JPS626564B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an anticancer drug sustained release complex composition.

The present inventors first brought a polymerizable monomer and a physiologically active substance into contact, and irradiated the monomer with light or ionizing radiation to polymerize the monomer, thereby releasing the physiologically active substance at a controlled rate. He invented a series of methods for producing sustained-release agent compositions, including a method for producing a polymer composition with a release function, and filed a patent application.

As a result of intensive research on how to impart sustained release properties to biocompatible polymers that enclose physiologically active substances in such sustained release compositions, the inventors of the present application have developed a silane coupling agent. When the vinyl groups contained in the modified substance obtained by suitably combining agents and performing a hydrolysis-condensation reaction are polymerized by irradiation with light or ionizing radiation, the polymer has high elasticity and anticoagulant properties. It is a polymer with more anticoagulant properties, that is, more biocompatible than polytetrafluoroethylene, which is known as a blood material, and the OH groups contained in natural polymers are hydrolyzed using a silane coupling agent. - When the condensation reaction is carried out, a silane compound is introduced into the natural polymer chain, and when the vinyl groups in this silane compound are irradiated with light or ionizing radiation and polymerized, the natural polymer exhibits a crosslinked structure, and the enclosing We have discovered that the release of physiologically active substances can be controlled over a long period of time, and that natural polymers obtained by crosslinking can be decomposed in vivo over time and can be fully assimilated into living tissues. Based on these findings, (1) general formula of the claimed invention is or One or more vinylsilane compounds [A] represented by R ³ _o (SiOR ² ) _4-o or 0.1 to 7 parts by weight of one or more anticancer agents are dispersed or dissolved in 5 parts by weight of the hydrolysis-condensation reaction product of one or more silane compounds [B] represented by A method for producing an anticancer drug sustained release complex composition, which comprises preparing a dosage form and irradiating it with light or ionizing radiation, provided that in the above general formula, R ¹ is a straight chain or Branched alkyl group; R ² is a straight chain or branched alkyl group with 4 or less carbon atoms; R ³
is OR ² or a linear or branched alkyl group having up to 4 carbon atoms; and (2) one or more vinyl silane compounds [A] and one or more silane compounds [B] After performing a hydrolysis-condensation reaction in the coexistence of two or more natural polymers and washing and removing unreacted substances with alcohol, one or more types of polymers are added to 5 parts by weight of the remaining treated natural polymer. We have completed a method for producing an anticancer drug sustained release composite composition, which comprises adsorbing 1 to 10 parts by weight of an aqueous solution containing a cancer drug, freeze-drying it, and then irradiating it with light or ionizing radiation.

Therefore, the vinylsilane compound [A] used in the present invention is vinyltrimethoxysilane, vinyltriethoxysilane, vinyltripropoxysilane, methacryloxymethyltrimethoxysilane, methacryloxymethyltriethoxysilane, methacryloxymethyltripropoxy Silane, methacryloxyethyltrimethoxysilane, methacryloxyethyltriethoxysilane, methacryloxyethyltripropoxysilane, methacryloxypropyltrimethoxysilane, methacryloxypropyltriethoxysilane, methacryloxypropyltripropoxysilane, acryloxymethyltrimethoxysilane , acryloxymethyltriethoxysilane, acryloxymethyltripropoxysilane,
Examples include acryloxyethyltrimethoxysilane, acryloxyethyltriethoxysilane, acryloxyethyltripropoxysilane, acryloxypropyltrimethoxysilane, acryloxypropyltriethoxysilane, and acryloxypropyltripropoxysilane.

Moreover, the silane compound [B] is N-aminomethyl-aminomethyltrimethoxysilane, N-aminomethyl-aminomethyltriethoxysilane, N-aminomethyl-aminomethyltripropoxysilane, N-aminomethyl-aminomethyltributoxy Silane, N-β-aminoethyl-β-aminoethyltrimethoxysilane, N-β-aminoethyl-β-aminoethyltriethoxysilane, N-β-aminoethyl-β-aminoethyltripropoxysilane, N-β -Aminoethyl-β-aminoethyltributoxysilane, N-γ-aminopropyl-γ-aminopropyltrimethoxysilane, N-γ-aminopropyl-γ-aminopropyltriethoxysilane, N-γ-aminopropyl-γ -aminopropyltripropoxysilane, N-γ-aminopropyl-γ-aminopropyltributoxysilane, N-aminomethyl-β-aminoethyltrimethoxysilane, N-aminomethyl-β-aminoethyltributoxysilane, N- Aminomethyl-γ-aminopropyltrimethoxysilane, N-aminomethyl-γ-aminopropyltributoxysilane, N-β-aminoethyl-aminomethyltrimethoxysilane, N-β-aminoethyl-aminomethyltributoxysilane, N-aminomethyl-γ-aminopropyltrimethoxysilane, N-aminomethyl-γ-aminopropyltributoxysilane, N-γ-aminopropyl-aminomethyltrimethoxysilane, N-γ-aminopropyl-aminomethyltributoxy Silane, N-γ-aminopropyl-β-aminoethyltrimethoxysilane, N-γ-aminopropyl-β-aminoethyltributoxysilane, N-β-aminoethyl-γ-aminopropyltrimethoxysilane, N-β -Aminoethyl-γ-aminopropyltributoxysilane, γ-glycidoxypropylmethyldipropoxysilane, γ-glycidoxypropylmethyldibudoxysilane, β-glycidoxypropylmethyldimethoxysilane, β-glycidoxy Propylmethyldiethoxysilane, β-glycidoxypropylmethyldipropoxysilane, β-glycidoxypropylmethyldibutoxysilane, β-glycidoxyethylethyldimethoxysilane, β-glycidoxyethylethyldiethoxysilane, β -Glycidoxyethyldipropoxysilane, β-glycidoxyethyl ethyldibutoxysilane, γ-glycidoxypropylethyldimethoxysilane, γ-glycidoxyethyl ethyldiethoxysilane, γ-glycidoxypropylethyldipropoxy Silane, γ-glycidoxyethylethyldibutoxysilane, β-glycidoxypropylmethyldimethoxysilane, β-glycidoxyethylethyldiethoxysilane, β-glycidoxypropylethyldipropoxysilane, β-glycidoxy Ethyl ethyldibutoxysilane, β-glycidoxyethylpropyldimethoxysilane, β-glycidoxyethylpropyldiethoxysilane, β-glycidoxyethylpropyldipropoxysilane, β-glycidoxyethylpropyldibutoxysilane, γ -Glycidoxyethylpropyldimethoxysilane, γ-glycidoxyethylpropyldiethoxysilane, γ-glycidoxyethylpropyldipropoxysilane, γ-glycidoxyethylpropyldibutoxysilane, β-glycidoxyethylpropyldimethoxy Silane, β-glycidoxyethylpropyldiethoxysilane, β-glycidoxyethylpropyldipropoxysilane, β-glycidoxyethylpropyldibutoxysilane, β-glycidoxyethyltrimethoxysilane, β-glycidoxy Ethyltriethoxysilane, β-glycidoxyethyltripropoxysilane, β-glycidoxyethyltributoxysilane, γ-glycidoxypropyltrimethoxysilane, γ-glycidoxypropyltriethoxysilane, γ-glycidoxy Propyltripropoxysilane, γ-glycidoxypropyltributoxysilane, β-glycidoxypropyltrimethoxysilane, β-glycidoxypropyltriethoxysilane, β-glycidoxypropyltripropoxysilane, β-glycidoxy Propyltributoxysilane, β-glycidoxyethylmethyldimethoxysilane, β-glycidoxyethylmethyldiethoxysilane, β-glycidoxyethylmethyldipropoxysilane, β-glycidoxyethylmethyldibutoxysilane, γ- Glycidoxypropylmethyldimethoxysilane, γ-glycidoxypropylmethylethoxysilane, tetramethoxysilane, tetraethoxysilane, tetrapropoxysilane, tetrabutoxysilane, methyltrimethoxysilane, methyltriethoxysilane, methyltripropoxysilane, methyl Tributoxysilane, ethyltriethoxysilane, ethyltriethoxysilane, ethyltributoxysilane, dimethyldimethoxysilane, dimethyldiethoxysilane, dimethyldipropoxysilane, dimethyldibutoxysilane, diphenyldimethoxysilane, diphenyldiethoxysilane,
Examples include trimethylmethoxysilane, trimethylethoxysilane, trimethylpropoxysilane, and trimethylbutoxysilane.

Specific examples of the water-soluble organic solvent used in the hydrolysis-condensation reaction of the vinyl silane compound [A] and the silane compound [B] include alcohols, polyethylene glycols, and acetones. Further, the natural polymer to be allowed to coexist in the hydrolysis-condensation reaction may be any polymer substance that is a product of the natural world, and includes natural rubber, celluloses, starches, collagen, gelatin, polypeptides, and the like. Specific examples of crosslinking agents for natural polymers include glutaraldehyde, osmic acid, isocyanates, diisocyanates, organic dibasic acids and acid halides used for crosslinking natural polymers having OH groups. However, the type does not matter as long as it significantly promotes cross-linking of natural molecules when added in a trace amount when used in combination with radiation.

Therefore, the anticancer agents used in the present invention are classified as follows according to their mechanism of action: (1) Alkylating agents: Alkylating agents that have the effect of introducing alkyl groups into the constituent components of capsules. The intracellular components that undergo alkylation include nucleic acids (DNA); cyclophosphamide, chlorambucil, natyulan, etc.; (2) Substitute antagonists: A substance that has a competitive inhibitory effect on enzymatic reactions or an antagonist of intermediate metabolites that are substrates for enzymatic reactions, and these have the function of blocking DNA synthesis; methotrexate, 6-
Mercaptopurine, 5-fluorouracil, ketosine arabinonde, etc.; (3) Antibiotics: Substances that exhibit anticancer properties have been discovered in bacterial culture solutions, and the mechanism of anticancer action has been elucidated through these cell proliferation models. is being done;
Mitomacin C and bleomycin are used as DNA inhibitors, and chromomycin A ₃ and daunomycin are used as RNA inhibitors; (4) Hormone drugs: Hormone-dependent cancers such as breast cancer and prostate cancer are treated with RNA, Can inhibit protein synthesis; corticosteroids, sex hormones, etc.

The anticancer agent used in the present invention includes chlormethine, nitrogen mustard-N-oxide, cyclophosphamide, chlorambutyl, mannomustine, dibromomannitol, melphalan, ulamustine, triethylenemelamine, and thiotepa as alkylating agents. , Improquone, triaziquone, carbazylquinone, carmustine, lomustine, ifosamide, etogluside, epipropidine; as antimetabolites, cytosine arabinoside, 6
-Mercaptopurine, thioinosine, cytarabine, 8-azaguanine, 5-fluorouracil,
1-(2-tetrahydrofuryl)-5-fluorouracil, cyclocytidine, methotrexate,
Aminopriten sodium; Plant fission poisons include vinbrakekene sulfate, vincriskene sulfate, podophyllotoxin,
Demecolcin; As anticancer antibiotics, sarcomycin, actinomycin C, dakumonomycin, carcinophyllin, mitomine C, chromomycin
_A3 , bleomycin hydrochloride, daunorubicin hydrochloride, doxorubicin hydrochloride, neocarzinostatin, mitalamycin; Other anticancer substances include 864T, guanylhydrazone, mercury hematoporphyrin, cobalt protoporphyrin, acegratone, L-asparaginase, procarbazine hydrochloride. , PC-B-
45, dromostanolone propionate, fusfestrol, mitodeine, and hydroxycarbamide. Anticancer substances also include steroids, alkaloids, and adrenal corticosteroids. Furthermore, any substance exhibiting anti-cancer properties can be used for the purposes of the present invention.

In the hydrolysis-condensation reaction of the present invention, the products obtained vary significantly depending on the hydrolysis temperature, time, combination and composition of silane coupling agents, type of hydrolysis solvent, etc.

The action of light or ionizing radiation depends on the irradiation temperature -
It is possible in the range of 100 to 50°C, and in methods (1) and (2) above, low-temperature irradiation polymerization, especially around -55°C, is possible for polymerization of monomers or anticancer drugs in the system. It is effective in terms of maintaining the dispersion state and irradiation stability of the anticancer drug. Also, the irradiation dose is 5×10 ⁴
A dose range of ~3×10 ⁶ R is possible, but preferably 1×10 ⁶ R is optimal. Further, the irradiation atmosphere is preferably such that no oxygen exists in the system.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 Adriamycin 100mg, mitomycin C60
mg, 300 mg of 1-(2-tetrahydrofuryl)-5-fluorouracil, 40 g of γ-methacryloxypropyltrimethoxysilane, 30 g of tetramethoxysilane, 30 g of 0.5% HCl aqueous solution,
A mixture of 70 g of MeOH was treated at 50°C for 20 hours and mixed with 0.6 g of the hydrolysis-condensation reaction product (the amount after removing the HCl aqueous solution and MeOH from the system) to uniformly disperse the anticancer agent. 60 C at a temperature of ⁶⁰ C. The sample was irradiated with γ-rays from -55° C. at a dose rate of 5×10 ⁵ R/hr for 2 hours in a nitrogen atmosphere to obtain a sustained-release agent containing an anticancer drug.

The in vitro elution amount of anticancer drugs from sustained-release preparations ground to 500-1000 μm showed sustained release over 3 months, with adriamycin being 60%, mitomycin being 95%, and 1-(2-tetrahydro- 78% was reached with furil)-5-fluorouracil.

We investigated the performance of this sustained-release drug in vivo from the viewpoint of survival prolongation, and investigated the effects of this drug on patients with Ehrlich ascites cancer.
The experiment was carried out using ICR female mice. 100% of the mice implanted with Ehrlich ascites cancer died on day 15 (20 mice/group), but when the sustained-release drug was inserted intraperitoneally, 80% survived even after 6 months. . Furthermore, the living tissue around this sustained release agent did not undergo any change.

Example 2 10 g of soluble gelatin, 40 g of γ-methacryloxypropyltrimethoxysilane, 20 g of γ-glycidoxypropyltrimethoxysilane, 20 g of N-β-(aminoethyl)-γ-aminopropyltrimethoxysilane, 10 g of tetramethoxysilane ,0.5%
Mix 30g of HCl aqueous solution and 70g of MeOH, and
Time processed. Thereafter, in order to remove unreacted silane coupling agent, the gelatin was washed with excess MeOH, filtered, and dried. This processed gelatin 3
g, 200 mg of 5-FU prepared in advance,
The anticancer drug was absorbed into 3 ml of an aqueous solution containing 100 mg of bleomycin. After that, the gelatin containing the anticancer drug was freeze-dried and exposed to an electron beam 1x.
It was irradiated with 10 ⁶ R.

The elution amount of the anticancer drug in vitro from the obtained sustained-release drug showed sustained release over 50 days, and both were 80.
% has been reached.

In vivo tests were conducted in the same manner as in Example 1, and survival was extended by 90% even after 4 months.
In this case, when the abdomen was incised 8 months later, it was found that the sustained release agent had dissolved from the surface area and was compatible with living tissue.

Claims (1)

[Claims] 1. The general formula is or One or more vinylsilane compounds [A] represented by and the general formula is or R ³ _o (SiOR ² ) _4-o or 1 per 5 parts by weight of the hydrolysis-condensation reaction product of one or more silane compounds [B] represented by
An anticancer drug sustained release complex composition comprising dispersing or dissolving 0.1 to 7 parts by weight of one or more anticancer drugs, adjusting the dosage form to an appropriate dosage form, and then irradiating the same with light or ionizing radiation. However, in the above general formula, R ¹ is a straight chain or branched alkyl group with up to 6 carbon atoms, R ² is a straight chain or branched alkyl group with up to 4 carbon atoms, and R ³ is OR ² or a straight-chain or branched alkyl group having up to 4 carbon atoms. 2. The hydrolysis-condensation reaction product consists of 10 parts by weight of a mixture of the vinyl silane compound [A] and the silane compound [B], and 0.01 to 5 parts by weight of an aqueous hydrochloric acid solution.
parts by weight and 7 parts by weight of a water-soluble organic solvent,
The method of item 1 obtained by treating this at a temperature of 20 to 80°C for 1 hour or more. 3 The general formula is or One or more vinylsilane compounds [A] represented by and the general formula is or R ³ _o (SiOR ² ) _4-o or One or more silane compounds [B] represented by are subjected to a hydrolysis-condensation reaction in the coexistence of one or more natural polymers, and unreacted substances are washed and removed with alcohol. , 1 to 10 parts by weight of an aqueous solution containing one or more anticancer agents is adsorbed onto 5 parts by weight of the remaining treated natural polymer, freeze-dried, and then irradiated with light or ionizing radiation. A method for producing an anticancer drug sustained release complex composition, provided that in the above general formula, R ¹ is a carbon atom of 6
straight-chain or branched alkyl group of up to 4 carbon atoms, R ² is a straight-chain or branched alkyl group of up to 4 carbon atoms, R ³
is OR ² or a straight or branched alkyl group of up to 4 carbon atoms. 4 In the hydrolysis-condensation reaction, the amount of the natural polymer is 1 to 10 parts by weight per 10 parts by weight of the mixture of the vinyl silane compound [A] and the silane compound [B].
The method of paragraph 3, which is parts by weight.