WO2008047857A1 - Procédé de production d'une composition comprenant un composé difficilement soluble dans l'eau incorporé dans une matrice hydrophile et préparation pour une utilisation externe comprenant un agent ou médicament anticancéreux ayant un coefficient de partage octanol/eau (log p) de -3,0 ou plus mais pas plus de 3,0, incorporé - Google Patents

Procédé de production d'une composition comprenant un composé difficilement soluble dans l'eau incorporé dans une matrice hydrophile et préparation pour une utilisation externe comprenant un agent ou médicament anticancéreux ayant un coefficient de partage octanol/eau (log p) de -3,0 ou plus mais pas plus de 3,0, incorporé 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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English (en)
Japanese (ja)
Inventor
Shouji Ooya
Tetsuo Hiratou
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Fujifilm Corporation
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Publication of WO2008047857A1 publication Critical patent/WO2008047857A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—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.

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Abstract

La présente invention concerne un procédé de production d'une composition comprenant un composé difficilement soluble dans l'eau incorporé à l'état finement dispersé dans une matrice hydrophile et une préparation pour une utilisation externe contenant un agent anticancéreux. En l'occurrence, l'invention concerne un procédé de production d'une composition comprenant un composé difficilement soluble dans l'eau incorporé dans une matrice hydrophile qui comprend l'immersion de la matrice hydrophile dans un composé organofluoré contenant le composé difficilement soluble dans l'eau et donc l'incorporation du composé difficilement soluble dans l'eau dans la matrice hydrophile ; et une préparation pour une utilisation externe contenant un agent anticancéreux qui comprend une base hydrophile dans laquelle est incorporé un agent anticancéreux.
PCT/JP2007/070331 2006-10-18 2007-10-18 Procédé de production d'une composition comprenant un composé difficilement soluble dans l'eau incorporé dans une matrice hydrophile et préparation pour une utilisation externe comprenant un agent ou médicament anticancéreux ayant un coefficient de partage octanol/eau (log p) de -3,0 ou plus mais pas plus de 3,0, incorporé WO2008047857A1 (fr)

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JP2011526934A (ja) * 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 日光角化症の処置のための局所用組成物
JP2013525482A (ja) * 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 小分子治療剤の組成物
CN103655455A (zh) * 2012-09-11 2014-03-26 上海交通大学医学院附属第九人民医院 纳米级传递体载5-氟尿嘧啶凝胶及其制备方法

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