CN113248466B - Rhodamine B dye, preparation method thereof and application thereof in preparing contact lenses for correcting red-green color blindness - Google Patents

Rhodamine B dye, preparation method thereof and application thereof in preparing contact lenses for correcting red-green color blindness Download PDF

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CN113248466B
CN113248466B CN202110410473.9A CN202110410473A CN113248466B CN 113248466 B CN113248466 B CN 113248466B CN 202110410473 A CN202110410473 A CN 202110410473A CN 113248466 B CN113248466 B CN 113248466B
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dye
rhodamine
contact lens
red
lens
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CN113248466A (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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Hydron Contact Lens Co ltd
Southeast University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/46—Polymerisation initiated by wave energy or particle radiation
    • C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
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    • C08F230/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal
    • C08F230/04—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal
    • C08F230/08—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal containing silicon
    • C08F230/085—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and containing phosphorus, selenium, tellurium or a metal containing a metal containing silicon the monomer being a polymerisable silane, e.g. (meth)acryloyloxy trialkoxy silanes or vinyl trialkoxysilanes
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    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B11/00—Diaryl- or thriarylmethane dyes
    • C09B11/04—Diaryl- or thriarylmethane dyes derived from triarylmethanes, i.e. central C-atom is substituted by amino, cyano, alkyl
    • C09B11/10—Amino derivatives of triarylmethanes
    • C09B11/24—Phthaleins containing amino groups ; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B57/00—Other synthetic dyes of known constitution
    • G—PHYSICS
    • G02—OPTICS
    • G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
    • G02C7/00—Optical parts
    • G02C7/02—Lenses; Lens systems ; Methods of designing lenses
    • G02C7/04—Contact lenses for the eyes
    • G02C7/049—Contact lenses having special fitting or structural features achieved by special materials or material structures

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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 preparing a contact lens for correcting the red-green color blindness. According to the invention, through structural adjustment of rhodamine B dye molecules, namely, the rhodamine B base ring carboxyl is connected with a substituent group with large steric hindrance and at least one unsaturated double bond, the obtained dye molecule absorption band is still kept at 540-570nm, specific wavelength absorption is realized, the effect of correcting color blindness 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 wavelength fluctuation caused by conjugation due to the generation of intra-ring bonds; the dye molecule has enhanced lipophilicity due to the existence of unsaturated bond in the molecule, reduces the diffusion of dye in water or PBS solution, and effectively prevents eye injury caused by dye release when the contact lens is worn; in addition, through the cross-linking copolymerization of dye molecules and contact lens raw material monomers, the problems of easy diffusion of dye, uneven dye distribution and unstable combination of dye and lens base materials in the contact lens are effectively overcome.

Description

Rhodamine B dye, preparation method thereof and application thereof in preparing contact lenses for correcting red-green color blindness
Technical Field
The invention relates to a rhodamine B dye, and also relates to a preparation method of the rhodamine B dye, and finally relates to application of the rhodamine B dye in preparing a contact lens for correcting red and green color blindness.
Background
The eye diseases which are common in clinic are the congenital color vision disorder. People with red-green blindness cannot distinguish between red and green in the natural spectrum, they will 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 eyes of normal people can distinguish colors because three different cone cells exist on the retina, and the three different photopigments respectively comprise red, green and blue. When light with different wavelengths enters the retina, three cone cells are stimulated to different degrees and transmitted to the brain, so that the color can be accurately distinguished. When any one of the cone cells is missing or defective, it is possible to cause achromatopsia. The photosensitive area of the cone cells of the achromatopsia patient is deviated, so that the overlapped area is enlarged, and the color vision perception is blocked, so that the color cannot be correctly distinguished, and a lot of inconvenience is brought to the work and daily life of the achromatopsia patient. No effective method for curing achromatopsia is currently found, but correction can be performed by increasing the color perception of achromatopsia patients.
In order to increase the color perception of achromatopsia patients, a common method is to wear achromatopsia correcting glasses, and currently, contact lenses with achromatopsia correcting function are hot spots for research. For contact lenses, from a technical route, there are mainly two technical directions: (1) Filtering or enhancing the transmittance of light with specific wavelength by coating films and utilizing the difference of refractive indexes and reflective indexes of different films; (2) Dyes can be doped in the lens base material to adjust the wavelength of transmitted light so as to filter out a specific wavelength band (540-570 nm), thereby enhancing the perception of red-green color blindness.
Wherein, for the first technical direction, patent CN108803077B adopts a coating technique, and the contact lens manufactured by the patent comprises an outer surface layer, an intermediate layer, a achromatopsia correcting film and an inner layer. When in manufacture, the middle layer, the achromatopsia correcting film and the inner layer are compounded into a compound body, and the upper surface of the compound body is molded to wrap the outer surface layer, thereby molding the lens. The contact lens manufactured by the method has high stability, but the manufacturing process involves more steps and is complex. Us patent 4,998,817 (AU 7174291 a) proposes to center a thin layer of red dye on the outer surface of a transparent contact lens, the center red being in line with the axis of the pupil, the center red area covering the light entering the pupil. However, since the dye film of such a contact lens is often in contact with foreign substances, damage to the dye film tends to occur.
For the second technical direction, the current methods for doping dye into contact lenses 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 direct casting of the dye onto the lens surface to ensure uniform coverage of the dye in the center of the lens. However, when the drop casting method is used, uneven distribution of dye on the surface of the lens occurs, and in addition, the dye layer on the surface of the lens is in contact with air for a long time, so that on one hand, oxidation is easy, on the other hand, the dye layer is easy to fall off, and the condition that the dye is dissolved when the lens is soaked in a solution occurs. Therefore, the contact lens prepared by the method has low stability (poor binding force between dye and lens), and is not suitable for industrial application. For the second immersion method, it is mentioned in the literature that after immersing the contact lens in the Atto 565 dye solution for a period of time, color filter contact lenses can be successfully manufactured and the customizability of color blind correcting contact lenses 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, the dye is easily diffused in the PBS solution due to poor curing effect of the dye in the contact lens substrate and hydrophilicity of the dye. And diffusion of the dye can affect contact lens wear and even cause damage to the eye. Currently, most of the color blindness correcting contact lenses adopt a drop casting method or an intrusion 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 and lipophilic properties of the dye can influence the use of the color blindness correcting contact lenses.
Disclosure of Invention
The invention aims to: aiming at the problems of poor curing effect and easy diffusion of dye and a lens substrate existing in the prior art of doping dye into a contact lens, the invention provides a rhodamine B dye, and also provides a preparation method of the rhodamine B dye and a contact lens with a red-green color blindness correcting function.
The technical scheme is as follows: the rhodamine B dye has a structural general formula as follows:
in the formula (I), R isA is a substituent containing at least one unsaturated double bond.
Wherein A isWherein R1 is H or alkyl; n is any integer from 0 to 20; or A is an olefin or contains carbonyl, alkoxy, amido, arylAromatic, heterocyclic olefin derivatives.
The preparation method of the rhodamine B dye comprises the steps of carrying out acyl chlorination treatment on rhodamine B, and carrying out substitution reaction on the rhodamine B and piperazine derivatives after the acyl chlorination treatment; wherein, the substituent connected with N at one side of the piperazine ring in the piperazine derivative is a group containing at least one unsaturated double bond.
The reaction formula of the reaction process is as follows:
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 solvent by rotary evaporation to obtain rhodamine B acyl chloride;
(2) By CH 2 Cl 2 Dissolving rhodamine B acyl chloride obtained in the step (1), firstly dropwise adding triethylamine into the rhodamine B acyl chloride, and then dropwise adding piperazine derivatives; stirring at room temperature to obtain red liquid solution;
(3) After the reaction is completed, a proper amount of isopropanol/CH is used 2 Cl 2 Extracting for three times, adding saturated sodium chloride aqueous solution into the combined organic phases, washing, separating liquid and filtering; anhydrous Na is used for filtrate 2 SO 4 Drying, filtering, and concentrating under reduced pressure; and (5) after vacuum drying, recrystallizing to obtain a mauve solid.
The rhodamine B dye is applied to the preparation of the contact lens for correcting the red-green color blindness.
Wherein, the contact lens is prepared by the following method: adding rhodamine B dye into the contact lens raw material monomer mixture, obtaining a dry sheet after thermal polymerization curing or photopolymerization curing, and washing and hydrating the obtained dry sheet.
Wherein the contact lens raw material monomer mixture comprises a lens raw material monomer, a polymerization initiator and a crosslinking agent; when a thermal polymerization curing mode is adopted, the polymerization initiator is a thermal initiator; when a photopolymerization curing mode is adopted, the polymerization initiator is a photoinitiator.
Wherein the addition amount of the rhodamine B dye is 0.05 to 0.15 weight percent of the weight of the lens raw material monomer; preferably 0.1wt%.
Wherein, the washing hydration treatment is as follows: immersing the obtained initial product in water, physiological saline or buffer physiological saline, washing to remove unpolymerized residues, and replacing the immersed solution for 2-3 times.
Wherein, the mixed materials are uniformly stirred and then injected into a lens mould for polymerization reaction; the reaction conditions for thermal polymerization curing are: curing in an oven at 60-130 ℃ for 8-30 hours; the reaction conditions for photopolymerization and curing are as follows: at a wavelength of 275-398 nm and an intensity of 4-30 mW/cm 2 Curing for 0.5-4 hours under the ultraviolet lamp.
The dye takes rhodamine B as a matrix, the absorption wavelength of the rhodamine B is between 540 and 570nm, and the wavelength region can compensate the defects of the cone cells of the patients with the red and green color blindness, thereby being beneficial to the normal color differentiation of the patients with the red and green color blindness; rhodamine B is generally ring-opened under an acidic condition, ring-closed under an alkaline condition, and the dye does not fluoresce and becomes colorless under the condition of ring closure, but the rhodamine B parent molecule is connected with piperazine ring substituent which has large steric hindrance, so that the molecule is not easy to form a ring-in bond, and the absorbance and color change caused by ring closure are avoided; in addition, since the piperazine ring is not conjugated with rhodamine B matrix, the maximum absorption wavelength of the dye of the present invention does not undergo a significant red shift or blue shift, and remains between 540nm and 570nm (as shown in fig. 9). By substituting an unsaturated double bond for the H group connected with N on one side of the piperazine ring, the oleophilic property of rhodamine B is effectively improved, and the diffusion of dye in the contact lens is further reduced. In addition, the dye and the contact lens monomer are subjected to crosslinking copolymerization to prepare the contact lens with the function of correcting the red-green color blindness, and dye molecules play a bridging role in the polymerization process, so that the contact lens monomers in the form of linear molecules are mutually bonded and crosslinked (shown in figure 10) to form a network structure, and the dye molecules can be effectively bound in the contact lens by the network structure, so that the dye is difficult to diffuse, the problem of diffusion of the dye is further solved, and the biocompatibility and wearing safety of the contact lens for correcting the red-green color blindness are improved.
The beneficial effects are that: according to the invention, through structural adjustment of rhodamine B dye molecules, namely, the rhodamine B base ring carboxyl is connected with a substituent group with large steric hindrance and at least one unsaturated double bond, the obtained dye molecule absorption band is still kept at 540-570nm, specific wavelength absorption is realized, the effect of correcting color blindness 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 absorption wavelength fluctuation caused by conjugation due to the generation of intra-ring bonds; the existence of unsaturated bonds in the molecules can increase the lipophilicity of dye molecules, reduce the diffusion of dye in water or PBS solution, and effectively prevent the eye injury caused by dye release when the contact lens is worn; in addition, through the cross-linking copolymerization of dye molecules and contact lens raw material monomers, the problems of easy diffusion of dye, uneven dye distribution and unstable combination of dye and lens base materials in the contact lens are effectively overcome.
Drawings
FIG. 1 is an absorbance curve for different concentration gradients for a red-green color-blind correcting contact lens;
FIG. 2 is a graph showing the color change of a solution after immersing a contact lens containing rhodamine B parent molecular dye in a PBS solution;
FIG. 3 is a graph showing the color change of the solution of example 5 after immersing the dye I-containing contact lens in PBS solution;
FIG. 4 is a graph showing the color change of the solution of example 4 after immersing the dye II-containing contact lens in PBS solution;
FIG. 5 is a graph showing the color change of a solution of example 6 after immersing a contact lens containing 0.125% dye I in PBS;
FIG. 6 is a graph showing the color change of the solution of example 7 after immersing the dye III-containing contact lens in PBS solution;
FIG. 7 is a graph of cytotoxicity assays of three A, B, C contact lenses;
FIG. 8 is a graph of cytotoxicity assays of three A, D, E contact lenses;
FIG. 9 is an absorbance plot for rhodamine B parent dye and dye I;
FIG. 10 is a block diagram of a cross-linked copolymer network;
FIG. 11 shows dye I prepared in example 1 1 H-NMR；
FIG. 12 shows dye II obtained in example 2 1 H-NMR；
FIG. 13 shows dye III prepared in example 3 1 H-NMR。
Detailed Description
Example 1: synthesis of dye I
Rhodamine B (0.2417 g, about 0.5 mmol) was dissolved in excess thionyl chloride (6 mL) 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 CH 2 Cl 2 (20 mL) dissolving rhodamine B acyl chloride obtained in the first step, slowly dropwise adding 0.3mL of triethylamine (an acid binding agent is used for absorbing acid generated in the reaction, and weak alkaline substances form salts with the acid so as to avoid the influence of the acid on the reaction or the reaction balance) into the solution, and then dropwise adding 1-allylpiperazine (0.0655 g, about 0.5 mmol) into the solution; after stirring at room temperature for 4 hours, a red liquid solution was obtained.
After the reaction is completed, a proper amount of isopropanol/CH is used 2 Cl 2 (1:1, v/v) extraction was performed three times, and the combined organic phases were washed with an appropriate amount of saturated aqueous sodium chloride solution, separated and filtered. Anhydrous Na is used for filtrate 2 SO 4 Drying, filtering, and concentrating under reduced pressure. After drying in vacuo, recrystallization from methylene chloride and petroleum ether gave a reddish-purple solid. 1H NMR (300 MHz, DMSO). Delta.7.64 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.8 Hz, 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＝2.0,1.0Hz,1H),3.69(q,J＝7.1Hz,4H),3.58–3.56(m,2H),3.56–3.54(m,2H),3.54–3.50(m,4H),3.13(dt,J＝5.7,1.0Hz,2H),2.57–2.55(m,2H),2.55–2.53(m,2H),1.33(t,J＝7.1Hz,6H),1.16(t,J＝7.1Hz,6H).
example 2: synthesis of dye II
Rhodamine B (0.2443 g, about 0.5 mmol) was dissolved in excess thionyl chloride (6 mL) 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 CH 2 Cl 2 (20 mL) dissolving rhodamine B acid chloride obtained in the first step, slowly dropwise adding 0.3mL of triethylamine to the solution, and dropwise adding phenylpropenyl piperazine (0.1014 g, about 0.5 mmol) to the solution; after stirring at room temperature for 4 hours, a mauve liquid solution was obtained.
After the reaction is completed, a proper amount of isopropanol/CH is used 2 Cl 2 (1:1, v/v) extraction was performed three times, and the combined organic phases were washed with an appropriate amount of saturated aqueous sodium chloride solution, separated and filtered. Anhydrous Na is used for filtrate 2 SO 4 Drying, filtering, and concentrating under reduced pressure. After drying in vacuo, recrystallization from methylene chloride and petroleum ether gave a reddish-purple solid. 1H NMR (300 mhz, dmso) delta 7.65 (d, j=5.5 hz, 1H), 7.64-7.60 (m, 1H), 7.60-7.57 (m, 1H), 7.54 (d, j=1.6 hz, 1H), 7.35 (d, j=2.6 hz, 2H), 7.33 (d, j=0.7 hz, 2H), 7.29-7.24 (m, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.96 (d, j=2.0 hz, 1H), 6.89 (d, j=2.2 hz, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 6.52 (dt, j=14.7, 0.9hz, 1H), 6.19 (dt, j=14.7, 4.4hz, 1H), 3.69 (q, j=7.7, 1H), 6.96 (d, j=2.0 hz), 6.0 hz, 1H), 6.9 (3.9 hz), 3.9 (d, 3.4 hz, 3H), 3.18 (d, 1H), 6.96 (d, j=2.5 hz, 1H), 6.9 (j=2.5 hz, 1H), 6.85 (s, 1H), 6.52 (j=2H).
Example 3: synthesis of dye III
Rhodamine B (0.2413 g,0.5 mmol) was dissolved in excess thionyl chloride (6 mL) 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.
1-piperazinylpropanol (0.0722 g,0.5 mmol), triethylamine (0.3 mL) and CH were charged to a three-necked flask with stirring 2 Cl 2 (10 mL), stirring in an ice-water bath for 10 minutes, and adding methacryloyl chloride (0.0631 g,0.6 mmol); 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 added 2 CO 3 Powder escape until no bubbles; the organic layer was washed 2 times with water, the organic layer was separated, and the aqueous phase was extracted with ethyl acetate; the organic phases were combined and CaCl was used 2 Drying; filtering, drying, and removing the volatile solution by using a rotary evaporator to obtain a crude product; finally, the product of the 2-piperazin-1-yl-propyl methacrylate is collected by reduced pressure distillation.
By CH 2 Cl 2 (20 mL) rhodamine B acid chloride obtained in the first step was dissolved, 0.3mL of triethylamine was slowly added dropwise thereto, and further 3-piperazin-1-yl-propyl 2-methacrylate (0.5 mmol) was added thereto. After stirring at room temperature for 4 hours, a red liquid solution was obtained.
After the reaction is completed, a proper amount of isopropanol/CH is used 2 Cl 2 (1:1, v/v) extraction was performed three times, and the combined organic phases were washed with an appropriate amount of saturated aqueous sodium chloride solution, separated and filtered. Anhydrous Na is used for filtrate 2 SO 4 Drying, filtering, and concentrating under reduced pressure. After drying in vacuo, recrystallization from methylene chloride and petroleum ether gave a reddish-purple solid. 1H NMR (300 MHz, DMSO). Delta.7.65 (d, J=5.5 Hz, 1H), 7.64-7.61 (m, 1H), 7.61-7.57 (m, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 5.97 (p, J=1.5 Hz, 1H), 5.66 (dq, J=2.7, 1.3Hz, 1H), 4.14 (t, J=6.8 Hz, 2H), 3.69 (q, J=7).1Hz,4H),3.57–3.55(m,2H),3.55–3.54(m,2H),3.54–3.50(m,4H),2.65(t,J＝6.7Hz,2H),2.58–2.55(m,2H),2.55–2.53(m,2H),1.93(s,3H),1.92–1.86(m,2H),1.33(t,J＝7.1Hz,6H),1.16(t,J＝7.1Hz,6H).
Example 4: preparation of hydrogel red-green contact lens
4.7g of hydroxyethyl methacrylate (HEMA) and 0.3g of N-vinyl pyrrolidone (NVP) are weighed, a cross-linking agent Ethylene Glycol Dimethacrylate (EGDMA) accounting for 1.5 percent of the total mass of the lens raw material monomers, an initiator Azobisisobutyronitrile (AIBN) accounting for 0.5 percent of the total mass of the lens raw material monomers and dye II accounting for 0.1 percent of the total mass of the lens raw material monomers are added into the mixture, the mixture is mixed and stirred for 1h, the mixture is added into a lens mold, the mixture is cured in an oven at 130 ℃ for 8 hours, the mold is opened, and the mixture is put into normal saline for washing and hydration treatment, so that the hydrogel contact lens for correcting the achromatopsia is obtained.
Example 5: preparation of silica hydrogel red and green contact lenses
2g of 3- (3-methacryloyloxy-2-hydroxypropyl) propyl bis (trimethylsiloxane) methylsilane (SIGMA), 2.5g of hydroxyethyl methacrylate (HEMA) and 0.5g of methacrylic acid (MAA) are weighed, and a cross-linking agent of Ethylene Glycol Dimethacrylate (EGDMA) accounting for 1% of the total mass of the lens raw material monomers, an initiator of Benzoyl Peroxide (BPO) accounting for 0.5% of the total mass of the lens raw material monomers and a dye I accounting for 0.1% of the total mass of the lens monomers are added into the mixture, mixed and stirred for 1.5h, then the mixture is added into a lens mold, cured for 30 hours in an oven at 60 ℃, the mold is opened, and the mixture is put into normal saline for washing and hydration treatment, so that the silicon hydrogel contact lens for correcting the red-green blindness is obtained.
Example 6: preparation of silica hydrogel red and green contact lenses
2g of 3- (3-methacryloyloxy-2-hydroxypropyl) propyl bis (trimethylsiloxane) methylsilane (SIGMA), 2.5g of hydroxyethyl methacrylate (HEMA) and 0.5g of methacrylic acid (AA) are weighed, a cross-linking agent of Ethylene Glycol Dimethacrylate (EGDMA) accounting for 1% of the total mass of the lens raw material monomers, an initiator of Benzoyl Peroxide (BPO) accounting for 0.5% of the total mass of the lens raw material monomers and a dye I accounting for 0.125% of the total mass of the lens monomers are added into the mixture, the mixture is mixed and stirred for 1.5 hours, the mixture is added into a lens mold, the mixture is cured in an oven at 60 ℃ for 30 hours, the mold is opened, and the mixture is put into normal saline for washing hydration treatment, so that the silicon hydrogel contact lens with the correction of the red-green color blindness is obtained.
Example 7: preparation of fluorosilicone hydrogel red and green contact lenses
2g of methacryloxypropyl TRIS (trimethylsiloxy) silane (TRIS), 0.5g of mono-methacryloxypropyl polytrifluoropropyl methylsiloxane (MFS-M15), 1.5g of hydroxypropyl methacrylate (HPMA), 1g of N, N-Dimethylacrylamide (DMA) were weighed, a cross-linking agent polyethylene glycol diacrylate (PEGDA) accounting for 1.5% of the total mass of the lens raw material monomers, an initiator 2-hydroxy-2-methylpropenoyl ketone (D1173) accounting for 0.5% of the total mass of the lens raw material monomers and a dye III accounting for 0.1% of the total mass of the lens raw material monomers were added thereto, mixed and stirred for 2 hours, and then added to a lens mold at a wavelength of 280nm and an intensity of 24mW/cm 2 And (3) curing for 2 hours under an ultraviolet lamp, opening the mould, and putting into normal saline for washing and hydrating treatment to obtain the fluorosilicone hydrogel contact lens for correcting the red-green color blindness.
(1) Evaluation of light absorption Property of contact lens
The absorbance of the contact lens is measured, and the absorbance is measured as a function of dye content to evaluate the absorbance performance of the contact lens.
The specific process is as follows: material preparation: the dye content was 0.05wt%, 0.075wt%, 0.1wt%, 0.125wt%, 0.15wt% of the contact lens based on the mass of the contact lens starting monomers (contact lenses having different dye contents were made in the manner of example 5). Contact lenses of different dye concentrations were measured using an optical spectrophotometer scanning lens. 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, the higher the absorbance, which indicates that the customizable nature of the contact lenses for correcting color blindness can be achieved by controlling the concentration of the dye used (according to the condition of red and green color blindness, the contact lenses with different dye concentrations are adapted, and the degrees on the lenses are different, similar to the degree of myopia).
(2) Evaluation of dye diffusivity of contact lens
The dye diffusivity test was performed on contact lenses to evaluate the dye diffusivity of the contact lenses by observing the color change of the solution after immersion of the contact lenses in PBS solution.
The specific process is as follows: material preparation: PBS solution A dye-II contact lens prepared by the method of example 4 (dye II content: 0.1 wt.%), a dye-I contact lens prepared by the method of example 5 (dye I content: 0.1 wt.%), a dye-I contact lens prepared by the method of example 6 (dye I content: 0.125 wt.%), a dye-III contact lens prepared by the method of example 7 (dye III content: 0.1 wt.%), and a rhodamine B parent dye-containing contact lens prepared by the method of example 5 (rhodamine B parent dye content: 0.1 wt.%) (five comparative examples). 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 fig. 2 to 6, the diffusion of the dye in the PBS solution is obvious for the contact lens containing rhodamine B parent molecular dye, while the diffusion phenomenon is also shown in the PBS solution for the contact lens containing the dye I, dye II and dye III of the present invention, but the diffusion is very small, even if the dye I content is increased (0.125%), the diffusion amount is also obviously smaller than that of the contact lens containing rhodamine B parent molecular dye, which means that the combination firmness of the dye molecule and the substrate in the contact lens can be synergistically improved after the structural adjustment of the rhodamine B parent dye molecule, thereby effectively preventing the eye injury caused by the release of the dye when the contact lens is worn.
(3) Biocompatibility evaluation of contact lenses (cytotoxicity experiment)
In order to investigate the effect of modified dye molecules on the post-biocompatibility, the cytotoxicity results of the lenses are given here. Among them, the dye monomer used herein was dye I synthesized in example 1. The amount of dye I added to the contact lens was 0.1wt%. In vitro cytotoxicity experiments basic procedure reference GB/T16886.5-2017 medical device biological evaluation-part 5: in vitro cytotoxicity test, the relative proliferation rate of cells is tested by quantitatively inoculating the cells into the leaching solution of the contact lens to be tested and culturing for a certain time.
The specific process is as follows: material preparation: 24-well plate, tweezers, blank contact lens A, red-green color-blind correction contact lens B containing dye I prepared by the method of example 5, contact lens C containing rhodamine B parent molecular dye prepared by the method of example 5 (the dye content in contact lens B and contact lens C is consistent, both are 0.1 wt%) all materials are autoclaved at 121 ℃ before the experiment, repeatedly cleaned by sterilized water and naturally dried. Complete medium during the experiment refers to 89% dmem, 10% fetal bovine serum and 1% penicillin and streptomycin. Extracting contact lens A, B, C with forceps in 24-well plate, adding 1mL of complete medium, leaching at 37+ -2deg.C for 24 hr, extracting the leaching solution, adding into new well, digesting L929 cells with trypsin, and adjusting cell suspension concentration to 5×10 with complete medium 5 The relative proliferation rate of cells was measured and counted by adding a cell suspension to the wells containing the extract and culturing the cells in a medium at 37℃for 24 hours, and the results are shown in FIG. 7. It should be noted that the above contact lenses A, B, C were all washed in advance by the same procedure of washing hydration treatment until no dye diffusion occurred. If residual dye is present in the leach liquor again, it is the result of diffusion of dye in the contact lens. It can be seen that the relative cell proliferation rate of the blank contact lens A was highest after 24 hours of incubation, and the relative cell proliferation rate of the dye I-containing red-green-blind correction contact lens B was significantly higher than that of the rhodamine B parent molecular dye-containing contact lens C. The dye diffusion phenomenon of the contact lens C in the complete culture medium, which is obtained by adopting a crosslinking copolymerization mode of rhodamine B molecules before modification, is more serious than that of the contact lens B in the complete culture medium, which is obtained by adopting a crosslinking copolymerization mode of rhodamine B molecules after modification, and the stability of the red-green color blindness correcting contact lens B prepared by using the rhodamine B molecules after modification is higher, and the molecular structure after modification can be used for improving the dyeing together by a synergistic synthesis methodBinding force of material molecules and base materials.
(4) Biocompatibility evaluation of contact lenses (cytotoxicity experiment)
In order to investigate the effect of modified dye molecules on the post-biocompatibility, here cytotoxicity results after lens formation are given. Among them, the dye monomer used herein was dye I synthesized in example 1. The amount of dye I added to the contact lens was 0.1wt%. In vitro cytotoxicity experiments basic procedure reference GB/T16886.5-2017 medical device biological evaluation-part 5: in vitro cytotoxicity test, the relative proliferation rate of cells is tested by quantitatively inoculating the cells into the contact lens leaching solution to be tested and culturing for a certain time.
The specific process is as follows: material preparation: 24-well plate, tweezers, blank contact lens A, dye I drop cast onto contact lens prepared from the contact lens monomer stock of example 5 using the prior art drop casting method to obtain contact lens D, rhodamine B parent molecule dye drop cast onto contact lens prepared from the contact lens monomer stock of example 5 using the drop casting method to obtain contact lens E (the drop casting amounts of contact lens D and contact lens E are identical). All materials were autoclaved at 121 ℃ before the experiment, 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. Extracting contact lens A, D, E with forceps in 24-well plate, adding 1mL of complete medium, leaching at 37+ -2deg.C for 24 hr, extracting the leaching solution, adding into new well, digesting L929 cells with trypsin, and adjusting cell suspension concentration to 5×10 with complete medium 5 The relative proliferation rate of cells was measured and counted by adding a cell suspension to the wells containing the extract and culturing the cells in a medium at 37℃for 24 hours, and the results are shown in FIG. 8. It should be noted that the above contact lenses A, D, E were all washed in advance by the same procedure of washing hydration treatment until no dye diffusion occurred. If residual dye is present in the leach liquor again, it is the result of diffusion of dye in the contact lens. It can be seen that the relative proliferation rate of cells of the blank contact lens A is highest after 24 hours of culture, and the blank contact lens A contains dye IThe cell proliferation rate of the red-green color-blind correction contact lens D is higher than that of the contact lens E containing rhodamine B parent molecular dye and that of the contact lens C obtained by adopting a crosslinking copolymerization mode of rhodamine B molecules before modification, so that the binding force of dye molecules and a contact lens substrate is better than that of the contact lens C obtained by adopting a crosslinking copolymerization mode of rhodamine B molecules before modification even if the dye molecules with the structure are dripped on the surface of the contact lens by adopting a dripping method, and the modified molecular structure can improve the binding force of dye molecules and the substrate.
(5) Contact lens use test
In order to judge the correction effect of the contact lens for the red-green color blindness on a real red-green color blindness patient, the contact lens for the red-green color blindness patient is used and tested.
The specific process is as follows: material preparation: a sixth edition of color blindness inspection chart, the method of example 5 was used to produce a contact lens containing dye I (the dye I content is 0.1 wt%). The dye I-containing contact lens was held by two transparent glass slides and a small clip, and the glass slides were held by a patient with a red-green color blindness, and the partial content on the color blindness inspection chart was identified by the dye I-containing contact lens, the identification results are shown in Table 1, and Table 1 shows the test results before and after the patient with a red-green color blindness using the contact lens prepared in example 5 of the present invention based on the color blindness inspection chart. As can be seen from Table 1, the success rate of patient identification is greatly improved, and thus, the effectiveness of the dye provided by the invention for correcting the red-green color blindness can be seen.
TABLE 1
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Claims (5)

1. The application of rhodamine B dye in preparing the contact lens for correcting the red-green color blindness is characterized in that the rhodamine B dye has the following structural general formula:
in the formula (I), R isA is-CH 2 -CH＝CH 2 、-CH 2 -ch=ch-Ph or
The contact lens is prepared by the following method: adding rhodamine B dye into the contact lens raw material monomer mixture, obtaining a dry sheet after thermal polymerization curing or photopolymerization curing, 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 mode is adopted, the polymerization initiator is a photoinitiator.
2. The application of rhodamine B dye in preparing a contact lens for correcting red-green color blindness according to claim 1, which is characterized in that the rhodamine B dye is prepared by the following method: performing acyl chlorination treatment on rhodamine B, and then performing substitution reaction on rhodamine B and piperazine derivatives; wherein, the substituent connected with N at one side of the piperazine ring in the piperazine derivative is a group containing at least one unsaturated double bond.
3. The application of rhodamine B dye in preparing a contact lens for correcting red-green color blindness according to claim 2, characterized in that 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 solvent by rotary evaporation to obtain rhodamine B acyl chloride;
(2) By CH 2 Cl 2 Dissolving rhodamine B acyl chloride obtained in the step (1), firstly dropwise adding triethylamine into the rhodamine B acyl chloride, and then dropwise adding piperazine derivatives; stirring at room temperature to obtain red liquid solution;
(3) After the reaction is completed, a proper amount of isopropanol/CH is used 2 Cl 2 Extracting for three times, adding saturated sodium chloride aqueous solution into the combined organic phases, washing, separating liquid and filtering; anhydrous Na is used for filtrate 2 SO 4 Drying, filtering, and concentrating under reduced pressure; and (5) after vacuum drying, recrystallizing to obtain a mauve solid.
4. Use of rhodamine B dye according to claim 1 for the preparation of contact lenses for the correction of the red-green colour blindness, characterized in that: the addition amount of the rhodamine B dye is 0.05 to 0.15 weight percent of the weight of the lens raw material monomer.
5. Use of rhodamine B dye according to claim 1 for the preparation of contact lenses for the correction of the red-green colour blindness, characterized in that: uniformly stirring the mixed materials, and then injecting the mixed materials into a lens mold for polymerization reaction; the reaction conditions for thermal polymerization curing are: curing in an oven at 60-130 ℃ for 8-30 hours; the reaction conditions for photopolymerization and curing are as follows: at a wavelength of 275-398 nm and an intensity of 4-30 mW/cm 2 Curing for 0.5-4 hours under the ultraviolet lamp.
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