JP6706040B2 - Sustained-release gelling agent - Google Patents

Description

The present invention relates to a gelling agent for sustained release drugs. More specifically, the present invention relates to a sustained-release gelling agent suitable for cosmetics, fragrances/deodorants, insect repellents/insecticides, agricultural chemicals/liquid fertilizer retainers, and the like.

The sustained-release gelling agent for pharmaceuticals is used as an agent capable of stably releasing functional ingredients such as aroma components, deodorant components, repellent components (components that do not prevent harmful insects, etc.) over a long period of time from cosmetics, aroma and It is useful in applications such as deodorants, insect repellents/insecticides, agricultural chemicals and liquid fertilizer retainers.
Conventionally, an acrylic acid-based cross-linked polymer has been developed as a gelling agent for a sustained-release drug, but since a surfactant and water are required for the polymer to absorb the drug, the polymer ( The amount of drug that can be absorbed into the gel) was small.

As a water absorbent resin capable of absorbing such a chemical, a cyclodextrin containing a fragrance, a dextrin derivative containing a fragrance, an unsaturated aliphatic aldehyde having 6 to 10 carbon atoms and an unsaturated aldehyde having 6 to 10 carbon atoms A water-absorbent resin composition containing at least one substance selected from the group consisting of aliphatic alcohols and a polycarboxylic acid-based water-absorbent resin is disclosed (see Patent Document 1).

Also, as a polymer used as a disintegration promoter for beverage fining agents, laxatives and tablets, a monoethylenically unsaturated monomer that forms a popcorn polymer in controlling the particle size of the popcorn polymer during popcorn polymerization. In a process in which a reaction mixture consisting of and a cross-linking agent is polymerized at temperatures up to 200° C. in the absence of oxygen and polymerization initiators, popcorn polymerization is carried out as a precipitation polymerization in water or in the form of bulk polymerization, and the particle size of the popcorn polymer is A method for controlling the particle size of the popcorn polymer during popcorn polymerization is disclosed, characterized in that it is adjusted in the range of 1 μm to 10 mm by passing an inert gas stream through the reaction mixture (Patent Document 1). 2).

Japanese Patent Publication No. 2009-501803 Special table 2003-526721 gazette

As mentioned above, although a drug absorbing agent has been developed, it is not sufficient in liquid absorbing ability and sustained release property, and development of an agent excellent in liquid absorbing ability and also in sustained release property is required. It was being done.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a gelling agent for a sustained-release drug, which has excellent liquid absorbing ability and excellent sustained-release property.

The present inventor conducted various studies on gelling agents for sustained-release drugs, and found that a polymer having a linalool absorption capacity of 10 g or more per 1 g of the polymer was also excellent in linalool sustained-release property, The present invention has been achieved by realizing that the above problems can be solved satisfactorily.

That is, the present invention relates to a polymer-containing sustained-release drug gelling agent, wherein the sustained-release drug gelling agent has a linalool absorption capacity of 10 g or more per 1 g of the polymer. It is a gelling agent for release drug.
The present invention is described in detail below.
It should be noted that a combination of two or more of the individual preferred embodiments of the present invention described below is also a preferred embodiment of the present invention.

<Gelizer for sustained-release drug>
The gelling agent for sustained release drug of the present invention absorbs and uses the sustained release drug. The sustained-release drug is a drug that exerts its effect by being gradually released over a long period of time.
The sustained-release gelling agent for drugs according to the present invention contains a polymer having a linalool absorption capacity of 10 g or more per 1 g of the polymer, so that cosmetics, fragrances/deodorants, insect repellents/insecticides, It can fully absorb chemicals such as pesticides and liquid fertilizers, and is also excellent in sustained release of chemicals. The liquid absorption capacity of linalool per 1 g of the polymer is more preferably 13 g or more, further preferably 15 g or more.
The evaluation of the liquid absorption capacity can be performed by the method described in the examples.

The sustained-release drug gelling agent preferably has a sustained-release property of linalool at 24° C. of 0.01 to 5 mg/min. Sustained release is the ability to release a drug over a certain period when the drug is absorbed by an absorbent material, and can be expressed by the decreasing rate (release rate) of the absorbed drug. .. If the sustained-release property of the gelling agent for sustained-release drug of the present invention at 24°C is 0.01 mg/min or more, general cosmetics, fragrances/deodorants, insect repellents/insecticides, agricultural chemicals/liquid fertilizer retention It can be preferably used in agent applications. When the sustained-release property of the gelling agent for sustained-release drug of the present invention at 24°C is 5 mg/min or less, the drug can be stably released over a long period of time.
The evaluation of the sustained-release property can be performed by the method described in Examples.

The drug absorbed by the gelling agent for sustained release drug is not particularly limited, and examples thereof include perfume, aroma/deodorant, insect repellent/insecticide, pesticide/liquid fertilizer and the like. Among these, those containing alcohol, phenol, lactone and carboxylic acid are preferable.
When the drug contains alcohol, the content of alcohol is not particularly limited, but is preferably 50 to 100 mass% with respect to 100 mass% of the drug. It is more preferably 60 to 100% by mass, and even more preferably 70 to 100% by mass.

The alcohol is not particularly limited, for example, linalool, geraniol, citronellol, lavandulol, nerol, isopulegol, terpineol, borneol, monoterpene alcohol such as menthol, farnesol, santalol, nerolidol, cedrol, oidesmol, Aromatic alcohol compounds such as sesquiterpene alcohols such as globulol and elemol, diterpene alcohols such as phytol, isophytol and sclareol, benzyl alcohol, cumin alcohol, dimethylbenzylcarbinol, cinnamyl alcohol, phenethyl alcohol, methyl salicylate and anis alcohol. , And polyethers such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, and the like. More preferred are monoterpene alcohols and polyethers, with linalool, geraniol, citronellol, diethylene glycol and dipropylene glycol being more preferred.
The phenol is not particularly limited, and examples thereof include carvacrol, eugenol, cavicol, thymol, cresol and the like.
The lactone is not particularly limited, and examples thereof include γ-butyrolactone, cineol, coumarin, furocumarine, jasmine lactone, jasmon, and bergapten.
The carboxylic acid is not particularly limited, but examples thereof include propionic acid, benzoic acid, and cinnamic acid.

The shape of the gelling agent for sustained release drug of the present invention is not particularly limited, and examples thereof include spherical shape, cubic shape, rectangular shape, sheet shape and the like.
When the shape of the gelling agent for sustained release drug is spherical, cubic, or rectangular, the average particle diameter is preferably 100 to 6000 μm. If the average particle size of the sustained-release gelling agent for drugs is in the above range, the surface area of the particles will be in a suitable range, the release rate of the drug will be in a more suitable range, and the sustained-release property of the drug will be superior. Become.
The particle diameter, when the particle is spherical, means the diameter of the particle, when the particle is cubic, means the length of the side of the particle, and when the particle is rectangular, the shortest side of the particle. Shall mean length.
The average particle diameter is more preferably 200 to 5000 μm, further preferably 300 to 4000 μm. The average particle diameter can be measured by the method described in Examples.

Further, when the gelling agent for sustained release drug has a sheet shape, the film thickness of the sheet is preferably 0.1 to 1000 μm. If the film thickness of the sheet is in the above range, the surface area will be in a suitable range, so that the drug release rate will be in a more suitable range, and the sustained release property of the drug will be superior. The thickness of the above sheet is more preferably 0.5 to 800 μm, further preferably 1 to 500 μm.
The film thickness can measure the length of the cross section when the sheet is cut by a micrometer.

The polymer contained in the sustained-release drug gelling agent of the present invention is not particularly limited, but the sustained-release drug gelling agent is a polymer having a structural unit derived from an N-vinyllactam monomer. It is preferable that it contains.
When the above-mentioned gelling agent for sustained-release drug contains a polymer having a structural unit derived from an N-vinyllactam monomer, the drug can be more sufficiently absorbed and the sustained-release property can be obtained. Will be even better. In particular, since the structural unit derived from the N-vinyllactam-based monomer and the alcohol have a high affinity, the liquid absorbing ability with respect to the drug containing alcohol is more excellent.

The N-vinyllactam-based monomer is not particularly limited, but is represented by the following formula (1);

(In the formula, R represents a hydrogen atom or a methyl group. m represents an integer of 1 to 3.) It is preferable that the compound represented by the formula. Examples of the compound represented by the above formula (1) include N-vinylpyrrolidone, N-vinylpiperidone, N-vinylcaprolactam and the like, and one kind or two or more kinds can be used. N-vinylpyrrolidone is particularly preferable as the N-vinyllactam-based monomer.

The content ratio of the structural unit derived from the N-vinyllactam monomer in the polymer having the structural unit derived from the N-vinyllactam monomer is not particularly limited, but the structural units derived from all the monomers ( It is preferably 50 to 100 mol% with respect to 100 mol% of the N-vinyllactam-based monomer and structural units derived from other monomers.
It is more preferably 60 to 100 mol %, and even more preferably 70 to 100 mol %.

The polymer having a structural unit derived from the N-vinyllactam-based monomer may have a structural unit derived from another monomer other than the N-vinyllactam-based monomer. The other monomer is not particularly limited as long as it can be copolymerized with the N-vinyllactam-based monomer, but for example, 1) methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate. , (Meth)acrylic acid esters such as cyclohexyl (meth)acrylate; 2) hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, 3-(meth)allyloxy-1,2-dihydroxypropane, (meth) Allyl alcohol, isoprenol, and unsaturated alcohols obtained by adding alkylene oxide to these hydroxyl groups, 3) (meth)acrylamide, N-monomethyl (meth)acrylamide, N-monoethyl (meth)acrylamide, N,N-dimethyl (meth)acrylamide (Meth)acrylamide derivatives such as; 4) Basic unsaturated monomers such as dimethylaminoethyl (meth)acrylate, dimethylaminoethyl (meth)acrylamide, vinylpyridine, vinylimidazole, and salts or quaternary compounds thereof 5) Vinylamides such as vinylformamide, vinylacetamide and vinyloxazolidone; 6) Carboxyl group-containing unsaturated monomers such as (meth)acrylic acid, itaconic acid, maleic acid and fumaric acid and salts thereof; 7) Maleic anhydride Unsaturated anhydrides such as acids and itaconic anhydride; 8) Vinyl esters such as vinyl acetate and vinyl propionate; 9) Vinyl ethylene carbonate and its derivatives; 10) Styrene and its derivatives; 11) (Meth)acrylic acid Ethyl-2-sulfonate and its derivatives; 12) Vinyl sulfonic acids such as 3-allyloxy-2-hydroxypropanesulfonic acid, (meth)allylsulfonic acid, isoprenesulfonic acid and their salts; 13) Methyl vinyl ether , Vinyl ethers such as ethyl vinyl ether and butyl vinyl ether; 14) olefins such as ethylene, propylene, octene and butadiene; and the like. Examples of the alkylene oxide in the above 2) include ethylene oxide, propylene oxide and the like, preferably an alkylene oxide having 1 to 20 carbon atoms, and more preferably an alkylene oxide having 1 to 4 carbon atoms. The number of moles of alkylene oxide added in 2) above is preferably 0 to 50 moles, and more preferably 0 to 20 moles per 1 mole of the compound of 2) above. These may be used alone, or two or more kinds may be mixed and copolymerized with the N-vinyllactam-based monomer. Among these, 1) to 9) are preferable, and 1) to 6) are more preferable from the viewpoint of copolymerizability with N-vinyllactam-based monomer.

In the polymer having the structural unit derived from the N-vinyllactam-based monomer, the content ratio of the structural units derived from other monomers is not particularly limited, but the structural units derived from all the monomers in the polymer. It is preferably 0 to 50 mol% with respect to 100% by mass. It is more preferably 0 to 40 mol %, still more preferably 0 to 30 mol %.

The polymer having a structural unit derived from the N-vinyllactam-based monomer preferably has a crosslinked structure. When the polymer has a crosslinked structure, the drug can be more sufficiently absorbed.
The present invention is also a gelling agent for sustained-release drugs, which comprises a polymer having a crosslinked structure, wherein the polymer comprises structural units derived from N-vinyllactam-based monomers derived from all monomers. It is also a gelling agent for a sustained-release drug having 50 to 100 mol% with respect to 100 mol% of structural units.
The cross-linking structure is a structure derived from a cross-linking agent having at least two polymerizable double bond groups per molecule, and the cross-linking agent is not particularly limited, but specifically, for example, N, N' -Methylenebis(meth)acrylamide, (poly)ethylene glycol di(meth)acrylate, (poly)propylene glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, trimethylolpropane di(meth)acrylate, glycerin tri( (Meth)acrylate, glycerin acrylate methacrylate, ethylene oxide modified trimethylolpropane tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, dipentaerythritol hexa(meth)acrylate, triallyl cyanurate (triallyl cyanurate), triallyl isocyanate Nulate, triallyl phosphate, triallylamine, pentaerythritol tetra(tri,di)allyl ether, poly(meth)allyloxyalkane, divinylbenzene, divinyltoluene, divinylxylene, divinylnaphthalene, divinylether, divinylketone, trivinylbenzene, Examples include tolylene diisocyanate and hexamethylene diisocyanate. These may use only 1 type and may use 2 or more types together. The cross-linking agent is preferably triallyl cyanurate, triallyl isocyanurate, triallyl phosphate, triallylamine, pentaerythritol tetra(tri,di)allyl ether, more preferably triallyl cyanurate, triallyl isocyanurate. .

When the polymer having a structural unit derived from the N-vinyllactam-based monomer has a crosslinked structure, the content ratio of the structural unit derived from the crosslinking agent in the polymer is a structural unit derived from all monomers. It is preferably 0.001 to 10 mol% with respect to 100 mol %. If the content ratio of the structural unit derived from the cross-linking agent is in the above range, the cross-linking density will be more sufficient, the liquid absorption capacity and the gel strength will be more excellent, and the holding power when the gel absorbs the drug will be further improved. The drug can be released over a long period of time. The content of the structural unit derived from the cross-linking agent in the polymer is more preferably 0.005 to 5 mol%, further preferably 0.01 to 5 mol%, and particularly preferably 0.01 to 1 mol%. Yes, and most preferably 0.05 to 0.8 mol %.

The gelling agent for sustained release drugs of the present invention may contain a polymer having a structural unit derived from an N-vinyllactam-based monomer, and another polymer other than the polymer.
The above-mentioned other polymers are not particularly limited, but those having no structural unit derived from the N-vinyllactam-based monomer, for example, those having the structural units derived from the above-mentioned other monomers Can be mentioned.

In the sustained-release gelling agent for drugs of the present invention, the content ratio of the polymer having the structural unit derived from the N-vinyllactam monomer is 50 to 100 mol% based on 100 mol% of the total polymer. Preferably. It is more preferably 60 to 100 mol %, and even more preferably 70 to 100 mol %.

In the sustained-release gelling agent for drugs of the present invention, the content ratio of the other polymer is preferably 0 to 50 mol% based on 100 mol% of the total polymer. It is more preferably 0 to 40 mol %, still more preferably 0 to 30 mol %.

In the sustained-release drug gelling agent of the present invention, the content of the polymer having a structural unit derived from an N-vinyllactam monomer is 100% by mass based on the total amount of the sustained-release drug gelling agent. , 50 to 100% by mass is preferable. It is more preferably 60 to 100% by mass, and even more preferably 70 to 100% by mass.

The pH of the sustained-release gelling agent for drugs is preferably 4 to 10. More preferably, it is 5-9. The pH can be measured by the method described in Examples.

In the sustained-release gelling agent for drugs of the present invention, the amount of the remaining N-vinyllactam-based monomer in the polymer is preferably 100 ppm or less based on 100% by mass of the polymer. The N-vinyllactam-based monomer is mainly contained as a residual monomer when the N-vinyllactam-based monomer is used as a monomer component in the production of a polymer. If the content of the N-vinyllactam-based monomer in the above-mentioned polymer is within the above range, it is excellent in safety, and therefore cosmetics, fragrances/deodorants, insecticides/insecticides and It is suitable for applications such as agricultural chemicals and liquid fertilizer retention agents. It is more preferably 90 ppm or less, still more preferably 80 ppm or less.
The amount of the N-vinyllactam-based monomer can be measured by the method described in Examples.

The gelling agent for sustained release drug of the present invention is not particularly limited as long as it contains a polymer as an essential component, and may contain other components in addition to the above polymer.
Other components are not particularly limited, and examples thereof include organic acids and/or salts thereof. Above all, it is preferable to contain malonic acid and/or its salt.
When the gelling agent for sustained release drug contains malonic acid and/or its salt, the content ratio of malonic acid and/or its salt is 0 with respect to 100% by mass of the gelling agent for sustained release drug. It is preferably 0.01 to 10% by mass.

<Method for producing gelling agent for sustained-release drug>
The method for producing the gelling agent for sustained-release drug according to the present invention is not particularly limited, but the above-mentioned production method preferably includes a step of reacting a monomer component as a raw material. A method for producing such a gelling agent for sustained release drug is also one aspect of the present invention.
The monomer component preferably contains an N-vinyl lactam monomer. Specific examples and preferable examples of the N-vinyllactam-based monomer are the same as the N-vinyllactam-based monomer in the gelling agent for sustained release drug according to the present invention.
When the N-vinyllactam-based monomer is included as the monomer component, the N-vinyllactam-based monomer is preferably 50 to 100 mol% based on 100 mol% of all the monomer components. It is more preferably 60 to 100 mol %, and even more preferably 70 to 100 mol %.

In the method for producing a gelling agent for a sustained-release drug described above, a monomer other than the N-vinyllactam-based monomer may be used. The other monomer is the same as the other monomer in the gelling agent for sustained release drug according to the present invention.
The amount of the other monomer used is not particularly limited, but is preferably 0 to 50 mol% with respect to 100% by mass of all the monomers used in the production of the polymer of the present invention. It is more preferably 0 to 40 mol %, still more preferably 0 to 30 mol %.

A cross-linking agent may be used in the step of reacting the monomer component as a raw material in the method for producing a gelling agent for a sustained-release drug described above. Specific examples and preferable examples of the crosslinking agent are the same as those of the crosslinking agent according to the present invention.
When the crosslinking agent is used, the amount of the crosslinking agent used is not particularly limited, but it is preferably 0.001 to 10 mol% with respect to 100 mol% of all the monomers. If the amount of the cross-linking agent used is in the above range, the cross-linking density of the obtained polymer will be more sufficient, the water absorption capacity and the gel strength will be more excellent, and the holding power when the gel absorbs the drug will be further improved, The drug can be released over a long period of time. The amount of the cross-linking agent used is more preferably 0.005 to 5 mol%, further preferably 0.01 to 5 mol%, particularly preferably 0.01 to 1 mol%, and most preferably 0.1. It is from 05 to 0.8 mol %.

In the above production method, the method of reacting the monomer components as raw materials to obtain a polymer is not particularly limited, and examples thereof include bulk polymerization method, solution polymerization method, emulsion polymerization method, suspension polymerization method, precipitation polymerization method, and the like. Is mentioned. The solution polymerization method is preferred.

When a solvent is used in the above polymerization reaction, water is preferably used as the solvent, but it is selected from other solvents, for example, alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, and diethylene glycol. They may be used alone or in combination of two or more kinds with water. No solvent may be used.
When a solvent is used for the polymerization reaction, the concentration of the monomer component in the solution is preferably 20% by mass or more and 80% by mass or less. When the concentration of the monomer component is less than 20% by mass, it may be difficult to obtain a crosslinked liquid-absorbent resin, and if obtained, it may be difficult to disintegrate the gel after polymerization. Further, it takes a long time to dry, and the resin may deteriorate during the drying.
On the other hand, when the concentration of the monomer component exceeds 80% by mass, it becomes difficult to control the polymerization and the residual monomer tends to increase.

In the polymerization reaction, the reaction conditions such as reaction temperature and pressure are not particularly limited, but for example, the reaction temperature is preferably 20 to 150° C., and the pressure in the reaction system is atmospheric pressure or reduced pressure. preferable.

The means for initiating the polymerization of the above monomer components is not particularly limited, but a method of adding a polymerization initiator, a method of irradiating with UV, a method of applying heat, a method of irradiating with light in the presence of a photoinitiator, etc. Is mentioned.

It is preferable to use a polymerization initiator as the above-mentioned polymerization initiation means. The polymerization initiator is not particularly limited as long as radicals are generated by heating, UV irradiation, etc., but a water-soluble initiator that is uniformly dissolved in water at a concentration of 5% by weight or more at room temperature is preferable. Specifically, for example, hydrogen peroxide, peroxides such as t-butyl hydroperoxide; 2-(carbamoylazo)isobutyronitrile, 2,2′-azobis(2-amidinopropane)dihydrochloride, 2,2'-azobis(2-methyl-N-phenylprorionamidine) dihydrochloride, 2,2'-azobis[2-(N-allylamidino)propane] dihydrochloride, 2,2'-azobis[ 2-(5-hydroxy-3,4,5,6-tetrahydropyrimidin-2-yl)propane] dihydrochloride, 2,2'-azobis[2-(2-imidazolin-2-yl)propane], 2 ,2'-Azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride, 2,2'-azobis[2-(2-imidazolin-2-yl)propane]disulfate hydrate, 4 , 4'-azobis(4-cyanopentanoic acid), 2,2'-azobis[N-(2-carboxyethyl)-2-methylpropionamidine] n-hydrate, 2,2'-azobis[2-methyl- N-(2-hydroxyethyl)propionamide] and the like azo compounds; potassium persulfate, ammonium persulfate, sodium persulfate and other persulfates; ascorbic acid and hydrogen peroxide, sodium sulfoxylate and t-butyl hydroperoxide, Examples thereof include a redox initiator that generates a radical by combining an oxidizing agent and a reducing agent such as persulfate and a metal salt. These may use only 1 type and may use 2 or more types together. As the above-mentioned polymerization initiator, an azo compound is preferable, and among them, 2,2′-azobis(2-amidinopropane)dihydrochloride, 2,2′-azobis[2-(2-imidazolin-2-yl)propane]2 The hydrochloride salt is more preferred.

The amount of the above-mentioned polymerization initiator to be used is not particularly limited, but is 0.002 to 100% by mass of the total monomers (N-vinyllactam-based monomer and other monomers) and the crosslinking agent. 15 mass% is preferable, and 0.01-5 mass% is more preferable. In carrying out the above-mentioned polymerization reaction, a conventionally known basic pH adjusting agent may be used for the purpose of promoting the polymerization reaction or preventing hydrolysis of the N-vinyllactam-based monomer. The pH adjustor can be added by any method, for example, it may be added to the system from the beginning of the polymerization or may be added successively during the polymerization. Specific examples of the pH adjuster include ammonia; aliphatic amines such as monoethanolamine, diethanolamine, and triethanolamine; aromatic amines such as aniline; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Etc. These may use only 1 type and may use 2 or more types together. Among these, ammonia, monoethanolamine, diethanolamine, sodium hydroxide and potassium hydroxide are preferable. When a pH adjuster is used, the amount used is not particularly limited, but it is preferable to use it so that the solution during polymerization has a pH range of 5 to 10, preferably 7 to 9.

When carrying out the above-mentioned polymerization reaction, conventionally known transition metal salts may be used for the purpose of promoting the polymerization reaction and the like. Specific examples of the transition metal salt include carboxylates and chlorides of copper, iron, cobalt, nickel and the like. These may be used alone or in combination of two or more. May be. When a transition metal salt is used, the amount used is not particularly limited, but the weight ratio to the polymerizable monomer component is preferably 0.1 to 20,000 ppb, more preferably 1 to 5,000 ppb. When carrying out the above-mentioned polymerization reaction, in addition to the above-mentioned polymerization initiator and, if necessary, the above-mentioned pH adjusting agent and the above-mentioned transition metal salt, it is also possible to use any chain transfer agent, buffer agent or the like, if necessary. ..

When a cross-linking agent is used in the above-mentioned production method, in the presence of a cross-linking agent, a cross-linked polymer may be obtained by a method of polymerizing a monomer component, and a cross-linking treatment is performed by a method of polymerizing a monomer component. A polymer may be obtained. It is preferable to obtain a crosslinked polymer by a method of polymerizing a monomer component in the presence of a crosslinking agent.
Examples of the method of crosslinking after polymerization include (i) a method of irradiating a polymer with UV, γ rays, and an electron beam, (ii) a method of applying heat to the polymer to self-crosslink, and (iii) a polymer. To contain self-crosslinking after adding a radical generator to the polymer, (iv) heating and/or irradiating light after adding a radical polymerizable crosslinker and a radical polymerization initiator to the polymer Is mentioned.

When carrying out the above-mentioned polymerization reaction, the method of adding the above-mentioned respective charging components is not particularly limited, and it may be carried out by an arbitrary method such as a batch system or a continuous system.

In the case of using the N-vinyllactam-based monomer as a monomer component in the production of the above-mentioned gelling agent for a sustained-release drug, it includes a step of adding an organic acid to the obtained polymer after the polymerization reaction. Is preferred. By adding an organic acid to the obtained polymer, the amount of residual N-vinyllactam-based monomer in the polymer can be reduced.
The organic acid is not particularly limited, and examples thereof include organic compounds having an acid group such as a carboxyl group, a sulfonic acid group, a phosphonic acid group, a sulfuric acid group, and a phosphoric acid group. Examples of such an organic acid include malonic acid, oxalic acid, succinic acid, aspartic acid, citric acid, glutamic acid, fumaric acid, malic acid, maleic acid, phthalic acid, trimellitic acid, pyromellitic acid, propionic acid, Heptanoic acid, octanoic acid, glycolic acid, salicylic acid, lactic acid, L-ascorbic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, laurylbenzenesulfonic acid, p-toluenesulfonic acid, benzenephosphonic acid, laurylsulfate and the like can be mentioned. .

The amount of the organic acid used is not particularly limited, but is preferably 0.01 to 5 mass% with respect to 100 mass% of the N-vinyllactam-based monomer charged in the reaction step. When the amount of the organic acid used is in the above range, the amount of the organic acid (salt) can be reduced while reducing the amount of the residual N-vinyllactam monomer in the obtained polymer. The amount of the organic acid used is more preferably 0.05 to 3% by mass, further preferably 0.1 to 1% by mass.
The organic acid (salt) represents the organic acid and the salt of the organic acid, and the salt of the organic acid is a neutralized product of the base and the organic acid, which is mainly added in the neutralization step described later.

The reaction time between the organic acid and the polymer when the above organic acid is added to the polymer is not particularly limited, but is preferably 10 minutes to 3 hours. When the polymer is a cross-linked polymer, it takes longer for the organic acid to penetrate into the polymer (gel) than for the non-cross-linked polymer, but the reaction time between the organic acid and the polymer is 10 minutes. When the amount is above, the organic acid can sufficiently penetrate into the polymer, and the amount of the residual N-vinyllactam-based monomer in the obtained polymer can be more sufficiently reduced. Further, the reaction time is preferably 3 hours or less from the viewpoint of productivity. The reaction time is more preferably 30 minutes to 2 hours.

The method for producing a gelling agent for a sustained-release drug described above preferably includes a step of aging the polymer after the polymerization reaction. The temperature in the aging step is not particularly limited, but is preferably 70 to 150°C. When the aging temperature is within the above range, the decomposition of the residual N-vinyllactam-based monomer can be promoted. More preferably, it is 80 to 100°C.
The aging time in the aging step is not particularly limited, but is preferably 10 minutes to 5 hours. More preferably, it is 30 minutes to 3 hours.
When the method for producing a gelling agent for a sustained-release drug includes a step of adding an organic acid, the aging step is preferably performed before the step of adding the organic acid.

The aging step is preferably performed while crushing the polymer. When the step of adding the organic acid is included, the organic acid is sufficiently permeated into the polymer by crushing, so that the amount of the remaining N-vinyllactam-based monomer in the obtained polymer is more sufficient. Can be reduced to Crushing of the above-mentioned polymer can be carried out by a commonly used method, and examples thereof include a method of crushing using a kneader or the like.

When the organic acid is added, the method for producing the gelling agent for sustained release drug preferably includes a neutralization step after the addition step of the organic acid. The method of neutralization is not particularly limited, but it is preferable to add a base after reacting the organic acid with the polymer. The base is not particularly limited, and examples thereof include ammonia; aliphatic amines such as monoethanolamine, diethanolamine, and triethanolamine; aromatic amines such as aniline; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. Etc. These may use only 1 type and may use 2 or more types together. Of these, ammonia, aliphatic amines, and alkali metal hydroxides are preferable, and ammonia, monoethanolamine, diethanolamine, sodium hydroxide, and potassium hydroxide are more preferable.

The method for producing a gelling agent for a sustained-release drug described above may include other steps than the above. Other processes include, for example, a drying process, a pulverizing process, a classifying process, a granulating process and the like.

The method for producing a gelling agent for sustained-release drug preferably includes a drying step, and drying refers to an operation of increasing solid content, and normally, solid content may be increased as compared with that before drying. It is preferable to increase the solid content to 95% by mass or more, and more preferably to 96% by mass or more. The upper limit of the solid content is preferably about 99% by mass. Drying may be performed at the same time as the polymerization, or drying at the time of polymerization and drying after the polymerization may be used in combination, but more preferably, a drying step of drying using a drying device after the polymerization is performed. When the manufacturing method includes an organic acid addition step, it is preferably performed after the organic acid addition step. Here, the solid content of the polymer means a value measured by the method described in Examples.

The drying step is preferably performed in the range of 80°C to 250°C for 50% or more of the entire time of the drying step. When the drying temperature and the time are within the above ranges, various physical properties of the polymer tend to be further improved. More preferably, it is carried out at the above temperature through substantially all the drying steps. The drying temperature is specified by the temperature of the heating medium, but when it cannot be specified by the temperature of the heating medium such as microwaves, it is specified by the material temperature. The drying method is not particularly limited as long as the drying temperature is within the above range, and hot air drying, windless drying, reduced pressure drying, infrared drying, microwave drying and the like can be preferably used. Above all, it is more preferable to use hot air drying. When using hot air drying, the amount of dry air is preferably in the range of 0.01 to 10 m/sec, more preferably 0.1 to 5 m/sec. The drying temperature range is more preferably 110°C to 220°C, and further preferably 120°C to 200°C. Further, the drying may be performed at a constant temperature or may be performed by changing the temperature, but it is preferable that substantially all the drying steps are performed within the above temperature range.

The crushing step is preferably performed using a crusher. When the production method of the present invention includes a drying step, the pulverization may be performed before, during or after the drying, but is preferably after the drying. The crusher is not particularly limited, for example, a roll crusher such as a roll mill, a hammer crusher such as a hammer mill, an impact crusher, a cutter mill, a turbo grinder, a ball mill, a flash mill, a jet. A mill or the like is used. Among these, it is more preferable to use a roll mill in order to control the particle size distribution. In order to control the particle size distribution, it is more preferable to continuously grind twice or more, and it is further preferable to grind continuously three or more times. When pulverizing twice or more, the pulverizers may be the same or different. It is also possible to use a combination of different types of crushers.

For example, a classification step or a granulation step may be provided in order to control the crosslinked product of the present invention to have a specific particle size distribution. The classification may use a sieve having a specific opening. The classifier used for classifying with a sieve is not particularly limited, but for example, a vibrating sieve (unbalance weight drive type, resonance type, vibration motor type, electromagnetic type, circular type, etc.), in-plane motion sieve (Horizontal motion type, horizontal circular-linear motion type, three-dimensional circular motion type, etc.), movable mesh type sieve, forced stirring type sieve, mesh surface vibrating type sieve, wind type sieve, sonic sieve, etc. are used, preferably vibrating sieve. In-plane motion screens are used.

<Gel composition containing sustained-release drug>
The present invention is also a sustained-release drug-containing gel composition containing the sustained-release drug gelling agent of the present invention and a sustained-release drug.
The content ratio of the gelling agent for sustained-release drug in the composition is not particularly limited, but is preferably 2 to 99.99% by mass relative to 100% by mass of the sustained-release drug-containing gel composition. , And more preferably 2.2 to 99.99 mass %.

Specific examples and preferable examples of the sustained-release drug contained in the above-described sustained-release drug-containing gel composition are as described above.
The content ratio of the sustained-release drug in the composition is not particularly limited, but is preferably 0.01 to 4900% by mass, and more preferably 100% by mass of the gelling agent for sustained-release drug. It is 0.01 to 4450 mass %.

The above-mentioned sustained-release drug-containing gel composition may contain other components other than the gelling agent for sustained-release drug and the sustained-release drug of the present invention. Other components include, for example, water, ethanol, isopropyl alcohol, phenoxyethanol, polyethylene glycol, and other gelling agents for sustained-release drugs, and compounds having an affinity for sustained-release drugs.
The content ratio of the other components in the composition is not particularly limited, but is preferably 0 to 4899% by mass, and more preferably 0 to 4449% by mass with respect to 100% by mass of the gelling agent for sustained release drug. It is% by mass.

The sustained-release gelling agent for pharmaceuticals of the present invention has the above-mentioned constitution, is excellent in liquid absorption ability, and is also excellent in sustained-release, therefore, cosmetics, aroma/deodorant, insect repellent/insecticide, agricultural chemicals. -It can be suitably used as a liquid fertilizer retention agent and the like.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. In addition, "part" means "part by mass" and "%" means "% by mass" unless otherwise specified.

<Evaluation of liquid absorption capacity>
About 0.1 g of the polymer was accurately weighed (mass W2 (g)), placed in a 4 cm×5 cm non-woven tea bag, and sealed by heat sealing. The tea bag was immersed in linalool at room temperature. After 24 hours, the tea bag was pulled up, placed on a Kim towel (manufactured by Nippon Paper Crecia Co., Ltd.) and drained for 10 seconds, and then the mass (W3 (g)) of the tea bag was measured. Separately, the same operation was performed without using the polymer, and the mass of the tea bag (W1 (g)) at that time was determined as a blank. The liquid absorption capacity calculated according to the following formula was defined as the liquid absorption capacity.
Liquid absorption ratio (g/g)=(W3(g)-W1(g))/W2(g)

<Evaluation of sustained release>
The polymer was immersed in a sustained release drug (linalol, eugenol, propionic acid, etc.) at room temperature. After 24 hours, the sample was placed on a Kim towel (manufactured by Nippon Paper Crecia Co., Ltd.) and drained for 10 seconds. Then, about 2000 mg of the absorbent gel on the Kim towel was accurately weighed into a weighing can and left in a room at 24°C. .. The mass of the weighing can containing the absorbent gel was measured at at least three points during 20 hours to 32 hours after the absorbent gel was left in the room. In the case of propionic acid, the mass of the weighing can containing the absorbent gel was measured at at least 3 points during 2 to 8 hours.
During the above 20 hours to 32 hours (2 to 8 hours in the case of propionic acid), the mass of the absorbent gel (y: dependent variable) and the elapsed time (x: independent) obtained by measuring at least 3 points at different times. The absolute value of the slope of the regression line was obtained from the data of (variable) and used as the sustained release rate (mg/min). The slope of the straight line is a value obtained by dividing the distance in the vertical direction between two points on the straight line by the distance in the horizontal direction, and corresponds to the rate of change of the regression line.
Specifically, the obtained data was used to determine the “gradient of mass change of the absorbent gel with respect to elapsed time” using the Microsoft Excel Slope function, and the absolute value of the value was used as the sustained release rate (mg/min). did.
Table 2 shows the calculation results for the linalool of Examples 1 to 4 and Comparative Example 1 described below.

<Measurement of average particle size>
The method for measuring the average particle diameter when the particles are spherical is shown. When the particles are cubic and rectangular, the length of each side was measured with a ruler or an optical microscope, and the shortest side length was defined as the average particle diameter.
The sieves were combined from the top in order from the largest opening, the crosslinked polymer was put in the uppermost sieve, and shaken for 10 minutes with a micro electromagnetic vibrating sieve (M-2 type manufactured by Tsutsui Rikagaku Kikai Co., Ltd.). After measuring the mass of the mixture remaining on each sieve, the size of the openings of each sieve and the particles that could not pass through the sieve (the particles that remained on the sieve and the particles that remained on the sieve with a larger opening) Mass ratio (residual percentage) R to the whole is plotted on a semilogarithmic graph (horizontal axis: particle diameter (logarithmic scale), vertical axis: residual percentage), and the particle diameter corresponding to R=50% is calculated. The average particle diameter was obtained.

<Determination of N-vinyllactam monomer content>
About 110 g of the polymer (mass W4 (g)) and about 100 g of deionized water (mass W5 (g)) were weighed into a screw tube having a rotor and having a capacity of 110 ml, and the cap was sealed. Then, the mixture was stirred at room temperature using a magnetic stirrer for 16 hours or longer (rotation speed 600 rpm). By the above operation, the residual N-vinyllactam-based monomer of the polymer was extracted. This extract was quantitatively analyzed by liquid chromatography under the following conditions.
Equipment: Shiseido "NANOSPACE SI-2"
Column: Shiseido "CAPCELL PAK C18 UG120", 20°C
Eluent: methanol for LC (Wako Pure Chemical Industries, Ltd.)/ultra pure water=1/24 (mass ratio), sodium 1-heptanesulfonate 0.4 mass% Addition flow rate: 100 μL/min
N-vinyllactam-based monomer content (ppm)=measured value (ppm)×(W4(g)+W5(g))/W4(g)

<Quantification of water content>
In the polymer, it represents the proportion of components that volatilize at 150°C. The relationship with the solid content is as follows.
Water content (mass %)=100-solid content (mass %)
The solid content was measured as follows.
About 1 g of the polymer is weighed into a weighing can (mass W6 (g)) having a bottom diameter of about 5 cm (mass W7 (g)), and allowed to stand in a windless dryer at 150° C. for 1 hour to be dried. .. The weight of the weighed can+polymer after drying (W8 (g)) was measured, and the solid content was determined from the following formula.
Solid content (mass %)=((W8(g)−W6(g))/W7(g))×100

<Measurement of pH>
In a 110 ml-capacity screw tube containing a rotor, 1.0 g of the polymer and 100 g of deionized water were weighed and sealed. Then, the mixture was stirred at room temperature using a magnetic stirrer for 16 hours or longer (rotation speed 600 rpm). The pH of the solution after stirring was measured with a pH meter (HORIBA D-51 electrode: 6367-10D). The pH was measured at 25 to 30° C. while stirring the solution with a magnetic stirrer, and the value 3 minutes after the electrode was attached to the solution was taken as the measured value.

<Example 1>
130.0 parts of N-vinylpyrrolidone (manufactured by Nippon Shokubai Co., Ltd., hereinafter also referred to as VP), 0.52 parts of triallyl cyanurate (hereinafter also referred to as CTA) as a cross-linking agent, and 304.6 parts of deionized water are tabletop types. It was placed in a kneader (PNV-1H type manufactured by Chuo Rika Co., Ltd.). Then, nitrogen substitution was performed at 100 ml/min for 30 minutes. Then, nitrogen was introduced at 30 ml/min and the temperature was raised to 56°C. After stabilizing the liquid temperature at 56° C., 15 mass of 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (hereinafter, also referred to as “VA-044”) as an initiator % Aqueous solution was added to start polymerization. After the polymerization reaction proceeded and a gel was generated, the gel was crushed by rotating the blade of a kneader and aged at 90° C. for 60 minutes to complete the polymerization. Then, 65.0 parts of a 1% by mass aqueous solution of malonic acid was added over 3 minutes, and the mixture was stirred at 90° C. for 60 minutes. Furthermore, 32.5 parts of a 2 mass% aqueous solution of diethanolamine was added over 3 minutes, and the mixture was stirred for 30 minutes. Then, the obtained gel was dried at 120° C. for 2 hours to obtain a dried VP crosslinked polymer. Next, the obtained crosslinked polymer was pulverized with a pulverizer until it passed through a JIS standard sieve having an opening of 500 μm to obtain a particulate VP crosslinked polymer (the crosslinked polymer (1) of the present invention). With respect to the obtained crosslinked polymer (1), the liquid absorption capacity of linalool and various solutions, the average particle size, the N-vinyllactam-based monomer content, the water content, and the pH were measured according to the above-described measurement methods. . Table 1 shows the measured performances.
Furthermore, the cross-linked polymer (1) obtained above was evaluated for sustained release of linalool and various solutions.

<Example 2>
The procedure was carried out as in Example 1 until the obtained gel was dried at 120° C. for 2 hours. The obtained crosslinked polymer was pulverized with a pulverizer until it passed through a JIS standard sieve having an opening of 2.00 mm to obtain a particulate VP crosslinked polymer (crosslinked polymer (2) of the present invention). Next, various physical properties of the obtained crosslinked polymer (2) were measured by the same measurement methods as in Example 1.

<Example 3>
A 50 ml screw bottle was charged with 8.4 parts of VP, 0.03 part of CTA as a crosslinking agent, 0.015 part of VA-044 as an initiator and 12.6 parts of deionized water. Next, while stirring with a magnetic stirrer, nitrogen replacement was performed at 100 ml/min for 30 minutes. Then, the solution in the screw bottle after nitrogen substitution was transferred to a petri dish having a diameter of 10 cm, and was irradiated with a UV irradiation device (Ushio Electric Co., Ltd., lamp power source: HB-25103BY-C, integrated light amount (1 minute): 1310 mJ/cm ² ). Irradiated with UV for 8 minutes. The polymerization reaction proceeds, the obtained crosslinked polymer is cut into about 5 mm×5 mm with scissors, and vacuum dried at 100° C. for 3 hours to give a cubic VP crosslinked polymer (the crosslinked polymer of the present invention ( 3)) was obtained. Next, various physical properties of the obtained crosslinked polymer (3) were measured by the same measurement methods as in Example 1.

<Example 4>
50.0 parts of VP, 6.4 parts of butyl acrylate (manufactured by Nippon Shokubai Co., Ltd., hereinafter also referred to as BA), 0.23 parts of CTA as a cross-linking agent, 56.6 parts of deionized water are 250 ml polypropylene (hereinafter also referred to as “PP”) ) I put it in a container. Then, stirring was started with a magnetic stirrer, and nitrogen substitution was performed at 100 ml/min for 30 minutes. Then, the temperature was raised to 56° C. while continuing stirring. After stabilizing the liquid temperature at 56° C., 1.27 parts of a 10 mass% aqueous solution of VA-044 was added as an initiator to start polymerization. After the polymerization reaction proceeded and a gel was formed, aging was carried out at 90° C. for 30 minutes to complete the polymerization. The obtained gel was crushed with a table kneader (PNV-1H type manufactured by Chuo Rika Co., Ltd.) and dried at 120° C. for 2 hours to obtain a dried VP/BA crosslinked polymer. Next, the obtained crosslinked polymer was pulverized with a pulverizer until it passed through a JIS standard sieve having an opening of 2000 μm to obtain a particulate VP crosslinked polymer (the crosslinked polymer (4) of the present invention). Next, various physical properties of the obtained crosslinked polymer (4) were measured by the same measurement methods as in Example 1.

<Comparative Example 1>
30.0 parts of VP, 1.5 parts of CTA as a crosslinking agent, and 73.5 parts of deionized water were charged into a 250 ml PP container. Then, stirring was started with a magnetic stirrer, and nitrogen substitution was performed at 100 ml/min for 30 minutes. Next, while continuing stirring, nitrogen introduction was set to 30 ml/min, and the temperature was raised to 56°C. After stabilizing the liquid temperature at 56° C., 0.71 part of a 10 mass% aqueous solution of VA-044 was added as an initiator to start polymerization. After the polymerization reaction proceeded and a gel was formed, aging was carried out at 90° C. for 60 minutes to complete the polymerization. The obtained gel was disintegrated with Labo Millser (LM-PLUS type manufactured by Osaka Chemical Co., Ltd.) and washed 5 times with deionized water (about 800 ml). Then, the obtained gel was dried at 120° C. for 2 hours to obtain a dried VP crosslinked polymer. Next, the obtained crosslinked polymer was pulverized with a pulverizer until it passed through a JIS standard sieve having an opening of 500 μm to obtain a particulate VP crosslinked polymer (comparative crosslinked polymer (1) of the present invention). ..
Next, various physical properties of the obtained comparative crosslinked polymer (1) were measured by the same measurement methods as in Example 1.

<Comparative example 2>
50 parts of polyethylene glycol 20000 was placed in a 50 ml glass separable flask and dissolved at 128° C. with stirring. The stirring was consistently performed at 50 rpm. After confirming the dissolution, 2.5 parts of CTA was added as a crosslinking agent, and the mixture was stirred for 5 minutes. Next, 0.12 parts of perbutyl I-75 (manufactured by NOF CORPORATION) was added as an initiator, and stirring was continued at 128°C for 3 hours. The gel obtained was allowed to cool to 80° C. and then crushed with a table kneader (PNV-1H type manufactured by Chuo Rika Co., Ltd.) to obtain a polyethylene oxide crosslinked polymer. Then, the obtained crosslinked polymer was pulverized with a pulverizer to obtain a particulate polyethylene oxide crosslinked polymer (comparative crosslinked polymer (2) of the present invention). Next, various physical properties of the obtained comparative crosslinked polymer (2) were measured by the same measurement methods as in Example 1.

<Comparative example 3>
As the comparative crosslinked polymer (3), the above various performances of Acryhope GH2 (manufactured by Nippon Shokubai Co., Ltd.) were measured as a partially crosslinked sodium salt of an acrylic acid polymer.

Table 1 shows the measurement results of various physical properties of the crosslinked polymers (1) to (4) and the comparative crosslinked polymers (1) to (3).

Claims (3)

A gelling agent for sustained-release drug containing a polymer having a cross-linked structure ,
The polymer has a ratio of the structural unit derived from N- vinyl lactam monomer to the structure units 100 mole% from the total monomer 9 0-100 mol%, structural units derived from a crosslinking agent In a proportion of 0.001 to 1 mol %,
The sustained-release gelling agent for drugs has a linalool absorption capacity of 10 g or more per 1 g of the polymer, and the amount of the remaining N-vinyllactam-based monomer in the polymer is 100% by mass of the polymer. sustained-release pharmaceutical gelling agent characterized by containing 100ppm Ri der below the organic acid and / or salts thereof with respect. The gelling agent for sustained release drug according to claim 1, wherein the sustained release property of the linalool at 24°C is 0.01 to 5 mg/min. A gelling agent for sustained-release drug containing a polymer having a cross-linked structure,
The polymer has a ratio of the structural unit derived from N- vinyl lactam monomer to the structure units 100 mole% from the total monomer 9 0-100 mol%, structural units derived from a crosslinking agent In a proportion of 0.001 to 1 mol %,
The sustained-release pharmaceutical gelling agent, the amount of residual N- vinyl lactam monomer in the polymer state, and are 100ppm or less with respect to the polymer 100 wt%, the organic acid and / or salts thereof A gelling agent for sustained-release drug, which comprises: