JPH0688949A - Transparent water-containing gel material - Google Patents

Abstract

PURPOSE:To obtain a water-contg. gel material useful as a medical material such as contact lens having such a property that contamination such as protein or lipid hardly permeate or adhere to the inside of a lens by incorporating a specified number of microvoids having a specified size. CONSTITUTION:This material contains <=1000 pieces of microvoids of 10-250Angstrom max. diameter per 1mum cross section and contains no microvoid having >250Angstrom max. diameter. The microvoid is such a vacancy that contains water as almost free water and exists in a hydrophilic resin containing water adsorbed by hydrogen bond. The water-contg. gel is obtd. by copolymerizing mixted monomers essentially consisting of hydroxyethyl methacrylate, glyceryl methacrylate, or N-vinylpyrrolidone, and swelling with water. The water-contg. gel having <=1000 pieces of microvoids is obtd. by controlling the polymn. rate of the resin during polymn. under conditions to produce no microvoid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transparent hydrogel material, and provides a hydrogel useful as an ophthalmic material such as medical materials, particularly contact lenses and intraocular lenses.

[0002]

2. Description of the Related Art Conventionally, a resin containing at least one monomer selected from hydroxyethyl methacrylate and N-vinylpyrrolidone as a main component and having a water content of 30 to 90 is used.
Various hydrogel materials having a weight percentage are known and are mainly used as hydrous soft contact lenses. Contact lenses made of these materials are soft and comfortable to wear, but proteins and lipids in tears easily penetrate into the lens, resulting in stains and bacterial growth. In order to improve this, for example, JP-A-58-912
No. 1 discloses a water-containing soft contact lens material copolymerized with 2,3-dihydroxypropyl methacrylate, and JP-B No. 62-62323 describes a water-containing soft contact lens copolymerized with a fluorine-containing monomer. There is.

Conventionally known hydrated gel materials, especially hydrated soft contact lenses, cause proteins and lipids in tear fluid and foreign substances mixed in during handling to penetrate into the lens during wearing, which causes eye diseases. It was easy, and it was easy for bacteria to breed and cause abnormalities such as cloudy lenses. It is considered that the reason for the permeation of these foreign substances is that the size of the gel network of the hydrous gel is larger than the size of the protein or lipid molecule.Therefore, as described above, a monomer that changes the gel network structure is copolymerized or stains are removed. For the purpose of facilitating the removal, a fluorine-containing monomer is copolymerized, but it is still insufficient.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a hydrous gel which is excellent in optical transparency and is less likely to be contaminated with stains such as proteins and lipids inside the lens, and which is useful as a medical material such as a contact lens or an intraocular lens. Intended to provide material.

[0005]

Means for Solving the Problems
In order to solve the problem, various structures of hydrogels and various synthetic methods have been proposed.
By examining and making the microstructure of hydrous gel a specific structure
It is possible to reduce the penetration of proteins, lipids and other foreign substances.
As a result, they have completed the present invention. That is,
In the present invention, microvoids having a maximum diameter of 10 to 250 Å are
Cross section 1 μm ²The average is less than 1000 and the maximum
Does not contain microvoids with a large diameter larger than 250Å
Is a hydrous gel material.

The microvoids referred to in the present invention are cavities which exist in the hydrophilic resin containing water adsorbed by hydrogen bonds, and which are mostly free water and contain water. The present invention is a hydrogel having a structure in which the size of the microvoids is reduced and the number thereof is reduced. Conventionally, a hydrogel has a uniform structure, and it has been considered that these foreign substances are incorporated into the gel because proteins and lipids diffuse and permeate between the molecules of the resin that have spread due to the inclusion of water. The present inventors have found that the gel structure is not uniform,
250 Å micro voids 1500 per 1 μm ²
It was discovered for the first time that there are more than one individual, and by reducing this microvoid, we succeeded in extremely reducing the penetration of proteins and lipids.

The microvoids in the present invention are obtained by successively replacing the hydrogel with an aqueous alcohol solution having a high concentration, and finally displacing 100%.
% Immersed in alcohol, then immersed in a mixed monomer of butyl methacrylate and methyl methacrylate, embedded, polymerized, and then observed by observing a section with a transmission electron microscope. The size is about 10 to 250Å. . In the present invention, the size of the microvoid means the maximum diameter of the microvoid.

When the number of the microvoids is large, proteins, lipids and other foreign substances permeate into the voids, so that when used as a contact lens, stains are attached and bacteria are easily proliferated due to this, which is preferable. Absent. Furthermore, the presence of these microvoids makes the contact lens appear cloudy, which makes it difficult to determine the presence or absence of stains by visual inspection of the lens, which is not preferable. A hydrogel having a microvoid size of 250 Å or less and 1000 or less per 1 μm ² is preferable because it has a small amount of adsorbed proteins and lipids and almost no cloudiness. 250
Less than 500 micro voids less than Å and 100 Å
It is more preferable that the water-containing gel having the number of 250 Å or less is 30 or less because the performance thereof is further improved. Also,
If a microboy larger than 250Å is present, it will appear cloudy when making a contact lens.
It is necessary that no larger microvoids be present.

In the present invention, the hydrous gel is obtained by swelling a resin obtained by copolymerizing a mixed monomer containing hydroxyethyl methacrylate, glyceryl methacrylate or N-vinylpyrrolidone as a main component with water, and the water content. Is preferably 20 to 85% by weight. Generally, a copolymer of these hydrophilic monomers with a copolymerizable monomer is used. For example, 60 to 85% by weight of hydroxyethyl methacrylate, 3 to 30% by weight of glyceryl methacrylate, and 1 to 1 of cyclohexyl methacrylate.
~ 15% by weight, fluorine-containing unsaturated organic acid ester 1-1
5% by weight, ethylene glycol dimethacrylate 0.1
Copolymerized with 10 to 10% by weight of mixed monomers, 50 to 95% by weight of hydroxyethyl methacrylate, 5 to 25% by weight of fluorine-containing unsaturated organic acid ester, and unsaturated fatty acid having one or more carboxyl groups in the molecule, 1 to 40 or more monomers selected from monomethacrylates and polymethacrylates of polyhydric alcohols having 3 or more valences
% By weight, ethylene glycol dimethacrylate 0.1
Copolymerization of 10 wt%, hydroxyethyl methacrylate 60 to 95 wt%, propylene glycol monomethacrylate 5 to 30 wt%, ethylene glycol dimethacrylate 0.1 to 10 wt%,
A copolymer of N-vinylpyrrolidone 50 to 70% by weight, hydroxyethyl methacrylate 5 to 20% by weight, methyl methacrylate 20 to 40% by weight, and tetraethylene glycol dimethacrylate 0.1 to 10% by weight can be used.

These copolymers are obtained by heat-polymerizing a mixture of the above-mentioned monomers by adding an azo compound such as azobisisobutyronitrile, azobisdimethylvaleronitrile, benzoylperoxide or lauroylperoxide, or an organic peroxide. It is produced by a method of mixing a photopolymerization initiator such as benzophenone, benzoin, and benzyldimethylketal and irradiating with ultraviolet rays to polymerize. In the case of producing a contact lens, the lens can be produced by a method of polymerizing into a rod shape, followed by cutting and polishing, a method of putting a monomer mixture in a lens-shaped mold and polymerizing, and the like. The hydrogel of the present invention is obtained by immersing the copolymer thus polymerized in water and swelling it at room temperature to 100 ° C.

The hydrogel having 1000 or less microvoids of the present invention is produced by strictly controlling the polymerization rate at the time of polymerization of the above-mentioned resin and polymerizing under the condition that microvoids are not formed. This condition varies depending on the copolymer composition of the resin to be produced, but the polymerization rate is usually 15 to
It is achieved by setting the polymerization rate to 40%. Furthermore, it is preferable that the initial rate of polymerization up to a polymerization rate of 60% is a polymerization rate of 15 to 40% per hour. In order to control the polymerization rate within the above range, the amount of the polymerization initiator and the polymerization initiation temperature are changed according to the composition of the polymerization monomer, or the type and amount of the polymerization retarder and the polymerization inhibitor in the monomer are changed. It

In the production of contact lenses, monomers are put in a test tube and bulk polymerization is carried out. The polymerization rate is controlled at this time even if the polymerization initiation temperature is different by 2 or 3 ° C. Even if the amount differs by a few ppm, the polymerization rate changes greatly. Therefore, in order to control the polymerization rate within the above range, the amount of polymerization inhibitor, retarder and polymerization initiator should be 1 ppm within the range of 1 ° C. It is achieved only by controlling in the range of. When the polymerization rate is less than 15% per hour, the number of microvoids exceeds 1000, and the size of most of them is 100 Å or more, and the ratio of large voids increases, so that the adsorption of proteins, lipids, etc. increases and the cloudiness becomes severe. Become.

Further, when the polymerization rate exceeds 40% per hour, distortion is likely to remain in the resin due to volume contraction that occurs during the polymerization. Particularly, in manufacturing contact lenses, polymerization occurs in a test tube, and this distortion is large. However, when the lens is processed into a lens and then swells with water to form a hydrous contact lens, the lens is distorted or the shape is changed, which is not preferable.

[0014]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Reference Examples. The characteristic values in the examples were measured by the following methods. 1. Slice a sample of hydrogel containing microvoids to a thickness of 1 mm, and
30% by weight ethanol water for 30 minutes, 70% ethanol water for 30 minutes, 90% ethanol water for 30 minutes, 9
Immerse in 9.5 wt% ethanol for 30 minutes twice, then in 100 wt% ethanol dried over anhydrous copper sulfate for 30 minutes, 1
00% by weight ethanol 50 parts by weight Butyl methacrylate 20 parts by weight Methyl methacrylate 30 parts by weight 30 minutes, butyl methacrylate 40 parts by weight Methyl methacrylate 60 parts by weight 30 minutes in a mixed solution respectively, and finally benzoyl peroxide 2 It was embedded in a mixed solution of 40 parts by weight of butyl methacrylate containing 60% by weight of methyl methacrylate and heated at 40 ° C. for polymerization. The obtained embedded sample was cut into a section with a glass knife using a microtome (Ultracut N / FC-4 manufactured by Reichert), and a transmission electron microscope [manufactured by JEOL Ltd. 2
000 FX] and observed at 120 KV. Two samples were photographed at 30,000 times, and the size and number of void-shaped black spots in a square of 1 μm ² randomly selected from three spots were measured for each photograph. It should be noted that minute voids were observed and measured using a 10 times magnifying glass. 2. Water content A disk-shaped sample having a diameter of 11.4 mm and a thickness of 0.5 mm when dried is prepared, and the weight after hydration and swelling (W1) and the weight after re-drying (W2) are precisely weighed. The water content (Wg) was calculated from the following formula.

Wg = (W1-W2) × 100 / W1 3. Transparency and white turbidity The sample whose water content was measured was placed in water, and a spot light flux with a condenser lens was irradiated from the side surface of the sample to visually observe it with a black background. 4. Protein adsorption Base curve 7.80 mm, center thickness 0.09 mm, size 13.5 mm, power-3.00 lens-shaped product was manufactured, and 1 wt% egg white lysozyme or 1 wt% bovine serum albumin in saline solution After immersing in (pH7.31 phosphate buffer) at 24 ° C. for 24 hours, it was immersed in physiological saline for 10 minutes and lightly drained. Then, the protein was extracted by immersing it in 1 ml of 1% by weight sodium dodecylsulfate and 1 ml of 1% by weight sodium carbonate aqueous solution at 24 ° C. for 24 hours. To 0.2 ml of this extract, 2 ml of BCA reagent (Protein quantification reagent manufactured by PIERCE) was added and shaken at 60 ° C. for 1 hour under constant temperature, and the absorbance at a wavelength of 562 nm was immediately measured. The amount of each protein was obtained from the calibration curves of lysozyme and albumin obtained in advance. 5. Polymerization rate The polymerization rate is determined by measuring the volumetric shrinkage of the monomer mixture or measuring the refractive index. In the present invention, the volume shrinkage rate is used. When performing bulk polymerization in a test tube, set a scale at 2 mm intervals based on the position of the liquid surface containing the monomer mixture, record the change in the position of the liquid surface during the polymerization process, and obtain the polymerization rate by the following formula. The amount of change in the polymerization rate per unit time was defined as the polymerization rate.

Polymerization rate = {Change in liquid level (mm) / Change in liquid level at the end of polymerization (mm)} × 100

[0017]

Example 1 Hydroxyethyl methacrylate (containing 50 ppm of methoxyhydroquinone as a polymerization inhibitor) 7
9.8% by weight, propylene glycol monomethacrylate (Methoxyhydroquinone 250 p as a polymerization inhibitor
20% by weight of ethylene glycol dimethacrylate and 0.2% by weight of ethylene glycol dimethacrylate are mixed, 1000 ppm of azoisobutyronitrile is dissolved and filled in a polypropylene test tube having an inner diameter of 16 mm, 40 ° C. for 16 hours, 60 ° C. for 24 hours, After polymerization at 90 ° C. for 72 hours (polymerization is 20
It started at a polymerization rate of 38% and reached a polymerization rate of 60% at this rate, after which the polymerization proceeded slowly. ), A rod-shaped polymer was taken out from the test tube and further polymerized at 90 ° C. for 48 hours. The obtained copolymer is processed by a known cutting and polishing method to have a center thickness of 0.075 mm and a diameter of 11.34 mm.
It has a lens shape. Further, the thickness is 0.5 mm and the diameter is 11.
A 4 mm disc-shaped sample was prepared. The sample and the lens-shaped product were immersed in physiological saline at 70 ° C. for 16 hours for hydration and swelling. As a result, soft contact lenses and disks having a water content of 38% by weight were obtained. The transparency of the lens and the disk was good, and the white turbidity was good with no visible white turbidity. The size of the microvoids measured on the disc is less than 200Å, and the number is 270 on average / 1 μm ^2.
Met. Further, the number of voids of 100 Å or more and 200 Å or less was very small on average, 13 voids / 1 μm ² . As a result of measuring protein adsorption with a lens, albumin was 0.4 μg and lysozyme was 0.2 μg per one lens, which was about half the adsorption amount of a conventional water-containing soft contact lens (water content 38% by weight).

[0018]

[Example 2] Hydroxyethyl methacrylate (containing 50 ppm of methoxyhydroquinone as a polymerization inhibitor)
68% by weight, glyceryl methacrylate 21% by weight, cyclohexyl methacrylate 4.8% by weight, 2,2,2
-A mixed solvent of 5% by weight of trifluoroethyl methacrylate and 1.2% by weight of ethylene glycol dimethacrylate was mixed and dissolved with 900 ppm of azobisisobutyronitrile and placed in a polypropylene test tube, 40 ° C for 16 hours, 60 ° C for 24 hours, After polymerizing at 90 ° C. for 72 hours (polymerization was started at a polymerization rate of 22% per hour, the polymerization rate reached to 60% at this rate, and thereafter, the polymerization proceeded slowly). Remove the item for another 90
It was polymerized at 48 ° C. for 48 hours. The obtained copolymer was subjected to a known cutting and polishing method to have a center thickness of 0.075 mm and a diameter of 1
The lens shape was 1.34 mm. Also, thickness 0.5m
A disk-shaped sample having a diameter of 11.4 mm was prepared. When this sample and the lens-shaped product were hydrated and swollen by immersing them in a physiological saline solution at 70 ° C. for 16 hours, the water content was 39% by weight.
Soft contact lenses and discs were obtained. The transparency of the lens and the disk was good, and the white turbidity was good with no visible white turbidity. The size of the microvoids measured on the disc is less than 200Å and the number is 250 on average.
The number was 1 / μm ² . The average number of voids of 100 Å or more and 200 Å or less was 11 / μm ^2, which was very small. As a result of measuring protein adsorption with a lens, albumin was 0.4 μg and lysozyme was 0.4 μg per one lens, and the conventional water-containing soft contact lens (water content 38%) was used.
The amount of adsorption was about half of (wt%).

[0019]

[Example 3] Hydroxyethyl methacrylate (containing 50 ppm of methoxyhydroquinone as a polymerization inhibitor)
70% by weight, glyceryl methacrylate 19% by weight, cyclohexyl methacrylate 4.5% by weight, 1,1,
700 ppm of azobisisobutyronitrile and 300 ppm of azobisdimethylvaleronitrile are mixed and dissolved in a mixed monomer of 5% by weight of 2,2, -tetrafluoroethoxy-2-hydroxypropyl methacrylate and 1.5% by weight of ethylene glycol dimethacrylate, Base curve 6.7 mm size 11.7 mm polypropylene cast polymerization mold, polymerized at 90 ° C. for 8 hours, then opened the mold and immersed it in a vat containing purified water to form a lens-shaped product from the mold. Was peeled off. Also, the thickness is 0.5 mm
A disk-shaped sample having a diameter of 11.4 mm was similarly prepared in a mold and immersed in purified water to obtain a disk-shaped sample.
This sample and lens-shaped object were immersed in saline solution at 70 ° C for 16
When hydrated and swollen by soaking for a period of time, the water content is 4
0% by weight of soft contact lenses and discs were obtained. The transparency of the lens and the disk was good, and the white turbidity was good with no visible white turbidity. The size of the microvoids measured by the disc was 200 Å or less, and the number was 235 on average / 1 μm ² . Also, 100 Å or more 2
The number of voids having a size of 00 Å or less was 12 pieces / 1 μm ^{2 on} average, which was extremely small. As a result of measuring protein adsorption with a lens, albumin 0.3 μg, lysozyme 0.
The amount adsorbed was 3 μg, which was less than half the adsorption amount of the conventional water-containing soft contact lens (water content 38% by weight).

[0020]

[Comparative Example 1] Hydroxyethyl methacrylate [HEMA manufactured by Mitsubishi Gas Co., Ltd., containing 2150 ppm of methoxyhydroquinone as a polymerization inhibitor] 79.8 wt%, propylene glycol monomethacrylate (containing 250 ppm of methoxyhydroquinone as a polymerization inhibitor) 20 wt% , 0.2% by weight of ethylene glycol dimethacrylate, 1000 ppm of azoisobutyronitrile were dissolved and filled in a polypropylene test tube having an inner diameter of 16 mm, and polymerized at 40 ° C. for 16 hours, 60 ° C. for 24 hours, and 90 ° C. for 72 hours. After that (polymerization started at a polymerization rate of 6 to 10% per hour and proceeded to a polymerization rate of 90% at this rate), a rod-shaped polymer was taken out from the test tube and further polymerized at 90 ° C. for 48 hours. The obtained copolymer was formed into a lens shape having a center thickness of 0.075 mm and a diameter of 11.34 mm by a known cutting and polishing method. In addition, thickness 0.5mm diameter 11.4
A mm-shaped disc-shaped sample was prepared. The sample and the lens-shaped product were immersed in a physiological saline solution at 70 ° C. for 16 hours for hydration and swelling. As a result, a soft contact lens and a disc having a water content of 38% by weight were obtained. The transparency of the lens and the disk was slightly inferior, and the cloudiness was poor because the cloudiness was visually observed. The size of the microvoids measured by the disc is 250 Å or less, but the number is 1800 on average.
The number was 1 / μm ² . In addition, the number of voids of 100 Å or more and 250 Å or less was 1300 / μm ^{2 on} average, which was very large. As a result of measuring protein adsorption with the lens, the lens 1
Albumin 1.5 μg, Lysozyme 1.3 μg per plate
It was a very large adsorption amount.

[0021]

INDUSTRIAL APPLICABILITY The hydrogel of the present invention is useful as a medical material, particularly ophthalmic materials such as contact lenses and intraocular lenses, is excellent in transparency, has no cloudiness, and provides less adsorption of proteins.

Claims (1)

[Claims] 1. A hydrogel material characterized in that the number of microvoids having a maximum diameter of 10 to 250 Å is 1000 or less per 1 μm ² in cross section, and that no Mictovoid having a maximum diameter of more than 250 Å is contained.