A laser-resistant viscoelastic composition, its preparation method and uses

Abstract

This invention provides a laser-resistant viscoelastic composition, its preparation method, and its uses. The viscoelastic composition comprises a rheologically active ingredient, a laser-resistant dye, and a co-solvent. The laser-resistant viscoelastic composition exhibits a transmittance of over 90% in the visible light wavelength range of 550-675 nm, a transmittance of less than 70% in the 300-450 nm and / or 800-1100 nm bands, and a transmittance of 40%-45% in a specific laser wavelength range of 1060-1068 nm. This invention successfully adds a laser-resistant dye to the viscoelastic formulation. This laser-resistant dye has good spectral transmittance in the visible light range, does not affect the surgical field of vision, and does not stain normal intraocular tissues during surgical procedures. It also has good absorption properties at specific laser wavelengths, reducing the impact and damage of lasers on other intraocular tissues. Furthermore, it has certain moisturizing and anti-inflammatory effects and features postoperative removal visualization, ensuring the complete removal of the viscoelastic composition and reducing complications such as high intraocular pressure caused by postoperative residues.

Description

Technical Field

[0001] This invention belongs to the field of medical biomaterials technology, specifically relating to a laser-resistant viscoelastic composition, its preparation method, and its applications. Background Technology

[0002] Phacoemulsification surgery for cataracts is currently the most advanced and effective treatment technique in the world. The surgery is painless, short, involves a small incision, and allows for rapid recovery. Laser emulsification can effectively emulsify the lens nucleus, especially in complex surgical situations. It offers advantages such as smaller corneal incisions, less damage to intraocular tissues, and higher safety. However, the high energy and frequency of the laser used still carry the potential for serious complications that threaten vision, presenting a certain degree of surgical risk. Based on wavelength range, the spectrum can be divided into ultraviolet light (200nm~<400nm), visible light (400nm~<780nm), and infrared light (780nm~1mm). Commonly used lasers or optical instruments include the 532nm potassium titanate oxyphosphate laser, the 585 / 595nm pulsed dye laser, the 694nm ruby ​​laser, the 755nm alexandrite laser, the 800 / 810nm semiconductor laser, the 1064nm neodymium:yttrium aluminum garnet laser, the 2940nm erbium laser, the 10600nm carbon dioxide (CO2) laser, and intense pulsed light (IPL) with wavelengths of 400-1200nm. Various types of lasers are used in dermatology to treat pigmentary disorders, vascular diseases, scars, and photoaging, and are also widely used in ophthalmic surgery, such as the treatment of refractive errors, cataracts, glaucoma, fundus diseases, and lacrimal duct diseases. Currently, there are many lasers used in ophthalmic treatment both domestically and internationally (see Table 1).

[0003] Table 1. Commonly Used Ophthalmic Laser Wavelengths (nm)

[0004]

[0005] For treating posterior cataracts, the primary treatment is a 1064nm continuous-wave YAG laser. Lasers used for fundus diseases include argon lasers, krypton lasers, dye lasers, and 532nm frequency-doubled YAG lasers. Different wavelengths are selected based on the specific condition to achieve the desired treatment. Femtosecond lasers with a wavelength of 1053nm have also been successfully applied in ophthalmic surgery. Studies have found that Nd:YAG laser peripheral iridectomy and posterior capsulotomy cause some damage to the corneal endothelium.

[0006] To improve surgical quality, create surgical space, protect corneal endothelial cells, and reduce damage to corneal endothelial cells during surgical procedures, viscoelastic agents are essential auxiliary materials for ophthalmic surgeries such as cataract surgery. They are a type of biomaterial with a certain degree of viscoelasticity, sterile and pyrogen-free properties. Their main function is for clinicians to use as a surgical pad in ophthalmic microsurgery, providing temporary support for the surgical space, protecting tissues from mechanical damage by surgical instruments, and facilitating the smooth implementation of the surgery. Commonly used viscoelastic active rheological components include sodium hyaluronate, sodium chondroitin sulfate, hydroxypropyl methylcellulose, and polyacrylamide. Sodium hyaluronate, a chain-like polyanionic acidic mucopolysaccharide, is currently the most common rheologically active component in ophthalmic viscoelastic agents. Based on their rheological properties, they are classified into cohesive, diffuse, and mixed types. Cohesive viscoelastics, due to their high shear viscosity, offer superior support; commercially available products like Alcon and Chisun are representative examples. Their larger molecular weight makes them easier to remove postoperatively. Diffuse viscoelastics, with lower shear viscosity, offer better corneal endothelial cell protection; commercially available products like Viscoat are representative examples, but postoperative removal is relatively more difficult. Mixed viscoelastics, represented by AlCON's DuoVisc and ALBOMED's Pe-Ha-Luron F, theoretically combine support and endothelial protection, making them suitable for complex surgical situations. In particular, some formulations that combine sodium hyaluronate with different molecular weights provide better support, while the smaller molecular weight components offer better wetting, protection, and a certain degree of anti-inflammatory effect.

[0007] Currently, most commercially available viscoelastic agents are prepared by dissolving rheology-active ingredients in a buffer system, and mainly serve to support and protect the corneal endothelium. There are very few products with other functional ingredients added. Patents related to medical sodium hyaluronate gel / viscoelastic agent include single-component, composite-component, or functional-component types. For example, (1) CN1524579B discloses a drug-loaded chromogenic composite viscoelastic agent containing an anti-cellular metabolism drug and a drug with color or fluorescence as an indicator component; (2) CN105903088A discloses a method for preparing an ophthalmic viscoelastic agent with selective anterior capsule staining function, adding 0.002-0.6% trypan blue staining agent, with an in vitro release rate of about 15% after 60 minutes. During use, it is continuously and slowly released to the surgical site to achieve selective staining, while not causing much damage to tissue cells. However, the viscoelastic agents provided above only add a chromogenic agent as an indicator and do not have the ability to prevent laser penetration or absorb laser energy. Therefore, in terms of laser treatment or laser protection, commercially available viscoelastic agents do not have a special protective effect against lasers. At present, there is no viscoelastic agent product or technology that has both light transmittance, chromogenicity, and laser protection. Therefore, the market urgently needs a viscoelastic product with laser protection properties to match the development of existing ophthalmic surgical techniques (especially cataract surgery). It can also be applied to other laser surgeries for postoperative protection and care of the surgical site and surrounding areas. Summary of the Invention

[0008] The primary objective of this invention is to provide a laser-resistant viscoelastic composition to better meet the needs of current ophthalmic surgical techniques.

[0009] Specifically, the laser-resistant viscoelastic composition provided by the present invention includes a rheological active ingredient, a laser-resistant dye, and a cosolvent; the laser-resistant viscoelastic composition has a transmittance of more than 90% in the visible light wavelength range of 550-675nm, and a transmittance of less than 70% in the wavelength range of 300-450nm and / or 800-1100nm.

[0010] Preferably, the laser-resistant viscoelastic composition has a transmittance of more than 93% in the visible light wavelength range of 550-675nm and a transmittance of less than 75% in the 800-1100nm band.

[0011] In some embodiments provided by the present invention, the transmittance of the laser-resistant viscoelastic composition is 8%-70% at a laser wavelength of 800-1100nm; or, at a laser wavelength of 800-1070nm, the transmittance is 8%-50%; more preferably, the transmittance is less than 10% (including 10%) at a laser wavelength of 1000±10nm.

[0012] In some embodiments provided by the present invention, the transmittance of the laser-resistant viscoelastic composition is 40%-45% at a specific laser wavelength of 1060-1068nm, thereby reducing the transmittance by 55%-60%.

[0013] In some embodiments provided by the present invention, the transmittance of the laser-resistant viscoelastic composition at a laser wavelength of 300-450 nm is less than 40%.

[0014] In some embodiments provided by the present invention, the transmittance of the laser-resistant viscoelastic composition at a laser wavelength of 450-500nm is 0-30%.

[0015] Preferably, the transmittance of the laser-resistant viscoelastic composition is reduced by 50%-70% at the characteristic laser wavelength of 1064nm.

[0016] The laser-resistant viscoelastic composition of the present invention has good light transmittance, color rendering and laser protection properties in ophthalmic surgery. It exhibits laser protection properties under specific wavelengths, especially laser protection properties under specific surgical wavelengths. It can effectively absorb light sources of specific wavelengths, reducing their transmittance by 50% to 70%, and effectively protect intraocular tissues.

[0017] The laser-resistant viscoelastic composition provided by the present invention comprises an azo dye with a transmittance of 30%-40% at a laser wavelength of 300-450nm; or a quinone dye with a transmittance of 0-15% at a laser wavelength of 300-450nm.

[0018] Preferably, the laser-resistant viscoelastic composition provided by the present invention has a 1s [response time]. -1 The lower shear viscosity is 10-120 Pa·s, and / or the absolute complex viscosity at 0.1 Hz is 10-120 Pa·s.

[0019] More preferably, the laser-resistant viscoelastic composition is effective in 1 second. -1 The lower shear viscosity is 40-90 Pa·s, and / or the absolute complex viscosity at 0.1 Hz is 35-85 Pa·s.

[0020] The present invention also provides another laser-resistant viscoelastic composition comprising:

[0021] The molar ratio is 2.5 * 10. -6 ~6*10 -3 Rheology-active component at mol / L;

[0022] Laser-resistant dye with a mass content of 0.0001~0.05%;

[0023] Cosolvent;

[0024] pH buffer;

[0025] Osmotic pressure regulator.

[0026] The dosage of solubilizers, pH buffers, and osmotic pressure regulators can be determined as needed based on the formulation requirements.

[0027] Preferably:

[0028] The laser-resistant viscoelastic composition provided by the present invention comprises rheological active ingredients selected from one or more of sodium hyaluronate, chondroitin sulfate, and sodium hydroxypropyl methylcellulose, preferably sodium hyaluronate.

[0029] In a preferred embodiment of the present invention, the sodium hyaluronate is selected from a mixture of two or three rheology-active ingredients with different molecular weights of high, medium and low; for example, two or three of the following: low molecular weight fraction of 5 to 100 kDa (inclusive) (LMWHA), medium molecular weight fraction of 100 to 2000 kDa (inclusive) (MMWHA), and high molecular weight fraction of 2000 to 4000 kDa (inclusive) (HMWHA).

[0030] When sodium hyaluronate is selected as the rheologically active ingredient, the molar percentage of sodium hyaluronate in the viscoelastic composition is 2.5*10. -6 ~6*10 -3 mol / L is preferred; 1.5*10 mol / L is the ideal concentration. -5 ~1.0*10 -4 mol / L; more preferably, the molar percentage of the LMWHA portion in the sodium hyaluronate is 0~1*10 mol / L. -3 The molar percentage of the mol / L MMWHA portion is 0~1.5*10 -4 mol / L; the molar percentage of the HMWHA portion is 0~1.4*10 -5 mol / L. Particularly preferred is that the molar percentage of LMWHA in the sodium hyaluronate is 10. -5 ~10 -3 The molar ratio of mol / L MMWHA is 5*10 -7 ~1.5*10 -4 mol / L; the molar percentage of HMWHA is 10 -6 ~1.4*10 -5 mol / L.

[0031] The laser-resistant viscoelastic composition provided by this invention includes a laser-resistant dye, which is selected from one or more of quinone dyes, azo dyes, and cyanine dyes. Quinone dyes include 2-hydroxy-1,4-naphthoquinone, anthraquinone dyes such as alizarin green and transparent green 5B; azo dyes include azobenzene, disperse yellow 7, and aniline brown; cyanine dyes include 3H-indoleketone cyanine dyes, quinalidine-type cyanine cyanine dyes, and 4-tetranitrophthalocyanine copper dyes. The laser-resistant dye of this invention is particularly preferably transparent green 5B or aniline brown. These dyes are particularly suitable for the viscoelastic composition system of this invention at specific concentrations and can be directly dissolved in an aqueous system under the action of a cosolvent and dispersant.

[0032] The laser-resistant viscoelastic composition provided by the present invention contains a laser-resistant dye content of 0.0001~0.05% of the laser-resistant viscoelastic composition; preferably 0.001~0.01%, more preferably 0.002~0.006%, for example 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, etc.

[0033] In some preferred embodiments of the present invention, sodium hyaluronate is selected as the rheologically active ingredient and combined with transparent green 5B or aniline brown as a laser-resistant dye. With the help of a cosolvent for wetting and thickening, the resulting laser-resistant viscoelastic composition has particularly outstanding effects (especially in terms of laser protection). Its effect is superior to that of existing viscoelastic agents used in ophthalmic surgery. Especially in laser cataract surgery, the laser-resistant dye component helps to achieve laser protection, strong wettability, good light transmittance, satisfactory maintenance of intraocular space and protection of eye tissues during the operation. Moreover, it is easy to remove at the end of the procedure due to color visualization, and provides significant protection against laser-induced light damage during the operation.

[0034] The laser-resistant viscoelastic composition provided by the present invention uses a co-solvent selected from one or more of propylene glycol, glycerol, mannitol, P188, RH40, and cocamidopropyl betaine, preferably propylene glycol or glycerol.

[0035] In some preferred embodiments provided by the present invention, the co-solvent accounts for 0.5-5% of the laser-resistant viscoelastic composition, preferably 1-3%, for example 1%, 1.5%, 1.8%, 2%, 2.5%, 3%, etc.

[0036] The laser-resistant viscoelastic composition provided by the present invention has a pH value of 6.0 to 8.0, preferably 6.8 to 7.6, more preferably 7.1 to 7.3, such as 7.10, 7.12, 7.15, 7.18, 7.19, 7.20, 7.22, 7.25, 7.26, etc. Within the above range, the composition of the invention has a stable pH value similar to aqueous humor, which provides better protection during surgery.

[0037] The laser-resistant viscoelastic composition provided by the present invention comprises a pH buffer selected from one or more of boric acid / borax, disodium hydrogen phosphate / sodium dihydrogen phosphate, citric acid / sodium citrate, and aminocaproic acid, preferably disodium hydrogen phosphate / sodium dihydrogen phosphate, especially disodium hydrogen phosphate / sodium dihydrogen phosphate in a ratio of 2:1 to 15:1.

[0038] Preferably, the total amount of the pH buffer in the laser-resistant viscoelastic composition does not exceed 1%; more preferably 0.35% to 0.6%; more preferably 0.385% to 0.545%.

[0039] In addition, the pH buffer of the present invention also contains hydrochloric acid or sodium hydroxide as a pH adjuster, and the amount of hydrochloric acid or sodium hydroxide is determined according to the amount required to adjust the pH value of the anti-laser viscoelastic composition, and usually does not exceed 0.5% of the anti-laser viscoelastic composition.

[0040] The laser-resistant viscoelastic composition provided by this invention uses an osmotic pressure regulator selected from one or more of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, preferably sodium chloride. The amount of this osmotic pressure regulator is adjusted to a osmotic pressure of 270-400 mOsmol / kg, preferably 280-360 mOsmol / kg. Within this range, the composition of the invention has a stable osmotic pressure value similar to that of aqueous humor, providing better protection during surgery.

[0041] In some preferred embodiments provided by the present invention, the osmotic pressure regulator accounts for 0.1-0.5% of the laser-resistant viscoelastic composition, preferably 0.1-0.3%, more preferably 0.15%-0.2%, such as 0.15%, 0.16%, 0.18%, 0.2%, etc.

[0042] As a preferred embodiment of the present invention, the laser-resistant viscoelastic composition formulation is as follows:

[0043] The molar ratio is 2.5 * 10. -6 ~6*10 -3 A sodium hyaluronate composition at mol / L;

[0044] Transparent green 5B or aniline brown with a mass content of 0.001~0.01%;

[0045] Co-solvents propylene glycol or glycerol;

[0046] pH buffer: disodium hydrogen phosphate;

[0047] Sodium chloride, an osmotic pressure regulator.

[0048] More preferably, the amount of co-solvent used is 1-3% of the laser-resistant viscoelastic composition;

[0049] The laser-resistant viscoelastic composition has a pH value of 6.8~7.6 and an osmotic pressure of 280~360 mOsmol / kg.

[0050] In the above-mentioned sodium hyaluronate composition, the molar percentage of the LMWHA portion is 0~10. -3 The molar percentage of the mol / L MMWHA portion is 0~1.5*10 -4 mol / L; the molar percentage of the HMWHA portion is 0~1.4*10 -5 mol / L.

[0051] The laser-resistant viscoelastic composition with the above formulation allows the dye to be more fully and uniformly incorporated into the laser-resistant viscoelastic agent, resulting in a particularly outstanding protective effect against laser energy.

[0052] A second objective of this invention is to provide a method for preparing the above-mentioned laser-resistant viscoelastic composition, the method comprising:

[0053] The anti-laser dye is first pre-dispersed with a dispersant, then added to a buffer solution containing a cosolvent, an osmotic pressure regulator, and a pH buffer. The dispersant is then removed by vacuum drying, and finally the rheology active ingredient is added and mixed evenly.

[0054] To overcome the shortcomings of incomplete removal and poor observation of viscoelastic agents after ophthalmic surgery, and to meet the special requirements of laser protection in laser cataract surgery, how to select a suitable anti-laser dye and mix it evenly into the viscoelastic agent formulation, and provide an anti-laser viscoelastic agent with good light transmittance, color development, and easy removal for ophthalmic surgery, has become an urgent research topic.

[0055] As is well known, laser protection materials mainly consist of polymer dye particles such as fullerene C60, carbon nanotubes, porphyrins, metal phthalocyanines, and polyacetylenes, as well as metal oxide films. These materials are sensitive to both wavelength and light intensity, meeting the requirements for absorbance or optical density at one or more wavelengths while maximizing the visible light transmittance of thermoplastic resins, glass, or other substrates. Different protective materials exhibit variations in laser protection wavelength, optical density, transparency, laser damage threshold, and protection angle. However, dye powders are only soluble in organic solvents to a certain extent, especially dyes suitable for ophthalmic surgical protection wavelengths. Therefore, those skilled in the art cannot directly add laser-resistant dyes to water-based viscoelastic formulations to obtain laser-resistant viscoelastic agents.

[0056] Furthermore, although laser-absorbing dyes such as quinone dyes (such as Transparent Green 5B) and azo dyes (such as Aniline Brown) can effectively absorb light sources in the 900-1100 nm wavelength range, covering the 1064 nm laser wavelength commonly used in cataract surgery, and copper 4-tetranitrophthalocyanine can provide effective laser protection in the 300-400 nm range, these dyes are only soluble in organic solvents and cannot be directly dissolved in aqueous systems. To address this issue, this invention selectively adds laser-resistant dyes to the viscoelastic agent formulation by adding a co-solvent and pre-dispersing. Different laser-resistant dyes exhibit good spectral transmittance (above 93%) within the visible light range of the surgical procedure, without affecting the surgical field of vision. During the surgical procedure, the dyes do not diffuse from the composition into surrounding tissues, preventing staining of normal intraocular tissues. They also exhibit good absorption at specific laser wavelengths, effectively absorbing lasers of different wavelengths during surgery and reducing the impact and damage of lasers on other intraocular tissues.

[0057] The method for preparing the laser-resistant viscoelastic composition provided by the present invention uses a dispersant selected from one of ethanol, n-propanol, and isopropanol, preferably ethanol or isopropanol.

[0058] When used, the preferred mass ratio of the anti-laser dye in the dispersant is 1:1000 to 1:10000; more preferably, the mass ratio is 1:1000 to 1:5000; for example, 1:1000, 1:1500, 1:2000, 1:2500, 1:3000, 1:5000, etc.

[0059] The method for preparing the laser-resistant viscoelastic composition provided by the present invention further includes the step of preparing a buffer solution, specifically: weighing a co-solvent, an osmotic pressure regulator, and a pH buffer, dissolving them in sterile water for injection, mixing them evenly, and then filtering to remove bacteria.

[0060] And further includes:

[0061] The anti-laser dye is pre-dispersed in a dispersant, and impurities are removed by filtration. The dye pre-dispersed solution is then added to the buffer solution, and the dispersant is removed by vacuum drying at low temperature. Rheology active ingredients (such as sodium hyaluronate composition) are then added to the solution, mixed, filled, and sterilized by moist heat to obtain the viscoelastic agent for ophthalmic surgery.

[0062] The present invention does not specifically limit the specific conditions for removing the dispersant by vacuum drying at low temperature. Suitable conditions include vacuum drying at 40°C for 10-30 min, vacuum drying at 30°C for 20-30 min, and vacuum drying at 50°C for 10-30 min. These conditions can be vacuum drying ovens or equivalent equipment, with a vacuum condition of 100 Pa or higher, as long as the dispersant can be removed.

[0063] The inventors discovered that adding a specific cosolvent can increase the solubility of laser dyes in viscoelastic agents. However, since the cosolvent itself also has a certain viscosity, it is not conducive to the dissolution of the dye. Moreover, adding more than 5% will cause the osmotic pressure of the entire system to exceed the ophthalmic standard. Therefore, the inventors have pioneered a method to break down the process of adding the dye to the traditional viscoelastic agent buffer system into three steps: First, add the cosolvent to the buffer solution; then, pre-disperse the dye in a highly soluble dispersant to form a pre-dispersion; then, add the pre-dispersion to the buffer solution, mix evenly, and dry to remove the dispersant. This successfully allows the anti-laser dye to be gradually added to the viscoelastic agent system. Finally, add the rheology active ingredient, fill and sterilize to obtain the anti-laser viscoelastic agent.

[0064] This invention effectively solves the problem of water insolubility of anti-laser dyes through pre-dispersion, and combines the characteristics of both cohesive and dispersible viscoelastic agents. It is simple to operate, and the hydrogen bonding between the dye, cosolvent, and rheology-active ingredient ensures stable dispersion of the dye within the viscoelastic agent. The anti-laser viscoelastic agent provided by this invention consists of rheology-active ingredients, cosolvent, anti-laser dye, pH adjuster, and osmotic pressure adjuster. It effectively provides laser protection during laser cataract surgery, utilizing the laser dye to absorb laser energy, reducing damage to other unintended areas of the eye. It has good visible light transmittance and displays color during postoperative removal, allowing surgeons to directly observe the areas of residual viscoelastic agent in the anterior chamber, accurately flushing away local viscoelastic agent, effectively removing residual viscoelastic agent from the eye, and reducing postoperative complications such as high intraocular pressure caused by residual agent.

[0065] The present invention also provides the use of the above-mentioned laser-resistant viscoelastic composition in laser surgery, especially in ophthalmic laser surgery;

[0066] Preferred ophthalmic surgeries include intracapsular cataract extraction, phacoemulsification cataract extraction, corneal transplantation, intraocular lens implantation and removal, iridectomy, anterior chamber hemorrhage surgery, foreign body and tumor removal, trabeculectomy, vitrectomy or foreign body removal, retinal detachment and epiretinal membrane resection, glaucoma, diabetic retinopathy, and femtosecond laser surgery.

[0067] The laser-resistant viscoelastic composition provided by this invention can be used to assist in ophthalmic surgery, especially laser cataract surgery. The laser-resistant viscoelastic agent of this invention exhibits good light transmittance, color rendering, and laser protection properties in laser surgery, particularly ophthalmic surgery (it can absorb laser energy during surgery, reducing laser damage to other unintended areas of the eye). It also features postoperative removal visualization, ensuring the viscoelastic composition is removed as completely as possible, helping the surgeon assess the removal status, effectively preventing corneal endothelial cell damage caused by lasers during ophthalmic surgery, and reducing postoperative complications such as high intraocular pressure caused by residual lasers. Attached Figure Description

[0068] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0069] Figure 1 This is a schematic diagram showing the color development of the laser-resistant viscoelastic composition after soaking in physiological saline for 15 minutes.

[0070] Figure 2 It is the ultraviolet-visible-near-infrared transmittance spectrum of the laser-resistant viscoelastic composition.

[0071] Figure 3 This is a weight-average molecular weight characterization spectrum of the laser-resistant viscoelastic composition.

[0072] Figure 4 This is a schematic diagram of the rheological properties-shear viscosity of the laser-resistant viscoelastic composition.

[0073] Figure 5 This is a schematic diagram of the rheological properties of the laser-resistant viscoelastic composition – absolute complex viscosity. Detailed Implementation

[0074] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0075] The following is combined with Figures 1-5 The various specific embodiments of the present invention are described.

[0076] Example 1

[0077] This embodiment provides a laser-resistant viscoelastic composition with the following formulation (sterile water for injection is added to bring the total to 98g): disodium hydrogen phosphate 0.50g, sodium dihydrogen phosphate 0.45g, sodium chloride 0.15g, glycerol 2g, 6.82*10 -6 HMWHA with a molecular weight of 2200 kDa and a concentration of 2.08 × 10⁻⁶ mol / L -6 MMWHA with a molecular weight of 1200 kDa and mol / L and 4.17*10 -4 LMWHA with a molecular weight of 6 kDa and 0.0015 g of aniline brown: This was achieved by adding 1.5 g of pre-dispersion solution and then vacuum drying to remove ethanol. The pre-dispersion solution was prepared by dispersing 0.006 g of aniline brown with 1000 times its mass of ethanol.

[0078] This embodiment also provides a method for preparing the above-mentioned laser-resistant viscoelastic composition, specifically including:

[0079] Weigh out 0.50g of disodium hydrogen phosphate, 0.45g of sodium dihydrogen phosphate, 0.15g of sodium chloride, and 2g of glycerol. Dissolve them in sterile water for injection to a final volume of 98g. Mix thoroughly and filter to obtain a buffer solution.

[0080] Weigh 0.006 g of aniline brown, disperse it in 1000 times its weight of ethanol, filter to remove impurities, and obtain a pre-dispersion.

[0081] Take 1.5g of the pre-dispersion from step 2 and add it to the buffer solution obtained in step 1. Dry under vacuum at 40℃ for 10 minutes to remove ethanol, then add 6.82*10 g of the pre-dispersion solution. -6 HMWHA with a molecular weight of 2200 kDa and a concentration of 2.08 × 10⁻⁶ mol / L -6 MMWHA with a molecular weight of 1200 kDa and mol / L and 4.17*10 -4 LMWHA with a molecular weight of 6 kDa (mol / L) was mixed evenly to obtain a laser-resistant composition; then 1.0 mL was filled into a pre-filled syringe and sterilized by moist heat to obtain a mixed laser-resistant viscoelastic agent.

[0082] The laser-resistant viscoelastic composition prepared in this embodiment was tested and found to have a pH of 7.12 and an osmotic pressure of 335 mOsmol / kg.

[0083] The implementation process of the remaining embodiments and comparative examples is the same as that of Embodiment 1. The component parameters of each embodiment and comparative example are shown in Tables 2 and 3.

[0084] Table 2 Component Parameter Table

[0085]

[0086] The high molecular weight sodium hyaluronate (HMWHA) raw material has a molecular weight of 2200 kDa, the medium molecular weight sodium hyaluronate (MMWHA) raw material has a molecular weight of 1200 kDa, and the low molecular weight sodium hyaluronate (LMWHA) raw material has a molecular weight of 6 kDa.

[0087] Table 3 Component Parameters

[0088]

[0089] The high molecular weight sodium hyaluronate (HMWHA) raw material has a molecular weight of 2000 kDa, the medium molecular weight sodium hyaluronate (MMWHA) raw material has a molecular weight of 1000 kDa, and the low molecular weight sodium hyaluronate (LMWHA) raw material has a molecular weight of 10 kDa.

[0090] The performance test data of the laser-resistant viscoelastic compositions obtained in Examples 1-8 and Comparative Examples 1-2 are shown in Table 4. The performance test data of the laser-resistant viscoelastic compositions obtained in Examples 9-15 are shown in Table 5.

[0091] Table 4 Performance Summary Table

[0092]

[0093] Table 5 Performance Summary Table

[0094]

[0095] As shown in Table 4, although the transmittance in the visible light region (represented by 660nm) decreased slightly after adding aniline brown or transparent green anti-laser dyes compared to the control group, the decrease was less than 7%, and the solution was visually clear and did not affect the surgical field of view. At 300-450nm and / or 800-110nm, the transmittance was below 70%. At 1064nm, a commonly used laser in ophthalmic surgery, the transmittance of the comparative examples was 100.3% and 100.0%, respectively, while the transmittance of Examples 1-8 was 20%-50%, a decrease of 50%-80%. This indicates that the added anti-laser dyes can effectively absorb at the wavelength of 1064nm, which is the wavelength used in commonly used ophthalmic surgery, thus protecting the intraocular tissues from laser energy damage.

[0096] Experimental Example 1

[0097] The performance of the anti-laser viscoelastic agents obtained in the above-mentioned comparative examples was tested and analyzed, and the results are as follows:

[0098] 1. The laser-resistant viscoelastic composition prepared by the method described in this invention has the characteristic of being colored but not stained. After soaking in physiological saline for 15 minutes, the viscoelastic composition remains colored, with a clear gel-water interface, and no laser-resistant dye spills out. Figure 1 As shown, where, Figure 1 a is the sample from Example 1, with a lower layer of light orange-yellow clear gel and an upper layer of physiological saline; Figure 1 b is the sample from Comparative Example 1, with a colorless and clear gel in the lower layer and physiological saline in the upper layer; Figure 1 c is the sample from Example 2, with a light green gel at the bottom and physiological saline at the top. This indicates that the dye in the composition is uniformly and stably dispersed in the composition. During short-term use in surgical procedures, the dye will not migrate to adjacent tissues. The color intensity of the composition is related to the proportion of dye in the formulation.

[0099] 2. The UV-Vis-NIR spectrum of the anti-laser viscoelastic agent obtained in Example 1 is shown below. Figure 2As shown in the curves, the absorbance at 660 nm is basically the same as that of Comparative Example 1, indicating that the viscoelastic agent prepared in this invention has similar light transmittance to Comparative Example 1 and Comparative Example 2 under visible light and will not affect the surgical field of view; the transmittance at the 300-450 nm laser wavelength is 30%-40%; in the 800-1100 nm band, it is a broadband laser-resistant dye with a certain absorption across the entire band, and the overall transmittance is below 70%; especially at the 1064 nm laser commonly used in ophthalmic surgery, the transmittance is significantly lower than that of Comparative Example 1 and Comparative Example 2, with a transmittance of 40.7%; indicating that the viscoelastic agent formulated in this invention has a good laser protection effect, and the transmittance at 1064 nm is 59.3% lower than that of Comparative Example 1 and Comparative Example 2 (100.29% and 100.01% respectively, calculated as 100%), indicating that it has a laser protection effect against nitrogen lasers, neodymium-yttrium aluminum garnet lasers, etc.

[0100] The UV-Vis-NIR spectrum of the anti-laser viscoelastic agent obtained in Example 2 is shown below. Figure 2 As shown in the curves, the absorbance at 660 nm is basically the same as that of Comparative Example 2, indicating that the viscoelastic agent prepared in this invention has similar light transmittance to Comparative Examples 1 and 2 under visible light and will not affect the surgical field of view; the transmittance is 0-15% under laser wavelengths of 300-450 nm; the transmittance is 0-30% under laser wavelengths of 450-500 nm; and in the 800-1100 nm band, it is a broadband laser-resistant dye with a certain absorption across the entire band, and overall transmittance is good. The transmittance is below 80%; especially in ophthalmic surgery, the transmittance at 1064nm is significantly lower than that of Comparative Example 1 and Comparative Example 2, with a transmittance of 45.9%; indicating that the viscoelastic agent formulated in this invention has a good laser protection effect. The transmittance at 1064nm is 54.1% lower than that of Comparative Example 1 and Comparative Example 2 (100.3% and 100.0% respectively, calculated as 100%), indicating that it has a laser protection effect against nitrogen lasers, argon lasers, neodymium-yttrium aluminum garnet lasers, etc.

[0101] 3. The weight-average molecular weight and molecular weight distribution data of the anti-laser viscoelastic agent obtained in Example 1 were tested, and the results are as follows: Figure 3 As shown, three peak segments can be clearly observed in both the laser signal and the differential signal. PEAK 1, PEAK 2, and PEAK 3 are the peaks corresponding to HMWHA, MMWHA, and LMWHA, respectively, which characterize the composition of three different molecular weight sodium hyaluronates in the anti-laser viscoelastic agent. The detection results show that the peaks of the three different molecular weight components can be separated and their molecular weights can be independently calculated. The combination of sodium hyaluronates with different molecular weights endows the composition with the anti-inflammatory and protective properties of small molecular weight sodium hyaluronate and the moisturizing and supportive properties of large molecular weight sodium hyaluronate.

[0102] 4. The rheological properties of the laser-resistant viscoelastic composition obtained in Example 1 are shown in [reference needed]. Figure 4 and Figure 5 As can be seen in Example 1, the anti-laser viscoelastic agent [results in a certain effect] within 1 second. -1 The shear viscosity is 67.8 Pa·s, and the absolute complex viscosity at 0.1 Hz is 60.3 Pa·s. The low viscosity at high shear viscosity facilitates the movement of surgical instruments and devices, as well as the injection of the composition into the relevant application site, such as the anterior chamber of the eye, using a syringe; the moderate viscosity at low shear viscosity indicates that the composition can provide both support and surface coating properties during use, thus protecting the application site.

[0103] 5. To ensure the dye can be quickly, uniformly, and stably added to the viscoelastic composition, in addition to designing a co-solvent in the buffer system, ethanol was creatively used for pre-dispersion of the dye in the pre-dispersion stage. After adding the buffer solution, vacuum drying was performed to remove the ethanol. This operation facilitates the pre-dispersion of the dye, allowing for rapid dispersion and dissolution when uniformly added to the buffer system. Vacuum drying removes the ethanol solvent, preventing irritation to the application area. Furthermore, this operation and the use of the co-solvent ensure that the dye components are stably dispersed in the composition, preventing dye diffusion or precipitation. Comparative Examples 1 and 2 implemented two operations: adding ethanol followed by vacuum drying and not adding ethanol, respectively. Neither operation affected the final viscoelastic agent's performance.

[0104] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A laser-resistant viscoelastic composition, characterized in that, The viscoelastic composition comprises: a molar ratio of 2.5*10 -6 ~6*10 -3 The composition comprises: a rheologically active ingredient at a concentration of mol / L; a laser-resistant dye at a mass content of 0.0001-0.05%; a co-solvent; a pH buffer; and an osmotic pressure regulator; wherein the laser-resistant dye is transparent green 5B or aniline brown; the co-solvent is selected from propylene glycol or glycerol; the laser-resistant viscoelastic composition has a transmittance of over 90% in the visible light wavelength range of 550-675 nm, and a transmittance of less than 70% in the visible light wavelength range of 300-450 nm; a transmittance of 8%-70% in the laser wavelength range of 800-1100 nm; or, a transmittance of 8%-50% in the laser wavelength range of 800-1070 nm; and a transmittance of 40%-45% in a specific laser wavelength range of 1060-1068 nm.

2. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The transmittance at a laser wavelength of 1000±10nm is less than 10%.

3. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The transmittance decreases by 50%-70% at the characteristic laser wavelength of 1064nm.

4. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The transmittance at 300-450nm laser wavelength is less than 40%; and / or, the transmittance at 450-500nm laser wavelength is 0-30%.

5. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The laser-resistant dye is aniline brown, with a transmittance of 30%-40% at a laser wavelength of 300-450nm; and / or, the laser-resistant dye is transparent green 5B, with a transmittance of 0-15% at a laser wavelength of 300-450nm.

6. The laser-resistant viscoelastic composition according to claim 1, characterized in that, In 1s -1 The lower shear viscosity is 10-120 Pa·s, and / or the absolute complex viscosity at 0.1 Hz is 10-120 Pa·s.

7. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The rheological active ingredient is selected from one or more of sodium hyaluronate, sodium carboxymethyl cellulose, and chondroitin sulfate.

8. The laser-resistant viscoelastic composition according to claim 7, characterized in that, The rheology-active ingredient is sodium hyaluronate; the sodium hyaluronate is selected from two or three of the following: low molecular weight LMWHA (5 to 100 kDa), medium molecular weight MMWHA (100 to 2000 kDa), and high molecular weight HMWHA (2000 to 4000 kDa).

9. The laser-resistant viscoelastic composition according to claim 7, characterized in that, The sodium hyaluronate has a molar ratio of 1.5*10 in the viscoelastic composition. -5 ~1.0*10 -4 mol / L.

10. The laser-resistant viscoelastic composition as described in claim 8, characterized in that, The molar percentage of LMWHA in the sodium hyaluronate is 0~10. -3 The molar percentage of MMWHA is 0~1.5*10 mol / L. -4 mol / L; the molar percentage of HMWHA is 0~1.4*10 -5 mol / L.

11. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The laser-resistant dye has a mass content of 0.001~0.01% of the laser-resistant viscoelastic composition.

12. The laser-resistant viscoelastic composition according to claim 11, characterized in that, The mass content of the laser-resistant dye is 0.002~0.006% of the laser-resistant viscoelastic composition.

13. The laser-resistant viscoelastic composition as described in claim 1, characterized in that, The co-solvent accounts for 0.5-5% of the laser-resistant viscoelastic composition.

14. The laser-resistant viscoelastic composition as described in claim 13, characterized in that, The co-solvent accounts for 1-3% of the laser-resistant viscoelastic composition.

15. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The pH buffer is selected from one or more of boric acid / borax, disodium hydrogen phosphate / sodium dihydrogen phosphate, citric acid / sodium citrate, and aminocaproic acid.

16. The laser-resistant viscoelastic composition as described in claim 15, characterized in that, The pH buffer is disodium hydrogen phosphate / sodium dihydrogen phosphate.

17. The laser-resistant viscoelastic composition as described in claim 16, characterized in that, The pH buffer is a disodium hydrogen phosphate / sodium dihydrogen phosphate in a ratio of 2:1 to 15:

1.

18. The laser-resistant viscoelastic composition as described in claim 15, characterized in that, The total amount of the pH buffer in the laser-resistant viscoelastic composition does not exceed 1%.

19. The laser-resistant viscoelastic composition as claimed in claim 17, characterized in that, The total amount of the pH buffer in the laser-resistant viscoelastic composition is 0.35% to 0.6%.

20. The laser-resistant viscoelastic composition as described in claim 19, characterized in that, The total amount of the pH buffer in the laser-resistant viscoelastic composition is 0.385% to 0.545%.

21. The laser-resistant viscoelastic composition according to any one of claims 1, 15-20, characterized in that, The pH value of the laser-resistant viscoelastic composition is 6.0~8.

0.

22. The laser-resistant viscoelastic composition according to claim 21, characterized in that, The pH value of the laser-resistant viscoelastic composition is 6.8~7.

6.

23. The laser-resistant viscoelastic composition as described in claim 22, characterized in that, The pH value of the laser-resistant viscoelastic composition is 7.1-7.

3.

24. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The osmotic pressure of the laser-resistant viscoelastic composition is 270~500 mOsmol / kg.

25. The laser-resistant viscoelastic composition as described in claim 24, characterized in that, The osmotic pressure of the laser-resistant viscoelastic composition is 280~360 mOsmol / kg.

26. The laser-resistant viscoelastic composition according to claim 1, characterized in that, The osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

27. The laser-resistant viscoelastic composition as described in claim 26, characterized in that, The osmotic pressure regulator is sodium chloride.

28. The laser-resistant viscoelastic composition as described in claim 26 or 27, characterized in that, The osmotic pressure regulator accounts for 0.1-0.5% of the laser-resistant viscoelastic composition.

29. The laser-resistant viscoelastic composition as described in claim 28, characterized in that, The osmotic pressure regulator accounts for 0.1-0.3% of the laser-resistant viscoelastic composition.

30. The laser-resistant viscoelastic composition as described in claim 29, characterized in that, The osmotic pressure regulator accounts for 0.15% to 0.2% of the laser-resistant viscoelastic composition.

31. A method for preparing the laser-resistant viscoelastic composition according to any one of claims 1-30, characterized in that, include: The anti-laser dye is first pre-dispersed with a dispersant, then added to a buffer solution containing a cosolvent, an osmotic pressure regulator, and a pH buffer. The dispersant is then removed by vacuum drying, and finally the rheology active ingredient is added and mixed evenly.

32. The preparation method according to claim 31, characterized in that, The dispersant is selected from one of ethanol, n-propanol, and isopropanol.

33. The preparation method according to claim 31, characterized in that, The mass ratio of the anti-laser dye in the dispersant is 1:1000 to 1:10000.

34. The preparation method according to claim 33, characterized in that, The mass ratio of the anti-laser dye in the dispersant is 1:1000 to 1:5000.

35. The preparation method according to claim 31, characterized in that, The vacuum drying is performed at 40°C for 10-30 minutes, at 30°C for 20-30 minutes, or at 50°C for 10-30 minutes.

36. Use of the laser-resistant viscoelastic composition according to any one of claims 1 to 30 in the preparation of medical devices or materials for laser surgery.

37. Use of the laser-resistant viscoelastic composition according to any one of claims 1 to 30 in the preparation of medical devices or materials for ophthalmic laser surgery.

38. The use according to claim 37, characterized in that, The ophthalmic laser surgeries include intracapsular cataract extraction, phacoemulsification cataract extraction, corneal transplantation, intraocular lens implantation and removal, iridectomy, anterior chamber hemorrhage surgery, foreign body and tumor removal, trabeculectomy, vitrectomy, retinal detachment and epiretinal membrane resection, glaucoma, diabetic retinopathy, and femtosecond laser surgery.

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