WO2001093826A1 - Preparations polymere synthetiques biocompatibles - Google Patents

Preparations polymere synthetiques biocompatibles Download PDF

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Publication number
WO2001093826A1
WO2001093826A1 PCT/JP2001/004719 JP0104719W WO0193826A1 WO 2001093826 A1 WO2001093826 A1 WO 2001093826A1 JP 0104719 W JP0104719 W JP 0104719W WO 0193826 A1 WO0193826 A1 WO 0193826A1
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Prior art keywords
prodrug
enzyme
drug
preparation
substance
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PCT/JP2001/004719
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English (en)
Japanese (ja)
Inventor
Shusuke Moriuchi
Toshiki Yoshimine
Miho Maeda
Akihiko Sano
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Sumitomo Pharmaceuticals Company, Limited
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Publication of WO2001093826A1 publication Critical patent/WO2001093826A1/fr

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    • 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
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a biocompatible synthetic polymer containing the prodrug and capable of controlling the release rate of the prodrug, which is used in combination with a substance that converts a prodog into a compound having a desired medicinal effect.
  • a biocompatible synthetic polymer containing the prodrug capable of controlling the release rate of the prodrug, which is used in combination with a substance that converts a prodog into a compound having a desired medicinal effect.
  • a prodrug is a substance that is converted enzymatically or non-enzymatically in a living body into a compound having a medicinal effect (that is, a drug). It also includes substances whose distribution and the like change. In recent years, a new therapeutic method has been reported in which a prodrug is used in combination with a substance that converts the prodrug into a drug (prodrug converting agent), instead of administering prodrug alone. For example,
  • HSVtk herpes simplex tnymidine kinase
  • E. coli purine nucleotide phosphorylase (Escnerichia coli purine nucleotide phosphorylase (PNP)) for the treatment of vulnerable mefnotherapy;
  • DFUR platelet-derived endothelial cell growth factor
  • PD-ECGf human thymidine phosphorylase, dThdPase
  • the prodrug When a prodrug is administered in a usual manner, it is difficult to maintain the prodrug at an effective concentration in a living body. Therefore, the prodrug is converted into a conjugate having a medicinal effect using a prodrug converting agent. However, it is often difficult to obtain a therapeutic effect.
  • the prodrug converting agent is a gene for an enzyme, it is difficult to administer the prodrug so as to match the expression time of the enzyme. If the effective concentration of the prodrug is not maintained for the time required for the drug to show its efficacy, a sufficient therapeutic effect cannot be obtained.
  • the ability to rapidly diffuse and disappear from the site of administration and the sustained local effective concentration cannot be obtained.
  • a preparation comprising an inner layer of a material and (b) an outer layer of a biocompatible substance which surrounds the inner layer, is impermeable to water, and can control the swelling of the inner layer is known (JP-A-7-187994).
  • E PA-481 drug and polylactic acid and glycolic acid / arsenate Dorokishikarupon acid in 732 [HOCH (C 2 - 8 Al Kill) COOH]
  • Xu comprising a copolymer
  • Japanese Patent Application Laid-Open No. 121222/1990 discloses that a release preparation has a microcapsule comprising a hormonally acting polypeptide, a biodegradable polymer and a polymer hydrolyzable preparation.
  • a pharmaceutical composition comprising borylactide, a copolymer of lactic acid and glycolic acid, a mixture of such polymers and a water-insoluble peptide is described.
  • JP-A-57-150609 discloses a method for producing a pharmaceutical composition containing a polylactide and an acid-stable polypeptide
  • JP-A-57-150609 discloses a method for producing a polylactide and an acid
  • EP-A-0467389 describes a method for preparing drug delivery systems for proteins or polypeptides by the polymer precipitation method or the microsphere method. The manufacturing method is described.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that the prodrug is used in combination therapy with a substance that converts the prodrug into a compound having a desired medicinal effect.
  • a drug containing a biocompatible synthetic polymer that can control the release rate of the prodrug as a carrier efficiently converts prodrug into a compound having a desired medicinal effect in a living body.
  • the present inventors have found that the present invention has an excellent therapeutic effect and that the dosage of the prodrug can be reduced, thereby reducing or avoiding side effects, thereby completing the present invention. That is, the present invention:
  • a biocompatible synthetic polymer that contains the open drug and that can control the release rate of the prodrug, which is used in combination with a substance that converts the prodrug into a compound having the desired medicinal effect.
  • a preparation containing a prodrug and containing a biocompatible synthetic polymer capable of controlling the release rate of the prodrug as a carrier, and a substance that converts the prodrug into a compound having a desired effect consisting of:
  • the prodrug is a compound that is enzymatically converted, and the substance that converts the prodrug into a compound having a desired medicinal effect is an enzyme, a modified enzyme, a gene encoding an enzyme, or a nucleic acid molecule.
  • FIG. 1 is a graph showing the time-dependent change in the cumulative release rate of ganshiku mouth building in an in-vitro release test of Formulation 1 of the present invention.
  • FIG. 2 shows the genotype of the T1 virus used in the test examples.
  • FIG. 3 is a graph showing the antitumor effect of Test Example 2 in a Kaplan-Meier survival plot.
  • the “prodrug” in the present specification is a compound that is converted (eg, phosphorylated, ester-cleaved, deamino, deformyl, oxidized, reduced, etc.) in vivo by a prodrug converting agent and exhibits a medicinal effect.
  • “To show medicinal effect” means that the prodrug is converted into a compound having medicinal effect by being converted, and shows a desired therapeutic effect.
  • a compound having a desired medicinal effect, which is produced by the conversion may be referred to as a “drug” for convenience.
  • the prodrug may be used as a salt, in which case a pharmacologically acceptable salt is used.
  • the “substance that converts a prodrug into a compound having a desired medicinal effect” in the present invention is not particularly limited as long as it is pharmaceutically acceptable and gives the desired conversion to the prodrug.
  • Such substances may be referred to herein as "prodrug converters” or simply “converters.”
  • the converting agent include enzymes. Enzymes may be endogenous enzymes or foreign enzymes, modified with antibodies, etc. May be done. Further, a gene encoding the enzyme may be used, and the enzyme may be expressed in vivo. Specific examples of the enzyme include hydrolases such as esterase, glycosidase, and peptidase, phosphorylase, deformylase, and other oxidase reductases. Further, a gene or a nucleic acid molecule encoding the same may be used.
  • prodrugs include those that exhibit anticancer activity, antiviral activity, antibacterial activity, antiinflammatory activity, and vasodilatory activity after conversion.
  • prodrugs that exhibit anticancer activity after conversion include nucleic acid synthesis inhibitors (eg, antifolates, nucleoside analogs, and the like). Specific examples include:
  • HSVtk herpes simplex thymidine kinase
  • carboxypeptidase A 1 carboxypeptidase Al (CPA)
  • trypsin trypsin
  • 5,5-deoxy-5-fluorouridine (5,1-DFUR), platelet-derived endothelial cell growth factor (PD-ECGF), human thymidine phospnorylase (dThdPase));
  • 6-thioxanthine (6-TX) and Escherichia coli xanthinguanine phospholiposyltransferase (XGPRT);
  • the synthetic polymer that can be used in the preparation of the present invention is not particularly limited as long as it is biocompatible.
  • biocompatible means that when administered to a living body, it does not cause an unfavorable reaction to the living body.
  • it means that when administered to a living body, it does not cause undesired reactions with fibrous tissues, molecules, and the like in the living body.
  • synthetic polymer refers to a polymer obtained by a chemical reaction or the like. Specifically, it refers to those that are not obtained from living organisms but are manufactured by industrial means.
  • the biocompatible synthetic polymer of the present invention includes a biodegradable polymer and a biodegradable polymer.
  • Biodegradable polymer refers to a polymer that is degraded and metabolized by a reaction in a living body. Specifically, it refers to a macromolecule that is decomposed and metabolized in the living body by acids, bases, enzymes and the like.
  • In vivo non-degradable polymer refers to a polymer that is not decomposed by Refers to a molecule. Specifically, it refers to a macromolecule that is not decomposed in vivo by acids, bases, enzymes and the like.
  • non-degradable polymer in vivo examples include silicone, ethylene-butyl acetic acid copolymer, polyurethane, polyethylene, polytetrafluoroethylene, polypropylene, polyatalylate, and polymethacrylate. Silicone is preferred from the viewpoint of easy molding.
  • biodegradable polymer examples include, for example, ⁇ -hydroxycarboxylic acids (eg, glycolic acid, lactic acid, hydroxybutyric acid, etc.), hydroxydicanoleponic acids (eg, malic acid, etc.), hydroxytricarboxylic acid (Polmers, copolymers, or mixtures thereof synthesized from one or more of these compounds by non-catalytic dehydration polycondensation, such as, for example, citric acid, etc .; And polyanhydrides such as maleic anhydride copolymers (eg, styrene-maleic acid copolymers).
  • the type of polymerization may be random, block, or graft.
  • the degradation rate of the biodegradable polymer can be varied by chemical modification and / or the composition ratio and / or molecular weight, etc., so that a biodegradable polymer having a desired degradation rate can be easily obtained. Can be obtained at
  • the method of administration of the preparation of the present invention can be systemic administration or local administration by injection (implant) or non-injection, depending on the purpose.
  • systemic administration for example, it is administered subcutaneously, intradermally, intramuscularly, or transdermally or transmucosally.
  • topical administration administration is performed by implant or percutaneous transmucosal injection into or near the affected area or lesion, and for example, in the case of a tumor, it is administered into or near the tumor.
  • cerebral diseases intracerebral administration is possible, and efficient intracerebral drug delivery is possible by avoiding the cerebral blood flow barrier ( ⁇ ).
  • the formulation of the present invention is not particularly limited as long as it is a dosage form suitable for sustained administration of a prodrug according to the purpose using a biocompatible polymer as a carrier.
  • any dosage form suitable for implantation is required.For example, for placement during surgery, mouth, tablet, disk, finolem, sphere, sponge, padder In the case of injectable administration without surgery, mouth or microspheres, oily or aqueous suspensions of powder, etc. may be mentioned.
  • the diameter is usually 10 mm or less, preferably 3 mm or less for subcutaneous or intracerebral administration, and lmm or less for intramuscular administration.
  • formulation can be designed by selecting the proper formulation and structure to achieve the physical properties of the prodrug and the desired release profile.
  • the structure there is a preparation comprising only a single layer or a preparation comprising a plurality of layers of an inner layer and an outer layer, and each layer may contain the same content or different content of one or a plurality of different prodrugs.
  • the biocompatible polymer carrier and the prodrug may be present in different layers, for example, the prodrug can be placed in a capsule-shaped biocompatible polymer.
  • the preparation of the present invention When the preparation of the present invention is transdermally or transmucosally administered, for example, it is directly adhered to the surface of a living body such as skin or mucous membrane. When implanting, it should be placed at the time of surgery, or administered with an indwelling needle, a special injector, an endoscope, etc. without any manipulation.
  • a powdery preparation by microencapsulation or grinding it can be administered as an aqueous suspension or an oily suspension dispersed with a vegetable oil such as sesame oil or corn oil.
  • the amount of the prodrug in the preparation containing the biocompatible synthetic polymer of the present invention as a carrier is selected from the usual total dose or less of the prodrug.
  • the dose should be selected to be less than 1/10.
  • the specific amount is not more than 30 Omg in each case.
  • Additives can be used in the preparation of the present invention, if necessary, for the purpose of controlling the release of the drug, etc. Any additives may be used as long as they are pharmacologically acceptable; salts such as sodium tlX sodium and sodium citrate; amino acids such as glycine, allaene and sodium glutamate; and sugars such as lactose and mannitol; Examples include, but are not limited to, proteins such as lupmin.
  • Administration of a substance that converts a prodrug into a compound having a desired medicinal effect, that is, a prodrug converting agent may be either systemic or topical, and the route of administration is not particularly limited, and may be selected depending on the purpose.
  • normal administration methods such as oral administration, injection administration, continuous infusion, ribosome preparation, suspension, sustained release by sustained-release preparation, and transdermal / transmucosal administration.
  • the prodrug converting agent is an enzyme
  • the method for expressing the enzyme by introducing the gene GDRPT (gene-directed enzyme-prodrug therapies)) or the method using an antibody-binding enzyme (ADRPT (antibody-directed enzyme- prodrug therapies))
  • ADRPT antibody-directed enzyme- prodrug therapies
  • the preparation containing the biocompatible polymer of the present invention capable of controlling the release rate of the prodrug as a carrier and the prodrug converting agent can be administered by any of the following methods.
  • formulation of the present invention is administered systemically, and the prodrug conversion agent is locally administered to the affected area;
  • the formulation of the present invention is administered locally, and the prodrug converting agent is administered systemically;
  • Intracerebral administration the preparation of the present invention is administered intraventricularly, and a prodrug converting agent is administered into a brain tumor;
  • the preparation of the present invention is administered by a brain administration device
  • the preparation containing the biocompatible synthetic polymer of the present invention as a carrier is characterized by maintaining the effective concentration of the prodrug by sustained release of the prodrug.
  • Administered to work for the duration of the effective concentration Depending on the purpose, it can be administered once or multiple times at the same site or at different sites simultaneously with the preparation of the present invention, or during or before or after the sustained release period of the prodrug.
  • the prodrug converting agent is an enzyme and the enzyme is expressed by gene transfer
  • the enzyme gene is administered simultaneously with or after administration of the preparation of the present invention, or the enzyme gene is administered first, and then the enzyme expression is performed.
  • the preparation of the present invention can be administered within a period.
  • the enzyme or enzyme gene can be administered several times during the prodrug sustained release period.
  • the duration of the sustained release of the prodrug may be any as long as it achieves the object of the present invention, and depends on the nature of the desired pharmacological effect of the prodrug and the duration of the effect, for example, gancicrovir and gancicrovir.
  • Pessimplex ⁇ When combined with thymidine-kinase (herpes simplex thymidine kinase (HSVtk)), it is desirable to release the ganshiku mouth building for about 3 days to about 1 week.
  • silicone When silicone is used as a high molecule for producing a preparation containing the biocompatible synthetic polymer of the present invention as a carrier, for example, Silastic® Medical Grade ETR Elastomer Q 7—4750 , Dow Corning (registered trademark) MD X 4-4 210 Silicone such as medical grade elastomer can be used.
  • the amount of the prodrug varies depending on the type of the prodrug, the desired pharmacological effect and the duration of the effect, but is about 0.01% relative to silicone, about 50% (w / w ) Is used.
  • about 0.1 to about 40% (w / w) is used, particularly preferably about 1 to about 30% (w / w).
  • the prodrug is ganciclovir (GCV)
  • GCV ganciclovir
  • about 1% to about 50%, preferably about 5 to about 40%, more preferably about 10 to about 30% (w / w) is used. Can be.
  • the dosage form is not particularly limited as long as it is a dosage form suitable for achieving the object of the present invention.
  • a rod form pellet form, cylindrical form
  • Needles, etc. tablets, discs, films, spheres and the like.
  • cylindrical rod preparations can be injected by using an indwelling needle or a special injector.
  • a sheet-shaped preparation may be used.
  • the structure of the preparation is The structure can be selected from a single-layer or multi-layer structure.
  • the prodrug is a GCV
  • the above-mentioned silicone compound lj can be produced by mixing a silicone before hardening with a prodrug, an additive and the like, forming the mixture, and then shading.
  • the prodrug and additives to be contained in the silicone may be solid or liquid.
  • the prodrug and additives may form the same solid or separate solids, and may be ground or sieved as necessary.
  • the inner layer and the outer layer may be prepared separately, or the inner layer and the outer layer may be prepared simultaneously.
  • a method in which a rod-shaped inner layer is prepared and then coated with a solution in which the outer layer substance is dissolved and dried or There are a method of inserting an inner layer separately manufactured into a tube made of a substance, a method of forming an inner layer in a tube made of an outer layer material, and a method of simultaneously injection-molding an inner layer and an outer layer using a nozzle.
  • a preparation in which both ends of the preparation are open and the inner layer is exposed can be obtained by cutting the columnar composition thus obtained into an appropriate length.
  • a biocompatible synthetic polymer for example, a hydroxycarboxylic acid polymer that is a biodegradable polymer
  • one or more hydroxycarboxylic acid copolymers are mixed and used as a formulation base. be able to.
  • the type and mixing ratio of these hydroxy sulfonic acids By changing the type and mixing ratio of these hydroxy sulfonic acids, the release of the prodrug can be adjusted, and the type and mixing ratio of the hydroxycarboxylic acid polymer achieve the purpose of the formulation of the present invention. It is not particularly limited as long as it is performed.
  • the hydroxycarboxylic acid constituting the polymer may be any of D-form, L-form and D, L-form.
  • D-form ZL-form (mol 0 /.) Is about 75-2 Those having a range of 5 to about 20/80 are used.
  • the weight average molecular weight of the polymer used is, for example, about 3,000 to about 20,000 for a glycolic acid copolymer, and about 1,500 to about 200,000 for a polylactic acid. 2 0, 0 0 0.
  • These polymers are prepared by known methods, e.g. For example, it can be synthesized according to the method described in Japanese Patent Application Laid-Open No. Sho 61-28521.
  • the ratio of the glycolic acid copolymer / polylactic acid should be in the range of about 10/90 to about 90/10. Desirably.
  • lactic acid-Z glycolic acid copolymer When a lactic acid-Z glycolic acid copolymer is used, it is possible to control the rate of decomposition or disappearance of the copolymer itself and the release of the prodrug depending on the composition or molecular weight of the copolymer.
  • the composition ratio, molecular weight, etc. of lactic acid-Z glycolic acid are not particularly limited as long as the object of the invention is achieved.
  • the composition ratio (lactic acid / glycolic acid) is about 100 ZO to about 40 Z 60 (molar 0/0), weight average molecular weight of from about 3, 0 0 0 to about 2 0 0 0 0 is used.
  • These copolymers can be synthesized according to known production methods, for example, the method described in Japanese Patent Application Laid-Open No. 61-28521.
  • the amount of the prodrug varies depending on the type of the prodrug, the desired pharmacological effect and the duration of the effect, etc., but is preferably from about 0.01 to about 50% (w / w) is used.
  • Preferred loadings are from about 0.1 force to about 40% (w / w), and particularly preferred loadings are from about 1 to about 30% (w / w).
  • the dosage form is not particularly limited as long as it is a dosage form suitable for achieving the object of the present invention.
  • Preparation of tablets, tablets, discs, films and spherical preparations can be performed by a known method such as pressurized-heated melting or curing by irradiation with light, electron beam or radiation. It can be produced by molding a carboxylic acid polymer. That is, the base polymer is placed in a mold and molded at room temperature or under heating by compression molding or radiation irradiation. At this time, the prodrug is added to the base polymer. Alternatively, the prodrug may be added at the point where the base polymer has been molded in advance.
  • the microcapsules can be prepared by a known method such as a liquid drying method, a phase separation method (a coacervation method), and a spray drying method.
  • the prodrug and the base polymer may be once dissolved in a solvent that is substantially immiscible with water, and then the solvent may be removed in an aqueous solution.
  • the solvent that is substantially immiscible with water may be any solvent that is substantially immiscible with water, dissolves the base polymer, and the resulting polymer solution further dissolves the prodrug.
  • dichloromethane is used.
  • an organic solvent solution (oil phase) of a prodrug and a base polymer is added to an aqueous phase to form an O (oil phase), a ZW (aqueous phase) emulsion, and then an oil.
  • the solvent in the phase may be evaporated. If the prodrug is water-soluble and does not dissolve in the same solvent as the base polymer, the aqueous solution of the prodrug and the base polymer solution are used to form w (aqueous phase) Zo (oil phase) emulsion.
  • the microcapsenolle can be prepared by a method of forming w (aqueous phase) ⁇ (oil phase) / W (aqueous phase) emulsion in addition to the aqueous phase.
  • the solvent is removed by a method of evaporating the solvent at normal pressure or gradually reducing the pressure while stirring, or a method of evaporating the solvent while adjusting the degree of vacuum using a rotary evaporator or the like.
  • a coacervation agent is slowly added to an organic solvent solution of a prodrug and a base polymer with stirring at a constant speed to precipitate and solidify the base polymer. Is taken.
  • the coacervation agent may be a high molecular weight compound, a mineral oil type or a vegetable oil type compound that is miscible with a high molecular weight base solvent and does not dissolve the high molecular weight base material.
  • the microcapsules thus obtained are filtered, fractionated, washed with heptane, etc. to remove the coacervation agent, and then the solvent is removed in the same manner as in the liquid drying method. .
  • an organic solvent solution of the above prodrug and the base polymer is sprayed into a drying chamber of a spray dryer (spray drying) using a nozzle.
  • the organic solvent in the micronized droplets is volatilized in a short time to prepare micronized microcapsules.
  • a ganciclovir freeze-dried product (Denosine (registered trademark): Tanabe Seiyaku) was ground to obtain a powder.
  • 0.58 g of the Silastic (registered trademark) Medical Grade ETR Elastomer Q7-4750A component (manufactured by Dow Koeng) and 0.58 g of the same B component were mixed.
  • 0.3 g of the above-mentioned ganshiku mouth building powder was further kneaded with force and filled into a syringe.
  • Silicastic (registered trademark) Medical Grade ETR Elastomer Q7-4750 50 g of the A component and 50 g of the B component were mixed and filled into another syringe.
  • Each packing is pressured from concentrically arranged 0.8 mm diameter and 1.0 mm diameter nozzles so that the kneaded material containing ganciclovir is on the inside and the kneaded material not containing gancik mouth building is on the outside. And left to cure at room temperature to 60 ° C. This was cut to obtain Formulation 1 of the present invention.
  • a ganciclovir freeze-dried product (Denosine (registered trademark): Tanabe Seiyaku) was pulverized to obtain a powder.
  • silastic (TM) Medical Grade ETR Heras Tomah one Q7 - were mixed 4750 A component 0. 6 ⁇ same 8 component 0. 6 g.
  • 0.5 g of the above-mentioned ganshiku mouth building powder was calored and further kneaded, and filled into a syringe.
  • Silylstic (registered trademark) Medical Grade ETR Elastomer — 50 g of the Q7-4750A component and 50 g of the same B component were mixed and filled into another syringe.
  • Formulation 1 of the present invention prepared in Example 1 was placed in 5 mL of a phosphate buffer (containing 0.03% polysorbate 20), allowed to stand at 37 ° C, and ganciclovir released from the formulation was subjected to high-performance liquid chromatography. Quantification was performed by means of chromatography to determine the cumulative release. Figure the result Shown in 1. Sustained release of the Gangsik mouth building for more than 3 days was observed.
  • a phosphate buffer containing 0.03% polysorbate 20
  • the F isher 344 rats weighing about l OO g were anesthetized with pentobarbital (Nenbuta Lumpur), frontal lobe in 1 X 10 5 cells of Rattogurioma cells (9 L cells)
  • the group in which T1 virus was administered intraperitoneally with a gansik mouth aqueous solution intraperitoneally for 7 days showed a high survival rate
  • the group in which T1 Vinoles and the preparation 1 of the present invention were used together showed a 1/100 or less survival rate. The same effect was observed with the dose of ganshiku mouth building.
  • rat glioma cells 9 L cells
  • the preparation of the present invention containing 0.15 mg of T1 virus and ganciclovir in the same site 1 was administered at the same time.
  • Ganciclovir aqueous solution administered intraperitoneally 3mg / day (30mg / kgZday) for 7 days, a total of 21mg, a group receiving only formulation 1 without T1 virus, and a group receiving only T1 virus with Ganshikuguchi building The group without administration was used as a comparative example.
  • the rats in each group were sacrificed and the brain tissue was stained with HE (hematoxylin-eosin) to compare the tumor sizes.
  • HE hematoxylin-eosin

Abstract

La présente invention concerne des préparations contenant, en tant que porteur, un polymère synthétique biocompatible utilisable avec une substance transformant un promédicament en médicament. Cette préparation contient ce promédicament et elle peut commander la vitesse de libération de ce promédicament
PCT/JP2001/004719 2000-06-06 2001-06-05 Preparations polymere synthetiques biocompatibles WO2001093826A1 (fr)

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JP2000168862 2000-06-06

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219076A2 (fr) * 1985-10-11 1987-04-22 Sumitomo Pharmaceuticals Company, Limited Composition à effet retardé
WO1988007378A1 (fr) * 1987-03-09 1988-10-06 Cancer Research Campaign Technology Ltd. Amelioration apportees a des systemes d'administration de medicaments
EP0302473A2 (fr) * 1987-08-04 1989-02-08 Bristol-Myers Squibb Company Conjugues anticorps-enzyme associés à des prodrogues pour la libération d'agents cytotoxyques dans les cellules tumorales
WO1996016179A1 (fr) * 1994-11-18 1996-05-30 The Wellcome Foundation Limited Therapie genique enzymatique catalysant la conversion extracellulaire d'un precurseur

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0219076A2 (fr) * 1985-10-11 1987-04-22 Sumitomo Pharmaceuticals Company, Limited Composition à effet retardé
WO1988007378A1 (fr) * 1987-03-09 1988-10-06 Cancer Research Campaign Technology Ltd. Amelioration apportees a des systemes d'administration de medicaments
EP0302473A2 (fr) * 1987-08-04 1989-02-08 Bristol-Myers Squibb Company Conjugues anticorps-enzyme associés à des prodrogues pour la libération d'agents cytotoxyques dans les cellules tumorales
WO1996016179A1 (fr) * 1994-11-18 1996-05-30 The Wellcome Foundation Limited Therapie genique enzymatique catalysant la conversion extracellulaire d'un precurseur

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HIROTAKA ENDOH ET AL.: "Controlled Release of 5-fluoro-2'-deoxyuridine by the combination of prodrug and polymer matrix", CHEM. PHARM. BULL., vol. 39, no. 2, 1991, pages 458, 464, XP002944701 *
TATEO KAWAGUCHI: "Koubunshi matrix to syousei wo seigyo shita prodrug no kumiawase ni yoru drug delivery system", YAKKUGAKU KENKYU NO SHINPO, vol. 12, 1995, pages 87 - 94, XP002944702 *

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