JP5504758B2 - Prepolymer - Google Patents

Description

  The present invention generally relates to compositions comprising a prepolymer containing phosphorylcholine-like groups and used in the manufacture of medical devices. More particularly, it relates to a prepolymer containing a phosphorylcholine-like group having a reactive functional group provided by a residue having at least one reactive functional group. This prepolymer is useful as a means for surface modification of medical devices such as ophthalmic lenses.

  Although medical devices such as ophthalmic lenses made from silicone-containing materials have been studied for a long time, especially hydrogel ophthalmic lenses generally have a moisture content of about 15 to about 80% by weight. In many cases, the surface is hydrophobic and lipids and proteins are easily adsorbed. Therefore, a technique is known in which the surface is hydrophilized by plasma treatment or is made hydrophilic by impregnating with a water-soluble polymer.

  Developed a composition containing phosphorylcholine-like group-containing monomers, siloxane-containing monomers, and hydrophilic monomers to produce highly oxygen permeable hydrogels used to make biomedical devices including ophthalmic lenses (Patent Document 1, Patent Document 2). Usually, a phosphorylcholine-like group-containing monomer and a hydrophobic siloxane group-containing monomer such as 3- [tris (trimethylsiloxy) silyl] propyl methacrylate (TRIS) are poorly compatible with each other and do not mix uniformly. Although these alcohol solution compositions can be cured by polymerization, the resulting polymer is cloudy and therefore unsuitable as an ophthalmic lens. According to Patent Document 2, a transparent polymer containing a phosphorylcholine-like group-containing monomer and TRIS is obtained by using a special silicone monomer having a hydroxyl group such as SiGMA as a compatibilizing agent.

したがって特殊な設計を有するシリコーンモノマーを用いることでホスホリルコリン類似基をヒドロゲル中に導入することができる。
またホスホリルコリン類似基含有重合体を表面偏析させることでレンズ表面を改質し表面を親水化することが提案されている（特許文献３）。本系もＳｉＧＭＡやヒドロキシエチルメタクリレート（ＨＥＭＡ）が使用されており、特殊な系における例であるといえる。

Accordingly, phosphorylcholine-like groups can be introduced into the hydrogel by using a silicone monomer having a special design.
Further, it has been proposed that the surface of a lens is modified by hydrophobizing the phosphorylcholine-like group-containing polymer to make the surface hydrophilic (Patent Document 3). SiGMA and hydroxyethyl methacrylate (HEMA) are also used in this system, which can be said to be an example in a special system.

  So far, a manufacturing process using a surface treatment such as a plasma treatment for a silicone hydrogel using TRIS provides a lens having an appropriate hydrophilicity, but this process has a problem of increasing the manufacturing cost. In addition, the technique for dissolving the phosphorylcholine-like group-containing monomer and TRIS according to the technique described in Patent Document 2 has a narrow compatible range even if a special monomer is required. For this reason, there was a problem that advantageous hydrophilicity could not be obtained.

  As a method of hydrophilizing the lens surface using a phosphorylcholine-like group-containing monomer, A) A method of hydrophilizing the lens surface by graft polymerization of a phosphorylcholine-like group-containing monomer on the lens surface (Patent Document 4) or B) A method of hydrophilizing a lens surface by polymerizing using a template coated with a polymer containing both a reactive group and a phosphorylcholine-like group monomer is known (Patent Document 5). However, these manufacturing methods have a problem that the manufacturing cost increases due to an increase in the number of steps.

  To date, no means has been proposed for hydrophilizing the surface while having practical transparency and mechanical strength using a reactive hydrophilic polymer having a phosphorylcholine-like group without surface treatment.

  Here, when adding a polymer, 1) a phosphorylcholine-like group-containing monomer and allyl methacrylate, 2) a phosphorylcholine-like group-containing monomer and TRIS, and 3) a polymer having TRIS and allyl methacrylate as constituent components have been developed. However, 1) A polymer comprising a phosphorylcholine-like group-containing monomer and allyl methacrylate (Patent Document 5) can be surface-modified by coating on a curable composition, but cannot be dissolved in a silicone component.

  That is, no investigation has been made on dissolution in a hydrophilic lens formulation. In addition, there is 2) a polymer composed of a phosphorylcholine-like group-containing monomer and TRIS (Patent Document 6). Since this does not have a reactive functional group, it has a disadvantage of elution and cannot be used from the viewpoint of safety. 3) There is a polymer containing TRIS and allyl methacrylate as constituent components (Patent Document 7). This is used for the purpose of obtaining a solid or gel-like substance, and has not been studied as a prepolymer dissolved in a monomer solution.

  Furthermore, a polymer composed of three components composed of a phosphorylcholine-like group-containing monomer, TRIS and allyl methacrylate has not been studied so far.

JP 2007-197513 A Japanese Patent Laid-Open No. 2007-9060 JP 2007-314723 A JP 2001-117054 A Special Table 2002-520463 JP 2007-056220 A JP 1996-334732 A

  An object of the present invention is to provide a prepolymer for modifying the surface of an ophthalmic lens and a transparent solution composition containing the same. Another object of the present invention is to provide an ophthalmic lens comprising a prepolymer for modifying the surface of an ophthalmic lens which has a reactive functional group and further contains a phosphorylcholine-like group.

  As a result of intensive studies to solve these problems, the present inventors have come to the present invention. That is, a pre-polymer obtained by copolymerizing 2-methacryloyloxyethyl phosphorylcholine, TRIS, and allyl methacrylate dissolves well in a siloxanyl-containing compound and is cured together with a hydrophilic monomer to obtain a transparent lens material. As a result, the present invention has been completed.

The present invention is the following [1 ] .
[1], (a) 2-methacryloyloxyethyl phosphorylcholine, 20 to 30 mol%
(B) 3- [Tris (trimethylsiloxy) silyl] propyl methacrylate, 50-70 mol%
(C) Allyl methacrylate, 5 to 30 mol%
(A) + (b) + (c) = 100 mol%, (b) ÷ (a)> 2.0, (a) component, (b) component, (c) component A prepolymer having a molecular weight of 10,000 to 50,000.

  Although 2-methacryloyloxyethyl phosphorylcholine is not compatible with siloxanyl-containing compounds, the prepolymer of the present invention obtained by copolymerizing 2-methacryloyloxyethyl phosphorylcholine, TRIS, and allyl methacrylate is good for siloxanyl-containing compounds. And can be cured together with other hydrophilic monomers to obtain a transparent lens material.

It is a ¹ H-NMR spectrum of the copolymer synthesized in Example 1-1.

The prepolymer of the present invention comprises (a) 2-methacryloyloxyethyl phosphorylcholine, 20 to 30 mol%, (b) 3- [tris (trimethylsiloxy) silyl] propyl methacrylate (sometimes abbreviated as TRIS), 50 to 70 mol%, (c) allyl methacrylate, 5 to 30 mol%, (a) + (b) + (c) = 100 mol%, (b) ÷ (a)> 2.0 , (A), (b), and (c) are prepolymers having a molecular weight of 10,000 to 50,000.
2-Methacryloyloxyethyl phosphorylcholine and TRIS are generally poorly compatible with each other, and a uniformly transparent polymer cannot be obtained. This is because the phosphorylcholine-like group has a structure having zwitterions and cannot be mixed with highly hydrophobic TRIS.

The prepolymer of the present invention is composed of (a) 2-methacryloyloxyethyl phosphorylcholine, (b) 3- [tris (trimethylsiloxy) silyl] propyl methacrylate, and (c) allyl methacrylate monomers, and is uniformly dissolved in TRIS. It has a copolymer composition ratio. Moreover, it can melt | dissolve uniformly in the hydrophilic monomer required for creating hydrogel.
As such a prepolymer of the present invention, specifically, the structure of the following formula (4) can be shown.

（式中、ｌ、ｍ、ｎはモル比を表し、ｌ＝０．１〜０．３、ｍ＝０．５〜０．６５、ｎ＝０．１〜０．３である数である）。

(In the formula, l, m, and n represent molar ratios, and l = 0.1 to 0.3, m = 0.5 to 0.65, and n = 0.1 to 0.3) .

  When the prepolymer of the present invention is polymerized together with a composition containing TRIS and a hydrophilic monomer, it has hydrophilicity due to a phosphorylcholine-like group and has high oxygen permeability characteristic of silicone hydrogel. It is possible to provide an ophthalmic lens that is transparent and has sufficient mechanical strength for practical use. Therefore, if the prepolymer of the present invention is used, surface hydrophilicity can be imparted without requiring a special surface treatment operation such as plasma treatment, which is useful for producing an ophthalmic lens.

  The prepolymer of the present invention can be used as a prepolymer for modifying the surface of an ophthalmic lens for use in a copolymerizable polymer system used in ophthalmic lenses, particularly soft contact lenses. The ophthalmic lens surface modifying prepolymer can be used in the production of ophthalmic lenses, and is an ophthalmic lens for use in either “soft” or “hard” contact lenses, preferably “soft” hydrogel contact lenses. It is useful as a prepolymer for surface modification.

  The prepolymers of the present invention are used in both “hard” and “soft” ophthalmic lenses, but are particularly useful as ophthalmic lens surface modification prepolymers for soft hydrogel ophthalmic lenses. The prepolymer of the present invention can modify the surface of an ophthalmic lens.

Since the prepolymer of the present invention comprises monomers (a) 2-methacryloyloxyethyl phosphorylcholine, (b) 3- [tris (trimethylsiloxy) silyl] propyl methacrylate, and (c) allyl methacrylate,
a) a phosphorylcholine-like group,
b) Siloxanyl group,
c) allyl group,
It is a prepolymer characterized by having. Since the polarities of a) to c) are significantly different, the prepolymer is prepared by solution polymerization. The polymerization of the prepolymer is preferably performed under conditions where the allyl group does not significantly participate in the addition polymerization. The polymerization conditions at this time are disclosed in, for example, EP 0207640 and US Pat. No. 4,544,572.

  As the solvent used for the polymerization of the prepolymer of the present invention, it is preferable to use an alcohol system capable of simultaneously dissolving a highly polar phosphorylcholine-like group and a less polar siloxanyl group. More preferably, methanol, ethanol 1-propanol, or 2-propanol is used. The total concentration of the monomers (a) to (c) is preferably adjusted to 5% to 40%. When the amount is 5% or less, the pot efficiency deteriorates, and when the amount is 40% or more, a decrease in handling property due to an increase in viscosity becomes a problem. The polymerization temperature is preferably 40 ° C. or higher at which the reaction easily proceeds and 80 ° C. or lower in order to prevent the solvent from evaporating. More preferably, it is good to be the range of 55-65 degreeC which can complete reaction within several hours. As the polymerization initiator, it is desirable to select and use a peroxide-based polymerization initiator in order to prevent the allyl group from reacting and deactivating during the polymerization.

  The prepolymer is synthesized by polymerizing 10 to 30 mol% of 2-methacryloyloxyethyl phosphorylcholine, 50 to 65 mol% of 3- [tris (trimethylsiloxy) silyl] propyl methacrylate, and 10 to 30 mol% of allyl methacrylate, It is obtained as a prepolymer having a weight average molecular weight of 2,000 to 50,000.

The prepolymer of the present invention may be mixed with other monomers to form a mixture. In that case, both a thermal initiator and a photoinitiator for the purpose of curing may be included. Such a monomer mixture may further comprise at least one additional siloxanyl group-containing monomer. Furthermore, the monomer mixture may comprise at least one hydrophilic group-containing monomer. Further, it may contain at least one crosslinkable group-containing monomer. When obtaining such a monomer mixture, the mixture of the prepolymer of the present invention and the siloxanyl group-containing monomer cannot be poured into the mold unless it is dissolved or dispersed, and it is difficult to obtain a uniform lens. The relative weight percent of the prepolymer relative to the total amount of monomer mixture is from about 0.1% to 20%, more preferably from about 0.2% to 10%, and most preferably from 0.5% to 5%.
The prepolymer of the present invention is desirably dissolved or dispersed in 3- [tris (trimethylsiloxy) silyl] propyl methacrylate , which is a siloxanyl group-containing monomer, and particularly desirably dissolved.

0.1 to 5.0 parts by weight of the prepolymer of the present invention can be mixed with 95 to 99.9 parts by weight of 3- [tris (trimethylsiloxy) silyl] propyl methacrylate to form a transparent solution composition. Furthermore, it is good to set it as the polymerizable transparent solution composition formed by mix | blending such transparent solution composition 25.0-80.0 weight part and 20.0-75.0 weight part of hydrophilic monomers. .

Such parent Specific examples of the aqueous monomer, (meth) acrylic acid, succinic acid-containing monomer selected from [2- (2-methyl-1-oxo-2-propenyloxy) ethyl] 2-hydroxyethyl (meth) acrylate, 2,3-dihydroxypropyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, 3-hydroxypropyl (meth) acrylate, 2-hydroxybutyl (meth) acrylate, 3- Hydroxyl-containing monomer selected from hydroxybutyl (meth) acrylate, 4-hydroxybutyl (meth) acrylate, hydroxymethyl (meth) acrylamide, polyethylene glycol (meth) acrylate, glycerol methacrylate; (meth) acrylamide, N-vinyl- 2-pyrrolidone (VP), N, N-dimethylacrylic Bromide (DMA), isopropyl (meth) acrylamide, morpholyl (meth) acrylamide, amide group-containing monomer selected from vinyl carbamate monomers; and the like.

  Of these, hydroxyethyl (meth) acrylate is preferred because it imparts hydrophilicity and is easy to obtain. In addition, N-vinyl-2-pyrrolidone and N, N-dimethylacrylamide are preferred because they are easily available, and further, impart softness and mechanical strength to the resulting soft contact lens. Is preferred.

  A crosslinker monomer may be further added to the polymerizable transparent solution composition of the present invention. Examples of the crosslinking agent monomer include ethylene glycol di (meth) acrylate, diethylene glycol di (meth) acrylate, triethylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, trimethylolpropane tri (meth) acrylate, and pentaerythritol. Mention may be made of polyfunctional (meth) acrylates such as tri (meth) acrylate.

  The polymerizable transparent solution composition of the present invention can be copolymerized and is easily cured and shaped by methods such as UV polymerization, use of a free radical thermal initiator and heat, or a combination thereof. Free radical thermal polymerization initiators that may be used include organic peroxides such as acetyl peroxide, lauroyl peroxide, decanoyl peroxide, stearoyl peroxide, benzoyl peroxide, tertiary butyl pivalate peroxide, peroxydicarbonate, And commercially available thermal initiators such as LUPERSOL® 256, 225 (Atofina Chemicals, Philadelphia, Pa.), About 0.01-2% by weight of the total monomer mixture Can be used in concentration. UV initiators that may be used are known in the art, such as benzoin methyl ether, benzoin ethyl ether, DAROCUR®-1173, 1164, 2273, 1116, 2959, 3331, IGRACURE (registered) 651 and 184 (Ciba Specialty Chemicals, Ardsley, New York).

  In addition to the polymerization initiator, the polymerizable transparent solution composition of the present invention may also contain other components known to those skilled in the art. For example, additional colorants known in the ophthalmic lens field, or UV absorbers, and reinforcing agents may be included.

  Polymerization of the polymerizable transparent solution composition of the present invention can be carried out, for example, by a centrifugal molding method or a molding method so as to match the shape of a desired ophthalmic lens. The ophthalmic lens thus obtained can be further subjected to mechanical finishing as required. Polymerization can also be carried out in a suitable mold or container to give a lens material in the form of a button, plate or rod, which is then processed (eg, lathe or laser cut) to produce the desired ophthalmic lens. Can be obtained.

  Although the polymerizable transparent solution composition of the present invention can be usefully used as an optical ophthalmic lens or film in some cases, it is preferably used for an ophthalmic lens.

Hereinafter, the present invention will be described specifically by way of examples.
The synthesized prepolymer was evaluated by the following method.
-Solubility test in TRIS 95 parts by weight of TRIS and 5 parts by weight of a prepolymer were mixed and vigorously stirred at 25 ° C. After stirring, the mixture was allowed to stand and the mixture was visually observed. Judgment was performed using the following indices.
Dissolves uniformly → ○
Insoluble solid content → ×
¹ H-NMR measurement method measuring device: JNM-AL400 manufactured by JEOL Ltd.
Solvent: CDCl ₃ (TMS standard)

Example 1-1: Synthesis of (MPC _0.3 -tris (trimethylsiloxy) silylpropyl methacrylate _0.6 -allyl methacrylate _0.1 ) copolymer MPC; 9.98 g, tris (trimethylsiloxy) silylpropyl methacrylate; 28.60 g, allyl methacrylate; 1.42 g dissolved in ethanol; 280 g, put into a four-necked flask, blown with nitrogen for 30 minutes, and then t-butyl peroxyneodecanoate at 60 ° C .; 3.91 g In addition, the polymerization reaction was carried out for 12 hours. The obtained polymerization solution was dropped into 50 times the amount of water, and the deposited precipitate was filtered and vacuum-dried to obtain 32.5 g of the title polymer powder.
When the molecular weight was evaluated by GPC using methanol / chloroform (4/6; weight ratio) as an eluent, the weight average molecular weight was 37,000 according to polyethylene glycol standard.
The evaluation results are shown in Table 1. The structure was confirmed from the ¹ H-NMR spectrum (400 MHz). The results are shown in FIG. Signals of protons derived from the allyl site of allyl methacrylate were observed at 5.24-5.34 ppm and 5.89 ppm. In addition, signals derived from MPC at 2.82 ppm, 3.38 ppm, 3.86-4.45 ppm, signals from TRIS at 0.10-0.15 ppm, 0.43 ppm, and 0.86-1.14 ppm. Observed. When the copolymer composition of the polymer was determined from the signal area ratio, MPC was 30 mol%, tris (trimethylsiloxy) silylpropyl methacrylate was 50 mol%, and allyl methacrylate was 20 mol%. confirmed.

Example 1-2 and Comparative Examples 1-1 to 1-6 were obtained in the same manner as Example 1-1.

Reference Example 2-1: Preparation of hydrogel film-obtained from the prepolymer described in Example 1-1 (thermosetting).
Prepolymer, TRIS, HEMA, VP, EDMA, and Vazo® 52 initiator (mass ratio 1.0 / 40/20 / 38.8 / 0.1 / 0.1) DuPont) was mixed to prepare a monomer mixture solution. The prepared mixture solution was filtered through a 0.5 μm filter and poured between polypropylene sheets having a 100 μm spacer. Polymerized and cured at 100 ° C. for 4 hours and processed into a hydrogel film.

Reference Example in the same manner as in Reference Example 2-1 2-2～4-6 were Reference Comparative Example 2-1～4-8.

Evaluation The prepared hydrogel film was evaluated by measuring 1) transparency, 2) contact angle, and 3) Young's modulus by the following methods.
1) Evaluation of transparency The transparency of the hydrogel film was determined by visual observation of the appearance with the following indicators.
・ Transparent → ○
・ It is slightly turbid → △
・ It is cloudy → ×
2) Measurement of contact angle In order to investigate the surface wettability of the hydrogel film, the contact angle was measured by a bubble method using a contact angle meter (DropMaster 500) manufactured by Kyowa Interface Science Co., Ltd. The interface contact angle when a droplet of 1.0 μL of pure water pushed out by a glass syringe lands on the hydrogel film,
3) Measurement of Young's modulus 20 strips 15 mm long and 2 mm wide were cut out from the water-containing sheet, and a tensile tester
The elastic modulus of the water-containing strips was measured using Leoner Re-3 3 0 5 (manufactured by Yamaden Co., Ltd.). The unit of elastic modulus in the table is MPa. The results are shown in Tables 2 and 3.

  It is apparent that the ophthalmic lens produced using the prepolymer of the present invention exhibits hydrophilicity without the need for surface treatment such as plasma treatment or corona discharge treatment.

  The prepolymer of the present invention is particularly effectively used as an ophthalmic lens surface modifying polymer in the ophthalmic lens field.

Claims (1)

(A) 2-methacryloyloxyethyl phosphorylcholine, 20-30 mol%
(B) 3- [Tris (trimethylsiloxy) silyl] propyl methacrylate, 50-70 mol%
(C) Allyl methacrylate, 5 to 30 mol%
(A) + (b) + (c) = 100 mol%, (b) ÷ (a)> 2.0, (a) component, (b) component, (c) component A prepolymer having a molecular weight of 10,000 to 50,000.

Images