CN113248466A - Rhodamine B dye, preparation method thereof and application thereof in preparing RGB blind correction contact lenses - Google Patents

Rhodamine B dye, preparation method thereof and application thereof in preparing RGB blind correction contact lenses Download PDF

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CN113248466A
CN113248466A CN202110410473.9A CN202110410473A CN113248466A CN 113248466 A CN113248466 A CN 113248466A CN 202110410473 A CN202110410473 A CN 202110410473A CN 113248466 A CN113248466 A CN 113248466A
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dye
rhodamine
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CN113248466B (en
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王志飞
宋佳
邢肖肖
韩雪莲
陈平
王玉东
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Hydron Contact Lens Co ltd
Southeast University
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Southeast University
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Abstract

The invention discloses a rhodamine B dye, and also discloses a preparation method of the rhodamine B dye and application of the rhodamine B dye in preparation of a contact lens for correcting the red-green achromatopsia. According to the invention, through structural adjustment of rhodamine B dye molecules, namely, a substituent group which is large in steric hindrance and contains at least one unsaturated double bond is connected at the carboxyl of a bottom ring of rhodamine B, the absorption band of the obtained dye molecules can be still maintained at 540-570nm, the absorption of specific wavelength is realized, the color blindness correction effect is achieved, and the group with large steric hindrance in the molecule can effectively improve the structural stability of the rhodamine B dye molecules and prevent the wavelength fluctuation caused by conjugation due to the generation of an intra-ring bond; the lipophilicity of dye molecules is enhanced due to the existence of unsaturated bonds in the molecules, the diffusion of the dye in water or PBS solution is reduced, and the eye injury caused by the release of the dye when the contact lens is worn is effectively prevented; in addition, the problems of easy diffusion of the dye, uneven dye distribution and weak combination of the dye and a lens base material in the contact lens are effectively solved by carrying out crosslinking copolymerization on the dye molecules and the raw material monomers of the contact lens.

Description

Rhodamine B dye, preparation method thereof and application thereof in preparing RGB blind correction contact lenses
Technical Field
The invention relates to a rhodamine B dye, a preparation method of the rhodamine B dye, and finally an application of the rhodamine B dye in preparing a red-green-color-blindness correction contact lens.
Background
The red-green achromatopsia, a clinically common eye disease, is a congenital dyschromatopsia. People with red-green blindness cannot distinguish between the red and green colors in the natural spectrum, and they see the spectrum as two basic hues: the long wave part (red, orange, yellow, green) is yellow and the short wave part (cyan, blue, violet) is blue. The normal human eye can distinguish colors because there are three different cone cells on the retina, which contain three different photopigments of red, green and blue. When light with different wavelengths enters the retina, the three types of cone cells are stimulated to different degrees and transmitted to the brain, so that accurate color discrimination can be realized. Color blindness may result when any one of the cones is missing or defective. The photosensitive area of the cone cells of the achromate is shifted, so that the overlapped area becomes larger, the color perception is obstructed, and the colors cannot be correctly distinguished, which brings much inconvenience to the work and daily life of the achromate. No effective cure for achromatopsia is currently found, but correction can be made by increasing the color perception of achromatopsia.
In order to increase the color perception of color blindness patients, the common method is to wear color blindness correcting glasses, and the current contact lenses with color blindness correcting function are the hot spots of research. For contact lenses, there are mainly two technical directions from the technical route: (1) through film coating, the refraction and reflectivity of different films are different, so that filtering is carried out or the transmittance of light with specific wavelength is enhanced; (2) the lens base material can be doped with dye to adjust the wavelength of the transmitted light so as to filter out a specific wavelength band (540) and 570nm), thereby enhancing the perception of the red-green achromatopsia.
In the first technical direction, patent CN108803077B adopts a film coating technique, and the contact lens manufactured by the patent comprises an outer surface layer, an intermediate layer, a color blindness correction film and an inner layer. When in manufacturing, the intermediate layer, the achromatopsia correcting film and the inner layer are compounded into a complex, and the outer surface layer is formed and wrapped on the upper surface of the complex, thereby forming the lens. The contact lens prepared by the method has high stability, but the manufacturing process involves more steps and is complex. Us patent 4,998,817(AU7174291A) teaches placing a thin layer of red dye centrally on the outer surface of a transparent contact lens, the central red color being aligned with the axis of the pupil, and the central red region covering the light entering the pupil. However, since the dye film of such contact lenses is often in contact with foreign substances, the dye film is often damaged.
For the second technical direction, the current methods for doping contact lenses with dyes are mainly divided into two types: one is a drop casting method and the other is an immersion method. The first drop casting method, generally requires that the dye be cast directly onto the lens surface to ensure uniform coverage of the dye in the center of the lens. However, when the lens is manufactured by the drop casting method, the dye may be unevenly distributed on the surface of the lens, and the dye layer on the surface of the lens is easily oxidized and easily dropped off due to the contact with air for a long time, so that the dye may be dissolved when the lens is soaked in the solution. Therefore, the contact lenses prepared by the method have low stability (poor binding force of dye and lens) and are not suitable for industrial application. For the second immersion method, it is mentioned in the literature that a color filter contact lens can be successfully manufactured by immersing the contact lens in Atto 565 dye solution for a period of time, and that customizability of the contact lens for correction of achromatopsia can be achieved by controlling the concentration of the dye used. The dye can be uniformly distributed in the contact lens by the method, and the lens has high transmissivity and good stability. However, due to the poor curing effect of the dye in the contact lens substrate and the hydrophilic nature of the dye, the dye will diffuse easily in the PBS solution. The diffusion of the dye may affect the wearing of the contact lens and even cause damage to the eye. Most of the current color blindness correction contact lenses adopt a drop casting method or an invasion method to add dye into the contact lenses, so that the curing of the dye in the contact lenses, the distribution condition of the dye and the hydrophilic-lipophilic property of the dye can influence the use of the color blindness correction contact lenses.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems of poor curing effect of dye and lens base material and easy diffusion of dye existing in the prior art when the dye is doped into the contact lens, the invention provides rhodamine B dye, a preparation method of the rhodamine B dye and the application of the rhodamine B dye in preparing the contact lens with the function of correcting the red-green achromatopsia.
The technical scheme is as follows: the rhodamine B dye has a structural general formula as follows:
Figure BDA0003023954540000021
in the formula (I), R is
Figure BDA0003023954540000022
A is a substituent containing at least one unsaturated double bond.
Wherein A is
Figure BDA0003023954540000023
Wherein R1 is H or alkyl; n is any integer of 0-20; or A is olefin or olefin derivative containing carbonyl, alkoxy, amido, aryl or heterocycle.
The preparation method of the rhodamine B dye comprises the steps of firstly carrying out acyl chlorination on rhodamine B, and then carrying out substitution reaction on the rhodamine B and piperazine derivatives; wherein, the substituent group connected with N on one side of the piperazine ring in the piperazine derivative is a group containing at least one unsaturated double bond.
The reaction process has the following reaction formula:
Figure BDA0003023954540000031
the preparation method of the rhodamine B dye specifically comprises the following steps:
(1) dissolving rhodamine B parent dye in excessive thionyl chloride, refluxing the solution at high temperature, cooling, and removing the solvent by rotary evaporation to obtain rhodamine B acyl chloride;
(2) by CH2Cl2Dissolving the rhodamine B acyl chloride obtained in the step (1), and dripping triethylamine and then dripping piperazine derivatives into the rhodamine B acyl chloride; stirring at room temperature to obtain a red liquid solution;
(3) after the reaction is finished, using proper amount of isopropanol/CH2Cl2Extracting for three times, adding saturated chlorine into the combined organic phaseWashing, separating and filtering the sodium chloride aqueous solution; anhydrous Na is used for filtrate2SO4Drying, filtering, and concentrating under reduced pressure; after vacuum drying, recrystallization was carried out to obtain a magenta solid.
The rhodamine B dye is applied to the preparation of the contact lenses for correcting the red-green achromatopsia.
The contact lens is prepared by the following method: adding rhodamine B dye into the contact lens raw material monomer mixture, carrying out thermal polymerization curing or photopolymerization curing to obtain a dry sheet, and washing and hydrating the obtained dry sheet.
The contact lens raw material monomer mixture comprises a lens raw material monomer, a polymerization initiator and a cross-linking agent; when a thermal polymerization curing mode is adopted, the polymerization initiator is a thermal initiator; when a photopolymerization curing method is used, the polymerization initiator is a photoinitiator.
Wherein the adding amount of the rhodamine B dye is 0.05 to 0.15 percent of the weight of the lens raw material monomer; preferably 0.1 wt%.
Wherein the washing hydration treatment comprises the following steps: the obtained initial product is immersed in water, normal saline or buffered normal saline, and unpolymerized residue is washed off, and the immersion liquid needs to be replaced for 2-3 times.
Wherein, the mixed materials are stirred uniformly and then injected into a lens mould for polymerization reaction; the reaction conditions for thermal polymerization curing are as follows: curing for 8-30 hours in an oven at 60-130 ℃; the reaction conditions of photopolymerization curing are as follows: at a wavelength of 275-398 nm and an intensity of 4-30 mW/cm2Curing for 0.5-4 hours under an ultraviolet lamp.
The dye takes rhodamine B as a matrix, the absorption wavelength of the rhodamine B is 540-570nm, and the wavelength region can make up for the cone cell defect of a patient with anerythrochloropsia and is beneficial to the normal color discrimination of the patient with anerythrochloropsia; the rhodamine B is generally subjected to ring opening under an acidic condition and closed ring under an alkaline condition, and the dye does not have fluorescence and becomes colorless under the closed ring condition; in addition, because the piperazine ring is not conjugated with the rhodamine B parent, the maximum absorption wavelength of the dye of the present invention does not undergo a large red shift or blue shift, and remains between 540nm and 570nm (as shown in FIG. 9). By replacing the H group connected with N on one side of the piperazine ring with an unsaturated double bond, the oleophylic property of rhodamine B is effectively improved, and the diffusion of dye in the contact lens is further reduced. In addition, the contact lens with the RGB blindness correction function is prepared by crosslinking copolymerization of the dye and the contact lens monomer, and in the polymerization process, dye molecules play a bridging role, so that the contact lens monomers in linear molecules are bonded and crosslinked with each other (as shown in figure 10) to form a network structure, and the network structure can effectively bind the dye molecules in the contact lens, so that the dye is difficult to diffuse, the problem of diffusion of the dye is further reduced, and the biocompatibility and wearing safety of the RGB blindness correction contact lens are improved.
Has the advantages that: according to the invention, through structural adjustment of rhodamine B dye molecules, namely, a substituent group which is large in steric hindrance and contains at least one unsaturated double bond is connected at the carboxyl of a bottom ring of rhodamine B, the absorption band of the obtained dye molecules can be still maintained at 540-570nm, the absorption of specific wavelength is realized, the color blindness correction effect is achieved, and the group with large steric hindrance in the molecule can effectively improve the structural stability of the rhodamine B dye molecules and prevent the absorption wavelength fluctuation caused by conjugation due to the generation of an intra-ring bond; the lipophilicity of dye molecules is increased due to the existence of unsaturated bonds in the molecules, the diffusion of the dye in water or PBS solution is reduced, and the eye injury caused by the release of the dye when the contact lens is worn is effectively prevented; in addition, the problems of easy diffusion of the dye, uneven dye distribution and weak combination of the dye and a lens base material in the contact lens are effectively solved by carrying out crosslinking copolymerization on the dye molecules and the raw material monomers of the contact lens.
Drawings
FIG. 1 is a graph of absorbance curves for different concentration gradient RGB blindness correction contact lenses;
FIG. 2 is a color change plot of a solution of a contact lens containing a rhodamine B parent molecular dye immersed in a PBS solution;
FIG. 3 is a graph of the color change of a contact lens of example 5 containing dye I after immersion in a PBS solution;
FIG. 4 is a graph of the color change of the solution of example 4 after immersion of a contact lens containing dye II in PBS;
FIG. 5 is a graph of the color change of the solution of example 6 after immersion of a contact lens containing 0.125% dye I in PBS;
FIG. 6 is a graph of the color change of the solution of example 7 after immersion of a contact lens containing dye III in PBS;
FIG. 7 is a cytotoxicity test chart of A, B, C three contact lenses;
FIG. 8 is a cytotoxicity test chart of A, D, E three contact lenses;
FIG. 9 is an absorbance curve of a rhodamine B parent dye and dye I;
FIG. 10 is a diagram showing the structure of a cross-linked copolymer network;
FIG. 11 shows dye I obtained in example 11H-NMR；
FIG. 12 shows dye II prepared in example 21H-NMR；
FIG. 13 shows the dye III prepared in example 31H-NMR。
Detailed Description
Example 1: synthesis of dye I
Figure BDA0003023954540000051
Rhodamine B (0.2417g, ca. 0.5mmol) was dissolved in excess thionyl chloride (6mL) in a 50mL single-neck flask, the solution was refluxed at 87 ℃ for 6 hours, cooled, and the solvent was removed by rotary evaporation to give rhodamine B acid chloride, which was used in the next step without purification.
By CH2Cl2(20mL) the rhodamine B acyl chloride obtained in the first step is dissolved, 0.3mL of triethylamine (which is used as an acid-binding agent and is used for absorbing acid generated in the reaction, weak alkaline substances and the acid) is slowly dropped into the solutionSalifying to avoid the influence of acid on the reaction or reaction equilibrium), and then dropwise adding 1-allylpiperazine (0.0655g, about 0.5mmol) inwards; after stirring at room temperature for 4 hours, a red liquid solution was obtained.
After the reaction is finished, using proper amount of isopropanol/CH2Cl2(1: 1, v/v) extracting for three times, adding a proper amount of saturated sodium chloride aqueous solution into the combined organic phase, washing, separating liquid and filtering. Anhydrous Na is used for filtrate2SO4Drying, filtering and concentrating under reduced pressure. After vacuum drying, recrystallization was carried out with dichloromethane and petroleum ether to obtain a magenta solid. 1H NMR (300MHz, DMSO) δ 7.64(s,1H),7.62(s,1H),7.59(s,1H),7.54(s,1H),7.18(d, J ═ 8.1Hz,1H),7.06(d, J ═ 8.8Hz,1H),6.95(dd, J ═ 8.9,1.9Hz,1H),6.89(dd, J ═ 8.1,2.2Hz,1H),6.85(s,1H),6.79(s,1H),5.80(tt, J ═ 16.9,5.7Hz,1H),5.17(dt, J ═ 2.0,0.9Hz,1H),5.16(dt, J ═ 2.0, 1H),3.69(q, 7.56, 3.54H), 3.54H (t, 3.54H, 3.55H, 3.5.5.5H, 3.5.5H, 3.5H, 3H, 3.5H, 3, 3.5H, 3H, 3H, 3H, 3, 5H, 3H, 5H, 3H, 3H, 3H, 5H, 3H, 3H, 3H, 5, 3H, 5H, 3H, 5H, 3H, 5H, 3H, 5H, 3H, 5H, 3, 5, 3H, 5H, 3H, 5, 3, 5H, 5, 3, 5H, 3H, 5, 3, 5H, 3H, 5H, 3, 2H, 5, 3, 5H, 2H, 5H, 3H, 5H, 2H, 3H, 5H, 3, 2H, 3, 2H, 5H, 3, 6H) in that respect
Example 2: synthesis of dye II
Figure BDA0003023954540000061
Rhodamine B (0.2443g, ca. 0.5mmol) was dissolved in excess thionyl chloride (6mL) in a 50mL single-neck flask, the solution was refluxed at 87 ℃ for 6 hours, cooled, and the solvent was removed by rotary evaporation to give rhodamine B acid chloride, which was used in the next step without purification.
By CH2Cl2(20mL) the rhodamine B chloride obtained in the first step was dissolved, 0.3mL of triethylamine was slowly dropped into the solution, and phenylpropenylpiperazine (0.1014g, about 0.5mmol) was dropped into the solution; after stirring at room temperature for 4 hours, a liquid solution of a purple color was obtained.
After the reaction is finished, using proper amount of isopropanol/CH2Cl2(1: 1, v/v) extracting for three times, adding a proper amount of saturated sodium chloride aqueous solution into the combined organic phase, washing, separating liquid and filtering. Anhydrous Na is used for filtrate2SO4Drying, filtering and concentrating under reduced pressure. After vacuum drying, recrystallization was carried out with dichloromethane and petroleum ether to obtain a magenta solid. 1H NMR (300MHz, DMSO) δ 7.65(d, J ═ 5.5Hz,1H), 7.64-7.60 (m,1H), 7.60-7.57 (m,1H),7.54(d, J ═ 1.6Hz,1H),7.35(d, J ═ 2.6Hz,2H),7.33(d, J ═ 0.7Hz,2H), 7.29-7.24 (m,1H),7.18(d,1H),7.06(d,1H),6.96(d, J ═ 2.0Hz,1H),6.89(d, J ═ 2.2Hz,1H),6.85(s,1H),6.79(s,1H),6.52(dt, J ═ 14.7,0.9, 1H),6.19, 19 (J ═ 4.5 Hz, 3.5H), 3.5H, 3.5J ═ 3.5H, 3.5J ═ 3H, 3.5H, 3H, 3.5J ═ 3H, 2H) 2.53(t, J ═ 3.8Hz,2H),1.33(t, J ═ 7.1Hz,6H),1.16(t, J ═ 7.1Hz,6H).
Example 3: synthesis of dye III
Figure BDA0003023954540000062
Rhodamine B (0.2413g, 0.5mmol) was dissolved in excess thionyl chloride (6mL) in a 50mL single-neck flask, the solution was refluxed at 87 ℃ for 6 hours, cooled and the solvent removed by rotary evaporation to give rhodamine B acid chloride, which was used in the next step without purification.
A three-necked flask with stirring was charged with 1-piperazinylpropanol (0.0722g, 0.5mmol), triethylamine (0.3mL) and CH2Cl2(10mL), stirred in an ice-water bath for 10 minutes, methacryloyl chloride (0.0631g, 0.6mmol) was added; after a period of reaction, removing the ice water bath, heating to room temperature, and detecting the reaction progress by Thin Layer Chromatography (TLC); after the reaction, the reaction solution was poured into ice water, and solid Na was added2CO3The powder escapes until no bubbles escape; washing the organic layer with water for 2 times, separating the organic layer, and extracting the water phase with ethyl acetate; combining the organic phases with CaCl2Drying; filtering, drying, and removing volatile solution with a rotary evaporator to obtain a crude product; finally, decompressing and distilling, and collecting the product 2-methacrylic acid 3-piperazine-1-yl-propyl ester.
By CH2Cl2(20mL) the rhodamine B chloride obtained in the first step is dissolved, 0.3mL of triethylamine is slowly dropped into the solution, and then the solution is added into the solution3-piperazin-1-yl-propyl 2-methacrylate (0.5mmol) was added. After stirring at room temperature for 4 hours, a red liquid solution was obtained.
After the reaction is finished, using proper amount of isopropanol/CH2Cl2(1: 1, v/v) extracting for three times, adding a proper amount of saturated sodium chloride aqueous solution into the combined organic phase, washing, separating liquid and filtering. Anhydrous Na is used for filtrate2SO4Drying, filtering and concentrating under reduced pressure. After vacuum drying, recrystallization was carried out with dichloromethane and petroleum ether to obtain a magenta solid. 1H NMR (300MHz, DMSO) δ 7.65(d, J ═ 5.5Hz,1H), 7.64-7.61 (m,1H), 7.61-7.57 (m,1H),7.54(d, J ═ 1.6Hz,1H),7.18(d, J ═ 8.1Hz,1H),7.06(d, J ═ 8.8Hz,1H),6.96(d, J ═ 2.0Hz,1H),6.89(d, J ═ 2.2Hz,1H),6.85(s,1H),6.79(s,1H),5.97(p, J ═ 1.5Hz,1H),5.66(dq, J ═ 2.7,1.3, 1H),4.14(t, J ═ 6.8, 3H, 69.5 Hz, 3H, 1H), 3.55H, 3H, 3.55H, 3H, etc., 1.33(t, J ═ 7.1Hz,6H),1.16(t, J ═ 7.1Hz,6H).
Example 4: preparation of hydrogel RGB blind contact lenses
Weighing 4.7g of hydroxyethyl methacrylate (HEMA) as a lens raw material monomer and 0.3g of N-vinyl pyrrolidone (NVP), adding a crosslinking agent Ethylene Glycol Dimethacrylate (EGDMA) accounting for 1.5 percent of the total mass of the lens raw material monomer, an initiator Azobisisobutyronitrile (AIBN) accounting for 0.5 percent of the total mass of the lens raw material monomer and a dye II accounting for 0.1 percent of the total mass of the lens raw material monomer, mixing and stirring for 1h, adding into a lens mold, curing in an oven at 130 ℃ for 8h, opening the mold, and putting into normal saline for washing and hydrating to obtain the hydrogel contact lens for correcting the achromatopsia.
Example 5: preparation of silicone hydrogel contact lens for red-green achromatopsia
Weighing 2g of lens raw material monomer 3- (3-methacryloyloxy-2-hydroxypropyl) propyl bis (trimethylsiloxane) methylsilane (SIGMA), 2.5g of hydroxyethyl methacrylate (HEMA) and 0.5g of methacrylic acid (MAA), adding a crosslinking agent Ethylene Glycol Dimethacrylate (EGDMA) accounting for 1% of the total mass of the lens raw material monomer, an initiator Benzoyl Peroxide (BPO) accounting for 0.5% of the total mass of the lens raw material monomer and a dye I accounting for 0.1% of the total mass of the lens monomer, mixing and stirring for 1.5h, adding the mixture into a lens mold, curing in an oven at 60 ℃ for 30 h, opening the mold, and putting the mixture into physiological saline for washing and hydrating to obtain the silicone hydrogel contact lens for correcting the achromatopsia and the dyschromatopsia.
Example 6: preparation of silicone hydrogel contact lens for red-green achromatopsia
Weighing 2g of lens raw material monomer 3- (3-methacryloyloxy-2-hydroxypropyl) propyl bis (trimethylsiloxane) methylsilane (SIGMA), 2.5g of hydroxyethyl methacrylate (HEMA) and 0.5g of methacrylic acid (AA), adding a crosslinking agent Ethylene Glycol Dimethacrylate (EGDMA) accounting for 1% of the total mass of the lens raw material monomer, an initiator Benzoyl Peroxide (BPO) accounting for 0.5% of the total mass of the lens raw material monomer and a dye I accounting for 0.125% of the total mass of the lens monomer, mixing and stirring for 1.5h, adding the mixture into a lens mold, curing in an oven at 60 ℃ for 30 h, opening the mold, and putting the mixture into physiological saline for washing and hydrating to obtain the silicone hydrogel contact lens for correcting achromatopsia and dyschromatopsia.
Example 7: preparation of fluorosilicone hydrogel anerythrochloropsia contact lenses
Weighing 2g of raw material monomer of a lens, namely methacryloxypropyl TRIS (trimethylsiloxy) silane (TRIS), 0.5g of monomethacryloxypropyl polytrifluoropropylmethylsiloxane (MFS-M15), 1.5g of hydroxypropyl methacrylate (HPMA) and 1g of N, N-Dimethylacrylamide (DMA), adding 1.5 percent of cross-linking agent polyethylene glycol diacrylate (PEGDA) of the total mass of the raw material monomer of the lens, 0.5 percent of initiator 2-hydroxy-2-methyl propiophenone (D1173) of the total mass of the raw material monomer of the lens and 0.1 percent of dye III of the total mass of the raw material monomer of the lens into the raw material monomer of the lens, mixing and stirring for 2h, adding the mixture into a lens mold, and adding the mixture into the lens mold, wherein the mixture has the wavelength of 280nm and the strength of 24mW/cm2Curing for 2 hours under an ultraviolet lamp, opening the mould, and putting the mould into normal saline for washing and hydrating treatment to obtain the fluorosilicone hydrogel contact lens for correcting the achromatopsia.
(1) Evaluation of light absorption Properties of contact lenses
Absorbance measurements were made on the contact lenses and the absorbance properties of the contact lenses were evaluated by measuring the change in absorbance with dye content.
The specific process is as follows: preparing materials: contact lenses having dye contents of 0.05 wt%, 0.075 wt%, 0.1 wt%, 0.125 wt%, 0.15 wt% based on the mass of the raw material monomers for contact lenses were prepared (various contact lenses having different dye contents were prepared in the manner of example 5). The contact lenses of different dye concentrations were measured by scanning the lenses using an optical spectrophotometer. The measurement results are shown in fig. 1. From fig. 1, it can be seen that the wavelength corresponding to the highest absorption peak of all the contact lenses is between 540nm and 570nm, and the higher the content of the dye added in the contact lenses is, the higher the absorbance is, which indicates that the customizability of the contact lenses for correcting achromatopsia can be realized by controlling the concentration of the dye used (according to the condition of red-green achromatopsia, the contact lenses with different dye concentrations are adapted, and the powers on the lenses are different similarly to the myopic powers).
(2) Evaluation of dye diffusibility of contact lenses
The dye diffusivity of the contact lenses is evaluated by observing the color change of the solution after the contact lenses are soaked in the PBS solution for correcting the achromatopsia.
The specific process is as follows: preparing materials: PBS solution, dye II-containing contact lenses (0.1 wt% dye II) prepared according to example 4, dye I-containing contact lenses (0.1 wt% dye I) prepared according to example 5, dye I-containing contact lenses (0.125 wt% dye I) prepared according to example 6, dye III-containing contact lenses (0.1 wt% dye III) prepared according to example 7, and rhodamine B precursor molecular dye-containing contact lenses (0.1 wt% rhodamine B precursor dye) prepared according to example 5 were compared (five controls). The five contact lenses are respectively soaked in 10mL of PBS solution, the solution is photographed every 1 hour, and finally the PBS solution soaked in the contact lenses for 6 hours is photographed. The results are shown in FIGS. 2 to 6. As can be seen from FIGS. 2 to 6, the dye diffusion of the contact lens containing the rhodamine B parent molecular dye in the PBS solution is obvious, while the contact lens containing the dye I, the dye II and the dye III has little diffusion phenomenon in the PBS solution, and even if the content of the dye I is increased (0.125%), the diffusion amount is obviously less than that of the contact lens containing the rhodamine B parent molecular dye, so that the structural adjustment of the rhodamine B parent dye molecules can synergistically improve the bonding firmness of the dye molecules and the base material in the contact lens, and the eye injury caused by the dye release when the contact lens is worn can be effectively prevented.
(3) Evaluation of biocompatibility of contact lens (cytotoxicity test)
In order to investigate the effect of the modified dye molecules on the later biocompatibility, the lens cytotoxicity results are given here. Wherein, the dye monomer used here is the dye I synthesized in example 1. The amount of dye I added to the contact lens was 0.1 wt%. The basic process of the in vitro cytotoxicity test refers to GB/T16886.5-2017 medical instrument biological evaluation-part 5: in vitro cytotoxicity test, the relative proliferation rate of cells is tested by quantitatively inoculating the cells into the leaching liquor of the contact lens to be tested and culturing for a certain time.
The specific process is as follows: preparing materials: 24-well plate, tweezers, blank control contact lens A, red-green-blind correction contact lens B containing dye I prepared by the method of example 5, and contact lens C containing rhodamine B parent molecular dye prepared by the method of example 5 (the dye content in the contact lens B and the dye content in the contact lens C are consistent and are 0.1 wt%), all materials before the experiment were autoclaved at 121 ℃, and were repeatedly washed with sterilized water and naturally dried. Complete medium during the experiment refers to 89% DMEM, 10% fetal bovine serum and 1% penicillin and streptomycin. Taking out contact lens A, B, C with tweezers, placing into 24-well plate, adding 1mL complete culture medium, leaching at 37 + -2 deg.C for 24h, taking out the leaching solution, adding into new well, digesting L929 cell with trypsin, and adjusting cell suspension concentration to 5 × 10 with complete culture medium5And each/mL, adding the cell suspension into the hole containing the extract, culturing for 24 hours in a culture medium at 37 ℃, and performing test statistics on the relative proliferation rate of the cells, wherein the results are shown in FIG. 7. It is noted that the above contact lenses A, B, C are all previously subjected to the same washing and hydrating process, cleaningWashing until no dye diffuses. If residual dye is re-present in the leach solution, it is the result of dye diffusion from the contact lens. It can be seen that after 24 hours of culture, the cell relative proliferation rate of the blank control contact lens A is the highest, and the cell relative proliferation rate of the red-green-color-blindness correction contact lens B containing the dye I is obviously higher than that of the contact lens C containing the rhodamine B parent molecular dye. The dye diffusion phenomenon of the contact lens C obtained by the rhodamine B molecule before modification in the complete culture medium in a crosslinking copolymerization mode is serious compared with the dye diffusion phenomenon of the contact lens B obtained by the rhodamine B molecule after modification in the complete culture medium in a crosslinking copolymerization mode, the stability of the contact lens B for correcting the red-green blindness prepared by the rhodamine B molecule after modification is higher, and the binding force of the dye molecule and the base material can be improved by the modified molecular structure in a synergetic synthesis method.
(4) Evaluation of biocompatibility of contact lens (cytotoxicity test)
To investigate the effect of the modified dye molecules on the later biocompatibility, the cytotoxicity results after lens formation are given here. Wherein, the dye monomer used here is the dye I synthesized in example 1. The amount of dye I added to the contact lens was 0.1 wt%. The basic process of the in vitro cytotoxicity test refers to GB/T16886.5-2017 medical instrument biological evaluation-part 5: the in vitro cytotoxicity test is carried out, and the relative proliferation rate of cells is tested by quantitatively inoculating the cells into the contact lens leaching liquor to be tested and culturing for a certain time.
The specific process is as follows: preparing materials: a 24-well plate, tweezers, blank contact lens a, dye I drop cast onto the contact lens prepared from the contact lens monomer raw material of example 5 using a prior art drop casting method to obtain contact lens D, and rhodamine B parent molecular dye drop cast onto the contact lens prepared from the contact lens monomer raw material of example 5 using a drop casting method to obtain contact lens E (the drop cast amounts of contact lens D and contact lens E are the same). All materials were autoclaved at 121 ℃ before the experiment, washed repeatedly with sterile water and dried naturally. The complete culture medium in the experimental process refers to 89% DMEM and 10% fetal calf bloodClear and 1% penicillin and streptomycin. Taking out contact lens A, D, E with tweezers, placing into 24-well plate, adding 1mL complete culture medium, leaching at 37 + -2 deg.C for 24h, taking out the leaching solution, adding into new well, digesting L929 cell with trypsin, and adjusting cell suspension concentration to 5 × 10 with complete culture medium5The cell suspension was added to the wells impregnated with the extract, and the cells were cultured at 37 ℃ for 24 hours, and the relative proliferation rate of the cells was measured and counted, and the results are shown in FIG. 8. It is noted that the above contact lenses A, D, E are all washed to be free of dye diffusion by the same washing and hydrating process. If residual dye is re-present in the leach solution, it is the result of dye diffusion from the contact lens. After 24 hours of culture, the cell relative proliferation rate of the blank control contact lens A is the highest, and the cell proliferation rate of the red-green-color blindness correction contact lens D containing the dye I is higher than that of the contact lens E containing rhodamine B parent molecular dye and is also higher than that of the contact lens C obtained by adopting a crosslinking copolymerization mode through rhodamine B molecules before modification, so that even if the dye molecules of the structure are cast on the surface of the contact lens by adopting a drop casting method, the binding force between the dye molecules and the contact lens base material is better than that between the dye molecules and the contact lens base material in the contact lens C obtained by adopting a crosslinking copolymerization mode through the rhodamine B molecules before modification, and the binding force between the dye molecules and the base material can be improved through the modified molecular structure.
(5) Contact lens use test
In order to judge the correction effect of the contact lens for the anerythrochloropsia on the real patient with the anerythrochloropsia, the patient with the anerythrochloropsia carries out use test on the contact lens for the anerythrochloropsia.
The specific process is as follows: preparing materials: a sixth edition, color blindness inspection Picture, was used to prepare contact lenses containing dye I (dye I content 0.1 wt.%) by the method of example 5. The contact lens containing the dye I is fixed by two transparent glass slides and a small clip, so that a patient with red and green achromatopsia can identify partial contents on a color blindness inspection chart through the contact lens containing the dye I by holding the glass slides, the identification result is shown in table 1, and the table 1 is a test result before and after the contact lens prepared in example 5 of the invention is used by the patient with red and green achromatopsia based on the color blindness inspection chart. As can be seen from Table 1, the success rate of patient identification is greatly improved, and the effectiveness of the dye provided by the invention on correction of red-green achromatopsia can be seen.
TABLE 1
Figure BDA0003023954540000111
Figure BDA0003023954540000121

Claims (9)

1. A rhodamine B dye is characterized in that the structural general formula is as follows:
Figure FDA0003023954530000011
in the formula (I), R is
Figure FDA0003023954530000012
A is a substituent containing at least one unsaturated double bond.
2. The rhodamine B dye according to claim 1, wherein: a is
Figure FDA0003023954530000013
Wherein R1 is H or alkyl; n is any integer of 0-20; or A is olefin or olefin derivative containing carbonyl, alkoxy, amido, aryl or heterocycle.
3. The method for producing a rhodamine B dye according to claim 1 or 2, characterized in that: firstly, acylating chlorination is carried out on rhodamine B, and then substitution reaction is carried out on the rhodamine B and piperazine derivatives; wherein, the substituent group connected with N on one side of the piperazine ring in the piperazine derivative is a group containing at least one unsaturated double bond.
4. The method for preparing rhodamine B dye according to claim 3, comprising the following steps:
(1) dissolving rhodamine B parent dye in excessive thionyl chloride, refluxing the solution at high temperature, cooling, and removing the solvent by rotary evaporation to obtain rhodamine B acyl chloride;
(2) by CH2Cl2Dissolving the rhodamine B acyl chloride obtained in the step (1), and dripping triethylamine and then dripping piperazine derivatives into the rhodamine B acyl chloride; stirring at room temperature to obtain a red liquid solution;
(3) after the reaction is finished, using proper amount of isopropanol/CH2Cl2Extracting for three times, adding saturated sodium chloride aqueous solution into the combined organic phase, washing, separating liquid and filtering; anhydrous Na is used for filtrate2SO4Drying, filtering, and concentrating under reduced pressure; after vacuum drying, recrystallization was carried out to obtain a magenta solid.
5. Use of the rhodamine B dye of claim 1 or 2 in the preparation of a contact lens for correcting red-green blindness.
6. The use of rhodamine B dye according to claim 5 for the preparation of a contact lens for the correction of achromatopsia, wherein the contact lens is prepared by the following method: adding rhodamine B dye into the contact lens raw material monomer mixture, carrying out thermal polymerization curing or photopolymerization curing to obtain a dry sheet, and washing and hydrating the obtained dry sheet.
7. The use of a rhodamine B dye according to claim 6 for the preparation of a contact lens for correcting red-green blindness, wherein: the contact lens raw material monomer mixture comprises a lens raw material monomer, a polymerization initiator and a cross-linking agent; when a thermal polymerization curing mode is adopted, the polymerization initiator is a thermal initiator; when a photopolymerization curing method is used, the polymerization initiator is a photoinitiator.
8. The use of a rhodamine B dye according to claim 6 for the preparation of a contact lens for correcting red-green blindness, wherein: the adding amount of the rhodamine B dye is 0.05 wt% -0.15 wt% of the weight of the lens raw material monomer.
9. The use of a rhodamine B dye according to claim 6 for the preparation of a contact lens for correcting red-green blindness, wherein: uniformly stirring the mixed materials, and injecting the mixture into a lens mold for polymerization reaction; the reaction conditions for thermal polymerization curing are as follows: curing for 8-30 hours in an oven at 60-130 ℃; the reaction conditions of photopolymerization curing are as follows: at a wavelength of 275-398 nm and an intensity of 4-30 mW/cm2Curing for 0.5-4 hours under an ultraviolet lamp.
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