WO2021020512A1 - Drug-containing ophthalmic lens - Google Patents

Abstract

The present invention addresses the problem of providing a drug-containing ophthalmic lens that is superior regarding the amount of a drug incorporated into the lens, the release action of the drug, and the transparency of the lens. An ophthalmic lens material for sustained drug release containing a polymer obtained through copolymerization of a reaction mixture containing a monopolydimethylsiloxane compound represented by general formula (1), N,N-dimethyl acrylamide, 2-hydroxyethyl methacrylate, polyvinyl pyrrolidone, and a crosslinking agent. (In formula (1), X represents a vinyl group, an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group, Y represents a bond, ꟷR₁ꟷ, ꟷR₁ꟷR₂ꟷ, ꟷR₁ꟷR₂ꟷR₃ꟷ, ꟷR₁ꟷR₂ꟷR₃ꟷR₄ꟷ, or ꟷR₁ꟷR₂ꟷR₃ꟷR₄ꟷR₅ꟷ, wherein R₁, R₃, and R₅ each represent a C1-C3 alkylene group optionally having a substituent, R₂ and R₄ each represent an oxygen atom, ꟷNHꟷC(O)Oꟷ, ꟷNHꟷC(O)NHꟷ, ꟷOꟷC(O)Oꟷ, or ꟷOꟷC(O)NHꟷ, Z represents a C1-C6 alkyl group, a C3-C6 cyclic alkyl group, or an aryl group, and n represents an integer of 1-1500.)

Description

Drug-containing eye lens

The present invention relates to a material for an ocular lens for sustained release administration of a drug, and a drug-containing ophthalmic lens containing the drug.

Currently, the most widely used dosage form as an ophthalmic pharmaceutical preparation is liquid eye drops. Generally, the administration of liquid eye drops is performed by dropping an appropriate amount of eye drops onto the eyeball portion. The dropped ophthalmic solution is first stored in the conjunctival sac, then permeates the conjunctival epithelium or corneal epithelium, and migrates into the eye. The drug absorbed in the conjunctival epithelium further diffuses the sclera and reaches the eye. In addition, the drug absorbed in the corneal epithelium first passes through the stroma of the cornea, reaches the anterior chamber, and then reaches the iris and lens. A part of it reaches the ciliary body and the posterior optic nerve head by the flow of aqueous humor flowing from the iris root to the ciliary interstitium and further to the posterior choroid (Non-Patent Document 1).

Usually, the rate of drug transfer of eye drops into the cornea is less than a few percent of the total dose of the drug. In addition, since the corneal epithelium has a high affinity for fat-soluble drugs, the corneal permeability of water-soluble drugs is lower than that of fat-soluble drugs. Therefore, eye drops containing a water-soluble drug as an active ingredient have a low drug utilization rate. After instillation, most unused drugs mix with tear fluid and flow out of the body and are lost, or they reach the nasal or pharyngeal mucosa from the punctum through the nasolacrimal duct, where they are absorbed and enter the systemic circulation. It has been known.
As described above, in the liquid eye drops, most of the drugs are not used in the eye.

To overcome this problem, it is possible to increase the concentration of the drug in liquid eye drops and enhance the intraocular transfer of the drug, but the high concentration of the drug is absorbed by the mucous membrane of the nose and throat through the nasolacrimal duct. If it enters the systemic circulation, side effects may appear strongly, so it cannot be said to be a preferable remedy.
In order for the drug to exert its efficacy in the eye efficiently, it is necessary to expose the drug to the target site at the target concentration for the target time. However, it is difficult to control this with ordinary liquid eye drops. In addition, liquid eye drops also have problems such as excessive application of eye drops, failure, and outflow of drug due to blinking.

Therefore, in order to overcome the problems of these liquid eye drops, focus on contact lenses, consider them not only as a means for correcting eyesight but also as a device for drug administration, and deliver the drug slowly from the contact lenses. Attempts have been made to make an ophthalmic pharmaceutical preparation in which the drug dose and drug administration time are controlled.
For example, Patent Document 1 discloses that a hydrogel material obtained by polymerizing a specific hydrophilic monomer has a large amount of drug uptake and enables sustained release administration of the drug.
Patent Document 2 discloses a silicone hydrogel-containing ophthalmic lens containing pranlukast as a drug, and further discloses that a water-soluble polymer such as polyvinylpyrrolidone may be contained.

Patent Document 3 discloses a drug sustained-release medical contact lens containing an amphipathic hydrogel holding a water-soluble drug having a cationic functional group. Such an amphipathic hydrogel is a copolymer obtained by copolymerizing a monomer mixed solution containing a specific amount of a silicone-containing monomer and an ionic monomer having a carboxyl group and a methacryl group.
Patent Document 4 discloses a drug sustained-release medical contact lens containing a silicone-based polymer having a specific structure and a drug having a solubility in water in a specific range.
However, it is necessary to develop materials that clear various hurdles such as adjusting the amount of drug taken up, controlling the dissolution behavior, and ensuring the transparency of the lens, and a satisfactory sustained-release contact lens for drugs has not yet been obtained. .. For example, various lens materials that hold a drug for a long period of time are known, but it is difficult to put it into practical use if the amount of the drug taken up is small. In addition, even if the problem of drug loading can be solved, it is not practical to design the specifications so that the drug is continuously released from the contact lens beyond the daily activity time of the wearer. .. This is because it is preferable for the wearer to wear the lens continuously for multiple days because of the effects of dryness of the lens during sleep, lack of oxygen, and stain of the lens due to protein contained in tears. Absent. Even if the contact lenses are removed during sleep, cleaning the lenses with hydrogen peroxide or proteolytic enzymes is difficult because it affects the therapeutic drugs contained in the lenses, and chloride is added to the preservative solution for lens preservation. It is not preferable to add preservatives such as benzalkonium, boric acid, and benzoic acid esters because there is a concern that they may have an adverse effect on the eyes. Therefore, in order to put a contact lens for sustained release of a drug into practical use, it is preferable to use it for one day, and a material for which the drug is completely discharged within the activity time from waking up to sleep of the wearer and the sustained release is administered. It is desirable to do. It is also desired that the lens material has low selectivity of a drug that can be released slowly, and can be applied to various drugs and has high versatility.

As a material for contact lenses used for vision correction, a material containing silicone for the purpose of improving oxygen permeability is known, and monomethacryloyloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane (hereinafter referred to as monodimethylsiloxane). (Also referred to as mPDMS), mono- (3-methacryloyloxy-2-hydroxypropoxy) propyl-terminated mono-n-butyl-terminated polydimethylsiloxane (hereinafter also referred to as OH-mPDMS) and the like are actually used. In addition, those using 2-hydroxyethyl methacrylate (hereinafter, also referred to as HEMA), N, N-dimethylacrylamide (hereinafter, also referred to as DMA), polyvinylpyrrolidone (hereinafter, also referred to as PVP) and the like are also known.
However, regarding contact lens materials for sustained release of drugs, it is still unclear what kind of monomer should be used in order to obtain contact lenses with good drug uptake, drug elution behavior, and lens transparency. Sufficient knowledge has not been obtained.

International Publication 2003/090805 JP-A-2009-204770 International Publication No. 2012/127927 International Publication No. 2017/0773739

An object of the present invention is to provide a drug-containing ophthalmic lens that is excellent in all of the amount of drug taken into the lens, the release behavior of the drug, and the transparency of the lens.

As a result of diligent studies, the present inventors have found that a copolymer polymer containing an mPDMS-based compound, DMA, HEMA, and PVP as a monomer unit exhibits excellent properties as an ophthalmic lens material for sustained drug release. The present invention has been completed.

That is, the present invention is as follows.
[1] Includes a polymer obtained by copolymerizing a reaction mixture containing a monopolydimethylsiloxane compound represented by the following general formula (1), N, N-dimethylacrylamide, 2-hydroxyethyl methacrylate, polyvinylpyrrolidone, and a cross-linking agent. , Eye lens material for sustained release of drugs.

(In equation (1),
X represents a vinyl group, an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group.
Y is a _{bond, -R 1 -, - R 1} -R 2 -, - R 1 -R 2 -R 3 -, - R 1 -R 2 -R 3 -R 4 -, or _-R 1 -R ₂ -R _3- R _4- R _5- , indicating
Here, R ₁ represents a C1-C3 alkylene group.
R ₂ represents an oxygen atom, -NH-C (O) O-, -NH-C (O) NH-, -OC (O) O-, or -OC (O) NH-.
R ₃ represents a C1-C3 alkylene group
R ₄ is an oxygen atom, -NH-C (O) O -, - NH-C (O) NH -, - O-C (O) O-, or -O-C (O) NH- indicates,
R ₅ represents a C1-C3 alkylene group
In addition, R ₁ , R ₃ , and R ₅ may each have an independent substituent.
As the substituent, a hydroxy group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkoxy C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkoxy group, or a C1-C3 alkoxy C1-C3 alkoxy C1 -Indicating a C3 alkyl group,
Z represents a C1-C6 alkyl group, a C3-C6 cyclic alkyl group, or an aryl group.
n represents an integer from 1 to 1500. )

[2] In the above formula (1)
X indicates an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group.
Y indicates binding, -R _1- , or -R _1- R _2- R _3-
R ₁ represents a C1-C3 alkylene group,
R ₂ indicates an oxygen atom,
R ₃ indicates a C1-C3 alkylene group, ocular lens material according to [1].
[3] The compound represented by the formula (1) is mono-methacryloyloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane and / or mono- (3-methacryloyloxy-2-hydroxyproproxy) propyl-terminated mono-n. The ophthalmic lens material according to [1] or [2], which is a butyl-terminated polydimethylsiloxane.
[4] The cross-linking agent comprises one or more selected from the group consisting of tetraethylene glycol dimethacrylate, triethylene glycol dimethacrylate, ethylenediamine dimethacrylate, and glycerol dimethacrylate, [1] to [ 3] The ophthalmic lens material according to any one of.
[5] The drug is one or more selected from the group consisting of antiallergic agents, anti-inflammatory agents, antibacterial agents, glaucoma therapeutic agents, and dry eye therapeutic agents, [1] to [4]. The ophthalmic lens material described in any of.
[6] The drug is selected from the group consisting of sodium cromoglycate, ketotifen fumarate, pemirolast potassium, planoprofen, levofloxacin, latanoprost, levamipid, timolol, brimonidine, ripasudil, and emedastin fumarate. The ophthalmic lens material according to any one of [1] to [4], which is one kind or two or more kinds.
[7] An eye lens containing the eye lens material according to any one of [1] to [6] and a drug.
[8] The eye according to [7], wherein the drug is one or more selected from the group consisting of antiallergic agents, anti-inflammatory agents, antibacterial agents, glaucoma therapeutic agents, and dry eye therapeutic agents. Lens for.
[9] The drug is selected from the group consisting of sodium cromoglycate, ketotifen fumarate, pemirolast potassium, planoprofen, levofloxacin, latanoprost, levamipid, timolol, brimonidine, ripasudil, and emedastin fumarate. The ophthalmic lens according to [7], which is one type or two or more types.
[10] The eye lens according to [7] to [9], which is a contact lens.

According to the present invention, an ocular lens material for sustained release of a drug, which has a behavior of sufficiently taking in a drug, sufficiently and gradually eluting the taken-in drug, and further having sufficient transparency as an ophthalmic lens. Is obtained. Such materials are suitable for drug-containing ophthalmic lenses.

Test Example 1: The graph which shows the time-dependent change of the elution amount of a drug due to the difference of a polymer component. Test Example 1: The graph which shows the time-dependent change of the relative elution rate of a drug due to the difference of a polymer component. Test Example 2: The graph which shows the time-dependent change of the elution amount of a drug by the difference in the content ratio of HEMA and DMA. Test Example 2: The graph which shows the time-dependent change of the relative elution rate of a drug by the difference in the content ratio of HEMA and DMA. Test Example 3: A graph showing the time course of the elution amount of the drug due to the difference in silicone. Test Example 3: A graph showing the time course of the relative elution rate of the drug due to the difference in silicone. Test Example 3: A graph showing the time course of the absolute dissolution rate of the drug due to the difference in silicone. Test Example 4: The graph which shows the time-dependent change of the elution amount of a drug due to the difference in the content of PVP. Test Example 4: A graph showing the time course of the relative dissolution rate of the drug due to the difference in the content ratio of the PVP content. Test Example 5: A graph showing the time course of the elution amount of the drug due to the difference in the concentration at the time of drug impregnation. Test Example 5: A graph showing the time course of the relative dissolution rate of the drug due to the difference in the concentration at the time of drug impregnation. Test Example 6: The graph which shows the time-dependent change of the elution amount of a drug due to the difference of the drug to be impregnated. Test Example 6: The graph which shows the time-dependent change of the elution amount of a drug due to the difference of the drug to be impregnated. Test Example 6: A graph showing the time course of the relative dissolution rate of the drug due to the difference in the drug to be impregnated. Test Example 6: Graph showing the time course of the relative dissolution rate of the drug due to the difference in the drug to be impregnated. Test Example 6: A graph showing the time course of the absolute dissolution rate of the drug due to the difference in the drug to be impregnated. Test Example 6: A graph showing the time course of the absolute dissolution rate of the drug due to the difference in the drug to be impregnated.

Next, the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and can be freely modified within the scope of the present invention.

The ophthalmic lens material of the present invention copolymerizes a reaction mixture containing a monopolydimethylsiloxane compound represented by the following general formula (1), N, N-dimethylacrylamide, 2-hydroxyethyl methacrylate, polyvinylpyrrolidone, and a cross-linking agent. Contains a polymer made from

(In equation (1),
X represents a vinyl group, an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group.
Y is a _{bond, -R 1 -, - R 1} -R 2 -, - R 1 -R 2 -R 3 -, - R 1 -R 2 -R 3 -R 4 -, or _-R 1 -R ₂ -R _3- R _4- R _5- , indicating
Here, R ₁ represents a C1-C3 alkylene group.
R ₂ represents an oxygen atom, -NH-C (O) O-, -NH-C (O) NH-, -OC (O) O-, or -OC (O) NH-.
R ₃ represents a C1-C3 alkylene group
R ₄ is an oxygen atom, -NH-C (O) O -, - NH-C (O) NH -, - O-C (O) O-, or -O-C (O) NH- indicates,
R ₅ represents a C1-C3 alkylene group.
In addition, R ₁ , R ₃ , and R ₅ may each have an independent substituent.
As the substituent, a hydroxy group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkoxy C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkoxy group, or a C1-C3 alkoxy C1-C3 alkoxy C1 -Indicating a C3 alkyl group,
Z represents a C1-C6 alkyl group, a C3-C6 cyclic alkyl group, or an aryl group.
n represents an integer from 1 to 1500. )
In addition, in this specification, the description "C1-C3" means "having 1 to 3 carbon atoms". The same applies to the description of "C1-C6" and the like.

The polymer can be paraphrased as a polymer containing a monopolydimethylsiloxane compound represented by the general formula (1), N, N-dimethylacrylamide, 2-hydroxyethyl methacrylate, polyvinylpyrrolidone, and a cross-linking agent as a monomer unit.

The monopolydimethylsiloxane compound used in the present invention is a linear silicone and is represented by the following general formula (1).

In the general formula (1), X represents a radically polymerizable polymerizable group, and specifically, a vinyl group, an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group. Of these, an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group is preferable, and an acryloyloxy group or a methacryloyloxy group is more preferable.

In the general formula (1), Y is a spacer group that connects the monopolydimethylsiloxane group and the polymerizable group, and specifically, the bond, -R _1- , -R _1- R _2- , -R _{1-. R 2 -R 3 -, - R} 1 -R 2 -R 3 -R 4 -, or _{-R 1 -R 2 -R 3 -R 4} -R 5 - shows a. Of these, -R ₁ -, or _-R 1 _-R 2 _{-R 3} - group represented by are preferred.
R ₁ represents a C1-C3 alkylene group. R ₂ represents an oxygen atom, -NH-C (O) O-, -NH-C (O) NH-, -OC (O) O-, or -OC (O) NH-. Of these, the oxygen atom is more preferred. R ₃ represents a C1-C3 alkylene group. R ₄ is an oxygen atom, a nitrogen atom, -NH-C (O) O -, - NH-C (O) NH -, - O-C (O) O-, or -O-C (O) NH- Is shown. R ₅ represents a C1-C3 alkylene group.

Further, R ₁ , R ₃ and R ₅ may each have an independent substituent, and the substituents include a hydroxy group, a C1-C3 alkyl group, a C1-C3 alkoxy group, and a C1-C3 alkoxy C1. -C3 alkyl group, C1-C3 alkoxy C1-C3 alkoxy group, or C1-C3 alkoxy C1-C3 alkoxy C1-C3 alkyl group.
The C1-C3 alkylene group represented by R ₁ , R ₃ or R ₅ is a divalent alkylene chain, and specifically indicates a group having a methylene chain, an ethylene chain or a propylene chain. These may have a substituent, specifically a methylene group, a hydroxymethylene group, a methylmethylene group, an ethylene group, a 2-hydroxyethylene group, a 2-methoxyethoxymethylethylene group, a propylene group, or 2-. A hydroxypropylene group and the like are mentioned, and an ethylene group, a propylene group, or a 2-hydroxypropylene group is preferably mentioned.

In the general formula (1), Z represents a C1-C6 alkyl group, a C3-C6 cyclic alkyl group, or an aryl group, and specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or an n-butyl group. Group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl group, sec-pentyl group, isopentyl group, 3-pentyl group, tert-pentyl group, neopentyl group, n-hexyl group, isohexyl group, neohexyl Examples thereof include a group, a texyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, and a benzyl group.

N in the formula (1) indicates the degree of polymerization of the siloxane, and is not particularly limited, but is preferably 1 to 1,500, more preferably 3 to 150, and even more preferably 3 to 25.
The weight average molecular weight of the monopolydimethylsiloxane compound represented by the formula (1) is preferably 250 to 120,000, more preferably 400 to 12,000, and even more preferably 400 to 2,500.

As the monopolydimethylsiloxane compound represented by the general formula (1), in the general formula (1), X represents an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group, and Y represents a bond, −R. ₁ -, or _-R 1 _-R 2 -R ₃ - indicates, _{R 1} is represents a C1-C3 alkylene group, _{R 2} is an oxygen atom, _{R 3} is a compound showing a C1-C3 alkylene group Is more preferable.
Particularly preferred monopolydimethylsiloxane compounds represented by the formula (1) are monomethacryloyloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane (mPDMS) and / or mono- (3-methacryloyloxy-2-hydroxypropoxy) propyl. Terminal mono-n-butyl end polydimethylsiloxane (OH-mPDMS) can be mentioned. In the ophthalmic lens material of the present invention, one or more monopolydimethylsiloxane compounds represented by the formula (1) can be used as a monomer.

The monopolydimethylsiloxane compound represented by the formula (1) imparts sustained drug release to the polymer.
The content of the monopolydimethylsiloxane compound represented by the formula (1) with respect to the entire reaction mixture is preferably 1 to 90% by weight, more preferably 5 to 70% by weight, still more preferably 10 to 60% by weight.
The content of the monopolydimethylsiloxane compound represented by the formula (1) with respect to the entire component constituting the polymer (that is, the component excluding the solvent and the like from the reaction mixture) in the reaction mixture is preferably 1 to 95% by weight. 5 to 80% by weight is more preferable, and 30 to 70% by weight is further preferable.

N, N-dimethylacrylamide (DMA) imparts transparency to the polymer.
The content of DMA in the entire reaction mixture is preferably 0.1 to 80% by weight, more preferably 0.5 to 65% by weight, still more preferably 1 to 50% by weight.
The content of the DMA reaction mixture with respect to the entire components constituting the polymer (that is, the components obtained by removing the solvent and the like from the reaction mixture) is preferably 0.1 to 90% by weight, more preferably 0.5 to 75% by weight. It is preferable, and 1 to 60% by weight is more preferable.

2-Hydroxyethyl methacrylate (HEMA) imparts sustained release to the polymer. However, if the blending amount is too large, the transparency of the polymer may be impaired.

The content of HEMA with respect to the entire reaction mixture is preferably 0.1 to 80% by weight, more preferably 0.5 to 65% by weight, still more preferably 1 to 50% by weight.
Further, the content of the HEMA reaction mixture with respect to the entire components constituting the polymer (that is, the components obtained by removing the solvent and the like from the reaction mixture) is preferably 0.1 to 90% by weight, more preferably 0.5 to 75% by weight. It is preferable, and 1 to 60% by weight is more preferable.

The ratio of the contents of DMA and HEMA in the reaction mixture is preferably DMA: HEMA = 10: 1 to 1:10, more preferably 4: 1 to 1: 4, 2: 1 to 1: 1 in terms of mass ratio. 2 is more preferable. In such a range, both the transparency of the lens and the sustained release of the drug tend to be sufficient.
The mass ratio of the content (so-called charged amount) in the reaction mixture can be regarded as the mass ratio of the monomer units in the polymer obtained by copolymerization.

Polyvinylpyrrolidone (PVP) imparts drug loading ability to the polymer, and the higher the content, the higher the drug loading capacity.
The degree of polymerization of pyrrolidone in PVP is not particularly limited, but is preferably 25 to 25,000, and more preferably 300 to 15,000. Further, the weight average molecular weight is preferably 3,000 to 3,000,000, more preferably 45,000 to 1,200,000. Further, the K value (viscosity characteristic value) is preferably 10 to 120, more preferably 30 to 90.

The content of PVP in the total reaction mixture is preferably 0.1 to 30% by weight, more preferably 0.5 to 25% by weight, still more preferably 1 to 15% by weight.
Further, the content of the PVP reaction mixture with respect to the entire components constituting the polymer (that is, the components obtained by removing the solvent and the like from the reaction mixture) is preferably 0.1 to 30% by weight, more preferably 0.5 to 25% by weight. It is preferable, and more preferably 1 to 20% by weight.

Crosslinking agent refers to a compound having two or more polymerizable groups. The polymerizable group is a group (reactive group) that can react under the polymerization conditions to which the reaction mixture is provided, and is, for example, a (meth) acrylate group, a styryl group, a vinyl group, a vinyl ether group, an itaconate group, or an acryloylamino. Examples thereof include a group, an N-vinyllactam group, an N-vinylamide group, a vinyl ether group, an epoxide group and the like. In addition, in this specification, the word "(meth) acrylate" represents a methacrylic group and an acrylic group.
The cross-linking agent may be hydrophilic or hydrophobic, but a hydrophobic cross-linking agent is preferable.
The hydrophilic cross-linking agent includes a compound having two or more polymerizable groups and a hydrophilic functional group such as a polyether group, an amide group, and a hydroxy group. Specifically, tetraethylene glycol dimethacrylate (TEGDMA), triethylene glycol dimethacrylate (TrEGDMA), ethylene glycol dimethacrylate (EGDMA), ethylenediamine dimethacrylate, glycerol dimethacrylate and the like are preferable.

By using a cross-linking agent, a three-dimensional cross-linked structure can be formed in the polymer, and the mechanical strength and hardness of the polymer can be improved to impart durability (chemical resistance, heat resistance, solvent resistance). When the polymer of the present invention is used as a material for an ophthalmic lens as described later, it can be made uniform, transparent, and excellent in optical properties without distortion.
The content of the cross-linking agent with respect to the entire reaction mixture is preferably 0.1 to 15% by weight, more preferably 0.25 to 10% by weight, still more preferably 0.5 to 5% by weight.
The content of the cross-linking agent in the reaction mixture with respect to the total components constituting the polymer (that is, the components excluding the solvent and the like from the reaction mixture) is preferably 0.2 to 20% by weight, preferably 0.5 to 15% by weight. More preferably, 1 to 7.5% by weight is further preferable.

The reaction mixture for obtaining the polymer according to the present invention by copolymerization may contain a polymerization initiator.
Examples of the polymerization initiator include lauryl peroxide, benzoyl peroxide, isopropyl percarbonate, azobisisobutyronitrile, and 2,2'-azobis (4-methoxy-2,4), which generate free radicals at a slightly high temperature. Examples include compounds such as -dimethylvaleronitrile) (V-70). In addition, photoinitiators such as aromatic α-hydroxyketone, alkoxyoxybenzoin, acetophenone, acylphosphine oxide, bisacylphosphine oxide and tertiary amine + diketone can also be used. Typical examples of photoinitiators are 1-hydroxycyclohexylphenyl ketone, 2-hydroxy-2-methyl-1-phenyl-propane-1-one, bis (2,6-dimethoxybenzoyl) -2,4- 4-trimethylpentylphosphine oxide, bis (2,4,6-trimethylbenzoyl) -phenylphosphine oxide, 2,4,6-trimethylbenzyldiphenylphosphine oxide and 2,4,6-trimethylbenzoyldiphenylphosphine oxide, benzoinmethyl Examples thereof include esters, phenylquinone and ethyl 4- (N, N-dimethylamino) benzoates.

The content of the polymerization initiator with respect to the entire reaction mixture is preferably 0.01 to 5.0% by weight, more preferably 0.05 to 2.5% by weight, still more preferably 0.1 to 1% by weight.

The reaction mixture for obtaining the polymer according to the present invention by copolymerization may contain a diluent. The diluent has a role of increasing the reaction rate of the copolymerization and also enhancing the releasability of the copolymerization polymer.
In the present invention, the diluent is preferably water-soluble, for example, 1-decanol, 1-octanol, 1-pentanol, 1-hexanol, 2-hexanol, 2-octanol, 3-methyl-3-pentanol, 2 -Pentanol, t-amyl alcohol (tAA), tert-butanol, 2-butanol, 1-butanol, 2-methyl-2-pentanol, 2-ethyl-1-butanol, 1-propanol, 2-propanol, ethanol , Methanol, 3,3-dimethyl-2-butanol, decanoic acid, octanoic acid, dodecanoic acid, 1-ethoxy-2-propanol, 1-tert-butoxy-2-propanol, EH-5, 2,3,6 7-Tetrahydroxy-2,3,6,7-Tetramethyloctane, 9- (1-methylethyl) -2,5,8,10,13,16-Hexoxaheptadecane, 3,5,7,9 , 11,13-Hexanol-1-tetradecanol, tripropylene glycol methyl ether, water and the like are preferably mentioned, and these may be used alone or in combination of two or more.

The content of the diluent with respect to the entire reaction mixture is preferably 1 to 75% by weight, more preferably 10 to 70% by weight, still more preferably 30 to 65% by weight.

The polymer according to the present invention may contain other monomers in the reaction mixture and contain the monomer units. The other monomer is not particularly limited as long as it is a commonly used monomer, and examples thereof include the following.

Methyl (meth) acrylate, ethyl (meth) acrylate, propyl (meth) acrylate, isopropyl (meth) acrylate, butyl (meth) acrylate, tert-butyl (meth) acrylate, isobutyl (meth) acrylate, pentyl (meth) acrylate, tert-pentyl (meth) acrylate, hexyl (meth) acrylate, heptyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, dodecyl (meth) Linear, branched and cyclic alkyl (meth) acrylates such as acrylates, stearyl (meth) acrylates, cyclopentyl (meth) acrylates, cyclohexyl (meth) acrylates and phenoxy (meth) acrylates;
Pentamethyldisyloxanylmethyl (meth) acrylate, pentamethyldisyloxanylpropyl (meth) acrylate, trimethylsilylmethyl (meth) acrylate, trimethylsilylethyl (meth) acrylate, trimethylsilylpropyl (meth) acrylate, trimethylsilylpropyl glyceryl (meth) ) Silicon-containing (meth) acrylates such as acrylate, pentamethyldisyloxylpropylglyceryl (meth) acrylate, tetramethyltriisopropylcyclotetrasiloxanylpropyl (meth) acrylate;
Trifluoroethyl (meth) acrylate, tetrafluoropropyl (meth) acrylate, pentafluoropropyl (meth) acrylate, hexafluoroisopropyl (meth) acrylate, tetrafluoro-tert-pentyl (meth) acrylate, hexafluorobutyl (meth) acrylate , Hexafluoro-tert-hexyl (meth) acrylate, octafluoropentyl (meth) acrylate, 2,3,4,5,5,5-hexafluoro-2,4-bis (trifluoromethyl) pentyl (meth) acrylate , Dodecafluoroheptyl (meth) acrylate, 2-hydroxyoctafluoro-6-trifluoromethylheptyl (meth) acrylate, 2-hydroxydodecafluoro-8-trifluoromethylnonyl (meth) acrylate, 2-hydroxyhexadecafluoro- Fluorine-containing (meth) acrylates such as 10-trifluoromethylundecyl (meth) acrylate;
Styrene, pentafluorostyrene, methylstyrene, trimethylstyrene, trifluoromethylstyrene, (pentamethyl-3,3-bis (trimethylsiloxy) trisiloxanyl) styrene, (hexamethyl-3-trimethylsiloxytrisiloxanyl) styrene, dimethylaminostyrene Styrene derivatives such as;
Hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, hydroxybutyl (meth) acrylate, dihydroxypropyl (meth) acrylate, dihydroxybutyl (meth) acrylate, diethylene glycol mono (meth) acrylate, triethylene glycol mono (meth) acrylate , Hydroxy group-containing (meth) acrylates such as dipropylene glycol mono (meth) acrylate;
(Meta) acrylic acid;
Vinyl lactams such as N-vinylpyrrolidone, α-methylene-N-methylpyrrolidone, N-vinylcaprolactam, N- (meth) acryloylpyrrolidone;
(Meta) acrylamide, N-methyl (meth) acrylamide, N-ethyl (meth) acrylamide, N-hydroxyethyl (meth) acrylamide, N, N-dimethyl (meth) acrylamide, N, N-diethyl (meth) acrylamide, (Meta) acrylamides such as N-ethyl-N-aminoethyl (meth) acrylamide;
Aminoalkyl (meth) acrylates such as aminoethyl (meth) acrylate, N-methylaminoethyl (meth) acrylate, N, N-dimethylaminoethyl (meth) acrylate;
Alkoxy group-containing (meth) acrylates such as methoxyethyl (meth) acrylate, ethoxyethyl (meth) acrylate, and methoxydiethylene glycol (meth) acrylate;
Aromatic ring-containing (meth) acrylates such as benzyl (meth) acrylate;
Alkyl esters that may be substituted with alkyl groups such as itaconic acid, crotonic acid, maleic acid, fumaric acid, fluorine-containing alkyl groups, and siloxanyl alkyl groups;
Glycidyl (meth) acrylate;
Tetrahydrofurfuryl (meth) acrylate;
4-vinylpyridine;
Heterocyclic N-vinyl monomers such as vinyl imidazole, N-vinyl piperidone, N-vinyl piperidine, N-vinyl succinimide;
N- (meth) acryloyl piperidine;
N- (meth) acryloyl morpholine.
Further, one or two or more of the above-mentioned copolymerization monomers can be selected and polymerized to obtain a macromonomer, which can be used as one of the copolymerization monomers for polymer production.
As the macromonomer, those obtained by polymerizing both a hydrophilic monomer and a hydrophobic monomer as a monomer unit are preferable. HEMA is preferable as the hydrophilic monomer constituting the macromonomer, and 2- (trimethylsiloxy) ethyl (meth) acrylate and / or monomethacryloyloxypropyl-terminated, n-butyl-terminated polydimethylsiloxane and the like are preferably mentioned as the hydrophobic monomer. Be done.

The polymer according to the present invention absorbs a polymerizable ultraviolet absorber, a polymerizable ultraviolet absorbing dye (mainly absorbing an ultraviolet portion), and a polymerizable dye (not having an ultraviolet absorbing performance, mainly in the blue region) in a reaction mixture. It may also contain these monomer units. By containing these polymerizable dyes, it is possible to adjust the color tone of the ophthalmic lens described later and impart an ultraviolet absorbing ability.
As the polymerizable ultraviolet absorber, for example, the benzophenone-based polymerizable ultraviolet absorber disclosed in Japanese Patent Application Laid-Open No. 2003-253248 and the benzotriazole-based polymerizable ultraviolet absorber disclosed in Japanese Patent No. 2685980 can be used. Specific examples include, for example, 2-hydroxy-4- (meth) acryloyloxybenzophenone, 2-hydroxy-4- (meth) acryloyloxy-5-t-butylbenzophenone, 2-hydroxy-4- (meth) acryloyloxy. Benzopenone-based polymerizable UV absorbers such as -2', 4'-dichlorobenzophenone, 2-hydroxy-4- (2'-hydroxy-3'-(meth) acryloyloxypropoxy) benzophenone; 2- (2'-hydroxy) -5'-(meth) acryloyloxyethylphenyl) -2H-benzotriazole, 2- (2'-hydroxy-5'-(meth) acryloyloxyethylphenyl) -5-chloro-2H-benzotriazole, 2-( 2'-Hydroxy-5'-(meth) acryloyloxypropylphenyl) -2H-benzotriazole, 2- (2'-hydroxy-5'-(meth) acryloyloxypropyl-3'-t-butylphenyl) -5 Bentriazoles such as -chloro-2H-benzotriazole, 2- (2'-hydroxy-5'-(2 "-methacryloyloxyethoxy) -3'-t-butylphenyl) -5-methyl-2H-benzotriazole, etc. Polymerizable UV absorber; Salicyl acid derivative-based polymerizable UV absorber such as 2-hydroxy-4-methacryloyloxymethylbenzoate phenyl; 2-cyano-3-phenyl-3- (3'-(meth) acryloyloxyphenyl) Examples thereof include propenylate methyl ester, which can be used alone or in combination of two or more.

As the polymerizable dye, for example, an azo-based, anthraquinone-based, nitro-based, or phthalocyanine-based polymerizable dye disclosed in JP-A-10-251537 can be used. These can be used alone or in combination of two or more.
Specific examples of the polymerizable azo dye include 1-phenylazo-4- (meth) acryloyloxynaphthalene, 1-phenylazo-2-hydroxy-3- (meth) acryloyloxynaphthalene, and 1-naphthylazo-2-hydroxy. -3- (Meta) acryloyloxynaphthalene, 1- (α-anthrylazo) -2-hydroxy-3- (meth) acryloyloxynaphthalene, 1-((4'-(phenylazo) -phenyl) azo) -2-hydroxy -3- (Meta) acryloyloxynaphthalene, 1- (2', 4'-kisilylazo) -2- (meth) acryloyloxynaphthalene, 1- (o-tolylazo) -2- (meth) acryloyloxynaphthalene, 2- (M- (meth) acryloylamide-anilino) -4,6-bis (1'-(o-tolylazo) -2'-naphthylamino) -1,3,5-triazine, 2- (m-vinylanilino)- 4- (4'-Nitrophenylazo) -anilino) -6-chloro-1,3,5-triazine, 2- (1'-(o-tolylazo) -2'-naphthyloxy) -4- (m-) Vinyl anilino) -6-chloro-1,3,5-triazine, 2- (p-vinylanilino) -4- (1'-(o-tolylazo) -2'naphthylamino) -6-chloro-1,3,5 -Triazine, N- (1'-(o-tolylazo) -2'-naphthyl) -3-vinylphthalic acid monoamide, N- (1'-(o-tolylazo) -2'-naphthyl) -6-vinylphthalic acid monoamide , 3-Vinylphthalic acid- (4'-(p-sulfophenylazo) -1'-naphthyl) monoester, 6-vinylphthalic acid- (4'-(p-sulfophenylazo) -1'-naphthyl) monoester , 3- (meth) acryloylamide-4-phenylazophenol, 3- (meth) acryloylamide-4- (8'-hydroxy-3', 6'-disulfo-1'-naphthylazo) -phenol, 3-( Meta) acryloylamide-4- (1'-phenylazo-2'-naphthylazo) -phenol, 3- (meth) acryloylamide-4- (p-tolylazo) phenol, 2-amino-4- (m- (2') -Hydroxy-1'-naphthylazo) anilino) -6-isopropenyl-1,3,5-triazine, 2-amino-4- (N-methyl-p- (2'-hydroxy-1'-naphthylazo) anilino) -6-isopropenyl-1,3,5-triazine, 2-amino-4 -(M- (4'-Hydroxy-1'-phenylazo) anilino) -6-isopropenyl-1,3,5-triazine, 2-amino-4- (N-methyl-p- (4'-hydroxyphenyl) Azo) Anilino) -6-isopropenyl-1,3,5-triazine, 2-amino-4- (m- (3'-methyl-1'-phenyl-5'-hydroxy-4'-pyrazolylazo) anilino ) -6-Isopropenyl-1,3,5-triazine, 2-amino-4- (N-methyl-p- (3'-methyl-1'-phenyl-5'-hydroxy-4'-pyrazolylazo)) Anilino) -6-isopropenyl-1,3,5-triazine, 2-amino-4- (p-phenylazoanilino) -6-isopropenyl-1,3,5-triazine, 4-phenylazo-7- (Meta) Acryloylamide-1-naphthol and the like can be mentioned.

Specific examples of the polymerizable anthraquinone dye include 1,5-bis ((meth) acryloylamino) -9,10-anthraquinone and 1- (4'-vinylbenzoylamide) -9,10-anthraquinone, 4 -Amino-1- (4'-vinylbenzoylamide) -9,10-anthraquinone, 5-amino-1- (4'-vinylbenzoylamide) -9,10-anthraquinone, 8-amino-1- (4') -Vinylbenzoylamide) -9,10-anthraquinone, 4-nitro-1- (4'-vinylbenzoylamide) -9,10-anthraquinone, 4-hydroxy-1- (4'-vinylbenzoylamide) -9, 10-Antraquinone, 1- (3'-vinylbenzoylamide) -9,10-anthraquinone, 1- (2'-vinylbenzoylamide) -9,10-anthraquinone, 1- (4'-isopropenylbenzoylamide)- 9,10-anthraquinone, 1- (3'-isopropenylbenzoylamide) -9,10-anthraquinone, 1- (2'-isopropenylbenzoylamide) -9,10-anthraquinone, 1,4-bis (4') -Vinylbenzoylamide) -9,10-anthraquinone, 1,4-bis (4'-isopropenylbenzoylamide) -9,10-anthraquinone, 1,5'-bis (4'-vinylbenzoylamide) -9, 10-Anthraquinone, 1,5-bis (4'-isopropenylbenzoylamide) -9,10-anthraquinone, 1-methylamino-4- (3'-vinylbenzoylamide) -9,10-anthraquinone, 1-methyl Amino-4- (4'-vinylbenzoyloxyethylamino) -9,10-anthraquinone, 1-amino-4- (3'-vinylphenylamino) -9,10-anthraquinone-2-sulfonic acid, 1-amino -4- (4'-Vinylphenylamino) -9,10-anthraquinone-2-sulfonic acid, 1-amino-4- (2'-vinylbenzylamino) -9,10-anthraquinone-2-sulfonic acid, 1 -Amino-4- (3'-(meth) acryloylaminophenylamino) -9,10-anthraquinone-2-sulfonic acid, 1-amino-4- (3'-(meth) acryloylaminobenzylamino) -9, 10-Anthraquinone-2-sulfonic acid, 1- (β-ethoxycarbonylallylamino) -9,10-anthraquinone, 1- (β-carboxyallylamino) -9,1 0-anthraquinone, 1,5-di- (β-carboxyallylamino) -9,10-anthraquinone, 1- (β-isopropoxycarbonylallylamino) -5-benzoylamide-9,10-anthraquinone, 2-( 3'-(Meta) acryloylamide-anilino) -4- (3'-(3 "-sulfo-4" -aminoanthraquinone-1 "-yl) -amino-anilino) -6-chloro-1,3,5 -Triazine, 2- (3'-(meth) acryloylamide-anilino) -4- (3'-(3 "-sulfo-4" -aminoanthraquinone-1 "-yl) -amino-anilino) -6-hydrazino -1,3,5-triazine, 2,4-bis-((4 "-methoxyanthraquinone-1" -yl) -amino) -6- (3'-vinylanilino) -1,3,5-triazine, 2 -(2'-Vinylphenoxy) -4- (4'-(3 "-sulfo-4" -aminoanthraquinone-1 "-yl-amino) -anilino) -6-chloro-1,3,5-triazine, etc. Can be mentioned.

Specific examples of the polymerizable nitro-based dye include o-nitroanilinomethyl (meth) acrylate and the like.
Specific examples of the polymerizable phthalocyanine dye include (meth) acryloylated tetraamino copper phthalocyanine, (meth) acryloylated (dodecanoylated tetraamino copper phthalocyanine) and the like.

Specific examples of the polymerizable ultraviolet-absorbing dye include 2,4-dihydroxy-3 (p-styrenoazo) benzophenone, 2,4-dihydroxy-5- (p-styrenoazo) benzophenone, and 2,4-dihydroxy-3. -(P- (meth) acryloyloxymethylphenylazo) benzophenone, 2,4-dihydroxy-5-(p- (meth) acryloyloxymethylphenylazo) benzophenone, 2,4-dihydroxy-3- (p- (meth) ) Acryloyloxyethylphenylazo) benzophenone, 2,4-dihydroxy-5-(p- (meth) acryloyloxyethylphenylazo) benzophenone, 2,4-dihydroxy-3- (p- (meth) acryloyloxypropylphenylazo) ) Benzophenone, 2,4-dihydroxy-5-(p- (meth) acryloyloxypropylphenylazo) benzophenone, 2,4-dihydroxy-3- (o- (meth) acryloyloxymethylphenylazo) benzophenone, 2,4 -Dihydroxy-5-(o- (meth) acryloyloxymethylphenylazo) benzophenone, 2,4-dihydroxy-3-(o- (meth) acryloyloxyethylphenylazo) benzophenone, 2,4-dihydroxy-5-( o- (meth) acryloyloxyethylphenylazo) benzophenone, 2,4-dihydroxy-3- (o- (meth) acryloyloxypropylphenylazo) benzophenone, 2,4-dihydroxy-5-(o- (meth) acryloyl) Oxypropylphenylazo) benzophenone, 2,4-dihydroxy-3- (p- (N, N-di (meth) acryloyloxyethylamino) phenylazo) benzophenone, 2,4-dihydroxy-5-(p- (N,) N-di (meth) acryloyloxyethylamino) phenylazo) benzophenone, 2,4-dihydroxy-3- (o- (N, N-di (meth) acryloyloxyethylamino) phenylazo) benzophenone, 2,4-dihydroxy- 5- (o- (N, N-di (meth) acryloyl ethylamino) phenylazo) benzophenone, 2,4-dihydroxy-3- (p- (N-ethyl-N- (meth) acryloyloxyethylamino) phenylazo) Benzophenone, 2,4-dihydroxy-5-(p- (N-ethyl-N- (meth) acryloyloxyethylamino) phenylazo) benzophenone, 2, 4-Dihydroxy-3- (o- (N-ethyl-N- (meth) acryloyloxyethylamino) phenylazo) benzophenone, 2,4-dihydroxy-5-(o- (N-ethyl-N- (meth) acryloyl) Oxyethylamino) phenylazo) benzophenone, 2,4-dihydroxy-3-(p- (N-ethyl-N- (meth) acryloylamino) phenylazo) benzophenone, 2,4-dihydroxy-5-(p- (N-) Ethyl-N- (meth) acryloylamino) phenylazo) benzophenone, 2,4-dihydroxy-3- (o- (N-ethyl-N- (meth) acryloylamino) phenylazo) benzophenone, 2,4-dihydroxy-5- (O- (N-ethyl-N- (meth) acryloylamino) phenylazo) Benzophenone-based polymerizable ultraviolet-absorbing dyes such as benzophenone, and benzoic acid-based polymerization such as 2-hydroxy-4- (p-styrenoazo) phenyl benzoate. Examples include sex UV absorbing dyes.
These can be used alone or in combination of two or more.

The polymer according to the present invention can be obtained by a copolymerization method usually performed in the art. For example, the uniformly mixed reaction mixture can be polymerized by gradually heating it in a temperature range of room temperature to about 130 ° C., or by irradiating it with electromagnetic waves such as microwaves, ultraviolet rays, and radiation (gamma rays). .. For the polymerization, various methods widely and generally used by those skilled in the art such as radical polymerization, bulk polymerization or solvent polymerization can be adopted, and in the case of thermal polymerization, the temperature is raised stepwise. You may let me.

Since the polymer of the present invention can carry a drug and can release the loaded drug slowly, it is suitable as an ocular lens material for sustained release of the drug.
Examples of such an ophthalmic lens include a contact lens and an intraocular lens, and it is preferable to apply the lens to a contact lens.
The ophthalmic lens may be in the form of a drug-loaded drug-containing ophthalmic lens, or in the form of a kit in which the drug to be immersed and the ophthalmic lens are combined.

The method of mounting the drug on the polymer is not particularly limited, and for example, a method of immersing the polymer in a solvent such as water is preferable.
The concentration of the immersion solution of the drug can be, for example, 0.001 to 5% by weight, and a high concentration can increase the loading amount.
The temperature at the time of immersion can be, for example, −10 to 80 ° C.
The immersion time can be, for example, 4 to 96 hours.

The polymer of the present invention can carry a drug, preferably 0.1 to 100 mg, more preferably 0.5 to 50 mg, still more preferably 1 to 25 mg, per 1 g of the polymer.
In addition, the polymer of the present invention can elute (release) the loaded drug after 24 hours, preferably in an amount of 50% by weight or more, more preferably 60% by weight or more, still more preferably 75% by weight or more. it can.
Further, the drug release rate of the polymer of the present invention is gradual, specifically, after 4 hours, the loading amount is preferably 85% by weight or less, more preferably 75% by weight or less, still more preferably 60% by weight or less. It can be eluted (released).

Due to such sustained release performance, when the polymer of the present invention is used as a drug-containing contact lens, it is preferable to use it for a so-called 1-day disposable.

The drug to be mounted on the polymer of the present invention is not particularly limited, and examples thereof include antiallergic agents, anti-inflammatory agents, antibacterial agents, glaucoma therapeutic agents, and dry eye therapeutic agents, and antiallergic agents are preferable. Preferred examples of the antiallergic agent include sodium cromoglycate, ketotifen fumarate, pemirolast potassium, emedastin fumarate and the like. Pranoprofen is preferably mentioned as an anti-inflammatory agent. Levofloxacin is preferably mentioned as the antibacterial agent. Preferred examples of the glaucoma therapeutic agent include latanoprost, timolol, brimonidine, and ripasudil. As the dry eye therapeutic agent, rebamipide and the like are preferably mentioned.

The polymer of the present invention having oxygen permeability is suitable for application to an ophthalmic lens.
Oxygen permeability is preferably 50 barrels or more, more preferably 100 barrels or more.

Further, the polymer of the present invention having an appropriate elastic property is suitable for application to an ophthalmic lens.
The elastic property is preferably 150 psi or less, more preferably 100 psi or less in terms of modulus.

In addition, the polymer of the present invention having transparency is suitable for application to an ophthalmic lens.
Here, transparency means that the transmittance of visible light (average transmittance of 400 to 700 nm) is preferably 70% or more, more preferably 80% or more.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

(Synthesis Example 1) Synthesis of OH-mPDMS First, 3-allyloxy-2-hydroxypropane methacrylate was synthesized by the following procedure.
In a 200 mL eggplant-shaped flask, methacrylic acid (120.6 g, 1.4 mol), allyl glycidyl ether (80.3 g, 0.7 mol), sodium methacrylate (22.7 g, 0.21 mol), 4-methoxyphenol (1. 14 g, 9.18 mmol) was added. The reaction vessel was heated to 100 ° C. and stirred for 24 hours. After adding toluene (300 mL), the mixture was separated 7 times with a 0.5 N aqueous sodium hydroxide solution (300 mL) to remove excess methacrylic acid. The solution was washed 3 times with saturated brine (300 mL), the solution was dried over anhydrous sodium sulfate, activated carbon was added, and the solution was filtered. The filtrate was depressurized with a rotary evaporator, excess solvent was distilled off, and the target compound 3-allyloxy-2-hydroxypropane methacrylate (93.9 g, 0.47 mol) was obtained in a yield of 67%.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ1.96 (3H, s), 3.54 (2H, m), 4.03 (3H, m), 4.24 (2H, m), 5.21 ( 1H, m), 5.29 (1H, m), 5.60 (1H, m), 5.90 (1H, m), 6.14 (1H, m)

Then, OH-mPDMS was synthesized by the following procedure.
3-allyloxy-2-hydroxypropane methacrylate (20.0 g, 99.9 mmol) and 2% palladium (0) -1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex in a 200 mL eggplant-shaped flask A xylene solution (50 μL) was added, and 40 mL, 45.1 mmol of n-butylpolydimethylsilane (MCR-H07 manufactured by Gelest, degree of polymerization 9-12, molecular weight 800-900) was added under ice-cooling. After the addition, the reaction vessel was taken out from the ice bath and stirred in a water bath for 24 hours. Then, N, N'-diethylethylenediamine (3 mg, 25.8 μmol) is added, the reaction solution is transferred to a separating funnel using hexane (20 mL), and the reaction solution is divided with ethylene glycol (1 time at 20 mL, 9 times at 10 mL). The solution was run to remove unreacted 3-allyloxy-2-hydroxypropane methacrylate. After adding ethyl acetate (50 mL), the mixture was washed with water (20 mL x 5 times) and saturated brine (20 mL x 3 times), dried over anhydrous sodium sulfate overnight, and filtered. Excess solvent of the filtrate was removed with a rotary evaporator to obtain OH-mPDMS (44.9 g, 42.7 mmol) as the target compound in a yield of 94.7%.
^{1 1} H NMR (400 MHz, CDCl ₃ ): δ0.05 (69H, m), 0.53 (4H, m), 0.89 (3H, t), 1.31 (4H, m), first 1.96 (3H, s), 3.47 (4H, m), 4.05 (1H, m), 4.24 (2H, m), 5.60 (1H, m), 6.14 (1H, m)

(Example 1)
0.67 g of N, N-dimethylacrylamide, 0.51 g of 2-hydroxyethyl methacrylate, 0.17 g of tetra (ethylene glycol) dimethacrylate, 1.50 g of OH-mPDMS of Synthesis Example 1, poly (vinylpyrrolidone) 0.49 g of (K-90) and 1.67 g of diluent t-acrylamide were added and mixed, and the mixture was stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. It was put into a polymerization mold (length 30 mm, width 30 mm, thickness 1 mm) made of a glass plate and a silicon spacer and polymerized. The polymer sheet was released by immersing the polymer sheet in purified water at 80 ° C. Immersion in 50 mL of ethanol at 50 ° C. for 24 hours was repeated twice to remove impurities such as unreacted monomers. The ethanol concentration in the immersion solvent was gradually lowered and replaced with water. Then, the immersion in 100 mL of purified water for 24 hours was repeated twice. Moisture on the surface of the removed polymer sheet was wiped off, and the polymer sheet was cut into a length of 10 mm and a width of 10 mm to obtain a polymer sheet AE1 (transparent).

(Example 2)
0.41 g of N, N-dimethylacrylamide, 0.75 g of 2-hydroxyethyl methacrylate, 0.17 g of tetra (ethylene glycol) dimethacrylate, 1.50 g of OH-mPDMS of Synthesis Example 1, poly (vinylpyrrolidone) 0.49 g of (K-90) and 1.67 g of diluent t-acrylamide were added and mixed, and the mixture was stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AH2 (transparent).

(Example 3)
0.79 g of N, N-dimethylacrylamide, 0.38 g of 2-hydroxyethyl methacrylate, 0.17 g of tetra (ethylene glycol) dimethacrylate, 1.50 g of OH-mPDMS of Synthesis Example 1, poly (vinylpyrrolidone) 0.50 g of (K-90) and 1.67 g of diluent t-acrylamide were added and mixed, and the mixture was stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AI1 (transparent).

(Example 4)
0.91 g of N, N-dimethylacrylamide, 0.50 g of 2-hydroxyethyl methacrylate, 0.17 g of tetra (ethylene glycol) dimethacrylate, 1.50 g of OH-mPDMS of Synthesis Example 1, poly (vinylpyrrolidone). 0.50 g of (K-90) and 1.67 g of diluent t-acrylamide were added and mixed, and the mixture was stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AH3 (transparent).

(Example 5)
1.33 g of N, N-dimethylacrylamide, 1.01 g of 2-hydroxyethyl methacrylate, 0.34 g of tetra (ethylene glycol) dimethacrylate, 2.00 g of OH-mPDMS of Synthesis Example 1, mPDMS (manufactured by Gelest: MCR-M11, degree of polymerization 5-9, molecular weight 600-800) was added in 1.00 g, poly (vinylpyrrolidone) (K-90) was added in 1.00 g, and diluent t-amyl alcohol was added in 3.34 g, and the mixture was mixed. Stirred for hours. 7.0 mg of the thermal polymerization initiator V-70 was added and dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AG1 (transparent).

(Example 6)
1.32 g of N, N-dimethylacrylamide, 1.00 g of 2-hydroxyethyl methacrylate, 0.34 g of tetra (ethylene glycol) dimethacrylate, 1.00 g of OH-mPDMS of Synthesis Example 1, mPDMS (manufactured by Gelest: 2.00 g of MCR-M11, degree of polymerization 5-9, molecular weight 600-800), 0.50 g of poly (vinylpyrrolidone) (K-90), and 3.34 g of diluent t-acrylamide are added and mixed. Stirred for hours. 7.0 mg of the thermal polymerization initiator V-70 was added and dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AG2 (transparent).

(Comparative Example 1)
2.17 g of N, N-dimethylacrylamide, 0.51 g of 2-hydroxyethyl methacrylate, 0.17 g of tetra (ethylene glycol) dimethacrylate, 0.50 g of poly (vinylpyrrolidone) (K-90), diluent 1.67 g of t-acrylamide alcohol was added, mixed, and stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AE4 (transparent).

(Comparative Example 2)
Diluent 2-hydroxyethyl methacrylate 1.16 g, tetra (ethylene glycol) dimethacrylate 0.17 g, OH-mPDMS of Synthesis Example 1 1.51 g, poly (vinylpyrrolidone) (K-90) 0.50 g. 1.67 g of agent t-amyl alcohol was added, mixed, and stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AE2 (translucent).

(Comparative Example 3)
1.17 g of N, N-dimethylacrylamide, 0.17 g of tetra (ethylene glycol) dimethacrylate, 1.50 g of OH-mPDMS of Synthesis Example 1, 0.50 g of poly (vinylpyrrolidone) (K-90), 1.67 g of diluent t-acrylamide alcohol was added, mixed, and stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AE3 (white turbidity).

(Comparative Example 4)
1.17 g of N, N-dimethylacrylamide, 0.50 g of 2-hydroxyethyl methacrylate, 0.17 g of tetra (ethylene glycol) dimethacrylate, 1.50 g of OH-mPDMS of Synthesis Example 1, and t-amyl diluent. 1.67 g of alcohol was added, mixed, and stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AE5 (transparent).

(Comparative Example 5)
Add 1.17 g of N, N-dimethylacrylamide, 0.50 g of 2-hydroxyethyl methacrylate, 0.17 g of tetra (ethylene glycol) dimethacrylate, 1.50 g of TRIS, and 1.67 g of diluent t-amyl alcohol. It was mixed and stirred for 24 hours. 3.5 mg of the thermal polymerization initiator V-70 was added and the mixture was dissolved by applying ultrasonic waves. The same polymerization and post-treatment as in Example 1 were carried out to obtain a polymer sheet AJ1 (transparent).

Each polymer sheet prepared was impregnated with a drug according to the following procedure and subjected to an dissolution test.
(1) Preparation of drug-containing solution (1-1) Preparation of sodium cromoglycate solution (SC) Weigh 500 mg of sodium cromoglycate into a 50 mL volumetric flask, align with PBS (-) to the marked line, and 1 wt% cromoglycic acid. A sodium solution was prepared. However, in Test Example 5, 0.1% by weight and 0.5% by weight solutions were also prepared and used for impregnation.
(1-2) Preparation of 0.069% Ketotifen Fumarate Solution (KF) Weigh 34.5 mg of ketotifen fumarate in a 50 mL volumetric flask, align with PBS (-) to the marked line, and 0.069% ketotifen. A fumarate solution was prepared.
(1-3) Preparation of 0.1% Pemirolast Potassium Solution (PP) Weigh 20.0 mg of Pemirolast Potassium into a 20 mL volumetric flask and mark it with 0.1 M phosphate buffer (pH 8.0). In total, a 0.1% pemirolast potassium solution was prepared.
(1-4) Preparation of 0.05% pranoprofen solution (PrP) Weigh 25.0 mg of pranoprofen into a 50 mL volumetric flask, and adjust to the marked line with 0.1 M phosphate buffer solution (pH 8.0). To prepare a 0.05% pranoprofen solution.
(1-5) Preparation of 0.5% Levofloxacin Solution (LVFX) 100.0 mg of levofloxacin was weighed in a 20 mL volumetric flask and aligned with PBS (−) to the marked line to prepare a 0.5% levofloxacin solution.

(1-6) Preparation of 0.5% Rebamipide Solution (RBM) 50.2 mg of rebamipide was weighed in a 10 mL volumetric flask and aligned with PBS (−) to the marked line to prepare a 0.5% rebamipide solution.
(1-7) Preparation of 0.4% Timolol Solution (TMO) Weigh 68.1 mg of timolol maleate into a 10 mL volumetric flask and align with PBS (-) to the marked line to prepare a 0.4% timolol solution. did.
(1-8) Preparation of 0.1% brimonidine solution (BRM) Weigh 20.1 mg of brimonidine into a 20 mL volumetric flask, add 1 mL of 0.05 mol / L fumaric acid aqueous solution, and mark with PBS (-). In total, a 0.1% brimonidine solution was prepared.
(1-9) Preparation of 0.4% Ripasudil Solution (RIP) Weigh 48.9 mg of Ripasudil Hydrochloride Hydrate into a 10 mL volumetric flask and align with PBS (-) to the marked line to prepare a 0.4% Ripasudil solution. Prepared.
(1-10) Preparation of 0.05% Emedastine Fumarate Solution (EME) Weigh 10.0 mg of emedastine difumarate in a 20 mL volumetric flask, align it with PBS (-) to the marked line, and 0. A 05% emedastine fumarate solution was prepared.

(2) Impregnation of Drug into Polymer Sheet The prepared polymer sheet was immersed in 2 mL of the drug-containing solution prepared in (1-1) to (1-10) at room temperature (25 ° C.) for 96 hours. After the immersion, the sheet was taken out and the excess solution adhering to the surface was wiped off with a Kimwipe to obtain a drug-impregnated polymer sheet.

(3) Measurement of drug loading amount The drug loading amount on the polymer sheet was measured by the following procedure.
The drug-impregnated polymer sheet was immersed in 10 mL of MeOH for 96 hours at 37 ° C. The total amount of drug loaded on the polymer sheet was measured by quantitative analysis of the MeOH solution after immersion by liquid chromatography.

(4) Drug dissolution test The drug dissolution test was performed according to the following procedure.
The drug-impregnated polymer sheet was immersed in 10 mL PBS (−) at 37 ° C. 200 μL of the immersion liquid was sampled at regular time intervals (0.5, 1, 2, 4, 8, 24, 32, 48, 72, 96 hours). The elution amount and elution rate of the drug over time were calculated by quantitatively analyzing each sample solution to which 200 μL of PBS (−) was added by liquid chromatography. The elution rate after the elution start t time was calculated using the following formula.
Relative elution rate (%) = (elution amount after t hours) ÷ (elution amount after 96 hours) × 100
Absolute elution rate (%) = (elution amount after t hours) ÷ (total loading amount) x 100

(Test Example 1) Examination of Polymer Constituents As shown in Table 1, the polymer sheet of Example 1 and the polymer of Comparative Example prepared by removing one of the constituent monomers were compared. In addition, each polymer sheet was impregnated with sodium cromoglycate as a drug.
The results are shown in Table 1 and FIGS. 1 and 2. From Comparative Example 4, it was recognized that PVP was required for loading the drug into the polymer. In addition, from Comparative Examples 1 and 3, it was recognized that OH-mPDMS and HEMA are required to impart sustained drug release to the polymer. Furthermore, from Comparative Example 2, it was found that the larger the amount of HEMA, the higher the sustained release property.

(Test Example 2) Examination of Content Ratio of HEMA and DMA As shown in Table 2, polymer sheets prepared by changing the content ratio of HEMA and DMA were compared. In addition, each polymer sheet was impregnated with sodium cromoglycate as a drug.
The results are shown in Table 2 and FIGS. 3 and 4. It was found that the sustained release of the drug increased as the proportion of HEMA increased. However, from the viewpoint of the transparency of the polymer sheet, an appropriate range of the content ratio of HEMA and DMA was suggested. No effect of the drug loading amount was observed due to the difference in the content ratio between HEMA and DMA.

(Test Example 3) Examination of Silicone As shown in Table 3, polymer sheets prepared by changing the silicone constituting the polymer to another silicon-containing monomer were compared. In addition, each polymer sheet was impregnated with sodium cromoglycate as a drug.
The results are shown in Table 3 and FIGS. 5, 6 and 7. No difference was observed between OH-mPDMS and mPDMS in terms of drug loading and sustained drug release. When Tris was used, the drug loading amount was small, the absolute dissolution rate at 24 hours was low, and the drug use efficiency was poor.

(Test Example 4) Examination of PVP content As shown in Table 4, polymer sheets prepared by changing the PVP content were compared. In addition, each polymer sheet was impregnated with sodium cromoglycate as a drug.
The results are shown in Table 4 and FIGS. 8 and 9. It was found that the higher the PVP content, the higher the drug loading. No effect of PVP content was observed on drug sustained release.

(Test Example 5) Examination of concentration at the time of drug impregnation As shown in Table 5, the polymer sheet produced in Example 2 was used, and as shown in Table 5, drug impregnation into the polymer was compared with a polymer sheet obtained by changing the concentration of the drug solution. did. In addition, each polymer sheet was impregnated with sodium cromoglycate at various concentrations as a drug.
The results are shown in Table 5 and FIGS. 10 and 11. It was found that the higher the drug concentration, the larger the drug loading amount. Regarding the sustained release of the drug, no effect of the drug concentration at the time of impregnation was observed.

(Test Example 6) Examination of effects with various drugs Using the polymer sheet produced in Example 2, the loading amount of various drugs per gram of the polymer sheet, the change over time in the elution amount, the change over time in the relative elution rate, The change over time in the absolute elution rate was measured. Drugs include sodium cromoglycate (SC), ketotifen fumarate (KF), pemilolast potassium (PP), planoprofen (PrP), levofloxacin (LVFX), levamipid (RBM), timolol (TMO), brimonidine. (BRM), ripasudil (RIP), and emedastin fumarate (EME) were used.
The results are shown in Table 6 and FIGS. 12, 13, 14, 15, 16 and 17. Although there are some variations in dissolution behavior depending on the drug used, all of the polymer sheets of the present invention have an absolute drug dissolution rate of 85% by weight or less after 4 hours, and are highly versatile and applicable to various drugs. It was a thing.

Claims (10)

1. A drug containing a polymer obtained by copolymerizing a reaction mixture containing a monopolydimethylsiloxane compound represented by the following general formula (1), N, N-dimethylacrylamide, 2-hydroxyethyl methacrylate, polyvinylpyrrolidone, and a cross-linking agent. Eye lens material for release.
   

   

   (In equation (1),
   X represents a vinyl group, an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group.
   Y is a _{bond, -R 1 -, - R 1} -R 2 -, - R 1 -R 2 -R 3 -, - R 1 -R 2 -R 3 -R 4 -, or _-R 1 -R ₂ -R _3- R _4- R _5- , indicating
   Here, R ₁ represents a C1-C3 alkylene group.
   R ₂ represents an oxygen atom, -NH-C (O) O-, -NH-C (O) NH-, -OC (O) O-, or -OC (O) NH-.
   R ₃ represents a C1-C3 alkylene group
   R ₄ is an oxygen atom, -NH-C (O) O -, - NH-C (O) NH -, - O-C (O) O-, or -O-C (O) NH- indicates,
   R ₅ represents a C1-C3 alkylene group
   In addition, R ₁ , R ₃ , and R ₅ may each have an independent substituent.
   As the substituent, a hydroxy group, a C1-C3 alkyl group, a C1-C3 alkoxy group, a C1-C3 alkoxy C1-C3 alkyl group, a C1-C3 alkoxy C1-C3 alkoxy group, or a C1-C3 alkoxy C1-C3 alkoxy C1 -Indicating a C3 alkyl group,
   Z represents a C1-C6 alkyl group, a C3-C6 cyclic alkyl group, or an aryl group.
   n represents an integer from 1 to 1500. )
2. In the above formula (1)
   X indicates an acryloyloxy group, a methacryloyloxy group, an acryloylamino group, or a methacryloylamino group.
   Y indicates binding, -R _1- , or -R _1- R _2- R _3-
   R ₁ represents a C1-C3 alkylene group,
   R ₂ indicates an oxygen atom,
   The ophthalmic lens material according to claim 1, wherein R ₃ represents a C1-C3 alkylene group.
3. The compounds represented by the formula (1) are monomethacryloyloxypropyl-terminated mono-n-butyl-terminated polydimethylsiloxane and / or mono- (3-methacryloyloxy-2-hydroxypropoxy) propyl-terminated mono-n-butyl-terminated poly. The ophthalmic lens material according to claim 1 or 2, which is dimethylsiloxane.
4. Any of claims 1 to 3, wherein the cross-linking agent comprises one or more selected from the group consisting of tetraethylene glycol dimethacrylate, triethylene glycol dimethacrylate, ethylenediamine dimethacrylate, and glycerol dimethacrylate. The ophthalmic lens material according to paragraph 1.
5. Any one of claims 1 to 4, wherein the drug is one or more selected from the group consisting of antiallergic agents, anti-inflammatory agents, antibacterial agents, glaucoma therapeutic agents, and dry eye therapeutic agents. Ophthalmic lens material described in.
6. One drug selected from the group consisting of sodium cromoglycate, ketotifen fumarate, pemirolast potassium, planoprofen, levofloxacin, latanoprost, levamipid, timolol, brimonidine, ripasudil, and emedastin fumarate. The ophthalmic lens material according to any one of claims 1 to 4, which is two or more kinds.
7. An ophthalmic lens containing the ophthalmic lens material according to any one of claims 1 to 6 and a drug.
8. The ophthalmic lens according to claim 7, wherein the drug is one or more selected from the group consisting of antiallergic agents, anti-inflammatory agents, antibacterial agents, glaucoma therapeutic agents, and dry eye therapeutic agents.
9. One drug selected from the group consisting of sodium cromoglycate, ketotifen fumarate, pemirolast potassium, planoprofen, levofloxacin, latanoprost, levamipid, timolol, brimonidine, ripasudil, and emedastin fumarate. The ophthalmic lens according to claim 7, which is two or more kinds.
10. The eye lens according to any one of claims 7 to 9, which is a contact lens.

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