JPS6232456B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to contact lenses comprising copolymers of alkyl acrylates or alkyl methacrylates and dihydroxyacrylates or dihydroxymethacrylates. As is known to those skilled in the art, conventional contact lenses have been made from methyl methacrylate. Lenses made from this material are known as "hard contact lenses," but many people are unable to adapt to having them in their eyes and/or due to the physiological effects required for corneal metabolism. It is only used in a limited range because lenses interfere with this. Many people experience minor pain from small particles and dust that get under the lens and rub against the cornea. Furthermore, after wearing hard contact lenses for an extended period of time, such as one to five years, many people experience discomfort and are forced to stop wearing the lenses. In view of the above facts, considerable research has been conducted to develop new contact lens materials that would solve some of the problems of methyl methacrylate lenses mentioned above. Certain types of such materials are described in U.S. Pat.
3220960, and will be explained here for reference. The materials described in the above-mentioned patents are a small amount of cross-linked hydrophilic polymers and a substantial amount of an aqueous liquid such as water.
The hydrophilic polymer is in fact a polymerizable monoester of an olefinic acid selected from the group consisting of acrylic or methacrylic with a large amount of single olefinic double bonds and a small amount of a polymerizable diester of the above-mentioned acids. In the group of materials described in the above-mentioned patents, a slightly cross-linked polymer consisting of a large amount of 2-hydroxyethyl methacrylate, known in the prior art as "Hema", is primarily used in contact lenses. I've been exposed to it. Hema, for example, has the important property of forming a hydrophilic polymer that can be hydrated with water, typically about 40% by weight. (However, the proportion can vary between about 35 and 65% by weight.) This high water content
This makes contact lenses made from this material very pliable and soft, so that the lens quickly shapes itself to the curvature of the eye.
This is significantly different from traditional hard contact lenses, which retain a rigid profile and do not conform to the curvature of the eye. The most significant advantage of hema hydrogel soft lenses is that they can be worn with immediate and continued comfort, with less corneal pain, at least initially, compared to conventional contact lenses. A second advantage of hema-hydrogel lenses, compared to hard lenses, is that they reduce the problem of dust and foreign objects that can get under the lens and rub against the cornea. Another advantage of Hema hydrogel soft lenses is improved peripheral vision as a result of using larger diameter lenses compared to traditional hard lenses. Despite the advantages of hema-hydrogel lenses, problems remain that have prevented their use from gaining widespread acceptance, at least to date. One such problem is the lack of central visual clarity. For many people,
Hema hydrogel soft lenses provide adequate and reliable vision due to the nature of the material that the optical surface changes constantly when the eye moves and blinks, possibly because it is too soft, i.e. not rigid. Not provided. The second problem is that of astigmatism correction. Traditional hard contact lenses were usually able to correct corneal astigmatism by providing a new surface on the cornea. Due to the extreme flexibility of hema hydrogel contact lenses, they conform to the shape of the eye and therefore do not provide the new surface needed to correct astigmatism in most cases. Hema
There are also other physiological problems with using hydrogel contact lenses. It is the pain in the cornea and the overlap of the membranes of the eye. The exact cause or significance of these phenomena is unknown, and no solutions have been reported. However, there are reports that this is because there is less tear exchange in the case of Hema lenses compared to conventional lenses. This is likely because the lens conforms to the outer surface of the eye, preventing tears from flowing underneath the lens. A reduction in the amount of fresh tears is undesirable because it substantially reduces the eye's contact with oxygen and promotes the accumulation of decomposition products. After all, hydrogel soft lenses have a tendency to tear easily,
Whenever that happens it becomes necessary to transform the tears. Hydrophilic polymers selected from copolymers of substantially water-insoluble monomers selected from dihydroxyalkyl acrylates and methacrylates, and alkyl acrylates and methacrylates, preferably prepared by bulk free radical polymerization reactions, as discussed in more detail below. We provide contact lenses with a wide variety of products. Preferred reactants are glyceryl methacrylate and certain proportions of methyl methacrylate. Similar copolymers made from the two preferred monomers are known in the art and are described in Makromol. Chem. No. 118 by H. Yasuada, CELamazo and LDIkenberry.
Vol., p. 1935 (1968) and H. Yasuada, C.E.
Ramazo and A. Peterline
J.Polym.Sc. Part A-2, Volume 996, No. 1117
-Also described on page 1131 (1971). The copolymers described in the first of the two publications mentioned above are polymerized in a 70/30 solvent of acetic acid/water. This solution was made from 5 weight percent monomer and 95% solvent, and about 0.5% K ₂ S ₂ O ₈ and 1% based on the weight of monomer.
Started _{with 5 Na2S2O} . Oxygen in the solution is purged by passing nitrogen through the solution. After standing for 8 to 10 days at room temperature, precipitation of the polymer occurred in the water. The molar ratio of methyl methacrylate and glyceryl methacrylate is 95:5 to 70:
A series of 6 copolymers ranging from 30 to 30% were prepared. The method according to the second publication mentioned above is similar to the first method except that 2,2'-azobis-(2-methylpropionitrile) is used as the initiator in a non-aqueous solvent. For reasons discussed in more detail below, the copolymers of the two references above differ from the copolymers of the present application described below in the polymerization method used and the ratio of components, and the copolymers of the cited examples differ from the copolymers of the present invention described below, and the copolymers of the cited examples differ from the present copolymers described below. In particular, it is not suitable for the production of contact lenses. As mentioned above, the present invention provides hydrophilic monomers selected from dihydroxyalkyl acrylates and methacrylates, and substantially water-insoluble monomers selected from alkyl acrylates and methacrylates (hereinafter referred to as "dihydroxyacrylates" and "acrylates", respectively). A contact lens comprising a copolymer made from In order that the process of the present application provides a copolymer that is substantially superior to other processes, particularly for the production of contact lenses, the copolymer is subjected to free radical bulk polymerization in the substantial absence of a solvent or diluent. Preferably, it is manufactured by.
Preferably, dihydroxy acrylates are used primarily and alkyl acrylates are used in small amounts. The copolymers used in the present invention have similar properties to the hema materials described above, so that they are suitable for the manufacture of objects to be assimilated with biological tissue, such as contact lenses and surgical implants. . However, contact lenses made from the copolymers of the present invention do not have many of the disadvantages of lenses made from Hema materials. In this regard, the copolymers of the present invention have the softness and pliability required for soft contact lenses, but are stronger and somewhat more rigid than Hema materials. As a result, the copolymer provides adequate and reliable vision since there is no constant change in the optical surface as the eye moves and blinks that would interfere with vision. Additionally, because the copolymers used in the present invention are more rigid than the hema materials, lenses made from the copolymers of the present invention provide an external curvature that maximizes tear flow, oxygenation, and Provides fresh tears to remove decomposition products and dust or dirt particles deposited beneath. Additionally, and perhaps more importantly, the greater stiffness allows for the production of thinner cross-section lenses than lenses made from hema materials. The thin cross-section creates substantial permeability that allows tears to flow through and around the edges of the lens. Pain such as that experienced with hemalens is thus avoided.
Advantages of contact lenses made from the copolymers of the present invention are improved properties when cleaning with water and resistance to tearing. One component of the copolymer, a hydrophilic dihydroxyalkyl acrylate, has the following general formula: In the formula, R is hydrogen or a methyl group, and n is 0
An integer between 0 and 4, including 0 and 4. Dihydroxyalkyl acrylates are prepared by hydrolysis according to the method described in British Patent No. 852,384. In this patent, certain dioxolanoalkyl acrylates or methacrylates are hydrolyzed in dilute solutions of strong mineral acids for extended periods at room temperature, as described below. Example 1 50 g of isopropylidene glyceryl methacrylate, 150 ml of water, 0.3 g of concentrated sulfuric acid, and 0.02 of hydroquinone were stirred at 25-30° C. for 16 hours. A colorless and transparent solution was obtained. A small amount of solid barium hydroxide was added to neutralize the sulfuric acid. The barium sulfate precipitate was removed by filtration and the precipitate on the paper was washed with a small amount of water. The liquid and wash solution were combined to give 212 ml of a clear colorless solution, which was approximately a 20% solution of 2,3-dihydroxypropyl methacrylate in diluted acetone solution (12/1). The product was isolated by saturation with sodium chloride and extracted with benzene or ether.
After removing the solvent under reduced pressure, 2,3-dihydroxypropyl methacrylate was obtained as a slightly viscous oil. The preferred comonomer for making the hydrogel copolymers of the present invention was glyceryl methacrylate (2,3-dihydroxypropyl methacrylate). This material may be manufactured by the method described in the above-mentioned British patent, published in the Journal of Applied Polymer Science, Vol.
Pages 3161-3170 (Journal of Applied Polymer
Science, Volume9, Pages3161to3170) (1965)
Preferably, it is prepared according to the method described by MF Refojo in 1999. The method involves hydrolysis of glycidyl methacrylate and solvent extraction from the reaction mixture following the hydrolysis reaction as described below. Example 2 100g of commercially available glycidyl methacrylate (American Aniline and Extract)
Company (American Aniline and Extract
Company, Inc-GMA)), 150 ml of distilled water and
0.25 ml of concentrated sulfuric acid was stirred for 6 days. During the experiment, the flask used for the reaction was kept in a water bath at 24-29°C. No inhibitor was added to the reaction mixture other than that contained in the commercially available glycidyl methacrylate. Glycidyl methacrylate is poorly miscible with water, but as the reaction progressed the solubility increased until a clear solution was obtained. As the reaction progressed, glyceryl methacrylate was formed which dissolved together with unreacted glycidyl methacrylate. The reaction mixture was neutralized with 10% sodium hydroxide and then extracted 5 times with 100 ml of ether. The ether extract was washed three times with 20 ml of water and the aqueous solution was washed again with 50 ml of ether. The combined ether extracts were dried over anhydrous sodium sulfate. The ether was then evaporated in a rotary evaporation can with the rotating flask held in a cold water bath.
The residue from the 18.8 g ether extract was mainly
Furthermore, it was a glycidyl methacrylate that could be used to produce glyceryl methacrylate. The aqueous extract from the ether solution was saturated with sodium chloride. Glyceryl methacrylate separated as an oily layer above the saturated salt solution.
The oil was dissolved in methylene chloride. The organic solution was dried over anhydrous sodium sulfate and the ether extract was evaporated as described above without heating. The residue of the evaporation (11.6 g) was a viscous clear liquid, consisting primarily of glyceryl methacrylate. The aqueous reaction medium, extracted with ether, was saturated with sodium chloride and separated into two layers. After dissolving the organic layer with methylene chloride and drying over sodium sulfate, the solution was evaporated in a rotary evaporation can with the rotating flask held in a cold water bath. The yield of glyceryl methacrylate was 71.6 g. This reaction product also contains unreacted glycidyl methacrylate.
It contained 1.8-2.2%. This unreacted component was not removed in the extraction step. Other impurities such as methacrylic acid, glyceryl methacrylate diester and/or glyceryl methacrylate triester were also present in small amounts. It should be understood that other dihydroxyalkyl acrylates can also be prepared from the corresponding epoxyalkyl by the method described in Example 2 above. Other comonomers used with dihydroxyacrylates are substantially water-insoluble alkyl acrylates or methacrylates corresponding to the following general formula: where R is hydrogen or methyl, and R' is 1
alkyl having 6 to 6 carbon atoms.
Materials conforming to the above general structure are commercially available and do not require further elaboration. Illustrative examples of materials conforming to this formula are methyl acrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate, propyl methacrylate, butyl acrylate and butyl methacrylate. Methyl methacrylate is a preferred material. The ratio of dihydroxyalkyl acrylate to alkyl acrylate can vary within a relatively wide range. Thus, the molar ratio of dihydroxyalkyl acrylate to alkyl acrylate is within the range of 1:3 to 20:1. However, it is preferred that the dihydroxyalkyl acrylate is present in at least an equal amount or in excess of the alkyl acrylate; in this regard, the preferred molar ratio is about 1:1 to 10:1, more preferably 1.2:1.0 to 10:1. The range is 2:1.
For use in contact lenses, the above molar ratio is most preferably about 1.5:1.0. Therefore, although effective polymerization methods and catalyst materials are conventional techniques applied to similar monomers, it is preferred to use bulk polymerization methods for the monomers described below, preferably in the substantial absence of solvent.
The copolymers made by bulk polymerization have different properties than similar prior art copolymers made by solution polymerization. According to this preferred method, the monomers were mixed without the use of a solvent, held at elevated temperature for an extended period of time, and the resulting polymer was regenerated. Typically, the temperature of the polymerization reaction is 20
Within the range of 35 to 60℃, preferably 35 to 60℃
It was to be maintained at 42°C, most preferably at about 40°C. The concentration of catalyst may vary over a wide range depending on the particular catalyst used, but is generally in the range of 0.001 to 0.2 weight percent, preferably 0.01 to 0.04 weight percent, based on the hydroxyalkyl acrylate. . The preferred catalyst is about
Isopropyl percarbonate in an amount of 0.02 weight percent. Because of the presence of residual unreacted epoxy alkyl ester in the dihydroxyalkyl acrylate reaction product, it is likely that at least a majority of the dihydroxyalkyl acrylate/alkyl acrylate polymer chains will be crosslinked, if at all. Even after repeated solvent extraction steps, a significant amount of unreacted epoxy alkyl ester typically remains in the reaction mixture. This is apparently due to the dihydroxyalkyl acrylate acting as a co-solvent for the ester in the aqueous phase. However, if the amount of unreacted ester present in the dihydroxyalkyl acrylate product differs from that required to obtain the desired degree of crosslinking, the amount may be adjusted by adding an epoxyalkyl ester to increase the degree of crosslinking. This can be adjusted by decreasing the amount of ester in the product to increase or decrease the degree of crosslinking. The amount of ester can be lowered.
For example, it can be reduced by further repeating the solvent extraction step as is well known in the art. The amount of epoxy alkyl ester that should be present in the reaction product depends on the degree of crosslinking desired in the final hydrogel product. Generally, the higher the amount of epoxy alkyl ester, the higher the degree of crosslinking that will be obtained. Conversely, the lower the amount of ester, the lower the degree of crosslinking. Generally, it is preferred that about 1 to 3 weight percent of epoxy alkyl ester be present in the dihydroxyalkyl acrylate that is reacted with the alkyl acrylate. In the preferred glyceryl methacrylate/methyl methacrylate system, for example, a reaction using glyceryl methacrylate containing about 1 wt% glycidyl methacrylate will typically produce a copolymer that is about 53% hydrated. This value of 53% means a relatively low degree of crosslinking. In contrast, reactions using glyceryl methacrylate containing about 3% glycidyl methacrylate:
Typically, this will produce a copolymer that is about 32% hydrated. This value of 32% means a relatively high degree of crosslinking. The preferred range of epoxy alkyl ester is about 1.8-2.2 wt%. Within this range, preferred systems produce glyceryl methacrylate/methyl methacrylate copolymers with hydration rates of about 39-43%. Without wishing to be bound by theory, it is believed that this cross-linking reaction proceeds by generating a free radical on the tertiary hydrogen-containing carbon atom alpha to the epoxide oxygen atom. be able to. The radical of glycidyl methacrylate thus obtained is represented by the following formula. If other impurities are present, such as dimers or trimers of methacrylic acid and/or glyceryl methacrylate due to possible acid hydrolysis of glycidyl methacrylate, these will react with the glyceryl methacrylate/methyl methacrylate copolymer. Will. And it can help slightly increase the degree of crosslinking. However, it is clear that the essential crosslinking agent is an epoxyalkyl ester and that this compound can be used effectively to control the degree of crosslinking obtained. Other polymerizable bifunctional compounds having only one olefinic double bond and the other functional groups being non-olefinic can be used as crosslinking agents as well. Other suitable crosslinking agents are well known to those skilled in the art. Example 3 56.8 g of 2,3-dihydroxypropyl methacrylate (prepared by the method of Example 2 above) and 23.7 g of methyl methacrylate (Rohm and
Haas Company, Inc., molar ratio 1.5:1.0) was thoroughly stirred. Approximately 3 g of sodium sulfate was added to the mixture with stirring. This acts as a desiccant to remove all traces of moisture. The mixture was then filtered to remove the sodium sulfate and 15.5 mg of isopropyl percarbonate (0.02 weight percent 2,2-dihydroxypropyl methacrylate) was added. The mixture thus prepared was thoroughly stirred and placed in a large tube. Place the tube containing the mixture in a cold bath of dry ice in methylene chloride to bring the temperature of the mixture in the tube to -
The temperature was maintained at 20°C to -30°C. The tube was purged three times with nitrogen, sealed under vacuum, and placed in a constant temperature bath maintained at 35° to 40°C to allow the polymerization reaction to occur.
After about 90 to 95 minutes, the temperature was held for about 4 hours to allow the mixture to solidify indicating that the reaction had occurred. This time in the reaction is hereinafter referred to as the polymerization time. The tubes were then placed in a furnace maintained at 75°C for 16 hours (overnight). The furnace temperature was then raised to 90°C and held at this temperature for 1 hour. The tube was then allowed to cool. The polymer produced by the above method was removed from the tube in the form of a solid rod. When the material was cut into thin disks or in the form of lenses and placed in water, it hydrated and took on a soft, rubbery consistency. Example 4-8 2, for methyl methacrylate (MMA)
The method of Example 3 was repeated several times with varying ratios of 3-dihydroxypropyl methacrylate (GMA). The catalyst concentration was maintained at 0.02 weight percent of 2,3-dihydroxypropyl methacrylate, and the polymerization temperature was carefully maintained at 40°C. Following the reaction method, hydration (percent),
Polymers were evaluated for linear expansion (percent), diurometer hardness and appearance of hydrated state. The ratios used and the results obtained are shown in the table below.

[Table] Although the cross section of the button is slightly cloudy, the material of Example 6 is preferable for manufacturing contact lenses. This is probably due to defects in homogeneity that may explain the improved strength of the hydrated polymer. The advantage of Example 6 is that the physical properties of the polymer (hardness and stiffness) are optimal for lens manufacturing.
This is due to In fact, it is known in conventional contact lens manufacturing that the optimum property standard according to the present invention is the slightly cloudy appearance of the polymer when viewed from the end or cross-section of the button with the above-mentioned dimension. Considering the optical clarity of lenses made from the preferred polymers, the thin sections (0.05-0.15 mm) used gave the lenses a substantially completely optically clear appearance. Examples 9-14 The method of Example 3 was repeated several times with increasing catalyst concentrations. The polymerization temperature was kept constant at 40°C. The result of increasing the concentration of catalyst was, as expected, a decrease in the reaction temperature (time for solid formation in the tube containing the monomer). The results are shown in the table below.

[Table] Example 9 represents a polymer preferred for the production of contact lenses, and when a cross section of a standard size button was observed, it also had a slightly cloudy appearance. Example 15-17 The method of Example 3 was repeated several times keeping all conditions constant except for changing the temperature.
The following results were obtained.

Table: The copolymer of Example 15 was good for making contact lenses. Considering Example 4-17, the ratio of 2,3-dihydroxypropyl methacrylate to methyl methacrylate was about 1.5:1 2,
The concentration of isopropyl percarbonate to 3-dihydroxypropyl methacrylate is approximately 0.02.
Weight percentages and reaction temperatures of 40° C. and preferably curing have been found to be preferred for the production of contact lenses. Example 18 Similar results were expected when the method of Example 13 was repeated substituting ethyl methacrylate for methyl acrylate. Example 19 Similar results were expected when the method of Example 3 was carried out replacing methyl methacrylate with methyl acrylate. Example 20 The method of Example 3 was repeated substituting 2,3-dihydroxypropyl acrylate for 2,3-dihydroxypropyl methacrylate. Example 21 200 g (1.406 mol) of glycidyl methacrylate, 300 ml of water and 0.5 ml of concentrated sulfuric acid were mixed at 24-29°C.
The mixture was stirred for several days. The pH of the resulting clear solution was 2.0. Neutralized to pH 7.0 with 10% aqueous sodium hydroxide solution. This solution was then diluted with one portion of ether.
Extracted 6 times with 100 ml. The aqueous phase was stirred and saturated with sodium chloride. The resulting two-phase mixture was separated by filtration. The two-phase system was then extracted six times with 100 ml portions of methylene chloride. The extracts were combined and stored in a separatory funnel in the refrigerator overnight to clarify. The organic phase is separated and concentrated under reduced pressure;
118.7 g of clear viscous liquid was obtained. It consisted primarily of glyceryl methacrylate, but contained 2.19 wt% of unreacted glycidyl methacrylate. A portion of this reaction product was mixed with 26.1 g of methyl methacrylate. The solution was treated with sodium sulfate to dryness and the resulting mixture was filtered. Isopropyl percarbonate solution
18.2g and placed in four large treated test tubes. Blow nitrogen gas into each tube for 2 minutes,
The tube was cooled to -30°C, evacuated, and filled three times with nitrogen gas and sealed under vacuum. After covering the tube opening with wax, the tube was left standing in a constant temperature bath at 40° C. for 5 hours. The tube was then heated to 75°C.
It was left in the oven overnight. The next morning, the temperature was raised to 90°C for one hour. Thereafter, the test tube was cooled. Test buttons were made from this batch, which showed a hydration rate of 39.3% and an expansion rate of 17.9%. When glyceral methacrylate is further extracted with solvent until the content of unreacted epoxide is 1.06%, the hydration rate increases.
52.8% polymer was obtained. The hydrogel has excellent material properties for application in soft contact lenses. Thus water (physiological saline water or water containing physiologically active solutes such as bacteriostatic agents)
After adsorption, the hydrogel becomes soft and pliable, but at the same time tough and resistant to tearing. The lenses are somewhat more rigid than materials traditionally used for hydrogel contact lenses, and as a result may provide a wider range of eye contours and a thicker cross-section than prior art materials. , typically 0.05 to 0.15mm
thickness, and this thinner surface provides substantially better tear penetration than prior art materials. Additionally, the increased stiffness prevents deformation due to blinking and prevents a constantly changing visual surface resulting from changes and distortions in the visual field. If made correctly, they are suitably pliable to conform to the cornea, but also sufficiently rigid to hold their shape and allow tears to flow under the lens.
This is beneficial to supply fresh tears and nutrients to the lens-covered area and to remove breakdown products that have accumulated under the lens. Additionally, the curvature of the outer surface of the lens is a material with sufficient stiffness to allow for manipulation and manipulation to maximize tear flow.

Claims (1)

[Claims] 1 A contact lens produced by copolymerization of 2,3-dihydroxypropyl methacrylate and methyl methacrylate, which is a hydrogel that undergoes linear expansion of about 17 to 19% upon hydration, and about 37 to 42% A contact lens having a diurometer hardness of about 46 to 49.