CH655322A5 - Water-absorbent composition and catheter, suture or glass sheet coated with this composition - Google Patents

Description

The present invention relates to a composition capable of absorbing more than 45% of its weight of water without dissolving at room temperature, to form a hydrogel. It has for obyet a mixture as finished in claim 1.

It has previously been proposed to insolubilize polymeric N-vinyl lactams such as poly (vinyl pyrrolidone) by reaction with water-soluble polymers containing carboxyl groups, the reaction product precipitating from the solution when mixing the two, like this is described in US Patent No. 2,901,457 in the name of Stoner. As indicated by Stoner and others in column 4, lines 56-73, the reaction product described always has substantially the same properties and contains the two polymer components in the same proportions regardless of the proportions of the two used to form the product. The compositions of the present invention, moreover, vary in properties and in proportions of the components according to the proportions of the raw materials. In US Patent No. 3,700,761 in the name of O'Driscoll et al., In US Patent No. 3,807,398 in the name of Grucza and in US Patent No. 4,018,853 in the name of Le Bœuf et al. also proposed to form crosslinked hydrogels in a suitable manner by polymerizing hydrophylated methacrylate monomers in the presence of poly (vinyl pyrrolidone).

The compositions according to the present invention are capable of absorbing more than 45% of their own weight of water when they are immersed in water at room temperature, and they can even absorb more than ten times their own weight of water. . Despite the absorption of such large quantities of water, the compositions retain their consistency and dimensional integrity and do not dissolve; these characteristics make them particularly useful in various biomedical fields which require that the hydrogel come into intimate contact with the tissues or cavities of the body.

The mechanism of interaction between poly (vinyl pyrrolidone) and the copolymer in the blend is not fully understood, but the blend behaves as a physical blend rather than a chemical reaction product because it can be re-separated into its two polymer components by gel permeation chromatography. The mixtures are optically clear and substantially free from haze, indicating that the mixture is homogeneous despite the fact that the poly (vinyl pyrrolidone) is soluble in water and that the copolymer is insoluble in water. Examination at high magnification under an electron microscope shows the presence of microphase domains (4000 Å or less in diameter) of the water-insoluble material dispersed in the continuous phase of the water-soluble poly (vinyl pyrrolidone). The presence of these domains of the water-insoluble copolymer prevents dissolution of the polymer in the continuous phase in water, but unlike a covalent crosslinking of polymers, this does not make the mixture non-thermoplastic. On the contrary, the mixture has the ability to be repeatedly configured or formed at moderate pressure and at a temperature as low as 150 ° C, or even in some cases less. The formed or configured composition retains its shape at room temperature by being subjected to deformation when it is swollen with water. The compositions according to the present invention where the dispersed submicroscopic particles (microphase domains) act as multiple crosslinks to prevent the dissolution of the continuous hydrophilic phase (which, by itself, is soluble in water), form a new class d hydrogels, distinct from those where the crosslinking is formed by weak molecular attractions, hydrogen bonds, ionic bonds or covalent bonds.

The water-soluble poly (vinyl pyrrolidone) used in the compositions according to the invention may have a molecular weight varying over a wide range from 10,000 to 1,000,000 or more, but polymers having molecular weights of 100 are preferred. 000 to 1,000,000.

The copolymers which can be used as mixtures with poly (vinyl pyrrolidone) in the compositions according to the invention comprise water-insoluble copolymers of a water-insoluble and hydrophobic ethylenically unsaturated monomer such as alkyls esters of acrylic or methacrylic acids in which the alkyl group has from 1 to 16 carbon atoms, styrene, acrylonitrile, vinyl acetate, vinyl butyrate, vinyl chloride, 'vinylidene chloride , ethylene, propylene, butylene, butadiene and other polymerizable alkadienes, vinylalkyl ethers and vinylalkyl ketones where the alkyl group has 3 or more carbon atoms. The copolymers also contain, as other essential monomer, an ethylenically unsaturated monomer containing an acid group such as

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a carboxylic, sulfonic or phosphonic acid group; among the suitable acid monomers, mention may be made of acrylic acid, methacrylic acid, crotonic acid, maleic acid, 2-sulfo ethyl methacrylate and 1-phe-nylvinyl-phosphonic acid. The third monomer is chosen from a group of hydrophilic ethylenically unsaturated monomers having a solubility parameter greater than 11 [calories / cm 3] ':, devoid of acid groups, such as methacrylamide, acrylamide, p-styrene Sulfonamide, hydroxyethyl methacrylate, dieethylene glycol monomethacrylate, triethylene glycol monomethacrylate and glyceryl methacrylate.

In the case of each of the three types of monomers, a mixture of two or more individual monomers of the same type can be used.

The compatibility or incompatibility of the water-insoluble co-polymer with the water-soluble polymer of N-vinyl-2-pyrrolidone, in the hydrated form of the mixture, that is to say its adaptability to a use in the present invention can easily be determined, in each case, by visual examination of a mixture of the two polymers after equilibration in water at room temperature. If the mixture is transparent and optically clear and thus remains after immersion in water at 20 ° C without dissolving in water, it forms a satisfactory hydrogel. If the mixture is foggy or opaque after equilibration in water, or if it dissolves in water at 20 ° C, the mixture formed from this copolymer is not satisfactory and has poor mechanical properties. For a mixture composition to have satisfactory mechanical properties in hydrated form, the size of the microphase domains of the terpolymer in the hydrogel must not be greater than 4000 Å, and preferably less than about 1000 Å.

The relative proportions of the different monomers in the copolymer can vary widely; the hydrophobic ethylenically unsaturated and water-insoluble monomer can reach 50 to 83% by weight, based on the total weight of the copolymer, while the ethylenically unsaturated monomer containing an acid group can reach 2 to 12% by weight ; the ethylenically unsaturated hydrophyl monomer can reach 15 to 45% by weight. The exact proportions of the three types of monomers are determined by the hydrophobic-hydrophilic balance required in each case.

Thus, in the case of a preferred class of copolymers, the amount of methyl methacrylate (or of styrene or of 2-ethylhexyl acrylate) is of the order of 55 to 70% by weight based on the total weight of the copolymer, the amount of acrylic acid is 2 to 12% by weight and the amount of methacrylamide is 25 to 43% by weight.

In the case of another preferred copolymer, the amount of n-butyl methacrylate is 65 to 80% by weight based on the total weight of the copolymer, the amount of acrylic acid is 2 to 12% by weight and the amount of methacrylamide is 15 to 35% by weight.

In the case of another preferred copolymer, the amount of n-butyl methacrylate is 50 to 78% by weight of the total copolymer, the amount of acrylic acid is 2 to 12% by weight and the amount of p- Hydrophilic sulfonamide styrene is 20 to 35% by weight. In another preferred copolymer, the amount of n-butyl methacrylate is 55 to 70% by total weight of the copolymer, acrylic acid represents from 2 to 12% and hydroxyethyl methacrylate from 25 to 43%.

The relative proportions of the poly (vinyl pyrrolidone) and of the copolymer in the mixture vary over a wide range, from 40 to 98% by weight, preferably from 50 to 98%, based on the total weight of the mixture, for the first and from 2 to 60% by weight, preferably from 2 to 50% for the copolymer; the optimum proportions of each in the ranges indicated vary according to the particular properties desired in the mixture as well as according to the identity of the particular copolymer present in the mixture. The greater the proportion of the copolymer in the mixture, the lower the equilibrium water content of the resulting gel. The water content in the poly (vinyl pirrolydene) -mix hydrogels according to the invention can vary on the order of 30 to 95% or more by a judicious choice of the copolymer and of its proportion in the mixture. In general, the mechanical properties of the hydrogel become less and less good with increasing water content.

The mixture can be obtained by mixing together solutions or dispersions of the poly (vinyl pyrrolidone) and the copolymer in any desired vehicle or solvent miscible with each other, then removing the vehicle or solvent, for example by evaporation. It may also be possible to mix the polymer and the copolymer on a hot cylinder mill in an extruder or other traditional mixing equipment. Mixed-shaped articles can be prepared by pouring in a suitable solvent or by a molding process under the influence of heat and pressure.

The thermoplasticity of these hydrogel-forming mixtures gives them a special processing advantage over covalently crosslinked synthetic hydrogels. Determination of the mechanical and physical properties (i.e. water content, solute and water permeability, softness, flexibility, tensile strength) of the hydrogel is easily accomplished by controlling the physical- 30 chemical and the proportion in the mixture of the water-insoluble copolymer. Given these advantages, the hydrogel compositions according to the invention lend themselves to several applications such as dressings for burns or wounds, coatings for catheters and surgical sutures, soft contact lenses, implants for administration of drugs to controlled doses, and other items coming into intimate contact with body tissue or cavities (such as vitreous and corneal prostheses).

These new hydrogel-forming materials can also be used for the manufacture of devices for the controlled administration of sparingly water-soluble drugs. When a drug (soluble in the water-insoluble copolymer) is incorporated into these hydrogels, it remains dispersed in hundreds of thousands of "deposits" of 45 water-insoluble domains. The rate of drug administration is therefore regulated by the coefficient of distribution of the drug in the aqueous and nonaqueous phases, the geometry of the membrane and the size and number of the dispersed domains. Such a device has an advantage because a mechanical break or a pinhole cannot cause any increase in the rate of drug delivery.

The new compositions according to the invention have a non-medical use for coating glass surfaces, 55 such as the internal sides of automobile and aircraft windshields, to make them anti-fog. This is accomplished by pouring a thin coating of a mixture composition, such as that described in Example 18, onto a glass surface with a suitable solvent. The coating of the polymeric mixture 60 can also be accomplished by spraying its dilute solution in a suitable solvent. The coating has good adhesion to glass, it is colorless, optically clear and anti-fog when exposed to hot and humid air.

The specific examples which follow are intended to better illustrate the nature of the present invention without however limiting its scope.

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Examples 1 to 11

Each of the copolymers of these examples was prepared by a traditional process of polymerization in solution by dissolving the desired proportions of the monomers in an appropriate solvent and by using, as initiator of polymerization, a small quantity (0.2-0.4% in weight of the monomers) of a free radical generator such as azobisisobutyronitrile or 2-t-butylazo-2-cyanopropane. The polymerization was carried out at 80-95 ° C to a high degree of conversion. The composition of the copolymerization mixtures is indicated in Table I. The copolymers of Examples 1 to 3 were isolated from the reaction mixture by precipitation in methanol, collected by filtration and dried at 100 ° C. under vacuum, while the copolymer of Example 4 was isolated by removal of the volatiles by heating under vacuum at 100 ° C.

Table I Example No.

Reaction ingredients 12 3 4

Comonomeres - grams methyl methacrylate

65

-

-

-

methacrylamide

30

30

15

30

styrene

-

65

-

-

acrylic acid

5

5

5

5

n-butyl methacrylate

-

-

80

-

2-acrylamido-2- acid

sulfonic methyl propane

-

-

-

-

2-ethylhexyl acrylate

-

-

-

65

Solvents - milliliters

ethanol

100

100

100

100

dioxane

100

100

100

-

N, N-dimethylformamide

-

-

-

100

Each of the compositions of these examples was prepared by dissolving, in N, N-dimethylformamide, the desired proportions of the water-insoluble copolymer and of poly (vinyl pyrrolidone) (quality K-90, molecular weight 360,000) to obtain a solution containing 10-15% by weight of the polymer mixture. The mixture solution was then heated to 100 ° C under vacuum to evaporate the solvent, leaving a mass of mixed solid material and optically transparent. The mixture, which was thermoplastic, was pressed into a disc in a mold heated to 150 ° C. The molded disc was placed in deionized water for 72 hours, during which time it absorbed the water and swelled to form a hydrogel. The compositions of the mixtures, their physical appearance and the equilibrium water content of the hydrogels are described in Table II.

Table II

Exam-Composition Physical aspect Copoly content Copoly-shaped parts water to

Weight no. Of dry hydrated PVP equilibrates

the example (K-90) for bre,

100% by weight of the mixture

5 1 70 transparent, transparent, 68

strong strong

6 1 90 transparent, transparent, 91

strong strong

7 2 70 transparent, transparent, 58

strong strong

8 2 90 transparent, transparent, 80

strong strong

Exam- Composition Physical aspect Copoly content Copoly parts in the form of water to

Weight no. Of dry hydrated PVP equilibrates

the example (K-90) for bre,

100% by weight of the mixture

9

3

90

transparent, translucent, 90 solid coherent

10

4

70

transparent, transparent, 77 strong strong

11

4

90

transparent, transparent, 90 solid strong

PVP = poly (vinyl pyrrolidone)

Examples 12-13

A 20.8 g (0.10 mole) portion of phosphorous pentachloride was placed in a 500 ml round bottom flask and 17.4 g (0.084 mole) of slowly added, with ice-bath cooling. p-sodium styrenesulfonate sprayed. The mixture was carefully stirred using a mechanical stirrer. After 30 minutes, it was heated under reflux at 50-60 ° C 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-styrenesulfonyl chloride was separated, washed several times with distilled water and dried over magnesium sulfate.

The solution in chloroform (100 ml) containing p-styrenesulfonyl chloride was added, with mechanical stirring, to 340 ml of 30% ammonia (density 0.90) while cooling with ice over a period of the order 30 minutes. The mixture was heated at 50 ° C for 5 hours under a reflux condenser then it was cooled to room temperature.

The organic layer was separated, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a white and solid powder of crude p-styrenesulfonamide, which was purified by recrystallization from a methanol-water mixture to give about 6.0 g of Sulfonamide , melting point: 130-132 ° C.

The infrared spectrum of Sulfonamide showed absorptions at 3350 and 3260 cm-1 (NH stretch), 1600 cm ~ l (aromatic c = c), 1305 and 1160 cm-1 (S stretch O) and 840 cm-1 (benzene p-disubstituted, agitation of 2 adjacent CHs).

A copolymer composed of 62% n-butyl methacrylate, 30% p-styrenesulfonamide prepared as described above, and 8% acrylic acid was prepared in the traditional way, as described in Examples 1-11, using a concentration of 33% of the monomers in a mixture of ethyl alcohol and dioxane. The copolymer was purified by precipitation of the reaction mixture in chloroform, then isolated by filtration and dried under vacuum at 100 ° C.

Mixtures of the copolymer with poly (vinyl pyrrolidone) (PVP, quality K-90, molecular weight 360,000) were prepared, as described in Examples 1 to 11, by dissolving the copolymer and the PVP in dimethylformamide and by subsequent evaporation of the solvent at 100 ° C under vacuum. Mixtures containing 10 and 30% by weight of the copolymer respectively, the remainder being poly (vinyI pyrrolidone), in each case, appeared to be optically transparent solids. The molded discs of the two mixtures, prepared as described in Examples 1 to 11, were found to absorb water and form transparent hydrogels containing 84.6 and 65.2% by weight of water respectively, when equilibrated with deionized water at room temperature for 72 hours.

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Examples 14-17

Hydroxyethyl methacrylate (H EM A) was purified by extracting (4 to 6 times) a 1: 1 solution of the polymer in water with petroleum ether, then saturating the aqueous solution of the monomer with sodium chloride and extracting the monomer with chloroform. The combined chloroform extracts were dried over anhydrous magnesium sulfate and the solution was distilled in vacuo (0.1 mm Hg) using cuprous chloride as an inhibitor. The monomeric fraction distilled at 70-82 ° C.

A copolymer of 52% butyl methacrylate, 40% HEMA and 8% acrylic acid was prepared in the usual manner, as described in Examples 1-11 using a concentration of 25% of the monomers in a mixture of ethyl alcohol and dioxane.

Optically clear mixtures of the copolymer were prepared in variable proportions with poly (vinyl pyrrolidone) (PVP, quality K-90, molecular weight: 360,000),

as described in Examples 1-11 by dissolving the copolymer and the PVP in dimethylformamide and by subsequent evaporation of the solvent at 100 ° C. under vacuum. Sheets of the mixture having a thickness of 0.203 to 0.305 mm were compression molded, then they were equilibrated in deionized water at room temperature for

72 hours. It was found that the mixtures containing 70, 80 to 90% by weight, respectively, of PVP, formed hydrogels containing respectively 75.8%, 82.3% and 88.9% by weight of water.

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Examples 18-24

A copolymer of 62% butyl methacrylate, 8% acrylic acid and 30% methacrylamide was prepared by the same general method as that described in Examples 1-11, and optically clear mixtures of the resulting copolymer were prepared with variable amounts of the same poly (vinyl pyrrolidone), quality K-90, as described in Examples 14-17.

It was found that there was a linear relationship between the proportion (10 to 40%) of the copolymer in the mixture and the equilibrium water content of the hydrogels as indicated by column A of Table III below. below. In order to take account of the change in the properties of PVP in the mixture due to the incorporation of the copolymer, the hydration of the PVP fraction alone was calculated assuming that the swelling of the polymer in water was negligible, as indicated in the last column of Table III. It was again found that the equilibrium water uptake of the PVP fraction was inversely proportional to the amount of the copolymer in the mixture.

Table III

Composition of the Copoly-mother PVP mixture% in% by weight weight

% H2O in hydrated PVP

Hydrogel compositions A * B * C *

IOOxPhiQ _ Ax 100 Ppvp + PhzO A + C

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

25

75

69.6

30.4

22.80

75.32

30

70

64.3

35.7

24.99

72.01

35

65

61.7

38.3

24,895

71.25

40

60

55.3

44.7

26.92

67.34

lOOx PH, o 100X

F \ nélanee - c * = -Mi Ppyp

^ i-O mixture Pf mix: 0 PH mix: 0

The mixtures according to the invention have the properties of thermoplasticity, fusibility and solubility in organic solvents as well as hydratability. But while they retain the thermoplasticity, the fusibility and the solubility in the sol-

5o organic wings of the PVP portion of the mixture, they have variable hydration characteristics of the PVP portion depending on the amount of the copolymer present.

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Claims (9)

655,322 1. Composition capable of absorbing more than 45% of its weight of water without dissolving at room temperature to form an optically clear hydrogel, characterized in that it essentially consists of an optically clear mixture of (1) 40 98% by weight, based on the total weight of the mixture, of a water-soluble polymer of N-vinyl-2-pyrrolidone, having a molecular weight of at least 10,000 and (2) 2 to 60% by weight of a water-insoluble copolymer consisting of (A) 50 to 83% by weight, based on the total weight of the copolymer, of a hydrophobic and water-insoluble ethylenically unsaturated monomer, (B) 2 to 12% by weight of an ethylenically unsaturated monomer containing an acid group, and (C) 15 to 45% by weight of a hydrophilic ethylenically unsaturated monomer devoid of acid groups. 2. Composition according to Claim 1, characterized in that the abovementioned copolymer (2) consists of 55 to 70% by weight, based on the total weight of the copolymer, of a monomer chosen from methyl methacrylate, the styrene and 2-ethylhexyl acrylate, from 2 to 12% by weight of acrylic acid and from 25 to 43% by weight of methacrylamide. 2 3. Composition according to claim 1, characterized in that the abovementioned copolymer (2) consists of 65 to 80% by weight, based on the total weight of the copolymer, of n-butyl methacrylate, of 2 to 12% in weight of acrylic acid and 15 to 35% by weight of methacrylamide. 4. Composition according to claim 1, characterized in that the abovementioned copolymer (2) consists of 50 to 78% by weight, based on the total weight of the copolymer, of n-butyl methacrylate, from 2 to 12% by weight of acrylic acid and from 20 to 35% by weight of p-styrene sulfonamide. 5. Composition according to Claim 1, characterized in that the abovementioned copolymer (2) consists of 55 to 70% by weight, based on the total weight of the copolymer, of n-butyl methacrylate, of 2 to 12% by weight of acrylic acid and from 25 to 43% by weight of hydroxyethyl methacrylate. 6. Composition according to one of claims 1 to 5, characterized in that the above-mentioned copolymer (1) has a molecular weight of between 10,000 and 1,000,000. 7. Composition according to one of claims 1 to 6, characterized in that a medicament is incorporated therein. 8. Catheter, characterized in that it is coated with a composition according to one of claims 1 to 7. 9. Glass plate, characterized in that it is coated with a composition according to one of claims 1 to 6.