JPH0312104B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to compositions capable of forming hydrogels at room temperature without dissolving and absorbing more than 45% of their weight in water, and more particularly to water-soluble poly(vinyl lactams) or polymerizable ethylenically unsaturated Copolymerizable monomer with bond 1-90
a water-soluble copolymer of mol% and vinyllactam;
50-90% by weight of hydrophobic water-insoluble ethylenically unsaturated monomers, based on the total weight of the copolymer;
Optically transparent copolymers derived from ethylenically unsaturated monomers containing 12% by weight of acid groups and from 15 to 45% by weight of hydrophilic ethylenically unsaturated monomers free of acid groups. Concerning mixtures.
A preferred vinyl lactam is N-vinyl-2-pyrrolidone. Traditionally, N such as poly(vinyl-pyrrolidone)
- It has been proposed to insolubilize vinyl lactam polymers by reacting them with water-soluble polymers containing carboxyl groups; this reaction product is described in Stoner, US Pat. No. 2,901,457. As shown, when the two were mixed, they precipitated out of solution. Stoner, etc. is 56th in the 4th column.
As pointed out in lines ~73, the reaction products described therein always have substantially the same properties, and regardless of the proportions of the two copolymers used to make the product. , containing two types of polymer components in equal proportions. On the other hand, the properties and component ratios of the composition of the present invention vary depending on the ratio of starting materials. Also, U.S. Patent No. 3700761 to O'Driscoll et al., U.S. Patent No. 3807398 to Grusza,
and Buch et al., U.S. Pat. No. 4,018,853,
It has been proposed to polymerize hydrophilic methacrylate monomers in the presence of poly(vinyl-pyrrolidone) to obtain covalently crosslinked hydrogels. Furthermore, Boyer-Kawenoki Compt.Rend.
Sec.C, Vol. 263 , page 278 (Chem.Abs.Vol. 65 ,
20283d) In 1966, the addition product of poly(vinylpyrrolidone) and poly(acrylic acid)
The IR spectrum shows the presence of hydrogen bonds between the carbonyl groups of pyrrolidone and the carboxyl groups of poly(acrylic acid). Ono et al., U.S. Pat. No. 3,975,570, discloses that the moisture infiltration properties of conventional pressure sensitive adhesives, which are copolymers of alkyl acrylates and acrylic or methacrylic acids, can be improved by incorporating hydroxyethyl cellulose therein. Suggestions for improvement have been made, stating that mixtures of such adhesives and poly-(vinylpyrrolidone) did not exhibit improved moisture permeability. Other mixtures of poly(vinyl lactam) and various copolymers are disclosed in U.S. Patent Application No. 137,297, filed April 4, 1980 by Shah;
Shah and Temin, U.S. Patent Application No. 142,986, filed April 23, 1980 (co-pending). This invention is made from an optically transparent mixture of (1) and (2) below that can absorb 45% or more of its weight in water without dissolving at room temperature to form an optically transparent hydrogel. (1) 40 to 98% by weight, based on the total weight of the mixture, of the following structural formula: (wherein, X is an alkylene group having 3 to 5 carbon atoms) or a copolymerizable monomer having a polymerizable ethylenically unsaturated bond in an amount of 1 to 90 mol%. a water-soluble copolymer with this lactam, in which the molecular weight of said polymer or copolymer is at least 10,000; (2) methyl methacrylate, in an amount of 2 to 60% by weight, based on the total weight of the mixture; 50-90% by weight of monomers selected from the group of n-butyl methacrylate, styrene and 2-ethylhexyl acrylate, 2-12% by weight of acrylic acid and selected from the group of methacrylamide, p-styrene sulfonamide and hydroxyethyl methacrylate. A water-insoluble copolymer derived from 15 to 45% by weight of monomers. The compositions of this invention can absorb more than 45% of their weight in water when soaked in water at room temperature, and may even absorb more than 10 times their weight in water. Despite absorbing such large amounts of water, the composition remains cohesive and shaped and does not dissolve. These characteristics make the compositions of the invention particularly useful for several biomedical purposes where the hydrogel is required to be in intimate contact with living tissues or body cavities. Although the mechanism of interaction between the water-soluble vinyl lactam (preferably vinyl pyrrolidone) polymer or copolymer and the water-insoluble copolymer in the mixture is not fully understood, this mixture is suitable for gel permeation chromatography. It behaves more like a physical mixture than a chemical reaction product in that it can be separated graphically into two polymeric components. The mixture is optically clear and substantially non-hazy, so even though the vinyl lactam polymer or copolymer is water-soluble and the (2) copolymer is water-insoluble, the mixture is homogeneous. It shows that. When observed under high magnification using an electron microscope, microphase zones (4000 Å in diameter) of water-insoluble substances in the continuous phase of the water-soluble vinyllactam polymer or copolymer can be seen.
(below) can be seen dispersed. The presence of these water-insoluble copolymer microphase zones prevents the continuous phase polymer from dissolving in water. However, unlike covalently crosslinked polymers, the mixture is not non-thermoplastic. That is, this mixture has the ability to be repeatedly molded at a temperature of about 150° C., sometimes even lower, under moderate pressure. The molded composition bends when expanded with water and retains its shape at room temperature. Semi-microscopically dispersed particles (microphase zone) form a hydrophilic continuous phase (itself water-soluble)
Acting as multiple crosslinks to prevent dissolution of distinguished from things. In the present invention, N-vinyl lactam, which can be used as a water-soluble polymer and a water-soluble copolymer, has the following structural formula: (In the formula, X represents an alkylene group having 3 to 5 carbon atoms.) For example, 1-vinyl-2-pyrrolidone, 1-vinyl-5-methyl-2-pyrrolidone, 1-vinyl -2-piperidone and N-vinyl-ε-caprolactam. N
- the vinyl lactam is copolymerized to form a copolymer containing 1 to 99, preferably 25 to 99 mol % of N-vinyl lactam and thus 1 to 90, preferably 1 to 75 mol % of the copolymer; Copolymerizable monomers that can be used include N,N-dimethylacrylamide, glyceryl methacrylate, diethylene or triethylene glycol monomethacrylate or other hydrophilic monomers, as well as vinyl acetate, alkyl acrylate or methacrylate, vinyl alkyl ether, acrylonitrile. , vinyl chloride, or other hydrophobic monomers. In the case of monomers such as vinyl acetate which themselves form water-insoluble homopolymers, the upper limit of such monomers that can be used to make the desired water-soluble polymer is the water-soluble homopolymer. lower than for monomers such as N,N-dimethylacrylamide, which form coalescence. These polymers and copolymers have a molecular weight of 10,000 to 1,000,000 or more, but those with a molecular weight of 100,000 to 1,000,000 are preferred. Polymers and copolymers of 1-vinyl-2-pyrrolidone are preferred. In the composition of this invention, the water-insoluble copolymer that can be used in combination with the vinyl lactam polymer or copolymer is a copolymer of three types of monomers, the first monomer having a weight of 50 to 90% by weight. % of a hydrophobic, water-insoluble ethylenically unsaturated monomer selected from the group of methyl methacrylate, n-butyl methacrylate, styrene and 2-ethylhexyl acrylate, the second monomer containing 2 to 12% by weight % and has a carboxyl group, and the third monomer is 15 to 45% by weight, has a solubility coefficient of 11 [calories/cm ² ] ^1/2 or more, and contains acid groups. A hydrophilic, ethylenically unsaturated monomer selected from the group of methacrylamide, p-styrene sulfonamide and hydroxyethyl methacrylate. For each of the three types of monomers,
The same type of monomer can be used as a mixture of two or more separate monomers. The compatibility or incompatibility of the water-insoluble copolymer with the water-soluble vinyllactam polymer or copolymer in the hydrated form of the mixture, i.e. its stability for use in this invention, in each case This can be easily determined by visual observation of a mixture of the two polymers after equilibration in water at room temperature. If the mixture is transparent and optically clear and remains optically clear after immersion in water at 20° C. without dissolving in water, a satisfactory hydrogel has been formed. Mixtures made from such copolymers are not satisfactory if the mixture is cloudy or translucent after equilibration in water, and if it dissolves in water at 20°C. Weak mechanical properties. In order for the mixed composition to have satisfactory mechanical properties in hydrated form, the size of the microphase area of the water-insoluble polymer in the hydrogel should not be more than 4000 Å.
Preferably it should be about 1000 Å or less. The relative proportions of different monomers in the water-insoluble polymer can vary widely. The exact proportions of the three types of monomers are determined by the hydrophobic-hydrophilic balance required in each case. Therefore, examples of suitable water-insoluble copolymers include 55 to 70% by weight of methyl methacrylate (or styrene, or 2-ethylhexyl acrylate) and 2 to 12% by weight of acrylic acid, based on the total weight of the copolymer. % by weight, and methacrylamide is 25
~45% by weight. An example of another suitable water-insoluble copolymer is that n-butyl methacrylate is 55% by weight based on the total weight of the copolymer.
-80% by weight, 2-12% by weight of acrylic acid, and 15-35% by weight of methacrylamide. Examples of other suitable water-insoluble copolymers include n-butyl methacrylate ranging from 50% to 50% based on the total amount of copolymer.
78% by weight, 2-12% by weight of acrylic acid, hydrophilic p
- 20-35% by weight of styrene sulfonamide. Another suitable water-insoluble copolymer contains n-butyl methacrylate at 55-70% by weight of the total copolymer, acrylic acid at 2-12% by weight, and hydroxyethyl-methacrylate at 25-70% by weight of the total copolymer.
It is 43% by weight. The relative proportions of the water-soluble vinyl lactam polymer or copolymer and the water-insoluble copolymer in the mixture are:
The former may vary within a wide range, with the former amounting to 40 to 98%, preferably 50 to 98%, and the water-insoluble copolymer ranging from 2 to 60%, preferably 2 to 50% by weight, relative to the total weight of the mixture. It is something. The optimum proportions of each component within that range will vary depending on the properties desired in the mixture, as well as the nature of the polymers or copolymers present in the mixture. The higher the proportion of water-insoluble copolymer in the mixture, the lower the equilibrium water content of the resulting hydrogel. The water content of the formulated hydrogels of this invention is determined by the proportion of water-soluble and water-insoluble polymers and copolymers and their mixtures, particularly poly-(N-vinyl-2-pyrrolidone), which is the water-soluble component of the mixture. In some cases, by making appropriate selections, approximately
It can vary from 30 to 90% or more. Generally, the higher the water content of a hydrogel, the weaker its mechanical properties. The mixture is prepared by mixing together solutions or dispersions of the water-soluble polymer or copolymer and the water-insoluble copolymer using a suitable mutually miscible vehicle or solvent, and then removing the vehicle or solvent, such as by evaporation. It can be made by removing. It is also possible to mix the components on a hot roll mill or in an extruder or in other suitable mixers. A molded article of the mixture can be made by pouring it using a suitable solvent or by putting it into a mold under heat and pressure. The thermoplasticity of these hydrogel-forming mixtures is
Gives the mixture particularly superior processability over covalently crosslinked synthetic hydrogels. The mechanical and physical properties of the hydrogel (e.g. water content, solute-water permeability, softness, flexibility, tensile strength) can be controlled by adjusting the physicochemical properties of the water-insoluble copolymer and its proportion in the mixture. It can be easily set. Additionally, the physical properties of the mixture may be influenced by the presence of compatible, water-soluble liquid plasticizers such as ethylene glycol, diethylene glycol, glycerin, or Carbowax.
This can be changed by incorporating liquid polyethylene glycol (oxide) with a molecular weight of up to about 600, which is commercially available under the trade name . This advantage makes the novel hydrogel compositions of the present invention useful for use in burn and wound dressings, catheter and surgical suture coatings, soft contact lenses, controlled rate drug delivery tubes, and other biological applications. It serves several applications, such as components that come into close contact with body cavities (eg, vitreous and corneal prostheses). These new hydrogel-forming materials can also be used to produce controlled delivery of drugs that are poorly soluble in water. When drugs (soluble in water-insoluble copolymers) are added to these hydrogels, they are dispersed into hundreds of thousands of "reservoirs" of water-insoluble areas. Consequently, the drug delivery rate depends on the partition coefficient of the drug in the aqueous and non-aqueous phases, the film geometry, and the size and number of dispersion zones. Such a method is advantageous because lack of mechanical strength or pinholes do not increase the drug delivery rate. Non-medical applications of the novel compositions of this invention include anti-fog coatings on glass surfaces, such as the interior of automobile and aircraft windows. The coating is applied by pouring with a suitable solvent as shown in Example 19.
This is done by applying a thin coating of a mixed composition, such as that described in , to the glass surface. Coating of the polymer mixture can also be carried out by spraying dilute solutions in suitable solvents. The coating has good adhesion to glass, is colorless, optically clear, and does not fog when exposed to hot, humid air. The following specific examples will more fully explain the nature of the invention, but are not intended to limit its scope. Example 1-13 Each of the copolymers in these examples (hereinafter simply referred to as a copolymer means a water-insoluble copolymer unless otherwise specified) is prepared by adding monomers in a desired proportion in a suitable solvent. A small amount (0.2-0.4% by weight of monomer) of azobisisobutylnitrile or 2-tert-butylazo-
It was prepared by using a free radical generator such as 2-cyanopropane. Polymerization reaction is 80~
It was carried out at 95°C with high conversion. The composition of the mixture for forming the water-insoluble copolymer is shown in Table 1. Example 1
The copolymer of ~3 was isolated from the reaction mixture by precipitation in methanol, collected by filtration, and incubated under vacuum at 100°C.
It was dried. On the other hand, the copolymer of Example 5 was
It was isolated by heating at 100°C to remove volatiles.

[Table] Each of these example mixture compositions was prepared by dissolving the desired proportions of the water-insoluble copolymer and poly(vinyl pyrrolidone) (grade K-90, molecular weight 360,000) in N,N-dimethylformamide. Mixed composition 10
A solution containing ~15% by weight was obtained. The solution of the mixture was then heated under vacuum at 100° C. to evaporate the solvent and leave an optically clear mass with mixed solids. Since the mixture is thermoplastic, in the mold
It was heated to 150℃ and press-molded into a disk. The molded disks were placed in deionized water for 72 hours, during which time they absorbed water and swelled to form a hydrogel. The components of the mixture, its physical appearance, and the equilibrium water content of the hydrogel are shown in the table.

[Table] Example 14-15 20.8 g (0.10 mol) of phosphorus pentachloride is placed in a 500 ml round bottom flask, and 17.4 g
(0.084 mol) of ground p-sodium styrene sulfonate was added slowly with ice bath cooling and the mixture was carefully mixed with a magnetic stirrer. After 30 minutes, it was heated at reflux for 2 hours at 50-60°C. The mixture was cooled, poured into 100 g of crushed ice and extracted with 100 ml of chloroform. The organic phase containing p-styrenesulfonyl chloride was separated, washed several times with distilled water and dried over magnesium sulfate. A chloroform solution (100 ml) containing p-styrenesulfonyl chloride was added to 340 ml of 30% ammonium hydroxide (specific gravity 0.90) under mechanical stirring and cooled on ice for about 30 minutes. The mixture is 5
It was heated to 50° C. in a reflux condenser for an hour and then cooled to room temperature. The organic phase was separated and dried over anhydrous magnesium sulfate. It was then evaporated to give a solid white powder of crude p-styrene sulfonamide. This was purified by recrystallization using an ethanol-water mixture,
Approximately 6.0 g of sulfonamide with a melting point of 130-132°C was obtained. The infrared spectrum of sulfonamide is 3350 and 3260
cm ^-1 (NH branch), 1600 cm ^-1 (aromatic C=C), 1305 and
It exhibited absorptions at 1160 cm ^-1 (S=O branch) and 840 cm ^-1 (p-disaturated benzene, two adjacent CH end groups). A copolymer of 62% n-butyl methacrylate, 30% p-styrene sulfonamide prepared as described above, and 8% acrylic acid was prepared in a mixture of ethyl alcohol and dioxane as described in Example 1-13. was produced in the usual way using monomers at a concentration of 33%. The copolymer was purified by precipitating the reaction mixture in chloroform, then isolated by filtration and dried under vacuum at 100°C. This copolymer poly(vinyl-pyrrolidone)
(PVP, grade K-90, molecular weight 360,000) was prepared by dissolving the copolymer and PVP in dimethylformamide and then removing the solvent as described in Examples 1-13.
Produced by evaporation under vacuum at 100°C. 10% and 30% by weight of copolymer, the remainder being poly(vinyl-pyrrolidone), respectively.
The mixture was found to be an optically transparent solid. Molded discs of the two mixtures, prepared in the manner described in Examples 1-13, absorbed water when equilibrated with deionized water for 72 hours at room temperature, with concentrations of 84.6% and 62.5% by weight. It was found that a transparent hydrogel containing water was formed. Example 16-19 Hydroxyethyl methacrylate (HEMA) is prepared by extracting a 1:1 aqueous solution of monomer to water with petroleum ether (4 to 6 times), then saturating the aqueous monomer solution with sodium chloride, and extracting the monomer with chloroform. It was purified by The chloroform extract was dried over anhydrous magnesium sulfate, and the solution was vacuum distilled (~1.0 mmHg) using copper chloride as an inhibitor. The monomer portion was distilled at 70-82°C. A copolymer of 52% butyl methacrylate, 40% HEMA, and 8% acrylic acid was prepared in a conventional manner using a 25% concentration of the monomers in a mixture of ethyl alcohol and dioxane, as described in Examples 1-13. Manufactured in Poly(vinyl pyrrolidone) (PVP, grade K-
Optically clear mixtures of copolymers with varying proportions of 90% and 360,000 molecular weights were prepared by dissolving the copolymers and PVP in methylformamide and then removing the solvent from 100% Prepared by evaporation under vacuum at °C. After pressing a sheet approximately 8-12 x 10 ^-3 inches thick from the mixture, it was equilibrated in deionized water for 72 hours at room temperature. Mixtures containing 70, 80 and 90% by weight of PVP, respectively,
Hydrogels containing 75.8%, 82.3%, and 88.9% water by weight were formed. Example 20-26 A copolymer of 62% butyl methacrylate, 8% acrylic acid and 30% methacrylamide is Example 1-13
Manufactured using the same general method as described. The same poly(vinyl-pyrrolidone), grade K-90, was then used in Example 16 with varying amounts of the resulting copolymer.
An optically clear mixture was prepared as described in ~19. Proportion of copolymer in the mixture (10-40%)
It was found that a linear relationship exists between the equilibrium water content of the hydrogel and the equilibrium water content of the hydrogel, as seen in column A of the table below. In order to take into account the change in the properties of PVP in the mixture due to the addition of the copolymer, the hydration of only the PVP portion and the expansion of the copolymer in water are assumed to be negligible, and the last column of the table Calculated as shown in It was again observed that the equilibrium water absorption of the PVP moiety is inversely proportional to the amount of copolymer in the mixture.

[Table] Example 27-34 A series of water-soluble 1-vinyl-2-pyrrolidone copolymers containing vinyl acetate, N,N-dimethylacrylamide and mixtures thereof in various proportions,
The desired proportions of monomers were dissolved in an equal volume of methanol and prepared using about 0.15% by weight (based on monomer) of a free radical generator such as 2,2'-azobisisobutyronitrile as an initiator. Polymerization is carried out under refluxing conditions of the solvent, with a conversion rate of approximately 90-95
It went up to %. This water-soluble copolymer was obtained after evaporating the solvent and residual monomers by heating the reaction mixture to 100° C. under vacuum. A water-insoluble copolymer mixture consisting of 62 parts by weight of n-butyl methacrylate, 30 parts of methacrylamide and 8 parts of acrylic acid was prepared by the procedure described in Example 1-13. A mixture of water-soluble and water-insoluble copolymers is Example 16-
Prepared as described in 19. The composition of the vinylpyrrolidone copolymer, the amount of copolymer of the water-insoluble copolymer in the mixture, and the equilibrium water content of each hydrogel mixed in deionized water after 72 hours at room temperature are shown in the table. In each example, the mixture was an optically clear solid and formed an optically clear hydrogel when in equilibrium with water.

Table: The mixtures of the invention are thermoplastic, meltable, and hydratable, as well as soluble in organic solvents. However, while the mixture retains the thermoplasticity, meltability and solubility in organic solvents of the water-soluble polymer or water-soluble copolymer portion therein, it is possible to This indicates that the hydration properties of the water-soluble polymer or water-soluble copolymer portion change.

Claims (1)

[Scope of Claims] 1. The optically transparent material according to (1) and (2) below, which can absorb 45% or more of its weight in water without dissolving at room temperature to form an optically transparent hydrogel. (1) 40 to 98% by weight, based on the total weight of the mixture, of the following structural formula: (wherein, X is an alkylene group having 3 to 5 carbon atoms) or a copolymerizable monomer having a polymerizable ethylenically unsaturated bond in an amount of 1 to 90 mol%. a water-soluble copolymer with this lactam, in which the molecular weight of said polymer or copolymer is at least 10,000; (2) methyl methacrylate, in an amount of 2 to 60% by weight, based on the total weight of the mixture; 50-90% by weight of monomers selected from the group of n-butyl methacrylate, styrene and 2-ethylhexyl acrylate, 2-12% by weight of acrylic acid and selected from the group of methacrylamide, p-styrene sulfonamide and hydroxyethyl methacrylate. A water-insoluble copolymer derived from 15 to 45% by weight of monomers. 2. The composition according to claim 1, wherein the vinyl lactam is N-vinyl-2-pyrrolidone. 3 The water-insoluble copolymer contains methyl methacrylate, styrene and 2-
A composition according to claim 1 or 2, which is derived from 55-70% by weight of monomers selected from ethylhexyl acrylate, 2-12% by weight of acrylic acid and 25-43% by weight of methacrylamide. 4. The water-insoluble copolymer contains 55 to 80% by weight of n-butyl methacrylate, based on the total weight of the copolymer.
2-12% by weight of acrylic acid and methacrylamide
Claim 1 derived from 15-35% by weight
The composition according to item 1 or 2. 5 The water-insoluble copolymer contains 50 to 78% by weight of n-butyl methacrylate, based on the total weight of the copolymer.
3. A composition according to claim 1 or 2, which is derived from 2 to 12% by weight of acrylic acid and 20 to 35% by weight of p-styrene sulfonamide. 6. The water-insoluble copolymer contains 55 to 70% by weight of n-butyl methacrylate, based on the total weight of the copolymer.
A composition according to claim 1 or 2, which is derived from 2 to 12% by weight of acrylic acid and 25 to 43% by weight of hydroxyethyl methacrylate. 7. The composition according to any one of claims 1 to 6, wherein the water-soluble copolymer or the water-soluble copolymer has a molecular weight of 10,000 to 1,000,000.