7 JP-A-61-204125
  • Patent Document 8 JP 2002-255931 A
  • an object of the present invention is to provide a method for producing a composition in which a slightly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state. Further, the present invention provides an external preparation containing an anticancer agent, and a combination of a drug that dissolves in both water and an organic solvent and a base material made of a biopolymer containing a lot of water, which is almost unstudied in the prior art.
  • the topic to be solved was the preparation of a topical preparation using
  • an organic fluorine compound is used as an immersion solvent for a poorly water-soluble compound, whereby a highly concentrated poorly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state, which is a problem of the prior art.
  • a composition was prepared. That is, the hydrophilic matrix can be molded into an arbitrary shape in advance, and decomposition or modification of the poorly water-soluble compound during the molding process can be avoided.
  • the present inventors use an anticancer agent by using a hydrophilic substrate such as a protein as a substrate for encapsulating the anticancer agent, as opposed to a hydrophobic substrate that is an existing substrate.
  • the inventors have found that it is possible to stably encapsulate and achieve a desired therapeutic effect, and the present invention has been completed.
  • a hydrophilic substrate opposite to the existing hydrophobic substrate is used, and a drug that dissolves in both water and organic solvent is encapsulated in a substrate made of a hydrophilic biopolymer.
  • the present inventors have found that an external preparation with a high transdermal absorption efficiency with a high encapsulated amount of can be prepared, and the present invention has been completed.
  • the method comprises immersing a hydrophilic matrix in an organic fluorine compound containing a hardly water-soluble compound and encapsulating the hardly water-soluble compound in a hydrophilic matrix.
  • a method for producing a composition in which a water-soluble compound is encapsulated in a hydrophilic matrix is provided.
  • the hydrophilic matrix is dried after immersing the hydrophilic matrix in the organic fluorine compound containing the poorly water-soluble compound.
  • the hydrophilic matrix is a biopolymer.
  • the hydrophilic matrix is a protein.
  • the protein is at least one selected from the group consisting of collagen, gelatin, albumin, casein, fib mouth-in, fibrin, laminin, fibronectin, or vitronectin.
  • the protein is collagen, gelatin, albumin, casein, or fib mouth in.
  • the protein is collagen or gelatin.
  • the protein is gelatin.
  • the hydrophilic matrix is crosslinked by heat, light, or a crosslinking agent.
  • the cross-linking agent is an enzyme.
  • the enzyme is transdaltaminase.
  • the cross-linking of the hydrophilic matrix is performed using dartalaldehyde or transglutaminase.
  • the organic fluorine compound is a compound having 2 to 8 carbon atoms.
  • the organic fluorine compound is a compound having 2 to 3 carbon atoms.
  • the organic fluorine compound is 1,1,1, monohexafluoro-2-propanol, trifluoroethanol, hexafluoroacetone, trifluoroacetic acid, or pentafluoro-oral propionic acid.
  • the log P of the 1-octanol / water partition coefficient of the poorly water-soluble compound is 1-20.
  • the log P of the 1-octanol / water partition coefficient of the poorly water-soluble compound is 2-10.
  • the poorly water-soluble compound is a drug or a pigment.
  • the poorly water-soluble compound is a drug.
  • the drug is an immunosuppressant, an antiallergic agent, an antioxidant, an antithrombotic agent, an antiinflammatory agent, an anticancer agent, a cosmetic ingredient, or a supplement ingredient.
  • the drug is an anticancer drug.
  • the drug is paclitaxel.
  • the organic fluorine compound contains an additive together with the poorly water-soluble compound.
  • the additive is one or more selected from humectants, softeners, transdermal absorption enhancers, and surfactants.
  • a composition in which a poorly water-soluble compound is encapsulated in a hydrophilic matrix is used as a transdermal absorption agent, a topical therapeutic agent, an oral therapeutic agent, a cosmetic, a supplement, or a color material.
  • an anticancer agent-containing external preparation comprising a hydrophilic substrate encapsulating an anticancer agent is provided.
  • the hydrophilic substrate is a protein.
  • the protein is at least one selected from the group consisting of collagen, gelatin, albumin, laminin, casein, fibrin, fibronectin, and vitronectin.
  • the protein is collagen or gelatin.
  • the protein is a protein derived from human, cow, pig or fish, or a genetically modified protein.
  • the protein is cross-linked!
  • protein cross-linking is performed using heat, light, a condensing agent, or an enzyme.
  • protein cross-linking is enzymatic cross-linking.
  • the enzyme is transdaltaminase.
  • the anticancer agent is 5-fluorouracil, paclitaxel, cisplatin, or doxinolevicin.
  • the anticancer agent is 5-fluorouracil or paclitaxel.
  • the anticancer agent-containing external preparation of the present invention is used for the treatment of skin cancer or keratosis.
  • the anticancer agent-containing external preparation of the present invention contains at least one additive selected from a pigment, a softener, a transdermal absorption enhancer, a moisturizer, an emollient component, an antiseptic, a fragrance, or a pH adjuster.
  • a pigment selected from a pigment, a softener, a transdermal absorption enhancer, a moisturizer, an emollient component, an antiseptic, a fragrance, or a pH adjuster.
  • a solution containing a protein, an anticancer agent, and an enzyme for cross-linking the protein is prepared, and then the solution is poured onto a substrate and allowed to stand to form a gel.
  • An anticancer agent-containing external preparation is provided.
  • an anticancer agent-containing external preparation manufactured by the above process is provided.
  • an aqueous solution containing acid-treated gelatin, 5-fluorouracil or paclitaxel, and transdaltaminase is prepared, and then the solution is poured onto a substrate to stand to form a gel.
  • An anticancer agent-containing external preparation to be produced is provided.
  • a composition for external preparation wherein a drug having an octanol / water partition coefficient (LogP) of -3.0 or more and 3.0 or less is encapsulated in a structure mainly composed of a biopolymer. Things are provided.
  • LogP octanol / water partition coefficient
  • LogP here means the octanol / water partition coefficient of a compound, calculated using the Medicinal Chemistry Project.
  • Software PCModels developed by Pomona, ollege, Claremont, California and available from Daylight Chemical Information Systems, Inc. ( It is the logarithm of the value of P).
  • the LogP of the drug is -1.5 or more and 0 or less.
  • the molecular weight of the drug is 1500 or less.
  • the drug is an anticancer agent.
  • the anticancer agent is 5-fluorouracil or adriamycin.
  • the water content in the composition is 40% or more.
  • the biopolymer is a protein or a polysaccharide.
  • the protein is collagen, gelatin, albumin, laminin, casein, and And at least one selected from the group consisting of fibrin.
  • the protein is cross-linked.
  • the protein is cross-linked using dartalaldehyde or transdaltaminase.
  • the external preparation composition of the present invention is at least one selected from the group consisting of a pigment, a softener, a transdermal absorption enhancer, a moisturizer, a surfactant, an antiseptic, a fragrance, and a pH adjuster.
  • the additive is further contained.
  • the composition for external use of the present invention is used for the treatment of skin cancer or keratosis.
  • the present invention it is possible to provide a method for producing a composition in which a slightly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state.
  • the poorly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state! / )
  • the anticancer agent-containing external preparation of the present invention (1) the amount of highly hydrophilic drug encapsulated is increased, and (2) the hydrophilic-hydrophobic property difference from the hydrophobic stratum corneum Therefore, there is a possibility that the skin permeability of the hydrophobic drug may be increased. (3) Since the adhesion with the skin is increased, the effective contact area may be increased and the permeability to the skin may be increased. In addition, (4) for example, when there is a wound on the skin, the retention of liquid leaking from the tissue is enhanced, and an effect of healing the wound can be expected at the same time.
  • hydrophilic matrices represented by biopolymers have high biocompatibility. It is being used widely because of its large number. Among them, proteins such as collagen and gelatin have unique functions, and thus are applied to the medical field, such as tissue-building matrix materials and drug sustained-release carriers. Furthermore, by encapsulating a physiologically active substance such as the growth factor in these, tissue repair is improved. However, since many of these growth factors are hydrophilic, many of these drugs are encapsulated in a hydrophilic matrix by dissolving them in water and immersing them in the matrix.
  • the finely dispersed state means that the encapsulated poorly water-soluble drug is uniformly dispersed in the matrix with a compound having a size that cannot be detected with a stereomicroscope (manufactured by Leica, MZ16A). Or a state in which the drug is molecularly dispersed. More specifically, it means a state in which the particle size of the encapsulated compound is uniformly dispersed at 0.001 m to 10 m when observed with a scanning microscope (SEM).
  • the particle size of the compound is preferably 0.01 Hm to 211 m, and most preferably 0.01 am to 0.5 ⁇ m.
  • composition in which the poorly water-soluble compound prepared by the method is encapsulated in a hydrophilic matrix may be crosslinked as necessary.
  • degree of crosslinking of the hydrophilic matrix various properties such as biodegradability, strength, and structure can be created.
  • the crosslinking method is not particularly limited. Examples of the crosslinking method include physical crosslinking, chemical crosslinking, thermal crosslinking, and enzyme crosslinking. Chemical or enzymatic crosslinking is preferred. Widely used as chemical cross-linking agents!
  • Aldehydes such as rutartal aldehyde and formaldehyde, strength positimide, cyanamide, etc., vinylsulfone, diepoxide, cinnamyl group, bur group, coumarin and other photodimerizable groups
  • the crosslinking agent containing is mentioned. More preferred are daltal aldehyde and transdaltaminase. Most preferred is enzyme crosslinking with transdaltaminase.
  • the organic fluorine compound used in the method is not particularly limited, but it is necessary to dissolve or suspend both the hydrophilic matrix and the poorly water-soluble compound. Are preferred. Furthermore, a solvent that can be distilled off when the solution or suspension containing the poorly water-soluble compound and the hydrophilic matrix is applied is preferable.
  • non-aromatic organic fluorine compounds having 2 to 8 carbon atoms or aromatic fluorine-containing esters, carboxylic acids and nitriles having 6 to 12 carbon atoms are preferable.
  • Non-aromatic organic fluorine compounds having 2 to 8 carbon atoms include fluorine-containing alcohols, fluorine-containing amides, fluorine-containing esters, fluorine-containing carboxylic acids and fluorine-containing ethers having 2 to 8 carbon atoms. Is preferred. It may be partially substituted with a halogen atom other than fluorine. Of these, fluorine-containing alcohols having 2 to 3 carbon atoms are more preferable.
  • 1,1,1-3,3,3-hexafluoro-2-propanol 2,2,2-trifluoroethanol, trifluoroacetic acid, and pentafluoropropionic acid.
  • the solvent since the solvent is compatible with various solvents, it may be used as a mixed solvent with a compatible solvent.
  • the component of the hydrophilic matrix may be any of a biopolymer, a synthetic polymer, a lipid and the like as long as it is dissolved in a fluorine-containing solvent.
  • the biopolymer derived from a living body may be any of sugars, proteins and derivatives thereof, but proteins such as spheres and fibers are preferred, preferably collagen, gelatin, albumin, casein, and live mouth-in. , Fibrin, laminin, fibronectin, or vitronectin, more preferably collagen, gelatin, albumin, casein, fib mouthin, or ramun. Most preferred are collagen, gelatin, albumin, and casein, and among these, gelatin is most preferred.
  • the origin of the protein is not particularly limited, and any of cows, pigs, fish, and genetically modified organisms can be used.
  • the recombinant gene for example, those described in EP0926 543B, WO2004-085473, EP1398324A, EP1014176A, US6645712 can be used.
  • the poorly water-soluble compound may be a poorly water-soluble compound such as a coloring agent or a drug, and may be shifted.
  • the logarithm (Log P) of the distribution coefficient of 1-octanol / water ( ⁇ 7 ⁇ 4 buffer solution) obtained by the flask shaking method is widely used as an index of hydrophilicity / hydrophobicity of compounds. Instead, it may be obtained by calculation.
  • LogP in this specification is calculated using the Hansch-Leo fragment method CLOGP program embedded in the System: PCModels of Daylight Chemical Information Systems! It has been known that it is difficult to uniformly encapsulate a poorly water-soluble compound, that is, a compound having Log P of 1 or more in a hydrophilic matrix.
  • Log P of the poorly water-soluble compound to be encapsulated in the present invention is preferably 1 or more and 20 or less, more preferably 1 or more and 15 or less, particularly preferably 2 or more and 10 or less, and most preferably 3 or more and 5 or less. It is as follows.
  • preferred compounds have a solubility in 1,1,1-3,3,3-hexafluoro-2-propanol of 50 mg / ml to 1000 mg / ml. More preferably, the compound is 100 mg / ml to 500 mg / ml. These compounds can maintain the finely dispersed state referred to in the present invention even at a high concentration.
  • the solubility of the present invention in hexafluoroisopropanol can be measured as follows. Create a compound that is added to 1,1,1-3,3,3-hexafluoro-2-proanol by gradually changing the concentration of the compound, and confirm the concentration at which the precipitation occurs.
  • the solubility of the compound in 1,1,1-3,3,3-hexafluoro-2-2-propanol is obtained.
  • the above mixture was centrifuged for 20 seconds in a microcentrifuge (Chibitan II XX42CF00T; manufactured by Tech Jam Co., Ltd.) to confirm that precipitation occurred! You can do it.
  • the drug is a physiologically active ingredient.
  • specific examples include transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, cosmetic ingredients, and supplement ingredients.
  • Specific examples of the drug are preferably an immunosuppressant (eg, ravamycin, taximus limus, cyclosporine), an anticancer agent (eg, paclitaxel, topotecin, taxotere, docetaxel, enocitabine, 17-AAG), antipyretic analgesic (E.g., aspirin, acetaminophen, sulpyrine), antiepileptics (e.g., phenytoin, acetazolamide, carbamazepine, clonazepam, diazepam, nitrazebam), anti-inflammatory analgesics (e.g., alclofenac, aluminoprofen, ibuprofen, indomethacin, , Ketoprofen, diclo
  • Uses are not particularly limited, but are percutaneous absorption agents, topical treatment agents, oral treatment agents, cosmetics, supplements, and color materials. Preferred are transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, and cosmetics. More preferred are transdermal absorption agents, topical therapeutic agents, and oral therapeutic agents. Most preferred are transdermal absorption agents and topical treatment agents.
  • Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyl dimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hyaluronate, hexylene.
  • humectants for example, agar, diglycerin, distearyl dimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hyaluronate, hexylene.
  • the method for producing a composition in which a poorly water-soluble compound according to the present invention is encapsulated in a hydrophilic matrix will be further described.
  • the poorly water-soluble compound is encapsulated in the hydrophilic matrix by immersing the organic fluorine compound containing the poorly water-soluble compound in the hydrophilic matrix and drying it.
  • the form of the hydrophilic matrix is not particularly limited and may be any gel, sponge, film, nonwoven fabric, fiber, tube, particle, or the like. Any shape can be applied, but examples thereof include a pyramid, a cone, a prism, a cylinder, a sphere, a spindle-shaped matrix, and a matrix created by an arbitrary mold.
  • the size of the matrix is not particularly limited, but is preferably 500 cm square or less for gels, sponges, and nonwoven fabrics. Preferably it is 100 cm square or less. Especially preferred Is less than 50 cm square. Most preferably, it is 10 cm square or less.
  • the diameter of fiber or tube or one side is practically 0.001 nm or more and 10 cm or less. Preferably they are 0.01 nm or more and 1 cm or less.
  • the diameter is preferably 1 nm force, 1 mm, more preferably 10 nm to 200 m, even more preferably 50 nm to 100 ⁇ , particularly preferably 100 nm to 10 ⁇ m.
  • the thickness of the matrix is not particularly limited, but is preferably 1 nm or more. More preferably, it is 10 nm or more. More preferably, it is 100 nm or more. More preferably, it is 1 m or more. Furthermore, it is preferably 10 m or more. Most preferably, it is 100 m or more.
  • the concentration of the poorly water-soluble compound is not particularly limited as long as the effects of the present invention can be achieved, but one of the features of the present invention is that the hardly soluble compound can be encapsulated in a high concentration and in a finely dispersed state.
  • the ratio of the poorly water-soluble compound to the hydrophilic matrix in the hydrophilic matrix is not particularly limited as long as the effect of the present invention can be achieved. Generally, the ratio is 0.001% to 50%. Yes, preferably 0.01% to 10%, and most preferably 0.1% to 5%.
  • the hydrophilic matrix is further dried in a finely dispersed state by immersing the hydrophilic matrix in an organic fluorine compound containing the hardly water-soluble compound and then drying the hydrophilic matrix.
  • a composition encapsulated in a matrix can be made.
  • the drying conditions are not particularly limited as long as the effect of the present invention can be achieved.
  • the drying condition can be maintained by standing at room temperature to 50 ° C for 1 hour to 48 hours, preferably 2 hours to 15 hours. it can. In some cases, vacuum drying and / or washing with water and drying can be done with force S.
  • the solvent used for the production should not remain as much as possible.
  • the amount of the solvent in the composition is preferably 0% to 0.1%. Although preferred, usually only a small amount remains. Therefore, it is most preferably 0.00001% to 0.1%. Residual solvent amount Can decompose the composition and quantify using GC-MS.
  • An anticancer agent-containing external preparation comprising a hydrophilic substrate encapsulating an anticancer agent
  • transdermal and transmucosal routes are expected to be useful routes because they can avoid the first-pass effect and have high ore availability.
  • the hydrophilic substrate used in the present invention is not particularly limited as long as the substrate has an affinity for water.
  • water-soluble synthetic polymers and biopolymers can be used, Is a molecule.
  • the hydrophilic substrate is a protein.
  • the type of protein used in the present invention is not particularly limited, but it is preferable to use a protein having a molecular weight of about 1,000 to 1,000,000, which is preferred by a protein having a lysine residue and a glutamine residue. More preferably, a protein having a molecular weight of about 3,000 to 300,000 is used. More preferably, a protein having a molecular weight of about 10,000 to 100,000 is used.
  • the origin of the protein is not particularly limited, but it is preferable to use a human-derived protein. Specific examples are listed as proteins, but the present invention is not limited to these compounds. Collagen, gelatin, albumin, casein, transferrin, or globulin can be used.
  • gelatin preferred is gelatin, collagen, or albumin, more preferred is gelatin or collagen, and most preferred is acid-treated gelatin.
  • the origin of biopolymers such as proteins is not particularly defined, but any of humans, cows, pigs, birds, fish, and genetically modified organisms may be used. Preferred are humans, cattle, pigs, fish, and genetically modified organisms. More preferred are cows, pigs, fish, and genetically modified organisms. Examples of the genetically modified gelatin include those described in EP0926543B, WO2004-085473, EP1398324A, EP1014176A, US6645712, but are not limited thereto.
  • the biopolymer used for the hydrophilic substrate may be chemically modified. Chemical modification is the bonding of a part of the functional group to a low or high molecular compound. More preferably, it is a modified product by introducing an ester bond or an amide bond into the carboxyl group, hydroxyl group, and amino group site of the biopolymer, or by electrostatic interaction.
  • a composition in which a poorly water-soluble compound prepared by the above method is encapsulated in a hydrophilic matrix may be cross-linked as necessary. By controlling the degree of crosslinking of the hydrophilic matrix, various properties such as biodegradability, strength, and structure can be created.
  • the crosslinking method is not particularly limited. Examples of the crosslinking method include physical crosslinking, chemical crosslinking, thermal crosslinking, and enzyme crosslinking.
  • Crosslinking may be thermal, light, crosslinker, enzymatic, or polyion complex and hydrophobic interaction! /. Chemical or enzymatic crosslinking is preferred. Crosslinks containing photodimerizable groups such as aldehydes such as dartalaldehyde and formaldehyde, carposimide, cyanamide, vinyl sulfone, diepoxide, cinnamyl group, bur group, and coumarin, which are widely used as chemical crosslinking agents. Agents. More preferred are dartalaldehyde and transdaltaminase.
  • Cross-linking by heat is a method of cross-linking by heat-treating proteins, and it is preferable to carry out in the range of 50-200 ° C. If it is lower than 50 ° C, crosslinking is insufficient or crosslinking is not performed. On the other hand, when the temperature exceeds 200 ° C., protein denaturation is remarkable. Taking into account manufacturing and activity factors, 60 to 180 ° C is preferred, and 90 to 150 ° C is most preferred.
  • Cross-linking by light is, for example, a method of cross-linking by emitting radiation to proteins.
  • physical crosslinking is caused by irradiating physical energy such as ultraviolet irradiation, electron beam irradiation, and gamma rays.
  • chemical crosslinking is caused by irradiating a protein into which a photoreactive group or a polymerizable group is introduced directly or in the presence of another photoreactive group (for example, a polymerization initiator).
  • an inorganic or organic crosslinking agent can be used as the crosslinking agent.
  • inorganic or organic crosslinking agents include chromium salts (such as chromium alum and chromium acetate); calcium salts (such as calcium chloride and calcium hydroxide); aluminum salts (such as aluminum chloride and aluminum hydroxide); canolepositimides (EDC, WSC, N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), N-hydroxysuccinimide (HOSu), dicyclohexyl carbopositimide (DCC), etc.); N-hydroxysuccinimide; Forces that can include phosphorus chloride and the like are not limited to these.
  • chromium salts such as chromium alum and chromium acetate
  • calcium salts such as calcium chloride and calcium hydroxide
  • aluminum salts such as aluminum chloride and aluminum hydroxide
  • canolepositimides ECC, WSC, N-
  • the enzyme is not particularly limited as long as it has a cross-linking action of a protein, but preferably cross-linking with transdaltaminase and laccase, most preferably transdaltaminase. It can be performed.
  • a specific example of a protein that is enzymatically cross-linked with transglutaminase is not particularly limited as long as it has a lysine residue and a glutamine residue.
  • Transdaltaminase may be derived from mammals or from microorganisms. Specifically, it is derived from the Ajinomoto Co., Ltd. Activa series, which is derived from mammals sold as reagents.
  • Transglutaminase for example, guinea pig liver-derived transdaltaminase from Oriental Yeast Co., Ltd., Upstate USA Inc., Biodesign International, etc., goat-derived transdaltaminase, usagi-derived transdaltaminase, etc. blood coagulation factors (factor XHIa, Hae matologic Technologies, Inc. Co., Ltd.) force s like.
  • the amount of enzyme used can be appropriately set according to the type of protein, but it can be added in an amount of about 0.;! To 100% by weight based on the weight of the protein. Preferably, it can be added in a range of about! To 50% by weight.
  • the time for the cross-linking reaction with the enzyme can be appropriately set according to the type of protein, etc. Typically, the reaction can be performed for 1 to 72 hours, preferably 2 to 24 hours. Can react.
  • the temperature of the cross-linking reaction by the enzyme is a force S that can be set as appropriate according to the type of protein S, etc., and the reaction can be performed normally from 0 ° C to 80 ° C. The reaction can be carried out at temperatures up to 60 ° C.
  • the type of anticancer agent used in the present invention is not particularly limited.
  • fluorinated pyrimidine antimetabolites (5-fluorouracil (5FU), tegafur, doxyfluridine, force pecitabine, etc.); antibiotics (mitomycin ( MMC) and adriacin (DXR), etc .
  • Purine antimetabolite (folate antimetabolite, such as methotrexate, mercaptopurine, etc.); Active metabolite of vitamin A (antimetabolite, such as hydroxycarbamide, tretinoin, tamibarotene, etc.); molecule Target drugs (Noseceptin, Imatinib mesylate, etc.); Platinum preparations (Pribratin Nyala) (CDDP), paraplatin (CBDC), elplat (Oxa), vacpra, etc.); plant almyloid drugs (topotecin and campto (CPT), taxol (paclitaxel)
  • 5-fluorouracil paclitaxel
  • cisplatin doxorubicin and adriamycin. More preferred are 5-fluorouracil, paclitaxel, and cisplatin. Most preferred is 5-funoleouracil or paclitaxel.
  • the anticancer agent In order to encapsulate the anticancer agent in a hydrophilic substrate at a high concentration, it is desirable that the anticancer agent is hydrophilic. Even if it is a hydrophobic anticancer agent, it can be increased by using various additives such as a surfactant and a solubilizing agent. It becomes possible to enclose in the concentration.
  • additives may be added to the hydrophilic substrate together with the above-mentioned anticancer agent! /.
  • Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyl dimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol monoole, sodium hyaluronate, hexylene.
  • the form of the external preparation of the present invention is not particularly limited! /, And examples thereof include gels, sponges, films, nonwoven fabrics, fibers (tubes), and particles. Any shape can be applied, and examples thereof include a pyramid, a cone, a prism, a cylinder, a sphere, a spindle-shaped structure, and a substrate made of any mold.
  • the use (application disease) of the external preparation of the present invention is not particularly limited.
  • skin cancer, keratosis, malignant melanoma, mycosis fungoides, breast cancer, prostate cancer, uterine cancer, vaginal cancer, penis Cancer and colon cancer Preferred are skin cancer and keratosis.
  • the external preparation of the present invention can be used preferably as a skin external preparation or a transdermal absorption preparation.
  • the external preparation of the present invention can be embedded in the tissue as necessary. For example, in order to preserve the function of the removed tissue after surgery, it may be embedded in the missing tissue, or it may be accompanied by severely damaged skin coating. In the case of an external preparation having a high affinity for the living body, it may help repair surrounding tissues.
  • collagen, gelatin, and glycosaminodarican have unique properties such as moisture retention, growth factor storage, and cell adhesion (collagen, gelatin), which are highly biocompatible. Can be done simultaneously.
  • the dosage of the external preparation of the present invention can be appropriately set according to the type and amount of an anticancer agent that is an active ingredient, the weight of a patient, the state of a disease, etc. About 100 mg / kg can be administered per dose, and preferably about 20 ⁇ g to 50 mg / kg can be administered.
  • the anticancer agent is preferably encapsulated in a finely dispersed state in a hydrophilic base material.
  • the definition of fine dispersion is the same as that described in (1).
  • LogP octanol / water partition coefficient
  • the biopolymer used in the present invention is not particularly limited, but is preferably a protein or a polysaccharide. More preferred is collagen, gelatin, albumin, laminin, casein, or fibrin, and more preferred is collagen, gelatin, or albumin. Most preferred is collagen or gelatin.
  • the origin of the biopolymer is not particularly defined, and any of humans, cows, pigs, birds, fish, and genetically modified organisms may be used. Preferred are humans, cows, pigs, fish, and genetically modified organisms. More preferred are cows, pigs, fish, and gene recombinants.
  • Examples of the genetically modified gelatin include those described in EP0926543B, WO 2004-085473, EP1398324A, EP1014176A, US6645712 V, force S, force S, and the like.
  • the biopolymer used for the substrate can be used alone or mixed with a plurality of types of biopolymers or synthetic polymers.
  • the biopolymer used for the base material may be chemically modified! /.
  • the chemical modification is to bond a part of the functional group to a low molecular or high molecular compound. More preferred is a modified form of an ester bond or amide bond of a biopolymer.
  • the biopolymer may be crosslinked. Crosslinking may be thermal, light, crosslinker, or enzymatic crosslinks! /, Or may be cross-linked by polyion complexes and hydrophobic interactions. Chemical or enzymatic crosslinking is preferred.
  • a chemical cross-linking agent Generally used as a chemical cross-linking agent, it contains aldehydes such as daltalaldehyde and formaldehyde, carpositimide, cyanamide, etc., and includes photodimerizable groups such as vinyl sulfone, diepoxide, cinnamyl group, bur group, and coumarin.
  • aldehydes such as daltalaldehyde and formaldehyde, carpositimide, cyanamide, etc.
  • photodimerizable groups such as vinyl sulfone, diepoxide, cinnamyl group, bur group, and coumarin.
  • a crosslinking agent is mentioned. More preferred are dartalaldehyde and transglutaminase.
  • the transdaltaminase may be derived from a mammal or a microorganism. Specifically, the transactaminase is marketed as a reagent by Ajinomoto Co., Ltd. Activa. Transglutaminase derived from Oriental Yeast Industry Co., Ltd., Upstate USA In, Biodesign International, etc., guinea pig liver-derived transglutaminase, goat-derived transglutaminase, Usagi-derived transdaltaminase, etc. It is done. In addition, human-derived recombinant transdaltaminase can also be used.
  • the transdermal absorption efficiency of a drug is determined by the molecular weight of the drug, the solubility of the drug in the base material, the partition coefficient between the base material and the skin, and the like. Therefore, when considering the transdermal administration of drugs, the combination of drug and substrate is very important. In general, it is known that transdermal absorbability of low molecular weight drugs is high.
  • the molecular weight of the drug is preferably 1500 or less. More preferably, it is 1000 or less. More preferably, it is 500 or less.
  • the log ratio of logarithmic coefficient of octanol / water (Log P) is widely used as an index of hydrophilicity and hydrophobicity of drugs.
  • the logarithmic ratio (Log P) of the octanol / water partition coefficient is as described in (1), and the drug that can be used in the present invention is a drug having Log P of ⁇ 3.0 or more and 3.0 or less.
  • LogP is preferably ⁇ 1.5 or more and 1.5 or less, and more preferably ⁇ 1.5 or more and 0.5 or less. Most preferably, LogP is -0.8 or more and 0.5 or less.
  • transdermal absorption enhancer having a property of making the stratum corneum sparse
  • Ethanol and surfactants are known as typical components used in this technique, and these components are used in various transdermal preparations.
  • transdermal absorption efficiency is not necessarily high, water is also known to increase transdermal absorption efficiency. For example, it is known that the percutaneous absorption efficiency of a drug after the skin is softened with warm water is increased. Therefore, water is an important candidate component as a component that causes little damage to the skin and enhances the transdermal absorption efficiency of the drug.
  • water is a substance that is safe for the living body, so that it can be made to act at a higher concentration and for a longer time than other transdermal absorption enhancers. Further, since water can dissolve various salts present in the living body, it is possible to prepare a composition having an ionic composition close to that of the living body.
  • the composition produced in the present invention contains a high concentration of water in the composition, and since the water is safe, the composition can be used for a long time. It can be advantageous to use as
  • the water content in the composition prepared according to the present invention is not particularly defined as long as the effect of the present invention is exhibited, but the water content is preferably 30% or more. More preferably, it is 40% or more. More preferably, it is 50% or more. Particularly preferred is 60% or more. Most preferably, it is 70% or more.
  • the drug is a physiologically active ingredient.
  • transdermal absorption agents, topical treatment agents, oral treatment agents examples include cosmetic ingredients and supplement ingredients.
  • Specific examples of the drug include, but are not limited to, preferably, an anticancer agent, an antiallergic agent, an antioxidant agent, an antithrombotic agent, an antiinflammatory agent, an immunosuppressive agent, an antipsychotic agent, an anesthetic, and a nucleic acid drug. Particularly preferred are anticancer agents.
  • the anticancer agent that can be used in the present invention is not particularly limited as long as it dissolves in both water and an organic solvent.
  • 5-fluorouracil 5FU
  • tegafur doxyfluridine
  • force pecitabine mitomycin (MMC)
  • MMC mitomycin
  • adriamycin methotrexate
  • Examples include mercaptopurine, elprat (Oxa), etoposide, busulfan, cyclophosphamide, ifomide, tamoxifen taenoate, and fuadrozole hydrochloride.
  • 5-Fluorouracil and adriamycin are preferable. More preferred is 5-fluorouracil.
  • antiallergic agents used in the present invention is not limited to these compounds in the present invention.
  • mediator release inhibitors such as sodium cromoglycate and thromboxane inhibitors such as ozadarel hydrochloride.
  • antioxidant used in the present invention are listed, but the present invention is not limited to these compounds.
  • An example is force rice.
  • antithrombotic agent used in the present invention is not limited to these compounds in the present invention.
  • examples include aspirin and potassium sulfarine.
  • anti-inflammatory agent used in the present invention examples include prednisolone.
  • Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyl dimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hydranolate, hexyleneda Recall, okuinin extract, petrolatum), softener (eg, glycerin, mineral oil), emollient component (surfactant, etc.) (eg, isopropyl isostearate, polyglyceryl isostearate, isotridecyl isononanoate, octyl isononanoate, oleic acid) , Glyceryl oleate, cocoa butter, cholesterol, mixed Fatty acid triglycerides, dioctyl succinate, sucrose acetate stearate, cyclopentasiloxane, sucrose distearate
  • humectants for example, agar,
  • the form of the composition for external use is not particularly limited! /, And examples thereof include gels, sponges, films, nonwoven fabrics, fibers (tubes), and particles. Any shape can be applied, and examples thereof include a pyramid, a cone, a prism, a cylinder, a sphere, a spindle-shaped structure, and a substrate made of an arbitrary mold.
  • the use of the external preparation is not particularly limited, and examples thereof include skin cancer, keratosis, malignant melanoma, mycosis fungoides, breast cancer, prostate cancer, uterine cancer, vaginal cancer, penile cancer, and colon cancer. . Preferred are skin cancer and keratosis. Most preferred is skin cancer.
  • a transdermal absorption preparation is preferable.
  • the external preparation can be embedded in the tissue as necessary. For example, after surgery, in order to preserve the function of the part removed by surgery, it may be embedded in the missing tissue, or it may be accompanied by a severely damaged skin covering. In the case of an external preparation having a high affinity for a living body, it may help repair surrounding tissues.
  • the anticancer agent is preferably encapsulated in a finely dispersed state in a hydrophilic substrate.
  • the definition of fine dispersion is the same as that described in (1).
  • Example 1 Encapsulation of paclitaxel in a cross-linked gelatin gel
  • a 25% aqueous solution of Daltal Aldehyde was added to a PBS solution containing acid-treated gelatin (PSP gelatin, manufactured by Futsubi) and allowed to stand at 4 ° C for 17 hours (final concentration: Gelatin: 10%, Dartal Aldehyde: 0.25%, thickness) (2 mm).
  • PBS solution containing acid-treated gelatin PBS solution containing acid-treated gelatin (PSP gelatin, manufactured by Futsubi) and allowed to stand at 4 ° C for 17 hours (final concentration: Gelatin: 10%, Dartal Aldehyde: 0.25%, thickness) (2 mm).
  • the obtained gelatin gel was washed with water and then immersed in a 5 mM glycine aqueous solution at 37 ° C. for 1 hour to inactivate unreacted dartalaldehyde.
  • the obtained gel was lyophilized to obtain a crosslinked gelatin sponge.
  • HFIP 1,1,1,3,3,3-hexafluoro-2-propanol
  • Paclitaxel could be encapsulated in 0.5 mg (per 10 mg of gelatin) in gel immersed in ethanol solution, whereas 1.9 mg (per 10 mg of gelatin) in paclitaxel could be encapsulated in gel immersed in HFI P solution.
  • the paclitaxel-encapsulated gelatin gel prepared in Example 1 was observed with a stereomicroscope (Leica Co., Ltd., MZ16A).
  • the paclitaxel-encapsulated gelatin film prepared from HFIP was similar to the gelatin film containing no paclitaxel without precipitation of paclitaxel (Fig. 2, left, middle). Since no precipitation of paclitaxel was observed by observation with a stereomicroscope (Leica MZ16A), paclitaxel-encapsulated gel made from HFIP
  • the size of paclitaxel in chin film is less than 10 m.
  • Examples 1 and 2 similar results were obtained using transdaltaminase (Activa TG_S, manufactured by Ajinomoto Co., Inc.) as the cross-linking agent and methyl yellow (manufactured by Wako Pure Chemical Industries, Ltd.) as the poorly water-soluble compound.
  • transdaltaminase Activa TG_S, manufactured by Ajinomoto Co., Inc.
  • methyl yellow manufactured by Wako Pure Chemical Industries, Ltd.
  • An anticancer agent-containing external preparation comprising a hydrophilic base material encapsulating an anticancer agent
  • Acid-treated gelatin (10%, PSP gelatin, manufactured by Futsubi), 5_FU (1 mg / mL, 5 mg / mL, 10 mg / mL), and transgnoretaminase (0 ⁇ 8%, Actinoku TG_S, A PBS solution containing Ajinomoto Co.) was prepared.
  • the PBS solution (1.8 mL) was poured into a square dish (3 cm ⁇ 3 cm ⁇ 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours.
  • Gelatin was formed into a gel, and a 5-FU-encapsulated gelatin gel (3 cm X 3 cm X 2 mm) was prepared as usual. At the 5-FU concentration, the gel was as transparent as the gel without 5-FU.
  • a 5-FU-encapsulated gelatin gel and paclitaxel-encapsulated gelatin gel were prepared in the same manner as in Examples 3 and 4 except that recombinant gelatin (Fibrogen) was used instead of acid-treated gelatin. Results were obtained.
  • PBS solution containing 25% dartalaldehyde (GA) solution was prepared in PBS solution containing acid-treated gelatin (PSP gelatin) (final concentration: 10% (gelatin), 0.3% (GA), temperature: 30 ° C) .
  • PSP gelatin acid-treated gelatin
  • 1.8 mL of the solution was poured into a square dish (3 cm ⁇ 3 cm ⁇ 1 cm) (liquid thickness: 2 mm) and allowed to stand at 4 ° C. for 17 hours to obtain GA cross-linked gelatin.
  • the crosslinked gelatin was immersed in a 50 mM glycine solution at 37 ° C for 1 hour. Continued! 2 hours of immersion in 37 ° C deionized water for 1 hour Repeatedly, unreacted GA was washed.
  • Example 7 Encapsulation of anticancer agent in GA cross-linked gelatin
  • an aqueous solution 100 L, anticancer drug concentration: 1 mg / mL
  • 5-FU 5-FU
  • cisbratin cisbratin
  • carpoplatin adriamycin
  • An anticancer agent-encapsulated gelatin in which an anticancer agent was immersed in GA cross-linked gelatin was prepared. That is, the anticancer agent-containing gelatin is a wet type anticancer agent-containing gelatin gel.
  • the anticancer agent-encapsulated gelatin gel was further freeze-dried to obtain a sponge-like anticancer agent-encapsulated gelatin.
  • Example 9 Tumor reduction effect by gelatin containing anticancer agent
  • a mouse skin cancer model is created by causing ultraviolet skin cancer in hairless mice (6 weeks of age).
  • Anticancer drug-containing gelatin gel prepared in Examples 3 and 4 on the affected area of the mouse (size: 3 cm ⁇ 3 cm, thickness: 2 mm, drug concentration; 5-FU: 5 mg / mL, nocritaxenole: 0.5 mg / mL) is applied, and the gel is further coated (BAND-AID, manufactured by Johnson & Johnson).
  • BAND-AID manufactured by Johnson & Johnson
  • a composition for external use wherein a drug having an octanol / water partition coefficient (LogP) of ⁇ 3.0 or more and 3.0 or less is encapsulated in a structure mainly composed of a biological polymer.
  • LogP octanol / water partition coefficient
  • Acid-treated gelatin (10%, PSP gelatin, manufactured by Futsubi), 5_FU (1 mg / mL, 5 mg / mL, 10 mg / mL), and transgnoretaminase (0 ⁇ 8%, Actinoku TG_S, A PBS solution containing Ajinomoto Co.) was prepared.
  • the LogP of 5-FU used here is -0.58, and the molecular weight is 130.
  • the PBS solution (1.8 mL) was poured into a square dish (3 cm ⁇ 3 cm ⁇ 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours.
  • Gelatin was formed into a gel, and a 5-FU-encapsulated gelatin gel (3 cm ⁇ 3 cm ⁇ 2 mm) as usual was prepared.
  • the gel contains 5-FU It was as transparent as no gel.
  • the water content in the composition was about 90%.
  • the amount of 5-FU encapsulated in the 5-FU-encapsulated gelatin gel was the same as the concentration of the solution for gel preparation.
  • a PBS solution containing the acid-treated gelatin, carpoplatin (1, 5, 10 mg / mL), and transdaltaminase (0.8%) was similarly prepared.
  • the LogP of carpoplatin used here is -2.3 and the molecular weight is 371.
  • the solution (1.8 mL) was poured into a square dish (3 cm ⁇ 3 cm ⁇ 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours.
  • Gelatin was formed into a gel, and a carpoplatin-encapsulated gelatin gel was prepared as usual (3 cm x 3 cm x 2 mm).
  • the amount of encapsulated carpoplatin in the gelatin gel encapsulated in carpoplatin in the gel was the same as the solution concentration for gel preparation.
  • Example 12 Tumor reduction effect by gelatin containing anticancer agent
  • a mouse skin cancer model was prepared by developing ultraviolet skin cancer in hairless mice (6 weeks old).
  • the 5-FU-containing gelatin gel prepared in Example 10 was applied to the affected area of the mouse, and the gel was covered with a polyethylene film and fixed. One month later, both formulations showed a significant reduction in tumor size.
  • hydrophilic carpoplatin has a large residual amount in gelatin, which is a hydrophilic substrate, and has a superior tumor size compared to 5-FU. It was a force that did not allow a decrease.
  • a PBS solution containing the acid-treated gelatin, cisplatin (1 mg / mL) and transdaltaminase (0 • 8%) was prepared.
  • the log P of cisplatin used here is -1.7 and the molecular weight is 300.
  • the solution (1.8 mL) was poured into a square dish (3 cm ⁇ 3 cm ⁇ 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours.
  • Gelatin was formed into a gel, and a cisplatin-encapsulated gelatin gel that was normal (3 cm ⁇ 3 cm ⁇ 2 mm) could be prepared.
  • the amount of cisplatin encapsulated in the gelatin gel encapsulating cisplatin in the gel was the same as the solution concentration for gel preparation.
  • Example 14 Preparation of adriamycin-encapsulated gelatin gel
  • a PBS solution containing the acid-treated gelatin, adriamycin (1 mg / mL), and transgnoretaminase (0.8%) was similarly prepared.
  • the cisplatin used here has a LogP of 0.32 and a molecular weight of 543.
  • 1.8 mL of the solution was poured into a square dish (3 cm ⁇ 3 cm ⁇ 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours.
  • Gelatin formed into a gel, and an adriamycin-encapsulated gelatin gel as usual (3 cm X 3 cm X 2 mm) could be prepared.
  • the amount of cisplatin encapsulated in the gelatin gel encapsulating adriamycin in the gel was the same as the solution concentration for gel preparation.
  • composition produced by the method of the present invention is useful in fields such as pharmaceuticals and cosmetics.
  • Fig. 1 shows gelatin gel immersed in ethanol containing paclitaxel (left) and HFIP (right)! /, Immediately after soaking (top) and after natural drying (bottom) .
  • FIG. 2 shows a stereomicrograph of gelatin gel. Gelatin gel soaked in HFIP without paclitaxel (left) and gelatin gel soaked in HFIP with paclitaxel (right) are shown.

Abstract

It is intended to provide a method of producing a composition comprising a hardly water soluble compound enclosed in a finely dispersed state in a hydrophilic matrix and a preparation for external use containing an anticancer agent. Namely, a method of producing a composition comprising a hardly water soluble compound enclosed in a hydrophilic matrix which comprises immersing the hydrophilic matrix in an organofluoro compound containing the hardly water soluble compound and thus enclosing the hardly water soluble compound in the hydrophilic matrix; and a preparation for external use containing an anticancer agent which comprises a hydrophilic base having the anticancer agent enclosed therein.

Description

明 細 書  Specification
難水溶性化合物を親水性マトリックスに封入した組成物の製造方法及び 抗癌剤又はォクタノール/水の分配係数（LogP)が- 3.0以上 3.0以下である薬物 を親水性基材に封入した外用剤  Method for producing a composition in which a poorly water-soluble compound is encapsulated in a hydrophilic matrix, and an external preparation in which an anticancer agent or a drug having an octanol / water partition coefficient (LogP) of -3.0 or more and 3.0 or less is encapsulated in a hydrophilic substrate
技術分野  Technical field
[0001] 本発明は、難水溶性化合物を高濃度に封入した親水性マトリックスの製造方法に 関する。さらに本発明は、抗癌剤又はォクタノール/水の分配係数 (LogP)が- 3.0以 上 3.0以下である薬物を親水性基材に封入した外用剤に関する。  The present invention relates to a method for producing a hydrophilic matrix in which a poorly water-soluble compound is encapsulated at a high concentration. Furthermore, the present invention relates to an external preparation in which an anticancer agent or a drug having an octanol / water partition coefficient (LogP) of −3.0 or more and 3.0 or less is encapsulated in a hydrophilic substrate.
背景技術  Background art
[0002] 近年、再生医療やドラッグデリバリーシステム（DDS)に代表される先端技術が精力 的に研究されている。中でも細胞や薬剤の足場や貯蔵庫として機能する材料 (バイ ォマテリアル）の設計やそれらの加工について広く研究されており、合成高分子や生 体由来高分子 (生体高分子)等種々の材料が検討されてレ、る。  In recent years, advanced technologies typified by regenerative medicine and drug delivery systems (DDS) have been energetically studied. In particular, extensive research has been conducted on the design and processing of materials (biomaterials) that function as scaffolds and storages for cells and drugs, and various materials such as synthetic polymers and biopolymers (biopolymers) have been studied. It has been done.
[0003] 生体由来の高分子である生体高分子はそれらに固有の機能を有していることから、 組織構築用の足場材料や薬剤の徐放担体として利用されてレ、る。該生体高分子を 薬剤の徐放担体として利用する際には、生体高分子が一般に親水性であることから 、グロースファクタ一等の水溶性の薬剤を封入した構造物として利用され、またそれら の有効性が報告されている（特許第 3639593号、特許第 3771510号)。薬剤の徐放担 体には、水溶性から難水溶性に渡る種々の薬剤が保持できることが望ましい。しかし 、タンパク質は多くの有機溶媒に不溶なことから、親水性マトリックス内部にまで薬剤 を浸漬させることが困難であった。また、薬剤を親水性マトリックスの成形途中に封入 すると、例えば、ダルタルアルデヒド等の反応性の高い架橋剤を用いると、薬剤が架 橋剤と反応し、安定にマトリックス内部に封入できない恐れがある。  [0003] Biopolymers, which are macromolecules derived from living organisms, have unique functions, and are therefore used as scaffold materials for tissue construction and as sustained release carriers for drugs. When the biopolymer is used as a sustained-release carrier for a drug, since the biopolymer is generally hydrophilic, it is used as a structure enclosing a water-soluble drug such as a growth factor of 1 or more. Effectiveness has been reported (Patent No. 3639593, Patent No. 3771510). It is desirable that the drug sustained-release carrier can hold various drugs ranging from water-soluble to poorly water-soluble. However, since the protein is insoluble in many organic solvents, it is difficult to immerse the drug in the hydrophilic matrix. In addition, if the drug is encapsulated in the middle of the molding of the hydrophilic matrix, for example, if a highly reactive crosslinking agent such as dartalaldehyde is used, the drug may react with the cross-linking agent and cannot be stably encapsulated inside the matrix. .
[0004] 1，1，1，3，3，3-へキサフルォ口- 2-プロパノール（HFIP)およびトリフルォロエタノール（ TFE)はコラーゲンやゼラチンといったタンパク質を溶解することから、組織構築用マ トリックス（特表 2002-531182号公報）やエレクトロスピユング法による繊維状マトリック スの作成（特表 2004— 532802号公報、特開 2004-321484号公報）に用いられている。 しかし、これらは単にマトリックスを作成するにとどまつており、該マトリックスへ封入し た薬剤の状態にっレ、ては言及してレヽなレ、。 [0004] 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) and trifluoroethanol (TFE) dissolve proteins such as collagen and gelatin. (Special Table 2002-531182) and creation of fibrous matrix by electrospinning method (Special Table 2004-532802, JP 2004-321484). However, these are merely used to create a matrix, and the state of the drug encapsulated in the matrix is not enough to mention.
[0005] また、特表 2003-500368号公報には、溶解度が不十分な薬剤のためのェマルジヨン ビヒクルとして、溶解度が低い治療薬、 1種以上のトコール、 1種以上の補助溶剤、及 び 1種以上の界面活性剤を含む医薬組成物が記載されている。  [0005] In addition, Japanese translation of PCT publication No. 2003-500368 discloses a low-solubility therapeutic drug, one or more tocols, one or more co-solvents, as an emulsion vehicle for drugs with poor solubility. A pharmaceutical composition comprising more than one surfactant is described.
[0006] 一方、癌の治療には外科手術、放射線療法、化学療法、および免疫療法が施され ている。通常治療には外科手術が選ばれるため、その他の治療方法は外科手術の 補助的手法として用いられてレ、る。  [0006] On the other hand, surgery, radiation therapy, chemotherapy, and immunotherapy are performed for the treatment of cancer. Because surgery is usually selected for treatment, other treatment methods are used as ancillary procedures for surgery.
[0007] 抗癌剤を用いる化学療法は通常飲み薬または静脈注射がほとんどであり、血管を 通して全身に作用される。従って、正常組織への副作用が多ぐ重度の脱毛等が見 られる。現在、癌組織へのターゲットを目指し、癌組織へ誘導される新生血管の未熟 さを狙い、抗癌剤のナノ粒子化パッシブターゲッティング、および癌細胞の抗体を用  [0007] Most chemotherapy using anticancer drugs is usually taken or intravenously administered, and acts on the whole body through blood vessels. Therefore, severe hair loss with many side effects on normal tissues is observed. At present, aiming at targeting to cancer tissue, aiming at immaturity of new blood vessels induced to cancer tissue, using passive targeting of anti-cancer drugs to nanoparticles, and cancer cell antibodies
[0008] 近年、薬剤の投与経路の研究が盛んであり、経皮、経肺等、皮膚や粘膜を投与経 路に利用する製剤が研究されている。これらの投与方法は、バイオアベイラビリティ 一が高い、患者のコンプライアンスが高い、また過剰投与の際の投与中止が容易で ある、また身体の不自由な患者への投与が容易であるといった利点が挙げられる。こ れらの利点を活かし、鎮痛剤を含んだ製品（Duragesic)やインシュリンの製品（Exuber a)が上市され、これらの投与経路の有効性を示して!/、る。 [0008] In recent years, research on drug administration routes has been active, and preparations utilizing the skin and mucous membranes for administration routes such as transdermal and transpulmonary are being studied. These administration methods have advantages such as high bioavailability, high patient compliance, easy discontinuation of overdose, and ease of administration to patients with physical disabilities. . Taking advantage of these advantages, analgesic-containing products (Duragesic) and insulin products (Exuber a) are marketed to demonstrate the effectiveness of these routes of administration!
[0009] 抗癌剤を封入した皮膚外用剤の例としては、例えば、特開昭 61— 204125号公報 に、 5—フルォロウラシル（5— FU)、 1ードデシルァザシクロヘプタンー2—オン、お よびカルボポール（Carbopol)を含有することを特徴とする皮膚浸透性に優れた制癌 剤含有軟膏が記載されている。し力、しながら、抗癌剤を封入した皮膚外用剤はほとん ど上巿されていない。上市されている外用剤としては、ワセリンを主成分とする基材に 5—フルォロウラシル（5— FU)を封入した 5— FU軟膏（協和発酵製）が挙げられる程 度である。すなわち、抗癌剤を含有した外用剤の基材はほとんど工夫されていない のが現状である。  [0009] Examples of external preparations for skin encapsulating an anticancer agent include, for example, JP-A 61-204125, 5-Fluorouracil (5-FU), 1-dedecylazacycloheptan-2-one, and An anti-cancer agent-containing ointment excellent in skin permeability characterized by containing Carbopol is described. However, the topical skin preparation encapsulating an anticancer drug has hardly been promoted. Examples of external preparations on the market include a 5-FU ointment (Kyowa Hakko) in which 5-fluorouracil (5-FU) is encapsulated in a base material mainly composed of petrolatum. In other words, the base material for external preparations containing anticancer agents is hardly devised.
[0010] 薬物の経皮吸収効率は薬物の分子量、薬物の基材への溶解度、基材と皮膚の分 配係数等により決定される。従って、薬物の経皮投与を検討する際、薬物と基材の組 み合わせは非常に重要となる。し力もながら、それぞれの薬物についての基材の検 討が単独で行われている程度で、薬物の親水，疎水性と基材の性質の及ぼす経皮 吸収効率の検討は行われてレ、なレ、。 [0010] The transdermal absorption efficiency of a drug is the molecular weight of the drug, the solubility of the drug in the base material, It is determined by the distribution coefficient. Therefore, the combination of drug and substrate is very important when considering the transdermal administration of drugs. However, the examination of the transdermal absorption efficiency of the hydrophilicity / hydrophobicity of the drug and the nature of the substrate has been conducted to the extent that the investigation of the substrate for each drug has been conducted independently. Les.
[0011] 薬物の経皮吸収効率を高めるためには、角質層を疎にする性質を有する経皮吸収 促進剤を用いる方法が挙げられる。該手法で使用される成分として代表的なものに、 エタノールや界面活性剤が知られており、該成分は種々の経皮吸収製剤に利用され ている。経皮吸収効率は必ずしも高くはないが、水も経皮吸収効率を高めることが知 られている。例えば、温水で皮膚をふやけさせた後の薬物の経皮吸収効率が高まる ことも知られている。したがって、皮膚へのダメージが少なぐかつ薬物の経皮吸収効 率を高める成分として、水は重要な候補成分として挙げられる。 [0011] In order to enhance the transdermal absorption efficiency of a drug, a method using a transdermal absorption enhancer having a property of making the stratum corneum sparse can be mentioned. Ethanol and surfactants are known as typical components used in the technique, and the components are used in various transdermal preparations. Transdermal absorption efficiency is not necessarily high, but water is also known to increase transdermal absorption efficiency. For example, it is also known that the percutaneous absorption efficiency of drugs after increasing the skin with warm water increases. Therefore, water is an important candidate component as a component that causes little skin damage and enhances the transdermal absorption efficiency of the drug.
[0012] 一方、一般に生体高分子は水および生体組織との親和性が高い。さらに、ゼラチン に代表されるように、皮膚表面へのなじみが良い素材が多い。従って、皮膚一基材 界面の有効な接触面積が高ぐ同濃度の薬物を含む、同程度の親水性基材を用い た外用剤に比べて経皮吸収効率が高くなることが期待できる。し力もながら、これまで は生体高分子を経皮吸収製剤として用いた例はほとんどなレ、。  On the other hand, biopolymers generally have a high affinity for water and biological tissues. In addition, there are many materials that are familiar to the skin surface, such as gelatin. Therefore, it can be expected that the transdermal absorption efficiency is higher than that of an external preparation using the same level of hydrophilic base material containing the same concentration of drug with a high effective contact area at the interface between the skin and the base material. However, until now, there have been few examples of using biopolymers as a transdermal absorption preparation.
[0013] また、特開 2002— 255931号公報には、食品および動物飼料の分野または医薬 品および化粧品の用途に好適な少なくとも 1種の水溶性、水難溶性または水不溶性 活性化合物の固体調製物を製造する方法であって、 a)上記の活性化合物のうちの 少なくとも 1種をタンパク性保護コロイドの水性分子分散体または水性コロイド分散体 に溶解または分散させる工程と、 b)該活性化合物と一緒に該タンパク性保護コロイド を該分散体力 凝集析出させる工程と、 c)凝集させた固体を水および追加使用した 任意の溶媒から分離し、続いてそれを乾燥粉末に変換する工程とにより行われる方 法が記載されている。  [0013] In addition, JP 2002-255931 A discloses a solid preparation of at least one water-soluble, poorly water-soluble or water-insoluble active compound suitable for the field of food and animal feed or for use in pharmaceuticals and cosmetics. A) a step of dissolving or dispersing at least one of the above active compounds in an aqueous molecular dispersion or aqueous colloidal dispersion of a proteinaceous protective colloid; and b) together with the active compound A method comprising the step of coagulating and precipitating the proteinaceous protective colloid, and c) separating the agglomerated solid from water and any additional solvent used and subsequently converting it to a dry powder. Is described.
[0014] 特許文献 1：特許第 3639593号  [0014] Patent Document 1: Japanese Patent No. 3639593
特許文献 2：特許第 3771510号  Patent Document 2: Japanese Patent No. 3771510
特許文献 3：特表 2002-531182号公報  Patent Document 3: Japanese Translation of Special Publication 2002-531182
特許文献 4 :特表 2004— 532802号公報 特許文献 5：特開 2004-321484号公報 Patent Document 4: Japanese Translation of Special Publication 2004-532802 Patent Document 5: Japanese Patent Application Laid-Open No. 2004-321484
特許文献 6：特表 2003-500368号公報  Patent Document 6: Special Table 2003-500368
特許文献 7：特開昭 61— 204125号公報  Patent Document 7: JP-A-61-204125
特許文献 8 :特開 2002— 255931号公報  Patent Document 8: JP 2002-255931 A
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0015] 本発明は、従来技術において問題であった、あらかじめ作成したマトリックス内部に 難水溶性化合物を封入する問題、および薬剤封入後の架橋による架橋効率の低レヽ 問題を解決することを解決すべき課題とする。即ち、本発明は、難水溶性化合物を 微分散状態で親水性マトリックスに封入した組成物の製造方法を提供することを解決 すべき課題とする。さらに本発明は、抗癌剤を含む外用剤を提供すること、及び従来 技術においてほとんど検討のな力、つた、水、有機溶媒ともに溶解する薬物と水を多く 含んだ生体高分子による基材との組み合わせによる外用剤を作製することを解決す べき課題とした。 [0015] The present invention solves the problem of encapsulating a poorly water-soluble compound in a matrix prepared in advance and the problem of low cross-linking efficiency due to cross-linking after encapsulating a drug, which were problems in the prior art. It should be a challenge. That is, an object of the present invention is to provide a method for producing a composition in which a slightly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state. Further, the present invention provides an external preparation containing an anticancer agent, and a combination of a drug that dissolves in both water and an organic solvent and a base material made of a biopolymer containing a lot of water, which is almost unstudied in the prior art. The topic to be solved was the preparation of a topical preparation using
課題を解決するための手段  Means for solving the problem
[0016] 本発明では、有機フッ素化合物を難水溶性化合物の浸漬溶媒に利用することで、 従来技術の問題点である微分散状態で高濃度の難水溶性化合物を親水性マトリック スに封入した組成物を作成した。すなわち、該親水性マトリックスはあらかじめ任意の 形状に成形が可能であり、また成形プロセス中での難水溶性化合物の分解や変性を 回避できる。さらに本発明者らは、既存の基材である疎水性基材とは反対に、タンパ ク質などの親水性基材を、抗癌剤を封入するための基材として用いることにより、抗 癌剤を安定に封入し、かつ所望の治療効果を達成できることを見出し、本発明を完 成するに至った。また、既存の基材である疎水性の基材とは正反対の親水性の基材 とし、水、有機溶媒ともに溶解する薬物を親水性の生体高分子からなる基材に封入 することにより、薬物の封入量が高ぐ経皮吸収効率の高い外用剤を作製できること を見出し、本発明を完成するに至った。  [0016] In the present invention, an organic fluorine compound is used as an immersion solvent for a poorly water-soluble compound, whereby a highly concentrated poorly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state, which is a problem of the prior art. A composition was prepared. That is, the hydrophilic matrix can be molded into an arbitrary shape in advance, and decomposition or modification of the poorly water-soluble compound during the molding process can be avoided. Furthermore, the present inventors use an anticancer agent by using a hydrophilic substrate such as a protein as a substrate for encapsulating the anticancer agent, as opposed to a hydrophobic substrate that is an existing substrate. The inventors have found that it is possible to stably encapsulate and achieve a desired therapeutic effect, and the present invention has been completed. In addition, a hydrophilic substrate opposite to the existing hydrophobic substrate is used, and a drug that dissolves in both water and organic solvent is encapsulated in a substrate made of a hydrophilic biopolymer. The present inventors have found that an external preparation with a high transdermal absorption efficiency with a high encapsulated amount of can be prepared, and the present invention has been completed.
[0017] 即ち、本発明によれば、難水溶性化合物を含有する有機フッ素化合物に親水性マ トリックスを浸漬して難水溶性化合物を親水性マトリックスに封入することを含む、難 水溶性化合物を親水性マトリックスに封入した組成物の製造方法が提供される。 [0017] That is, according to the present invention, the method comprises immersing a hydrophilic matrix in an organic fluorine compound containing a hardly water-soluble compound and encapsulating the hardly water-soluble compound in a hydrophilic matrix. A method for producing a composition in which a water-soluble compound is encapsulated in a hydrophilic matrix is provided.
[0018] 好ましくは、難水溶性化合物を含有する有機フッ素化合物に親水性マトリックスを 浸漬した後に、該親水性マトリックスを乾燥する。 [0018] Preferably, the hydrophilic matrix is dried after immersing the hydrophilic matrix in the organic fluorine compound containing the poorly water-soluble compound.
[0019] 好ましくは、親水性マトリックスは生体高分子である。 [0019] Preferably, the hydrophilic matrix is a biopolymer.
好ましくは、親水性マトリックスはタンパク質である。  Preferably, the hydrophilic matrix is a protein.
好ましくは、タンパク質はコラーゲン、ゼラチン、アルブミン、カゼイン、フイブ口イン、 フイブリン、ラミニン、フイブロネクチン、又はビトロネクチンからなる群より選ばれる少 なくとも一種である。  Preferably, the protein is at least one selected from the group consisting of collagen, gelatin, albumin, casein, fib mouth-in, fibrin, laminin, fibronectin, or vitronectin.
好ましくは、タンパク質はコラーゲン、ゼラチン、アルブミン、カゼイン、フイブ口イン である。  Preferably, the protein is collagen, gelatin, albumin, casein, or fib mouth in.
好ましくは、タンパク質はコラーゲン、ゼラチンである。  Preferably, the protein is collagen or gelatin.
好ましくは、タンパク質はゼラチンである。  Preferably the protein is gelatin.
[0020] 好ましくは、親水性マトリックスは、熱、光、または架橋剤により架橋されている。 [0020] Preferably, the hydrophilic matrix is crosslinked by heat, light, or a crosslinking agent.
好ましくは、架橋剤は酵素である。  Preferably, the cross-linking agent is an enzyme.
好ましくは、酵素はトランスダルタミナーゼである。  Preferably the enzyme is transdaltaminase.
好ましくは、親水性マトリックスの架橋はダルタルアルデヒド、又はトランスグルタミナ ーゼを用いて行われる。  Preferably, the cross-linking of the hydrophilic matrix is performed using dartalaldehyde or transglutaminase.
[0021] 好ましくは、有機フッ素化合物は、炭素数 2から 8の化合物である。 [0021] Preferably, the organic fluorine compound is a compound having 2 to 8 carbon atoms.
好ましくは、有機フッ素化合物は、炭素数 2から 3の化合物である。  Preferably, the organic fluorine compound is a compound having 2 to 3 carbon atoms.
好ましくは、有機フッ素化合物は、 1 , 1 , 1一へキサフルオロー 2—プロパノール、ト リフルォロエタノール、へキサフルォロアセトン、トリフルォロ酢酸、又はペンタフルォ 口プロピオン酸である。  Preferably, the organic fluorine compound is 1,1,1, monohexafluoro-2-propanol, trifluoroethanol, hexafluoroacetone, trifluoroacetic acid, or pentafluoro-oral propionic acid.
好ましくは、難水溶性化合物の 1ーォクタノール/水の分配係数の対数 log Pは 1〜 20である。  Preferably, the log P of the 1-octanol / water partition coefficient of the poorly water-soluble compound is 1-20.
好ましくは、難水溶性化合物の 1ーォクタノール/水の分配係数の対数 log Pは 2〜 10である。  Preferably, the log P of the 1-octanol / water partition coefficient of the poorly water-soluble compound is 2-10.
[0022] 好ましくは、難水溶性化合物は薬剤、色素である。  [0022] Preferably, the poorly water-soluble compound is a drug or a pigment.
好ましくは、難水溶性化合物は薬剤である。 好ましくは、薬剤は免疫抑制剤、抗アレルギー剤、抗酸化剤、抗血栓剤、抗炎症剤 、抗癌剤、化粧品成分、またはサプリメント成分である。 Preferably, the poorly water-soluble compound is a drug. Preferably, the drug is an immunosuppressant, an antiallergic agent, an antioxidant, an antithrombotic agent, an antiinflammatory agent, an anticancer agent, a cosmetic ingredient, or a supplement ingredient.
好ましくは、薬剤は抗癌剤である。  Preferably, the drug is an anticancer drug.
好ましくは、薬剤はパクリタキセルである。  Preferably, the drug is paclitaxel.
[0023] 好ましくは、有機フッ素化合物中に、難水溶性化合物と一緒に添加物が含まれて いる。 [0023] Preferably, the organic fluorine compound contains an additive together with the poorly water-soluble compound.
好ましくは、添加物は、保湿剤、柔軟剤、経皮吸収促進剤、及び界面活性剤から選 択される 1種以上のものである。  Preferably, the additive is one or more selected from humectants, softeners, transdermal absorption enhancers, and surfactants.
好ましくは、難水溶性化合物を親水性マトリックスに封入した組成物は、経皮吸収 剤、局所治療剤、経口治療剤、化粧品、サプリメント、又は色素材として使用される。  Preferably, a composition in which a poorly water-soluble compound is encapsulated in a hydrophilic matrix is used as a transdermal absorption agent, a topical therapeutic agent, an oral therapeutic agent, a cosmetic, a supplement, or a color material.
[0024] さらに本発明によれば、抗癌剤を封入した親水性基材からなる抗癌剤含有外用剤 が提供される。 [0024] Further, according to the present invention, an anticancer agent-containing external preparation comprising a hydrophilic substrate encapsulating an anticancer agent is provided.
[0025] 好ましくは、親水性基材はタンパク質である。 [0025] Preferably, the hydrophilic substrate is a protein.
好ましくは、タンパク質は、コラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、フ イブリン、フイブロネクチン、及びビトロネクチンからなる群より選ばれる少なくとも一種 である。  Preferably, the protein is at least one selected from the group consisting of collagen, gelatin, albumin, laminin, casein, fibrin, fibronectin, and vitronectin.
好ましくは、タンパク質はコラーゲンまたはゼラチンである。  Preferably the protein is collagen or gelatin.
好ましくは、タンパク質が、ヒト、牛、豚又は魚に由来するタンパク質、又は遺伝子組 み換えタンパク質である。  Preferably, the protein is a protein derived from human, cow, pig or fish, or a genetically modified protein.
[0026] 好ましくは、タンパク質は架橋されて!/、る。 [0026] Preferably, the protein is cross-linked!
好ましくは、タンパク質の架橋は熱、光、縮合剤、又は酵素を用いて行われている。 好ましくは、タンパク質の架橋は酵素による架橋である。  Preferably, protein cross-linking is performed using heat, light, a condensing agent, or an enzyme. Preferably, protein cross-linking is enzymatic cross-linking.
好ましくは、酵素はトランスダルタミナーゼである。  Preferably the enzyme is transdaltaminase.
[0027] 好ましくは、抗癌剤は 5—フルォロウラシル、パクリタキセル、シスプラチン、又はドキ シノレビシンである。 [0027] Preferably, the anticancer agent is 5-fluorouracil, paclitaxel, cisplatin, or doxinolevicin.
好ましくは、抗癌剤が 5—フルォロウラシル又はパクリタキセルである。  Preferably, the anticancer agent is 5-fluorouracil or paclitaxel.
好ましくは、本発明の抗癌剤含有外用剤は、皮膚癌、又は角化症の治療のために 用いる。 好ましくは、本発明の抗癌剤含有外用剤は、色素剤、柔軟剤、経皮吸収促進剤、 保湿剤、ェモリエント成分、防腐剤、香料、又は pH調整剤から選択される 1種以上の 添加剤をさらに含む。 Preferably, the anticancer agent-containing external preparation of the present invention is used for the treatment of skin cancer or keratosis. Preferably, the anticancer agent-containing external preparation of the present invention contains at least one additive selected from a pigment, a softener, a transdermal absorption enhancer, a moisturizer, an emollient component, an antiseptic, a fragrance, or a pH adjuster. In addition.
[0028] さらに本発明によれば、タンパク質、抗癌剤、及びタンパク質を架橋するための酵 素含む溶液を調製した後、該溶液を基板上に流し込んで静置することによりゲルを 形成することにより製造される、抗癌剤含有外用剤が提供される。  [0028] Further, according to the present invention, a solution containing a protein, an anticancer agent, and an enzyme for cross-linking the protein is prepared, and then the solution is poured onto a substrate and allowed to stand to form a gel. An anticancer agent-containing external preparation is provided.
[0029] さらに本発明によれば、酸処理ゼラチン、 5—フルォロウラシル又はパクリタキセル、 およびトランスダルタミナーゼを含む水溶液を調製した後、該溶液を基板上に流し込 んで静置することによりゲルを形成することにより製造される、抗癌剤含有外用剤が 提供される。  [0029] Further, according to the present invention, after preparing an aqueous solution containing acid-treated gelatin, 5-fluorouracil or paclitaxel, and transdaltaminase, the solution is poured onto a substrate and left to stand to form a gel. Thus, an anticancer agent-containing external preparation manufactured by the above process is provided.
さらに本発明によれば、酸処理ゼラチン、 5—フルォロウラシル又はパクリタキセル、 およびトランスダルタミナーゼを含む水溶液を調製した後、該溶液を基板上に流し込 んで静置することによりゲルを形成することにより製造される、抗癌剤含有外用剤が 提供される。  Furthermore, according to the present invention, an aqueous solution containing acid-treated gelatin, 5-fluorouracil or paclitaxel, and transdaltaminase is prepared, and then the solution is poured onto a substrate to stand to form a gel. An anticancer agent-containing external preparation to be produced is provided.
[0030] さらに本発明によれば、ォクタノール/水の分配係数 (LogP)が- 3.0以上 3.0以下で ある薬物が生体高分子を主成分とする構造物中に封入されている、外用剤用組成 物が提供される。  [0030] Further, according to the present invention, a composition for external preparation, wherein a drug having an octanol / water partition coefficient (LogP) of -3.0 or more and 3.0 or less is encapsulated in a structure mainly composed of a biopolymer. Things are provided.
こで言つ LogPとは Medicinal Chemistry Project. Pomona し ollege, Claremont, Cali orniaで開発され、 Daylight Chemical Information Systems, Inc.より入手できるソフトゥ エア PCModelsを用いて算出した、化合物のォクタノール/水分配係数（P)の値の対 数である。  LogP here means the octanol / water partition coefficient of a compound, calculated using the Medicinal Chemistry Project. Software PCModels developed by Pomona, ollege, Claremont, California and available from Daylight Chemical Information Systems, Inc. ( It is the logarithm of the value of P).
[0031] 好ましくは、薬物の LogPは- 1.5以上 0以下である。  [0031] Preferably, the LogP of the drug is -1.5 or more and 0 or less.
好ましくは、薬物の分子量は 1500以下である。  Preferably, the molecular weight of the drug is 1500 or less.
好ましくは、薬物は抗癌剤である。  Preferably, the drug is an anticancer agent.
好ましくは、抗癌剤は 5—フルォロウラシル又はアドリアマイシンである。  Preferably, the anticancer agent is 5-fluorouracil or adriamycin.
[0032] 好ましくは、組成物中の含水率は 40%以上である。 [0032] Preferably, the water content in the composition is 40% or more.
好ましくは、生体高分子はタンパク質、又は多糖である。  Preferably, the biopolymer is a protein or a polysaccharide.
好ましくは、タンパク質はコラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、及 びフイブリンからなる群より選ばれる少なくとも一種である。 Preferably, the protein is collagen, gelatin, albumin, laminin, casein, and And at least one selected from the group consisting of fibrin.
好ましくは、タンパク質が架橋されている。  Preferably the protein is cross-linked.
好ましくは、タンパク質の架橋がダルタルアルデヒド、又はトランスダルタミナーゼを 用いて行われている。  Preferably, the protein is cross-linked using dartalaldehyde or transdaltaminase.
好ましくは、タンパク質の架橋がトランスダルタミナーゼを用いて行われている。 好ましくは、本発明の外用剤組成物は、色素剤、柔軟剤、経皮吸収促進剤、保湿 剤、界面活性剤、防腐剤、香料、及び pH調整剤からなる群より選ばれる少なくとも一 種以上の添加剤をさらに含有する。  Preferably, protein cross-linking is performed using transdalminase. Preferably, the external preparation composition of the present invention is at least one selected from the group consisting of a pigment, a softener, a transdermal absorption enhancer, a moisturizer, a surfactant, an antiseptic, a fragrance, and a pH adjuster. The additive is further contained.
好ましくは、本発明の外用剤用組成物は、皮膚癌又は角化症の治療のために使用 される。  Preferably, the composition for external use of the present invention is used for the treatment of skin cancer or keratosis.
発明の効果  The invention's effect
[0033] 本発明によれば、難水溶性化合物を微分散状態で親水性マトリックスに封入した組 成物の製造方法を提供することが可能になった。本発明の方法で製造される組成物 にお!/、ては難水溶性化合物が微分散状態で親水性マトリックスに封入されて!/、ること により、該難水溶性化合物 (例えば、薬剤など）の放出量、速度、および薬効の制御 に有利であり、さらに、本発明の組成物を経皮吸収製剤として利用する際には経皮 吸収効率が向上するという利点がある。  [0033] According to the present invention, it is possible to provide a method for producing a composition in which a slightly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state. In the composition produced by the method of the present invention, the poorly water-soluble compound is encapsulated in a hydrophilic matrix in a finely dispersed state! / ) Is advantageous in controlling the release amount, rate, and drug efficacy, and further, when the composition of the present invention is used as a transdermally absorbable preparation, there is an advantage that the transdermal absorption efficiency is improved.
[0034] さらに本発明の抗癌剤含有外用剤を実施することにより、（1 )親水性の高い薬剤の 封入量が多くなる、（2)疎水性である角質層との親水一疎水性の性質差が大きくなる ため、疎水性を有する薬剤の皮膚浸透性が高くなる可能性がある。 （3)皮膚との密 着性が高まるため、有効接触面積が増加し、皮膚への浸透性が高まる可能性がある 。また、（4)例えば皮膚に傷のある場合、組織から漏出する液の保持性が高まり、傷 を治癒する効果も同時に期待できる。  [0034] Further, by implementing the anticancer agent-containing external preparation of the present invention, (1) the amount of highly hydrophilic drug encapsulated is increased, and (2) the hydrophilic-hydrophobic property difference from the hydrophobic stratum corneum Therefore, there is a possibility that the skin permeability of the hydrophobic drug may be increased. (3) Since the adhesion with the skin is increased, the effective contact area may be increased and the permeability to the skin may be increased. In addition, (4) for example, when there is a wound on the skin, the retention of liquid leaking from the tissue is enhanced, and an effect of healing the wound can be expected at the same time.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0035] 以下、（1)難水溶性化合物を親水性マトリックスに封入した組成物の製造方法、 (2 )抗癌剤を封入した親水性基材からなる抗癌剤含有外用剤、及び (3)ォクタノール/ 水の分配係数 (LogP)が- 3.0以上 3.0以下である薬物が生体高分子を主成分とする 構造物中に封入されている外用剤用組成物、について順番に説明する。 [0036] ( 1 )難水溶性化合物を親水性マトリッタスに封入した組成物の製造方法 近年、再生医療やバイオマテリアルにおいて、生体高分子に代表される親水性マト リックスが生体親和性の高いものが多いことから広く利用されつつある。中でも、コラ 一ゲンやゼラチンのようなタンパクはそれぞれ固有の機能を有することから、組織構 築用マトリックス材料や薬剤徐放担体等、医療分野への応用が行われている。さらに これらにグロースファクタ一等の生理活性物質を封入することで、組織の修復が改善 される。しかしながら、これらグロースファクターの多くは親水性であるため、多くはこ れらの薬剤を水に溶解し、マトリックスに浸漬させることにより親水性マトリックス中に 薬剤を封入している。 [0035] Hereinafter, (1) a method for producing a composition in which a poorly water-soluble compound is encapsulated in a hydrophilic matrix, (2) an anticancer agent-containing external preparation comprising a hydrophilic substrate encapsulating an anticancer agent, and (3) octanol / water The composition for external use in which a drug having a distribution coefficient (LogP) of −3.0 or more and 3.0 or less is encapsulated in a structure mainly composed of a biopolymer will be described in order. [0036] (1) Method for producing a composition in which a poorly water-soluble compound is encapsulated in hydrophilic matrix. Recently, in regenerative medicine and biomaterials, hydrophilic matrices represented by biopolymers have high biocompatibility. It is being used widely because of its large number. Among them, proteins such as collagen and gelatin have unique functions, and thus are applied to the medical field, such as tissue-building matrix materials and drug sustained-release carriers. Furthermore, by encapsulating a physiologically active substance such as the growth factor in these, tissue repair is improved. However, since many of these growth factors are hydrophilic, many of these drugs are encapsulated in a hydrophilic matrix by dissolving them in water and immersing them in the matrix.
[0037] 本発明にお!/、ては難水溶性化合物が微分散状態で封入されて!/、ることが好ましレ、 。本明細書で言う微分散状態とは、封入されている難水溶性薬剤が、実体顕微鏡 (ラ イカ社製、 MZ16A)にて検出不能であるサイズの化合物がマトリックス中に均一に分 散している状態か、薬剤が分子分散している状態をさす。更に詳細には、走査型顕 微鏡（SEM)で観察した場合に、封入されて!/、る化合物の粒径が 0.001 m〜10 m で均一に分散している状態を言う。化合物の粒径として好ましくは 0.01 H m〜211 m、 最も好ましくは 0.01 a m〜0.5 μ mである。  [0037] In the present invention, it is preferable that a slightly water-soluble compound is encapsulated in a finely dispersed state! In the present specification, the finely dispersed state means that the encapsulated poorly water-soluble drug is uniformly dispersed in the matrix with a compound having a size that cannot be detected with a stereomicroscope (manufactured by Leica, MZ16A). Or a state in which the drug is molecularly dispersed. More specifically, it means a state in which the particle size of the encapsulated compound is uniformly dispersed at 0.001 m to 10 m when observed with a scanning microscope (SEM). The particle size of the compound is preferably 0.01 Hm to 211 m, and most preferably 0.01 am to 0.5 μm.
[0038] 該手法により作成した難水溶性化合物を親水性マトリックスに封入した組成物は必 要に応じて架橋を行っても良い。親水性マトリックスの架橋度を制御することで、生体 内分解性、強度、構造等の各種性質を作り分けることが可能となる。架橋方法は特に 限定することはない。架橋方法としては例えば物理架橋、化学架橋、熱架橋、酵素 架橋等が挙げられる。好ましくは化学または酵素架橋である。化学架橋剤としては一 般的に広く利用されて!/、るダルタルアルデヒドやホルムアルデヒド等のアルデヒド、力 ルポジイミド、シァナミド等、ビニルスルホン、ジエポキシド、シンナミル基、ビュル基、 クマリン等の光二量化性基を含む架橋剤が挙げられる。より好ましくはダルタルアル デヒド、トランスダルタミナーゼである。最も好ましくはトランスダルタミナーゼによる酵 素架橋である。  [0038] The composition in which the poorly water-soluble compound prepared by the method is encapsulated in a hydrophilic matrix may be crosslinked as necessary. By controlling the degree of crosslinking of the hydrophilic matrix, various properties such as biodegradability, strength, and structure can be created. The crosslinking method is not particularly limited. Examples of the crosslinking method include physical crosslinking, chemical crosslinking, thermal crosslinking, and enzyme crosslinking. Chemical or enzymatic crosslinking is preferred. Widely used as chemical cross-linking agents! /, Aldehydes such as rutartal aldehyde and formaldehyde, strength positimide, cyanamide, etc., vinylsulfone, diepoxide, cinnamyl group, bur group, coumarin and other photodimerizable groups The crosslinking agent containing is mentioned. More preferred are daltal aldehyde and transdaltaminase. Most preferred is enzyme crosslinking with transdaltaminase.
[0039] 該手法に用いる有機フッ素化合物は特に限定するものではないが、親水性マトリツ タスと難水溶性化合物をともに溶解または懸濁できることが必要であり、常温で液体 のものが好ましい。さらに、難水溶性化合物と親水性マトリックスを含む該溶液または 懸濁液を、塗布した際に溶媒が留去可能である溶媒が好ましい。 [0039] The organic fluorine compound used in the method is not particularly limited, but it is necessary to dissolve or suspend both the hydrophilic matrix and the poorly water-soluble compound. Are preferred. Furthermore, a solvent that can be distilled off when the solution or suspension containing the poorly water-soluble compound and the hydrophilic matrix is applied is preferable.
このうち、好ましくは炭素数 2〜8である非芳香族有機フッ素化合物又は炭素数 6〜 12の芳香族含フッ素エステル類、カルボン酸類、二トリル類である。炭素数 2〜8であ る非芳香族有機フッ素化合物としては、炭素数 2〜8のフッ素含有アルコール類、フ ッ素含有アミド類、フッ素含有エステル類、フッ素含有カルボン酸、フッ素含有エーテ ノレ類が好ましい。フッ素以外のハロゲン原子で一部が置換されていても構わない。こ のうちより好ましくは炭素数が 2から 3であるフッ素含有アルコールである。最も好まし くは 1，1，1-3，3，3-へキサフルォ口- 2-プロパノール、 2,2,2-トリフルォロエタノール、トリ フルォロ酢酸、およびペンタフルォロプロピオン酸である。また、該溶媒は種々の溶 媒と相溶性があるため、相溶性のある溶媒との混合溶媒として利用しても構わなレ、。  Of these, non-aromatic organic fluorine compounds having 2 to 8 carbon atoms or aromatic fluorine-containing esters, carboxylic acids and nitriles having 6 to 12 carbon atoms are preferable. Non-aromatic organic fluorine compounds having 2 to 8 carbon atoms include fluorine-containing alcohols, fluorine-containing amides, fluorine-containing esters, fluorine-containing carboxylic acids and fluorine-containing ethers having 2 to 8 carbon atoms. Is preferred. It may be partially substituted with a halogen atom other than fluorine. Of these, fluorine-containing alcohols having 2 to 3 carbon atoms are more preferable. Most preferred are 1,1,1-3,3,3-hexafluoro-2-propanol, 2,2,2-trifluoroethanol, trifluoroacetic acid, and pentafluoropropionic acid. Also, since the solvent is compatible with various solvents, it may be used as a mixed solvent with a compatible solvent.
[0040] 該親水性マトリックスの成分としてはフッ素含有溶媒に溶解すれば生体高分子、合 成高分子、脂質等いずれでも構わない。さらに、生体由来の生体高分子は糖、タン パク質およびそれらの誘導体のいずれでも構わないが、球状、繊維状等のタンパク 質が好ましぐ好ましくはコラーゲン、ゼラチン、アルブミン、カゼイン、フイブ口イン、フ イブリン、ラミニン、フイブロネクチン、又はビトロネクチンである、より好ましくはコラー ゲン、ゼラチン、アルブミン、カゼイン、フイブ口イン、ラミュンである。最も好ましくはコ ラーゲン、ゼラチン、アルブミン、カゼインであり、このなかでもゼラチンが最も好まし い。また、タンパク質の由来は特に限定するものではなぐ牛、豚、魚、および遺伝子 組み換え体のいずれも用いることができる。遺伝子組替え体としては、例えば EP0926 543B，WO2004-085473号明細書、 EP1398324A、 EP1014176A、 US6645712に記載の ものを用いること力 Sできる。  [0040] The component of the hydrophilic matrix may be any of a biopolymer, a synthetic polymer, a lipid and the like as long as it is dissolved in a fluorine-containing solvent. Furthermore, the biopolymer derived from a living body may be any of sugars, proteins and derivatives thereof, but proteins such as spheres and fibers are preferred, preferably collagen, gelatin, albumin, casein, and live mouth-in. , Fibrin, laminin, fibronectin, or vitronectin, more preferably collagen, gelatin, albumin, casein, fib mouthin, or ramun. Most preferred are collagen, gelatin, albumin, and casein, and among these, gelatin is most preferred. The origin of the protein is not particularly limited, and any of cows, pigs, fish, and genetically modified organisms can be used. As the recombinant gene, for example, those described in EP0926 543B, WO2004-085473, EP1398324A, EP1014176A, US6645712 can be used.
[0041] 難水溶性化合物は色素剤、薬剤等、難水溶性の化合物であれば!/、ずれでも構わ ない。一般に化合物の親水一疎水性の指標として、フラスコシエイキング法により得ら れる 1ーォクタノール/水（ρΗ7·4緩衝溶液）の分配係数の対数 (Log P)が広く用いら れているが、実測する代わりに計算により求めても良い。 （本明細書における LogPは 、 Daylight Chemical Information Systems社のシステム： PCModelsに組み込まれた Ha nsch-Leoのフラグメント法 CLOGPプログラムを使用して計算して!/、る。） 難水溶性化合物、すなわち Log Pが 1以上の化合物の親水性マトリックスへの均一 な封入は困難であることが知られていた。本発明で封入する難水溶性化合物の Log Pは好ましくは 1以上 20以下であり、さらに好ましくは 1以上 15以下であり、特に好まし くは 2以上 10以下であり、最も好ましくは 3以上 5以下である。 [0041] The poorly water-soluble compound may be a poorly water-soluble compound such as a coloring agent or a drug, and may be shifted. In general, the logarithm (Log P) of the distribution coefficient of 1-octanol / water (ρΗ7 · 4 buffer solution) obtained by the flask shaking method is widely used as an index of hydrophilicity / hydrophobicity of compounds. Instead, it may be obtained by calculation. (LogP in this specification is calculated using the Hansch-Leo fragment method CLOGP program embedded in the System: PCModels of Daylight Chemical Information Systems!) It has been known that it is difficult to uniformly encapsulate a poorly water-soluble compound, that is, a compound having Log P of 1 or more in a hydrophilic matrix. Log P of the poorly water-soluble compound to be encapsulated in the present invention is preferably 1 or more and 20 or less, more preferably 1 or more and 15 or less, particularly preferably 2 or more and 10 or less, and most preferably 3 or more and 5 or less. It is as follows.
[0042] 本発明で封入される難水溶性化合物のうち、好ましい化合物は、 1，1，1-3，3，3-へキ サフルォ口- 2-プロパノールに対する溶解度が 50mg/ml〜1000mg/mlの化合物であり 、更に好ましくは 100mg/ml〜500mg/mlの化合物である。これらの化合物は高濃度で も本発明でいう微分散状態を保持できる。なお、本発明のへキサフルォロイソプロパ ノールに対する溶解度は以下のように測定できる。 1，1，1-3，3，3-へキサフルォ口- 2-プ ロバノールへ、化合物の濃度を段階的に変化させて添加した物を作成し、どの濃度 で析出が起きているかを確認することで、その化合物の 1，1，1-3，3，3-へキサフルォ口- 2_プロパノールへの溶解度とする。尚、溶解 .不溶解の判断は、上記混合液を超小 型遠心機（チビタン II XX42CF00T ;テックジャム株式会社製）にて 20秒間遠心し、沈 殿が生じて!/、る力、を確認することでできる。 [0042] Among the poorly water-soluble compounds encapsulated in the present invention, preferred compounds have a solubility in 1,1,1-3,3,3-hexafluoro-2-propanol of 50 mg / ml to 1000 mg / ml. More preferably, the compound is 100 mg / ml to 500 mg / ml. These compounds can maintain the finely dispersed state referred to in the present invention even at a high concentration. The solubility of the present invention in hexafluoroisopropanol can be measured as follows. Create a compound that is added to 1,1,1-3,3,3-hexafluoro-2-proanol by gradually changing the concentration of the compound, and confirm the concentration at which the precipitation occurs. Therefore, the solubility of the compound in 1,1,1-3,3,3-hexafluoro-2-2-propanol is obtained. For determination of dissolution or insolubility, the above mixture was centrifuged for 20 seconds in a microcentrifuge (Chibitan II XX42CF00T; manufactured by Tech Jam Co., Ltd.) to confirm that precipitation occurred! You can do it.
[0043] 薬剤は生理活性成分である。具体的には経皮吸収剤、局所治療剤、経口治療剤、 化粧品成分、サプリメント成分が挙げられる。薬剤の具体例としては、好ましくは、免 疫抑制剤（例えば、ラバマイシン、タク口リムス、シクロスポリン）、抗癌剤（例えば、パク リタキセル、トポテシン、タキソテール、ドセタキセル、エノシタビン、 17-AAG)、解熱性 鎮痛剤（例えばアスピリン、ァセトァミノフェン、スルピリン）、抗てんかん剤（例えばフエ ニトイン、ァセタゾラミド、カルバマゼピン、クロナゼパム、ジァゼパム、ニトラゼバム）、 消炎鎮痛剤（例えばアルクロフエナク、アルミノプロフェン、イブプロフェン、インドメタ シン、ェピリゾール、ォキサプロジン、ケトプロフェン、ジクロフェナクナトリウム、ジフル 二サル、ナプロキセン、ピロキシカム、フェンブフェン、フルフエナム酸、フルルビプロ フェン、フロクタフェニン、ペンタゾシン、メチアジン酸、メフエナム酸、モフエゾラク）、 脂溶性ビタミン（例えばビタミン A、ビタミン D2、ビタミン D3、ビタミン E、ビタミン K2)、合 成抗菌剤（エノキシン、オフロキサシン、シノキサシン、スバルフロキサシン、チアンフ ェニコール、ナリジタス酸、トシル酸トスフロキサシン、ノルフロキサシン、ピぺミド酸三 水和物、ピロミド酸、フレロキサシン、レポフロキサシン）、抗真菌剤（例えばイトラコナ ゾーノレ、ケトコナゾーノレ、 フノレコナゾ一ノレ、 フノレシトシン、ミコナゾーノレ、ピマリシン）、 エリスロマイシン、クラリスロマイシン、テリスロマイシン、アジスロマイシン）、抗ゥイノレス 剤（ァシクロビル、ガンシクロビル、ジダノシン、ジドブジン、ビタラビン）、ホルモン剤（ 例えばインスリン亜鉛、プロピオン酸テストステロン、安息香酸エストラジオール）、循 環器官用薬 (例えばアルプロスタジル)、抗血栓剤、消化器管用薬 (オメブラゾール、 ランソプラゾール、テプレノン、メトクロプラミド、ソファルコン）、糖尿病用剤（例えば塩 酸ピオグリタゾン）、抗酸化剤、抗アレルギー剤（フマル酸クレマスチン、口ラタジン、メ キタジン、ザフィルルカスト、プランルカスト、ェバスチン、タザノラスト、トラニラスト、ラ マトロバン、ォキサトミド）、ステロイド抗炎症剤（例えば酢酸コルチゾン、ベタメタゾン、 プレドニゾロン、プロピオン酸フルチ力ゾン、デキサメタゾン、ブデソニド、プロピオン 酸べクロメタゾン、トリアムシノロン、ロトプレドノール、フルォロメトロン、ジフルプレドナ ード、フランカルボン酸モメタゾン、プロピオン酸クロべタゾール、酢酸ジフロラゾン、 吉草酸ジフルコルトロン、フルオシノニド、アムシノニド、ハルシノニド、フルオシノロン ァセトニド、トリアムシノロンァセトニド、ピバル酸フルメタゾン、酪酸クロベタゾン）、化 粧品成分、サルファ剤（例えばサラゾスルフアビリジン、スルフアジメトキシン、スルファ メチゾ一ノレ、スノレファメトキサゾーノレ、スノレファメトピラジン、スノレファモノメトキシン）、麻 酔薬 (例えばフェンタニル）、潰瘍性大腸炎治療剤（例えばメサラジン）またはサブリメ ント成分を用いることができる。 [0043] The drug is a physiologically active ingredient. Specific examples include transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, cosmetic ingredients, and supplement ingredients. Specific examples of the drug are preferably an immunosuppressant (eg, ravamycin, taximus limus, cyclosporine), an anticancer agent (eg, paclitaxel, topotecin, taxotere, docetaxel, enocitabine, 17-AAG), antipyretic analgesic (E.g., aspirin, acetaminophen, sulpyrine), antiepileptics (e.g., phenytoin, acetazolamide, carbamazepine, clonazepam, diazepam, nitrazebam), anti-inflammatory analgesics (e.g., alclofenac, aluminoprofen, ibuprofen, indomethacin, , Ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam, fenbufen, flufenamic acid, flurbiprofen, fructophenine, pentazocine, methiadi Acid, mefenamic acid, mofezolac), fat-soluble vitamins (eg vitamin A, vitamin D2, vitamin D3, vitamin E, vitamin K2), synthetic antibacterial agents (enoxin, ofloxacin, sinoxacin, subalfloxacin, thianphenicol, narigitas) Acid, tosufloxacin tosylate, norfloxacin, pipemetic acid trihydrate, pyromido acid, fleroxacin, lepofloxacin), antifungal agents (eg itracona Zonole, Ketoconazonole, Funoreconazo Monole, Funorecytosine, Myconazonore, Pimaricin), Erythromycin, Clarithromycin, Terithromycin, Azithromycin, Anti-Winores (Acyclovir, Ganciclovir, Zidanocine, Zidovudine, Vitamins) Testosterone propionate, estradiol benzoate), cardiovascular drugs (eg alprostadil), antithrombotics, gastrointestinal drugs (omebrazol, lansoprazole, teprenone, metoclopramide, sofalcone), diabetics (eg pioglitazone hydrochloride) ), Antioxidants, antiallergic agents (clemastine fumarate, oral latazine, mequitazine, zafirlukast, pranlukast, ebastine, tazanolast, tomato Nilast, ramatroban, oxatomide), steroidal anti-inflammatory drugs (eg cortisone acetate, betamethasone, prednisolone, flutizone propionate, dexamethasone, budesonide, beclomethasone propionate, triamcinolone, rotopredonol, fluormethorone, diflupredone , Clobetasol propionate, diflorazone acetate, diflucortron valerate, fluocinonide, amsinonide, harcinonide, fluocinolone acetonide, triamcinolone acetonide, flumethasone pivalate, clobetasone butyrate, cosmetic ingredients, sulfa drugs (eg, lyazosulfide) Sulfadimethoxine, sulfamethizinole, sunolefamethoxazonole, sunolefamethopyrazine, snow Fan monomethoxy down), anesthetics (e.g. fentanyl), can be used ulcerative colitis treating agent (e.g., mesalazine) or Saburime cement component.
用途は特に限定することはないが、経皮吸収剤、局所治療剤、経口治療剤、化粧 品、サプリメント、色素材である。好ましくは経皮吸収剤、局所治療剤、経口治療剤、 化粧品である。さらに好ましくは経皮吸収剤、局所治療剤、経口治療剤である。最も 好ましくは経皮吸収剤、局所治療剤である。  Uses are not particularly limited, but are percutaneous absorption agents, topical treatment agents, oral treatment agents, cosmetics, supplements, and color materials. Preferred are transdermal absorption agents, topical therapeutic agents, oral therapeutic agents, and cosmetics. More preferred are transdermal absorption agents, topical therapeutic agents, and oral therapeutic agents. Most preferred are transdermal absorption agents and topical treatment agents.
また、難水溶性化合物には、各種添加物を加えてもよい。本発明で用いることがで きる添加物としては、保湿剤（例えば、カンテン、ジグリセリン、ジステアリルジモニゥム ヘクトライト、ブチレングリコーノレ、ポリエチレングリコーノレ、プロピレングリコーノレ、ヒア ルロン酸ナトリウム、へキシレンダリコール、ョタイニンエキス、ワセリン）、柔軟剤（例え ば、グリセリン、ミネラルオイル）、ェモリエント成分（例えば、イソステアリン酸イソプロ ピル、イソステアリン酸ポリグリセリル、イソノナン酸イソトリデシル、イソノナン酸ォクチ ノレ、ォレイン酸、ォレイン酸グリセリル、カカオ脂、コレステロール、混合脂肪酸トリダリ セリド、コハク酸ジォクチル、酢酸ステアリン酸スクロース、シクロペンタシロキサン、ジ ステアリン酸スクロース、パルミチン酸ォクチル、ヒドロキシステアリン酸ォクチル、ベへ ン酸ァラキル、ポリべヘン酸スクロース、ポリメチルシルセスキォキサン、ミリスチルァ ルコール、ミリスチン酸セチル、ミリスチン酸ミリスチル、ラウリン酸へキシル）、及び経 皮吸収促進剤（例えば、エタノール、ミリスチン酸イソプロピル、クェン酸、スクヮラン、 ォレイン酸、メントール、 N-メチル -2-ピロリドン、アジピン酸ジェチル、アジピン酸ジィ ソプロピル、セバシン酸ジェチル、セバシン酸ジイソプロピル、パルミチン酸イソプロピ ル、ォレイン酸イソプロピル、ォレイン酸オタチルドデシル、イソステアリルアルコール 、 2-ォクチルドデカノール、尿素、植物油、動物油）、防腐剤（例えば、安息香酸、安 息香酸ナトリウム、ェチルパラベン、ソルビン酸カリウム、ソルビン酸ナトリウム、ソルビ ン酸、デヒドロ酢酸ナトリウム、メチルパラベン）、色素剤（例えば、カオリン、カルミン、 グンジヨウ、酸化クロム、酸化鉄）、香料、 pH調整剤（例えば、クェン酸ナトリウム、酢酸 ナトリウム、水酸化ナトリウム、水酸化カリウム、リン酸)を挙げること力 Sできる。また本発 明の好ましい態様によれば、本発明の組成物は、添加物として界面活性剤を含まな いものである。 Various additives may be added to the poorly water-soluble compound. Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyl dimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hyaluronate, hexylene. Daricol, goyonin extract, petrolatum), softeners (eg glycerin, mineral oil), emollient ingredients (eg isoprostearate) Pills, polyglyceryl isostearate, isotridecyl isononanoate, octinole isononanoate, oleic acid, glyceryl oleate, cocoa butter, cholesterol, mixed fatty acid tridalylide, dioctyl succinate, sucrose acetate stearate, cyclopentasiloxane, sucrose distearate, Octyl palmitate, octyl hydroxystearate, aralkyl behenate, sucrose polybehenate, polymethylsilsesquioxane, myristyl alcohol, cetyl myristate, myristyl myristate, hexyl laurate), and transdermal absorption promotion Agents (eg, ethanol, isopropyl myristate, citrate, squalane, oleic acid, menthol, N-methyl-2-pyrrolidone, jetyl adipate, disodium adipate Pills, decyl sebacate, diisopropyl sebacate, isopropyl palmitate, isopropyl oleate, octyldodecyl oleate, isostearyl alcohol, 2-octyldodecanol, urea, vegetable oil, animal oil), preservatives (eg, benzoic acid) , Sodium benzoate, Ethylparaben, Potassium sorbate, Sodium sorbate, Sorbic acid, Sodium dehydroacetate, Methylparaben), Colorant (eg, Kaolin, Carmine, Gundiio, Chromium oxide, Iron oxide), Fragrance, pH adjustment It is possible to list agents (for example, sodium citrate, sodium acetate, sodium hydroxide, potassium hydroxide, phosphoric acid). According to a preferred embodiment of the present invention, the composition of the present invention does not contain a surfactant as an additive.
本発明による難水溶性化合物を親水性マトリックスに封入した組成物の製造方法 についてさらに説明する。本発明においては、親水性マトリックスに難水溶性化合物 を含有する有機フッ素化合物を浸漬させて乾燥させることにより、難水溶性化合物を 親水性マトリックスに封入する。親水性マトリックスの形態は特に限定されず、例えば 、ゲル、スポンジ、フィルム、不織布、ファイバー、チューブ、粒子などであればよい。 形状はいずれの形状でも適用可能であるが、例えば角錐、円錐、角柱、円柱、球、 紡錘状のマトリックスおよび任意の型により作成したマトリックスが挙げられる。好まし くは、角柱、円柱、紡錘状のマトリックスおよび任意の型により作成したマトリックスで ある。より好ましくは、角錐、円錐、角柱、円柱である。最も好ましくは角柱、円柱であ る。該マトリックスの大きさは特に限定されないが、ゲル、スポンジ、不織布であれば 好ましくは 500 cm四方以下である。好ましくは 100 cm四方以下である。特に好ましく は 50 cm四方以下である。最も好ましくは 10 cm四方以下である。ファイバー（チュー ブ）であれば、ファイバーまたはチューブの直径ほたは一辺）は現実的には 0.001 n m以上 10 cm以下である。好ましくは 0.01 nm以上 1 cm以下である。より好ましくは 0. 1 nm以上 100 である。特に好ましくは 1 nm以上 1 m以下である。最も好ましくは 1 n m以上 10 nm以下である。また、長さは特に限定されるものではないが、好ましくは 10 ^ m以上 100 m以下である。より好ましくは 100 ^ m以上 10 m以下である。さらに好ま しく ίま 1 mm以上 1 m以下である。最も好ましく ίま 1 cm以上 30 cm以下である。粒子で れば、直径は好ましくは 1 nm力、ら 1 mm、より好ましくは 10 nmから 200 m、さらに好ま しくは 50 nmから 100 μ πι、特に好ましくは 100 nmから 10〃 mである。マトリックスの厚さ については特に限定されないが、好ましくは 1 nm以上である。より好ましくは、 10 nm 以上である。より好ましくは 100 nm以上である。より好ましくは 1 m以上である。さら に好ましくは 10 m以上である。最も好ましくは 100 m以上である。 The method for producing a composition in which a poorly water-soluble compound according to the present invention is encapsulated in a hydrophilic matrix will be further described. In the present invention, the poorly water-soluble compound is encapsulated in the hydrophilic matrix by immersing the organic fluorine compound containing the poorly water-soluble compound in the hydrophilic matrix and drying it. The form of the hydrophilic matrix is not particularly limited and may be any gel, sponge, film, nonwoven fabric, fiber, tube, particle, or the like. Any shape can be applied, but examples thereof include a pyramid, a cone, a prism, a cylinder, a sphere, a spindle-shaped matrix, and a matrix created by an arbitrary mold. Preferred are prisms, cylinders, spindle-shaped matrices and matrices made of any mold. More preferable are a pyramid, a cone, a prism, and a cylinder. Most preferred are prisms and cylinders. The size of the matrix is not particularly limited, but is preferably 500 cm square or less for gels, sponges, and nonwoven fabrics. Preferably it is 100 cm square or less. Especially preferred Is less than 50 cm square. Most preferably, it is 10 cm square or less. In the case of fiber (tube), the diameter of fiber or tube or one side is practically 0.001 nm or more and 10 cm or less. Preferably they are 0.01 nm or more and 1 cm or less. More preferably, it is 0.1 nm or more and 100. Particularly preferably, it is 1 nm or more and 1 m or less. Most preferably, it is 1 nm or more and 10 nm or less. The length is not particularly limited, but is preferably 10 ^ m or more and 100 m or less. More preferably, it is 100 ^ m or more and 10 m or less. More preferably, it is 1 mm or more and 1 m or less. Most preferably, it is from 1 cm to 30 cm. In the case of particles, the diameter is preferably 1 nm force, 1 mm, more preferably 10 nm to 200 m, even more preferably 50 nm to 100 μπι, particularly preferably 100 nm to 10 μm. The thickness of the matrix is not particularly limited, but is preferably 1 nm or more. More preferably, it is 10 nm or more. More preferably, it is 100 nm or more. More preferably, it is 1 m or more. Furthermore, it is preferably 10 m or more. Most preferably, it is 100 m or more.
[0046] 難水溶性化合物の濃度は、本発明の効果が達成できる限りは特に限定されないが 、難溶性化合物を高濃度かつ微分散状態で封入できることが本発明の特徴のひとつ である。親水性マトリックス中の難水溶性化合物と親水性マトリックスの比 (難水溶性 化合物/親水性マトリックス）は、本発明の効果が達成できる限りは特に限定されない ヽ一般的には 0.001%から 50%であり、好ましくは 0.01 %から 10%であり、最も好まし くは 0. 1 %から 5 %である。  [0046] The concentration of the poorly water-soluble compound is not particularly limited as long as the effects of the present invention can be achieved, but one of the features of the present invention is that the hardly soluble compound can be encapsulated in a high concentration and in a finely dispersed state. The ratio of the poorly water-soluble compound to the hydrophilic matrix in the hydrophilic matrix (slightly water-soluble compound / hydrophilic matrix) is not particularly limited as long as the effect of the present invention can be achieved. Generally, the ratio is 0.001% to 50%. Yes, preferably 0.01% to 10%, and most preferably 0.1% to 5%.
[0047] 本発明では、さらに、難水溶性化合物を含有する有機フッ素化合物に親水性マトリ ックスを浸漬した後に、該親水性マトリックスを乾燥させることにより、難水溶性化合物 が微分散状態で親水性マトリックスに封入されている組成物を作成することができる。 乾燥条件は本発明の効果が達成できる限り特に限定されず、例えば、常温から 50°C において 1時間から 48時間、好ましくは 2時間から 1 5時間程度静置することにより、 乾燥を行うこと力できる。また、場合によっては真空乾燥及び/又は水洗し、乾燥を行 うこと力 Sでさる。  In the present invention, the hydrophilic matrix is further dried in a finely dispersed state by immersing the hydrophilic matrix in an organic fluorine compound containing the hardly water-soluble compound and then drying the hydrophilic matrix. A composition encapsulated in a matrix can be made. The drying conditions are not particularly limited as long as the effect of the present invention can be achieved. For example, the drying condition can be maintained by standing at room temperature to 50 ° C for 1 hour to 48 hours, preferably 2 hours to 15 hours. it can. In some cases, vacuum drying and / or washing with water and drying can be done with force S.
[0048] 本発明の方法で製造された組成物には作製に用いた溶媒が出来る限り残存してい ないことが好ましぐ組成物中の溶媒量は 0%〜0. 1 %であることが好ましいが、通常 わずかの量は残存する。従って最も好ましくは 0.00001 %〜0. 1 %である。残存溶媒量 は組成物を分解し、 GC-MSを用いて定量することが可能である。 [0048] In the composition produced by the method of the present invention, it is preferable that the solvent used for the production should not remain as much as possible. The amount of the solvent in the composition is preferably 0% to 0.1%. Although preferred, usually only a small amount remains. Therefore, it is most preferably 0.00001% to 0.1%. Residual solvent amount Can decompose the composition and quantify using GC-MS.
[0049] (2)抗癌剤を封入した親水性基材からなる抗癌剤含有外用剤  [0049] (2) An anticancer agent-containing external preparation comprising a hydrophilic substrate encapsulating an anticancer agent
近年、製剤開発において、新薬の開発とともに、新規の投与経路の開発も行われ ている。中でも、経皮や経粘膜の経路は初回通過効果を回避でき、ノ^オアベイラビ リティーが高いため、有用な投与経路として期待されている。  In recent years, new drug administration routes have been developed along with the development of new drugs. Among them, the transdermal and transmucosal routes are expected to be useful routes because they can avoid the first-pass effect and have high ore availability.
[0050] 本発明で用いる親水性基材は、基材が水と親和性があれば特に限定されないが、 例えば、水溶性の合成高分子および生体高分子を用いることができ、好ましくは生体 高分子である。より好ましくは、親水性基材は、タンパク質である。  [0050] The hydrophilic substrate used in the present invention is not particularly limited as long as the substrate has an affinity for water. For example, water-soluble synthetic polymers and biopolymers can be used, Is a molecule. More preferably, the hydrophilic substrate is a protein.
[0051] 本発明で用いるタンパク質の種類は特に限定されないが、リジン残基およびグルタ ミン残基を有するタンパク質が好ましぐ分子量 1000から 100万程度のタンパク質を 用いること力 S好ましい。より好ましくは、分子量が 3千から 30万程度のタンパク質を用い ることである。より好ましくは、分子量 1万から 10万程度のタンパク質を用いることであ る。タンパク質の由来は特に限定されないが、ヒト由来のタンパク質を用いることが好 ましい。タンパク質として具体例を列挙するが、本発明においてはこれらの化合物に 限定されるものではない。コラーゲン、ゼラチン、アルブミン、カゼイン、トランスフェリ ン、又はグロブリンなどを使用することができる。その中で好ましいものは、ゼラチン、 コラーゲン、又はアルブミンであり、より好ましいものはゼラチン、又はコラーゲンであ り、最も好ましいものは酸処理ゼラチンである。タンパク質などの生体高分子の由来 は特に規定されないが、ヒト、牛、豚、トリ、魚、および遺伝子組み換え体のいずれで もよい。好ましくは、ヒト、牛、豚、魚、および遺伝子組み換え体である。より好ましくは 牛、豚、魚、および遺伝子組み換え体である。また、遺伝子組み換えゼラチンとして は、例えば EP0926543B，WO2004-085473号明細書、 EP1398324A, EP1014176A, U S6645712に記載のものを用いることができるがこれらに限定されるものではない。  [0051] The type of protein used in the present invention is not particularly limited, but it is preferable to use a protein having a molecular weight of about 1,000 to 1,000,000, which is preferred by a protein having a lysine residue and a glutamine residue. More preferably, a protein having a molecular weight of about 3,000 to 300,000 is used. More preferably, a protein having a molecular weight of about 10,000 to 100,000 is used. The origin of the protein is not particularly limited, but it is preferable to use a human-derived protein. Specific examples are listed as proteins, but the present invention is not limited to these compounds. Collagen, gelatin, albumin, casein, transferrin, or globulin can be used. Among them, preferred is gelatin, collagen, or albumin, more preferred is gelatin or collagen, and most preferred is acid-treated gelatin. The origin of biopolymers such as proteins is not particularly defined, but any of humans, cows, pigs, birds, fish, and genetically modified organisms may be used. Preferred are humans, cattle, pigs, fish, and genetically modified organisms. More preferred are cows, pigs, fish, and genetically modified organisms. Examples of the genetically modified gelatin include those described in EP0926543B, WO2004-085473, EP1398324A, EP1014176A, US6645712, but are not limited thereto.
[0052] 親水性基材に用いる生体高分子は化学修飾が施されていても構わない。化学修 飾は、官能基の一部と低分子あるいは高分子化合物を結合することである。より好ま しくは生体高分子のカルボキシル基、ヒドロキシル基、およびアミノ基部位にエステル 結合またはアミド結合を導入する、あるいは静電相互作用させることによる修飾体で ある。 [0053] 該手法により作成した難水溶性化合物を親水性マトリックスに封入した組成物は必 要に応じて架橋を行っても良い。親水性マトリックスの架橋度を制御することで、生体 内分解性、強度、構造等の各種性質を作り分けることが可能となる。架橋方法は特に 限定することはない。架橋方法としては例えば物理架橋、化学架橋、熱架橋、酵素 架橋等が挙げられる。 [0052] The biopolymer used for the hydrophilic substrate may be chemically modified. Chemical modification is the bonding of a part of the functional group to a low or high molecular compound. More preferably, it is a modified product by introducing an ester bond or an amide bond into the carboxyl group, hydroxyl group, and amino group site of the biopolymer, or by electrostatic interaction. [0053] A composition in which a poorly water-soluble compound prepared by the above method is encapsulated in a hydrophilic matrix may be cross-linked as necessary. By controlling the degree of crosslinking of the hydrophilic matrix, various properties such as biodegradability, strength, and structure can be created. The crosslinking method is not particularly limited. Examples of the crosslinking method include physical crosslinking, chemical crosslinking, thermal crosslinking, and enzyme crosslinking.
[0054] 架橋は、熱、光、架橋剤、又は酵素による架橋でもよいし、またはポリイオンコンプレ ックスおよび疎水性相互作用による架橋でもよ!/、。好ましくは化学または酵素架橋で ある。化学架橋剤としては一般的に広く利用されているダルタルアルデヒドやホルム アルデヒド等のアルデヒド、カルポジイミド、シァナミド等、ビニルスルホン、ジエポキシ ド、シンナミル基、ビュル基、クマリン等の光二量化性基を含む架橋剤が挙げられる。 より好ましくはダルタルアルデヒド、トランスダルタミナーゼである。  [0054] Crosslinking may be thermal, light, crosslinker, enzymatic, or polyion complex and hydrophobic interaction! /. Chemical or enzymatic crosslinking is preferred. Crosslinks containing photodimerizable groups such as aldehydes such as dartalaldehyde and formaldehyde, carposimide, cyanamide, vinyl sulfone, diepoxide, cinnamyl group, bur group, and coumarin, which are widely used as chemical crosslinking agents. Agents. More preferred are dartalaldehyde and transdaltaminase.
[0055] 熱による架橋では、タンパク質を熱処理することで架橋する方法であり、 50-200 °Cの範囲で行うのがよい。 50°Cより低いと架橋が不充分または架橋が行われなくな つてしまう。一方、 200°Cを越えるとタンパク質の変性が顕著であるからである。製造 と活性の要因を考慮すると、好ましくは 60〜； 180°Cであり、 90〜； 150°Cが最も好まし い。  [0055] Cross-linking by heat is a method of cross-linking by heat-treating proteins, and it is preferable to carry out in the range of 50-200 ° C. If it is lower than 50 ° C, crosslinking is insufficient or crosslinking is not performed. On the other hand, when the temperature exceeds 200 ° C., protein denaturation is remarkable. Taking into account manufacturing and activity factors, 60 to 180 ° C is preferred, and 90 to 150 ° C is most preferred.
[0056] 光による架橋は、例えば、タンパク質に放射線を放射することで架橋する方法であ る。具体的には、紫外線照射、電子線照射、ガンマ線などの物理的エネルギーを照 射することによって物理的架橋を生起させる。また、例えば、光反応性基あるいは重 合性基を導入したタンパク質に直接あるいは他の光反応性基 (例えば、重合開始剤 )との共存下で光照射することによって化学的架橋を生起させる。  [0056] Cross-linking by light is, for example, a method of cross-linking by emitting radiation to proteins. Specifically, physical crosslinking is caused by irradiating physical energy such as ultraviolet irradiation, electron beam irradiation, and gamma rays. In addition, for example, chemical crosslinking is caused by irradiating a protein into which a photoreactive group or a polymerizable group is introduced directly or in the presence of another photoreactive group (for example, a polymerization initiator).
[0057] 架橋剤としては、無機または有機の架橋剤を用いることができる。無機または有機 の架橋剤の具体例としては、クロム塩（クロム明ばん、酢酸クロムなど）；カルシウム塩（ 塩化カルシウム、水酸化カルシウムなど）；アルミニウム塩 (塩化アルミニウム、水酸化 アルミニウムなど）；カノレポジイミド類（EDC，WSC、 N-ヒドロキシ- 5-ノルボルネン- 2, 3- ジカルボキシイミド（HONB)、 N-ヒドロキシコハク酸イミド（HOSu)、ジシクロへキシルカ ルポジイミド（DCC)など）； N—ヒドロキシスクシンイミド;ォキシ塩化リンなどを挙げるこ とができる力 これらに限定されるものではない。上記した架橋剤は、単独で使用して もよいし、 2種以上を組み合わせて用いることもできる。架橋剤を使用する場合、タン パク質の重量に対して、好ましくは 0.；!〜 100重量％の架橋剤を添加して架橋処理を fiうこと力 Sでさる。 [0057] As the crosslinking agent, an inorganic or organic crosslinking agent can be used. Specific examples of inorganic or organic crosslinking agents include chromium salts (such as chromium alum and chromium acetate); calcium salts (such as calcium chloride and calcium hydroxide); aluminum salts (such as aluminum chloride and aluminum hydroxide); canolepositimides (EDC, WSC, N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), N-hydroxysuccinimide (HOSu), dicyclohexyl carbopositimide (DCC), etc.); N-hydroxysuccinimide; Forces that can include phosphorus chloride and the like are not limited to these. Use the above cross-linking agent alone It can also be used in combination of two or more. When using a cross-linking agent, it is preferable to add 0 to 100% by weight of the cross-linking agent with respect to the weight of the protein.
[0058] 酵素による架橋を行う場合、酵素としては、タンパク質の架橋作用を有するものであ れば特に限定されないが、好ましくはトランスダルタミナーゼおよびラッカーゼ、最も 好ましくはトランスダルタミナーゼを用いて架橋を行うことができる。トランスグルタミナ ーゼで酵素架橋するタンパク質の具体例としては、リジン残基およびグルタミン残基 を有するタンパク質であれば特に制限されない。トランスダルタミナーゼは、哺乳類由 来のものであっても、微生物由来のものであってもよぐ具体的には、味の素（株）製 ァクティバシリーズ、試薬として発売されている哺乳類由来のトランスグルタミナーゼ、 例えば、オリエンタル酵母工業（株）製、 Upstate USA Inc.製、 Biodesign International 製などのモルモット肝臓由来トランスダルタミナーゼ、ャギ由来トランスダルタミナーゼ 、ゥサギ由来トランスダルタミナーゼなど、ヒト由来の血液凝固因子（Factor XHIa, Hae matologic Technologies, Inc.社)など力 s挙げられる。 [0058] In the case of carrying out cross-linking with an enzyme, the enzyme is not particularly limited as long as it has a cross-linking action of a protein, but preferably cross-linking with transdaltaminase and laccase, most preferably transdaltaminase. It can be performed. A specific example of a protein that is enzymatically cross-linked with transglutaminase is not particularly limited as long as it has a lysine residue and a glutamine residue. Transdaltaminase may be derived from mammals or from microorganisms. Specifically, it is derived from the Ajinomoto Co., Ltd. Activa series, which is derived from mammals sold as reagents. Transglutaminase, for example, guinea pig liver-derived transdaltaminase from Oriental Yeast Co., Ltd., Upstate USA Inc., Biodesign International, etc., goat-derived transdaltaminase, usagi-derived transdaltaminase, etc. blood coagulation factors (factor XHIa, Hae matologic Technologies, Inc. Co., Ltd.) force s like.
[0059] 酵素の使用量は、タンパク質の種類に応じて適宜設定することが出来るが、標準的 には、タンパク質の重量に対して、 0.；!〜 100重量％程度を添加することができ、好ま しくは、；!〜 50重量％程度を添加することができる。  [0059] The amount of enzyme used can be appropriately set according to the type of protein, but it can be added in an amount of about 0.;! To 100% by weight based on the weight of the protein. Preferably, it can be added in a range of about! To 50% by weight.
[0060] 酵素による架橋反応の時間は、タンパク質の種類などに応じて適宜設定することが できる力 標準的には、 1時間から 72時間反応することができ、好ましくは、 2時間か ら 24時間反応することができる。酵素による架橋反応の温度は、タンパク質の種類な どに応じて適宜設定することができる力 S、標準的には、 0°Cから 80°Cで反応すること ができ、好ましくは、 25°Cから 60°Cで反応することができる。  [0060] The time for the cross-linking reaction with the enzyme can be appropriately set according to the type of protein, etc. Typically, the reaction can be performed for 1 to 72 hours, preferably 2 to 24 hours. Can react. The temperature of the cross-linking reaction by the enzyme is a force S that can be set as appropriate according to the type of protein S, etc., and the reaction can be performed normally from 0 ° C to 80 ° C. The reaction can be carried out at temperatures up to 60 ° C.
[0061] 本発明で使用する抗癌剤の種類は特に限定されないが、例えば、フッ化ピリミジン 系代謝拮抗薬（5-フルォロウラシル (5FU)やテガフール、ドキシフルリジン、力ぺシタ ビンなど）；抗生物質 (マイトマイシン (MMC)やアドリアシン (DXR)など）；プリン代謝 拮抗薬 (メソトレキサートなどの葉酸代謝拮抗薬、メルカプトプリンなど）；ビタミン Aの 活性代謝物 (ヒドロキシカルバミドなどの代謝拮抗薬、トレチノインやタミバロテンなど） ；分子標的薬 (ノヽーセプチンやメシル酸イマチニブなど）；白金製剤（プリブラチンゃラ ンダ（CDDP)、パラプラチン（CBDC)、エルプラット（Oxa)、ァクプラなど）；植物アル力 ロイド薬（トポテシンやカンプト（CPT)、タキソール（パクリタキセル）（PTX)、タキソテー ル（DTX)、エトポシドなど）；アルキル化剤（ブスルファンゃシクロホスフアミド、ィホマイ ドなど）；抗男性ホルモン薬（ビカルタミドゃフルタミドなど）；女性ホルモン薬 (ホスフエ ストロールや酢酸クロルマジノン、リン酸エストラムスチンなど）； LH-RH薬（リュープリ ンゃゾラデックスなど）；抗エストロゲン薬（タエン酸タモキシフェンやタエン酸トレミフエ ンなど）；ァロマターゼ阻害薬（塩酸フアドロゾールゃアナストロゾール、ェキセメスタン など）；黄体ホルモン薬 (酢酸メドロキシプロゲステロンなど）などが挙げられる。好まし くは、 5—フルォロウラシル、パクリタキセル、シスプラチン、ドキソルビシン、アドリアマ イシンである。より好ましくは、 5—フルォロウラシル、パクリタキセル、およびシスプラ チンである。最も好ましくは、 5—フノレオロウラシル、パクリタキセルである。 [0061] The type of anticancer agent used in the present invention is not particularly limited. For example, fluorinated pyrimidine antimetabolites (5-fluorouracil (5FU), tegafur, doxyfluridine, force pecitabine, etc.); antibiotics (mitomycin ( MMC) and adriacin (DXR), etc .; Purine antimetabolite (folate antimetabolite, such as methotrexate, mercaptopurine, etc.); Active metabolite of vitamin A (antimetabolite, such as hydroxycarbamide, tretinoin, tamibarotene, etc.); molecule Target drugs (Noseceptin, Imatinib mesylate, etc.); Platinum preparations (Pribratin Nyala) (CDDP), paraplatin (CBDC), elplat (Oxa), vacpra, etc.); plant almyloid drugs (topotecin and campto (CPT), taxol (paclitaxel) (PTX), taxotere (DTX), etoposide, etc.) Alkylating agents (such as busulfan N-cyclophosphamide, ifomide); anti-androgen drugs (such as bicalutamide N-flutamide); female hormone drugs (such as phosfetrol, chlormadinone acetate, estramustine phosphate); LH-RH drugs ( Such as leuplin and zoladex); antiestrogens (such as tamoxifen taenoate and toremifene taenoate); aromatase inhibitors (such as fadrozole hydrochloride, anastrozole, exemestane); progesterone drugs (such as medroxyprogesterone acetate) It is done. Preferred are 5-fluorouracil, paclitaxel, cisplatin, doxorubicin and adriamycin. More preferred are 5-fluorouracil, paclitaxel, and cisplatin. Most preferred is 5-funoleouracil or paclitaxel.
[0062] 抗癌剤を親水性基材に高濃度に封入するには、抗癌剤は親水性のものが望ましい 力 疎水性の抗癌剤でも、界面活性剤や溶解補助剤等の各種添加剤を用いることで 高濃度に封入することが可能となる。  [0062] In order to encapsulate the anticancer agent in a hydrophilic substrate at a high concentration, it is desirable that the anticancer agent is hydrophilic. Even if it is a hydrophobic anticancer agent, it can be increased by using various additives such as a surfactant and a solubilizing agent. It becomes possible to enclose in the concentration.
[0063] 親水性基材には上記の抗癌剤と一緒に各種添加剤を加えてもよ!/、。本発明で用い ること力 Sできる添加物としては、保湿剤（例えば、カンテン、ジグリセリン、ジステアリノレ ジモニゥムヘクトライト、ブチレングリコーノレ、ポリエチレングリコーノレ、プロピレングリコ 一ノレ、ヒアルロン酸ナトリウム、へキシレングリコーノレ、ョタイニンエキス、ワセリン）、 柔軟剤（例えば、グリセリン、ミネラルオイル）、ェモリエント成分（例えば、イソステアリ ン酸イソプロピル、イソステアリン酸ポリグリセリル、イソノナン酸イソトリデシル、イソノ ナン酸ォクチル、ォレイン酸、ォレイン酸グリセリル、カカオ脂、コレステロール、混合 脂肪酸トリグリセリド、コハク酸ジォクチル、酢酸ステアリン酸スクロース、シクロペンタ シロキサン、ジステアリン酸スクロース、パルミチン酸ォクチル、ヒドロキシステアリン酸 ォクチル、ベヘン酸ァラキル、ポリべヘン酸スクロース、ポリメチルシルセスキォキサン 、ミリスチノレアノレコーノレ、ミリスチン酸セチル、ミリスチン酸ミリスチノレ、ラウリン酸へキシ ル）、経皮吸収促進剤（例えば、エタノール、ミリスチン酸イソプロピル、クェン酸、スク ヮラン、ォレイン酸、メントール、 N-メチル -2-ピロリドン、アジピン酸ジェチル、アジピ ン酸ジイソプロピル、セバシン酸ジェチル、セバシン酸ジイソプロピル、パルミチン酸 イソプロピル、ォレイン酸イソプロピル、ォレイン酸オタチルドデシル、イソステアリルァ ルコール、 2-オタチルドデカノール、尿素、植物油、動物油）、防腐剤（例えば、安息 香酸、安息香酸ナトリウム、ェチルパラベン、ソルビン酸カリウム、ソルビン酸ナトリウム 、ソルビン酸、デヒドロ酢酸ナトリウム、メチルパラベン）、色素剤（例えば、カオリン、力 ルミン、グンジヨウ、酸化クロム、酸化鉄）、香料、 pH調整剤（例えば、クェン酸ナトリウ ム、酢酸ナトリウム、水酸化ナトリウム、水酸化カリウム、リン酸）などを挙げることができ [0063] Various additives may be added to the hydrophilic substrate together with the above-mentioned anticancer agent! /. Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyl dimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol monoole, sodium hyaluronate, hexylene. Glyconole, Gyotinin extract, Petrolatum), Softener (eg, glycerin, mineral oil), Emollient component (eg, isopropyl isostearate, polyglyceryl isostearate, isotridecyl isononanoate, octyl isononanoate, oleic acid, glyceryl oleate, cacao) Fat, cholesterol, mixed fatty acid triglyceride, dioctyl succinate, sucrose acetate stearate, cyclopentasiloxane, sucrose distearate, octyl palmitate, Octyl hydroxystearate, aralkyl behenate, sucrose polybehenate, polymethylsilsesquioxane, myristic noreconole, cetyl myristate, myristic myristate, hexyl laurate), transdermal absorption enhancer ( For example, ethanol, isopropyl myristate, citrate, squalane, oleate, menthol, N-methyl-2-pyrrolidone, jetyl adipate, diisopropyl adipate, jetyl sebacate, diisopropyl sebacate, palmitic acid Isopropyl, isopropyl oleate, octyldodecyl oleate, isostearyl alcohol, 2-octyldodecanol, urea, vegetable oil, animal oil), preservatives (eg, benzoic acid, sodium benzoate, ethylparaben, potassium sorbate, Sodium sorbate, sorbic acid, sodium dehydroacetate, methylparaben), coloring agent (for example, kaolin, strength lumine, gundiio, chromium oxide, iron oxide), flavor, pH adjuster (for example, sodium citrate, sodium acetate, water) (Sodium oxide, potassium hydroxide, phosphoric acid)
[0064] 本発明の外用剤の形態は特に限定されな!/、が、例えばゲル、スポンジ、フィルム、 不織布、ファイバー（チューブ）、粒子などが挙げられる。形状はいずれの形状でも適 用可能であるが、例えば角錐、円錐、角柱、円柱、球、紡錘状の構造物および任意 の型により作成した基材が挙げられる。 [0064] The form of the external preparation of the present invention is not particularly limited! /, And examples thereof include gels, sponges, films, nonwoven fabrics, fibers (tubes), and particles. Any shape can be applied, and examples thereof include a pyramid, a cone, a prism, a cylinder, a sphere, a spindle-shaped structure, and a substrate made of any mold.
[0065] 本発明の外用剤の用途 (適用疾患）は特に限定されないが、例えば、皮膚癌、角化 症、悪性黒色腫、菌状息肉症、乳癌、前立腺癌、子宮癌、膣癌、陰茎癌、大腸癌で ある。好ましくは、皮膚癌、角化症である。  [0065] The use (application disease) of the external preparation of the present invention is not particularly limited. For example, skin cancer, keratosis, malignant melanoma, mycosis fungoides, breast cancer, prostate cancer, uterine cancer, vaginal cancer, penis Cancer and colon cancer. Preferred are skin cancer and keratosis.
[0066] また、本発明の外用剤は、好ましくは皮膚外用剤または経皮吸収製剤として用いる こと力 Sできる。本発明の外用剤は、必要に応じて組織内部に埋め込むこともできる。 例えば、手術後の除去組織の機能保持のために、欠落した組織に埋め込む形では め込むこと、あるいは、損傷の激しい皮膚の被覆を伴うこともありうる。生体に親和性 の高い外用剤である場合、周辺組織の修復を助けることもありうる。例えば、コラーゲ ン、ゼラチン、およびグリコサミノダリカンは生体適合性が高ぐ保湿性、増殖因子の 貯蔵、細胞接着性（コラーゲン、ゼラチン）といった特異な性質を有することから、治 療と組織修復を同時に行うことができる。  [0066] Further, the external preparation of the present invention can be used preferably as a skin external preparation or a transdermal absorption preparation. The external preparation of the present invention can be embedded in the tissue as necessary. For example, in order to preserve the function of the removed tissue after surgery, it may be embedded in the missing tissue, or it may be accompanied by severely damaged skin coating. In the case of an external preparation having a high affinity for the living body, it may help repair surrounding tissues. For example, collagen, gelatin, and glycosaminodarican have unique properties such as moisture retention, growth factor storage, and cell adhesion (collagen, gelatin), which are highly biocompatible. Can be done simultaneously.
[0067] 本発明の外用剤の投与量は、活性成分である抗癌剤の種類及び使用量、患者の 体重、疾患の状態などに応じて適宜設定することができる力 一般的には、 1回の投 与につき 10〃 g〜； 100mg/kg程度を投与することカでき、好ましくは、 20 μ g〜50 mg/kg程度を投与することができる。  [0067] The dosage of the external preparation of the present invention can be appropriately set according to the type and amount of an anticancer agent that is an active ingredient, the weight of a patient, the state of a disease, etc. About 100 mg / kg can be administered per dose, and preferably about 20 μg to 50 mg / kg can be administered.
[0068] 本発明の組成物は抗癌剤が親水性基材中に微分散状態で封入されていることが 好ましい。微分散の定義は（1)で記載されたものと同様である。 [0069] (3)ォクタノール/水の分配係数 (LogP)が- 3.0以上 3.0以下である薬物が生体高分 子を主成分とする構造物中に封入されている、外用剤用組成物。 [0068] In the composition of the present invention, the anticancer agent is preferably encapsulated in a finely dispersed state in a hydrophilic base material. The definition of fine dispersion is the same as that described in (1). [0069] (3) A composition for external use, wherein a drug having an octanol / water partition coefficient (LogP) of -3.0 or more and 3.0 or less is encapsulated in a structure mainly composed of a biological polymer.
[0070] 本発明で用いる生体高分子は特に限定されないが、好ましくは、タンパク質または 多糖である。より好ましくはコラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、又 はフイブリンであり、さらに好ましくはコラーゲン、ゼラチン、又はアルブミンである。最 も好ましくは、コラーゲン、又はゼラチンである。生体高分子の由来は特に規定されな いが、ヒト、牛、豚、トリ、魚、および遺伝子組み換え体のいずれでもよい。好ましくはヒ ト、牛、豚、魚、および遺伝子組み換え体である。より好ましくは牛、豚、魚、および遺 伝子組み換え体である。遺伝子組み換えゼラチンとしては、例えば EP0926543B，WO 2004-085473号明細書、 EP1398324A、 EP1014176A、 US6645712に記載のものを用 V、ること力 Sできる力 Sこれらに限定されるものではなレ、。該基材に用いる生体高分子は 単独、または複数種類の生体高分子や合成高分子と混合しても使用できる。  [0070] The biopolymer used in the present invention is not particularly limited, but is preferably a protein or a polysaccharide. More preferred is collagen, gelatin, albumin, laminin, casein, or fibrin, and more preferred is collagen, gelatin, or albumin. Most preferred is collagen or gelatin. The origin of the biopolymer is not particularly defined, and any of humans, cows, pigs, birds, fish, and genetically modified organisms may be used. Preferred are humans, cows, pigs, fish, and genetically modified organisms. More preferred are cows, pigs, fish, and gene recombinants. Examples of the genetically modified gelatin include those described in EP0926543B, WO 2004-085473, EP1398324A, EP1014176A, US6645712 V, force S, force S, and the like. The biopolymer used for the substrate can be used alone or mixed with a plurality of types of biopolymers or synthetic polymers.
[0071] 本発明にお!/、て基材に用いる生体高分子は化学修飾が施されて!/、ても構わな!/、。  [0071] In the present invention, the biopolymer used for the base material may be chemically modified! /.
該化学修飾は、官能基の一部と低分子あるいは高分子化合物を結合することである 。より好ましくは生体高分子のエステル結合またはアミド結合による修飾体である。ま た、該生体高分子は架橋を施しても良い。架橋は、熱、光、架橋剤、又は酵素による 架橋でもよ!/、し、またはポリイオンコンプレックスおよび疎水性相互作用による架橋で もよい。好ましくは化学または酵素架橋である。化学架橋剤としては一般的に広く利 用されてレ、るダルタルアルデヒドやホルムアルデヒド等のアルデヒド、カルポジイミド、 シァナミド等、ビニルスルホン、ジエポキシド、シンナミル基、ビュル基、クマリン等の 光二量化性基を含む架橋剤が挙げられる。より好ましくはダルタルアルデヒド、トラン スグルタミナーゼである。  The chemical modification is to bond a part of the functional group to a low molecular or high molecular compound. More preferred is a modified form of an ester bond or amide bond of a biopolymer. In addition, the biopolymer may be crosslinked. Crosslinking may be thermal, light, crosslinker, or enzymatic crosslinks! /, Or may be cross-linked by polyion complexes and hydrophobic interactions. Chemical or enzymatic crosslinking is preferred. Generally used as a chemical cross-linking agent, it contains aldehydes such as daltalaldehyde and formaldehyde, carpositimide, cyanamide, etc., and includes photodimerizable groups such as vinyl sulfone, diepoxide, cinnamyl group, bur group, and coumarin. A crosslinking agent is mentioned. More preferred are dartalaldehyde and transglutaminase.
[0072] トランスダルタミナーゼは、哺乳類由来のものであっても、微生物由来のものであつ てもよく、具体的には、味の素 (株)製ァクティバシリーズ、試薬として発売されている 哺乳類由来のトランスグルタミナーゼ、例えば、オリエンタル酵母工業 (株)製、 Upstat e USA In 製、 Biodesign International製などのモルモット肝臓由来トランスグルタミナ ーゼ、ャギ由来トランスグルタミナーゼ、ゥサギ由来トランスダルタミナーゼなどが挙げ られる。また、ヒト由来の組み換えトランスダルタミナーゼを用いることもできる。 [0073] 薬物の経皮吸収効率は、薬物の分子量、薬物の基材への溶解度、基材と皮膚の 分配係数等により決定される。従って、薬物の経皮投与を検討する際、薬物と基材の 組み合わせは非常に重要となる。一般に、低分子薬物の経皮吸収性が高いことが知 られている。本発明で作製する組成物を経皮吸収用途で使用する際には、薬物の分 子量は好ましくは 1500以下である。より好ましくは 1000以下である。さらに好ましくは 5 00以下である。 [0072] The transdaltaminase may be derived from a mammal or a microorganism. Specifically, the transactaminase is marketed as a reagent by Ajinomoto Co., Ltd. Activa. Transglutaminase derived from Oriental Yeast Industry Co., Ltd., Upstate USA In, Biodesign International, etc., guinea pig liver-derived transglutaminase, goat-derived transglutaminase, Usagi-derived transdaltaminase, etc. It is done. In addition, human-derived recombinant transdaltaminase can also be used. [0073] The transdermal absorption efficiency of a drug is determined by the molecular weight of the drug, the solubility of the drug in the base material, the partition coefficient between the base material and the skin, and the like. Therefore, when considering the transdermal administration of drugs, the combination of drug and substrate is very important. In general, it is known that transdermal absorbability of low molecular weight drugs is high. When the composition prepared in the present invention is used for percutaneous absorption, the molecular weight of the drug is preferably 1500 or less. More preferably, it is 1000 or less. More preferably, it is 500 or less.
[0074] 薬物の親水 疎水性の指標として、ォクタノール/水の分配係数の対数比（Log P) が広く用いられている。ォクタノール/水の分配係数の対数比（Log P)は（1)で述べ たとおりであり、本発明で使用可能な薬物は、 LogPが- 3.0以上 3.0以下の薬物である 。好ましくは LogPは- 1.5以上 1.5以下であり、さらに好ましくは- 1.5以上 0.5以下である 。最も好ましくは LogPは- 0.8以上 0.5以下である。  [0074] The log ratio of logarithmic coefficient of octanol / water (Log P) is widely used as an index of hydrophilicity and hydrophobicity of drugs. The logarithmic ratio (Log P) of the octanol / water partition coefficient is as described in (1), and the drug that can be used in the present invention is a drug having Log P of −3.0 or more and 3.0 or less. LogP is preferably −1.5 or more and 1.5 or less, and more preferably −1.5 or more and 0.5 or less. Most preferably, LogP is -0.8 or more and 0.5 or less.
[0075] 別に、薬物の経皮吸収効率を高めるためには、角質層を疎にする性質を有する経 皮吸収促進剤を用いる方法が挙げられる。該手法で使用される成分として代表的な ものに、エタノールや界面活性剤が知られており、該成分は種々の経皮吸収製剤に 利用されている。経皮吸収効率は必ずしも高くはないが、水も経皮吸収効率を高め ることが知られている。例えば、温水で皮膚をふやけさせた後の薬物の経皮吸収効 率が高まることも知られている。したがって、皮膚へのダメージが少なぐかつ薬物の 経皮吸収効率を高める成分として、水は重要な候補成分として挙げられる。周知のよ うに水は生体に安全な物質であるため、他の経皮吸収促進剤に比べて高濃度、長 時間に作用させることも可能である。また、水は生体内に存在する各種塩類を溶解さ せることが可能なため、生体に近いイオン組成の組成物を作成することも可能である 。本発明で作製した組成物は、組成物中に高濃度の水が含まれており、また水が安 全なことから長時間の作用が可能となることから、該組成物を経皮吸収製剤として利 用するのに有利となりうる。本発明で作製する組成物中の含水率に関しては、本発明 による効果をあらわす限りは特に規定しないが、好ましくは含水率が 30%以上である 。より好ましくは 40%以上である。さらに好ましくは 50%以上である。特に好ましくは 60 %以上である。最も好ましくは 70%以上である。  [0075] Separately, in order to increase the transdermal absorption efficiency of a drug, a method using a transdermal absorption enhancer having a property of making the stratum corneum sparse can be mentioned. Ethanol and surfactants are known as typical components used in this technique, and these components are used in various transdermal preparations. Although transdermal absorption efficiency is not necessarily high, water is also known to increase transdermal absorption efficiency. For example, it is known that the percutaneous absorption efficiency of a drug after the skin is softened with warm water is increased. Therefore, water is an important candidate component as a component that causes little damage to the skin and enhances the transdermal absorption efficiency of the drug. As is well known, water is a substance that is safe for the living body, so that it can be made to act at a higher concentration and for a longer time than other transdermal absorption enhancers. Further, since water can dissolve various salts present in the living body, it is possible to prepare a composition having an ionic composition close to that of the living body. The composition produced in the present invention contains a high concentration of water in the composition, and since the water is safe, the composition can be used for a long time. It can be advantageous to use as The water content in the composition prepared according to the present invention is not particularly defined as long as the effect of the present invention is exhibited, but the water content is preferably 30% or more. More preferably, it is 40% or more. More preferably, it is 50% or more. Particularly preferred is 60% or more. Most preferably, it is 70% or more.
[0076] 薬物は生理活性成分である。具体的には経皮吸収剤、局所治療剤、経口治療剤、 化粧品成分、サプリ成分が挙げられる。薬物の具体例としては、特には限定されない 力 好ましくは、抗癌剤、抗アレルギー剤、抗酸化剤、抗血栓剤、抗炎症剤、免疫抑 制剤、抗精神薬、麻酔薬、核酸医薬であり、特に好ましくは制癌剤である。 [0076] The drug is a physiologically active ingredient. Specifically, transdermal absorption agents, topical treatment agents, oral treatment agents, Examples include cosmetic ingredients and supplement ingredients. Specific examples of the drug include, but are not limited to, preferably, an anticancer agent, an antiallergic agent, an antioxidant agent, an antithrombotic agent, an antiinflammatory agent, an immunosuppressive agent, an antipsychotic agent, an anesthetic, and a nucleic acid drug. Particularly preferred are anticancer agents.
[0077] 本発明に利用できる抗癌剤は水、有機溶媒ともに溶解する限りは特に限定はない 、例えば、 5-フルォロウラシル（5FU)、テガフール、ドキシフルリジン、力ぺシタビン 、マイトマイシン（MMC)、アドリアマイシン、メソトレキサート、メルカプトプリン、エルプ ラット（Oxa)、エトポシド、ブスルファン、シクロホスフアミド、ィホマイド、タエン酸タモキ シフェン、塩酸フアドロゾールなどが挙げられる。好ましくは、 5—フルォロウラシル、ァ ドリアマイシンである。より好ましくは、 5—フルォロウラシルである。  [0077] The anticancer agent that can be used in the present invention is not particularly limited as long as it dissolves in both water and an organic solvent. For example, 5-fluorouracil (5FU), tegafur, doxyfluridine, force pecitabine, mitomycin (MMC), adriamycin, methotrexate, Examples include mercaptopurine, elprat (Oxa), etoposide, busulfan, cyclophosphamide, ifomide, tamoxifen taenoate, and fuadrozole hydrochloride. 5-Fluorouracil and adriamycin are preferable. More preferred is 5-fluorouracil.
[0078] 本発明に用いられる抗アレルギー剤として具体例を列挙する力 本発明において はこれらの化合物に限定されるものではない。クロモグリク酸ナトリウムなどのメデイエ 一ター遊離抑制薬、塩酸ォザダレルなどのトロンボキサン阻害薬などが挙げられる。  [0078] The ability to enumerate specific examples of antiallergic agents used in the present invention is not limited to these compounds in the present invention. Examples include mediator release inhibitors such as sodium cromoglycate and thromboxane inhibitors such as ozadarel hydrochloride.
[0079] 本発明に用いられる抗酸化剤として具体例を列挙するが、本発明においてはこれ らの化合物に限定されるものではない。例えば、力イネチンが挙げられる。  [0079] Specific examples of the antioxidant used in the present invention are listed, but the present invention is not limited to these compounds. An example is force rice.
[0080] 本発明に用いられる抗血栓剤として具体例を列挙する力 本発明においてはこれ らの化合物に限定されるものではない。例えば、アスピリン、ヮルフアリンカリウムなど が挙げられる。  [0080] The ability to enumerate specific examples of the antithrombotic agent used in the present invention is not limited to these compounds in the present invention. Examples include aspirin and potassium sulfarine.
[0081] 本発明に用いられる抗炎症剤として例えば、プレドニゾロンが挙げられる。  [0081] Examples of the anti-inflammatory agent used in the present invention include prednisolone.
[0082] 本発明に用いられる免疫抑制剤として具体例を列挙するが、本発明にお!/、てはこ れらの化合物に限定されるものではない。例えば、プレドニゾロン、ァザチォプリンな どが挙げられる。  [0082] Specific examples of the immunosuppressive agent used in the present invention are listed, but the present invention is not limited to these compounds! Examples include prednisolone and azathioprine.
[0083] これらの薬物と同時に各種添加剤を加えても良い。本発明で用いることができる添 加物としては、保湿剤（例えば、カンテン、ジグリセリン、ジステアリルジモニゥムヘクト ライト、ブチレングリコーノレ、ポリエチレングリコーノレ、プロピレングリコーノレ、ヒアノレロン 酸ナトリウム、へキシレンダリコール、ョクイニンエキス、ワセリン）、柔軟剤（例えば、グ リセリン、ミネラルオイル）、ェモリエント成分（界面活性剤など）（例えば、イソステアリ ン酸イソプロピル、イソステアリン酸ポリグリセリル、イソノナン酸イソトリデシル、イソノ ナン酸ォクチル、ォレイン酸、ォレイン酸グリセリル、カカオ脂、コレステロール、混合 脂肪酸トリグリセリド、コハク酸ジォクチル、酢酸ステアリン酸スクロース、シクロペンタ シロキサン、ジステアリン酸スクロース、パルミチン酸ォクチル、ヒドロキシステアリン酸 ォクチル、ベヘン酸ァラキル、ポリべヘン酸スクロース、ポリメチルシルセスキォキサン 、ミリスチノレアノレコーノレ、ミリスチン酸セチル、ミリスチン酸ミリスチノレ、ラウリン酸へキシ ル）、及び経皮吸収促進剤（例えば、エタノール、ミリスチン酸イソプロピル、クェン酸 、スクヮラン、ォレイン酸、メントール、 N-メチル -2-ピロリドン、アジピン酸ジェチル、ァ ジピン酸ジイソプロピル、セバシン酸ジェチル、セバシン酸ジイソプロピル、パルミチ ン酸イソプロピル、ォレイン酸イソプロピル、ォレイン酸オタチルドデシル、イソステアリ ルアルコール、 2-オタチルドデカノール、尿素、植物油、動物油）、防腐剤（例えば、 安息香酸、安息香酸ナトリウム、ェチルパラベン、ソルビン酸カリウム、ソルビン酸ナト リウム、ソルビン酸、デヒドロ酢酸ナトリウム、メチルパラベン）、色素剤（例えば、力オリ ン、カルミン、グンジヨウ、酸化クロム、酸化鉄）、香料、 pH調整剤（例えば、タエン酸ナ トリウム、酢酸ナトリウム、水酸化ナトリウム、水酸化カリウム、リン酸)を挙げることがで きる。 [0083] Various additives may be added simultaneously with these drugs. Additives that can be used in the present invention include humectants (for example, agar, diglycerin, distearyl dimonium hectorite, butylene glycol, polyethylene glycol, propylene glycol, sodium hydranolate, hexyleneda Recall, okuinin extract, petrolatum), softener (eg, glycerin, mineral oil), emollient component (surfactant, etc.) (eg, isopropyl isostearate, polyglyceryl isostearate, isotridecyl isononanoate, octyl isononanoate, oleic acid) , Glyceryl oleate, cocoa butter, cholesterol, mixed Fatty acid triglycerides, dioctyl succinate, sucrose acetate stearate, cyclopentasiloxane, sucrose distearate, octyl palmitate, octyl hydroxystearate, arachile behenate, sucrose polybehenate, polymethylsilsesquioxane, myristino rare record Nore, cetyl myristate, myristic myristate, hexyl laurate, and transdermal absorption enhancers (eg, ethanol, isopropyl myristate, citrate, squalane, oleic acid, menthol, N-methyl-2-pyrrolidone, Jetyl adipate, diisopropyl adipate, decyl sebacate, diisopropyl sebacate, isopropyl palmitate, isopropyl oleate, octyldodecyl oleate, isostearyl Alcohol, 2 - OTA chilled octadecanol, urea, vegetable oils, animal oils), preservatives (e.g., benzoic acid, sodium benzoate, Echiruparaben, potassium sorbate, sorbic acid sodium, sorbic acid, sodium dehydroacetate, methylparaben), dye Agents (for example, force orin, carmine, gundiio, chromium oxide, iron oxide), fragrances, pH adjusters (for example, sodium taenoate, sodium acetate, sodium hydroxide, potassium hydroxide, phosphoric acid). it can.
[0084] 該外用剤用の組成物の形態は特に限定されな!/、が、例えばゲル、スポンジ、フィル ム、不織布、ファイバー（チューブ）、粒子などが挙げられる。形状はいずれの形状で も適用可能であるが、例えば角錐、円錐、角柱、円柱、球、紡錘状の構造物および任 意の型により作成した基材が挙げられる。  [0084] The form of the composition for external use is not particularly limited! /, And examples thereof include gels, sponges, films, nonwoven fabrics, fibers (tubes), and particles. Any shape can be applied, and examples thereof include a pyramid, a cone, a prism, a cylinder, a sphere, a spindle-shaped structure, and a substrate made of an arbitrary mold.
[0085] 該外用剤の用途は特に限定されないが、例えば、皮膚癌、角化症、悪性黒色腫、 菌状息肉症、乳癌、前立腺癌、子宮癌、膣癌、陰茎癌、大腸癌である。好ましくは、 皮膚癌、角化症である。最も好ましくは、皮膚癌、である。また、本発明の外用剤用の 組成物の用途として、好ましくは経皮吸収製剤である。該外用剤は必要に応じて組 織内部に埋め込むこともできる。例えば、手術後、手術により取り除かれた部分の機 能保持のために、欠落した組織に埋め込む形ではめ込むこと、あるいは、損傷の激 しい皮膚の被覆を伴うこともありうる。生体に親和性の高い外用剤である場合、周辺 組織の修復を助けることもありうる。  [0085] The use of the external preparation is not particularly limited, and examples thereof include skin cancer, keratosis, malignant melanoma, mycosis fungoides, breast cancer, prostate cancer, uterine cancer, vaginal cancer, penile cancer, and colon cancer. . Preferred are skin cancer and keratosis. Most preferred is skin cancer. Moreover, as a use of the composition for external preparations of the present invention, a transdermal absorption preparation is preferable. The external preparation can be embedded in the tissue as necessary. For example, after surgery, in order to preserve the function of the part removed by surgery, it may be embedded in the missing tissue, or it may be accompanied by a severely damaged skin covering. In the case of an external preparation having a high affinity for a living body, it may help repair surrounding tissues.
[0086] 本発明の組成物は抗癌剤が親水性基材中に微分散状態で封入されていることが 好ましい。微分散の定義は（1)で記載されたものと同様である。 [0087] 以下の実施例により本発明をさらに具体的に説明する力 本発明は実施例によつ て限定されるものではなレ、。 [0086] In the composition of the present invention, the anticancer agent is preferably encapsulated in a finely dispersed state in a hydrophilic substrate. The definition of fine dispersion is the same as that described in (1). [0087] The ability to explain the present invention more specifically by the following examples The present invention is not limited by the examples.
実施例  Example
[0088] (1)難水溶性化合物を親水性マトリックスに封入した組成物の製造方法に関する実 験例  [0088] (1) Experimental example relating to a method for producing a composition in which a poorly water-soluble compound is encapsulated in a hydrophilic matrix
実施例 1：架橋ゼラチンゲルへのパクリタキセルの封入  Example 1: Encapsulation of paclitaxel in a cross-linked gelatin gel
酸処理ゼラチン（PSPゼラチン、二ツビ社製）を含む PBS溶液に 25%ダルタルアルデ ヒド水溶液を加え、 4°Cで 17時間静置した（最終濃度：ゼラチン： 10%、ダルタルアル デヒド：0.25%、厚さ： 2 mm)。得られたゼラチンゲルを水で洗浄した後、 5mMグリシ ン水溶液に 37°Cで 1時間浸漬し未反応のダルタルアルデヒドを失活させた。得られた ゲルを凍結乾燥し、架橋ゼラチンスポンジを得た。該架橋ゼラチンスポンジにパクリタ キセルを含む 1，1，1，3，3，3-へキサフルォ口- 2-プロパノール（HFIP)溶液（パクリタキセ ル濃度： 10 mg/mL)を浸漬させると、 HFIPに浸漬したゲルは膨潤し、透明性を有した (図 1)。  A 25% aqueous solution of Daltal Aldehyde was added to a PBS solution containing acid-treated gelatin (PSP gelatin, manufactured by Futsubi) and allowed to stand at 4 ° C for 17 hours (final concentration: Gelatin: 10%, Dartal Aldehyde: 0.25%, thickness) (2 mm). The obtained gelatin gel was washed with water and then immersed in a 5 mM glycine aqueous solution at 37 ° C. for 1 hour to inactivate unreacted dartalaldehyde. The obtained gel was lyophilized to obtain a crosslinked gelatin sponge. When the 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solution (paclitaxel concentration: 10 mg / mL) containing paclitaxel is immersed in the crosslinked gelatin sponge, it is immersed in HFIP. The gel was swollen and transparent (Figure 1).
[0089] 一方、エタノール溶液を浸漬させると、ゲルはほとんど変化しなかった。さらに、該ゲ ルを、それぞれパクリタキセルを含まない溶媒にて洗浄した後、 17時間自然乾燥した 。得られたパクリタキセル封入架橋ゼラチンをァクチナーゼにより分解し、酢酸ェチル にて抽出することによりパクリタキセルを回収した。得られたパクリタキセルを HPLC ( 東ソー TSK-gel ODS_80T、 THF/H 0=9/1)にて定量した。エタノール溶液を浸漬し たゲルにはパクリタキセルは 0.5 mg (ゼラチン 10 mgあたり）封入できたのに対し、 HFI P溶液を浸漬したゲルにはパクリタキセルが 1.9 mg (ゼラチン 10 mgあたり）封入できた [0089] On the other hand, when the ethanol solution was immersed, the gel hardly changed. Furthermore, each gel was washed with a solvent not containing paclitaxel and then naturally dried for 17 hours. The obtained paclitaxel-encapsulated crosslinked gelatin was decomposed with lactinase and extracted with ethyl acetate to recover paclitaxel. The obtained paclitaxel was quantified by HPLC (Tosoh TSK-gel ODS_80T, THF / H 0 = 9/1). Paclitaxel could be encapsulated in 0.5 mg (per 10 mg of gelatin) in gel immersed in ethanol solution, whereas 1.9 mg (per 10 mg of gelatin) in paclitaxel could be encapsulated in gel immersed in HFI P solution.
〇 Yes
[0090] 実施例 2：架橋ゼラチンゲル内のパクリタキセルの観察  [0090] Example 2: Observation of paclitaxel in crosslinked gelatin gel
実施例 1により作成したパクリタキセル封入ゼラチンゲルを実体顕微鏡 (ライカ社製 、 MZ16A)により観察した。 HFIPより作成したパクリタキセル封入ゼラチンフィルムは パクリタキセルの析出を認めず、パクリタキセルを含まないゼラチンフィルムと同様で あった（図 2左、中）。実体顕微鏡 (ライカ社製、 MZ16A)により観察においてパクリタ キセルの析出が認められなかったことから、 HFIPより作成したパクリタキセル封入ゼラ チンフィルムにおけるパクリタキセルのサイズは 10 m以下である。実施例 1および 2 において、架橋剤にトランスダルタミナーゼ（ァクティバ TG_S、味の素社製）を、難水 溶性化合物にメチルイエロー（和光純薬製)を用いてもそれぞれ同様の結果を得た。 The paclitaxel-encapsulated gelatin gel prepared in Example 1 was observed with a stereomicroscope (Leica Co., Ltd., MZ16A). The paclitaxel-encapsulated gelatin film prepared from HFIP was similar to the gelatin film containing no paclitaxel without precipitation of paclitaxel (Fig. 2, left, middle). Since no precipitation of paclitaxel was observed by observation with a stereomicroscope (Leica MZ16A), paclitaxel-encapsulated gel made from HFIP The size of paclitaxel in chin film is less than 10 m. In Examples 1 and 2, similar results were obtained using transdaltaminase (Activa TG_S, manufactured by Ajinomoto Co., Inc.) as the cross-linking agent and methyl yellow (manufactured by Wako Pure Chemical Industries, Ltd.) as the poorly water-soluble compound.
[0091] (2)抗癌剤を封入した親水性基材からなる抗癌剤含有外用剤  [0091] (2) An anticancer agent-containing external preparation comprising a hydrophilic base material encapsulating an anticancer agent
実施例 3 : 5— FU封入ゼラチンゲノレの作製  Example 3: Preparation of 5-FU gelatin gelatine
酸処理ゼラチン（10%、 PSPゼラチン、二ツビ社製）、 5_FU (1 mg/mL, 5 mg/mL, 1 0 mg/mL)、およびトランスグノレタミナーゼ（0·8%、ァクテイノく TG_S、味の素社製）を含 む PBS溶液を調製した。該 PBS溶液 1.8 mLを角型ディッシュ（3 cm X 3 cm X 1 cm) に流し込み（液厚： 2 mm)、 25°Cで 17時間静置した。ゼラチンがゲル形成され、型通り (3 cm X 3 cm X 2 mm)の 5-FU封入ゼラチンゲルを作製できた。当該 5-FU濃度で は、ゲルは 5— FUを含まないゲルと同様に透明性を有した。  Acid-treated gelatin (10%, PSP gelatin, manufactured by Futsubi), 5_FU (1 mg / mL, 5 mg / mL, 10 mg / mL), and transgnoretaminase (0 · 8%, Actinoku TG_S, A PBS solution containing Ajinomoto Co.) was prepared. The PBS solution (1.8 mL) was poured into a square dish (3 cm × 3 cm × 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours. Gelatin was formed into a gel, and a 5-FU-encapsulated gelatin gel (3 cm X 3 cm X 2 mm) was prepared as usual. At the 5-FU concentration, the gel was as transparent as the gel without 5-FU.
[0092] 実施例 4：パクリタキセル封入ゼラチンゲルの作製  [0092] Example 4: Preparation of gelatin gel containing paclitaxel
酸処理ゼラチン（10%、 PSPゼラチン、二ツビ社製）、 Cremophor EL (16.7% , BASF 社製）、エタノール（8.3%)、トランスダルタミナーゼ（0·8%、ァクティバ TG_S、味の素 社製）、およびパクリタキセル (0.5 mg/mL)を含む PBS溶液を調製した。該溶液 1.8 m Lを角型ディッシュ（3 cm X 3 cm X 1 cm)に流し込み（液厚： 2 mm)、 25°Cで 17時間 静置した。ゼラチンゲルが形成され、型通り（3 cm X 3 cm X 2 mm)のパクリタキセ  Acid-treated gelatin (10%, PSP gelatin, manufactured by Futsubi), Cremophor EL (16.7%, manufactured by BASF), ethanol (8.3%), transdaltaminase (0.8%, Activa TG_S, manufactured by Ajinomoto Co.) , And a PBS solution containing paclitaxel (0.5 mg / mL). 1.8 mL of the solution was poured into a square dish (3 cm × 3 cm × 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours. Gelatin gel is formed, and paclitaxe is normal (3 cm x 3 cm x 2 mm)
[0093] 実施例 5 : [0093] Example 5:
酸処理ゼラチンの代わりにリコンビナントゼラチン (Fibrogen社製）を用いる以外は 実施例 3及び 4と同様にして、 5-FU封入ゼラチンゲル及びパクリタキセル封入ゼラチ ンゲルを作製した結果、実施例 3及び 4と同様の結果が得られた。  A 5-FU-encapsulated gelatin gel and paclitaxel-encapsulated gelatin gel were prepared in the same manner as in Examples 3 and 4 except that recombinant gelatin (Fibrogen) was used instead of acid-treated gelatin. Results were obtained.
[0094] 実施例 6：ダルタルアルデヒド架橋ゼラチンの作製 [0094] Example 6: Preparation of cross-linked gelatin of dartalaldehyde
酸処理ゼラチン (PSPゼラチン）を含む PBS溶液に 25%ダルタルアルデヒド（GA) 溶液を含む PBS溶液を調製した (最終濃度： 10% (ゼラチン）、 0.3% (GA)、温度： 30 °C)。該溶液 1.8mLを角型ディッシュ（3 cm X 3 cm X 1 cm)に流し込み（液厚： 2 m m)、 4°Cで 17時間静置し、 GA架橋ゼラチンを得た。該架橋ゼラチンを 37°Cの 50mM グリシン溶液に 1時間浸漬した。続!、て 37°Cの脱イオン水に 1時間浸漬する操作を 2 回行い、未反応の GAを洗浄した。ここで得られた GA架橋ゼラチンを円形にくり抜き ( φ = 12 mm)、凍結乾燥することで、ディスク状の GA架橋ゼラチンを得た。 PBS solution containing 25% dartalaldehyde (GA) solution was prepared in PBS solution containing acid-treated gelatin (PSP gelatin) (final concentration: 10% (gelatin), 0.3% (GA), temperature: 30 ° C) . 1.8 mL of the solution was poured into a square dish (3 cm × 3 cm × 1 cm) (liquid thickness: 2 mm) and allowed to stand at 4 ° C. for 17 hours to obtain GA cross-linked gelatin. The crosslinked gelatin was immersed in a 50 mM glycine solution at 37 ° C for 1 hour. Continued! 2 hours of immersion in 37 ° C deionized water for 1 hour Repeatedly, unreacted GA was washed. The GA cross-linked gelatin obtained here was cut into a circle (φ = 12 mm) and freeze-dried to obtain a disk-shaped GA cross-linked gelatin.
[0095] 実施例 7： GA架橋ゼラチン内への抗癌剤の封入  [0095] Example 7: Encapsulation of anticancer agent in GA cross-linked gelatin
実施例 6により作製した GA架橋ゼラチンに 5-FU,シスブラチン、カルポプラチンお よびアドリアマイシンを含む水溶液（100 L、抗癌剤濃度： 1 mg/mL)を 37°Cで滴下し 、 1時間静置することで、 GA架橋ゼラチン内部に抗癌剤を浸漬させた抗癌剤封入ゼ ラチンを作製した。すなわち、該抗癌剤含有ゼラチンはウエットタイプの抗癌剤含有 ゼラチンゲルである。一方、該抗癌剤封入ゼラチンゲルをさらに凍結乾燥させること で、スポンジ状の抗癌剤封入ゼラチンを得た。  By adding dropwise an aqueous solution (100 L, anticancer drug concentration: 1 mg / mL) containing 5-FU, cisbratin, carpoplatin and adriamycin to the GA cross-linked gelatin prepared in Example 6, and allowing to stand for 1 hour. An anticancer agent-encapsulated gelatin in which an anticancer agent was immersed in GA cross-linked gelatin was prepared. That is, the anticancer agent-containing gelatin is a wet type anticancer agent-containing gelatin gel. On the other hand, the anticancer agent-encapsulated gelatin gel was further freeze-dried to obtain a sponge-like anticancer agent-encapsulated gelatin.
[0096] 実施例 8 :  [0096] Example 8:
実施例 6, 7の酸処理ゼラチンの代わりにリコンビナントゼラチン（Fibrogen社製）を 用いても同様の結果を得た。  Similar results were obtained when recombinant gelatin (Fibrogen) was used instead of the acid-treated gelatin of Examples 6 and 7.
[0097] 実施例 9：抗癌剤含有ゼラチンによる腫瘍縮小効果  Example 9: Tumor reduction effect by gelatin containing anticancer agent
ヘアレスマウス（6週令）に紫外線性皮膚癌を発症させ、マウス皮膚癌モデルを作製 する。該マウスの患部に実施例 3及び 4にて作製した抗癌剤含有ゼラチンゲル (サイ ズ： 3 cm X 3 cm、厚さ： 2 mm、薬剤濃度； 5-FU： 5 mg/mL、ノ クリタキセノレ： 0.5 mg/ mL)を貼り付け、さらに該ゲルを被覆する（BAND-AID、ジョンソン &ジョンソン社製)。 該ゲルを貼り付けて 1週間後、腫瘍のサイズの大幅な減少を認めた。  A mouse skin cancer model is created by causing ultraviolet skin cancer in hairless mice (6 weeks of age). Anticancer drug-containing gelatin gel prepared in Examples 3 and 4 on the affected area of the mouse (size: 3 cm × 3 cm, thickness: 2 mm, drug concentration; 5-FU: 5 mg / mL, nocritaxenole: 0.5 mg / mL) is applied, and the gel is further coated (BAND-AID, manufactured by Johnson & Johnson). One week after the gel was applied, a significant decrease in tumor size was observed.
[0098] (3)ォクタノール/水の分配係数 (LogP)が- 3.0以上 3.0以下である薬物が生体高分 子を主成分とする構造物中に封入されている、外用剤用組成物。  [0098] (3) A composition for external use, wherein a drug having an octanol / water partition coefficient (LogP) of −3.0 or more and 3.0 or less is encapsulated in a structure mainly composed of a biological polymer.
実施例 10： 5— FU封入ゼラチンゲノレの作製  Example 10: 5—Preparation of FU Encapsulated Gelatin Genore
酸処理ゼラチン（10%、 PSPゼラチン、二ツビ社製）、 5_FU (1 mg/mL, 5 mg/mL, 1 0 mg/mL)、およびトランスグノレタミナーゼ（0·8%、ァクテイノく TG_S、味の素社製）を含 む PBS溶液を調製した。ここで用いた 5-FUの LogPは、 -0.58であり、分子量は 130で ある。  Acid-treated gelatin (10%, PSP gelatin, manufactured by Futsubi), 5_FU (1 mg / mL, 5 mg / mL, 10 mg / mL), and transgnoretaminase (0 · 8%, Actinoku TG_S, A PBS solution containing Ajinomoto Co.) was prepared. The LogP of 5-FU used here is -0.58, and the molecular weight is 130.
該 PBS溶液 1.8 mLを角型ディッシュ（3 cm X 3 cm X 1 cm)に流し込み（液厚： 2 mm )、 25°Cで 17時間静置した。ゼラチンがゲル形成され、型通り（3 cm X 3 cm X 2 mm )の 5-FU封入ゼラチンゲルを作製できた。当該 5-FU濃度では、ゲルは 5-FUを含ま ないゲルと同様に透明性を有した。組成物中の含水率は、約 90%であった。また、 5- FU封入ゼラチンゲル中における 5-FUの封入量は、ゲル作製用の溶液濃度と同様 であった。 The PBS solution (1.8 mL) was poured into a square dish (3 cm × 3 cm × 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours. Gelatin was formed into a gel, and a 5-FU-encapsulated gelatin gel (3 cm × 3 cm × 2 mm) as usual was prepared. At this 5-FU concentration, the gel contains 5-FU It was as transparent as no gel. The water content in the composition was about 90%. The amount of 5-FU encapsulated in the 5-FU-encapsulated gelatin gel was the same as the concentration of the solution for gel preparation.
[0099] 酸処理ゼラチンの代わりにリコンビナントゼラチン（Fibrogen社製）を用いても同様の 結果を得た。  [0099] Similar results were obtained when recombinant gelatin (Fibrogen) was used instead of acid-treated gelatin.
[0100] 実施例 11 [0100] Example 11
別に、同様に該酸処理ゼラチン、カルポプラチン（1、 5、 10 mg/mL)、およびトランス ダルタミナーゼ（0.8%)を含む PBS溶液を調製した。ここで用いたカルポプラチンの Lo gPは- 2.3であり、分子量は 371である。該溶液 1.8 mLを角型ディッシュ（3 cm X 3 cm X 1 cm)に流し込み（液厚： 2 mm)、 25°Cで 17時間静置した。ゼラチンがゲル形成さ れ、型通り（3 cm X 3 cm X 2 mm)のカルポプラチン封入ゼラチンゲルを作製できた 。該ゲル中のカルポプラチン封入ゼラチンゲル中におけるカルポプラチンの封入量 はゲル作製用の溶液濃度と同様であった。  Separately, a PBS solution containing the acid-treated gelatin, carpoplatin (1, 5, 10 mg / mL), and transdaltaminase (0.8%) was similarly prepared. The LogP of carpoplatin used here is -2.3 and the molecular weight is 371. The solution (1.8 mL) was poured into a square dish (3 cm × 3 cm × 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours. Gelatin was formed into a gel, and a carpoplatin-encapsulated gelatin gel was prepared as usual (3 cm x 3 cm x 2 mm). The amount of encapsulated carpoplatin in the gelatin gel encapsulated in carpoplatin in the gel was the same as the solution concentration for gel preparation.
[0101] 実施例 12：抗癌剤含有ゼラチンによる腫瘍縮小効果  [0101] Example 12: Tumor reduction effect by gelatin containing anticancer agent
ヘアレスマウス（6週令）に紫外線性皮膚癌を発症させ、マウス皮膚癌モデルを作製 した。該マウスの患部に実施例 10にて作製した 5-FU含有ゼラチンゲルを貼付け、ゲ ルをポリエチレンフィルムで被覆し、固定した。 1ヶ月後、いずれの製剤も腫瘍のサイ ズの大幅な減少を認めた。一方、 5-FUと同様にカルポプラチン封入ゼラチンゲルを 作用させたゲルでは、親水性のカルポプラチンが親水性基材であるゼラチン中での 残存量が多ぐ 5-FUに比べて優位な腫瘍サイズの減少を認めな力、つた。  A mouse skin cancer model was prepared by developing ultraviolet skin cancer in hairless mice (6 weeks old). The 5-FU-containing gelatin gel prepared in Example 10 was applied to the affected area of the mouse, and the gel was covered with a polyethylene film and fixed. One month later, both formulations showed a significant reduction in tumor size. On the other hand, in the gel in which carpoplatin-encapsulated gelatin gel was allowed to act like 5-FU, hydrophilic carpoplatin has a large residual amount in gelatin, which is a hydrophilic substrate, and has a superior tumor size compared to 5-FU. It was a force that did not allow a decrease.
[0102] 実施例 13：シスブラチン封入ゼラチンゲルの作製  [0102] Example 13: Preparation of gelatin gel encapsulating cisbratine
同様に該酸処理ゼラチン、シスプラチン（1 mg/mL)、およびトランスダルタミナーゼ（0 • 8%)を含む PBS溶液を調製した。ここで用いたシスプラチンの LogPは- 1.7であり、分 子量は 300である。該溶液 1.8 mLを角型ディッシュ（3 cm X 3 cm X 1 cm)に流し込 み（液厚： 2 mm)、 25°Cで 17時間静置した。ゼラチンがゲル形成され、型通り（3 cm X 3 cm X 2 mm)のシスプラチン封入ゼラチンゲルを作製できた。該ゲル中のシスプラ チン封入ゼラチンゲル中におけるシスブラチンの封入量はゲル作製用の溶液濃度と 同様であった。 [0103] 実施例 14：アドリアマイシン封入ゼラチンゲルの作製 Similarly, a PBS solution containing the acid-treated gelatin, cisplatin (1 mg / mL) and transdaltaminase (0 • 8%) was prepared. The log P of cisplatin used here is -1.7 and the molecular weight is 300. The solution (1.8 mL) was poured into a square dish (3 cm × 3 cm × 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours. Gelatin was formed into a gel, and a cisplatin-encapsulated gelatin gel that was normal (3 cm × 3 cm × 2 mm) could be prepared. The amount of cisplatin encapsulated in the gelatin gel encapsulating cisplatin in the gel was the same as the solution concentration for gel preparation. Example 14: Preparation of adriamycin-encapsulated gelatin gel
別に、同様に該酸処理ゼラチン、アドリアマイシン（1 mg/mL)、およびトランスグノレタ ミナーゼ（0.8%)を含む PBS溶液を調製した。ここで用いたシスプラチンの LogPは 0.3 2であり、分子量は 543である。該溶液 1.8 mLを角型ディッシュ（3 cm X 3 cm X 1 cm )に流し込み（液厚： 2 mm)、 25°Cで 17時間静置した。ゼラチンがゲル形成され、型通 り（3 cm X 3 cm X 2 mm)のアドリアマイシン封入ゼラチンゲルを作製できた。該ゲ ル中のアドリアマイシン封入ゼラチンゲル中におけるシスプラチンの封入量はゲル作 製用の溶液濃度と同様であった。  Separately, a PBS solution containing the acid-treated gelatin, adriamycin (1 mg / mL), and transgnoretaminase (0.8%) was similarly prepared. The cisplatin used here has a LogP of 0.32 and a molecular weight of 543. 1.8 mL of the solution was poured into a square dish (3 cm × 3 cm × 1 cm) (liquid thickness: 2 mm) and allowed to stand at 25 ° C. for 17 hours. Gelatin formed into a gel, and an adriamycin-encapsulated gelatin gel as usual (3 cm X 3 cm X 2 mm) could be prepared. The amount of cisplatin encapsulated in the gelatin gel encapsulating adriamycin in the gel was the same as the solution concentration for gel preparation.
産業上の利用可能性  Industrial applicability
[0104] 本発明の方法で製造される組成物は、医薬品又は化粧品などの分野において有 用である。  [0104] The composition produced by the method of the present invention is useful in fields such as pharmaceuticals and cosmetics.
図面の簡単な説明  Brief Description of Drawings
[0105] [図 1]図 1は、パクリタキセルを含むエタノール（左）および HFIP (右）に浸漬したゼラチ ンゲルにつ!/、て浸漬直後（上)及び自然乾燥後（下）のものを示す。  [0105] [Fig. 1] Fig. 1 shows gelatin gel immersed in ethanol containing paclitaxel (left) and HFIP (right)! /, Immediately after soaking (top) and after natural drying (bottom) .
[図 2]図 2は、ゼラチンゲルの実体顕微鏡写真を示す。パクリタキセルを含まない HFIP を浸漬したゼラチンゲル (左）、及びパクリタキセルを含む HFIPに浸漬したゼラチンゲ ノレ（右）を示す。  FIG. 2 shows a stereomicrograph of gelatin gel. Gelatin gel soaked in HFIP without paclitaxel (left) and gelatin gel soaked in HFIP with paclitaxel (right) are shown.

Claims

請求の範囲 The scope of the claims
[I] 難水溶性化合物を含有する有機フッ素化合物に親水性マトリックスを浸潰して難水 溶性化合物を親水性マトリックスに封入する工程を含む、難水溶性化合物を親水性 マトリックスに封入した組成物の製造方法。  [I] A composition in which a poorly water-soluble compound is encapsulated in a hydrophilic matrix, comprising the step of immersing the hydrophilic matrix in an organic fluorine compound containing the poorly water-soluble compound and encapsulating the poorly water-soluble compound in the hydrophilic matrix. Production method.
[2] 難水溶性化合物を含有する有機フッ素化合物に親水性マトリックスを浸漬した後に、 該親水性マトリックスを乾燥する、請求項 1に記載の方法。  [2] The method according to claim 1, wherein the hydrophilic matrix is dried after the hydrophilic matrix is immersed in the organic fluorine compound containing the poorly water-soluble compound.
[3] 親水性マトリックスが生体高分子である、請求項 1又は 2に記載の方法。 [3] The method according to claim 1 or 2, wherein the hydrophilic matrix is a biopolymer.
[4] 親水性マトリックスがタンパク質である、請求項 1から 3の何れかに記載の方法。 [4] The method according to any one of claims 1 to 3, wherein the hydrophilic matrix is a protein.
[5] タンパク質がコラーゲン、ゼラチン、アルブミン、カゼイン、フイブ口イン、フイブリン、ラ ミニン、フイブロネクチン、又はビトロネクチンからなる群より選ばれる少なくとも一種で ある、請求項 4に記載の方法。 [5] The method according to claim 4, wherein the protein is at least one selected from the group consisting of collagen, gelatin, albumin, casein, fib mouth-in, fibrin, laminin, fibronectin, and vitronectin.
[6] タンパク質がゼラチンである、請求項 4又は 5に記載の方法。 6. The method according to claim 4 or 5, wherein the protein is gelatin.
[7] 親水性マトリックス力 熱、光、または架橋剤により架橋されている、請求項 1から 6の 何れかに記載の方法。  [7] Hydrophilic matrix force The method according to any one of claims 1 to 6, which is crosslinked by heat, light, or a crosslinking agent.
[8] 親水性マトリックスの架橋がダルタルアルデヒド、又はトランスダルタミナーゼを用いて 行われる請求項 1から 7のいずれかに記載の方法。  [8] The method according to any one of [1] to [7], wherein the hydrophilic matrix is cross-linked using dartalaldehyde or transdaltaminase.
[9] 有機フッ素化合物が、炭素数 2から 8の化合物である、請求項 1から 8の何れかに記 載の方法。 [9] The method according to any one of claims 1 to 8, wherein the organic fluorine compound is a compound having 2 to 8 carbon atoms.
[10] 有機フッ素化合物が、炭素数 2から 3の化合物である、請求項 1から 9の何れかに記 載の方法。  [10] The method according to any one of claims 1 to 9, wherein the organic fluorine compound is a compound having 2 to 3 carbon atoms.
[I I] 有機フッ素化合物が、 1 , 1 , 1一へキサフルオロー 2—プロパノール、トリフルォロエタ ノール、トリフルォロ酢酸、又はペンタフルォロプロピオン酸である、請求項 1から 10 の何れかに記載の方法。  [I I] The method according to any one of claims 1 to 10, wherein the organic fluorine compound is 1,1,1,1-hexafluoro-2-propanol, trifluoroethanol, trifluoroacetic acid, or pentafluoropropionic acid.
[12] 難水溶性化合物の 1ーォクタノール/水の分配係数の対数 log Pが;!〜 20である、請 求項 1から 11の何れかに記載の方法。  [12] The method according to any one of claims 1 to 11, wherein the log P of the 1-octanol / water partition coefficient of the poorly water-soluble compound is;!-20.
[13] 難水溶性化合物の 1ーォクタノール/水の分配係数の対数 log Pが 2〜； 10である、請 求項 1から 12の何れかに記載の方法。 [13] The method according to any one of claims 1 to 12, wherein the log P of the 1-octanol / water partition coefficient of the poorly water-soluble compound is 2 to 10;
[14] 難水溶性化合物が薬剤である、請求項 1から 13の何れかに記載の方法。 [14] The method according to any one of [1] to [13], wherein the poorly water-soluble compound is a drug.
[15] 薬剤が免疫抑制剤、抗アレルギー剤、抗酸化剤、抗血栓剤、抗炎症剤、抗癌剤、化 粧品成分、またはサプリメント成分である、請求項 14に記載の方法。 [15] The method according to claim 14, wherein the drug is an immunosuppressant, an antiallergic agent, an antioxidant, an antithrombotic agent, an antiinflammatory agent, an anticancer agent, a cosmetic ingredient, or a supplement ingredient.
[16] 薬剤が抗癌剤である、請求項 14又は 15に記載の方法。 16. The method according to claim 14 or 15, wherein the drug is an anticancer drug.
[17] 薬剤がパクリタキセルである、請求項 14から 16の何れかに記載の方法。 17. The method according to any one of claims 14 to 16, wherein the drug is paclitaxel.
[18] 有機フッ素化合物中に、難水溶性化合物と一緒に添加物が含まれている、請求項 1 力、ら 17の何れかに記載の方法。 18. The method according to claim 1, wherein an additive is contained in the organic fluorine compound together with the poorly water-soluble compound.
[19] 添加物が、保湿剤、柔軟剤、経皮吸収促進剤、及び界面活性剤から選択される 1種 以上のものである、請求項 18に記載の方法。 [19] The method according to claim 18, wherein the additive is at least one selected from a humectant, a softener, a transdermal absorption enhancer, and a surfactant.
[20] 難水溶性化合物を親水性マトリックスに封入した組成物力 経皮吸収剤、局所治療 剤、経口治療剤、化粧品、サプリメント、又は色素材として使用される、請求項 1から 1[20] Power of composition in which poorly water-soluble compound is encapsulated in hydrophilic matrix, used as a transdermal absorption agent, topical treatment agent, oral treatment agent, cosmetics, supplement, or color material.
9の何れかに記載の方法。 10. The method according to any one of 9.
[21] 抗癌剤を封入した親水性基材からなる抗癌剤含有外用剤。 [21] An anticancer agent-containing external preparation comprising a hydrophilic substrate encapsulating an anticancer agent.
[22] 親水性基材がタンパク質である、請求項 21に記載の抗癌剤含有外用剤。 [22] The anticancer agent-containing external preparation according to claim 21, wherein the hydrophilic substrate is a protein.
[23] タンパク質力 コラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、フイブリン、フィ ブロネクチン、及びビトロネクチンからなる群より選ばれる少なくとも一種である、請求 項 22に記載の抗癌剤含有外用剤。 23. The protein strength The external preparation containing an anticancer agent according to claim 22, which is at least one selected from the group consisting of collagen, gelatin, albumin, laminin, casein, fibrin, fibronectin, and vitronectin.
[24] タンパク質がコラーゲンまたはゼラチンである、請求項 22に記載の抗癌剤含有外用 剤。 [24] The anticancer agent-containing external preparation according to claim 22, wherein the protein is collagen or gelatin.
[25] タンパク質力 ヒト、牛、豚又は魚に由来するタンパク質、又は遺伝子組み換えタンパ ク質である、請求項 21から 24の何れかに記載の抗癌剤含有外用剤。  [25] Protein power The external preparation containing an anticancer agent according to any one of claims 21 to 24, which is a protein derived from human, cow, pig or fish, or a genetically modified protein.
[26] タンパク質が架橋されている、請求項 21から 25の何れかに記載の抗癌剤含有外用 剤。 [26] The anticancer agent-containing external preparation according to any one of claims 21 to 25, wherein the protein is crosslinked.
[27] タンパク質の架橋が熱、光、縮合剤、又は酵素を用いて行われている、請求項 26に 記載の抗癌剤含有外用剤。  [27] The anticancer agent-containing external preparation according to claim 26, wherein the protein is crosslinked using heat, light, a condensing agent, or an enzyme.
[28] 親水性マトリックスの架橋がダルタルアルデヒド、又はトランスダルタミナーゼを用いて 行われる請求項 21から 27のいずれかに記載の抗癌剤含有外用剤。 [28] The anticancer agent-containing external preparation according to any one of claims 21 to 27, wherein the hydrophilic matrix is crosslinked using dartalaldehyde or transdaltaminase.
[29] 酵素がトランスダルタミナーゼである、請求項 27に記載の抗癌剤含有外用剤。 [29] The anticancer agent-containing external preparation according to claim 27, wherein the enzyme is transdaltaminase.
[30] 抗癌剤が 5—フルォロウラシル、パクリタキセル、シスプラチン、又はドキシルビシンで ある、請求項 21から 29の何れかに記載の抗癌剤含有外用剤。 [30] The anticancer drug is 5-fluorouracil, paclitaxel, cisplatin, or doxylubicin 30. An external preparation containing an anticancer agent according to any one of claims 21 to 29.
[31] 抗癌剤が 5—フルォロウラシル又はパクリタキセルである、請求項 21から 30の何れか に記載の抗癌剤含有外用剤。 [31] The anticancer agent-containing external preparation according to any of claims 21 to 30, wherein the anticancer agent is 5-fluorouracil or paclitaxel.
[32] 皮膚癌、又は角化症の治療のために用いる、請求項 21から 31の何れかに記載の抗 癌剤含有外用剤。 [32] The anticancer agent-containing external preparation according to any one of claims 21 to 31, which is used for the treatment of skin cancer or keratosis.
[33] 色素剤、柔軟剤、経皮吸収促進剤、保湿剤、ェモリエント成分、防腐剤、香料、又は pH調整剤から選択される 1種以上の添加剤をさらに含む、請求項 21から 32の何れ かに記載の抗癌剤含有外用剤。  [33] The method according to any one of claims 21 to 32, further comprising one or more additives selected from pigments, softeners, transdermal absorption enhancers, moisturizers, emollient ingredients, preservatives, perfumes, or pH adjusters. The anticancer agent-containing external preparation according to any one of the above.
[34] タンパク質、抗癌剤、及びタンパク質を架橋するための酵素を含む溶液を調製した後[34] After preparing a solution containing a protein, an anticancer agent, and an enzyme for cross-linking the protein
、該溶液を基板上に流し込んで静置することによりゲルを形成することにより製造され る、抗癌剤含有外用剤。 An anticancer agent-containing external preparation produced by forming a gel by pouring the solution onto a substrate and allowing it to stand.
[35] ゼラチン、 5—フルォロウラシル又はパクリタキセル、およびトランスダルタミナーゼを 含む溶液を調製した後、該溶液を基板上に流し込んで静置することによりゲルを形 成することにより製造される、抗癌剤含有外用剤。 [35] An anticancer agent-containing product produced by preparing a solution containing gelatin, 5-fluorouracil or paclitaxel, and transdaltaminase, and then pouring the solution onto a substrate and allowing it to stand to form a gel. Topical agent.
[36] 酸処理ゼラチン、 5—フルォロウラシル又はパクリタキセル、およびトランスグルタミナ ーゼを含む水溶液を調製した後、該溶液を基板上に流し込んで静置することにより ゲルを形成することにより製造される、抗癌剤含有外用剤。 [36] It is produced by preparing an aqueous solution containing acid-treated gelatin, 5-fluorouracil or paclitaxel, and transglutaminase, and then pouring the solution onto a substrate and allowing it to stand to form a gel. Anticancer drug-containing external preparation.
[37] ォクタノール/水の分配係数 (LogP)が- 3.0以上 3.0以下である薬物が生体高分子を 主成分とする構造物中に封入されている、外用剤用組成物。 [37] A composition for external use, wherein a drug having an octanol / water partition coefficient (LogP) of -3.0 or more and 3.0 or less is encapsulated in a structure mainly composed of a biopolymer.
[38] 薬物の LogPが- 1.5以上 0以下である、請求項 37に記載の外用剤用組成物。 [38] The composition for external use according to claim 37, wherein LogP of the drug is −1.5 or more and 0 or less.
[39] 薬物の分子量が 1500以下である、請求項 37又は 38に記載の外用剤用組成物。 [39] The composition for external use according to claim 37 or 38, wherein the molecular weight of the drug is 1500 or less.
[40] 薬物が抗癌剤である、請求項 37から 39の何れかに記載の外用剤用組成物。 [40] The composition for external use according to any one of claims 37 to 39, wherein the drug is an anticancer agent.
[41] 組成物中の含水率が 40%以上である、請求項 37から 40の何れかに記載の外用剤 用組成物。 41. The composition for external use according to any one of claims 37 to 40, wherein the water content in the composition is 40% or more.
[42] 生体高分子がタンパク質、又は多糖である、請求項 37から 41の何れかに記載の外 用剤用組成物。  [42] The composition for external use according to any one of claims 37 to 41, wherein the biopolymer is a protein or a polysaccharide.
[43] タンパク質がコラーゲン、ゼラチン、アルブミン、ラミニン、カゼイン、及びフイブリンか らなる群より選ばれる少なくとも一種である、請求項 42に記載の外用剤用組成物。 [43] The composition for external use according to claim 42, wherein the protein is at least one selected from the group consisting of collagen, gelatin, albumin, laminin, casein, and fibrin.
[44] タンパク質が架橋されている、請求項 42又は 43に記載の外用剤用組成物。 [44] The composition for external use according to claim 42 or 43, wherein the protein is crosslinked.
[45] タンパク質の架橋がダルタルアルデヒド、又はトランスダルタミナーゼを用いて行われ ている、請求項 44に記載の外用剤用組成物。  [45] The composition for external use according to claim 44, wherein the protein is cross-linked using dartalaldehyde or transdaltaminase.
[46] 色素剤、柔軟剤、経皮吸収促進剤、保湿剤、界面活性剤、防腐剤、香料、及び pH調 整剤からなる群より選ばれる少なくとも一種以上の添加剤をさらに含有する、請求項 3[46] The claim further comprising at least one additive selected from the group consisting of a coloring agent, a softening agent, a transdermal absorption enhancer, a moisturizer, a surfactant, an antiseptic, a fragrance, and a pH adjuster. Item 3
7から 45の何れかに記載の外用剤用組成物。 The composition for external preparation according to any one of 7 to 45.
[47] 皮膚癌又は角化症の治療のために使用される、請求項 37から 46の何れかに記載の 外用剤用組成物。 [47] The composition for external use according to any one of claims 37 to 46, which is used for the treatment of skin cancer or keratosis.
PCT/JP2007/070331 2006-10-18 2007-10-18 METHOD OF PRODUCING COMPOSITION COMPRISING HARDLY WATER-SOLUBLE COMPOUND ENCLOSED IN HYDROPHILIC MATRIX AND PREPARATION FOR EXTERNAL USE COMPRISING ANTICANCER AGENT OR DRUG HAVING OCTANOL/WATER PARTITION COEFFICIENT (Log P) OF -3.0 OR MORE BUT NOT MORE THAN 3.0 ENCLOSED IN HYDROPHILIC BASE WO2008047857A1 (en)

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JP2011526934A (en) * 2008-07-07 2011-10-20 アルミラル・へルマル・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Topical composition for the treatment of actinic keratosis
JP2013525482A (en) * 2010-05-04 2013-06-20 ネクスメッド ホールディングス，インコーポレイテッド Composition of small molecule therapeutic agent
CN103655455A (en) * 2012-09-11 2014-03-26 上海交通大学医学院附属第九人民医院 Nanoscale carrier loading 5-fluorouracil gel and preparation method thereof

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JPS58213709A (en) * 1982-06-05 1983-12-12 Teikoku Seiyaku Kk Application agent for gum mucosa
JPH08277229A (en) * 1995-04-04 1996-10-22 Hisamitsu Pharmaceut Co Inc Percutaneous absorbefacient and percutaneous absorbable type pharmaceutical preparation
JP2002531182A (en) * 1998-12-03 2002-09-24 ネアーリッヒ、ミヒャエル Porous composite matrix and method of making and using the same
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JP2007224012A (en) * 2006-01-30 2007-09-06 Fujifilm Corp Enzymatically crosslinked protein nanoparticle

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011526934A (en) * 2008-07-07 2011-10-20 アルミラル・へルマル・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Topical composition for the treatment of actinic keratosis
JP2013525482A (en) * 2010-05-04 2013-06-20 ネクスメッド ホールディングス，インコーポレイテッド Composition of small molecule therapeutic agent
CN103655455A (en) * 2012-09-11 2014-03-26 上海交通大学医学院附属第九人民医院 Nanoscale carrier loading 5-fluorouracil gel and preparation method thereof

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