JP2000290173A - Sustained relesability controlling agent, and controlling sustained releasability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject agent, capable of freely controlling release of an active medical component, by reacting a hydrophobic compound having a functional group containing active hydrogen atom with a specific bisoxazoline compound. SOLUTION: This agent is obtained by reacting (A) a compound having a functional group containing active hydrogen atom at the terminal of the hydrophobic main chain or in the side chain, e.g. hydroxyl, mercapto, carboxyl or amino, with (B) a bisoxazoline compound shown by the formula [D is a (substituted) alkylene, arylene or the like; and R1 to R4 are each H, a (substituted) alkyl or the like], e.g. 1,6-bis(1,3-oxazol-2-yl)hexane. The component A may be either a low-molecular-weight compound (preferably a compound having phenolic OH group, e.g. alkyl henol) or high-molecular-weight compound (e.g. olefin- or styrene-based polymer). The component B is used at 0.7 to 10 mols per mol of the functional group having active hydrogen group in the component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a sustained-release control agent for arbitrarily controlling the release of a drug active ingredient, a sustained-release composition containing the sustained-release control agent, and a method of controlling sustained-release control. .

[0002]

2. Description of the Related Art Techniques for releasing a drug active ingredient at a fixed release rate during a certain period of time or delaying the release of a drug active ingredient include agricultural chemicals, veterinary drugs, quasi-drugs, fragrances, and sterilizers. It is useful in the field of agents, antibacterial agents and the like. The conventional sustained-release base material has a problem that the release rate of the active pharmaceutical ingredient becomes too large when the matrix polymer is disintegrated. On the other hand, there are various kinds of active pharmaceutical ingredients, and it is necessary to control the sustained release according to the properties.

[0003]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to solve the above-mentioned problems of the prior art, and to provide a sustained-release control agent for arbitrarily controlling the release of a drug active ingredient. It is an object of the present invention to provide a sustained release composition containing an agent and a method for controlling sustained release.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that an oxazoline group-containing compound obtained by reacting a hydrophobic polymer or a hydrophobic compound having a functional group containing an active hydrogen atom with bisoxazoline. By using the product as a sustained-release control agent, they have found that the release of the active pharmaceutical ingredient can be arbitrarily controlled, and completed the present invention.

That is, the present invention is obtained by reacting a compound having a functional group containing an active hydrogen atom at the terminal or side chain of a hydrophobic main chain with a bisoxazoline compound represented by the following formula (I). Controlled release agent.

[0006]

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In the formula (I), D represents an alkylene group which may have a substituent, a cycloalkylene group which may have a substituent or an arylene group which may have a substituent. R ¹ , R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom, an alkyl group which may have a substituent or an aryl group which may have a substituent.

[0008] The present invention is also a sustained-release controlling agent having a hydrophobic main chain and a substituent represented by the following formula (II) at the terminal or main chain of the hydrophobic main chain.

[0009]

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In the formula (II), D represents an alkylene group which may have a substituent, a cycloalkylene group which may have a substituent or an arylene group which may have a substituent; X represents an oxygen atom, a sulfur atom, a COO group, an NH group,
Or a residue of a monomer having a functional group containing an active hydrogen atom, wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and are a hydrogen atom, an alkyl which may have a substituent. And an aryl group which may have a group or a substituent.

In the present invention, a preferred sustained-release control agent is represented by the following formula (III).

[0012]

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In the formula (III), Y ¹ and Z each represent a hydrocarbon group constituting the main chain of the polymer, Z may have an unsaturated bond, and a / (a + b) = 0.1 R ¹ , R ² , R ³ and R ⁴ are the same or different and each represent a hydrogen atom or a C _1-4 alkyl group, and at least one of R ¹ and R ² is a hydrogen atom , R ³ and R
^At least one of ⁴ is a hydrogen atom.

Preferred sustained-release controlling agents are also those represented by the following formula (IV).

[0015]

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In the formula (IV), Y^TwoIs a C6-30 fat
A group hydrocarbon group;¹, R^Two, R^ThreeAnd R^FourIs the same
One or different, a hydrogen atom or C_1-4Represents an alkyl group
Then R ¹And R^TwoAt least one is a hydrogen atom,
R^ThreeAnd R^FourAt least one is a hydrogen atom.

Further, the present invention is a sustained-release composition comprising an active ingredient and the above-mentioned sustained-release controlling agent in a thermoplastic resin and / or a thermosetting resin. Further, the present invention provides a sustained release control method for arbitrarily controlling the release of an active ingredient by mixing an active ingredient and the above-mentioned sustained release control agent in a thermoplastic resin and / or a thermosetting resin. It is.

In the present invention, the term "active ingredient" refers to aroma, bactericidal, antibacterial, herbicidal, and miticide in the fields of agricultural chemicals, veterinary drugs, antibacterial preparations (fiber films), pharmaceuticals, quasi-drugs, and fragrances. Means an active ingredient of a drug that exhibits such effects.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The sustained-release controlling agent of the present invention comprises (A) a compound having a functional group containing an active hydrogen atom at a terminal or a side chain of a hydrophobic main chain (hereinafter simply referred to as a hydrophobic compound). And (B) a bisoxazoline compound represented by the formula (I).

[Hydrophobic Compound (A)] The hydrophobic compound (A) may be a low molecular weight compound or a high molecular weight compound (polymer) as long as it has a hydrophobic main chain. Note that the high molecular weight compound also includes a polymer in an oligomer region having a relatively small molecular weight. In many cases, the main chain of the hydrophobic compound is usually mainly composed of a hydrocarbon group, preferably an aliphatic hydrocarbon group. The hydrocarbon group may be a saturated hydrocarbon group (eg, methylene, ethylene, propylene units, etc.) or an unsaturated hydrocarbon group (eg, butadiene units, etc.). The proportion of hydrocarbon groups in the main chain is, for example, 50 mol% or more, preferably 7 mol% or more.
It is about 0 to 100 mol%, more preferably about 80 to 100 mol%.

In the hydrophobic compound, examples of the functional group containing an active hydrogen atom include a hydroxyl group, which may be phenolic, a mercapto group, a carboxyl group, and an amino group. The hydrophobic compound may have the same functional group, or may have a plurality of different functional groups. Preferred functional groups include those having a high activity toward oxazoline, such as carboxyl and amino groups, especially carboxyl groups. Furthermore, the hydrophobic compound whose main chain is hydrophobic may be a hydrophilic compound, but usually is often hydrophobic and water-insoluble.

[Low molecular weight hydrophobic compound (Aa)] As the low molecular weight hydrophobic compound (Aa), a low volatile compound which is liquid or solid at normal temperature (for example, has a boiling point of 15 at normal pressure).
In many cases, a non-volatile compound having a temperature of 0 ° C. or higher is used, and a molecular weight of 1000 or less (preferably 100 to 750
(More preferably about 150 to 750) in many cases. The main chain of such a compound has 6 to 6 carbon atoms.
It is often composed of about 30 (preferably 8 to 26 carbon atoms, more preferably 10 to 24 carbon atoms) aliphatic hydrocarbon group.

Examples of the low molecular weight hydrophobic compound having a hydroxyl group include aliphatic alcohols having about 10 to 30 carbon atoms (eg, lauryl alcohol, tetradecyl alcohol, cetyl alcohol, octadecyl alcohol, aralkyl alcohol, ceryl alcohol). , Merisyl alcohol, oleyl alcohol, etc.), 1,4-
Aliphatic diols having about 4 to 10 carbon atoms, such as butanediol and 1,6-hexanediol, and compounds having a phenolic hydroxyl group (for example, phenol, alkylphenol (for example, when the alkyl moiety has 4 to 2 carbon atoms)
0, preferably about 8 to 14 carbon atoms). Preferred hydrophobic low molecular weight compounds include compounds having a phenolic hydroxyl group (eg, the above-mentioned alkylphenols and the like).

Examples of the low-molecular-weight hydrophobic compound having a mercapto group include thioalcohols corresponding to the aliphatic alcohols.

Examples of the low molecular weight hydrophobic compound having a carboxyl group include carboxylic acids having 6 or more carbon atoms,
For example, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid,
C such as dioxystearic acid, behenic acid and montanic acid
_6-30 saturated fatty acids, lindelic acid, palmito oleic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, eleostearic acid, arachidonic acid, erucic acid, etc.
_10-24 unsaturated fatty acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, azelaic acid, saturated polycarboxylic acid having about 4 to 40 carbon atoms such as sebacic acid, maleic acid, maleic anhydride, fumaric acid Acid, citraconic acid,
Examples thereof include unsaturated polycarboxylic acids such as itaconic acid and glutaconic acid, and dimer acids. One or more of these carboxylic acids can be used. Of these carboxylic acids, carboxylic acids having 6 or more carbon atoms, particularly aliphatic monocarboxylic acids, especially higher fatty acids, are often used.
The carbon number of the higher fatty acid is, for example, preferably about 10 to 26 carbon atoms, particularly preferably about 12 to 24 carbon atoms.
The higher fatty acid may be an unsaturated higher fatty acid, but a saturated higher fatty acid is advantageously used.

Examples of the low molecular weight hydrophobic compound having an amino group include caprylamine, laurylamine,
Primary amines such as myristylamine, palmitylamine, stearylamine and oleylamine; secondary amines such as didecylamine, didodecylamine, ditetradecylamine, dihexadecylamine and dioctadecylamine; and diamines such as hexamethylenediamine And the like. Preferred amine compounds include those having 10 to 2 carbon atoms.
6, preferably 12 to 24 carbon atoms (for example, 12 carbon atoms).
-18) higher amines, especially primary amines. One or more of these amine compounds can also be used.

Furthermore, low molecular weight hydrophobic compounds include:
Compounds having different functional groups, for example, compounds having a carboxyl group and an amino group, and compounds having a carboxyl group and a hydroxyl group are also included. Examples of such a compound include aminocarboxylic acids having about 6 to 18 carbon atoms, such as aminocaproic acid and aminoundecanoic acid. These low molecular weight hydrophobic compounds (A
a) may be used in combination of different kinds of compounds.

[High molecular weight hydrophobic compound (polymer)
(Ab)] High molecular weight hydrophobic compound (hydrophobic polymer)
(Ab) may be linear or branched. The type of the polymer having a hydrophobic main chain is not particularly limited, and examples thereof include an olefin polymer, a styrene polymer, and an acrylic polymer. Preferred polymers are olefin-based polymers and styrene-based polymers.

The olefin-based polymer includes, for example, olefins such as ethylene, propylene, 1-butene, isobutene, 1-pentene and 4-methyl-1-pentene;
It can be obtained from a polymerizable monomer such as a diene such as 3-butadiene and isoprene. Styrene-based polymers can be obtained from polymerizable monomers such as styrene-based monomers such as styrene and α-methylstyrene.

The hydrophobic polymer is not limited to a homopolymer or a copolymer of the polymerizable monomer, but may be a copolymer of the polymerizable monomer and a copolymerizable monomer. Good. The polymerization form of the copolymer is not particularly limited, and may be any of a random copolymer, a block copolymer, a graft copolymer, and the like. Examples of the copolymerizable monomer include acrylic monomers such as acrylates, methacrylates, and acrylonitrile; and vinyl ester monomers such as vinyl acetate and vinyl propionate. One or more copolymerizable monomers can be used.

Examples of the polymer having a hydrophobic main chain include polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-propylene-diene copolymer, ethylene-vinyl acetate copolymer, and ethylene-propylene copolymer.
Olefin polymers such as ethyl acrylate copolymer, polybutene, polybutadiene, acrylonitrile-butadiene copolymer, polyisobutylene, polyisoprene, and polymethylpentene; polystyrene, styrene-butadiene copolymer, styrene-acrylonitrile copolymer, styrene Styrene-based polymers such as acrylonitrile-butadiene copolymer, and hydrogenated products thereof.

The molecular weight of the hydrophobic polymer is not particularly limited, but may be variously changed depending on the properties of the active pharmaceutical ingredient whose release is to be controlled. Relatively low molecular weight polymers include low molecular weight polyethylene, low molecular weight polypropylene, low molecular weight or liquid polyolefins such as liquid polypropylene, liquid polybutadiene, polybutene, liquid polyisobutylene, and liquid butyl rubber; low molecular weight styrene-based polymers; included. Particularly preferred polymers include olefin-based polymers such as polyethylene.

Such a hydrophobic polymer, like the low molecular weight compound, has a functional group containing an active hydrogen atom, for example, a hydroxyl group, a mercapto group, a carboxyl group,
It has an amino group and the like. Such a functional group is formed by copolymerizing a monomer having a hydroxyl group, a mercapto group, a carboxyl group or an amino group, together with the polymerizable monomer and, if necessary, the copolymerizable monomer. It can be introduced into polymers having a hydrophobic backbone. Further, the functional group can be introduced by a polymer reaction of the hydrophobic polymer.

The monomers having a hydroxyl group include, for example, allyl alcohol, hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate and the like. In the monomer having a mercapto group,
Compounds corresponding to the above-mentioned monomers having a hydroxyl group are included. Examples of the monomer having a carboxyl group include acrylic acid, methacrylic acid, maleic acid, itaconic acid, crotonic acid, 10-undecylenic acid, vinylbenzoic acid, 5-norbornene-2-carboxylic acid, and maleic anhydride. Includes ethylenically unsaturated carboxylic acids and their anhydrides. The monomer having an amino group includes aminostyrene, vinylamine, allylamine and the like. Preferred monomers have a carboxyl group and an amino group, especially a carboxyl group.

Examples of the polymer having a carboxyl group introduced by a copolymerization reaction include a modified polyolefin, for example,
Ethylene- (meth) acrylic acid copolymer, propylene-
(Meth) acrylic acid copolymer, carboxyl-modified polyolefin (for example, ethylene-maleic anhydride copolymer, ethylene- (meth) acrylic acid-maleic anhydride copolymer) and the like.

As a method for introducing a hydroxyl group, a carboxyl group, or an amino group by a polymer reaction, a conventional method can be employed. For example, a hydroxyl group can be introduced by a copolymerization and hydrolysis reaction of vinyl acetate or ethylene carbonate, a reduction reaction of a carbonyl group or a carboxyl group generated by an oxidation reaction of an olefin-based polymer or the like. When the polymer has an unsaturated bond, it can be introduced by introducing a phenol by a Friedel-Crafts reaction, or by introducing acetic acid and a hydrolysis reaction by a Friedel-Crafts reaction. The carxyl group can be introduced by an oxidation reaction, a thermal decomposition reaction, a heat treatment using a peroxide, or a reaction with maleic anhydride in the presence of a peroxide when the polymer has an unsaturated bond. The amino group can be introduced by copolymerization of N-vinylformamide and a hydrolysis reaction,
The polymer having a carboxyl group is an acid chloride,
It can also be produced by reacting with a diamine such as p-phenylenediamine.

Although the molecular weight of the polymer having a hydrophobic main chain is not particularly limited, for example, the weight average molecular weight is 500 to 2
It is about 50,000, preferably about 700 to 100,000, and more preferably about 1,000 to 25,000. Particularly preferred polymers include those having a molecular weight of about 1,000 to 25,000 (for example, a molecular weight of 1,000 to 10,000, preferably 1 to 10,000).
(About 000-5000).

[Bisoxazoline compound (B)] In the bisoxazoline compound (B) represented by the formula (I), examples of the alkylene group of D include a C _1-10 alkylene group (for example, methylene, ethylene, Trimethylene,
Propylene, tetramethylene, pentamethylene, hexamethylene group, etc.). The cycloalkylene group includes, for example, a C _5-10 cycloalkylene group (for example,
1,3-cyclopentylene, 1,3-cyclohexylene, 1,4-cyclohexylene, etc.). The arylene group includes a C _6-12 arylene group (for example,
1,3-phenylene, 1,4-phenylene, 1,5-naphthylene, 2,5-naphthylene group, etc.).

The alkylene group, cycloalkylene group and arylene group may have a substituent. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.) Carbon number 1-6
And an alkoxy group (for example, an alkoxy group having about 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and butoxy).

The preferred D is an aryl group which may have a substituent, particularly a phenylene group which may have a substituent (for example, a 1,3-phenylene group or a 1,4-phenylene group). Is included.

In the above formula (I), R ¹ , R ² , R ³
And the alkyl group represented by R ⁴ include, for example, methyl,
Examples thereof include C _1-10 alkyl groups such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups. Preferred alkyl groups include lower alkyl groups having about 1 to 6 carbon atoms, particularly lower alkyl groups having 1 to 4 carbon atoms (for example, especially a methyl group, an ethyl group, a propyl group, and an isopropyl group). Aryl groups include phenyl, 1-naphthyl, 2
-Naphthyl group and the like.

The alkyl group and the aryl group may have a substituent. Examples of the alkyl group having a substituent include dichloromethyl, trichloromethyl, trifluoromethyl, 2,2,2-trichloroethyl, 2,2,2
-Halogenated C _1-4 alkyl groups such as trifluoroethyl and pentafluoroethyl. Aryl groups having a substituent include, for example, 2-chlorophenyl, 3
Phenyl group having a halogen atom such as -chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl group, 2-methylphenyl, 3
A C _1-4 alkyl-phenyl group such as -methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl group, 2-methoxyphenyl, 3-methoxyphenyl, C _1-4 such as -methoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-ethoxyphenyl, etc.
An alkoxy-phenyl group and the like.

Preferred R ¹ , R ² , R ³ and R ⁴ include
It includes a hydrogen atom or a C _1-4 alkyl group. In particular, R ¹
At least one (especially R ²⁾ is a hydrogen atom and R ^2, R
At least one of ³ and R ⁴ (in particular R ⁴⁾ is preferably a hydrogen atom. More preferably, R ¹ , R ² , R
³ and R ⁴ are both hydrogen atoms.

Preferred bisoxazoline compounds include those represented by the following formula (Ia).

[0045]

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In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom or a C _1-4 alkyl group.
As the compound represented by the formula (Ia), R ¹ , R ² ,
Compounds in which R ³ and R ⁴ are hydrogen atoms are often used.

Specific examples of preferred compounds among the compounds represented by the above formula (I) include, for example, 1,6-bis (1,3-oxazoli-2-yl) hexane, 1,8-
Bis (1,3-oxazoli-2-yl) octane, 1,
10-bis (1,3-oxazoli-2-yl) decane,
1,3-bis (1,3-oxazoli-2-yl) cyclohexane, 1,4-bis (1,3-oxazoli-2-yl) cyclohexane, 2,2 ′-(1,3- Phenylene) -bis (2-oxazoline), 2,2 ′-(1,4
-Phenylene) -bis (2-oxazoline), 2,2 ′
-(1,2-phenylene) -bis (2-oxazoline), 2,2 ′-(1,3-phenylene) -bis (4-
Methyl-2-oxazoline), 2,2 ′-(1,4-phenylene) -bis (4-methyl-2-oxazoline),
2,2 ′-(1,2-phenylene) -bis (5-methyl-2-oxazoline), 2,2 ′-(1,3-phenylene) -bis (5-methyl-2-oxazoline), 2,
2 '-(1,4-phenylene) -bis (5-methyl-2
-Oxazoline), 2,2 '-(1,3-phenylene)
-Bis (4-methylphenyl-2-oxazoline),
2,2 ′-(1,4-phenylene) -bis (4-methylphenyl-2-oxazoline), 2,2 ′-(1,3-
Phenylene) -bis (4-chlorophenyl-2-oxazoline), 2,2 ′-(1,4-phenylene) -bis (4-chlorophenyl-2-oxazoline) and the like.

The bisoxazoline compound represented by the above formula (I) can be used alone or in combination of two or more. The bisoxazoline compound (A) can be produced by a conventional method, for example, by reacting a fatty acid or its methyl ester with ethanolamine in the presence of a catalyst to form a 5-membered heterocyclic compound (“Plastic Age”, 114). Page, Mar. 1
According to 995), the compound can be obtained by reacting a dicarboxylic acid or a lower alkyl ester thereof corresponding to D in the above formula (I) with ethanolamine or a derivative thereof to form a 5-membered heterocyclic compound.

The sustained-release controlling agent obtained by reacting the above-mentioned hydrophobic compound (A) with the bisoxazoline compound (B) is represented by the following formula (II) at the terminal of the hydrophobic main chain or at the main chain. It has a substituent.

[0050]

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In the formula (II), X is a residue obtained by removing an active hydrogen atom from the functional group of the hydrophobic compound (A);
That is, a monomer having a functional group containing an oxygen atom, a sulfur atom, a COO group, an NH group, or an active hydrogen atom (for example,
(A monomer having a hydroxyl group, a mercapto group, a carboxyl group or an amino group). The residue X of the monomer is often derived from graft polymerization or copolymerization of the copolymerizable monomer. Preferred X generally includes an oxygen atom, a COO group, and an NH group, particularly a COO group, derived from a functional group introduced by a copolymerization reaction or a polymer reaction.

The substituent represented by the formula (II) forms a terminal and / or a side chain of the compound (Aa) (Ab). Preferred substituents are low molecular weight hydrophobic compounds (A
In the case of a), the compound is bonded to at least the terminal, and in the case of the high molecular weight hydrophobic compound (Ab), it is often bonded to at least the side chain.

Preferred sustained-release controlling agents include the following formula (III)
The compound represented by is included.

[0054]

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In the formula (III), Y ¹ and Z each represent a hydrocarbon group constituting the main chain of the polymer, Z may have an unsaturated bond, and a / (a + b) = 0.1 ~ 20 mol%. R ^1, R ^2, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group, at least one of R ¹ and R ² are hydrogen atoms, R ³ and R
^At least one of ⁴ is a hydrogen atom. The compound represented by the formula (III) is the high-molecular-weight hydrophobic compound (A
b) corresponds to the reaction product of the bisoxazoline compound (B). When the main chain of the polymer is composed of olefin-based polymer, wherein Y is represented by C _n H _2n-1 (n is an integer of 1 to 4), Z is C _n H _2n or C _n H
_2n-2 (n is the same as above). In the high molecular weight sustained release controlling agent represented by the formula (III), preferred a /
(A + b) is about 0.5 to 10 mol%, particularly about 0.5 to 7 mol%.

Preferred sustained-release controlling agents also include compounds represented by the following formula (IV).

[0057]

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In the formula (IV), Y^TwoIs a C6-30 fat
A group hydrocarbon group;¹, R^Two, R^ThreeAnd R^FourIs the same
One or different, a hydrogen atom or C_1-4Represents an alkyl group
Then R ¹And R^TwoAt least one is a hydrogen atom,
R^ThreeAnd R^FourAt least one is a hydrogen atom. Said
The compound represented by the formula (IV) is a compound having the low molecular weight hydrophobicity
Reaction of Compound (Aa) with Bisoxazoline Compound (B)
Corresponds to the product.

In the above formulas (III) and (IV),
R¹, R^Two, R^ThreeAnd R^FourAs the alkyl group of
, Ethyl, propyl, isopropyl, butyl, isobu
Butyl, sec-butyl and tert-butyl groups. Good
Preferred alkyl groups include methyl, ethyl, and especially methyl.
Groups are included. Preferred R¹And R^ThreeIs a hydrogen atom or
C _1-4An alkyl group (especially a methyl group);
^TwoAnd R^FourIs a hydrogen atom.

Since such a sustained-release controlling agent has a hydrophobic main chain and a remaining oxazoline group or amide bond, various agents in a matrix polymer composed of a thermoplastic resin and / or a thermosetting resin can be used. The release of the active ingredient can be controlled. Control of release can be adjusted by changing the length of the hydrophobic backbone, depending on the type of active pharmaceutical ingredient.

[Production Method of Sustained-Release Control Agent] The sustained-release control agent is obtained, for example, by reacting the hydrophobic compound (A) with the bisoxazoline compound (B) represented by the formula (I). To produce a compound having an oxazoline group. As described above, the hydrophobic compound (A) includes the low molecular weight hydrophobic compound (Aa) and the high molecular weight hydrophobic compound (Ab). The use of a low molecular weight hydrophobic compound (Aa) is advantageous because the reaction efficiency and reaction operability can be improved.

The amount of the bisoxazoline compound (B) to be used can be selected according to the type of the hydrophobic compound (A) and its functional group. The amount of the oxazoline group in excess mol, for example, 0.7 to 10 mol (for example, 0.1 mol) of the bisoxazoline compound (B) per mol of the functional group having an active hydrogen atom of the hydrophobic compound (A). 75-5 mol), preferably 0.8-5 mol (e.g. 0.85-
3 mol), more preferably 0.9 to 3 mol (for example,
0.9-1.5 mol). The bisoxazoline compound as a reaction component can be used as a reaction solvent.

The reaction between the hydrophobic compound (A) and the bisoxazoline compound (B) may be carried out in the absence or presence of a catalyst. The reaction may be performed in the absence of a solvent, in the presence of a solvent inert to the reaction,
The reaction may be performed in a homogeneous system or a suspension or dispersion system. Examples of the solvent include aliphatic hydrocarbons such as pentane, hexane and octane; alicyclic hydrocarbons such as cyclohexane and methylcyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; methyl chloride, methylene chloride, chloroform, Halogenated hydrocarbons such as trichloroethylene; esters such as ethyl acetate; ketones such as acetone and methyl ethyl ketone; ethers such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran; nitrogen-containing compounds such as N-methylpyrrolidone, acetonitrile and dimethylformamide A compound; and a mixed solvent thereof.

The reaction temperature can be selected, for example, from the range of about 50 to 150 ° C., preferably about 80 to 120 ° C. When a solvent is used, the reaction can be carried out at the reflux temperature of the solvent. The reaction is usually performed in an inert atmosphere such as nitrogen, helium, or argon while stirring. After the completion of the reaction, if necessary, a sustained-release control agent can be obtained by a conventional method such as concentration, drying, and solvent fractionation.

In the present invention, a drug active ingredient and the above-mentioned sustained-release controlling agent are mixed in a matrix composed of a thermoplastic resin and / or a thermosetting resin. Thermoplastic resin,
The thermosetting resin is not particularly limited as long as it is usually used as a matrix.

The mixing ratio of the active chemical ingredient and the sustained-release controlling agent in the matrix resin is not particularly limited, and the properties (parent / hydrophobicity, molecular size, etc.) of the active pharmaceutical ingredient and the sustained-release property are not limited. It may be appropriately determined according to the properties of the control agent (such as the parent / hydrophobic property and the length of the hydrophobic main chain). Of course, the intended sustained release is considered. Generally, a sustained-release control agent is used in an amount of 0.01 to 100 parts by weight based on 1 part by weight of the active pharmaceutical ingredient.
About 0.1 parts by weight of the sustained release controlling agent
In many cases, about 0 parts by weight is used. Depending on the properties of the active pharmaceutical ingredient and the sustained release controlling agent, it is preferable to use about 0.1 to 3 parts by weight of the sustained release controlling agent per 1 part by weight of the active pharmaceutical ingredient,
About 1 part by weight of the sustained-release control agent may be used. The amount of the active ingredient in the matrix resin varies depending on the type of the active ingredient (agrochemical, veterinary drug, quasi-drug, fragrance, bactericide, antibacterial agent, etc.). What is necessary is just to determine suitably according to the objective.

In the present invention, for example, if it is desired to obtain a slow sustained release property, if the parent / hydrophobicity of the sustained release control agent is controlled so that the properties of the sustained release control agent are close to the matrix, The ability to retain the active pharmaceutical ingredient is improved, and the release rate can be reduced. Conversely, if it is desired to obtain a rapid sustained release, by controlling the properties of the sustained release controlling agent to a different parent / hydrophobic property from the matrix, the ability of the matrix to retain the active ingredient of the drug is reduced and the release rate is reduced. Can be faster. In this way, the release of the active pharmaceutical ingredient in the matrix can be controlled arbitrarily.

The active pharmaceutical ingredient is not particularly restricted but includes, for example, N- (2-methyl-1-naphthyl) maleimide, thymol, isopropylmethylphenol, 1-[(diiodomethyl) sulfonyl] -4-. Methylbenzene, 4-chlorophenyl-3-iodopropargyl formal, 3-acetoxy-1,1,2-triiodo-1-propene, 2,5-dichloro-4-bromophenol, 2-n-octyl-4 -Isothiazolin-3-one, 1,2-benzisothiazolone, thiabendazole, dichlorophen, methyl 2-benzimidazolylcarbamate, 2- (4-thiocyanomethylthio)
Benzothiazole, N, N-dimethyl-N '-(fluorodichloromethylthio) -N'-phenylsulfamide, monochloro-2-phenylphenol, daconyl,
3,5,6-tetrachloro-4- (methylsulfonyl) -pyridine, proxel GXL, alpha-bromocinnamic aldehyde, fluorophorpet, p-
Chloro-m-xylenol, oxophosphoric acid, hexahydro-1,3,5-tris (2-hydroxyethyl) -s
-Triazine and the like.

[0069]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. [Example 1] 480 g of lauric acid [manufactured by Nacalai Tesque, Inc., molecular weight 200.3] and 2,2 ′-(1,3-phenylene) -bis (2-oxazoline) [manufactured by Takeda Pharmaceutical Co., Ltd. 1,3-BPO, molecular weight 216.2] 420 g
Was reacted at 150 ° C. for 15 minutes to obtain a sustained-release control agent. Polyethylene resin [Mirason NEO23H] manufactured by Mitsui Chemicals, Inc. at 180 ° C. by an extrusion kneader.
Parts by weight, 1 part by weight of the synthesized sustained-release control agent, and thiabendazole [manufactured by Aldrich Corporation] as a bactericidal agent
1 part by weight, melt-kneaded and molded to obtain a circular sheet-shaped (diameter 3 cm, thickness 0.5 mm) resin preparation.

(Sustained Release Test) The above resin preparation was treated at 25 ° C.
1 day, 30 days, 60 days at 50% humidity
Five types that were stored for 90 days, 90 days, and 120 days were prepared. The sterilization performance of each of the five resin formulations was evaluated as follows. Spread Aspergillus niger as a cell on an agar medium, place various resin preparations on it,
C. and 80% humidity were allowed to elapse for 24 hours. The distance (mm) from the end of the resin formulation to the circumference of the inhibition circle, which appeared around the resin formulation 24 hours later, was determined. The longer the distance, the higher the sterilization performance of the resin formulation. Table 1 shows the distance from the end of the resin formulation to the circumference of the blocking circle with respect to changes in the storage days of various resin formulations. In the case of the resin preparation for one day of storage, it was found that the inhibition circle spread to a distance of 25 mm from the resin preparation and the antibacterial performance was good.
In addition, even with the resin preparation for 120 days of storage, an inhibition circle was observed up to a distance of 10 mm, indicating that the maintenance of antibacterial performance over a long period of time was good.

[0071]

[Table 1]

Comparative Example 1 A polyethylene resin [Mirason NEO23H, manufactured by Mitsui Chemicals, Inc.] at 180 ° C. 100
A weight part and 1 part by weight of thiabendazole (manufactured by Aldrich Co., Ltd.) as a disinfectant were melt-kneaded and molded to obtain a circular sheet-shaped (diameter 3 cm, thickness 0.5 mm) resin preparation.

(Sustained Release Test) In the same manner as in Example 1, five types of preparations having different storage days were prepared, and the sterilization performance was evaluated under the same conditions. The distance from the end of the resin formulation to the circumference of the blocking circle with respect to changes in the storage days of various resin formulations is as shown in Table 2. In the resin preparation for one day of storage, an inhibition circle was observed up to a distance of 5 mm from the resin preparation, and the antibacterial performance was inferior to that of Example 1. In addition, the storage days 60
In the resin formulation of the day, the inhibition circle was no longer observed, and the release of the drug was terminated at an early stage. Thus, there was no sustained release effect.

[0074]

[Table 2]

[Example 2] 960 g of lauric acid [manufactured by Nacalai Tesque, Inc., molecular weight: 200.3] and 2,2'-
(1,3-phenylene) -bis (2-oxazoline)
[1,3-BPO manufactured by Takeda Pharmaceutical Co., Ltd., molecular weight of 216.
2] 420 g was reacted at 150 ° C. for 15 minutes,
It was a sustained-release control agent. Here, the purpose was to increase the ratio of the non-polar portion (the alkyl group in lauric acid) in the sustained release controlling agent to improve the affinity with the matrix resin. 100 parts by weight of a polyethylene resin [Mirason NEO23H, manufactured by Mitsui Chemicals, Inc.] at 180 ° C. by an extrusion kneader, 1 part by weight of the above-prepared sustained-release control agent, and thiabendazole [manufactured by Aldrich Corporation] as a bactericidal agent 1
The resulting mixture was melt-kneaded and molded to obtain a circular sheet-shaped (3 cm in diameter, 0.5 mm in thickness) resin preparation.

(Sustained Release Test) In the same manner as in Example 1, five preparations having different storage days were prepared, and the sterilization performance was evaluated under the same conditions. Table 3 shows the distance from the end of the resin formulation to the stop circumference with respect to the change in the storage days of various resin formulations. In the case of the resin preparation for one day of storage, it was found that the inhibition circle spread to a distance of 20 mm from the resin preparation and the antibacterial performance was good. In addition, even with the resin preparation for 120 days of storage, a blocking circle was observed up to a distance of 15 mm, indicating that the maintenance of the antibacterial performance over a long period of time was better than that of Example 1.

[0077]

[Table 3]

Example 3 480 g of lauric acid [manufactured by Nacalai Tesque, Inc., molecular weight: 200.3] 480 g and 2,2'-
(1,3-phenylene) -bis (2-oxazoline)
[1,3-BPO manufactured by Takeda Pharmaceutical Co., Ltd., molecular weight of 216.
2] 840 g at 150 ° C. for 15 minutes,
It was a sustained-release control agent. Here, the purpose was to increase the ratio of the polar moiety (oxazoline group) in the sustained-release control agent and reduce the affinity with the resin. 18 by extrusion kneader
At 0 ° C., 100 parts by weight of a polyethylene resin [Mirason NEO23H, manufactured by Mitsui Chemicals, Inc.], 1 part by weight of the synthesized sustained-release control agent, and 1 part by weight of thiabendazole [manufactured by Aldrich] as a bactericidal agent And melt-kneaded, molded, and shaped into a circular sheet (diameter 3 cm, thickness 0.5
mm).

(Sustained Release Test) In the same manner as in Example 1, five preparations having different storage days were prepared, and the sterilization performance was evaluated under the same conditions. Table 4 shows the distance from the end of the resin formulation to the circumference of the blocking circle with respect to the change in the storage days of various resin formulations. In the case of the resin preparation for one day of storage, it was found that the inhibition circle spread to a distance of 45 mm from the resin preparation, and the antibacterial performance in the initial stage was more favorable. In addition, it was found from the above-mentioned distance with respect to the change in the storage days that the early release of the drug was promoted.

[0080]

[Table 4]

Comparative Example 2 Polyethylene resin at 180 ° C. by an extrusion kneader [Mirason NE, manufactured by Mitsui Chemicals, Inc.]
O23H] melt-kneaded, molded and formed into a circular sheet (diameter 3
cm, thickness 0.5 mm). The sterilization performance of this circular sheet-shaped resin was evaluated under the same conditions as in Example 1. After 24 hours, no inhibition circle was observed, and it was confirmed that the matrix resin had no bactericidal performance.

Comparative Example 3 Polyethylene resin [Mirason NE, manufactured by Mitsui Chemicals, Inc.] at 180 ° C. using an extrusion kneader.
O23H], 100 parts by weight, and 1 part by weight of the sustained-release controlling agent synthesized in Example 1 were melt-kneaded and molded to obtain a circular sheet-shaped (diameter 3 cm, thickness 0.5 mm) resin. The sterilization performance of this circular sheet-shaped resin was evaluated under the same conditions as in Example 1. After 24 hours, no inhibition circle was observed, and it was confirmed that the sustained-release control agent had no bactericidal performance.

In the present invention, the type and amount of the matrix composed of a thermoplastic resin and / or a thermosetting resin and the type and amount of the sustained-release controlling agent are variously changed according to the type and purpose of use of the active chemical ingredient. Is possible. Further, the form of the sustained-release composition can be variously modified. Therefore, the present invention is not limited to the above embodiment.

[0084]

According to the present invention, there are provided a sustained release control agent for arbitrarily controlling the release of a drug active ingredient, a sustained release composition containing the sustained release control agent, and a sustained release control method. Provided.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C056 AA01 AB01 AC02 AD01 AE02 BA03 4C076 AA71 AA94 CC31 DD41 DD59 DD60 EE03 EE10 EE12 EE19 FF01 FF31

Claims (5)

[Claims] 1. A compound having a functional group containing an active hydrogen atom at a terminal or a side chain of a hydrophobic main chain, and a compound represented by the following formula (I): (Wherein D is an alkylene group which may have a substituent,
Substituted indicates also arylene group optionally having also good cycloalkylene group or a substituent, R ^1,
R ² , R ³ and R ⁴ are the same or different and are each a hydrogen atom,
It represents an alkyl group which may have a substituent or an aryl group which may have a substituent. The sustained release controlling agent obtained by the reaction with the bisoxazoline compound represented by the formula: 2. The method according to claim 1, wherein the hydrophobic main chain and the terminal or main chain of the hydrophobic main chain are represented by the following formula (II): (Wherein D is an alkylene group which may have a substituent,
X represents an optionally substituted cycloalkylene group or an optionally substituted arylene group, and X represents an oxygen atom, a sulfur atom, a COO group, an NH group, or a functional group containing an active hydrogen atom. represents a residue of a monomer having a, R ^1,
R ² , R ³ and R ⁴ are the same or different and are each a hydrogen atom,
It represents an alkyl group which may have a substituent or an aryl group which may have a substituent. And a substituent represented by formula (1): 3. A compound represented by the following formula (III): (Wherein, Y ¹ and Z each represent a hydrocarbon group constituting the main chain of the polymer, Z may have an unsaturated bond, and a / (a + b) = 0.1 to 20 mol% Yes,
R ^1, R ^2, R ³ and R ⁴ are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group, at least one of R ¹ and R ² is a hydrogen atom, R ³ and R ⁴ At least one is a hydrogen atom. ) Or the following formula (IV): (Wherein, Y ² represents an aliphatic hydrocarbon group having 6 to 30 carbon atoms, and R ¹ , R ² , R ³ and R ⁴ are the same or different;
A hydrogen atom or a C _1-4 alkyl group; at least one of R ¹ and R ² is a hydrogen atom; and at least one of R ³ and R ⁴ is a hydrogen atom. ).
3. The sustained-release control agent according to item 1. 4. A sustained-release composition comprising, in a thermoplastic resin and / or a thermosetting resin, an active ingredient and the sustained-release controlling agent according to any one of claims 1 to 3. object. 5. An effective method comprising mixing the active ingredient and the sustained-release controlling agent according to any one of claims 1 to 3 in a thermoplastic resin and / or a thermosetting resin. A controlled release control method for arbitrarily controlling the release of components.