JPS5927766B2 - Production method of new water-insoluble water-based copolymer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention can be used as a carrier for pharmaceuticals or other active ingredients, as a hydrophilic membrane in separation processes, as a dressing for wound treatment, or for implants in the body, such as artificial blood vessels, glass, metal, etc. It relates to cross-linked hydrophilic polymers suitable for use as coatings on wood or ceramics, and especially in applications where both strength and high water permeability of the polymeric article are required.

Biologically active and less It is well known to make slightly cross-linked water-insoluble but hydrophilic polymers that can be used as carriers for slightly water-soluble substances.

Monoolefinic monomers are in particular monoesters of acrylic or methacrylic acid with polyfunctional alcohols, such as ethylene glycol monomethacrylate, and cross-linking agents are in particular diesters of these acids and alcohols, such as ethylene glycol. bismethacrylate is used and the copolymerization is carried out in the presence of water (US Pat. No. 3,220
960) or in the absence of water (see US Pat. No. 3,520,949). Low- and high-molecular water-soluble substances such as polyethylene oxide monomethacrylate and small amounts of the corresponding bismethacrylate were used as monomers and cross-linking agents (US Pat. No. 3,220,960). Water-insoluble but hydrophilic copolymers and their method of preparation can be modified in a few ways for special purposes such as the production of soft contact lenses (U.S. Pat. No. 3,200,960 and Reissue No. 27,401). Specifications) and copolymerization in the presence of linear polyamide resins to improve or change the mechanical properties of molded articles made from the resulting polymers (US Pat. No. 3,520).
No. 949 specification). However, in all the variants, low molecular weight polyolefin crosslinkers, especially ethylene glycol bismethacrylate, were used in very small to moderate amounts, not exceeding 20% of the amount of monoolefin monomers. Copolymers of the type mentioned above use these 2
Although it could be modified to meet the requirements of ~3 different modalities, its mechanical properties in non-swollen, i.e., water-free or swollen, i.e., equilibrium with water, were sufficient to suit all forms of use. I couldn't do it. A hydrophilic polymer whose main component is a monoester of acrylic acid or methacrylic acid and a difunctional alcohol is 55 to 8
It is well known that it has a glass transition point or softening point of 0°C. For this reason, this conventional product is brittle and glassy in the dry state below 55°C. After equilibration in water, this conventional article becomes soft and somewhat pliable, but still weak in terms of its flexibility. Additionally, this prior art product is very susceptible to tearing and shear forces if it is struck or damaged in any way. Media made of stronger polymeric materials are used as physical supports to avoid the undesirable drawbacks of articles made with prior art techniques.

That is, filling the prepolymer mixture with an inert material such as silica gel. These techniques require a certain amount of cohesion (
(a hydrogel material that acts as a glue) but results in an article that is still susceptible to glassy fractures in the dry state and shear fractures in the swollen state within the interstitial region of the article. Additionally, the addition of fillers to the prepolymer changes the diffusivity and water permeability of this article. The object of the invention is to use hydrophilic membranes in separation processes or wound dressings or body implants, such as artificial blood vessels, or coatings on glass, metal, wood or ceramics, or biologically active substances such as pharmaceuticals, herbicides, etc. , both in a substantially water-free state as well as in a swollen state, i.e. in equilibrium with water or an aqueous fluid, such as an animal body fluid, suitable for use as a carrier for insecticides, fungicides, bactericides or fragrances. Another object of the present invention is to provide a cross-linked hydrophilic copolymer with high flexibility and high elasticity.

Another object of the invention is to have high tensile strength in the swollen state.
The object of the present invention is to provide a suitable cross-linked hydrophilic copolymer as described above. Yet another object of the present invention is to provide a cross-linked hydrophilic copolymer containing an effective amount of a biologically active substance, particularly a therapeutically active substance, having the improved properties mentioned above and which can be altered. It is.

As a result of research, the present inventor has determined that the present invention consists essentially of a hydrophilic polymer of monoolefinic monomers cross-linked with a large amount of diolefinic non-hydrophilic macromer, and contains no biologically active substance. It has now been discovered that optionally water-insoluble hydrophilic copolymers have the properties described above and additional desirable properties.

In these parent copolymers, the proportion of terminal diolefin-based non-hydrophilic macromer is higher than the proportion of cross-linking agent in known hydrophilic copolymers and is from about 10% to about 70% of the hydrophilic polymer, or preferably The main proportion of this system is about 5% to about 50%. This terminal diolefin-based non-hydrophilic macromer has a molecular weight of about 400 to about 8,000, or preferably about 600 to 5,000. The above-mentioned novel water-insoluble hydrophilic copolymer gel is produced by the method of the present invention characterized by the following features.

That is, from about 30% to about 90% by weight (based on the weight of the resulting hydrophilic gel) of (a) a hydrophilic polymer of at least one water-soluble monoolefin monomer; Seed water-soluble monoolefin monomer and 1 to 70% by weight
A hydrophilic copolymer with at least one water-insoluble monoolefin monomer (based on total monomer weight) of (B
It is copolymerized with a terminal diolefin hydrophobic macromer having a molecular weight of about 400 to about 800 and having a molecular weight of about 10 to about 70% (based on the weight of the resulting hydrophilic gel) and represented by Formula B or B2 below. Note that a biologically active substance can be added prior to or after the copolymerization. The present invention further describes insoluble polymeric hydrogels (hereinafter referred to as -F) suitable for use as carriers for pharmaceuticals delivered to an organism orally, bucally or in the form of subcutaneous or muscle implants. It is sometimes abbreviated as hydrogel.

). The hydrogels of the present invention can also be made into implants into the body, such as artificial blood vessels or devices inserted into the urethra, vagina, or anus, or in the form of bandages for controlled delivery of pharmaceuticals through the skin. can. Other applications using this new water-swellable gel include membranes for reverse osmosis and semi-permeable membranes, or hydrophilic membranes for separation processes;
They are also bandages for wound treatment, or coatings made of glass, metal, wood, or ceramics, and in short, these are applications that require both hydrophilicity and strength at the same time. The novel hydrogel of the present invention consists of a water-soluble monomer (As) capable of forming a water-soluble or water-swellable polymer, that is, a hydrophilic polymer (Ap), and a diolefin-based non-hydrophilic macromer (B) such as a vinyl polymer that can be polymerized. It is synthesized by free radical copolymerization, either in solution or in bulk, with divinyl compounds having long linear polycondensate chains, such as polytetramethylene ethers terminated at both ends.

In this way, a three-dimensional polymeric network is formed consisting of two types of segments, each segment giving the system its unique physical properties. The A segment provides water solubility and the hydrophobic B segment forms flexible cross-links. A wide range of mechanical properties and diffusivity can be obtained by varying the relative proportions of each compound.
For example, a polymer having excellent strength, elongation and tenacity and capable of absorbing water approximately equal to its own weight can be obtained by using appropriate relative proportions of A and B. This & cross bonds are short and inelastic, unlike ordinary hydrogels which are stiff and brittle in the dry state. The novelty of the polymers of the present invention is the inclusion of a difunctional polymer (B) as the main part of the system.

In this way, the bifunctional macromer not only serves as a structural cross-linker but also imparts its unique physical properties to the gel. One or two hydrophilic polymers (Ap)
Polymers of the water-soluble monoolefin monomers (As) of No. 3 are preferred, but also monoolefin water-soluble monomers and at most 70%, preferably at most 50% of the total amount of monomers are insoluble in water. It may also be a copolymer with a monoolefin monomer (Ai).

The water-soluble monomer is preferably acrylic acid and/or methacrylic acid (2-methylacrylic acid) or its like.
Water-soluble derivatives such as their hydroxyalkyl esters (
2-hydroxyethyl ester, 3-hydroxypropyl ester, 2-hydroxypropyl ester or 2,3-dihydroxypropyl ester), or also ethoxylated or polyethoxylated hydroxyalkyl esters, such as formula HO-CmH2m-O
-(CHrCH2-O)n -R (wherein R is a hydrogen atom or a methyl group, m is 2 to 5, and n is 1 to 20
), or esters of similar alcohols in which part of the ethylene oxide units are replaced with propylene oxide units.

Other suitable esters are dialkylaminoalkyl acrylates and -methacrylates such as 2-(dimethylamino)monoethyl ester, 2-(diethylamino)monoethyl ester or 3-(dimethylamino)-2
-Hydroxypropyl ester. Another class of suitable derivatives of such acids are water-soluble amides such as unsubstituted amides or amides substituted by lower hydroxyalkyl, lower oxaalkyl or lower dialkylaminoalkyl groups, e.g. hydroxymethyl)
-acrylamide or -methacrylamide, N-(3
-hydroxypropyl)-acrylamide, N-(2
-hydroxyethyl)-methacrylamide, N-(1
・1-dimethyl-3-oxabutyl)-acrylamide or N-[1,1-dimethyl-2-(hydroxymethyl)-3-oxabutyl]-acrylamide, or a water-soluble hydrazine derivative such as trimethylamine-methacrylimide or dimethyl-(2-hydroxypropyl) ) trialkylamine methacrylimides, such as amine methacrylimide, and corresponding derivatives of acrylic acid, or monoolefinic sulfonic acids and their salts, such as sodium ethylene sulfonate, sodium styrene sulfonate or 2-acrylamido-2-methylpropanesulfonic acid, Or N-[2-
dimethylamino)monoethyl]-acrylamide or -methacrylamide, N-[3-(dimethylamino)-2
-Hydroxypropyl]-methacrylamide, or monoolefinic derivatives of heterocyclic nitrogen-containing monomers such as N-vinylpyrrole, N-vinylsuccinimide, 1-vinyl-2-pyrrolidone, 1-vinylimidazole, 1- Vinyl indole, 2-vinylimidazole, 4(5)-vinylimidazole, 2-vinyl-1-methyl-imidazole, 5-vinyl-pyrazoline, 3-methyl-5-isopropenyl-pyrazole, 5
-methylene-hydantoin, 3-vinyl-2-oxazolidone, 3-methacrylyl-2-oxazolidone, 3-
Methacrylyl-5-methyl-2-oxazolidone, 3
-vinyl-5-methyl-2-oxazolidone, 2- or 4-vinyl-pyridine, 5-vinyl-2-methyl-pyridine, 2-vinyl-pyridine-1-oxide, 3-
Isopropenyl-pyridine, 2- or 4-vinyl-piperidine, 2- or 4-vinyl-quinoline, 2,4-
Dimethyl-6-vinyl-s-triazine, 4-acrylyl-morpholine. These monomers can be used alone or in combination with each other and other suitable vinyl monomers, which may also be hydrophobic.
The amount of such hydrophobic monomers should not exceed 60% of the total composition. And it is preferably 40% or less. Suitable hydrophobic monomers include alkyl acrylates or alkyl methacrylates in which the alkyl has from 1 to 18 carbon atoms, such as methyl- or ethyl-methacrylates or acrylates, or derived from alkanecarboxylic acids having from 1 to 5 carbon atoms. Water-insoluble olefinic systems such as vinyl esters such as vinyl acetate, acrylonitrile, styrene or vinyl alkyl ethers in which the alkyl part of the ether chain has 1 to 5 carbon atoms, such as (methyl, ethyl, propyl, butyl or amino)-vinyl ethers. It is a monomer. Water-soluble monomers that require comonomers for polymerization are maleates, fumarates or vinyl ethers; for example, the following monomer combinations are useful: Di(hydroxyalkyl) maleates, such as di(2-hydroxyethyl) maleate, ethoxylated hydroxyalkyl maleates, or 2-
hydroxyalkyl monomaleates, such as hydroxyethyl monomaleate, as well as hydroxylated hydroxyalkyl monomaleates and vinyl ethers,
vinyl esters, styrene, or maleates in combination with any monomer that commonly copolymerizes readily with maleate or fumarate, or with hydroxyalkyl vinyl ethers, such as, for example, 2-hydroxyethyl vinyl ether, 4-hydroxybutyl vinyl ether, Fumarate or generally in combination with all monomers that readily copolymerize with vinyl ethers. Of particular value as water-soluble monomers are hydroxyalkyl-acrylates or -methacrylates such as 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 2-
Hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 2-3-dihydroxypropyl methacrylate, or N-vinylpyrrolidone, acrylic acid, methacrylic acid or U.S. Pat. No. 3,627,802
tertiary amino-methacrylimides, such as trimethylamino-methacrylimide described in No.

The most preferred monomers are 2-hydroxyethyl methacrylate and N-vinylpyrrolidone.

In the diolefinic non-hydrophilic macromer (B), the olefin moiety is preferably provided by an acyl group of an α/β-monounsaturated lower aliphatic monocarboxylic acid or dicarboxylic acid, or a vinyloxy group. These groups are linked by polymeric non-hydrophilic chains containing repeating ester, amide or urethane but especially ether linkages. The molecular weight of this chain is from about 400 to about 8000, preferably from about 600 to 5000 and especially from about 1500 to
It may vary between 3000. Therefore, component (B) is preferably of the formula or [wherein R1 is a polycondensate chain with a molecular weight of about 200 to about 8000 containing hydrocarbon groups linked via an ether, ester, amide, urethane or urea bond, and R2 is a hydrogen atom, a methyl group or a CH2-COOR4 group (where R3 is a hydrogen atom or an alkyl group having up to 10 carbon atoms), R3 is a hydrogen atom or a COOR4 group, with the proviso that R2 at least one of and R3 is a hydrogen atom, and ) and
Y is a direct bond or -R6-Z1-CO-NH-R7-
NH-CO-Z2- group (where R.

is a branched or linear alkylene group with up to 7 carbon atoms connected to ), but when X is an oxo group, Y is different from a direct bond, and R2
and R3 are hydrogen atoms].

In the compounds of formula (B,) or (B2), R1 is in particular a polypropylene oxide chain or a poly-tetramethylene oxide chain, but also a dicarboxylic acid, a diol, a diamine or a diisocyanate by the well-known methods of polycondensation. It can also represent a chain derived from, etc.

The terminal groups of the compound of formula (B1) are as defined by R2 and R3. and when X represents a -COO- group or a -CONR group, an acyl group of acrylic acid or methacrylic acid, or an acyl group of maleic acid, fumaric acid or itaconic acid, or an acyl group of these acids and 1 to 10 carbon atoms. the acyl group of a monoalkyl ester with a straight-chain or branched alkanol such as methanol, ethanol, butanol, diisobutyl alcohol or decanol, or (in the case where X represents oxygen, the vinyloxy group of a vinyl ether). Y is a direct bond (B
The compound of formula 1) is a diester of a polymeric diol and an α/β monounsaturated acid, in which two hydroxyl groups are bonded to the polycondensate chain R, at opposite terminal positions or at most terminal positions. Such diesters may be 3 chlorides of acrylic or methacrylic acid, or chlorides of monoalkyl esters of maleic, fumaric or itaconic acid, or reactive acids of appropriate acids, such as maleic or itaconic anhydrides. Functional derivatives can be prepared from the polymeric 5-diols described above by well-known acylation methods. The compound of formula (B1) having an amide group X is a diamide obtained from a polymeric diamine by the well-known acylation reaction using the aforementioned acid chloride or acid anhydride. The diamine of polymer 4 is prepared, for example, by reacting the corresponding polymeric diol with twice the molar amount of an alkylene imine, such as propylene imine.
When using maleic anhydride as an acylating agent for a polymeric diamine, the polymeric bis-maleamic acid obtained in the above reaction can be further heated or reacted with a dehydrating agent to form a polymeric bismaleimide compound of formula (B2). can.

In these compounds, R may be, for example, one of the polymeric polycondensate chains listed as a part of the compound of formula (B1). According to the chain of formula (B1), Y is further a divalent group -
It may be R6-Z1-CO-NH-R7-NH-CO-Z, - group. Here, R6 is, for example, a methylene group, a propylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a neopentylene group (2,2-dimethyltrimethylene group), a 2-hydroxytrimethylene group, l.
1-dimethyl-2-(1-oxoethyl)-trimethylene or 1-(dimethylaminomethyl)-ethylene, especially ethylene. The divalent group R7 is derived from an organic diisocyanate and is an alkylene group such as an ethylene group, a tetramethylene group, a hexamethylene group, a 2, 2, 4
- an aliphatic group such as a trimethylhexamethylene group, a 2,4,4-trimethylhexamethylene group, or a fumaroyldiethylene group or a 1-carboxypentamethylene group,
Or for example 1.4. Cyclohexylene group or 2-
Cycloaliphatic groups such as methyl-1.4-cyclohexylene group, or e.g. n-phenylene group, p-phenylene group, 2-methyl-m-phenylene group, 1.2-,1
・3-, 1 ・5-, 1・6-, 1 ・7-, 1・8
-, 2, 3- or 2, 7-naphthylene group, 4-chloro-1 ・2- or 4-chlor-2 ・8-naphthylene group, 1-methyl-2 ・4-, 1-methyl-2 ・
7-,4-methyl-1 ・2-,6-methyl-1,3
- or 7-methyl-1,3-naphthylene group, 1.
8-dinitro 2 ・7-naphthylene group, 4 ・4'
-biphenylene group, 3 ・3'-dichloro4 ・4'
-biphenylene group, 3 ・3'-dimethoxy 4 ・4
'-biphenylylene group, 2,2'-dimethyl- or 3,3'-dimethyl-4,4'-biphenylylene group,
2 ・2'-dichlororu5 ・5'-dimethoxy4.
It is an aromatic group such as a 4'-biphenylene group, a methylene di-p-phenylene group, a methylenebis(3-chlorophenylene) group, an ethylene di-p-phenylene group or an oxydi-p-phenylene group.

In the (B,) structure, when Y is not a direct bond, R6 is always bonded to X. Therefore, Y is the above divalent group (
The compounds of formula B,) are bis-vinyl ethers when X is an oxygen atom, or bis-acrylates, bis-methacrylates, bis-maleates, bis-vinyl ethers when X is a -COO- group or a CONR5 group. It is fumarate or bis-itaconate.

A more preferred divinyl macromer (B) is end-capped with 2,4-toluene diisocyanate and about 2
molecular weight from about 1000 to about 40 when reacted with moles of 2-hydroxyalkyl-acrylate or -methacrylate.
00 polytetramethylene oxide glycol. Of particular value are polytetramethylene oxide glycols of molecular weight from about 1500 to about 3000 end-capped with 2,4-toluene diisocyanate and reacted with about 2 moles of 2-hydroxyethyl methacrylate. The novel hydrophilic copolymers of the present invention contain water-soluble monoolefinic monomers (As) or at least 30% water-soluble monomers (As) and at most 70% water-insoluble monoolefinic monomers (As). (Ai) with 10-70% of the total weight of the hydrogel, either in solution or in bulk, with macromers of formula (B, ) or (B2). It will be done.

This polymerization is suitably carried out using initiators that generate free radicals at temperatures ranging from about 40°C to about 150°C, with preferred temperatures ranging from about 50°C to about 100°C. If a therapeutic or otherwise bioactive substance is present during the polymerization, its thermal stability may be a limiting factor in the polymerization temperature; one preferred method of making this hydrogel article is to dissolving a desired concentration of the drug in a macromer-monomer solution at a macromer-monomer ratio selected to produce the desired mechanical and water absorption properties for the hydrogel;
About 0.02% to about 1% by weight of a suitable free radical initiator is mixed and the mixture is heated as a pseudo-solid solution in a closed mold at about 80° C. to form a flat sheet of drug-containing hydrogel. It consists of polymerizing for 2 hours.

The sheet is then subjected to high vacuum at about 100° C. for about 12 hours to remove residual monomer and initiator decomposition products. A preferred laboratory method for making hydrogels in the form of cylinders consists of filling a flexible polyethylene tube with the preferred composition of macromer, monomer, drug, and catalyst and allowing the mixture to react at 80° C. for approximately 2 hours.

The finished article is removed by cutting the tube lengthwise and peeling the tube from the hydrogel article. Yet another preferred method of preparing hydrogels in the form of globules or beads comprises incorporating the preferred composition of macromer, monomer, drug, and catalyst in a viscous medium that is not a solvent for any part of the hydrogel composition. It consists of high speed stirring at about 90°C.

Examples of suitable bead polymerization media are silicones, polyfluorinated oils, etc., such as mineral spirits or saturated aqueous salt solutions. Additionally, other preferred methods of making hydrogels in the form of foam-like objects include mixing a common swelling agent, such as sodium bicarbonate, into the preferred composition and placing this mixture in a mold at about 80°C. It consists of polymerizing for 1 hour.

The resulting closed cell foam is particularly suitable for fast water absorption and drug release. In formula (B,), Y is -R6-Z1-C
Compounds that are ONH-R7-NH-CO-Z2- groups are first prepared by combining two hydroxyl or amino groups bonded at opposite or most terminal positions to a polymeric diol or diamine, i.e., a polycondensate chain Rl. , with at least twice the amount of an aliphatic, cycloaliphatic or aromatic diisocyanate consisting of two isocyanate groups attached to the R7 group, and then the resulting polymeric diisocyanate has the formula HC-C-X- R6-ZIH(C) (wherein R2, R3, X.R6 and Z1 are the above (B1
) can be obtained in a two-step reaction by reacting with a compound represented by ).

When X represents an oxygen atom, (C) is a vinyl ether containing active hydrogen, such as a hydroxy-alkyl vinyl ether or aminoalkyl vinyl R5, and (C) is an acrylate or methacrylate containing active hydrogen in the alkyl group. , 7 leate, fumarate, itaconate or the corresponding amide.

Polymeric diols or diamines are preferably used in small excess. That is, the ratio of isocyanate groups to hydroxyl or amino groups during the first step of macromer synthesis must be at least 1:1, but preferably at least 1:1.05 or less. If the compound of formula (C) ρ used during the second step of the macromer synthesis is the same as that used as the hydrophilic monomer (As), a large excess of this compound can be used so that the resulting monomer A solution of macromer (B,) dissolved or dispersed in body (A) can be used directly for the preparation of the final hydrophilic copolymer. The synthesis of 7chromer (B) is suitably carried out at temperatures ranging from about room temperature to about 80°C.

Preferably the working temperature is not above 40°C, but about 30-40°C.
The most suitable range is ℃. Conversion of isocyanate groups is followed by infrared spectroscopy or titration. Another method of making macromers is to react hydroxyl-terminated prepolymers such as polybutylene- or polypropylene-oxide with acryloylchloride, methacryloyl chloride or maleic anhydride, e.g. ) is formed by forming a macromer without connecting urethane bonds.

Free radical copolymerization is initiated by an initiator capable of producing free peroxy or alkyl groups at concentrations high enough to initiate polymerization of the vinyl monomers used at the synthesis temperature.

Examples of suitable initiators are diisopropyl peroxydicarbonate, tertiary butyl peroctoate, benzoyl peroxide, decanoyl peroxide, lauroyl peroxide, succinic peroxide, methyl ethyl ketone peroxide, tert.
Butyl peroxyacetate or azoisobutyronitrile. When the polymerization is carried out in water, water-soluble peroxy compounds such as sodium persulfate, potassium persulfate,
Ammonium persulfate as well as free radical generating redox systems such as persulfate-bisulfite combinations can be used. Suitably, the initiator is used in an amount of approximately 0.02-1% by weight of the reaction mixture. Other free radical generation mechanisms e.g. γ
Radiation, electron beam, or ultraviolet radiation can also be used. When carried out in a release mold, it is preferable to carry out the reaction in an inert or anaerobic atmosphere (.

Oxygen inhibits polymerization and allows extended polymerization time to complete the reaction. When closed molds are used to make hydrogel articles, these molds are comprised of inert materials with low oxygen permeability and non-stick properties. An example of a suitable molding material is Teflon 8.
, silicone rubber, polyethylene or mylar? It is. Glass or metal molds may be used if a suitable mold release agent is used. Incorporating the drug into the hydrogel article can be accomplished by dissolving or dispersing the drug in the macromer solution, monomer solution, or mixture thereof before adding the free radical catalyst, or by diffusing the drug into the finished article after polymerization. This can be achieved with either of the following. If the drug is inert to free radical attack, it is preferred to dissolve or disperse the drug in the macromer solution, monomer solution, or mixtures thereof prior to polymerization. If the drug is susceptible to free radical attack, the drug is incorporated into the finished article by diffusion from the solvent after polymerization. Hydrogel systems consisting essentially of hydrophobic macromer segments (B) and hydrophilic segments (Ap) may vary widely in composition, thus varying degrees of hydrophilicity and mechanical strength as semipermeable membranes for reverse osmosis. It can be tailored to suit a wide range of applications, such as as a body implant or bandage, as a delivery system for pharmaceuticals, pesticides, herbicides, etc.

Hydrogels with skin-like consistency in the dry state and high elongation in the wet state can be synthesized with a range of water absorption ranging from low to high depending on the relative proportions of the components described above.

Hydrophilic membranes that combine relatively high wet strength and equilibrium, 5-50% water content, are particularly useful in applications such as body implants, bandages, or semipermeable membranes.

For example, subcutaneous or intramuscular implants for controlled release or dosing are capable of absorbing a moderate range of water (15-25% by weight), yet withstand insertion and extraction operations alike in dry and swollen states. Must be strong enough. In addition to their suitability as pharmaceutical carriers, the hydrogels of the present invention are suitable for use as carriers for preservatives, fragrances, colorants, nutrients, insecticides, herbicides, etc.

In particular, the hydrogels of the present invention can be swollen in a suitable solvent containing the drug to be delivered, and when the solvent evaporates, the drug remains within the hydrogel particles. Upon contact with an aqueous environment, the drug is released in a controlled manner. The hydrogels of the present invention are particularly suitable for use in intramuscular and subcutaneous implantation in warm-blooded animals because of their wide range of water absorption properties, strength, and elasticity.

For the same reason, the hydrogel materials of the present invention can be used with other relatively weak hydrogel materials to create vascular substitutes or extracorporeal channels without the necessary support matrix. The hydrogel materials of the invention are also suitable for use as hydrophilic and thrombogenic coatings.

This is because they adhere strongly to glass, metals and plastics. Due to the high strength and elasticity of these hydrogel materials, they are strong with high abrasion resistance and are useful for coating port hulls to disturb barnacle growth or coating lenses and glass to prevent fogging in high humidity environments. Make a covering. Another unique attribute of the hydrogels of the present invention is their flexibility in the dry state, which allows them to assume the desired shape for the application.

Another advantage of the hydrogel of the present invention is that it achieves a swollen state as long as it does not become brittle and retains its strength and elasticity even when in optical equilibrium in an aqueous environment. These properties are particularly useful in pressure membrane applications, such as reverse osmosis devices, for which the hydrogels of the present invention are suitable. The drug-loaded hydrogels of the present invention are also particularly suitable for use in the treatment of extrusion wounds and burns due to their flexible configurability as well as their ability to deliver the drug directly to the affected area.

A particular advantage of hydrogels in this application is their flexibility in the dry state. There is no need to pre-swell the hydrogel prior to application in order to make it soft and pliable enough to wrap around large injury sites, thus allowing the drug-loaded hydrogel to be stored in a dry rather than swollen state; This increases the shelf life of the contained drug. Any of the drugs used to treat the body locally and systemically can be incorporated as active agents into the copolymeric carriers of the present invention.

Drug is used herein in its broadest sense to include any composition that produces a pharmaceutical or biological response. Suitable drugs for use in treatment according to the present invention are described without limitation in U.S. Pat. Includes the medicines listed in the specification (columns 10 and 11).

Other medicaments with the same or different biological activities listed above can be used in the carrier within the scope of the present invention.

Suitable mixtures of medicaments can of course be applied with the same ease as single component systems. Pharmaceuticals are molecules with no charge, components of molecular complexes or non-irritating formulations with acceptable salts such as hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, It may also be in various forms such as tartrate, salicylic acid, etc.

As acidic medicaments metal salts, amines or organic cations (eg quaternary ammonium) can be used. The body's PH, which has more desirable retention and release properties,
Simple derivatives of drugs (eg, ethers, esters, amides, etc.) that are easily hydrolyzed by enzymes and the like can be used. The amount of drug mixed into the carrier depends on the specific drug,
It varies widely depending on the desired therapeutic effect as well as the time required for the drug to be released.

There is no strict upper limit to the amount of drug that can be incorporated into the carrier since a variety of carriers of a variety of sizes and shapes will provide a complete dosage regimen for treating a variety of diseases. The lower limit also depends on the activity of the drug and the time of release of the drug from the carrier. Therefore, it is impractical to limit the range of therapeutically effective amounts released by a carrier. Preferred medicaments to be mixed according to the invention are those designed for long-term treatment so that multiple daily dosages are avoided, e.g. anabolic agents such as methandrostenolone, or analgesics such as acetylsalicylic acid, phenylbutazone or methasone. or androgens such as methyltestosterone, or antibiotics such as funpin, or anti-depressants such as imipramine or maprotiline, or anti-diabetic agents such as fenformin, or antispasmodics such as carbamazepine, or tripelenamine. antihistamines, such as, or antihypertensive drugs, such as hydralazine,
Or an anti-infective drug like trimethoprim, or an anthelmintic like nihuatimotux, or an antiparkosone syndrome drug like levodopa, or an appetite suppressant like mazindol, or a bronchodilator like fenoterol, or a bronchodilator like fuenalcomine. coronary artery dilators, or corticoids such as dexamethasone,
or cellular embolic agents such as floxuridine, or diuretics such as hydrochlorothiazide, or hypnotics such as glutesimide, or neuroleptics such as resarpine or thioridazine, or psychostimulants such as methylphenidate, or These include tranquilizers such as diazepam, or uricosuric agents such as sulfinpyrazone, or vasodilators such as isoprotenol.

In addition to pharmaceuticals, the copolymer of the present invention may be used as a fragrance or food flavoring agent such as orange oil, citral, coffee, tea, lemon oil, synthetic lemon-lime flavor, strawberry flavor, vanilla, biacetyl, anise, lilac flavor, pine flavor, peppermint oil. , oily essence, anethole, ethyl propionate, ethyl acetate, acetaldehyde, menthol,
Dutch cabbage, as well as bactericides, fungicides, insecticides,
Pesticides, including nematicides, and also herbicides can be mixed. Other examples of such biologically active ingredients are listed in US Pat. No. 3,660,563 (columns 3-7).

Novel Hydrogels Due to the excellent physical properties in the dry and wet states of hydrogels, especially those containing polyurethane as a macromer component, this new hydrogel constitutes a mixture of classical hydrogels and polyurethane, and is useful for biomedical applications with non-thrombogenic properties. It is particularly useful as a commercial plastic.

Therefore, it is considered to be an excellent candidate for prosthetics of synthetic skin and its structure or as a covering material in the treatment of burns. They can also be used as suture materials. These hydrogel compositions may vary from 30 to 90% monomer (A), 10 to 70% macromer (B), and correspond to typical degrees of swelling of about 10 to 250%.

A preferred composition contains about 15-50% of McMurrow (B) and about 50-80% of monomer (A), and has a degree of swelling of 15%.
~120%. After the synthesis of the experimental partial gel is completed, a portion of it, 3V, is cut and kept in a bottle with about 50 cc of water at room temperature.

After 96 hours, the swollen sample is removed, excess surface water is removed with tissue paper, and the weight is measured again to determine the degree of swelling (DS).

Six drawbars are cut to fit from the remainder of this hydrogel sheet and swollen in water to the equilibrium water content of the three. The tensile strength and elongation of dry and wet samples are determined on an Instron tester using a ■-shaped test bar according to ASTM test method (D-638).

The release rate of the drug mixed in the hydrogel is determined by continuously measuring the characteristic ultraviolet absorption of stirred water containing a hydrogel disk 16 mm in diameter and 0.8-1.0 mwL thick.

Weight of wet sample - Weight of dry sample DS = x 100 Weight of dry sample In the following example, what is "isocyanate-terminated poly-tetramethylene oxide"? 2 - Polytetramethylene oxide chain-terminated at both ends with 4-toluene diisocyanate It refers to

These compounds are easily synthesized and are commercially available from DuPont, Wilmington, Del., under the trade name aziprene. The first seven examples demonstrate the effect of varying the amount of macromeric hydrophobic binder on the physical properties of polyhydroxyethyl methacrylate gels.

A: 2-Hydroxyethyl methacrylate (HEMA) B: Isocyanate-terminated polytetramethylene oxide + HEMA Example 1 Isocyanate-terminated polytetramethylene oxide (adiprene 167) 20y with a molecular weight of 1500 is 2-
Dissolve in hydroxyethyl methacrylate 18y and react at room temperature for 72 hours.

After 72 hours, the infrared spectrum confirms the disappearance of all isocyanate by noting the absence of the characteristic infrared band for isocyanate at 2270 (V7l-1).

This mixture was then mixed with 0.0% diisopropyl percarbonate.
08y, poured into a mold in the form of a flat sheet with a thickness of 1 mm, and placed in a circulating dryer at 60° C. for 2 hours. The resulting hard transparent sheet is immersed in water for 2 days and vacuum dried at 80°C. Equilibrium moisture and dry and wet tensile strength and elongation are measured. Example 2 The procedure of Example 1 is repeated except that 2.0V of isocyanate-terminated polytetramethylene oxide (adiprene L-42) of molecular weight 3000 is used.

A tenacious transparent sheet is obtained, which is soaked in water for 2 days, dried under vacuum at 80° C. and tested as described in Example 1. Example 3 The process of Example 1 is repeated using 5.0V of aziprene 167 (molecular weight 1500) and 15.0y of 2-hydroxyethyl methacrylate.

The product is a tenacious transparent sheet which is processed as described in Example 1. Example 4 Composition: Adiprene 167 (molecular weight 1500) 10.0V
The procedure of Example 1 is repeated except that 2=hydroxyethyl methacrylate and 10.0 V are used.

A tenacious transparent sheet is obtained, which is processed as in Example 1. Example 5 Composition is Adiprene L-42 (molecular weight 3000) 5.0V
The procedure of Example 2 is repeated except that 2-hydroxyethyl methacrylate and 15.0 V are used.

A tenacious transparent sheet is obtained, which is processed and tested as in Example 1. Example 6 Adiprene L-42 (molecular weight 3000) 10.0v and 2
- Repeat the method of Example 2 using a composition of 1.00 y of -hydroxyethyl methacrylate.

A tenacious transparent sheet is obtained, which is coated as in Example 1 with 0
Process and test. Example 7 As a control, a normal poly(2-hydroxy5 diethyl) methacrylate gel is prepared by using 1.2% ethylene glycol dimethacrylate as the cross-binder and otherwise using the same process as the gel described above.

A hard, brittle, transparent sheet is obtained, which is processed and tested as described above. Table 1 shows the decrease in degree of swelling with increasing amount of hydrophobic macromer B. The dry tensile strength is 0.0 times higher than the ordinary polyHEMA of Example 7. Wet tensile strength and dry and wet elongation increase substantially with increasing amounts of B. The following examples demonstrate the utility of N-vinylpyrrolidone as the hydrophilic monomer (A) as well as the use of hydrophobic comonomers to adjust equilibrium moisture.

Examples 8-12 Isocyanate-terminated polytetramethylene oxide 30y with a molecular weight of 3000 (adiprene L-42) was
-Dissolved in vinylpyrrolidone 40V and 2-hydroxyethyl methacrylate IOV, all free isocyanate disappeared after 72 hours.

This solution is then divided into four equal parts and the next monomer 5y is added. Example: 8N-vinylpyrrolidone (NVP) Example 9: Ethyl acrylate (EA) Example 10: Dimethyl maleate (DMM) Example 11: Vinyl acetate (VA) Example 12: Ethyl acrylate (EA) For all four samples Tertiary butyl peroctoate 0.
1y and pour this solution into a sheet mold with a thickness of 1n.

These were reacted at 80°C for 2 hours, taken out from the mold and 10
0.25m at 0℃? n Hold under vacuum for 15 hours. The sheets obtained are transparent and tenacious, and their degree of swelling is measured. In the two examples below, macromer (B) is a bisvinyl ether (Example 13) and a bismaleate (Example 14).

Example 13 Isocyanate-terminated polytetramethylene oxide (molecular weight 300
0) 30y and 4-hydroxybutyl vinyl ether (H
BVE) 10V in N-vinylpyrrolidone 30y, all free isocyanate disappears.

30V of ethyl acrylate and 0.4y of tert-butyl peroctoate are then added to this mixture. This mixture is poured into a flat sheet mold and after 2 hours at 80° C. the cross-bonded sheet is removed from the mold. These are then kept in a vacuum dryer (0.257!t?!LHg) at 100°C for 16 hours. This sample is a sticky transparent sheet whose degree of swelling is measured (see Table 3). Example 14 40 y of isocyanate-terminated polytetramethylene oxide (molecular weight 3000) and 10 y of 3-hydroxypropyl-butyl maleate (HPBM) were prepared in 50 V of N-vinylpyrrolidone using the same procedure described in Examples 8-11. The reaction is allowed to proceed until all free NCO disappears.

0.4y of tertiary butyl peroctoate is added and the mixture is poured into flat sheet molds and cured at 80°C for 2 hours. The cross-bonded sheet is then removed from the mold and kept at 100° C. for 16 hours in a vacuum dryer (0.25 mw LHg). This sample is a sticky transparent sheet whose degree of swelling is measured (see Table 3). In the following example, the macromer crosslinker contains linear polyester and polypropylene oxide chains. Examples 15-17 Isocyanate-terminated polyester of molecular weight 425 (Multratan E-4
10) Mix Mobay Chemical Corporation) with 2-hydroxyethyl methacrylate (HEMA) in the following proportions.

Example 15: Polyester diisocyanate 15y+HEM
A85y Example 16: Polyester diisocyanate 25y
+HEMA75y Example 17: Polyester diisocyanate 40y + HEMA6Oy The mixture was left at room temperature for 72 hours and all the isocyanates had reacted.

Each sample is mixed with 0.4y of tertiary butyl peroctoate and poured into a 17 nm thick flat sheet mold. These samples are cured at 80° C. for 2 hours, removed from the mold and kept at 100° C. for 16 hours in a vacuum dryer (0.25 mm IIg). This translucent sheet is tenacious and flexible. Their degree of swelling is listed in Table 4. Examples 18-19 Bis-maleimide type macromers (B) obtained by reaction of 2 moles of maleic anhydride with 1 mole of polypropylene oxide terminated with primary amino groups and having a molecular weight of about 2200 (polypropylene oxide-bismaleimide) )
are dissolved in 2-hydroxyethyl methacrylate in two different proportions.

Example 18: Polypropylene oxide bismaleimide 20%
/ HEMA 80% Example 19: 35% polypropylene oxide bismaleimide / 65% HEMA 0.1% tert-butyl peroctoate was added, the solution was cured at 80° C. for 2 hours in a flat sheet mold, the sheets were removed and vacuum Hold at 100° C. for 16 hours in a dryer (025 mm Hg).

These are tenacious and flexible. Their degree of swelling is listed in Table 5. Example 20 53.0 y of the polypropylene oxide-bismaleimide of Examples 18 and 19 was converted into 47.0 y of N-vinylpyrrolidone.
0.4y of tertiary butyl peroctoate is added, the mixture is filled into molds and cured as described in Example 18.

The product is a sticky light brown gel with a weight of 46.
0% water absorbed (DS=46.0) o Example 21 59.8y of the polypropylene oxide-bismaleimide of Examples 18 and 19 was mixed with 27.1f of N-vinylpyrrolidone.
7 and 13.0y of ethyl acrylate.
Butyl peroctoate 0.4f7 is added and the mixture is filled into molds and cured as described in Example 18.

This gel is a sticky, very pale yellow sheet that absorbs 26.5% of its weight in water (DS=26.5). Example 22 Example 21 is repeated except that the amounts of N-vinylpyrrolidone and ethyl acrylate are 3.10V and 26.4V, respectively.

The product is a sticky, colorless gel with a weight of 23.
Absorbs 0% water (DS=23.0). Example 23 The amounts of N-vinylpyrrolidone and ethyl acrylate were each 27. Repeat Example 21 except make If and 43.5y.

The product is a sticky, colorless gel that absorbs 15.8% of its weight in water (DS=15.8). Example 24
~26 Repeat the procedure of Example 2 except that isocyanate-terminated polytetramethylene oxide of molecular weight 3000 (Adiprene L-42) is used at a concentration of 15% in Example 24, 25% in Example 25, and 33% in Example 26. 82.0% by weight of pyribenzamine hydrochloride, a preparation with antihistamine properties, is dissolved in each sample immediately before polymerization.

Example 27 The procedure of Example 7 is repeated, except that 4% by weight of pyribenzamine HCI is dissolved in the monomer mixture immediately before polymerization.

Flat sheet samples of the same thickness were taken from Examples 24-27.
Extract in CI/NaCl solution (PH value 2.15) for 16 hours at 37°C.

The amount of medicine extracted from each sheet is
(2) Measure the values at various times during this process by measuring the magnitude of the characteristic absorption peak of pyribenzamine in this solution at 314 nm with an ultraviolet spectrophotometer. The time required to extract 50% of bilibenzamine was 2 for samples taken from Examples 24, 25, and 26, respectively.
time, 4 hours, and 6.5 hours, which demonstrates the flexibility of the diffusion pedestal of the present invention.

For comparison, a sample of the same thickness taken from the material of Example 27 was 1
In less than an hour, 50% of the dissolved drug was released. Example 28
~29 The molecular weight of the isocyanate-terminated polytetramethylene oxide is 600 (adiprene L-315),
The procedure of Example 1 is repeated, except that a concentration of 20% by weight in Example 28 and 40% by weight in Example 29 is used, and 3.7% of the synthetic steroid hormone dexamethasone is dissolved in each sample immediately before polymerization.

Example 30 The procedure of Example 7 is repeated except that 3.7% of dexamethasone is dissolved in the monomer mixture just before polymerization.

Flat sheet samples of approximately equal thickness are taken from Examples 28-30 and extracted in copious water at 25°C for 240 hours. The amount of drug extracted from each sheet was determined at various times during the process by measuring the magnitude of the characteristic absorption peak of dexamethasone in this solution at 242 nm using a Beckmann Acta C ultraviolet spectrophotometer. Ru. More than 95% of the initially dissolved steroid was extracted within 140 hours in a sample of the material from Example 30, whereas in the same time only 33% of the encapsulated drug was extracted from the material of Example 28. Only 12% of the steroid was extracted from the material, demonstrating the utility of long-term sustained release of water-insoluble materials from the present invention.

Example 31 N-vinylpyrrolidone 150y isocyanate-terminated polytetramethylene oxide (molecular weight 3000)
200V and 2-hydroxyethyl methacrylate 50y
and add.

The solution is stirred for one week at 25° C. under an inert atmosphere. During this period, completion of the reaction between the diisocyanate and HEMA is confirmed by noting the disappearance of the NCO band in the infrared spectrum of the product. This product was stored and Example 3
Serves as a masterbatch for the preparation of 2-44. Example 32 Masterbatch 201 from Example 31 is mixed with sufficient tertiary butyl peroctoate catalyst to give a final catalyst concentration of 0.4% by weight.

This mixture is poured into closed molds in the form of flat sheets approximately 1 mm thick. The mold is placed in a circulating air dryer at 80'C for 2 hours to accomplish polymerization. Next, this polymer sheet was removed from the mold and heated to 80°C under a pressure of 0.1 wtm for 1 hour.
Expose for 8 hours. The product is a sticky transparent sheet whose degree of swelling is measured. Example 33 HEMAI. The procedure of Example 32 is repeated except that 0y and N-vinylpyrrolidone 4y are added before addition of the peroxide.

Example 34 HEMA2.0V and N-VP3. The procedure of Example 32 is repeated except that OV is added before the peroxide addition.

Example 35 HEMA4.0V and N-VPl. OV and repeat the method of Example 32 except that the masterbatch is added before adding the peroxide.

Example 36 Repeat the method of Example 32 except that 5.0y of HEMA is added before adding the peroxide.

Example 37 N-VP3. Oy and HEMA27. The procedure of Example 32 is repeated except that Ot is added before the addition of the peroxide.

Example 38: (Repeat the method of Example 32 except that HEMA24.OV and N-VP6.Oy are added before mixing the peroxides.

Example 39 The procedure of Example 32 is repeated except that 15.0 V each of N-VP and HEMA are added before the peroxide addition.

Example 40 HEMA25.0y and N-VP5. The procedure of Example 32 is repeated except that Oy is mixed before addition of the peroxide.

Example 41 The procedure of Example 32 is repeated except that 3.53 t of ethyl acrylate are added before the peroxide addition.

Example 42 The procedure of Example 32 is repeated except that 6.671 ml of ethyl acrylate is added before the peroxide addition.

EXAMPLE 43 The procedure of Example 32 is repeated except that 10.8 V of ethyl acrylate is added before addition of peroxide. EXAMPLE 44 The procedure of Example 32 is repeated except that 20.0 V of ethyl acrylate is added before addition of peroxide.

The composition and degree of swelling of the gels of Examples 32-44 are listed in Table 7. Example 45 The polymer composition of Example 5 is cut into disks 2.5 m in diameter and 1.0 m in thickness.

These disks 5.8y were treated with pyribenzamine HCI in water.
The mixture was slurried in 50 ml of a 30% by weight solution of 100% by stirring at room temperature for 48 hours. The final weight of the swollen disk is 9.6V
It is. These were washed with distilled water and dried at 60° C. under vacuum (0.1×1 Hg) until a constant weight was reached. This weight is 6.85y, which is 15% of the pyribenzamine HCI in the polymer.
．． 1, which is equivalent to 3%. This sample contained 50% of the total drug content within 2 hours and 85% at 90°C in simulated gastric fluid at 37°C.
Release within hours.

Example 46 (^ Synthesis of macromer masterbatch) 2000 parts (1 mol) of polytetramethylene oxide (Polymeg 2000) with a molecular weight of 2000 was melted and poured into a 3-necked flask No. 51, and heated to 80°C for 1 hour under vacuum. Remove moisture.

Break the vacuum with dry nitrogen and cool the contents to 40°C. 444.6 parts (2 moles) of isophorone diisocyanate are added, followed by triethylamine 1y and the temperature is raised to 80°C. After 5 hours, after the NCO content had fallen to approximately 3.50% (determined by titration), the mixture was cooled to 40° C. and HEMA16
30 parts (12.4 moles) and then 0.24 V of dibutyltin dilaurate (DBTL) are added.

The mixture is allowed to cool to room temperature with stirring under nitrogen until all NCOs have disappeared (by infrared). (Uniform
Using the masterbatch prepared in synthesis (2) of cross-linked hydrophilic polymers, HEMA
By adding either NVP or NVP, a monomer-macromer mixture having the following composition is obtained.

Add 0.2 parts of tert-butyl peroctoate to each monomer-macromer mixture, dissolve and apply the solution to a glass plate lined with a Mylar (polyester) sheet and using 1.61 nm silicone cord as a spacer. Pour into a mold (30x30c-1n).

Polymerization is carried out in a forced air dryer at 80° C. for 3 hours and at 100° C. for 1 hour. The molds are removed, cooled to room temperature, and the sheets of hydrogel are removed and characterized. Swelling degree, tensile strength (wet, dry) and elongation (wet, dry) of hydrogels a-g Example 47 Polyoxypropylene 125.0y (0
．． 13 mol) into a 500 cc three-necked reaction flask and dried at 80° C./2 mwLHg for 1 hour.

The vacuum is broken with dry nitrogen gas and the contents are cooled to 40°C. Isophorone diisocyanate 55.9y (0.2
5 mol) and 127~ of triethylamine are added and the reaction temperature is raised to 80°C. NCO% after 18 hours is 5.80
% (theoretical value 584%NCO).

The reaction mixture was cooled to 40°C and the reaction mixture 115.
2V to hydroxyethyl methacrylate 172.8y (
1.3 mol) is added. Dibutyltin dilaurate9.
6mf7 is added and the reaction mixture is kept at 40° C. until all NCOs have disappeared. Example 48 Polyoxypropylene with a molecular weight of 2015 150.0V (
0.074 mol) was injected into a 500 cc three-necked reaction flask and dried at 80° C./2 mmHg for 1 hour.

The vacuum is broken with dry nitrogen gas and the contents are cooled to 40°C. Isophorone diisocyanate 33.1y (0.1
5 mol) and DABCO (1,4-diazabicyclo[2.2.
2] Octane, 1 mol %) is added and the reaction temperature is raised to 80°C. NCO% after 16 hours is 3.44%
(Theoretical value: 3.42% NCO).

The reaction mixture was cooled to 40° C. and the reaction mixture 119.
Hydroxyethyl methacrylate 179.3y (
1.4 mol) is added. Dibutyltin dilaurate 10
is added and the reaction mixture is kept at 40° C. until all NCOs have disappeared. Example 49 Polyoxypropylene 1439y (0
．． 050 mol) into a 500 cc three-necked reaction flask and dried at 80° C./2 mmHg for 1 hour.

The vacuum is broken with dry nitrogen gas and the contents are cooled to 40°C. Isophorone diisocyanate 22.2y (0.1
00 mol) and DABCO 56~(1 mol %) are added and the reaction temperature is raised to 80°C. NCO% after 12 hours is 2.4
It was 4% (theoretical value 2.53% NCO).

The reaction mixture was cooled to 40°C and the reaction mixture 205.
3y is hydroxyethyl methacrylate 308.0y (
2.37 mol) is added. Dibutyltin dilaurate 1
7? Add Nf7 and keep the reaction mixture at 40°C until all NCOs have disappeared.Example 50 Molten polyester diol 145 with molecular weight 1965
．． 9T (0.074 mol) was injected into a 3-necked reaction flask at 500 cC and dried at 8'C/2 nHg for 1 hour.

The vacuum is broken with dry nitrogen and the contents are cooled to 40°C.
33.0y (0.15 mol) of isophorone diisocyanate and 83m9 of DABCO are added and the reaction temperature is raised to 80°C. After 7 hours, NCO% was 3.48% (theoretical value 3.49)
%NCO).

The reaction mixture was cooled to 40° C. and the reaction mixture 148.
0V to hydroxyethyl methacrylate 222.0V (
1.7 mol) is added. Dibutyltin dilaurate 12
was added and the reaction was heated to 40°C until all NCOs disappeared.
to hold. Example 51 50V of the composition prepared in Examples 47-50 was added with 0.0% tert-butyl peroctoate. Add IV and dissolve under stirring.

The mixture is degassed at room temperature under 1 mm Hg until no bubbles are observed and poured into glass molds lined with Mylar-polyester sheets and sealed with 1 mm silicone cord. The molds are heated in a circulating air dryer to 80°C for 3 hours and then to 100'C for 1 hour. The sheets are removed from the cooled molds and samples are cut for analysis and physical testing. Swelling (DS) and Strength Data for Hydrogels Made in Examples 47-50 Example 52 The composition of Example 46d is polymerized into sheets ranging in thickness from 0.5 to 1.5 mTfL.

These sheets are washed in running water at 40° C. for 3 days and tablets of various diameters are cut from these sheets in the wet state.
These tablets have a diameter of 4 mm to 1.2 mm after drying at 80°C under vacuum.
The range was up to mwL. Example 53 The composition of Example 46c is repeated as before and the resulting sheet is ground in a grinder to produce a number of horizontal particles of varying average diameter.

The particles are then washed in running water at 40 DEG C. for 3 days, dried and the particles are sized by passing through a set of standard sieves with holes ranging from 2.4 to 0.18 mm. 0.18mm
Discard all materials with smaller particle size.

Example 54 One tablet is selected from the tablets prepared in Example 52 and swollen in a 40% aqueous solution of tripelenamine HCI for 48 hours, washed with water and dried to constant weight.

The weight obtained with this tablet is that the final composition is tripelenamine HCI3O. 7%, the sample thickness is 1.9m771
This indicates that the amount has increased. Tripelenamine HCI37.2
The tablets containing m9 are placed in simulated gastric fluid 11 at 37° C. and the amount of drug released as a function of time is measured spectrophotometrically. This release pattern shows that 25% of the total drug content is released in 30 minutes and 50%
is 2.2 hours, 75% is 5.5 hours, and 90% is 10 hours.
．． The amount is such that it is released in 5 hours. Example 53 A section of particles of Example 53 with an average diameter of 1.4 mm is swollen in a 40% aqueous solution of tripelenamine HCl for 48 hours, then washed with water and dried to constant weight.

The weight gain due to the particles indicates that the final composition is 7.5% tripelenamine HCl. This active ingredient 30
An amount of this portion corresponding to W9 is weighed into a fast dissolving capsule and placed in simulated gastric fluid 11 at 37°C. The amount of tripelenamine HCI released is measured spectrophotometrically as a function of time. This mode of release is such that 25% of the total drug content is in 0.17 hours, 50% in 0.81 hours, and 75% in 2 hours.
．． In 9 hours, 9'o% is released in 7.8 hours. Example 56 Example 5 corresponding to an average diameter of 1.7 mm
The particle o-portion of 3 is swollen in a 22% solution of phenformin HCI for 48 hours.

The solvent system used was ethanol-water (3:1). After drying, these particles gained weight indicating a total drug loading of 8% phenformin HCI1. Active ingredient 5
An amount of this portion corresponding to 0Tnf7 is weighed into a fast-dissolving capsule and placed in simulated gastric fluid 11 at 37°C. The amount of phenformin released is determined spectrophotometrically as a function of time. This mode of release is equivalent to 2% of the total drug content.
5% in 0.75 hours, 50% in 2.25 hours, 75
% is released in 5 hours and 90% is released in 9 hours. Example 57 Tablets from Example 52 are selected and swollen in a 30% aqueous solution of imipramine HCI for 72 hours.

After drying, the tablet was found to have a thickness of 0.75 mwL, the weight increase indicating a total drug load of imipramine HCI of 33.6%. imipramine HCI5O~
The tablet containing imipramine HCI is placed in simulated gastric fluid 1f at 37°C and the amount of imipramine HCI released is determined as a function of time using a spectrophotometer. This mode of release is such that 25% of the total drug content is in 1 hour, 50% in 2 and a half hours, 75% in 5 hours, and 9
0% is released in 8.75 hours. Example 58 A portion of the particles of Example 53 with an average diameter of 0.425 wtm is swollen in a 50% chloroform solution of sulfinpyrazone for 48 hours, then washed with chloroform and dried to constant weight.

The resulting weight of polymer indicates that the final composition is 10.3% sulfinpyrazone. An amount of this portion corresponding to 11.7~ of active ingredient is weighed into a fast-dissolving capsule and placed in simulated gastric fluid 11 at 37°C. The amount of sulfinpyrazone released is measured spectrophotometrically as a function of time. This mode of release is such that 25% of the total drug content is 0.21
50% is released in 1.20 hours and 75% is released in 4.20 hours.
In 94 hours, 90% is released in 10.20 hours. Example 59 Select tablets from those made in Example 52, and use 2 tablets of hydralazine.
Swell in 1% aqueous solution.

The above aqueous solution is obtained by dissolving hydralazine HClIOy in 2N sodium hydroxide until the solution is completely dissolved and its pH is
Make by melting until the value reaches 8.0. Absorption into the tablets was allowed to proceed for 72 hours, with a weight gain by the tablets on drying &t indicating a final composition of 10.7% hydralazine. Tablets containing hydralazine 11 are placed in simulated gastric fluid 11 at 37° C. and the amount of hydralazine released as a function of time is measured spectrophotometrically. This release pattern is such that 25% of the total drug content takes 0.53 hours, 50% takes 3.33 hours, and 7
5% is 7.87 hours, 90% is 13.3 hours, etc. Example 60 A portion of the particles of Example 53 with an average diameter of 1.4 mm are swollen in a 21% aqueous solution of hydralazine.

This aqueous solution of hydralazine becomes completely solution and its pH
Add 2N hydralazine HCIlOv until the value is 8.0.
Prepared by dissolving in sodium hydroxide. Absorption into the polymer was allowed to proceed for 72 hours and the weight gain by the polymer particles when dry was 11 indicating that the final composition contained 4.2% hydralazine. These particles are filled into fast-dissolving capsules for a total dosage of 20~. The capsule is placed in simulated gastric fluid 11, and the release of hydralazine is measured as a Samurai function using a spectrophotometer. This mode of release is such that 25% of the total dose is 0.20 hours and 50% is 0.8 hours.
6 hours, 75% 2.50 hours, 90% 4.94
It's like it's released over time. Example 61 Swelling of a portion of the particles of Example 53 having an average diameter of 0.6 mm in a 22% solution of maprotiline HClOy made by dissolving maprotiline HClIOy in a methanol/chloroform solvent composition of 33 parts methanol and 67 parts chloroform. let

Absorption into the polymer was allowed to proceed for 48 hours, and the weight gain due to the polymer particles upon drying was determined by this final composition.
It shows that l2.8%. These particles are filled into fast-dissolving capsules such that the total dosage is 90~. The capsules are placed in simulated gastric fluid 11 and the release of maprotiline HCI is measured spectrophotometrically as a function of time. The mode of release is such that 25% of the total dose is released in 0.67 hours, 50% in 3.67 hours, 75% in 13.4 hours, and 90% in 23.4 hours. be. Example 62 A portion of the particles of Example 53 having an average diameter of 1.7 mwL was dissolved in a 26% solution of methylphenidate HCI.
After swelling for 8 hours, wash with water and dry overnight.

The solvent system used is a methanol/water (27:73) mixture. The weight gain due to particles indicates that the final composition is 26.7% methylphenidate HCI. An amount of particles corresponding to 270 to 270 of the active ingredient is weighed into a fast-dissolving capsule and placed in 0.51 of simulated gastric fluid at 37°C. The amount of methylphenidate HCI released is measured spectrophotometrically as a Samurai function. This release was 0.67 hours for 25% of total dosing, 3.0 hours for 50%, and 7.0 hours for 75%.
In 8 hours, 90% is released in 14.2 hours. Example 63 The monomer-macromer 15f7 described in Example 46c is mixed with a compound as shown below.

0.08y of tert-butyl peroctoate was mixed in and the solution or dispersion was degassed and sealed with silicone cord).
0x30c1n). Polymerization is carried out in a forced air oven at 80° C. for 3 hours and at 100° C. for 1 hour. After cooling these molds, sample sheets are removed and used for diffusion measurements. Example 64 The monomer-macromer mixture 15y described in Example 46f is mixed with the compounds listed below.

Mix 0.08y of tertiary butyl peroctoate, degas the solution and seal with silicone cord to a thickness of 1.
477 Im mylar lined glass mold (30 x 30 (Vz
). Polymerization is carried out in a forced air dryer at 80'C for 3 hours and at 100'C for 1 hour. After cooling the mold, the sample is removed and used for diffusion measurements. Example 65 The hydrophilic polymer 9.89f7 made according to Example 46b was
-(cyclopropylmethyl)-α・α. Soak for 5 days in 20y of α-trifluoro-2.6-dinitro-N-propyl-p-toluidine (herbicide).

Next, this polymer is taken out, washed with methanol, air-dried, and weighed. The weight of this dry polymer was 11.22V, corresponding to a polymer composition containing 11.8% of active ingredient. Similarly, the polymer of Example 46e is soaked in sodium ferric ethylene diamine di[o-hydroxyphenylacetate] (iron supplement) dissolved at 5% in methanol.

This dry polymer contains 15% active ingredient. Example 66 Diffusion measurements are carried out at 25° C. by immersing samples of the release devices listed in the table below in water 11 warmed to a pH value of 5 with dibasic sodium citrate.

Aliquots are taken periodically and the percentage of total active ingredient released from the polymer is determined spectrophotometrically. Example 67 The composition of Example 63d is ground to a particle size of 0.18-0.25 mm, filled into a cylinder, and air is passed through at 40° C. at a rate of 201/min.

The weight loss is followed gravimetrically and the percentage of active ingredient evaporated is calculated. This release rate was 25% and 30% after 48 hours.
The rate is such that 50% is released at 0 hours, 75% at 1050 hours, and 90% at 2000 hours. Example 68 A perfume of known composition is mixed into a hydrogel polymer made by the method described in Example 46c by polymerization in the presence of 50% of the following mixture:

All fragrances give a bright transparent polymer sheet and emit fragrance for a long time.

Example 69 Example 47 is repeated except that instead of hydroxyethyl methacrylate, an equal amount of 3-hydroxypropyl methacrylate is used to make the macromer-monomer mixture.

This is polymerized as described in Example 51. The resulting sheet is tenacious, flexible and transparent and absorbs 15% of water (DS=15). Example 70 A portion of the particles of Example 53 having an average diameter of 0.6 mwL was added to 40 y of water with clomipramine H.
Clomipramine HCI 2 made by dissolving CIlOy
Swell in 0% solution.

Absorption into the polymer was allowed to proceed for 72 hours, and the weight gain achieved by the polymer particles when dry was such that the final composition was clomipramine HClIO. It shows that it is 6%. These particles are filled into fast dissolving capsules for a total dosage of 45Tf19. The capsule is placed in simulated gastric fluid 11 and the release of clomipramine HCI as a function of time is measured spectrophotometrically. This mode of release accounts for 25% of the total dosage.
% is 0.5 hours, 50% is 2.2 hours, 75% is 5 hours.
．． In 9 hours, 90% is released in 11.0 hours. Example 71 Example 46 except that the thickness of the sheet made is 1.15 mm
Repeat composition f.

The sheet is washed in running water at 40° C. for 3 days, and after the sheet is completely dry, it is cut into tablets with a diameter of 1.27 cwL. Example 72 Tablets from Example 71 are selected and swollen in a 20% aqueous solution of imipramine HCI for 48 hours.

After drying, the tablet was found to be 1.44 mwL thick, the weight increase indicating a total dosage loading of imipramine HCI 22.6%. Imipramine HC Engineering 46.
The tablet containing 3Tf9 is placed in simulated gastric fluid at 37° C. and the amount of imipramine HCI released is measured spectrophotometrically as a function of time. This release pattern is 25% of the total drug content in 1.28 hours, 50% in 3.72 hours,
Such that 75% is released in 9.40 hours and 90% in 17.3 hours. Example 73 Select p tablet from Example 71 and use 20% clomipramine HCI.
% aqueous solution for 48 hours.

After drying, the tablet was found to be 1.38 mm thick.
The weight increase indicates that 9.5% of clomipramine HCI1 is contained in the total drug. The tablets containing ~37.3 of the active ingredient are placed in simulated gastric fluid 11 at 37°C and the release of clomipramine HCI is measured spectrophotometrically as a function of time. The release pattern is such that 25% of the total dose is released in 1.33 hours, 50% in 4.03 hours, 75% in 10.2 hours, and 90% in 18.7 hours. be. Although the present invention has been described in detail above, specific examples of the configuration of the present invention can be summarized as follows. (1) Water-soluble monomer (A
) and the hydrophobic macromer (B) is carried out in the presence or absence of a solvent.

(2) The copolymerization of the water-soluble monomer (A) and the hydrophobic macromer (B) is carried out at about 40 to about 150°C in the presence of a suitable catalyst or a system capable of generating free radicals. The method described in the claims or the preceding paragraph (1).

(3) Presence of about 0.02 to 1.0% by weight of a suitable catalyst capable of copolymerizing the water-soluble monomer (A) and the hydrophobic macromer (B) to generate free radicals at about 50 to about 100°C. A method according to the claims or preceding paragraphs carried out under.

(4) The method according to the preceding claims or each of the preceding items, in which a catalyst capable of producing free radicals is a catalyst capable of producing free peroxy groups or alkyl groups.

(5) Catalysts capable of generating free radicals include diisopropyl purged carbonate, tert-butyl peroctoate, benzoyl peroxide, decanoyl peroxide, lauroyl peroxide, succinic peroxide, methyl ethyl ketone peroxide, tert-butyl peroxyacetate or azo A method as claimed in the preceding claims or preceding clauses using isobutyronitrile.

(6) The scope of the above claims or the preceding clauses (1)-(
The method described in 4).

(7) The scope of the above claims or the preceding paragraphs (1) to (4) or the preceding paragraph (
The method described in 6).

(8) The scope of the above-mentioned claim or the preceding paragraph (1) which uses gamma rays, electron beams, or ultraviolet irradiation as the mechanism for generating free radicals.
1) The method described in (2).

(9) As the water-soluble monomer (A) (a) acrylic acid or methacrylic acid, or a water-soluble ester thereof;
amide or imide, or (b) a monoolefinic salt thereof, or (c) a polymer of a monoolefinic, monocyclic azacyclic monomer as described in the claims or preceding paragraphs. Method.

The method according to the preceding claims or the preceding paragraphs, using acrylic acid or methacrylic acid or their hydroxyalkyl esters or dialkylaminoalkyl esters in which the alkyl group has 2 to 4 carbon atoms as the QO water-soluble monomer. .

As a water-soluble monomer, the formula HO-CmH2m-O-(CH2-CH2-0)n -
R (wherein R is a hydrogen atom or a methyl group, m is 2-
5 and n is 1 to 20).
- The method described in (9).

The N-substituent as a UJ water-soluble monomer is a hydroxyalkyl group, an oxaalkyl group or a dialkylaminoalkynole group (where alkyl has 2 to 4 carbon atoms)
A method as claimed in the preceding claims or in the preceding paragraphs, using an amide or imide of acrylic acid or methacrylic acid.

U3) Acrylic acid, methacrylic acid, as a water-soluble monomer
2-hydroxyethyl or 2- or 3-hydroxypropyl acrylate or -methacrylate, N
- A method as claimed in the preceding claims or in the preceding sections using vinylpyrrolidone or tertiary aminomethacrylimide.圓 The method according to the preceding claims or each of the preceding sections, in which 2-hydroxyethyl methacrylate is used as the water-soluble monomer. N-vinyl 2 as a water-soluble monomer
- the claims or the preceding paragraph (1) using pyrrolidone;
) ~ The method described in QJ.

Qf5/A hydroxyalkyl maleate or fumarate in which the alkyl group has 2 to 4 carbon atoms is used as a water-soluble monomer.
).

Qη The method according to the preceding claims or the preceding clauses (1) to (9), in which a hydroxyalkyl vinyl ether in which the alkyl group has 2 to 4 carbon atoms is used as the water-soluble monomer.

Mark Q: Process according to the preceding claims or the preceding clauses (1) to (9), in which acrylonitrile or an alkyl acrylate or alkyl methacrylate in which the alkyl has up to 18 carbon atoms is used as the water-soluble monomer.

Q1. Process according to the preceding claims or the preceding clauses (1) to (9), using as water-soluble monomer a vinyl ester derived from an alkanecarboxylic acid having up to 5 carbon atoms.

(To) The hydrophobic macromer (B) has the formula: [In the formula, R1 contains a hydrocarbon group bonded via an ether, ester, amide, urethane or urea bond, and has a molecular weight of about 200 to about 8
000 polycondensate chain, R2 is a hydrogen atom or a methyl group, or a -CH2-COOR4 group, where R4 is a hydrogen atom or an alkyl group with up to 10 carbon atoms. , R3 is a hydrogen atom or a COOR4 group, provided that at least one of R2 and R3 is a hydrogen atom, and X is an oxo group, a -COO- group, or a =CONR5 group (here, R5 is a hydrogen atom) Is there?
or an alkyl group having up to 5 carbon atoms), and Y is a direct bond or -R6-Z1-CO-NH-
R7-NO. -CO-Z2- group (where R6 is a branched or linear alkylene group connected to X and having up to 7 carbon atoms, Z1 and Z2 are an oxo group or NR5
group, R7 is a divalent group of aliphatic or aromatic diisocyanate), provided that when X is an oxo group, Y is different from a direct bond, and R2 and R3 are hydrogen atoms. ] The method described in the claims or the preceding paragraph (1) H, using a compound represented by the following.

Mouth υ As a hydrophobic macromer, R1 has a molecular weight of about 600~
4000 polypropylene oxide or polytetramethylene oxide chains using a compound of the above formula;
The method described in.

(2) The above patent claim uses a compound in which R is a chain obtained by co-condensation of an aliphatic, carbocyclic, or aromatic dicarboxylic acid or diisocyanate with an aliphatic diol or diamine as a hydrophobic macromer. or the method described in the preceding paragraph (1) H8) or the preceding paragraph 121.
As a hydrophobic macromer, a polytetramethylene oxide glycol having a molecular weight of about 600 to about 4000 is end-capped with toluene diisocyanate and reacted with 2 moles of a hydroxyalkyl acrylate or methacrylate in which the alkyl has 2 to 4 carbon atoms. The scope of the claims to be used or the preceding clauses (1) to (8) or the preceding clause F2l to
The method is strictly described.

, 4 as a hydrophobic macromer with a molecular weight of about 1500 to about 3
000 and the hydroxyalkyl methacrylate is 2-hydroxyethyl methacrylate.
The method described in.

ω A hydrophilic polymer (a) of the same or different water-soluble monoolefin monomers or a composition of 1 to 70% of the same or different water-insoluble monoolefin monomers and the water-soluble monomers. Aqueous copolymerization b) about 30 to about 90% (A
) is cross-linked with about 10 to about 70% (B) of a terminal diolefin-based hydrophobic macromer having a molecular weight of about 400 to about 8,000. :0 The water-soluble monomer is acrylic acid or methacrylic acid, or their water-soluble esters, amides, or imides, or their monoolefin salts (b), or monoolefin, monocyclic, or azacyclic monomers. The gel according to the preceding paragraph, which is a polymer c). The gel according to item 4 above, wherein the water-based monomer is acrylic acid or methacrylic acid, or a hydroxyalkyl ester or dialkylaminoalkyl ester thereof in which the alkyl group has 2 to 4 p carbon atoms.

” The water-soluble monomer has the formula HO-CmH2m-O=(CH2-CH2-O)n -
R (wherein R is a hydrogen atom or a methyl group, m is 2-
5 and n is 1 to 20).

(to) The water-soluble monomer is an acrylic or methacrylic acid in which the N-substituent is a hydroxyalkyl, oxaalkyl or dialkylaminoalkyl group, where alkyl has 2 to 4 carbon atoms. The gel described in the preceding item (2ω) which is an amide or imide.

O The gel according to item 4 above, wherein the water-soluble monomer is acrylic acid, methacrylic acid, 2-hydroxyethyl- or 2- or 3-hydroxypropyl-acrylate or -methacrylate, N-vinylpyrrolidone or tertiary aminomethacrylimide. .

Gυ The gel according to the preceding item, wherein the water-soluble monomer is 2-hydroxyethyl methacrylate.

C3 The gel according to item 4 above, wherein the water-soluble monomer is N-vinyl-2-pyrrolidone.

Nagi The water-soluble monomer is hydroxyalkyl maleate or hydroxyalkyl fumarate (where alkyl is 2
G4) The gel according to the above item 4, which is a gel having ~4 carbon atoms); Genore described.

G3ω Water-insoluble monomer is acrylonitrile or alkyl acrylate or alkyl methacrylate (
The gel according to the preceding paragraph, wherein alkyl has up to 18 carbon atoms.

(30) The gel according to item 4 above, wherein the water-insoluble monomer is a vinyl ester derived from an alkanecarboxylic acid having up to 5 carbon atoms.

(3η) The Geno2(-) macromer described in the preceding paragraph, which is a water-insoluble monomeric styrene or vinyl alkyl ether (where alkyl has up to 5 carbon atoms), has the formula [wherein R is an ether] , ester, amide, urethane, or a polycondensate chain with a molecular weight of about 8,000 containing hydrocarbon groups bonded via urea bonds, R2 is a hydrogen atom, a methyl group, or a =CH2-COOR4 group (where R4 is a hydrogen atom or an alkyl group having up to 10 carbon atoms), R3 is a hydrogen atom or a COOR4 group, provided that at least one of R2 and R3 is a hydrogen atom, X is oxo group, -COO-
group or -CONR5 group, where R5 is a hydrogen atom or an alkyl group with up to 5 carbon atoms, and Y is a direct bond or -R6-Zl-CONH
-R7-NHCO-Z.

one group (where R6 is a branched or linear alkylene group connected to X and having up to 7 carbon atoms, and Z1 and Z
2 is an oxo group or an NR5 group, and R7 is a divalent group of aliphatic or aromatic diisocyanate); however, when X is an oxo group, Y is different from a direct bond, and R2 and R3 is a hydrogen atom] The gel according to item 4 above.

Genoleo according to the preceding paragraph, wherein G and Rl are a polypropylene oxide chain or a polytetramethylene oxide chain with a molecular weight of about 600 to about 4000 (41R, is an aliphatic or carbocyclic, aromatic dicarboxylic acid or diisocyanate); The gel according to the above item, which is a chain obtained by co-condensation with an aliphatic diol or diamine.

(40 macromers end-capped with toluene diisocyanate and reacted with 2 moles of hydroxyalkyl acrylate or hydroxyalkyl methacrylate in which the alkyl group has 2 to 4 carbon atoms.)
The gel according to item 4 above, which is polytetramethylene oxide glycol of ~4000. (4 forces) Polytetramethylene oxide glycol has a molecular weight of about 1500 to about 3000, and hydroxyalkyl methacrylate has a 2-
Genore o (41) using about 15 to about 50% of the macromer according to the above item 4, which is hydroxyethyl methacrylate
The gel described in.

(4) A pharmaceutical composition comprising the gel described above and a pharmaceutically effective compound.

(4ω A pesticidal composition comprising the gel according to item 4-(41) and a pesticide.

(46) A herbicide composition comprising the gel described in F25) to 0J and a herbicide.

(47) The method for producing a pharmaceutical composition according to the preceding paragraph, in which the active ingredient on the formulation is mixed with the monomer component before polymerization.

(48) The method for producing a pharmaceutical composition according to the preceding paragraph, wherein the active ingredient on the pharmaceutical composition is mixed with the monomer-macromer mixture before polymerization. (49) Adsorbing the active ingredient or a salt thereof in the solution state into the hydrogel described in 4 to 0J above.
A method for producing the pharmaceutical composition described in the preceding paragraph.

(50) The method for producing a pesticide composition according to the preceding clause (4ω), in which the pesticide component is mixed with the monomer component before polymerization.
51) The method for producing a pesticide composition according to the preceding clause (4ω), in which the pesticide component is mixed with the monomer-macromer mixture before polymerization.

(52) The method for producing a herbicide composition according to the above item (46), wherein the herbicide component is mixed with the monomer component before polymerization.

(53) The method for producing a herbicide introduction product according to the preceding item (46), wherein the herbicide component is mixed with the monomer-macromer mixture before polymerization. (54) An aromatic composition comprising the gel described in (25) to (43) above and a fragrance.

(55) The method for producing an aromatic compound according to the above item (54), wherein the fragrance is mixed with the monomer-macromer mixture before polymerization.

Claims (1)

Claims: 1 (A) from about 30 to about 90% by weight (based on the weight of the resulting hydrophilic gel) of (a) a hydrophilic polymer of at least one water-soluble monoolefin monomer; b) a hydrophilic copolymer of at least one water-soluble monoolefin monomer and from 1 to 70% by weight (based on the total weight of monomers) of at least one water-insoluble monoolefin monomer; , (B) about 10~
about 70% by weight (based on the weight of the resulting hydrophilic gel) having a molecular weight of about 400 to about 800 and having the following formula B_1 or B_
Method for producing a water-insoluble hydrophilic gel characterized by copolymerization with a terminal diolefin hydrophobic macromer represented by 2: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. 〔 In the formula, R_1 is a polycondensate chain having a molecular weight of about 200 to about 8000 and containing hydrocarbon groups connected via an ether, ester, amide, urethane or urea bond, and R_2
is a hydrogen atom, a methyl group or -CH_2-COOR_4
(where R_4 is a hydrogen atom or an alkyl group with up to 10 carbon atoms) and R_3 is a hydrogen atom or COOR_4. However, at least one of R_2 and R_3 is a hydrogen atom. X is an oxo group, -COO- group or -CONR_5
(where R_5 is a hydrogen atom or an alkyl group with up to 5 carbon atoms) and Y is a direct bond or -R_6-Z_1-CO-NH-R_7-NH
-CO-Z_2- group, where R_6 is a branched or linear alkylene group connected to X and having up to 7 carbon atoms, and Z_1 and Z_2 are an oxo group or -N
R_5 group, and R_7 is a divalent group of aliphatic or aromatic diisocyanate). However, when X is an oxo group, Y is different from a direct bond, and R_2 and R_3 are hydrogen atoms]. 2 (A) About 30 to about 9
0% by weight (based on the resulting hydrophilic gel weight) of (a)
a hydrophilic polymer of at least one water-soluble monoolefin monomer, or (b) at least one water-soluble monoolefin monomer and from 1 to 70% by weight (based on the total weight of the monomers) of water. (B) a hydrophilic copolymer with at least one insoluble monoolefin monomer having a molecular weight of about 10 to about 70% (based on the weight of the resulting hydrophilic gel) of about 400 to about 80;
0 and is copolymerized with a terminal diolefin hydrophobic macromer represented by the following formula B_1 or B_2, and further, a biologically active substance is added prior to or after the copolymerization. Production method of water-insoluble hydrophilic gel: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is an ether, ester, amide, urethane, or urea bond It is a polycondensate chain with a molecular weight of about 200 to about 8000 containing connected hydrocarbon groups, and R_2
is a hydrogen atom, a methyl group or -CH_2-COOR_4
(where R_4 is a hydrogen atom or an alkyl group with up to 10 carbon atoms) and R_3 is a hydrogen atom or COOR_4. However, at least one of R_2 and R_3 is a hydrogen atom. X is an oxo group, -COO- group or -CONR_5
(where R_5 is a hydrogen atom or an alkyl group with up to 5 carbon atoms) and Y is a direct bond or -R_6-Z_1-CO-NH-R_7-NH
-CO-Z_2- group, where R_6 is a branched or linear alkylene group connected to X and having up to 7 carbon atoms, and Z_1 and Z_2 are an oxo group or -N
R_5 group, and R_7 is a divalent group of aliphatic or aromatic diisocyanate). However, when X is an oxo group, Y is different from a direct bond, and R_2 and R_3 are hydrogen atoms].