NL8002335A - WATER ABSORBING MIXTURE. - Google Patents

Description

t 5 (, VO 0372 TT Water absorbing mixture.

The invention relates to a mixture capable of absorbing more than 45% of its own weight of water at room temperature without dissolving to form a hydrogel. The invention relates in particular to an optically clear mixture of a poly (TT-vinyl-2-pyrrolidone) with a water-insoluble copolymer, derived from 50-90% by weight, based on the copolymer of a hydrophobic water-insoluble olefin-unsaturated monomer, 2-12% by weight of an olefin-unsaturated monomer containing an acid group and 15-2 * 5% by weight of a hydrophilic olefin-unsaturated monomer, that is free from acid groups.

It has previously been proposed to render insoluble polymeric vinyl vinyls, such as poly (vinylpyrrolidone), by reacting them with water-soluble polymers containing carboxyl groups, precipitating the reaction product from the solution when the two are mixed (United States Patent 2,901,457) »This patent states in column 4> lines 66 - 73» that the reaction product described there always has almost the same properties and contains the two polymeric components in the same proportions, regardless of the relationships, in which the two are merged. The mixtures prepared according to the invention, on the other hand, vary in properties and in the component ratio, depending on the properties and the proportions of the starting materials.

U.S. Pat. Nos. 3 * 700,761, 3 * 807,398 and 4 * 018,853 propose to prepare covalently cross-linked hydrogels by polymerizing hydrophilic methacrylate monomers in the presence of poly (vinyl pyrrolidone).

The mixtures according to the invention when immersed in water at room temperature can absorb more than 45% of their own weight of water and can sometimes absorb more than 10 times their own weight of water. Despite the absorption of such large amounts of water, the mixtures retain their cohesion and remain in one piece and do not dissolve; these 800 2335-2 properties make them particularly valuable for various biomedical applications, which cause the hydrogel to come into some contact with body tissues or cavities.

The mechanism of the interaction between the poly-5 (vinyl pyrrolidone) and the copolymer in the mixture is not very clear, but the mixture behaves more like a physical mixture than as a chemical reaction product, because it can be separated again into the two polymers components by gel permeation chromatography. The blends are optically clear and practically non-blurry, indicating that the blend is homogeneous despite the fact that the poly (vinyl pyrrolidone) is water soluble and the copolymer is water insoluble. High magnification examination under an electron microscope shows that microfase domains are present (midline 400 nm or less) consisting of water-insoluble material dispersed in the continuous phase of the water-soluble poly (vinyl pyrrolidone).

The presence of these water-insoluble copolymer microfase domains prevents dissolution of the polymer from the continuous phase in water, but does not prevent the mixture from remaining thermoplastic. In this regard, the mixture of polymers covalently cross-linked differs. The mixture according to the invention has the property of being able to be deformed repeatedly under moderate pressure at a temperature of only 150 ° C and in some cases even lower. The mixture so deformed retains its shape at room temperature apart from the deformation that occurs from swelling with water. The mixtures according to the invention, in which the dispersed sub-microscopic particles (microfase domains) act as numerous cross-links that prevent dissolution of the hydrophilic continuous phase (which phase itself dissolves in water) form a new class of hydrogels, which differs from that in which the cross-links consist of weak cohesion forces, of hydrogen bonds, of ionic bonds or of covalent bonds.

800 2 3 35 ..- 5 - Λ, - * Note that the water-soluble poly (vinyl pyrrolidone) used in the mixtures according to the invention may have a molecular weight within a wide range, eg, between 10,000 and 1,000,000 or more, but preferably the molecular weight is between 100,000 and 1,000,000.

The copolymers which can be used in admixture with the poly (vinylpyrrolidone) in the mixtures of the invention include the water-insoluble copolymers of a hydrophobic water-insoluble olefin-unsaturated monomer, such as alkyl esters of acrylic acid or methacrylic acid with 1 to 16 carbon atoms in the alkyl group, styrene, acrylonitrile, vinyl acetate, vinyl butyrate, vinyl chloride, vinylidene chloride, ethylene, propylene, butene, butadiene and other polymerizable alkadienes, vinyl alkyl ethers and vinyl alkyl ketones, with three or more carbon atoms in the alkyl group. As a second essential monomer, the copolymers also contain an olefin-unsaturated monomer with an acid group, such as a carboxylic acid group, a sulfonic acid group. or a phosphonic acid group; suitable acidic monomers are acrylic acid, methacrylic acid, crotonic acid, maleic acid, 2-sulfoethyl methyl methacrylate and 1-phenyl vinyl phosphonic acid. The monomer is selected from a group of hydrophilic olefin-unsaturated monomers which have a dissolution parameter greater than 2/2 than ii (calories / cnr) 'and are free from acid groups such as methacrylamide, acrylamide, hydroxyethyl methacrylate, diethyl-25 glycol monomethacrylate, triethylene glycol monomethacrylate and glyceryl methacrylate.

For each of the three types of monomers, one can also use a mixture of two or more individual monomers of the same type.

The compatibility or non-compatibility of the water-insoluble copolymer with the water-soluble polymer of N-vinyl-2-pyrrolidone in the hydrated form of the mixture, that is, its suitability for use according to the invention. in each case easily determined by a visual examination of the mixture 800 2 3 35-4 of the two polymers after equilibration with water at room temperature. When the mixture is transparent and optically clear and it remains after immersion in water at 20 ° C without dissolving in water, it forms a satisfactory hydrogel. If the mixture is cloudy or opaque after it has equilibrated with water or if it dissolves in water at 20 ° C, then the mixture prepared from that copolymer is unsatisfactory and has poor mechanical properties. For a mixture to have satisfactory mechanical properties in the hydrated form, the microphase domains of the terpolymer in the hydrogel should be no greater than 400 nm and preferably about 100 nm.

The interrelationships of the different monomers in the copolymer can vary widely. The amount of hydrophobic, water-insoluble olefin-unsaturated monomer may be from 50 to 90 weight percent based on the copolymer, while the amount of olefin-unsaturated monomer containing an acid group may be from 2 to 12 weight percent. The hydrophilic olefin-on-saturated monomer can release from 0 to 50 weight percent of the copolymer. The correct ratio of the three types of monomers is determined by the balance of hydrophobic and hydrophilic properties required for each case. In many cases it is necessary to process 15 - 45% hydrophilic monomer to achieve this balance.

In a preferred group of copolymers, the amount of methyl methacrylate (or styrene or 2-ethylhexyl acrylate) is 55-70 wt.%, Based on the copolymer, the amount of acrylic acid is 2-12 wt., And the amount of methacrylamide 25-55. wt.fi.

In another preferred copolymer, the amount of n-butyl methacrylate is 65-80 wt.%, Based on the copolymer, the amount of acrylic acid is 2-12 wt.%, And the amount of methacrylamide is 15-55 wt.

In a third preferred copolymer, the amount of methyl methacrylate is 88 - 90 wt.%, Based on the 800 2 3 35 - 5 - copolymer, while as any other monomer, 10-12 wt. 2-acrylamido. 2-methylpropanesulfonic acid is present. In this case, the presence of a non-acidic hydrophilic comonomer is not necessary.

In a fourth preferred copolymer, the amount of n-butyl methacrylate is 50-78% by weight, based on the copolymer, the amount of acrylic acid is 2-12% by weight and the amount of hydrophilic 2-styrene sulfonamide is 20-35% by weight. In a fifth preferred copolymer, the amount of 10 n-butyl methacrylate is 55-70 wt.%, Based on the copolymer, while additionally 2-12 wt.% Acrylic acid and 25-43 wt.% Hydroxy ethyl methacry are present.

The inter-proportions of poly (vinyl pyrrolidone) and copolymer in the mixture also vary over a wide range, with 40 - 98 wt.% And preferably 50 - 98 wt.% Poly (vinyl pyrrolidone) being present in addition to 2 - 60 wt. and preferably 2 - 50% by weight of the copolymer. The optimal amount of each varies within this range, depending on the properties desired in the blend and on the identity of the copolymer used. The greater the amount of copolymer in the mixture, the smaller the water content of the hydrogel obtained after equilibration. The water content of the hydrogels of the invention can be varied from about 30 ° to 95 ° or more by judicious choice of the copolymer and of the content in the mixture.

In general, the mechanical properties of the hydrogel deteriorate the more water it contains.

The mixture can be prepared by mixing solutions or dispersions of the poly (vinyl pyrrolidone) and of the copolymer in any desired carrier or solvent that are miscible with one another and then removing the carrier or solvent, e.g., by evaporation. It is also possible to mix the polymer and the copolymer together on a heated roller or in an extruder or in another conventional mixing equipment. Molded articles of the mixture can be obtained 800 2335-6 by pouring from a suitable solvent or by molding using heat and pressure.

The thermoplastic properties of these hydrogel-forming mixtures give them an advantage over processing the synthetic hydrogels, which are covalently cross-linked. The fine adjustment of the mechanical and physical properties (e.g. water content, permeability to solute and water, firmness, flexibility and tensile strength) of the hydrogel can be easily performed by controlling the physico-chemical properties and the percentage in the mixture of the water-insoluble copolymer. Because of these advantages, the new hydrogel mixtures according to the invention are suitable for various purposes, such as covering burns and other wounds, as a coating material for catheters and for surgical sutures, for soft contact lenses, for implantation materials to deliver drugs at a controlled rate and for other objects, which must come into intimate contact with body tissues or cavities (eg prostheses for vitreous bodies or for the cornea).

These new hydrogel-forming materials can also be used in the manufacture of controlled-release articles that are sparingly soluble in water. When a drug which is soluble in the water-insoluble copolymer is incorporated into these hydrogels, it remains dispersed in the form of hundreds of thousands of depots of water-insoluble domains. The drug release rate is then controlled by the distribution coefficient of the drug between the aqueous and non-aqueous phases, by the shape of the interface, and by the sizes and number of the dispersed domains. An advantage of such an article is that a mechanical break or pinhole does not cause an increase in the drug release rate.

A non-medical application of the new blends according to the invention is to coat Igga surfaces such as the insides of windshields of cars and aircraft. This is achieved by pouring a thin coating of a mixture according to the invention from a suitable solvent, e.g. pour the mixture described in Example XIX onto a glass surface. A coating of the polymer mixture can also be applied by spraying a dilute solution in a suitable solvent,

The coating adheres well to glass, is colorless, optically clear 10 and does not fog when exposed to hot, moist air.

The invention is illustrated, but not limited to, by the following examples.

Examples I-XIII

Each of the copolymers in these examples was prepared in a conventional manner by a polymerization in solution, the desired amounts of monomer being dissolved in a suitable solvent, after which, as a polymerization initiator, a small amount (0.2-0.4 wt. calculated on the monomers of a free radical former such as azobis-20 isobutyronitrile or 2-tert-butylazo-2-cyanopropane

uses. The polymerization was carried out at 80 - 95 ° C to a high degree of conversion. The composition of the copolymerization mixtures is shown in Table A. The copolymers of Examples I-IT were isolated from the reaction mixture by precipitation in methanol, filtering and drying at 100 ° C.

in vacuum, while the copolymer of Example V was isolated by evaporating the volatiles in vacuo at 100 ° C.

s '' 800 2 3 35 - 8 -

TABLE A

Reaction components I II III Γ7 V

Comonomers - (g)

Methyl methacrylate 65 - 90 - 5 Methacrylamide 30 30 15 - 50

Styrene -65 ---

Acrylic acid 555-5 n-Butyl methacrylate - - 80 -.- 2-Acrylamido-2-methyl- 10 propanesulfonic acid - - - 10 2-Ethylhexyl acrylate - - - - 65

Solvents - (ml)

Ethanol 100 100 100 - 100

Dioxane 100 100 100 15 ΪΓ, ΙΓ-Dimethylformamide - - - 100 100

Each of the blends of these examples was prepared by dissolving the desired amounts of the water-insoluble copolymer and poly (vinylpyrrolidone) (Type K-90, mol, weight 36Ο.ΟΟΟ) in ΪΓ, T-methylethylamide. 20 containing 10-15 wt.% Of the polymer mixture. The solution of the mixture was then heated to 100 ° C under vacuum, evaporating the solvent, leaving a mass of optically transparent solid mixture. This thermoplastic mixture was pressed into a disk in a press mold heated to 150 ° C. This pressed disc was placed in demineralized water for 2 hours during which time the material absorbed water and swelled into a hydrogel. The composition of the mixtures, their physical appearance and the water content of their hydrogels after equilibration are summarized in Table B.

800 2 3 35 - - 9 -

TABLE B

Premix Physical appearance water content

Image copolymer wt.% PVP dry form hydrated at equilibrium no. From premixed image sel x) form VI I 70 transparent and solid and strong, VII I 90 "91 10 VIII II 70 "" 58 IX II 90 "" 80 X III 90 "translucent and cohesive XI IV 90" transparent and cohesive 20 XII V 70 "transparent and strong XIII V 90" " 90x) poly (vinyl pyrrolidone (K-90)

25 Examples XIV-XV

20.8 g (0.10 mol) of phosphorus pentachloride was charged into a 500 ml round bottom flask and 1-7 * 4 g (0.084 mol) of powdered p-sodium styrene sulfonate was slowly added thereto while cooling in an ice bath. The mixture was gently stirred with a magnetic stirrer. After 30 minutes, the mixture was heated to 50-60 ° C and refluxed at that temperature for 2 hours. The product was cooled and poured into 100 g of crushed ice and extracted with 100 ml of chloroform. The organic layer containing p-styresnsulfonyl chloride 800 2 3 35-10 was separated, washed several times with distilled water and dried with magnesium sulfate.

The solution in chloroform (100 ml) containing p-styrene sulfonyl chloride was added over 340 minutes under mechanical stirring to 340 ml of 30% ammonium hydroxide (sg 0.90) under ice-cooling. The mixture was then refluxed at 50 ° C for 5 hours and then cooled back to room temperature.

The organic layer was separated, dried with anhydrous magnesium sulfate and then evaporated to dryness, yielding a solid white powder consisting of crude p-styrene sulfonamide, which was purified by recrystallization from a mixture of ethanol and water. Additionally, about 6.0 g of the sulfonamide was obtained; melting point 130 - 132 ° C "15 The IR spectrum of the sulfonamide showed absorbances at 3350 and 3260 cm" 1 (NH stretching vibrations), 1600 cm "1 (aromatic C = C), 1305 and 1160 cm" 1 (S = 0 stretching vibrations), and 840 cm -1 (p-disubstituted benzene, vibrations of 2 vicinal CH groups).

A copolymer of 62% n-butyl methacrylate, 30% p-styrene-20. sulfonamide (prepared as above) and 8% acrylic acid was prepared in the usual manner as indicated in Examples 1 - XIII at a concentration of 33% monomers in a mixture of ethanol and dioxane. The copolymer was purified by precipitating the reaction mixture in chloroform and then filtering it off and drying in vacuo at 100 ° C.

Blends of this copolymer with poly (vinyl pyrrolidone) (PVP, type K-90, molecular weight 36Ο.ΟΟΟ) were prepared, as described in Examples I - XIII, by dissolving the copolymer and the poly (vinyl pyrrolidone) in dimethylformamide 30 and then evaporating the solvent in vacuo at 100 ° C.

It was found that two blends containing $ 10 and $ 30 copolymer, respectively, which were otherwise poly (vinylpyrrolidone) were optically transparent solids. Discs pressed from these mixtures (analogous to Example I - XIII) were found to take up water and form transparent hydrogels, which contained 800 2 3 35 - 11 - containing 84.6 and 62.5% water ", respectively, after equilibrated with demineralized water at room temperature for 2 hours.

Examples XVI-XIX

Hydroxyethyl methacrylate (HEMA) was purified by extracting a 1 L 1 solution of the polymer in water 4 to 6 times with petroleum ether and then saturating the aqueous solution of the monomer with sodium chloride and then extracting the monomer with chloroform. The combined chloroform extracts were dried with anhydrous magnesium sulfate and the solution distilled in vacuo (0.1 mm mercury pressure) while cuprous chloride was added as inhibitor. The monomer fraction distilled at 70-82 ° C.

A copolymer of 52% butyl methacrylate, 40% HEMA and 8% 15 acrylic acid was prepared in the usual manner as indicated in Examples 1 - XIII, using a 25% concentration of the monomers in a mixture of ethanol and dioxane. Optically clear blends were prepared of the copolymer in varying ratio with poly (vinylpyrrolidone) 20 (PVP, type K-90, molecular weight 36Ο.Ο), analogous to Examples I-XIII, by dissolving the copolymer and the PVP in dimethylformamide and evaporating the solvent at 100 ° C in vacuo. Sheets of these blends of about 0.2-0.3 mm thickness were formed under heating and pressing and then placed in demineralized water at room temperature for 72 hours to equilibrate. It was found that mixtures containing 70, 80 and 90 wt% PVP formed hydrogels, containing 85.8, 82.3 and 88.9 wt% water, respectively,

30 Examples XX - XXVI

A copolymer of 62% by weight butyl methacrylate, 8% by weight acrylic acid and 30% by weight methacrylamide was prepared according to the same general methods as described in Examples 1 - XIII and then optically clear blends of the resulting copolymer were prepared in varying amounts. of the same 800 23 35 - 12 - poly (vinyl pyrrolidone), type K-90, as in examples XVI-XIX.

It was found that there is a linear relationship between the amount (10 - 40 ^) of copolymer in the mixture and the water content of the hydrogels after equilibrium, as shown in column a of Table C. To adjust the change in the properties of the PVP in taking into account the mixture resulting from the copolymer processing, the hydration of the PVP fraction alone was also calculated, assuming that a swelling of the copolymer in water is negligible, as shown in the latter column of table C. Again, it was found that the uptake of water after equilibration of the PVP fraction was inversely proportional to the amount of copolymer in the mixture.

8002335 - 13 - ¢ -

TABLE C

Composition mixture Hydrogel mixtures

Copolymer PVP 100XWH2Q = ax100 5 parts ^ parts ^ a * b * c * a + 0

WPVP + WI20 ^ H in a hydrated PYP

10 90 83.5 16.5 14.85 84.90 15 85 79.1 20.9 17.765 81.67 20 80 77.7 22.3 17.84 81.33 10 25 75 69.6 30.4 22 j 80 75.32 30 70 64.3 55.7 24.99 72.01 35 65 61.7 58.3 24.895 71.25 40 60 55.3 44.7 26.82 67.34 0 = 100 X V - n

JlgU

fBlend ♦ 15 11 - 100 X WBlSnd

Fri VT

wBlend + HgO

a = 100 x W? 7p w w 'Blend + H20

The mixtures according to the invention have the properties that they are thermoplastic, fusible and soluble in organic solvents and very hydratable. While retaining their thermoplastic properties, meltability and solubility in the organic solvents of the PYP portion of the mixture, they exhibit varying hydration properties of the PVP portion depending on the amount of copolymer present.

800 2 3 35

Claims (11)

1. Mixture which is capable of absorbing more than 45 ^ of its own weight of water at room temperature without dissolving to form an optically clear hydrogel, which mixture consists essentially of an optically clear mixture of 5 (a) 40 - 98 wt.%, based on the mixture, of a water-soluble polymer of N-vinyl-2-pyrrolidone having a molecular weight of at least 10,000 and (b) 2-60 wt.% of a water-insoluble copolymer obtained from 10 (a) 50-90 wt.%, based on the copolymer of a hydrophobic water-insoluble olefin-unsaturated monomer, (b) 2-12 wt. fa of an olefin-unsaturated monomer containing an acid group , and (C) 15-5 wt.% of a hydrophilic, olefin-unsaturated mono-15 lake free of acid groups, Mixture according to claim 1, characterized in that the copolymer b) contains 15 - 45% by weight of the monomer (c). 3. Mixture according to claim 2, characterized in that the copolymer b) is derived from 55-70 wt.%, Based on the copolymer, of methyl methacrylate, styrene or 2-ethylhexyl acrylate, 2-12 wt.% Acrylic acid and 25-43 wt.% methacrylamide. 4. Mixture according to claim 2, characterized in that the copolymer b) comprises 65 - 80 wt.%, Calculated on the copolymer, containing n-butyl methacrylate, 2-12 wt.%. acrylic acid and 15-35 wt. methacrylamide. 5. A mixture according to claim 1, characterized in that the copolymer b) is obtained from 88-90 wt.%, Based on the copolymer, of methyl methacrylate and 10-12 wt. # 2-acrylic-amido-2-methyl-propanesulfonic acid. Mixture according to claim 2, characterized in that the copolymer b), based on the copolymer, comprises 50 - 78 wt.% N-butyl methacrylate, 2-12 wt.% Acrylic acid and 20 - 35 wt.% P- styrene sulfonamide. 800 23 35 - 15 A mixture according to claim 2, characterized in that the copolymer h) is obtained from 55-70% by weight, based on the copolymer, of n-butyl methacrylate, 2-12% by weight acrylic acid and 25-45% by weight, $ hydroxyethyl methacrylate. 8. Mixture according to claims 1 - 7, characterized in that the polymer a) has a molecular weight of 10,000 - 1,000,000. Catheter or suture material, coated with a mixture according to claims 1-8. Mixture according to claims 1 to 8, characterized in that a medicament is also incorporated therein. Glass plate coated on one or both sides with a mixture according to claims 1-8. 800 2335