KR20220085264A - Silicone hydrogel monomer compounds and silicone hydrogel contact lens using thereof - Google Patents

Abstract

Disclosed are a silicone hydrogel monomer compound for use in a contact lens having excellent hydrophilicity, and a silicone hydrogel monomer compound for use in a contact lens having excellent hydrophilicity. Also disclosed are a contact lens composition including a silicone hydrogel monomer compound having excellent hydrophilicity on the lens surface, and a method for preparing a silicone hydrogel monomer compound for a contact lens. The silicone contact lens according to the present invention has a higher affinity for water and a surface due to an increase in hydrophilic substituents at the ends of the new monomers than conventional contact lenses, so that the contact angle is lowered and the hydrophilicity is increased. Therefore, the novel monomer synthesized according to the present invention can obtain a contact lens with improved hydrophilicity through copolymerization with an existing commercial monomer, and the physical properties of the contact lens can be adjusted by introducing a functional group.

Description

Silicone hydrogel monomer compounds and silicone hydrogel contact lenses using the same

The present invention relates to a silicone hydrogel monomer compound and a silicone hydrogel contact lens using the same, and more particularly, to a novel silicone hydrogel monomer compound synthesized through a thiol-ene reaction and a hydrophilic functional group by introducing it into an acrylic monomer solution. It relates to a silicone hydrogel contact lens with excellent hydrophilicity of the lens surface.

Contact lenses were most developed in the late 1900s. Although hard contact lenses using PMMA were first made by K. Touhy, several polymer materials were developed to compensate for the various disadvantages of hard lenses.

In general, contact lenses have adequate mechanical strength, biocompatibility, toxicity, optical transparency, refractive index, surface wettability, and moisture content suitable for the cornea. (water content), swelling ratio (swelling), oxygen permeability (oxygen transmissibility), it must meet the requirements such as flexibility (flexibility).

Modern soft contact lenses are made of soft materials, typically hydrogels. Recently, soft contact lenses made of silicone hydrogel have been introduced. Silicone hydrogels are water-swellable network polymers with high oxygen permeability. However, some users feel uncomfortable when using these lenses and experience excessive ocular deposits, resulting in reduced vision.

Efforts have been made to alleviate this problem by coating the surface of silicone hydrogel contact lenses with a hydrophilic coating such as a plasma coating. For example, a method for making the lens more compatible with the surface of the eye by applying the surface of a silicone hydrogel lens with a plasma coating or treating the surface of the lens with a reactive hydrophilic polymer has been disclosed. Reactive functional groups present on or near the surface of the medical device chemically bond to the reactive functional groups on the hydrophilic polymer to create a hydrophilic surface. As an example, a vinylpyrrolidone-co-4-vinylcyclohexyl-1,2-epoxide polymer was used to coat a silicone substrate.

Hydrogel lenses played a major role in reducing the reluctance to wear contact lenses by increasing the fit while satisfying wettability, flexibility and functionality, and led to the popularization of contact lenses. Nevertheless, there is still a need for synthesizing a silicone hydrogel monomer compound for manufacturing a contact lens having high oxygen permeability and excellent hydrophilicity, and a contact lens having excellent hydrophilicity using such a silicone hydrogel monomer compound is required.

Korean U.S. Patent Publication No. 10-2015-0129772 Korean US Registered Patent 10-1346004

In order to solve the above problems, an object of the present invention is to provide a silicone hydrogel monomer compound for use in contact lenses having excellent hydrophilicity.

Another object of the present invention is to provide a silicone hydrogel monomer compound for contact lenses having excellent hydrophilicity.

Another object of the present invention is to provide a contact lens composition comprising a silicone hydrogel monomer compound having excellent hydrophilicity on the lens surface.

Another object of the present invention is to provide a method for preparing a silicone hydrogel monomer compound for contact lenses having excellent hydrophilicity.

The present invention in order to solve the above object,

It provides a silicone hydrogel monomer compound represented by the following formula (1):

[Formula 1]

The present invention in order to solve the other object,

It provides a silicone hydrogel monomer compound for contact lenses represented by the following Chemical Formulas 1 to 3:

[Formula 1]

[Formula 2]

[Formula 3]

The present invention in order to solve the other object,

the silicone hydrogel monomer compound;

at least one compound selected from an acrylic monomer, vinyl pyrrolidone, methyl methacrylate, and alkoxysilylvinylmethacrylate;

crosslinking agent; and

Provided is a composition for a contact lens comprising an initiator.

The present invention in order to solve the other object,

Putting a vinyl siloxane compound containing two Si groups in a solvent to form a mixture with a thiol compound; and

It provides a method for preparing a silicone hydrogel monomer compound for a contact lens comprising a thiol siloxane; curing the mixture and removing the solvent.

The silicone contact lens according to the present invention has a higher affinity for water and a surface due to an increase in hydrophilic substituents at the ends of the new monomers than conventional contact lenses, so that the contact angle is lowered and the hydrophilicity is increased. Therefore, the novel monomer synthesized according to the present invention can obtain a contact lens with improved hydrophilicity through copolymerization with an existing commercial monomer, and the physical properties of the contact lens can be adjusted by introducing a functional group.

1 shows a form in which a partial π bond is generated between silicon and oxygen in the case of a Si—O bond according to the present invention.
Figure 2 shows the mechanism of hydrothiolation of the CC bond according to the present invention (Thiol-ene reaction).
3 shows a novel silicone acrylic monomer synthesized according to an embodiment of the present invention.
Figure 4 shows the synthesis process of the silicone monomer according to an embodiment of the present invention.
5 shows an FT-IR result according to an embodiment of the present invention.
6 shows a photograph of a contact lens manufactured according to an embodiment of the present invention.

In the present specification, when a part "includes" a certain component, this means that other components may be further included rather than excluding other components unless otherwise stated. And the terminology used in this specification is for describing the embodiments, and is not intended to limit the present invention.

Hereinafter, the present invention will be described in more detail.

The present invention provides a silicone hydrogel monomer compound represented by the following formula (1):

[Formula 1]

The present invention provides a silicone hydrogel monomer compound for contact lenses represented by the following Chemical Formulas 1 to 3:

[Formula 1]

[Formula 2]

[Formula 3]

The present invention, a silicone hydrogel monomer compound; at least one compound selected from an acrylic monomer, vinyl pyrrolidone, methyl methacrylate, and alkoxysilylvinylmethacrylate; crosslinking agent; And it provides a composition for a contact lens comprising an initiator.

The acrylic monomer is preferably HEMA [2-Hydroxyethyl methacrylate], the pyrrolidone is preferably NVP [N-vinyl pyrrolidone], and the alkoxysilyl vinyl methacrylate is preferably TMSPMA [3- (Trimethoxysilyl) propyl methacrylate].

The present invention comprises the steps of: putting a vinyl siloxane compound containing two Si groups in a solvent to form a mixture with a thiol compound; And curing the mixture and removing the solvent; provides a method for producing a silicone hydrogel monomer compound for a contact lens comprising a thiol siloxane.

Silicone monomers typically used in silicone hydrogel contact lenses are tris-(trimethyl-silyl-propyl-methacrylate) (TRIS) and hydroxyl-terminated polydimethylsiloxane (PDMS). These monomers can improve the low oxygen permeability due to the presence of hydrophobic siloxane groups, because of the unique oxygen affinity of silicone.

In the present invention, silicone hydrogel contact with excellent hydrophilicity by applying HEMA (2-Hydroxyethyl methacrylate), AA (Acrylic acid), NVP (N-Vinyl-Pyrrolidon), MMA (Methyl meth acrylate), etc. to the silicone hydrogel monomer compound to provide a lens.

The Si-O bond between silicon and oxygen is much stronger than the C-O bond, so silicon has a high affinity for oxygen. The relative strength of C-O and Si-O bonds is contrary to the general principle that bond strength decreases with increasing valence. This is because it was assumed that a single bond between two atoms could always be described as a single shared electron pair.

하이브리드궤도의 비결합 전자쌍을 수용하여 부분 π 결합이 생성된다. 이러한 상호 작용은 실리콘 뿐만 아니라 3주기 원소(P, S, Cl)의 중요한 화학적 특징이다. 즉, P, S, Cl 과 같은 원소는 비어있는 d오비탈을 이용하여 다른 원자와 여러 배위수를 가질 수 있으며, 이를 가변공유성이라 한다. 따라서 부분적인 pi 이중결합의 특성으로 인해 Si-O결합은 예상보다 훨씬 더 강하고 짧으며, 산소와 친화성이 높아지게 된다.However, in the case of Si-O bonding, p or O of O using a relatively low-energy vacant d orbital in Si

A partial π bond is created by accepting an unbonded pair of electrons in the hybrid orbital. This interaction is an important chemical characteristic of not only silicon but also three-period elements (P, S, Cl). That is, elements such as P, S, and Cl can have multiple coordination numbers with other atoms by using vacant d orbitals, which is called variable covalent property. Therefore, due to the nature of the partial pi double bond, the Si-O bond is much stronger and shorter than expected, and has a higher affinity for oxygen.

Thiol-ene reaction among various chemical reactions is widely used to form organic compounds of various polymers. In general, the thiol-ene reaction occurs under radical conditions and proceeds through a chain process including initiation, propagation and termination steps. When irradiated with UV with an initiator, thiyl radicals and other by-products are formed. The propagation process is a two-step process in which a carbon-centered radical is generated by the C=C bond and the Anti-Markovnikov reaction of the thiyl radical, and then reacts with other thiol molecules to form a new radical. Possible termination processes include typical radical-radical bonding processes.

Figure 2 shows the mechanism of hydrothiolation of C-C bonds according to the present invention (Thiol-ene reaction). Referring to FIG. 2 , the characteristics of the thiol-ene reaction include easy reaction initiation (heat, light, initiator, amine catalysis), high yield (sometimes quantitative reaction), high regioselectivity, and various solvents as well as water and oxygen. and resistance to functional groups. For this reason, the thiol-ene reaction is so simple and easy to synthesize that it is called a 'click' reaction.

Currently, a lot of research is being conducted on contact lenses. In particular, studies have been conducted using silicone monomers such as TRIS and SiGMA, which can impart high oxygen permeability to lenses. The structure of these monomers has a siloxane form of Si-O-Si, which can impart high oxygen affinity to a contact lens, but exhibit strong hydrophobic properties, resulting in a decrease in moisture absorption and surface wettability inside the lens. However, if a hydrophilic functional group is attached to a monomer having a siloxane structure, it can be expected that the surface wettability and moisture content can be improved while maintaining high oxygen permeability.

In the present invention, a thiol-ene “click” reaction was used to impart a hydrophilic functional group to polyfunctional vinyl siloxane (VSO). If thiol (SH) having a hydrophilic group is reacted with polyfunctional vinyl siloxane (VSO), a siloxane (VSO-SH) monomer having a hydrophilic group can be synthesized with high purity and high yield. In addition, it is expected to increase the surface hydrophilicity of the lens due to the hydrophilic functional group at the end of the new monomer.

Hereinafter, examples will be given to describe the present specification in detail. However, the embodiments according to the present specification may be modified in various other forms, and the scope of the present specification is not to be construed as being limited to the embodiments described below. The embodiments of the present specification are provided to more completely explain the present specification to those of ordinary skill in the art.

Example

Material and sample preparation

ingredient

In this embodiment, for convenience, terms are defined as follows.

VSO4: 2,4,6,8-Tetramethyl-2,4,6,8-tetravinylcyclo-tetrasiloxane

VSO2: 1,3-Divinyltetramethyl disiloxane

SHTMS : (3-mercaptopropyl) trimethoxy silane

SHOH: 2-mercaptoethanol

The VSO4, VSO2, SHTMS and SHOH were purchased from Tokyo Chemical Industry (TCI).

Acrylic monomers HEMA [2-Hydroxyethyl methacrylate] and NVP [N-vinyl pyrrolidone] purchased from DAEJUNG Hwageum were used, and MMA [Methyl methacrylate] purchased from TCI was used. In addition, TMSPMA [3-(Trimethoxysilyl)propyl methacrylate], EGDMA [Ethylene glycol dimethacrylate] as a crosslinking agent, and AIBN [2,2-Azobisisobutyronitrile] as an initiator were purchased from Junsei.

Detailed monomer structures and abbreviations are given below:

Phosphate buffered saline solution (PBS) aqueous solution was prepared by dissolving one tablet in 100 mL of DI water using a PBS tablet purchased from DEAJUNG Hwageum.

Synthesis of new monomers using thiol-ene reaction

VSO-SH novel monomer was synthesized by adding each compound in the amount shown in Table 1 below:

First, put vinyl siloxane (VSO) in a 20 mL vial and add 5 mL of methanol. Then, a thiol compound is added and stirred. After irradiating the mixed solution for 4 hours using a UV curing machine, the methanol in the solution is removed through vacuum reduced pressure.

The product was obtained as a colorless transparent liquid in yield: 96-90%, purity: 99%. Synthesis was confirmed by H-NMR. 5 is a view showing the synthesis process of the silicone monomer according to an embodiment of the present invention.

Polymerization of silicone hydrogel contact lenses

In the silicone hydrogel, in the presence of EGDMA, a crosslinking agent, and AIBN, a thermal initiator, HAMA, NVP, MMA, and TMSPMA monomers are added in the amounts shown in Table 2 below to make a monomer mixture:

0.1 g of the synthesized VSO-SH compound was added to 3 g of the prepared monomer mixture solution and stirred for 2 hours. 120ul of the homogeneously mixed monomer mixture was placed in a polypropylene mold and heated at 130°C for 2 hours. The prepared lens was peeled off, put in a PBS aqueous solution, hydrated and stored.

Analysis and measurement

In this example, changes and physical properties of a novel silicone hydrogel contact lens made by introducing a novel silicone monomer synthesized through the thiol-ene reaction of a contact lens into a commercially available acrylic monomer solution were confirmed. As representative physical properties of contact lenses, moisture content, oxygen permeability, and contact angle were measured and analyzed for comparison.

Analysis of novel thiol-ene silicone monomer synthesis

nuclear magnetic resonance spectrometer ( ^One H NMR)

Nuclear magnetic resonance spectroscopy was measured using Bruker's AVANCE III 500. ¹ H-NMR was measured by mixing the compound in CDCl ₃ .

Infrared Spectrophotometer (FT-IR)

Infrared spectroscopic analysis was measured using FT/IR 4100 manufactured by JASCO. After contacting the compound in solution using an ATR accessory, it was measured by reflection method.

Contact Lens Analysis

Water content measurement

는 함수된 콘택트 렌즈의 무게,

는 건조된 렌즈의 무게이다:The water content of the lens was measured using a moisture meter (METTLER TOLEDO HX204). Drying conditions were in accordance with the medical device standard of the Ministry of Food and Drug Safety of ISO 18369-4, and was calculated using Equation (1) below. here

is the weight of the contact lens as a function,

is the weight of the dried lens:

(1)

(One)

Oxygen transmissibility (Dk/t) measurement

Oxygen transmissibility (Dk/t) of the lens was measured by polarographic method. Contact lenses, polarographic cells, and cell mounting fixtures in PBS were placed in a thermo-hygrostat (WL1000S, with lab humidity 95%, temperature 35°C) and equilibrated for more than 2 hours, then the lenses were placed on the polarographic cell. The lens was fixed with a cell mount ting fixture covered with nylon mesh, and the current value was measured using a permeometer (Model 201T O2 permeometer, CHREATECH, USA). The center thickness of the lens was measured using a pressure dial gauge (Litematic: Model VL-50, Mitutoyo). The same material was calculated by measuring the current values of three lenses under the same conditions. The data derived from each current value were calculated and displayed as an average value.

는 측정 전류값(A),

는 암전류(dark current)값 (A),

는 산소증기압(155mmHg),

는 음극 표면적 넓이(

) (radius cell : 0.127),

는 측정 전류값(uA)이다. 그리고 식(3)에서

는 렌즈 중심부 두께측정값이다:The oxygen permeability (Dk/t) and the oxygen permeability (Dk) were calculated by substituting into the following formulas (2) and (3) and expressed as average values. In Equation (2) below

is the measured current value (A),

is the dark current value (A),

is the oxygen vapor pressure (155mmHg),

is the area of the cathode surface (

) (radius cell: 0.127),

is the measured current value (uA). And in Equation (3)

is the lens center thickness measurement:

(2)

(2)

(3)

(3)

Surface contact angle measurement

The surface contact angle of the lens was measured using a contact angle measuring instrument (Phoenix 150/Tilting) manufactured by S.E.O. The contact angle of the contact lens was measured using the sessile drop method in which a drop of pure distilled water was dropped after removing the surface moisture of the lens hydrated in PBS solution at room temperature for 24 hours. The contact angle for each sample was measured three times and the average value was displayed.

Results and evaluation

Monomer synthesis using thiol-ene 'click' reaction

The novel silicone acrylic monomer synthesized using the thiol-ene click reaction was synthesized as a colorless and transparent liquid.

B) VSO2-SHTMS

D) VSO2-SHOH

In order to confirm the structure of the synthesized novel monomer, it was analyzed using H-NMR and FT-IR. The H-NMR results are as follows:

¹ H NMR (500 MHz, CDCl ₃ ):

A) VSO4-SHTMS: δ=5.82(s, 3H), 3.40(t, 9H), 2.39(m, 4H), 1.53(s, 2H), 0.74(s, 2H), 0.58(s, 2H), 0.01 (m, 6H);

B) VSO2-SHTMS: δ=6.01-5.55(m, 9H), 3.42(t, 9H), 2.43(s, 4H), 1.53(s, 2H), 0.75(s, 2H), 0.61(s, 2H) ), 0.01 (t, 24H);

C) VSO4-SHOH: δ=6.00-5.56(m, 9H), 3.57(s, 2H), 3.30(s, 1H), 2.55(m, 2H), 2.42(s, 2H), 0.77(s, 2H) ), 0.01 (t, 24H);

D) VSO2-SHOH: δ=5.85 (m, 6H), 3.57 (t, 4H), 3.28 (m, 2H), 2.55 (m, 4H), 2.42 (m, 4H), 0.77 (m, 4H), 0.01 (t, 12H).

6 shows FT-IR results according to an embodiment of the present invention. Referring to FIG. 6 , when the IR of each product is checked, the SH peak near 2600 cm ⁻¹ does not appear, so it can be seen that all thiol reacted and the product was successfully obtained.

Polymerization of silicone contact lenses

6A shows a contact lens polymerized by copolymerizing a novel monomer synthesized according to an embodiment of the present invention and an existing commercially available monomer. Referring to FIG. 6a , in the case of contact lenses containing A)VSO4-SHTMS and B)VSO2-SHTMS containing trimethoxy silane (TMS) groups, phase separation occurred and the surface of the lens became cloudy. It can be understood that during polymerization, the TMS groups form sol-gel with each other, creating a hydrophobic Si-O-Si bond, and phase separation from the hydrophilic monomer. To compensate for this, it can be alleviated to some extent by copolymerization with an acrylic monomer having a TMS group having a similar structure, but it cannot be made completely transparent.

However, when C)VSO4 -SHOH and D)VSO2-SHOH with hydrophilic hydroxyl groups were added, phase separation from the hydrophilic monomer did not occur, so colorless and transparent contact lenses were obtained.

Figure 6b is a view showing to compare the physical properties of the contact lens according to the novel monomer synthesized according to an embodiment of the present invention. In order to compare and analyze the physical properties of the lens according to the content of the new monomer, 0.5 g of the new monomer was added to the monomer solution of composition No. 3, and it was expressed as 3' and compared with the lens containing 0.1 g. Referring to FIG. 6B , the lenses in which 0.5 g of A and B were added had more severe phase separation than the conventional lenses in which 0.1 g of A and B were added, thereby obtaining an opaque lens. It can be seen that the cause of this is also due to the sol-gel of the TMS group. On the other hand, a lens containing 0.5 g of C and D was obtained as a colorless and transparent lens.

Comparison of physical properties of lenses

moisture content

As for the water content, all lenses to which the newly synthesized monomer was applied tended to have a more reduced water content than the existing lenses. The reason for this is the structure of the novel monomer. At least two vinyl groups that can be polymerized per one molecule of VSO-SH to be used as a monomer act as a crosslinking agent when polymerized. It can be seen that the moisture content of the contact lenses with the increased degree of crosslinking is reduced because moisture is attached only to the surface and the amount of moisture that swells inside is reduced.

The moisture content of the contact lenses with 0.5 g added by increasing the content of the new monomer showed a slightly different trend. Contact lenses 3'A and 3'B containing A and B showed almost the same moisture content as 3A and 3B. However, it was confirmed that the moisture content of 3’C and 3’D was lower than that of 3C and 3D, which had a small content. The cause of this can be seen as a decrease in moisture content due to an increase in the degree of crosslinking. For the same example, when referring to the literature confirming the comparison of the moisture content according to the content of the crosslinking agent EGDMA, it can be seen that the moisture content decreases in a small amount, so it can be seen that the degree of crosslinking affects the moisture content:

Oxygen permeability comparison

As for the oxygen permeability ratio, it was thought that the oxygen permeability of the contact lens would increase by the application of a new monomer containing a siloxane group with high oxygen affinity, but interestingly, the result was different from the expected result.

In lenses to which A and B monomers with trimethoxy silane groups were applied, a slight increase was observed. However, the lenses to which C and D monomers with hydroxyl groups were applied showed a tendency to further decrease oxygen permeability.

The reason for this result is the structure of the novel monomer as well as the water content. At least two vinyl groups that can be polymerized per one molecule of VSO-SH to be used as a monomer act as a crosslinking agent when polymerized. Therefore, the lens to which the new monomer is applied will have a greater degree of crosslinking than a general lens. Due to the increased degree of crosslinking, the polymer in the contact lens has a low free volume, forming a structure through which oxygen is rather difficult to permeate.

These results showed a similar tendency of oxygen permeability even when the content of the new monomer was increased.

surface contact angle

Surface contact angle showed improved results, unlike results such as oxygen permeability or moisture content. It can be seen that the size of the surface contact angle of the contact lens containing the new monomer is smaller than that of the existing contact lens, indicating that the hydrophilicity is increased due to the new monomer.

This is because of the hydrophilic substituent at the end of the novel monomer. Although the degree of crosslinking was increased, moisture did not penetrate inside the lens, but the affinity between the surface and moisture was increased due to the increase of the hydrophilic substituent, and the contact angle was lowered.

Lenses with an increased content of novel monomers also showed a tendency to increase surface hydrophilicity. Rather, it can be seen that the surface hydrophilicity of the lens increases in proportion to the content of the novel monomer due to the increase of the hydrophilic substituent as the contact angle is lowered:

In the present invention, it was possible to synthesize four novel silicone vinyl monomers with high yield and high purity using the Thiol-ene “click” reaction. A novel silicone hydrogel contact lens was polymerized by mixing a novel monomer and a universal monomer solution. The new silicone contact lenses were expected to improve oxygen permeability through the introduction of silicone, but the results were different from those expected. The reason seems to be that due to the vinyl group left for copolymerization with the acrylic monomer, the new monomer acts as a crosslinking agent to reduce the free volume of the lens. When the surface contact angles of the lenses according to the present invention were compared, it was confirmed that the surface hydrophilicity of the contact lenses was greatly increased by the addition of the novel monomer.

Claims (8)

A silicone hydrogel monomer compound represented by Formula 1 below:
[Formula 1]

A silicone hydrogel monomer compound for contact lenses represented by the following Chemical Formulas 1 to 3:
[Formula 1]

[Formula 2]

[Formula 3]

The silicone hydrogel monomer compound according to claim 2;
at least one compound selected from an acrylic monomer, vinyl pyrrolidone, methyl methacrylate, and alkoxysilylvinylmethacrylate;
crosslinking agent; and
A composition for contact lenses comprising an initiator. 4. The method of claim 3,
The acrylic monomer is HEMA [2-Hydroxyethyl methacrylate], and the pyrrolidone is NVP [N-vinyl pyrrolidone]. 4. The method of claim 3,
The silicone hydrogel monomer compound is a composition for a contact lens, characterized in that the content is 5 to 8% by weight based on the composition. Putting a vinyl siloxane compound containing two Si groups in a solvent to form a mixture with a thiol compound; and
Curing the mixture and removing the solvent; Method for producing a silicone hydrogel monomer compound for a contact lens comprising a thiol siloxane. 7. The method of claim 6,
The silicone hydrogel monomer compound is a method for producing a silicone hydrogel monomer compound for a contact lens, characterized in that represented by the following Chemical Formulas 1 to 3:
[Formula 1]

[Formula 2]

[Formula 3]

7. The method of claim 6,
The vinyl siloxane compound is a method for producing a silicone hydrogel monomer compound for a contact lens, characterized in that represented by the following formula:

Images