JP5240959B2 - Drug and production method - Google Patents

Description

The present invention relates to a drug using a magnetically sensitive substance and a method for producing the same. More specifically, it is necessary if necessary using a magnetically sensitive substance that is used to separate a target compound from a mixture using a magnet in which a functional substance is bonded and fixed through an organic thin film covalently bonded to the surface of the magnetic fine particle. The present invention relates to a magnetically responsive drug that can be used in a drug system (that is, a drug for a drug delivery system (DDS)) for acting at a necessary site at a necessary time.

In the present invention, a “magnetically responsive drug for DDS” is a drug, amino acid, enzyme, antibody, antibiotic, antibacterial substance, or contrast agent, which contains an imino group drug on the surface of magnetic fine particles. Drugs included.

Currently, a number of drug systems have been researched and developed to act at the required site at the required time for the purpose of reducing or reducing the side effects of the drug.
Special Table 2002-500177 Special Table 2000-503763 JP 09-328438 A

However , a magnetically sensitive substance that can be separated from a mixture using magnetic force and a method for producing the same, and a drug used in a system that concentrates the drug on a necessary site using magnetic force and a method for producing the same have not yet been developed and provided. Absent.

The present invention is to produce a magnetically sensitive material which can be separated or integrated with a magnetic, as intended for the separation of substances used in the catalyst or the like at a high efficiency. In addition, it is possible to concentrate the necessary part in the living body using magnetic force and produce a drug for DDS that requires very little dosage, to reduce side effects caused by the drug, and to reduce the amount of drug used. The purpose is to do.

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A first invention provided as a means for solving the above-described problems is a magnetic responsive drug that can be used in a drug system for acting at a necessary site at a required time as required. An organic thin film composed of molecules covalently bonded to the surface and having an epoxy group at one end and covalently bonded to the surface of the magnetic particle via Si at the other end has an imino group via a —CH ₂ —N— bond. It is a magnetically responsive drug to which a drug that is one of an anti-cancer substance, antibiotic, antibacterial substance, and contrast agent is bound and fixed.

The second invention is the magnetically responsive drug according to the first invention, wherein the organic thin film is a monomolecular film.

According to a third aspect of the invention, magnetic particles are dispersed in a chemical adsorption solution prepared by mixing an alkoxysilane compound containing at least an epoxy group, a silanol condensation catalyst, and a non-aqueous organic solvent to react the alkoxysilane compound with the surface of the magnetic particles. a step of, forming a monomolecular film containing an epoxy group covalently bonded by washing the surface of the fine particles in an organic solvent to remove excess alkoxysilane compound magnetic particle surface, have a imino group, anticancer A method for producing a magnetically responsive drug, comprising a step of reacting a drug that is one of a substance, an antibiotic, an antibacterial substance, and a contrast agent to fix the drug on the surface of a magnetic fine particle.

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According to a third aspect of the invention, magnetic particles are dispersed in a chemical adsorption solution prepared by mixing an alkoxysilane compound containing at least an epoxy group, a silanol condensation catalyst, and a non-aqueous organic solvent to react the alkoxysilane compound with the surface of the magnetic particles. A step of forming a monomolecular film containing an epoxy group covalently bonded to the surface of the magnetic fine particle by reacting a drug having an imino group A method for producing a magnetically responsive drug, comprising the step of immobilizing the drug on the surface of the magnetic fine particles .

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The fourth invention is a magnetically responsive agent using a ketimine compound, or an organic acid, an aldimine compound, an enamine compound, an oxazolidine compound or an aminoalkylalkoxysilane compound in place of the silanol condensation catalyst in the third invention. It is a manufacturing method.

According to a fifth invention, in the third invention, the silanol condensation catalyst is mixed with at least one selected from a ketimine compound or an organic acid, an aldimine compound, an enamine compound, an oxazolidine compound, and an aminoalkylalkoxysilane compound as a co-catalyst. It is a manufacturing method of the magnetic responsive chemical | medical agent used as a result.

The contents of the present invention will be further described below.

On the other hand, in the present invention, the magnetic fine particles are dispersed in a chemical adsorption liquid prepared by mixing an alkoxysilane compound containing at least an epoxy group, a silanol condensation catalyst, and a non-aqueous organic solvent to react the alkoxysilane compound with the surface of the magnetic fine particles. And the step of forming a monomolecular film containing an epoxy group covalently bonded to the surface of the magnetic fine particle by removing the excess alkoxysilane compound by washing the surface of the fine particle with an organic solvent and covalently bonding to the surface of the magnetic fine particle. Response in which a drug, which is an anticancer substance, antibiotic, antibacterial substance, or contrast agent, having an imino group via a —CH ₂ —N— bond is bound and fixed to the organic thin film The gist is to manufacture and provide a sex medicine.

Here, it is convenient that the organic thin film is a monomolecular film because the characteristics of the functional substance are not impaired.
Further, since the monomolecular film covalently bonded is composed of molecules that are covalently attached to the magnetic particle surface through Si at the other end comprises an epoxy group at one end to the surface, convenient to fix the functional substance covalently Is good.

In this case further, after the step of forming a monomolecular film containing epoxy groups, since to secure the drug to the magnetic microparticle surface by reacting a drug having an imino group, it is advantageous in terms of securing the drug stability.
In addition, it is advantageous to use a ketimine compound, or an organic acid, an aldimine compound, an enamine compound, an oxazolidine compound, or an aminoalkylalkoxysilane compound instead of the silanol condensation catalyst because the production time can be shortened.
In addition, when a ketimine compound or at least one selected from organic acids, aldimine compounds, enamine compounds, oxazolidine compounds, and aminoalkylalkoxysilane compounds is used as a co-catalyst for the silanol condensation catalyst, the production time can be further reduced. Convenient.

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As described above, according to the present invention, a magnetically sensitive substance that can be separated or accumulated using magnetic force can be manufactured, and the substance used for a catalyst or the like can be separated efficiently.
In addition, it is possible to manufacture and provide a drug for DDS in which the drug is immobilized on the surface of the magnetic fine particles while maintaining almost the original function of the drug, and after administration to the human body, the effect is reduced by accumulating the drug at the necessary site using magnetic force. There is a special effect that the dose of the drug can be reduced and the side effects of the drug are alleviated.

The present invention comprises a step of reacting an alkoxysilane compound and the surface of a magnetic fine particle by dispersing the magnetic fine particle in a chemical adsorption solution prepared by mixing an alkoxysilane compound containing at least an epoxy group, a silanol condensation catalyst, and a non-aqueous organic solvent. Cleaning the surface of the fine particles with an organic solvent to remove excess alkoxysilane compound to form a monomolecular film containing an epoxy group covalently bonded to the surface of the magnetic fine particles, and a functional substance via the epoxy group In the present invention, a magnetically sensitive substance in which a functional substance is bonded and fixed through an organic thin film covalently bonded to the surface of a magnetic fine particle by the step of binding and fixing is provided.

In the present invention, the magnetic fine particles are dispersed in a chemical adsorption solution prepared by mixing an alkoxysilane compound containing at least an epoxy group, a silanol condensation catalyst, and a non-aqueous organic solvent to react the alkoxysilane compound and the surface of the magnetic fine particles, The surface of the fine particles is washed with an organic solvent to remove excess alkoxysilane compounds and form a monomolecular film containing an epoxy group covalently bonded to the surface of the magnetic fine particles. Proteins, amino acids, enzymes, antibodies, antibiotics, antibacterial substances Alternatively, a DDS in which a drug containing an imino group in a substance such as a contrast agent is reacted to fix the drug on the surface of the magnetic fine particle, whereby the drug is bound and fixed through a monomolecular film covalently bonded to the surface of the magnetic fine particle. Manufacturing and providing pharmaceuticals for use.

Therefore , the drug of the present invention has a function of accumulating the drug at a necessary site using magnetic force after administration to the human body, so that the dose of the drug can be reduced without reducing the effect, or the side effect of the drug can be reduced. There is an effect.

Hereinafter, although the detail of this invention is demonstrated using an Example, this invention is not limited at all by these Examples.

In addition, the magnetically sensitive substance related to the present invention includes a magnetically sensitive substance in which a catalyst or an aggregating agent is fixed as a functional substance, and magnetically responsive drugs include proteins, amino acids, enzymes, antibodies, antibiotics, There are drugs, such as antibacterial substances or contrast agents, in which a drug containing an imino group is immobilized on the surface of the magnetic fine particles. First, as a representative example, magnetic fine particles fixed with a functional substance, penicillin G, will be described. .

First, anhydrous magnetite 1 having a particle size of several tens of nanometers was prepared and dried well. Then, the chemical adsorbent as the functional sites on the drug having an alkoxysilyl group in the epoxy group and the other end, for example, 99 wt% of the drug represented by the following formula (Formula 1, as a silanol condensation catalyst, e.g., dibutyltin diacetyl acetonate 1% by weight and dissolved in a silicone solvent such as hexamethyldisiloxane to a concentration of about 1% by weight ( preferably the concentration of the chemical adsorbent is about 0.5 to 3%). A chemisorbed liquid was prepared.

The adsorbed liquid was mixed with the anhydrous magnetite fine particles and stirred and allowed to react for about 2 hours at room temperature in normal air (relative humidity 45%). At this time, since there are many hydroxyl groups 2 on the surface of the anhydrous magnetite fine particles (FIG. 1a), the -Si (OCH ₃ ) group of the chemical adsorbent and the hydroxyl group are dealcoholized in the presence of a silanol condensation catalyst. (In this case, de-CH ₃ OH) reacts to form a bond as shown in the following formula (Chemical Formula 2), and includes a chemical adsorption monomolecular film 3 including an epoxy group chemically bonded to the surface over the entire surface of the magnetic fine particle. Is formed with a film thickness of about 1 nanometer (FIG. 1b).

Thereafter, when a chlorine-based solvent such as trichlene was added and washed with stirring, magnetite fine particles 4 covered with a chemisorption monomolecular film having an epoxy group on the surface could be produced.

This treatment part did not impair the particle diameter because the coating was extremely thin with a film thickness of nanometer level.
Note that the reactivity does not substantially change when it is taken out into the air without washing, but the chemical adsorbent remaining on the particle surface reacts with the moisture in the air on the particle surface, and the chemical is adsorbed on the particle surface. Magnetite fine particles in which an ultrathin polymer organic thin film made of an adsorbent was formed were obtained. Even in this state, a thick film enough to cause a problem in the subsequent reaction was not formed, and the film could be handled in the same manner as a monomolecular film.

In addition, since the feature of this method is a dealcoholization reaction, it is possible to use a material that is destroyed by an acid such as magnetite fine particles.

Next, the magnetite fine particles 4 covered with the chemical adsorption monomolecular film having the epoxy group were dispersed in alcohol, and penicillin G was added to cause a heating reaction. Here, since penicillin G contains an imino group next to the β-lactam ring, an epoxy group and an imino group are added by the reaction shown in the following formula (Chemical Formula 3), so that penicillin G becomes the surface of the magnetic fine particle. After the unreacted unreacted penicillin G was washed and removed, a magnetically sensitive drug 5 for DDS having penicillin G immobilized on the surface could be produced (FIG. 1c).

Since this drug has a particle size of at most several tens of nanometers, it does not clog blood vessels even when dispersed in pure water and injected into blood vessels. Further, since this medicine has a function of being attracted to the magnet when the magnet is brought close to it, if the magnet is installed in the vicinity of the affected area, the drug can be concentrated on the affected area by the magnetic force while blood circulates in the body for a certain period of time.
Therefore, even if the total dose is extremely small, penicillin G can be increased in concentration only in the vicinity of the affected area, so that side effects can be reduced and efficient treatment is possible.

Note that this technique can be applied to all drugs that contain an imino group in the substance, such as proteins, amino acids, enzymes, antibodies, antibiotics, antibacterial substances, and contrast agents, as long as the drug efficacy is not reduced. For example, cephalexin can be similarly applied because it contains the same imino group and amino group.

Moreover, in the said Example, although the substance shown by Formula (Formula 1) was used as a chemical adsorption agent containing an epoxy group, the substance shown to following (1)-(10) other than the said thing can be utilized. It was.

(1) (CH ₂ OCH) CH ₂ O (CH ₂ ) ₇ Si (OCH ₃ ) ₃
(2) (CH ₂ OCH) CH ₂ O (CH ₂ ) ₁₁ Si (OCH ₃ ) ₃
(3) (CH ₂ CHOCH (CH ₂ ) ₂ ) CH (CH ₂ ) ₂ Si (OCH ₃ ) _{3
(4) (CH 2 CHOCH (} CH 2) 2) CH (CH 2) 4 Si (OCH 3) 3
_{(5) (CH 2 CHOCH (} CH 2) 2) CH (CH 2) 6 Si (OCH 3) 3
_{(6) (CH 2 OCH)} CH 2 O (CH 2) 7 Si (OC 2 H 5) 3
(7) (CH ₂ OCH) CH ₂ O (CH ₂ ) ₁₁ Si (OC ₂ H ₅ ) _{3
(8) (CH 2 CHOCH (} CH 2) 2) CH (CH 2) 2 Si (OC 2 H 5) 3
_{(9) (CH 2 CHOCH (} CH 2) 2) CH (CH 2) 4 Si (OC 2 H 5) 3
(10) (CH ₂ CHOCH (CH ₂ ) ₂ ) CH (CH ₂ ) ₆ Si (OC ₂ H ₅ ) ₃

Here, the (CH ₂ OCH) — group represents a functional group represented by the following formula (Formula 4), and the (CH ₂ CHOCH (CH ₂ ) ₂ ) CH— group is represented by the following formula (Formula 5). Represents a functional group.

Furthermore, Oite in Example 1, the silanol condensation catalyst, a carboxylic acid metal salt, carboxylic acid ester metal salt, metal carboxylate polymer, metal carboxylate chelate, titanate esters, and titanate chelates available It is. More specifically, stannous acetate, dibutyltin dilaurate, dibutyltin dioctoate, dibutyltin diacetate, dioctyltin dilaurate, dioctyl tin dioctate, dioctyl tin diacetate, stannous, lead naphthenate dioctanoate, cobalt naphthenate , 2-ethyl hexene iron, dioctyl tin bis octene dust thioglycolic acid ester salts, dioctyl tin maleate salt, dibutyl tin maleate polymer, dimethyl tin mercapto propionate polymers, dibutyl tin bis acetyl acetate, dioctyl tin bis-acetyl Laurate, tetrabutyl titanate, tetranonyl titanate and bis (acetylacetonyl) dipropyl titanate could be used.

Further, as a solvent for the film-forming solution, an organic chlorine solvent, hydrocarbon solvent, fluorocarbon solvent, silicone solvent, dimethylformamide or the like having a boiling point of about 50 to 250 ° C. and not containing water. It was possible to use a mixture. Furthermore, when the adsorbent is an alkoxysilane type and the organic film is formed by evaporating the solvent, in addition to the solvent, an alcohol type solvent such as methanol, ethanol, propanol, or a mixture thereof can be used. .

Specifically usable are organic chlorinated solvents, non-aqueous petroleum naphtha, solvent naphtha, petroleum ether, petroleum benzine, isoparaffin, normal paraffin, decalin, industrial gasoline, nonane, decane, kerosene, dimethyl silicone, phenyl silicone , Alkyl-modified silicone, polyether silicone, dimethylformamide, or a mixture thereof.

Fluorocarbon solvents include fluorocarbon solvents, Fluorinert (product of 3M), Afludo (product of Asahi Glass). In addition, these may be used individually by 1 type and may mix 2 or more types as long as it mixes well. Further, an organic chlorine solvent such as chloroform may be added.

On the other hand, when a ketimine compound or organic acid, aldimine compound, enamine compound, oxazolidine compound, aminoalkylalkoxysilane compound is used instead of the above-mentioned silanol condensation catalyst, the treatment time is reduced to about half to 2/3 even at the same concentration. did it.

Further, a silanol condensation catalyst and a ketimine compound, or an organic acid, an aldimine compound, an enamine compound, an oxazolidine compound, and an aminoalkylalkoxysilane compound can be used in a range of 1: 9 to 9: 1. )), The processing time can be increased several times faster (up to about 30 minutes), and the film forming time can be reduced to a fraction of a minute.

For example, replacing the dibutyl tin oxide silanol catalyst H3 of the Japan Epoxy Resin Co. is a ketimine compound, and other conditions were tried to the same, except that the reaction time was reduced to about 1 hour, nearly the same Results were obtained.

Further, a silanol catalyst, and Japan Epoxy Resins Co. of H3 is a ketimine compound, a mixture of dibutyl tin bis-acetyl acetonate silanol catalyst (mixing ratio 1: 1) replaced, but other conditions were tried to the same The same results were obtained except that the reaction time could be shortened to about 30 minutes.

Therefore, the above results revealed that ketimine compounds, organic acids, aldimine compounds, enamine compounds, oxazolidine compounds, and aminoalkylalkoxysilane compounds are more active than silanol condensation catalysts.

Furthermore, it was confirmed that the activity is further increased when one of a ketimine compound, an organic acid, an aldimine compound, an enamine compound, an oxazolidine compound, and an aminoalkylalkoxysilane compound is mixed with a silanol condensation catalyst.

Here, the ketimine compound that can be used is not particularly limited. For example, 2,5,8-triaza-1,8-nonadiene, 3,11-dimethyl-4,7,10-triaza-3 , 10-tridecadiene, 2,10-dimethyl-3,6,9-triaza-2,9-undecadiene, 2,4,12,14-tetramethyl-5,8,11-triaza-4,11-pentadeca Diene, 2,4,15,17-tetramethyl-5,8,11,14-tetraaza-4,14-octadecadiene, 2,4,20,22-tetramethyl-5,12,19-triaza- 4,19-trieicosadiene and the like.

Although not particularly limited as organic acids which can be used, for example, formic acid or acetic acid, propionic acid, butyric acid, there is and malonic acid, it had substantially the same effect.

In the above-described embodiment, magnetite fine particles have been described as an example. However, the present invention can be applied to any magnetic nanoparticles as long as the surface is a magnetic fine particle containing active hydrogen such as a hydroxyl group on the surface. . Specifically, the present invention can be applied to magnetic metal fine particles made of iron, chromium, nickel, and alloys thereof, magnetic metal oxide fine particles made of ferrite, magnetite, chromium oxide, and the like.

BRIEF DESCRIPTION OF THE DRAWINGS It is the conceptual diagram which expanded the reaction of the magnetic fine particle in Example 1 of this invention to the molecular level, (a) is a figure of the magnetic fine particle surface before reaction, (b) is the monomolecular film containing an epoxy group formed. The figure after (c) further shows the figure after penicillin G was bound and fixed.

1
Magnetite fine particles 2
Hydroxyl group 3
Monomolecular film containing epoxy groups
Magnetite fine particles coated with monomolecular film containing 4 epoxy groups
Magnetite fine particles with 5 penicillin G bound and immobilized

Claims (5)

A magnetically responsive drug that can be used in a drug system for acting at a necessary site at a required time as needed , covalently bonded to the surface of a magnetic fine particle, containing an epoxy group at one end and via Si at the other end An anti-cancer substance, antibiotic, antibacterial substance, and contrast agent having an imino group via a —CH ₂ —N— bond in an organic thin film composed of molecules covalently bonded to the surface of the magnetic particle A magnetically responsive drug characterized in that one of the drugs is bound and fixed. 2. The magnetically responsive drug according to claim 1, wherein the organic thin film is a monomolecular film. Dispersing magnetic fine particles in a chemical adsorption liquid prepared by mixing an alkoxysilane compound containing at least an epoxy group, a silanol condensation catalyst, and a non-aqueous organic solvent, and reacting the alkoxysilane compound with the surface of the magnetic fine particles; It was closed and forming a monomolecular film containing covalently bound epoxy groups washed to remove excess alkoxysilane compound magnetic fine particle surface with an organic solvent, an imino group, an anticancer agent, antibiotic, antimicrobial A method for producing a magnetically responsive drug, comprising a step of reacting a substance which is one of a substance and a contrast agent to fix the drug on the surface of a magnetic fine particle. The production of a magnetically responsive drug according to claim 3, wherein a ketimine compound or an organic acid, an aldimine compound, an enamine compound, an oxazolidine compound, or an aminoalkylalkoxysilane compound is used instead of the silanol condensation catalyst. Method. 4. The method according to claim 3, wherein at least one selected from a ketimine compound or an organic acid, an aldimine compound, an enamine compound, an oxazolidine compound, and an aminoalkylalkoxysilane compound is used as a co-catalyst for the silanol condensation catalyst. A method for producing a magnetically responsive drug.

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