KR20210149618A - Surface Modification and Application of Silicone Hydrogel Contact Lens - Google Patents

Abstract

The present invention relates to preparation of aminated hyaluronic acid and a method for surface treatment of a contact lenses with the aminated hyaluronic acid. The present invention chemically bonds hyaluronic acid to the surface of the contact lens having a low expansion rate due to moisture, thereby providing the contact lens with high oxygen permeability, surface wettability, and remarkably improved wearing comfort.

Description

Surface Modification and Application of Silicone Hydrogel Contact Lens

The present invention relates to the surface modification and application of silicone hydrogel contact lenses.

Among various types of wearable healthcare devices for the diagnosis and treatment of diseases, a contact lens type device that can diagnose various diseases and continuously monitor the patient's condition through various proteins and biomarkers in tears is attracting attention. . Contact lenses including devices must contain various elements stably without deformation in the lens for operation.

In order to satisfy these conditions, materials such as silicone hydrogel and silicone elastomer with high oxygen permeability and low expansion rate due to moisture have been developed using silicone-based materials. As a result, the wearing comfort is very bad and there is a risk of damage to the eyes and cornea. In order to solve this problem, a method of coating a hydrophilic polymer on the surface is used, but there is a disadvantage in that the polymer is easily dissolved when the number of the coated polymer is small or the polymer is coated with a physical bond.

The present invention intends to propose a technique for manufacturing a surface-modified contact lens having a surface layer of high moisture content through a chemical bond between hyaluronic acid in which a functional group is aminated and the contact lens. In this method, a stable bond can be formed because the number of functional groups capable of chemical bonding is large, and since hyaluronic acid having excellent biocompatibility and high water affinity is used, a stable and hydrophilic surface can be formed.

An object of the present invention is to provide a surface-modified contact lens.

The present invention is a contact lens; and

It contains hyaluronic acid bound to the surface of the contact lens,

Provided is a surface-modified contact lens in which an aldehyde group formed on the surface of the contact lens and an amine group of the aminated hyaluronic acid form a bond.

In addition, the present invention comprises the steps of S1) introducing a hydroxyl group to the surface of the contact lens;

S2) introducing an amine group to the surface of the contact lens by reacting the contact lens of S1) with the organosilanol;

S3) introducing an aldehyde group to the surface of the contact lens by reacting the contact lens of S2) with dialdehyde;

S4) There is provided a method for manufacturing the surface-modified contact lens according to claim 1, comprising the step of reacting the contact lens of S3) with the aminated hyaluronic acid.

The present invention provides a method for preparing hyaluronic acid in which a functional group is aminated, and surface-modifying a contact lens with the aminated hyaluronic acid.

In the present invention, by chemically bonding hyaluronic acid to the surface of a contact lens having a low expansion rate due to moisture, a surface-modified contact lens having high oxygen permeability and surface wettability and remarkably improved wearing comfort can be manufactured.

1 is a schematic diagram of the synthesis of aminated hyaluronic acid.
2 shows the results of 1H-NMR analysis of aminated hyaluronic acid.
3 shows the results of 1H-NMR analysis of commercially available PDMS and silicone elastomer.
4 shows the results of FT-IR analysis of commercially available PDMS and silicone elastomer.
5 shows a manufacturing process of a contact lens surface-modified with hyaluronic acid.
6 shows the contact angle of the contact lens surface according to the surface modification.
7 shows the change in contact angle for 60 days of the surface-modified contact lens.

The present invention is a contact lens; and

It relates to a surface-modified contact lens comprising hyaluronic acid bound to the surface of the contact lens.

Hereinafter, the surface-modified contact lens according to the present invention will be described in more detail.

In the present invention, the contact lens is an elastomer of silicone elastomer; And it may be based on one or more silicone-based compounds selected from the group consisting of a silicone hydrogel. The silicone elastomer may be polydimethyloxane (PDMS).

In the surface-modified contact lens according to the present invention, hyaluronic acid is bonded to the surface of the contact lens, and specifically, the aldehyde group formed on the surface of the contact lens and the amine group of the aminated hyaluronic acid may form a bond. In the present invention, the bonding between the aldehyde group on the surface of the contact lens and the amine group of the aminated hyaluronic acid can be expressed as surface modification or surface treatment.

That is, in the present invention, the hydrophilicity of the contact lens can be improved by surface-modifying the contact lens with hyaluronic acid. In addition, since the contact lens and hyaluronic acid form a bond through a chemical bond, a surface layer with high moisture content can be provided, and a stable bond can be formed because the number of functional groups capable of chemical bonding is large. In addition, it is possible to form a stable and hydrophilic surface using hyaluronic acid having excellent biocompatibility and high water affinity. Through this, oxygen permeability and surface wettability of the contact lens can be improved, and the wearing comfort can be remarkably improved.

In one embodiment, the aminated hyaluronic acid may refer to hyaluronic acid in which an amine is bound to a functional group, and may be a compound including a repeating unit represented by the following Chemical Formula 1.

[Formula 1]

Specifically, the aminated hyaluronic acid may have a structure in which the carboxyl group of D-glucuronic acid of hyaluronic acid is substituted with an amine group, and since the branch of hyaluronic acid, that is, the carboxyl group, is aminated, the branched hyaluronic acid is aminated. It can be expressed as ronic acid.

In Formula 1, n may be an integer of 25 to 10,000, m may be an integer of 1 to 10, an integer of 2 to 8, or an integer of 4 to 6.

In one embodiment, the contact angle of the surface-modified contact lens may be 40° or less or 30° or less. Oxygen permeability and surface wettability are high in the contact angle range, and wearability is excellent. The measuring method of the said contact angle is the same as the measuring method in an Example.

In addition, the present invention provides a method for manufacturing the above-described surface-modified contact lens.

The surface-modified contact lens according to the present invention comprises the steps of: S1) introducing a hydroxyl group to the surface of the contact lens;

S2) introducing an amine group to the surface of the contact lens by reacting the contact lens of step S1) with organosilanol;

S3) introducing an aldehyde group to the surface of the contact lens by reacting the contact lens of step S2) with dialdehyde; and

S4) It can be prepared through the step of reacting the contact lens of step S3) and the aminated hyaluronic acid.

In the present invention, the contact lens may be used commercially available products or manufactured in a laboratory.

In one embodiment, the contact lens may be manufactured by adding a contact lens material to a contact lens mold and then crosslinking the contact lens material.

The contact lens material may be of the above-mentioned type, and may include an elastomer of silicone elastomer; And it may be based on one or more silicone-based compounds selected from the group consisting of a silicone hydrogel. The silicone elastomer may be polydimethyloxane (PDMS).

Crosslinking may be performed by additionally adding a crosslinking agent and/or a polymerization initiator to the mold during crosslinking, and the types of crosslinking agent and polymerization initiator generally used in the art may be used. Specifically, one or more selected from the group consisting of ethylene glycol dimethacrylate and azobisisobutyronitrile as a crosslinking agent may be used, and a UV photoinitiator TPO (diphenyl (2) ,4,6-trimethylbenzoyl)phosphine oxide) can be used.

The content of the crosslinking agent and/or polymerization initiator may be 5 to 20 parts by weight based on 100 parts by weight of the contact lens material.

The crosslinking may be performed by heat treatment or ultraviolet (UV) irradiation on the mold, and specifically, contact lenses may be manufactured by hardening in an oven at 80 to 150° C. for 1 to 5 hours.

The present invention may further perform the step of washing the contact lens before performing step S1). The washing may be performed for 10 to 1 hour using acetone and/or ethane, and unreacted substances during contact lens manufacturing may be removed through the above step. After performing the above steps, drying may be further performed.

In the present invention, step S1) is a step of introducing a hydroxyl group to the surface of the contact lens. In the above step, the contact lens may be plasma-treated to introduce hydroxyl groups on the surface of the contact lens.

In one embodiment, the plasma may be an oxygen or hydrogen plasma, specifically, an oxygen plasma.

In one embodiment, the plasma treatment may be performed for 5 to 60 minutes or 10 to 30 minutes.

In the present invention, step S2) is a step of introducing an amine group to the surface of the contact lens by reacting the contact lens prepared in step S1) with organosilanol. In the above step, the hydroxyl group and organosilanol on the surface of the contact lens of step S1) form a bond, and an amine group (-NH ₂ ) may be introduced into the surface of the contact lens.

In one embodiment, the organosilanol is used to introduce an amine group into the contact lens to facilitate bonding with other functional groups. Since the reaction between amine and aldehyde is a reaction that occurs effectively within a short time even at room temperature, by using organosilanol to bond the dialdehyde to a contact lens having an amine group introduced to the surface, and finally reacting the aminated hyaluronic acid. It is possible to improve the surface moisture content and fit of contact lenses, which had a low surface moisture content and a high contact angle.

The type of the organosilanol is not particularly limited, and for example, 3-aminopropyltriethoxysilane ((3-Aminopropyl)ethyoxysilane, APTES), 3-aminopropyltrimethoxysilane ((3-Aminopropyl)methyoxysilane , APTMS), [3-(2-aminoethylamino)propyl]trimethoxysilane ([3-(2-Aminoethylamino)propyl]trimethoxysilane) and N-(3-trimethoxysilylpropyl)diethylenetriamine ( N-(3-Trimethoxysilylpropyl)diethylenetriamine) may be at least one selected from the group consisting of.

In one embodiment, the content of the organosilanol is not particularly limited, and 5 to 20 parts by weight or 5 to 15 parts by weight based on 100 parts by weight of the silicone-based compound may be used.

In one embodiment, step S2) may be performed at 40 to 70° C. or 45 to 60° C. for 1 to 10 hours or 1 to 3 hours.

In the present invention, step S3) is a step of introducing an aldehyde group to the surface of the contact lens by reacting the contact lens prepared in step S2) with dialdehyde. In the above step, the amine group on the surface of the contact lens in step S2) and the aldehyde group of the dialdehyde form a bond, and the aldehyde group may be introduced to the surface of the contact lens.

In one embodiment, one aldehyde group of the dialdehyde may be attached to the contact lens via an amine as a linker. Specifically, an imine bond, that is, -C=N-, may be formed through a shiff-base reaction between an amine group of a contact lens and an aldehyde group of a dialdehyde. In addition, an aldehyde group that does not form a bond in the dialdehyde may form a bond with an amine in the subsequent step S4).

In one embodiment, the type of dialdehyde is not particularly limited, and may include one or more selected from the group consisting of glutaraldehyde, glyoxal, and succinaldehyde.

In one embodiment, the content of the dialdehyde is not particularly limited, and may be used in an amount of 0.1 to 10 parts by weight or 1 to 5 parts by weight based on 100 parts by weight of the silicone-based compound.

In one embodiment, step S3) may be performed at 20 to 30° C. for 1 to 10 hours or 1 to 3 hours.

In the present invention, step S4) is a step of reacting the contact lens prepared in step S3) with the aminated hyaluronic acid. In the above step, the aldehyde group on the surface of the contact lens of step S3) and the amine group of the aminated hyaluronic acid form a bond, and the hyaluronic acid may be bonded to the surface of the contact lens.

In one embodiment, the aminated hyaluronic acid may be a compound including a repeating unit represented by the following formula (1).

[Formula 1]

Specifically, the aminated hyaluronic acid has a structure in which the carboxyl group of D-glucuronic acid of hyaluronic acid is substituted with an amine group, and in Formula 1, n may be an integer of 25 to 10,000, m is an integer of 1 to 10, It may be an integer of 2 to 8 or an integer of 4 to 6.

The aminated hyaluronic acid may be prepared by reacting hyaluronic acid with diamine.

Hyaluronic acid not only has biocompatibility and biodegradability, but also has transdermal delivery properties, so it can be safely applied to the human body, and has the advantage of being applicable to transdermal drug delivery systems of various protein drugs and chemical drugs including antigen proteins. .

In the present invention, unless there is an explicit description, 'hyaluronic acid (HA)' refers to a polymer having a repeating unit represented by the following general formula 1, and is used to include all salt forms of hyaluronic acid. .

[General formula 1]

In Formula 1, n may be an integer of 25 to 10,000.

The hyaluronic acid or salt of hyaluronic acid used in the present invention is not limited in its composition, but preferably has a molecular weight of 1,000 to 1,000,000 Daltons (Da), 5,000 to 500,000 Da, or 5,000 to 300,000 Da.

In one embodiment, when hyaluronic acid is reacted with diamine, one amine group in the diamine may react with a carboxyl group of hyaluronic acid to form aminated hyaluronic acid.

The type of the diamine is not particularly limited, and may be at least one selected from the group consisting of ethylenediamine, butylenediamine, hexamethylenediamine, pentaethylenehexaamine and 1,5-diamino-2-methylpentane. The diamine may be used in an amount of 1 to 30 moles or 10 to 20 moles compared to the hyaluronic acid unit.

The reaction may be carried out at pH 4 to 6 or pH 4.5 to 5 and 25 to 60° C., or 25 to 40° C. for 1 hour to 10 hours or 1 hour to 3 hours.

In one embodiment, the content of the hyaluronic acid aminated in step S4) is not particularly limited, and may be used in an amount of 0.1 to 5 parts by weight or 0.5 to 2 parts by weight based on 100 parts by weight of the silicone-based compound.

In one embodiment, step S4) may be performed at 20 to 30° C. for 1 to 24 hours or 2 to 5 hours.

In one embodiment, in step S4), the aldehyde group of the contact lens may form an imine bond, ie, -C=N-, through a shiff-base reaction with the amine group of the aminated hyaluronic acid. Through this, the surface-modified contact lens according to the present invention can be manufactured.

In the present invention, the hydrophilicity of the contact lens can be improved by surface-modifying the contact lens with hyaluronic acid. In addition, since the contact lens and hyaluronic acid form a bond through a chemical bond, a surface layer with high moisture content can be provided, and a stable bond can be formed because the number of functional groups capable of chemical bonding is large. In addition, it is possible to form a stable and hydrophilic surface using hyaluronic acid having excellent biocompatibility and high water affinity. Through this, oxygen permeability and surface wettability of the contact lens can be improved, and the wearing comfort can be remarkably improved.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.

Example

Preparation Example 1. Aminated hyaluronic acid (branched HA-NH) ₂ ) synthesis

1 shows a schematic diagram of the synthesis of aminated hyaluronic acid.

Hyaluronic acid and hexamethylenediamine (1,6-diaminohexane, DAH) were added to deionized water (DI water) and mixed well. At this time, the molecular weight of hyaluronic acid is 5, 10, 100 or 200 kDa, and hexamethylenediamine was put in 20 mole times of hyaluronic acid. Thereafter, the pH of the solution was adjusted to 4.7, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and Sulfo-N-Hydroxysuccinimide (Sulfo-NHS) were added thereto, followed by reaction for 2 hours or more.

The unreacted substances were removed by dialysis and dried by freeze drying.

The prepared aminated hyaluronic acid was analyzed by 1H-NMR.

FIG. 2 shows the results of 1H-NMR analysis of aminated hyaluronic acid, and as a result of the analysis, it can be confirmed that aminated hyaluronic acid was synthesized.

Preparation Example 2. Preparation of contact lenses

After mixing the silicone elastomer (MED-6015 Part A, Nusil) and the crosslinking agent (MED-6015 Part B, Nusil) in a ratio of 10:1, remove the foam, pour it into a lens mold, and harden it in an oven at 100℃ for 2 hours or more to make contact lenses. prepared.

A contact lens was placed in a mixture of acetone and ethanol, and sonication was performed for 30 minutes or longer to remove unreacted substances during contact lens manufacturing. Thereafter, it was dried in an oven at 100° C. for 1 hour or more.

Experimental Example 1. Comparison of physical properties of contact lenses

The physical properties of the contact lens prepared in Preparation Example 2 and commercially available polydimethylsiloxane (PDMS) were compared.

First, a solution was prepared by dissolving silicone elastomer (MED-6015 Part A, Nusil Corporation) and PDMS in dichloromethane at a concentration of 20 mg/ml, respectively. 1H-NMR analysis was performed on the two solutions.

3 shows the results of 1H-NMR analysis of commercially available PDMS and silicone elastomer.

As shown in FIG. 3, it can be confirmed that commercially available PDMS and silicone elastomer have the same structure.

In addition, in order to compare the functional groups and physical properties of the silicone elastomer and the commercially available PDMS, the silicone elastomer and the PDMS were cross-linked to prepare a film. Fourier-transform infrared spectroscopy (FT-IR) was performed on the film. At this time, for crosslinking, silicone elastomer and PDMS were mixed with a crosslinking agent (MED-6015 Part B, Nusil Co., Ltd.) in a ratio of 10:1, respectively, mixed well to form a shape, and then heated in an oven at 100° C. for 4 hours.

4 shows the results of FT-IR analysis of commercially available PDMS and silicone elastomer.

As shown in FIG. 4, it can be confirmed that commercially available PDMS and silicone elastomer have the same structure.

Preparation Example 3. Preparation of surface-modified contact lenses with hyaluronic acid

5 shows a manufacturing process of a contact lens surface-modified with hyaluronic acid.

First, the contact lens prepared in Preparation Example 2 was plasma-treated for at least 15 minutes using an oxygen plasma apparatus to introduce a hydroxyl group (-OH) to the surface of the contact lens.

A contact lens having a hydroxyl group introduced to the surface is put in a 10 wt% 3-aminopropyltriethoxysilane (APTES) solution and reacted in an oven at 50° C. or higher for 2 hours or more to introduce an _{amine group (-NH 2 ) to the surface} did

After removing the unreacted material with DI water, it was immersed in a 2.5 wt% glutaraldehyde solution and reacted at room temperature for at least 1 hour to introduce an aldehyde group (-CHO) to the surface of the contact lens.

After removing the unreacted material with DI water, it was put into the 0.5 wt% aminated hyaluronic acid solution prepared in Preparation Example 1, and then reacted for 12 hours or more.

Then, the unreacted material was removed with DI water.

Experimental Example 2. Hydrophilicity evaluation

The contact angle of the contact lens prepared in Preparation Example 2 and the surface-modified contact lens prepared in Preparation Example 3 was measured to confirm the hydrophilicity of the surface.

Specifically, the contact angle was measured immediately after dropping 5 μL of water on the contact lens manufactured using Smartdrop's equipment and after 1 hour.

6 shows the contact angle of the contact lens surface according to the surface modification. Specifically, the non-treated surface represents the contact lens prepared in Preparation Example 2, and branched HA-NH ₂ is the surface-modified contact lens prepared in Preparation Example 3, where 10 K and 100 K are the amounts of hyaluronic acid used in manufacturing, respectively. Molecular weight (Da) is shown. In addition, HA represents a case in which a contact lens is treated with pure hyaluronic acid (molecular weight: 10 kDa).

As shown in FIG. 6, when hyaluronic acid is bonded to the surface of a contact lens by the manufacturing method according to the present invention, it can be seen that a low contact angle is shown, and it can be confirmed that the higher the molecular weight of hyaluronic acid, the lower the contact angle. .

In addition, when pure hyaluronic acid is used instead of aminated hyaluronic acid, chemical bonding does not occur between the pure hyaluronic acid and the contact lens, and in this case, it can be confirmed that the contact angle is high because the hyaluronic acid is not stably coated on the surface.

In addition, FIG. 7 shows the change in the contact angle of the surface-modified contact lens with time. Specifically, HA-NH ₂ is the surface-modified contact lens prepared in Preparation Example 3, and 10 K and 100 K indicate the molecular weight of the hyaluronic acid used in the preparation, respectively.

As shown in FIG. 7 , when the surface-modified hyaluronic acid is stored in a lens storage solution for 30 days, it can be confirmed that the higher the molecular weight, the more stable bonding is achieved and a low contact angle is maintained. In the case of using hyaluronic acid with a molecular weight of 10 K, it can be seen that the change is insignificant after the contact angle increases up to 60° for 60 days. can confirm that

Claims (10)

contact lenses; and
It contains hyaluronic acid bound to the surface of the contact lens,
A surface-modified contact lens wherein the aldehyde group formed on the surface of the contact lens and the amine group of the aminated hyaluronic acid form a bond.
The method of claim 1,
Contact lenses are made of an elastomer of silicone elastomer; and a surface-modified contact lens based on one or more polymers selected from the group consisting of silicone hydrogel.
The method of claim 1,
Aminized hyaluronic acid is a surface-modified contact lens, which is a compound containing a repeating unit represented by the following formula (1):

[Formula 1]

In Formula 1, n is an integer from 25 to 10,000, and m is an integer from 1 to 10.
The method of claim 1,
Surface-modified contact lenses with a contact angle of 40° or less.
S1) introducing a hydroxyl group to the surface of the contact lens;
S2) introducing an amine group to the surface of the contact lens by reacting the contact lens of step S1) with organosilanol;
S3) introducing an aldehyde group to the surface of the contact lens by reacting the contact lens of step S2) with dialdehyde; and
S4) The method of manufacturing a surface-modified contact lens according to claim 1, comprising the step of reacting the contact lens of step S3) with the aminated hyaluronic acid.
6. The method of claim 5,
Step S1) is a method of manufacturing a surface-modified contact lens to introduce a hydroxyl group to the contact lens surface by treating the oxygen plasma.
6. The method of claim 5,
In step S2), the organosilanol is 3-aminopropyltriethoxysilane ((3-Aminopropyl)ethyoxysilane, APTES), 3-aminopropyltrimethoxysilane ((3-Aminopropyl)methyoxysilane, APTMS), [3-( 2-Aminoethylamino)propyl]trimethoxysilane ([3-(2-Aminoethylamino)propyl]trimethoxysilane) and N-(3-trimethoxysilylpropyl)diethylenetriamine (N-(3-Trimethoxysilylpropyl)diethylenetriamine ) of at least one selected from the group consisting of a surface-modified contact lens manufacturing method.
6. The method of claim 5,
In step S3), the dialdehyde is at least one selected from the group consisting of glutaraldehyde, glyoxal, and succinaldehyde. A method of manufacturing a surface-modified contact lens.
6. The method of claim 5,
The hyaluronic acid aminated in step S4) is a compound containing a repeating unit represented by the following Chemical Formula 1, and is prepared by reacting hyaluronic acid with diamine. Method for producing a surface-modified contact lens:

[Formula 1]

In Formula 1, n is an integer from 25 to 10,000, and m is an integer from 1 to 10.
10. The method of claim 9,
Hyaluronic acid is hyaluronic acid (HA) or a salt of hyaluronic acid,
The molecular weight of the hyaluronic acid is 1,000 to 1,000,000 daltons (Da) of a method for producing a surface-modified contact lens.

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