SE448544B - WATER ABSORPTION COMPOSITION AND USE THEREOF AS A CARRIER FOR A MEDICINE - Google Patents

Description

40 448 544 2 Kn. but the mixture appears like a physical mixture rather than a chemical reaction product, in that it can be separated into the two polymer components by gel permeation chromatography. The mixtures are optically clear and substantially free of turbidity, which shows that the mixture is homogeneous despite the fact that the poly (vinylpyrrolidone) is water-soluble and the copolymer is water-insoluble. An examination at high magnification under an electron microscope shows the presence of microphase areas (4000 Å or less in diameter) of water-insoluble material dispersed in the continuous phase of water-soluble poly (vinylpyrrolidone). The presence of these microphase regions in the water-insoluble copolymer prevents dissolution of the continuous phase polymer in water, but unlike covalent crosslinking of polymers, it does not render the mixture non-thermoplastic. Instead, the mixture can be repeatedly formed or processed under moderate pressure at a temperature as low as 150 ° C or in some cases even lower temperature. The shaped or processed composition retains its shape at room temperature except for distortion when caused to swell with water. The compositions of this invention, in which the dispersed submicroscopic particles (microphase regions) act as multiple crosslinks to prevent dissolution of the hydrophilic continuous phase (which is itself water soluble), form a new group of hydrogels, separate from those of which the crosslinking is formed by weak cohesive forces, hydrogen bonds, ionic bonds or covalent bonds.

The water-soluble poly (vinylpyrrolidone) used in this invention may have a molecular weight ranging from 1,000 to 1,000,000 or more, but those polymers having molecular weights from 100,000 to 1,000,000 are preferred.

The copolymers which can be used as mixtures with the poly (vinylpyrrolidone) in the compositions of the invention include water-insoluble copolymers of a hydrophobic water-insoluble ethylenically unsaturated monomer, such as alkyl esters of acrylic or methacrylic acid, in which the alkyl group has 1 to 16 carbon atoms , Styrene, acrylonitrite, vinyl acetate, vinyl butyrate, vinyl chloride, vinylidene chloride, ethylene, propylene, butene, butadiene and other polymerizable alkadienes, vinyl alkyl ethers and vinyl alkyl ketones in which the alkyl group has three or more carbon atoms. The copolymer also contains, as another essential monomer, an ethylenically unsaturated monomer containing an acid group, such as a carboxylic acid, sulfonic acid or phosphonic acid group. Suitable acidic monomers include acrylic acid, methacrylic acid, crotonic acid, maleic acid, 2-sulfoethyl methacrylate and 1-phenylvinylphosphonic acid.

The third monomer is selected from a group of hydrophilic ethylenically unsaturated monomers having a solubility parameter exceeding 1l (calories / cm 3) 1/2, free from acidic groups such as methacrylamide, acrylamide, hydroxyethyl methacrylate, diethylene glycol monomethacrylate; triethylene glycol monomethacrylate and glyceryl methacrylate.

For each of the three types of monomers, a mixture of two or more individual monomers of the same type may be used.

Combinability or non-combinability of the water-insoluble copolymer with the water-soluble polymer of N-vinyl-2-pyrrolidone in the hydrated form of the mixture, i.e. its suitability for use in the present invention, can in each case be easily determined by visual examination of a mixing of the two polymers after reaching equilibrium in water at room temperature. If the mixture is transparent and optically clear and remains so after immersion in water at 2006 without solution in the water, it forms a satisfactory hydrogel. If the mixture is cloudy or opaque after equilibrium in water, or if it dissolves in water at 20 DEG C., the mixture produced from this copolymer is not satisfactory but has poor mechanical properties. In order for a blend composition to have satisfactory mechanical properties in the hydrated form, the size of the microphase regions of the terpolymer in the hydrogel should not exceed 4000 Å and preferably should be below about 1000 Å. The relative proportions of the various monomers in the copolymer may vary. strongly. The hydrophobic water-insoluble ethylenically unsaturated monomer can amount to 50 to 90%, based on the total weight of the copolymer, while the ethylenically unsaturated monomer containing an acidic group can amount to 2 to 12% by weight. The hydrophilic ethylenically unsaturated monomer can amount to 0 to 50% by weight. The exact proportions between the three types of monomers are determined by the hydrophobic - hydrophilic equilibrium required in each case. In many cases, to achieve this equilibrium, 15 to 45% incorporation of a hydrophilic monomer is required to achieve this equilibrium.

Thus, within a preferred group of copolymers, the amount of methyl methacrylate (or styrene or 2-ethylhexyl acrylate) is 55 to 70%, 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 another preferred copolymer, the amount of n-butyl methacrylate is 65 to 80%, 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 to 35% by weight. For yet another preferred copolymer, the amount of methyl methacrylate is 88 to 90% by weight of the total copolymer, while 2-acrylamido-2-methylpropanesulfonic acid, which is the only other monomer component, is 10 to 12% by weight. In this case, the presence of a non-acidic hydrophilic comonomer is not necessary.

For yet 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 hydrophilic E-styrenesulfonamide is 20 to 35% by weight. In yet another preferred copolymer, the amount of n-butyl methacrylate is 55 to 70% of the total weight of the copolymer, acrylic acid is 2 to 12% and hydroxyethyl methacrylate is 25 to 43%. The relative amounts of poly (vinylpyrrolidone) and of copolymer in the mixture vary within wide limits, from 40 to 98% by weight, preferably from 50 to 98%, based on the total weight of the mixture, of the former and from 2 to 60% by weight, preferably 2 to 50% of the copolymer. Optimal amounts of each in the range will vary depending on the particular properties desired in the blend and the identity of the particular copolymer present in the blend. The higher the content of the copolymer in the mixture, the lower the equilibrium water content of the hydrogel formed. The water content of the PVP blend hydrogels of this invention can be varied from about to 95% or higher by the appropriate choice of the copolymer and the proportions thereof in the blend. In general, the higher the water content of the hydrogel, the worse its mechanical properties.

The mixture can be prepared by mixing together solutions or dispersions of the poly (vinylpyrrolidone) and of the copolymer in any desired carrier or solvents which are miscible with each other and then removing the carrier or solvent, for example by evaporation.

It may also be possible to mix the polymer and copolymer in a hot rolling mill or in a sprayer or in another conventional mixing apparatus. Molded particles of the mixture can be prepared by casting from 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 working advantage over covalently “crosslinked synthetic hydrogels. Tailored mechanical and physical properties (eg water content, solutes and water permeability, softness, flexibility, tensile strength) of the hydrogel are easily achieved by controlling the physico-chemical properties and proportions of the water-insoluble copolymer blend. Due to these advantages, the new hydrogel compositions of the invention are suitable for many uses, such as dressings for burns and other wounds, coatings for catheters and surgical sutures, soft contact lenses, implants for the delivery of controlled rate drugs, and other articles. which come into intimate contact with body tissues or cavities (for example, glass and corneal prostheses).

These new hydrogel-forming materials can also be used in the manufacture of devices for controlled release of drugs which are sparingly soluble in water. When a drug (soluble in the water-insoluble copolymer) is incorporated into these hydrogels, it remains dispersed in hundreds of thousands of "depots" of water-insoluble areas. - play and number of dispersed areas.An advantage of such a device is that a mechanical failure or a puncture hole would not cause any increase in the release rate of the drug.

A non-medical use of the new compositions according to the invention is for coating glass surfaces, such as insides of car and aircraft windscreens, to prevent the formation of mist on them. For this purpose, from a suitable solvent, a thin coating of a mixed composition, such as that described in Example 19, is poured onto a glass surface. Formation of the polymer blend coating can also be accomplished with a jet of its dilute solution in a suitable solvent. The coating has good adhesion to glass, is colorless, optically clear and non-imaging when exposed to hot, humid air.

The following specific examples are merely intended to illustrate the nature of this invention without limiting its scope.

Examples 1 - 13 All the copolymers in these examples are prepared by conventional solution polymerization procedure by dissolving the desired amounts of monomers in a suitable solvent and by using as polymerization initiator a small amount (0.2 - 0.4% by weight of the monomers) of a free radical generators such as azobisisobutyronitrile or 2-t-butylazo-2-cyanopropane. Polymerization was performed at 80-95 ° C to a high degree of conversion. The composition of the copolymerization mixtures is given in Table I. Copolymers in Examples 1 to 4 were isolated from the reaction mixture by precipitation in methanol, collection by filtration and drying at 10,000 under vacuum, while the copolymer in Example 5 was isolated by removing the volatiles by heating in vacuum at 10005.

IAÉELL_l Reaction components Example no = 2 "in" Comonomers - g É É 5 Methyl methacrylate š65 T- - 90 f- Methacrylamide: so so is - 'so Styrene' - 65 - -: - Acrylic acid 5 5 5 - 5 n-butyl methacrylate - - 80 - - 2-acrylamido2-methyl-'propanesulfonic acid - - - 10 - 2-ethylhexyl acrylate - - - - '65 Solvent - ml I Ethanol ï100 100 100 - 100 oioxane lioo 100: 100 - - n, N-methylpharmaceuticals. All mixed compositions of these examples were prepared by dissolving in N, N-dimethylformamide the desired amounts of the water-insoluble copolymer and poly (vinylpyrrolidone) (Grade K-90, molecular weight 360,000 ) to obtain a solution containing 10 to 15% by weight of the polymer mixture.

The solution of the mixture was then heated at 10,000 under vacuum to evaporate the solvent, leaving a mass of optically transparent mixed solids. The mixture, which was thermoplastic, was pressed into a sheet in a mold heated to 15,000. The shaped disk was placed in deionized water for 72 hours, during which time it absorbed water and swelled to form a hydrogel. The composition of the mixtures, their physical appearance and the equilibrium water content of their hydrogels are given in Table II.

TABLE II _ Example Composition mixture Physical behavior Equilibrium 1 in "" 1 - 1 - water content no. ~ Copolymer Weight parts PVP Dry form _Hydrated Weight_m, in ex. j (K-90) per 100 form ”1: parts of the mixture 6 É 1 70 transparent transparency 68 in solid strong 7 _ 1_ 90" "91 8 2 l7o 'g" "see 9 2 90" "so 3 ; 90 Å "translucent 90 1 1 coherent i 11 4 90" transparent: 84 'I coherent 12 5 70 1 "Atransparent 77 | Example 14 - 15 A 20.8 g (0.10 mol) portion of phosphorus pentachloride was placed in a 500 ml round bottom flask and 17.4 g (0.084 mol) of powdered β-sodium styrene sulfonate The mixture was added slowly with ice-bath cooling, the mixture was stirred gently with a magnetic stirrer and 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. The organic layer containing 3-styrenesulfonyl chloride was separated, washed several times with distilled water and dried over magnesium sulfate.

The chloroform solution (100 ml) containing p-styrene sulfonyl chloride was added with mechanical stirring to 340 ml of 30% ammonium hydroxide (specific gravity 0.90) under ice-cooling for a period of about 30 minutes. The mixture was heated to 50 ° C for 5 hours under a reflux condenser and then cooled to room temperature.

The organic layer was separated, dried over anhydrous magnesium sulfate and then evaporated to dryness to give a solid white powder of crude E-styrenesulfonamide, which was purified by recrystallization from ethanol-water mixture to give about 6.0 g of the sulfonamide, m.p. 130-13206. The infrared spectrum of the sulfonamide showed absorptions at 3350 and 3260 cm -1 (NH elongation), 1600 cm -1 (aromatic c = c), 1305 and 1160 cm -1 (S = 0 elongation) and 840 cm -1 (β-disubstituted benzene, 2 nearby CH oscillating).

A copolymer of 62% n-butyl methacrylate, 30% p-styrenesulfonamide, prepared as described above and 8% acrylic acid was prepared in the usual manner as described in Examples 1 to 13, using 33% concentration of the monomers in a mixture of ethyl alcohol and dioxane. The copolymer was purified by precipitation of the reaction mixture in chloroform and then isolated by filtration and dried in vacuo at 100 ° C.

Mixtures of the copolymer with poly (vinylpyrrolidone) (PVP, Grade K-90, molecular weight 360,000) were prepared as described in Examples 1 to 13, by dissolving the copolymer and PVP in dimethylformamide and subsequently evaporating the solvent at 100 ° C. in a vacuum. Mixtures containing 10 and 30% by weight of copolymer, respectively, while the remainder in each case were poly (vinylpyrrolidone), were found to be optically transparent solids. Shaped slices of the two mixtures, prepared as described in Examples 1 to 13, were found to absorb water and form transparent hydrogels containing 84.6 and 62.5% by weight of water, respectively, when equilibrated with deionized water at room temperature for 72 hours.

Examples 16 - 19 L Hydroxyethyl methacrylate (HEMA) was purified by extraction with a solution in a ratio of 1: 1 of the polymer in water with petroleum ether, then saturating the monomeric aqueous solution 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 (approximately 0.1 mm Hg) using copper chloride as an inhibitor. The monomer fraction over-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 to 13, using 25% concentration of the monomers in a mixture of ethyl alcohol and dioxane.

Optically clear blends of copolymers in varying proportions with poly (vinylpyrrolidone) (PVP, Grade K-90, molecular weight 360,000) were prepared as described in Examples 1 to 13 by dissolving the copolymer and PVP in dimethylformamide and subsequently evaporating the solvent at 10006 in a vacuum.

Approximately 0.2-0.3 mm thick sheets of the mixtures were compression molded, then equilibrated in deionized water at room temperature for 72 hours. It was found that the mixtures containing 70, 80 and 90% by weight of PVP formed hydrogels containing 75.8, 82.3 and 88.9% by weight of water, respectively.

Examples 20 - 26 A copolymer of 62% butyl methacrylate, 8% acrylic acid and% methacrylamide was prepared by the same general method as described in Examples 1 - 13, and optically clear mixtures of the obtained copolymer with varying amounts of the same poly (vinylpyrrolidone), Grade K -90, was prepared as described in Examples 16-19.

It was found that there was a linear relationship between the content (10 to 40%) of the copolymer in the mixture and the equilibrium water content of the hydrogels, as shown in column A of the following Table III. To take into account the change in the levels of PVP in the mixture due to incorporation of the polymer, hydration of the PVP fraction was calculated only on the assumption that the swelling of the copolymer in water was negligible, as shown in the last column of Table III. Again, it was found that the equilibrium water uptake of the PVP fraction was inversely proportional to the amount of copolymer in the mixture. 448 544 Mixture Composition TABLE III | Hydrogen Compositions §PvP IA * Éß * c * I100xwH20 Ax100 wt%% wt% “É in § 1WPvP * WH 0 A + c 2 |% H90 in hydrated PVP ï90; 88.5 § 16.5 14.85 §84.90 85 š79.1 320.9 17.765 i81.67 80 j77.7 §22.3 17.84 281.33 75 fi69.6 30.4 '22, 80 §75, s2 80 _70 564,3 §s5,7 24,90 §72,01 - .f - ~> 1 55 '65 61.7 §s8,3 24,895 571,25 40 Ü60 55.3 '44, 7 26,82 567,34 A * 100 x wH20 wg, _ andn1ng + WH 0 2 B * 100 X wßiandning wB1andning + WH 0 2 c * 100 x wpvp w _ B1andning + WH 0 '2 The mixtures according to this invention have the properties thermopiasticity, malleability and Tösiighet in organic ios together with hydratability, but while maintaining the thermopiasticity, malleability and solubility of organic solvents of the PVP moiety of the mixture, they exhibit varying hydration properties of the PVP moiety depending on the amount of copolymers present.

Claims (8)

CI 15 20 25 30 35 H 448 544 PATENTKRAV A water-absorbent composition characterized in that it is capable of absorbing more than 45% of its weight of water without dissolving at room temperature to form an optically clear hydrogel and essentially consisting of an optically clear mixture of (1 ) 40 to 98%, 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 5Û% by weight of a water-insoluble copolymer derived from ( A) 50 to 90%, based on the total weight of the copolymer, of a hydrophobic 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 free from acidic groups. Composition according to Claim 1, characterized in that the copolymer (2) is derived from 55 to 70%, based on the total weight of the copolymer, of a monomer selected from methyl methacrylate, styrene and 2-ethylhexyl acrylate, Z to 12% by weight. acrylic acid and 25 to 43% by weight of methacrylamide. Composition according to Claim 1, characterized in that the copolymer (2) is derived from 65 to 80%, based on the total weight of the copolymer, of 2-butyl methacrylate, 2 to 12% by weight of acrylic acid and 15 to 35% by weight. -% methacrylamide. Composition according to Claim 1, characterized in that the copolymer (2) is derived from 88-90%, based on the total weight of the copolymer, of methyl methacrylate and 10 to 12% by weight of 2-acrylamido-2-methylpropanesulfonic acid. . 5. A composition according to claim 1, characterized in that the copolymer (2) is derived from 50 to 78%, based on the total weight of the copolymer, of Q-butyl methacrylate. 2 to 12% by weight of acrylic acid and 20 to 35% by weight of B-styrenesulfonamide. Composition according to Claim 1, characterized in that the copolymer (2) is derived from 55 to 70%, based on the total weight of the copolymer, of n-butyl methacrylate, Z to 12% by weight of acrylic acid and 25 to 43% by weight of hydroxyethyl methacrylate. . Composition according to any one of claims 1 to 6, characterized in that the polymer (1) has a molecular weight of 448 544 12 10 000 to 1 000000. Use of the composition according to any one of the preceding claims as a carrier for a medicament in that it is incorporated into the composition.