Soft gel material having Anti-PCO properties and use thereof

Abstract

A soft gel material having anti-PCO properties and the use thereof. Provided is a "soft gel-type IOL material" that has injectability, suitability for minimally invasive surgery, a stepless zooming capability and biological resistance. A precursor of the material can be injected into an intraocular capsular bag by means of a syringe, resulting in an extremely small implantation incision, and then undergoes in-situ cross-linking into a soft gel in the intraocular capsular bag, mimicking the performance of a natural crystalline lens in young people, thereby enabling cataract patients to regain natural accommodation function after surgery. The implanted soft gel has properties such as anti-cell adhesion and anti-protein deposition, which prevent the occurrence of PCO. Compared with existing IOL products, the implanted soft gel has a longer service life while providing patients with better visual quality.

Description

Soft gel material with anti-PCO characteristics and application thereof TECHNICAL FIELD

[0001] The present application relates to the technical field of soft gel intraocular lens (IOL), in particular to a soft gel material with anti-PCO characteristics and application thereof. BACKGROUND

[0002] Cataract is a common blinding disease caused by the turbidity of the intraocular refractive media-lens, which leads to the decrease of transparency and the decrease of vision. It is the first blinding eye disease in China. Phacoemulsification combined with IOL implantation surgery is the preferred surgical method for treating cataract, that is, the cloudy lens nucleus and cortex are emulsified and removed by ultrasonic energy, the lens capsule bag is retained, and a replacement IOL is implanted.

[0003] At present, the artificial lens material is mainly composed of synthetic polymers, including polymethyl methacrylate (PMMA), silicone, hydrogel and acrylic. These IOL products are pre-formed lenses, which usually require a larger surgical incision of 3mm to 6mm. In addition, as the only refractive interval in the ocular refractive system with accommodation ability, whether the refractive performance of IOL is adjustable is the key to the development of IOL products. Moreover, the above IOL products have no accommodation function or limited accommodation function (<2D), which cannot meet the higher visual quality requirements of patients with different needs after surgery. In addition, the widely used "acrylic" IOL on the market has poor biocompatibility, potential toxicity and no biological resistance (such as anti-protein deposition and cell adhesion), during the postoperative wound healing response, the residual lens epithelial cells (LEC) will have potential proliferation and migration, adhere to the surface of the IOL, at the same time, the deposition of protein on the surface of the IOL, etc., will all lead to the decrease of lens transparency, eventually leading to light scattering and the decrease of visual quality, this phenomenon is called posterior capsular opacification (PCO). The PCO incidence of the currently used IOL products is high, which causes the service life to be less than ten years. Therefore, the development of soft gel material with anti-PCO characteristics is of great significance and has broad application prospects. SUMMARY

[0004] In order to solve the defects existing in the prior art, the present application provides a soft gel material with anti-PCO characteristics and application thereof, which solves the problem of posterior capsular opacification (PCO) existing in the current IOL for cataract surgery, and provides continuous zoom dynamic adjustment function for presbyopic patients.

[0005] The technical solution adopted by the present application is: a soft glue material with PCO resistance, which is prepared by the following steps.

[0006] (1) Synthesis of functional monomer: tetramethylcyclotetrasiloxane D4 with active hydrogen H reacting with an allyl functional group under the catalysis of Karstedt's Pt catalyst to introduce the required functional group R and obtain the functional monomer D4 R ;

[0007] (2) Synthesis of functional macromonomer: mixing octamethylcyclotetrasiloxane D4, functional monomer D4 R and a capping agent in a mixed solvent of xylene and acetonitrile, and reacting under the catalysis of TfOH acid to obtain a functional macromonomer, wherein the end group molecules are used to control the molecular weight and viscosity of the polymer, i.e. suitable injection degree;

[0008] (3) Light-cured crosslinking: mixing the functional macromonomer with a photoinitiator to obtain a colorless or slightly yellow transparent soft glue.

[0009] The functional group R is one or more of a crosslinkable group, a refractive index adjusting group, and a group resistant to cell adhesion and protein deposition.

[0010] The crosslinkable group is one or more of a methacrylate, an acrylate, a methacrylamide, an acrylamide, and an olefinic double bond.

[0011] The refractive index adjusting group and the group resistant to protein deposition and cell adhesion is one or more of polyvinyl alcohol, polyethylene glycol monohydroxy ether, polyethylene glycol monomethyl ether, trifluoromethyl, fluorine-containing short-chain hydrocarbon, propylbenzene, and short-chain alcohol.

[0012] The molecular weight of the functional macromonomer is 15-100 kDa, and the viscosity range is 0.6-4 kPa.s. The molar percentage of the crosslinkable group in the functional macromonomer is 0.15-5%, so as to ensure that the modulus of the soft glue material after crosslinking is below 5 KPa.

[0013] The molar percentage of the refractive index adjusting group and the group resistant to protein deposition and cell adhesion in the functional macromonomer is 10-99.5%, and the refractive index RI is controlled in the range of 1.41-1.46, and the optimal range is 1.43-1.45 (n 37 D).

[0014] The photo initiator in the step (3) is Irgacure 819 photo initiator, the photo initiator amount is 0.05-0.5wt%, the light source is 400-500nm blue light, the light intensity is controlled in 25-200mW / cm 2 , and the crosslinking reaction time is less than 8min, so that the mechanical strength and optical performance of the synthesized material are close to natural lens of young people.

[0015] The application of a soft gel material with anti-PCO characteristics in the preparation of an intraocular lens material.

[0016] The intraocular lens material is prepared by injecting the prepared functional macromonomer and photo initiator mixture into a cleaned lens capsule bag, and irradiating in the eye capsule bag using 400-500nm wavelength blue light with a light intensity density of 25-200mW / cm 2 for 1-8min to complete crosslinking and curing, replace and replace the cataract lens with pathological changes.

[0017] The application has the advantages that the application provides a soft gel material with anti-PCO characteristics and its application, and provides a "soft gel type IOL" which can be injected, is suitable for minimally invasive surgery, has no zooming ability and biological resistance, the material precursor can be injected into the eye capsule bag through a syringe, the implantation wound is extremely small, and the soft gel is crosslinked in the eye capsule bag to have the performance of a natural lens of young people, so that the natural accommodation function of the cataract patient after surgery is restored. The implanted soft gel has the characteristics of anti-cell adhesion and anti-protein deposition, avoids the occurrence of PCO, has a longer service life compared with existing IOL products, and provides better visual quality for patients. BRIEF DESCRIPTION OF DRAWINGS

[0018] Fig. 1 is a synthesis route of the product of the application.

[0019] Fig. 2 is a linear relationship between the refractive index and the mol% of PEG groups in the polymer.

[0020] Fig. 3 is a rheological test curve of a typical sample, wherein the initial viscosity η is 1.6Pa.s, and the storage modulus G' after crosslinking is 1650Pa.

[0021] Fig. 4 is a relationship between the storage modulus G' and the curing time of samples with different crosslinking group contents.

[0022] Fig. 5 is the light transmittance test result of the product (with the effect of preventing ultraviolet).

[0023] Fig. 6 is a relationship between the PEG group access amount and the contact angle.

[0024] Figure 7 is the product cycle compression test results: the relationship between time and deformation (Figure 7-1) and the relationship between time and force (Figure 7-2).

[0025] Figure 8 is the relationship between product density and PEG group grafting amount under human body temperature conditions.

[0026] Figure 9 is the product color difference test results (Figure 9-1) and the comprehensive color difference deviation results (Figure 9-2).

[0027] Figure 10 is the product thermal stability test results curve.

[0028] Figure 11 is the product water absorption ratio test results curve.

[0029] Figure 12 is the product anti-cell adhesion and proliferation properties.

[0030] Figure 13 is the product anti-bacterial adhesion and proliferation properties.

[0031] Figure 14 is the product anti-protein adsorption deposition properties.

[0032] Figure 15 is the product cytotoxicity test results. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0034] Embodiment 1

[0035] (1) Synthesis of functional monomer

[0036] A small molecule functional group reactant (1.1-1.2 molar equivalents) and 2-4 times the volume of a xylene / acetonitrile mixed solvent were added to the reactor, and a certain amount of Karstedt's Pt catalyst was added. Under the protection of continuous N2 atmosphere, at 55°C, the tetramethylcyclotetrasiloxane D4 with active hydrogen was slowly and uniformly added to the reactor at a speed of 20 mL / h in a precise and controllable manner using a syringe pump. H After the dropwise addition was completed, the reaction was stable for 2 h, and then the reaction was completed. A certain amount of activated carbon was added to the reactor, and the mixture was stirred overnight at room temperature in an air atmosphere to decolorize (to adsorb and remove the deactivated Karstedt's Pt catalyst in the reaction process). The activated carbon powder was filtered out under reduced pressure using a suction filtration device. The functional monomer D4 with a purity of greater than 98 wt% was obtained by rotary evaporation under high vacuum at 75-80°C for 20-30 min. R, add drying agent, put into 4-8℃ refrigerator, and use later.

[0037] Table 1. Functional monomer D4 R Synthesis

[0038] Note: 1) AMA: allyl methacrylate

[0039] 2) APEG: polyethylene glycol allyl methyl ether

[0040] 3) AO: methallyl alcohol

[0041] (2) Synthesis of functional macromonomer

[0042] Into the reactor, respectively add octamethylcyclotetrasiloxane (D4) 39.5 parts, add functional monomer (D4 R1 , D4 R2 , D4 R3 ), a total of about 60 parts and hexaethyl disiloxane (HEDS) 0.5 parts, add an equal volume of mixed solvent of xylene and acetonitrile, and stir uniformly. Under continuous N2 atmosphere protection and at 35℃, after blowing off N2 for 10 min, add a certain amount of trifluoromethanesulfonic acid (TfOH) catalyst to the reactor to start the reaction, and stop the reaction after 24 h. Open the reactor, add excess Na2CO3 particles to the reactor to neutralize TfOH to neutral, remove Na2CO3 solid particles by vacuum filtration, and distill under reduced pressure at 75℃ for 20 min. After distilling about 90% of the xylene and acetonitrile solvent, transfer the product to a dialysis device, use ethanol as the solvent, and dialyze repeatedly 3-5 times to remove unreacted raw materials and small molecule monomers to obtain a functional macromonomer and ethanol mixture. Pour the mixture into a round-bottom flask, remove more than 95% of the ethanol solvent by rotary evaporation under reduced pressure, and then transfer the concentrated sample to a sample bottle and place it in a vacuum oven at 40℃ under vacuum for 24 h to remove the residual ethanol.

[0043] Table 2. Synthesis of functional macromonomer

[0044] Note: 1) R1 is a crosslinking group, 2) R2 is a biological resistance group, etc.

[0045] (3) Preparation of photocured samples

[0046] Accurately weigh a certain amount of purified functional macromonomer into a reaction bottle, add 0.22wt% of Irgacure 819 photoinitiator, and then add a certain amount of CHCl3 solvent. After stirring and mixing uniformly in the dark, remove the CHCl3 solvent completely by rotary evaporation under reduced pressure at 35℃ for 30 min to obtain a light yellow clear transparent viscous liquid.

[0047] Finally, 2 mL of the product was filled into a glass syringe needle tube wrapped with tin foil for packaging, the air bubbles were discharged, and the product was plastic-wrapped and sterilized at 121°C for 30 min, and then stored in the refrigerator for use.

[0048] (4) Use of the product

[0049] Before use, the product needs to be warmed for 15-20 min; during the operation, the product is injected into the cleaned lens capsule, and the operation process needs to be carefully and slowly performed to avoid the generation of air bubbles and the outflow of the colloid. After the intraocular lens is filled, the product is irradiated with blue light with a wavelength of 400-500 nm and a light intensity density of 25-200 mW / cm 2 for 1-8 min to complete the curing and crosslinking.

[0050] Table 3. Comparison of the biological resistance of materials

[0051] Example 2 Relationship between the amount of PEG group introduced and the contact angle

[0052] The results are shown in FIG. 6. With the increase of the PEG content, the hydrophilicity gradually increases, and the contact angle gradually decreases.

[0053] Example 3

[0054] The results are shown in FIG. 7-1 and FIG. 7-2. The cyclic compression test of the product after curing shows that when the deformation is 40%, the compression force is small (≤0.9 N), and the product can be restored to the initial state after multiple compressions.

[0055] Example 4 Relationship between the density of the product and the amount of PEG group grafting under the condition of human body temperature

[0056] The results are shown in FIG. 8. The density of the sample increases with the increase of the amount of PEG group grafting. At the human body temperature of 37°C, the overall density ranges from 0.96 to 1.11 g / cm 3 , which is close to the density of water and the lens.

[0057] Example 5 Test results of the color difference of the product

[0058] The results are shown in FIG. 9-1 and FIG. 9-2. The color difference of the product is small (Red / Yellow is less than 2.5), which is close to the true color, and the overall color difference deviation ΔE*ab is less than or equal to 2.

[0059] Example 6 Test results of the thermal stability of the product

[0060] The results are shown in FIG. 10. The product has excellent thermal stability and no significant weight loss within 300°C, which proves that the product has excellent stability.

[0061] Example 7 product water absorption ratio experimental results curve

[0062] The results are shown in Figure 11. Compared with the high water absorption ratio-hydrogel product (water absorption ratio about 300wt%), the product water absorption ratio is lower, about 5-9wt%, and in the intraocular water environment, it will not cause adverse effects on the capsular bag and other eye tissues after surgery.

[0063] Example 8

[0064] The anti-cell proliferation and adhesion properties of the product prepared in Example 1 were verified, and the results are shown in Figure 12. The cell adhesion shows a trend of gradually decreasing with the increase of PEG content (L929 cells).

[0065] Example 9

[0066] The anti-bacterial adhesion and proliferation properties of the product prepared in Example 1 were verified, and the results are shown in Figure 13. There is no obvious bacterial adhesion in 20%, 40%, 60%, 70%, 80%, and 95% PEG content.

[0067] Example 10

[0068] The anti-protein adsorption deposition properties of the product prepared in Example 1 were verified, and the results are shown in Figure 14. It has good anti-protein adsorption deposition properties.

[0069] Example 11 cytotoxicity experiment

[0070] The results are shown in Figure 15. All the PEG-containing silicone materials have no potential cytotoxicity.

[0071] Conclusion

[0072] The organic siloxane material prepared by the present application and the prepared intraocular lens with anti-PCO properties can simulate the performance of natural lenses in young people, have no zoom adjustment function, introduce functional groups with anti-PCO function, prolong the service life, have low raw material cost, save the cost by eliminating the intermediate preforming process, can use the existing technology in the surgical process without introducing new operation equipment, and have smaller surgical incisions and faster patient recovery.

[0073] Note to all technical personnel: Although the present application has been described according to the above specific embodiments, the inventive idea of the present application is not limited to this invention, and any modification using the inventive idea will be included in the scope of protection of the present patent.

[0074] The above merely describes the preferred embodiments of the present application, and the protection scope of the present application is not limited to the above-described embodiments. Any technical solution falling within the concept of the present application shall fall within the protection scope of the present application. It should be noted that, for ordinary skilled persons in the art, some improvements and refinements without departing from the principles of the present application shall also be considered as falling within the protection scope of the present application.

Claims

1. A soft gel material having anti-PCO properties, characterized in that, The soft gel material is prepared by the following steps: (1) Synthesis of functional monomer: tetramethylcyclotetrasiloxane D4 with active hydrogen H reacting with allyl functional group in the presence of Karstedt's Pt catalyst to introduce the desired functional group R and obtain functional monomer D4 R ; (2) Synthesis of functional macromonomer: octamethylcyclotetrasiloxane D4, functional monomer D4 R and end-capping agent were mixed in a mixed solvent of xylene and acetonitrile, and reacted under the catalysis of TfOH acid to obtain a functional macromonomer, wherein the end group molecule is used to control the molecular weight and viscosity of the polymer, i.e. suitable injection degree; (3) photo-crosslinking: mixing the functional macromonomer with a photo initiator, and crosslinking under blue light to obtain a colorless or slightly yellow transparent soft gel.

2. The soft gel material with anti-PCO properties of claim 1, wherein, The functional group R is one or more of a crosslinkable group, a refractive index adjusting group, and a cell adhesion and protein deposition resistant group.

3. The soft gel material with anti-PCO properties of claim 2, wherein, The crosslinkable group is one or more of a methacrylate, an acrylate, a methacrylamide, an acrylamide, and an olefinic double bond.

4. The soft gel material with anti-PCO properties of claim 2, wherein, The refractive index adjusting group, the cell adhesion and protein deposition resistant group is one or more of a polyvinyl alcohol, a polyethylene glycol monohydroxy ether, a polyethylene glycol monomethyl ether, a trifluoromethyl group, a fluorine-containing short-chain hydrocarbon, a propylbenzene, and a short-chain alcohol.

5. The soft gel material with anti-PCO properties of claim 2, wherein, The functional macromonomer has a molecular weight of 15-100 kDa and a viscosity range of 0.6-4 kPa.s.

6. The soft gel material with anti-PCO properties of claim 3, wherein, The crosslinkable group accounts for 0.15-5% of the molar percentage of the functional macromonomer.

7. The soft gel material with anti-PCO properties of claim 4, wherein, The refractive index adjusting group and the cell adhesion and protein deposition resistant group account for 10-99.5% of the molar percentage of the functional macromonomer.

8. The soft gel material with anti-PCO properties of claim 1, wherein, The photo initiator used in the step (3) for photo initiated crosslinking is any initiator that can trigger photo crosslinking of the material, especially Irgacure 819 photo initiator for blue light crosslinking, the amount of photo initiator is 0.05-0.5wt%, the light source is blue light with wave length of 400-500nm, the light intensity is controlled at 25-200mW / cm 2 , and the crosslinking reaction time is 1-8min.

9. Use of a soft gel material with anti-PCO properties in the preparation of an intraocular lens material.

10. Use according to claim 9, characterized in that, The artificial lens material is prepared by mixing the prepared functional macromonomer with a photoinitiator mixture and injecting it into the cleaned lens capsule bag, and the material is irradiated by blue light with a wavelength of 400-500 nm and an optical intensity density of 25-200 mW / cm 2 for 1-8 min in the eye capsule to complete cross-linking and curing, and replace and replace the diseased cataract lens.

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