WO2001093826A1

WO2001093826A1 - Biocompatible synthetic polymer preparations

Info

Publication number: WO2001093826A1
Application number: PCT/JP2001/004719
Authority: WO
Inventors: Shusuke Moriuchi; Toshiki Yoshimine; Miho Maeda; Akihiko Sano
Original assignee: Sumitomo Pharmaceuticals Company, Limited
Priority date: 2000-06-06
Filing date: 2001-06-05
Publication date: 2001-12-13

Abstract

Preparations containing, as a carrier, a biocompatible synthetic polymer which is to be used together with a substance converting a prodrug into a drug, contains the prodrug and is capable of controlling the release speed of the prodrug.

Description

Description Biocompatible synthetic polymer formulation Technical field

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. Related to a formulation contained as

Background art

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,

(1) Application of 5-fluorocytosin and cytosine deaminase to cancer and medical treatment;

(2) Application to cancer treatment with gancicrovir or acyclovir and herpes simplex tnymidine kinase (HSVtk);

(3) 6-methylpurine

Deoxyriboside (6-MPDR)) and E. coli purine nucleotide phosphorylase (Escnerichia coli purine nucleotide phosphorylase (PNP)) for the treatment of vulnerable mefnotherapy;

(4) 5- (Aziridine-1_inole)-2,4—Jetrobenzamide (5-

(aziridin-1-yl) -2, 4-dini trobenzami e) and Niroreguta ¹ ~ "(nitroreductase (NTR)) for cancer treatment;

(5) Application of canolepoxypeptidase A 1 (carboxypeptidase Al (CPA)) and trypsin to cancer treatment; (6) Application of 4-ipomeanol (4-IM) and cytochrome (CYP4B1) to cancer treatment;

(7) Application of cyclophosphamide (CPA) and cytochrome P450 2B1 to cancer treatment;

(8) 5,1-Deoxy-5-fluorounidine (5, -deoxy-5-fluorouridine (5,-

DFUR)) and platelet-derived endothelial cell growth factor (PD-ECGf, human thymidine phosphorylase, dThdPase) for breast cancer treatment;

(9) For the treatment of cyclophosphamide (ifosfaraide) and CYP2B1 (major catalyst of oxazaphosphorine activation);

(10) 6 _ 6-methoxypurine arabinonucleoside (araM) and varicella zoster. Virus thymidine. Application;

(11) Application to cancer treatment with 6-thioxanthine (6-ΤΧ) and Escherichia coli xanthinguanine phosphoribosyltransferase (XGPRT).

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. For example, when 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. On the other hand, even when a prodrug is administered locally, the ability to rapidly diffuse and disappear from the site of administration and the sustained local effective concentration cannot be obtained. For these reasons, repeated administration of a high dose of the prodrug is required, and side effects of the prodrug itself or side effects of the converted substance are likely to occur. As a result, treatment has to be discontinued due to side effects and the dosage has to be reduced, and sufficient therapeutic effects have not been obtained at present.

On the other hand, various types of polymers have been used in sustained-release drug systems for the purpose of maintaining drug efficacy. Substances have been used as carriers for drugs. For example, in the case of using silicone, which is a non-degradable polymer in vivo, as a carrier, Japanese Patent Application Laid-Open No. 5-238929 describes a sustained-release preparation of a therapeutic agent for metabolic bone disease. There is a description of a drug product that contains albumin in silicone, thereby enabling drug stabilization and release control. In addition, it is not limited to silicone but a non-disintegrating biocompatible material as a carrier. It is an implantable columnar preparation that contains ( _a ) a non-disintegrating biocompatible material containing a uniformly dispersed water-soluble drug. 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).

As with biodegradable polymer, 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. In the production method, JP-A-57-150609 discloses a method for producing a pharmaceutical composition containing a polylactide and an acid-stable polypeptide, and 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.

However, there is no description of applying the above-mentioned preparation using a biocompatible synthetic polymer as a carrier to the above-mentioned combination therapy of a prodrug and its converting agent.

Disclosure of the invention

As described above, there is a demand for the development of a drug that can efficiently convert a prodrug into a compound having a desired drug effect in vivo, has fewer side effects, and can obtain a more effective therapeutic effect. . That is, for efficient conversion of prodrugs The timing of the action of the prodrug and its conversion agent can be adjusted in time, the duration of action and / or the place of action can be controlled, the required concentration for the onset of the drug effect can be maintained, and the required concentration can be maintained. By reducing the number of times or keeping the maximum blood concentration low, side effects can be reduced.It is also suitable for topical administration, and preparations that can avoid systemic side effects in local treatment and maintain and enhance local effects Development is desired.

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:

1. As a carrier, 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. Formulation containing;

2. 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. A kit consisting of:

3. A method of converting a prodrug into a drug,

(1) a preparation containing a prodrug, and a biocompatible synthetic polymer capable of controlling the release rate of the prodrug as a carrier; and

(2) a substance that converts the prodrug into a compound having a desired medicinal effect;

How to use together;

4. The method according to 1 above, wherein 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. Preparation of;

5. The method according to 1 or 4 above, wherein the prodrug contains 0.01 to 50% (w / w). Formulation;

6. The formulation according to 1, 4, or 5, wherein the sustained release period of the prodrug is 1 to 1 week, 1 week to several months or several months to 1 year;

7. The preparation according to the above 1, 4, 5 or 6, wherein the biocompatible synthetic polymer is silicone;

8. The preparation according to 4 above, wherein the substance that converts the prodrug into a compound having the desired medicinal effect is an enzyme or a modified enzyme;

9. The preparation according to 4 above, wherein the substance that converts the prodrug into a compound having the desired medicinal effect is a gene or a nucleic acid molecule encoding an enzyme;

Etc.

BRIEF DESCRIPTION OF THE FIGURES

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.

Figure 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.

BEST MODE FOR CARRYING OUT THE INVENTION

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. In the present specification, 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." Examples of 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.

In the present invention, as long as a prodrug and a substance that converts the prodrug into a compound having a desired medicinal effect, that is, a converting agent are used in combination, a combination of the prodrug and the converting agent applied to the preparation of the present invention, In addition, the indications of the preparation of the present invention and the method of use are not particularly limited. Specifically, for example, prodrugs include those that exhibit anticancer activity, antiviral activity, antibacterial activity, antiinflammatory activity, and vasodilatory activity after conversion. No. Examples of prodrugs that exhibit anticancer activity after conversion include nucleic acid synthesis inhibitors (eg, antifolates, nucleoside analogs, and the like). Specific examples include:

(1) 5-Huenoleocytosine (5_fluorocytosin) and cytosine deaminase

(Cytosine deaminase);

(2) gancicrovir or acyclovir and herpes simplex thymidine kinase (HSVtk);

(3) 6-methylpurine deoxyriboside

(6-MPDR)) and Escherichia coll purine nucleotide phosphorylase (PP);

(4) 5- (aziridin-1-yl) 1,2-dinitrobenzamide (5- (aziridin-1-yl) -2, ^ -dinitrobenzamide) and nitroreductase (NTR);

(5) carboxypeptidase A 1 (carboxypeptidase Al (CPA)) and trypsin (trypsin);

(6) 4-ipomeanol (4-IM) and cytochrome (CYP4B1); (7) cyclophosphamide (CPA) and cytochrome P450 2B1;

(8) 5,5-deoxy-5-fluorouridine (5,1-DFUR), platelet-derived endothelial cell growth factor (PD-ECGF), human thymidine phospnorylase (dThdPase));

(9) cyclophosphamide (if osfamide) CYP2B1 (major catalyst of oxazaphosphorine activation);

(10) 6-methoxypurine 'arabininonucleoside (6-Methoxypurine arabinonucleoside (araM)) and varicella-zoster virus thymidine kinase (VZV TK));

(11) 6-thioxanthine (6-TX) and Escherichia coli xanthinguanine phospholiposyltransferase (XGPRT);

(12) peptide carrier-bound doxorubicin and serine protease;

(13) Valproic acid prodrug and phospholipase A;

(14) Tazarotene and esterase;

And the like, but are not limited thereto.

The synthetic polymer that can be used in the preparation of the present invention is not particularly limited as long as it is biocompatible. As used herein, “biocompatible” means that when administered to a living body, it does not cause an unfavorable reaction to the living body. Preferably, 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. Specifically, it means that when administered to a living body, it does not cause an in vivo reaction such as antigenicity which is not desirable for 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. Specific examples of the non-degradable polymer in vivo include silicone, ethylene-butyl acetic acid copolymer, polyurethane, polyethylene, polytetrafluoroethylene, polypropylene, polyatalylate, and polymethacrylate. Silicone is preferred from the viewpoint of easy molding. Specific examples of the biodegradable polymer include, for example, α-hydroxycarboxylic acids (eg, glycolic acid, lactic acid, hydroxybutyric acid, etc.), hydroxydicanoleponic acids (eg, malic acid, etc.), hydroxytricarboxylic acid ( Polymers, 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. When α-hydroxycarboxylic acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have an optically active center in the molecule, D-, L-, DL- Any of the bodies can be used. 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. In the case of systemic administration, for example, it is administered subcutaneously, intradermally, intramuscularly, or transdermally or transmucosally. In 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. In cerebral diseases, intracerebral administration is possible, and efficient intracerebral drug delivery is possible by avoiding the cerebral blood flow barrier (ΒΒΒ).

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. For implant preparations, 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. In the case of rods, 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. In addition, formulation can be designed by selecting the proper formulation and structure to achieve the physical properties of the prodrug and the desired release profile. As 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. Alternatively, 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.

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. In the case of 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, the number of administrations of the preparation, the symptoms and their progress, the size and location of lesions, age, weight, dosage form (topical Administration or systemic administration). For example, in the case of systemic administration (such as subcutaneous administration), the amount of the prodrug in the preparation of the present invention is selected from the usual total dose or less of the prodrug. For local administration (eg, at the site of the lesion, eg, at or near the tumor), 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. And normal administration methods such as oral administration, injection administration, continuous infusion, ribosome preparation, suspension, sustained release by sustained-release preparation, and transdermal / transmucosal administration. Particularly when 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)) ))), Administration by ribosome, injection of aqueous solution, continuous infusion, or sustained release of enzyme by implant type sustained release.

That is, 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.

(1) Systemic administration of both the preparation of the present invention and a prodrug converting agent;

(2) The formulation of the present invention is administered systemically, and the prodrug conversion agent is locally administered to the affected area;

(3) Both the preparation of the present invention and the prodrug converting agent are locally administered to the affected part;

(4) The formulation of the present invention is administered locally, and the prodrug converting agent is administered systemically;

(5) The above-mentioned local administration is administered in or near the tumor;

(6) administration into the brain as the local administration described above;

(7) Intracerebral administration of both the preparation of the present invention and a prodrug converter into a brain tumor;

(8) Intracerebral administration, the preparation of the present invention is administered intraventricularly, and a prodrug converting agent is administered into a brain tumor;

(9) In the brain administration, the preparation of the present invention is administered by a brain administration device;

And the like.

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. When 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. 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. In this case, 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. Preferably, about 0.1 to about 40% (w / w) is used, particularly preferably about 1 to about 30% (w / w). When the prodrug is ganciclovir (GCV), about 1% to about 50%, preferably about 5 to about 40%, more preferably about 10 to about 30% (w / w) is used. Can be.

Even when silicone is used, the dosage form is not particularly limited as long as it is a dosage form suitable for achieving the object of the present invention. For example, in the case of an implant-type preparation, a rod form (pellet form, cylindrical form) , Needles, etc.), tablets, discs, films, spheres and the like. In particular, cylindrical rod preparations can be injected by using an indwelling needle or a special injector. In the case of a transdermal or transmucosal preparation, 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. For example, if the prodrug is a GCV, it is preferable to use a columnar structure consisting of multiple layers of the inner and outer layers, with a structure containing GCV only in the inner layer or a structure in which the outer layer contains a lower concentration of GCV than the inner layer.

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.

In order to produce a preparation comprising a plurality of inner layers and outer layers, the inner layer and the outer layer may be prepared separately, or the inner layer and the outer layer may be prepared simultaneously. For example, when manufacturing a dosage form in which the dosage form is columnar and the inner layer is covered with an outer layer, 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. However, it is not limited to these. 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.

When a biocompatible synthetic polymer, for example, a hydroxycarboxylic acid polymer that is a biodegradable polymer, is used, one or more hydroxycarboxylic acid copolymers are mixed and used as a formulation base. be able to. 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. For example, 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.

When a mixture of a glycolic acid copolymer and polylactic acid is used, the ratio of the glycolic acid copolymer / polylactic acid (% by weight) should be in the range of about 10/90 to about 90/10. Desirably.

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. For example, 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).

Even when a hydroxycarboxylic acid polymer is used, the dosage form is not particularly limited as long as it is a dosage form suitable for achieving the object of the present invention. Shape, disc shape, film shape, spherical shape, sponge shape, micro force capsule and powder shape by pulverization.For cylindrical mouth preparations and micro force capsules, injectable by indwelling needle or special injector Administration is possible.

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.

In the case of producing microcapsules by a submerged drying method, for example, 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. For example, dichloromethane is used. To form a micro force cell, 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) ΖΟ (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.

When microcapsules are produced by the phase separation method, 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. .

In the case of producing microcapsules by the spray 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. Next, the present invention will be described in detail with reference to examples and test examples, but the present invention is not limited to these examples and test examples.

Example 1 '

A ganciclovir freeze-dried product (Denosine (registered trademark): Tanabe Seiyaku) was ground to obtain a powder. On the other hand, 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. Immediately after mixing, 0.3 g of the above-mentioned ganshiku mouth building powder was further kneaded with force and filled into a syringe. In addition, 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.

Example 2

A ganciclovir freeze-dried product (Denosine (registered trademark): Tanabe Seiyaku) was pulverized to obtain a powder. On the other hand, silastic (TM) Medical Grade ETR Heras Tomah one Q7 - were mixed 4750 A component 0. 6 _§ same 8 component 0. 6 g. Immediately after mixing, 0.5 g of the above-mentioned ganshiku mouth building powder was calored and further kneaded, and filled into a syringe. In addition, 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. A pressure of 0.8 mm and a diameter of 1.Omm was applied concentrically to each packing so that the ganciclovinole-containing kneaded material was on the inside and the ganciclovir-free kneaded material was on the outside. Extruded and allowed to cure at room temperature to 60 ° C. This was cut to obtain Formulation 2 of the present invention.

Test example 1

i n- V i tr o Release evaluation

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.

Test example 2

Anti-tumor effect in rat brain tumor model (1)

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)

(Provided by Dr. Culver, K. Μ., ΝΙΗ (Science, 256: 1550-1552, 1992)), and 5 days later, a triple mutant herd with the genotype shown in FIG.ぺ Suinores (T 1 ゥ inores) (Dr. Glorioso JC (University of

Pittsburgh). Natl. Acad. Sci. USA. 93: 11319-11320, 1996), and 2 × 10 ⁶ pfu, and 0.15 mg of ganshiku mouth building 1 (length lmm) Was administered at the same time. Group administered 3 mg (3 Omg / kg / day) of ganciclovir aqueous solution intraperitoneally per day in the place of Formulation 1 for a total of 21 mg for 7 days, Group treated with Formulation 1 only and not treated with T1 virus, Group treated with T1 virus only The group that was administered with ganciclovir and the group that did not receive both T1 virus and ganciclovir (medium administration) were used as comparative examples. The antitumor effect was evaluated by the survival rate. The results are shown in Figure 3.

In the group to which only the formulation 1 of the present invention was administered without administration of the T1 virus or only the aqueous solution of ganshiku oral building was intraperitoneally administered for 7 days every day, only the medium was administered without administration of the T1 virus or ganshiku oral building There was almost no difference from the control group, and no antitumor effect was observed. Similarly, administration of the T1 virus alone without administration of the gansik-mouth building showed little difference from the control group. On the other hand, the group in which T1 virus was administered intraperitoneally with a gansik mouth aqueous solution intraperitoneally for 7 days showed a high survival rate, and 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.

Test example 3

Antitumor effect in rat brain tumor model (2)

As in Test Example 2, rat glioma cells (9 L cells) were injected into the brain of Fisher 344 rats, and 5 days later, 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. Instead of Formulation 1 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. On the 12th day after the administration of the tumor, the rats in each group were sacrificed and the brain tissue was stained with HE (hematoxylin-eosin) to compare the tumor sizes.

In the group to which either the preparation 1 of the present invention or the T1 virus was administered alone, fl severe swelling was observed. In Test Example 2, when rats that died on the 37th day in the group to which only Formulation 1 was administered alone were examined in the same manner, it was considered that the brain tumor occupied most of the hemisphere and the tumor died. In contrast, the group treated with both ganciclovir and T1 virus showed a clear inhibition of tumor growth 12 days after tumor administration. In particular, in the group to which the formulation 1 of the present invention and T1 Wi / less were administered, the same effect was obtained with a dose of 1 to 100 or less than that in the group to which the aqueous solution of ganshiku vinole was intraperitoneally administered. Was recognized.

The invention's effect

As described above, it was shown that high efficacy can be obtained with a small dose by using the preparation of the present invention. That is, by using the preparation of the present invention, the prodrug can be effectively acted on, and side effects can be avoided by reducing the dose.

Claims

The scope of the claims

1. A preparation containing the prodrug, which is used in combination with a substance that converts the prodrug into a drug, and containing a biocompatible synthetic polymer capable of controlling the release rate of the prodrug as a carrier.

2. The prodrug is a compound that undergoes enzymatic conversion, and the substance that converts the prodrug into a drug is an enzyme, a modifying enzyme, or a gene or a nucleic acid molecule that encodes an enzyme. Preparations.

3. The preparation according to claim 2, wherein the substance that converts the prodrug into a drug is an enzyme or a modified enzyme.

4. The preparation according to claim 2, wherein the substance that converts the prodrug into a drug is a gene or a nucleic acid molecule encoding an enzyme.

5. The preparation according to any one of claims 1 to 4, wherein the sustained release period of the prodrug is one day to one week, one week to several months, or several months to one year.

6. The preparation according to any one of claims 1 to 5, wherein the biocompatible synthetic polymer is silicone.

7. The preparation according to any one of claims 1 to 6, comprising 0.01 to 50% (wZw) of the prodrug.

8. A kit containing a prodrug and a biocompatible synthetic polymer capable of controlling the release rate of the prodrug as a carrier, and a kit for converting the prodrug into a drug.

9. The kit according to claim 8, wherein the prodrug is a compound that undergoes enzymatic conversion, and the substance that converts the prodrug into a drug is an enzyme, a modified enzyme, a gene encoding an enzyme, or a nucleic acid molecule. .

10. The kit according to claim 9, wherein the substance that converts the prodrug into a drug is an enzyme or a modified enzyme.

11. The kit according to claim 9, wherein the substance that converts the prodrug into a drug is a gene or a nucleic acid molecule encoding an enzyme.

1 2. The sustained release period of the prodrug is 1-1 week, 1 week-several months or several months- The kit according to any one of claims 8 to 11, which is one year.

13. The kit according to any one of claims 8 to 12, wherein the biocompatible synthetic polymer is silicone.

14. The kit according to any one of claims 8 to 13, wherein the preparation containing the biocompatible synthetic polymer as a carrier contains 0.01 to 50% (w / w) of a prodrug.

15. A method of converting a prodrug into a drug,

(1) a preparation containing a prodrug, and containing, as a carrier, a biocompatible synthetic polymer capable of controlling the release rate of the prodrug; and

(2) a substance that converts the prodrug into a drug;

How to use together.

16. The method of claim 15, wherein the prodrug is a compound that undergoes enzymatic conversion, and the substance that converts the prodrug to a drug is an enzyme, a modifying enzyme, or a gene or a nucleic acid molecule encoding an enzyme. .

17. The method according to claim 16, wherein the substance that converts the prodrug into a drug is an enzyme or a modified enzyme.

18. The kit according to claim 16, wherein the substance that converts the prodrug into a drug is a gene or a nucleic acid molecule encoding an enzyme.

19. The method according to any of claims 15 to 18, wherein the sustained release period of the prodrug is one day to one week, one week to several months or several months to one year.

20. The method according to any of claims 15 to 19, wherein said biocompatible synthetic polymer is silicone.

21. The method according to any one of claims 15 to 20, wherein the preparation containing the biocompatible synthetic polymer as a carrier contains 0.01 to 50% (w / w) of a prodrug.