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WO2023221870A1 - Polymère de polyuréthane à poids moléculaire élevé et son procédé de préparation, hydrogel de polymère de polyuréthane à poids moléculaire élevé, kit, et utilisation associée - Google Patents

Polymère de polyuréthane à poids moléculaire élevé et son procédé de préparation, hydrogel de polymère de polyuréthane à poids moléculaire élevé, kit, et utilisation associée Download PDF

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WO2023221870A1
WO2023221870A1 PCT/CN2023/093621 CN2023093621W WO2023221870A1 WO 2023221870 A1 WO2023221870 A1 WO 2023221870A1 CN 2023093621 W CN2023093621 W CN 2023093621W WO 2023221870 A1 WO2023221870 A1 WO 2023221870A1
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polyurethane polymer
glycol
hydrogel
group
polymer
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Chinese (zh)
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谢沁
张宇
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Zhejiang Ocuarmor Medtech Co Ltd
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Zhejiang Ocuarmor Medtech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/4009—Two or more macromolecular compounds not provided for in one single group of groups C08G18/42 - C08G18/64
    • C08G18/4018—Mixtures of compounds of group C08G18/42 with compounds of group C08G18/48
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
    • C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
    • C08G18/4269—Lactones
    • C08G18/4277—Caprolactone and/or substituted caprolactone
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4804—Two or more polyethers of different physical or chemical nature
    • C08G18/4808—Mixtures of two or more polyetherdiols
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    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4825—Polyethers containing two hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4833—Polyethers containing oxyethylene units
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/77—Polyisocyanates or polyisothiocyanates having heteroatoms in addition to the isocyanate or isothiocyanate nitrogen and oxygen or sulfur
    • C08G18/771—Polyisocyanates or polyisothiocyanates having heteroatoms in addition to the isocyanate or isothiocyanate nitrogen and oxygen or sulfur oxygen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2207/00—Foams characterised by their intended use
    • C08J2207/10—Medical applications, e.g. biocompatible scaffolds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2375/00—Characterised by the use of polyureas or polyurethanes; Derivatives of such polymers
    • C08J2375/04—Polyurethanes

Definitions

  • the present invention relates to the field of medical hydrogels, specifically to a polyurethane polymer and its preparation method, a polyurethane polymer hydrogel, a kit and its application.
  • the vitreous body is a colorless and transparent gel located behind the lens of the human eye. It fills the cavity between the lens and the retina and behind the lens. It has the functions of refraction and fixation of the retina. Its main component, water, accounts for about 99% of the volume of the vitreous body.
  • the lens and the vitreous body are better able to adhere tightly. As you age, the adhesion between the lens and the vitreous body gradually becomes worse, so it is easy to separate them during senile cataract surgery.
  • vitreous membrane There is a layer of very dense material around the vitreous body, called the vitreous membrane, which is divided into two parts: the anterior limiting membrane and the posterior limiting membrane.
  • the vitreous membrane There are no blood vessels in the vitreous body. The nutrients it needs come from the aqueous humor and choroid. Therefore, the metabolism is slow and cannot regenerate. If there is a defect, the space will be filled by the aqueous humor.
  • the vitreous body becomes cloudy due to various reasons, when you look at something, you will feel like there are mosquitoes flying in front of your eyes. In addition, with age or due to high myopia and other reasons, the semi-solid gel-like vitreous body will gradually become liquid, which is called vitreous liquefaction.
  • vitreous body, lens, aqueous humor, cornea, etc. together constitute the refractive stroma of the eye, and support the retina and eyeball wall, keeping the retina and choroid in contact.
  • Retinal detachment can easily occur if vitreous loss occurs during trauma or surgery.
  • vitreous substitutes have become important auxiliary materials in vitreoretinal-related surgeries and are used to treat a variety of eye diseases, such as rhegmatogenous retinal detachment, proliferative diabetic retinopathy, and macular holes.
  • retinal detachment is the fifth leading cause of blindness in developing countries, with an annual global incidence rate of 6.3 to 17.9 cases per 100,000 people. It is the most common vitreoretinal disease requiring emergency repair surgery.
  • Retinal detachment is the separation of the neuroepithelial layer and pigment epithelial layer of the retina. There is a potential gap between the two layers. The fluid retained in the gap after separation is called subretinal fluid.
  • the detached part of the retina cannot sense light stimulation, resulting in incomplete or missing images from the eye.
  • retinal detachment There are many causes of retinal detachment: high myopia; vitreous liquefaction, detachment, and concentration; certain eye injuries or periretinal vein inflammation; after vitreous hemorrhage, the organized and proliferated vitreous cords pull, causing retinal traction and detachment; systemic diseases such as Diabetic vitreoretinopathy; retinal detachment due to vitreous proliferation and traction.
  • the macular hole affects the fovea, which is the most important area for vision, and leads to visual impairment.
  • the medical community has confirmed that the tangential traction on the retinal surface in the macular area is the main cause of the formation of idiopathic macular holes. It is necessary to use vitreous surgery to treat the macula.
  • the hiatus provides the theoretical basis. This theory is proposed based on the adjacent anatomical relationship of the vitreoretinal interface. As the human body ages, the vitreous body liquefies and posterior vitreous detachment occurs. There is often residual part of the posterior vitreous cortex on the retinal surface.
  • a traction force parallel to the retinal surface is formed on the retinal surface in the foveal area. Initially, foveal detachment occurs, and then the fovea occurs. Detachment, eventually forming a full-thickness macular hole.
  • the global incidence rate of full-thickness macular holes is 7.8 to 16 cases per 100,000 people, and the incidence rate is particularly high in people with high myopia and the elderly.
  • Vitreous fillers currently used clinically include expanding gas, silicone oil, etc. Although these fillers have some suitable properties, such as optical clarity and chemical inertness, they also have a number of disadvantages and limitations, such as inaccurate postoperative positioning due to the buoyancy effects of gas and silicone oil fillers. It is often necessary to lie down after filling to maintain the normal state of the retina through the buoyancy of the filler itself.
  • hydrogels are often explored for eye applications due to their high water content, excellent physical and chemical properties, high transparency, and good tissue compatibility, and are considered to be suitable biomaterials for vitreous filling.
  • polymer temperature-sensitive polyurethane hydrogel is a material with broad prospects. It can usually be injected and can encapsulate unstable drugs and preserve biological activity. It can also be used as a drug carrier for implantation and lens replacement. , stem cell transport, wound repair and protective agent, etc.
  • the clinical needs and physical and chemical properties of hydrogels that can replace vitreous have been proven theoretically feasible, research in this area is still in its infancy, and various polymers of "ideal" hydrogels have been put on the market. There is still a big gap between it and the natural vitreous body, and the factors that evaluate the performance of fillers and their applicability in the eye are currently being studied to some extent.
  • Thermosensitive hydrogels are a type of physically cross-linked hydrogels that exhibit unique temperature-responsive behavior: they are flowing liquids at low temperatures and spontaneously form solid gels when heated.
  • the three-dimensional network structure of the gel can store a large number of water molecules in the swollen state.
  • PEG-based gels are increasingly used in the pharmaceutical field due to their good biocompatibility and excellent degradability.
  • PEG segments and PLGA, PCL, PLA, PPG and other segments can be polymerized to form A-B diblock or A-B-A/B-A-B triblock thermosensitive gels, whose physical and mechanical properties can be changed at the molecular structure level by changing the hydrophilicity and hydrophobicity.
  • the balance of the blocks can be adjusted and temperature-sensitive materials with different phase transition temperatures can be obtained by regulating the mass or ratio of the two blocks.
  • Thermoresponsive hydrogels follow several gel models, including micelle packing, micelle bridging, and more recently, permeable micelle networks.
  • micelle packing the hydrophobic blocks of the copolymer form into independent micelles, while the other blocks form bridge-like connections between micelles, leading to the gelation process.
  • Hydrophobic cross-linking is the process. key in.
  • Polyurethane compounds play an important role in temperature-sensitive hydrogels.
  • Polyurethane is the general name for a class of polymers. As long as the molecular chain contains a urethane group (-COONH), it can be called polyurethane.
  • Polyurethane can be synthesized from many types of substances, generally including polyether type and polyester type.
  • Polyurethane is a common polymer composed of hard and soft segments. It has good biocompatibility and plasticity. Due to its excellent physical properties and good biocompatibility, it has been found to have many applications such as as a biomaterial. .
  • stimulus-responsive polyurethane hydrogels there are two types of stimulus-responsive polyurethane hydrogels: one is prepared from hydrophilic polyols, stimulus-responsive diols and diisocyanates; the other is those containing a polyurethane matrix and stimulus-responsive polymers or particles. composite materials.
  • Hydrophilic polyols are usually polyethylene glycol (PEG) or PEG derivatives because these polymers have outstanding physicochemical and biological properties, including hydrophilicity and nontoxicity.
  • Commonly used raw materials for preparing polyurethane hydrogels are polyols and isocyanates, such as polyethylene glycol (PEG), hexamethylene diisocyanate (HDI) or diphenylmethane diisocyanate (MDI).
  • PEG is non-toxic and has good biocompatibility.
  • the prepared polyurethane hydrogel is usually better in biocompatibility than other hydrogels, so polyurethane hydrogel is a common hydrogel system. Since polyurethane has excellent mechanical properties, hydrogels based on its chemical properties are attractive for biomedical applications.
  • Polyurethane-based hydrogels form strong hydrogen-bonding structures that enable linear polymer systems with tunable swelling and mechanical properties.
  • Biodegradable hydrogels have been used to create tissue engineering scaffolds for muscles, nerves and bones.
  • aqueous biodegradable hydrogels based on PCL soft segments have good biocompatibility, and an aqueous method was also developed for the synthesis of biodegradable hydrogel nanoparticles based on mixed oligosaccharides.
  • the properties of hydrogel nanoparticle dispersions can be tuned by the chemistry and ratio of the two polyesters in the soft segments.
  • biodegradable polyurethane-based scaffolds can induce healing of cartilage lesions.
  • Polycaprolactone is used in the synthesis of biodegradable polyurethane and is considered a biocompatible polymer. Therefore, polyurethane hydrogel is a very good material and will have great development space and value in the field of ophthalmology in the future.
  • polyurethane hydrogel biomedical materials often use aromatic diisocyanate (such as MDI) or aliphatic diisocyanate (such as HDI) as the hard segment of the polyurethane polymer.
  • aromatic diisocyanate such as MDI
  • aliphatic diisocyanate such as HDI
  • the degradation products of aromatic diisocyanates are highly toxic to organisms and are also difficult to degrade.
  • aliphatic diisocyanates have slightly improved the toxicity of degradation products, the improvement is small and they are still difficult to degrade.
  • the poor degradability makes the above two materials only be used as biologically inert materials. They have no biological activity and are not easy to be firmly combined with tissues, which can easily lead to toxicity, allergic reactions, etc. Therefore, it is necessary to provide a new polyurethane hydrogel vitreous substitute that can improve the above problems and make it easy to degrade and have better biocompatibility and lower biotoxicity.
  • the main purpose of the present invention is to provide a polyurethane polymer and its preparation method, a polyurethane polymer hydrogel, a kit and its application, so as to solve the existing or difficult problems of polyurethane biomedical materials in the prior art. Degradation, poor biocompatibility, or high biological toxicity.
  • a polyurethane polymer is provided.
  • the polyurethane polymer is obtained by polymerizing prepolyethylene glycol, prepolypropylene glycol, prepolycaprolactone and a cementing agent.
  • the bonding agent has the structure shown in Formula I or Formula II:
  • R 1 is an amino acid and is removed The residue after the group, R 1 carries 0 to 5 -NH 2 , and each -NH 2 can be optionally replaced by -NCO;
  • R 2 is a C1 to C30 linear or branched alkylene group, C6-C30 arylene group, C6-C30 heteroarylene group, and the above-mentioned groups optionally carry at least one substituent, and each substituent is independently selected from C1-C5 linear alkyl group, C3 ⁇ C6 cycloalkyl, carboxyl, cyano or amino group, the carbon atom in R 2 can be optionally replaced by -O-, -NH-, -COO- or -CO-;
  • R 3 is C1 ⁇ C6 A linear or branched alkyl group, and the alkyl group carries a hydroxyl group.
  • R 3 is a C1 to C6 linear or branched alkyl group, and the carbon atom or hydrogen atom in R 3 may be
  • R 1 has the structure shown in formula III:
  • n is any integer between 1 and 6, preferably 1 to 3;
  • R 4 is a C1 to C8 linear or branched alkyl group, a C2 to C8 alkenyl group, a C3 to C8 cycloalkenyl group, C3 ⁇ C8 heterocyclic alkenyl, and the above group optionally carries at least one substituent, each substituent is independently selected from C1 ⁇ C3 linear alkyl group, the carbon atom in R 4 can optionally Substituted by -O- or -NH-; R 4 carries 0 to 5 -NH 2 , and each -NH 2 can be optionally substituted by -NCO; preferably, C3 to C8 heterocyclic alkenyl contains at least one heteroatom, and the heteroatom is selected from N or O; preferably, R 1 is selected from the following structure:
  • R 2 is a C1 to C5 linear or branched alkylene group, a C6 to C12 arylene group, or a C6 to C12 heteroarylene group, and the above groups optionally carry at least one substituent.
  • each substituent is independently selected from C1 to C3 linear alkyl group, C3 to C4 cycloalkyl group, carboxyl group, cyano group or amino group.
  • binding agent is selected from the compounds shown in the following structures:
  • the peak molecular weight of the polyurethane polymer is 35 to 60 kDa.
  • the weight ratio of the polyethylene glycol segment, the polypropylene glycol segment and the polycaprolactone segment is (4.20 ⁇ 4.80):1:(0.04 ⁇ 0.10).
  • the weight average molecular weight of prepolyethylene glycol, the weight average molecular weight of prepolypropylene glycol, and the weight average molecular weight of prepolycaprolactone are each independently 1900 to 2100.
  • a method for preparing the aforementioned polyurethane polymer includes: combining prepolyethylene glycol, prepolypropylene glycol, prepolycaprolactone and a cementing agent Carry out polymerization reaction to obtain polyurethane polymer; the bonding agent has the structure shown in Formula I or Formula II,
  • R 1 , R 2 and R 3 have the same definitions as in any one of claims 1 to 5.
  • the feeding weight ratio of prepolyethylene glycol, prepolypropylene glycol and prepolymer caprolactone is (3.5 ⁇ 3.7):1:0.05; and/or the dosage of the binding agent is prepolyethylene glycol, prepolymerized caprolactone. 9 to 13% of the total weight of propylene glycol and prepolymerized caprolactone.
  • the preparation method includes the following steps: step S1, dispersing prepolyethylene glycol, prepolypropylene glycol and prepolycaprolactone in a solvent to form a first dispersion; step S2, removing water in the first dispersion.
  • step S3 adding a binding agent and a catalyst to the second dispersion system to perform a polymerization reaction to obtain a polyurethane polymer.
  • the reaction time is 0.4 to 4 hours, and the reaction temperature is 110 to 140°C;
  • the catalyst is an organotin catalyst, more preferably stannous octoate and/or dibutyltin dilaurate; further
  • the amount of catalyst used is 5 to 7 ⁇ L per gram of prepolyethylene glycol.
  • the preparation method includes a purification step, which includes: sequentially performing precipitation treatment, suction filtration and drying on the product of the polymerization reaction to obtain a polyurethane polymer; preferably, the solvent for the precipitation treatment is diethyl ether, One or more of tert-butyl methyl ether or n-hexane; preferably, the drying treatment time is 8 to 24 hours, and the treatment temperature is 20 to 30°C.
  • a polyurethane polymer hydrogel includes: the aforementioned polyurethane polymer, or the polyurethane prepared by the aforementioned preparation method. Polymer-like polymers; and swelling solvents.
  • the swelling solvent is selected from one or more of 0.005 to 0.05 M phosphate buffer, artificial tears or water; preferably, the mass concentration of the polyurethane polymer in the polyurethane polymer hydrogel is It is 5 to 7%; preferably, the pH value of the polyurethane polymer hydrogel is 7.4 to 7.5; preferably, the refractive index of the polyurethane polymer hydrogel is 1.334 to 1.344.
  • a kit which contains the aforementioned polyurethane polymer hydrogel.
  • the aforementioned polyurethane polymer or the polyurethane polymer prepared by the aforementioned preparation method, or the aforementioned polyurethane polymer hydrogel, Or the medical use of the aforementioned kit, and the medical use includes use as a vitreous substitute.
  • the above-mentioned polymer of the present invention not only has better biocompatibility and lower toxicity, but also when used in subsequent preparation to form a hydrogel, the hydrogel has needle-passing properties, gelling temperature, 37°C elastic modulus, kinematic viscosity, Density, surface tension, light transmittance, refractive index and other properties are more suitable for the glass body. Furthermore, when the hydrogel is used as a vitreous substitute, it is more replaceable and has better use effects.
  • Figure 1 shows a diagram of the rheological properties of polymer hydrogels in Examples 2 to 7 of the present invention
  • Figure 2 shows the degradation curve of the polymer hydrogel in Example 1, Example 2, Example 5, Example 10, Example 12, Example 15, Example 16 and Example 20 of the present invention
  • Figure 3 shows the infrared spectra of the degradation products obtained after the polymer hydrogel in Example 5 of the present invention was degraded for 10 days, 20 days and 30 days respectively;
  • Figure 4 shows the survival rate curve of ARPE cells in the degradation products obtained after the degradation treatment of the polymer hydrogel in Example 5 and Comparative Example 1 of the present invention for 10 days, 20 days and 30 days respectively;
  • Figure 5 shows the SEM test pictures of the polymers in Examples 3, 4, 5 and 6 of the present invention
  • Figure 6 shows the kinematic viscosity curve of the polymer hydrogel in Example 5 of the present invention
  • Figure 7 shows the strain scanning curve of the polymer hydrogel in Example 5 of the present invention.
  • Figure 8 shows the needle penetration investigation chart of the polymer hydrogel in Example 5 of the present invention under a pressure of 400 to 2000 Pa;
  • Figure 9 shows the subcutaneous muscle tissue section of mice 7 days after the hydrogels corresponding to different mass concentrations of the polymers in Examples 4, 5, 6 and 20 of the present invention were subcutaneously implanted into mice;
  • Figure 10 shows the subcutaneous muscle tissue section of mice 14 days after the hydrogels corresponding to different mass concentrations of the polymers in Examples 4, 5, 6 and 20 of the present invention were subcutaneously implanted into mice;
  • Figure 11 shows the anatomy of the subcutaneous muscles of mice 14 days after the hydrogels corresponding to different mass concentrations of the polymers in Examples 4, 5, 6 and 20 of the present invention were subcutaneously implanted into mice;
  • Figure 12 shows the rabbit eye irritation observation diagram of the polymer hydrogel in Example 4, Example 11, Example 12, Example 16 and Example 23 of the present invention
  • Figure 13 shows the local nuclear magnetic H spectrum test pattern of the polymer in Comparative Example 1 of the present invention
  • Figure 14 shows the local nuclear magnetic H spectrum test pattern of the polymer in Example 5 of the present invention.
  • Figure 15 shows the local nuclear magnetic H spectrum test pattern of the polymer in Comparative Example 1 of the present invention
  • Figure 16 shows the local nuclear magnetic H spectrum test chart of the polymer in Example 5 of the present invention.
  • polyurethane biomedical materials in the prior art have problems such as difficulty in degradation, poor biocompatibility, or high biotoxicity.
  • the present invention provides a polyurethane polymer, which is composed of prepolyethylene glycol, prepolypropylene glycol, prepolycaprolactone and an adhesive. Obtained by polymerization.
  • the binding agent has a structure shown in formula I or formula II, wherein R 1 is an amino acid and is removed The residue after the group, R 1 carries 0 to 5 -NH 2 , and each -NH 2 can be optionally replaced by -NCO; R 2 is a C1 to C30 linear or branched alkylene group, C6-C30 arylene group, C6-C30 heteroarylene group, and the above-mentioned groups optionally carry at least one substituent, and each substituent is independently selected from C1-C5 linear alkyl group, C3 to C6 cycloalkyl, carboxyl, cyano or amino groups, the carbon atoms in the above groups may be optionally substituted by -O-, -NH-, -COO- or -CO-.
  • R 3 is a C1-C6 linear or branched alkyl group, and the alkyl group carries a hydroxyl group.
  • the carbon atom or hydrogen atom in R 3 may be optionally substituted by -O-, -NH-, -COO- or -CO-.
  • the invention proposes a polyurethane polymer, which is obtained by polymerizing polyethylene glycol, polypropylene glycol, polycaprolactone and a cement as raw materials.
  • polypropylene glycol (PPG) and polycaprolactone (PCL) in the hydrophobic segment aggregate into "micelles", and polyethylene glycol (PEG) in the hydrophilic segment are connected to form "bridges" between micelles.
  • the bonding agent is bonded to the PPG segment, PEG segment or PCL through polyurethane bonds.
  • PEG segments and PPG segments form complex entanglements and cross-links with each other, which can increase the viscosity and elastic modulus of the polymer.
  • the PCL segment has good biocompatibility, which can promote the polymer to have good biocompatibility.
  • endogenous amino acids can be produced, which are not only non-toxic but can also provide amino acid supply to organisms.
  • the PCL segment has good biocompatibility, it will be degraded preferentially in the body, and then the polyurethane bonds of the binder segment will continue to degrade and break, resulting in a series of degradation products, such as Source substances amino acids, PEG monomers and PPG monomers, etc. These degradation products are small molecules that produce almost no toxicity and can even supplement essential amino acids for organisms. Therefore, the above-mentioned polymer of the present invention has better biocompatibility and lower biotoxicity.
  • the above-mentioned polymer of the present invention not only has better biocompatibility and lower toxicity, but also has excellent needle-passing properties, gelling temperature, elastic modulus at 37°C, and movement when it is subsequently prepared to form a hydrogel. Characteristics such as viscosity, density, surface tension, light transmittance, and refractive index are all more consistent with the glass body. Furthermore, when the hydrogel is used as a vitreous substitute, it is more replaceable and has better use effects.
  • R 1 has the structure shown in formula III;
  • n is any integer between 1 and 6, preferably 1 to 3;
  • R 4 is a C1 to C8 linear or branched alkyl group, a C2 to C8 alkenyl group, a C3 to C8 cycloalkenyl group, C3 ⁇ C8 heterocyclic alkenyl, and the above group optionally carries at least one substituent, each substituent is independently selected from C1 ⁇ C3 linear alkyl group, the carbon atom in R 4 can optionally Substituted by -O- or -NH-; R 4 carries 0 to 5 -NH 2 , and each -NH 2 can be optionally substituted by -NCO; preferably, C3 to C8 heterocyclic alkenyl contains at least one heteroatom, and the heteroatom is selected from N or O.
  • R1 is selected from the following structures:
  • R 2 is a C1 to C5 linear or branched alkylene group, a C6 to C12 arylene group, or a C6 to C12 heteroarylene group, and the above groups optionally carry at least one substituent.
  • each substituent is independently selected from C1 to C3 linear alkyl group, C3 to C4 cycloalkyl group, carboxyl group, cyano group or amino group.
  • R 1 is selected from the above categories. After the polymer is subsequently degraded in the organism, it will produce small molecule endogenous substances such as L-lysine, histidine or arginine. These amino acids are not only non-toxic but also relatively biocompatible. Good, and it is an essential substance for living organisms.
  • the binding agent is selected from compounds represented by the following structures:
  • the bonding agent is
  • the peak molecular weight of the polyurethane polymer is 35 to 60 kDa, for example, it can be 35 kDa, 40 kDa, 45 kDa, 50 kDa, 55 kDa or 60 kDa.
  • the present invention unexpectedly found that when the weight average molecular weight of the polyurethane polymer is within the above range, the product has better biocompatibility and lower irritation and toxicity.
  • the weight ratio of polyethylene glycol segment, polypropylene glycol segment and polycaprolactone segment in the polyurethane polymer is (4.20 ⁇ 4.80):1 : (0.04 ⁇ 0.10), for example, it can be 4.20:1:0.04, 4.30:1:0.05, 4.40:1:0.06 or 4.80:1:0.10.
  • the weight average molecular weight of polyethylene glycol, the weight average molecular weight of polypropylene glycol and the weight average molecular weight of polycaprolactone are each independently 1900-2100, for example, they can be 1900, 2000 or 2100. Based on this, raw materials are easier to Obtained, and the polymerization reaction process is more controllable, so that the polyurethane polymer polymer obtained by polymerization has better structural properties.
  • the invention also provides a method for preparing the aforementioned polyurethane polymer.
  • the preparation method includes: polymerizing prepolyethylene glycol, prepolypropylene glycol, prepolycaprolactone and a binding agent to obtain a polyurethane polymer.
  • High molecular polymer; the binding agent has a structure shown in formula I or formula II, wherein R 1 , R 2 , and R 3 have the same definitions as mentioned above.
  • the present invention proposes a polyurethane polymer, which is obtained by polymerizing polyethylene glycol, polypropylene glycol, polycaprolactone and a cement as raw materials.
  • a polyurethane polymer obtained by polymerizing polyethylene glycol, polypropylene glycol, polycaprolactone and a cement as raw materials.
  • the hydrophobic segments of polypropylene glycol (PPG) and polycaprolactone (PCL) aggregate into “micelles", and the hydrophilic segments of polyethylene glycol (PEG) are connected to form “bridges” between micelles.
  • the bonding agent is bonded to the PPG segment, PEG segment or PCL through polyurethane bonds.
  • the PEG segment and the PPG segment form complex entanglements and cross-links with each other, which can increase the viscosity and elastic modulus of the polymer.
  • the PCL segment has good biocompatibility, which can promote the polymer to have good biocompatibility.
  • endogenous amino acids can be produced, which are not only non-toxic but can also provide amino acid supply to organisms.
  • the PCL segment has good biocompatibility, it will be degraded preferentially in the body, and then the polyurethane bonds of the binder segment will continue to degrade and break, resulting in a series of degradation products, such as Source substances amino acids, PEG monomers and PPG monomers, etc. These degradation products are small molecules that produce almost no toxicity and can even supplement essential amino acids for organisms. Therefore, the above-mentioned polymer of the present invention has better biocompatibility and lower biotoxicity.
  • the above preparation process of the present invention does not require additional addition of ethanol to remove excess cement. Compared with the prior art, the process is simplified and the introduction of ethanol is effectively avoided. Moreover, the above preparation method has better reproducibility, better batch production effect, and is more conducive to industrial application.
  • the feeding weight ratio of prepolyethylene glycol, prepolypropylene glycol and prepolycaprolactone is (3.5 ⁇ 3.7):1:0.05.
  • the amount of binding agent is 9 to 13% of the total weight of prepolyethylene glycol, prepolypropylene glycol and prepolycaprolactone, for example, it can be 9%, 10%, 11%, 12% or 13%.
  • the present invention is based on the above-mentioned specific preparation method and only needs a lower PEG feeding ratio to obtain products with excellent performance and lower cost.
  • the forward progress of the polymerization reaction is better, and it can further effectively balance the rheological properties and biocompatibility of the product, and is non-toxic.
  • the polymer concentration in the hydrogel is even lower, only 5 to 7%. In this way, the hydrogel has better fluidity and is easier to pass through the needle, and the hydrogel has better light transmittance, gel strength, surface tension and refractive index.
  • the preparation method includes the following steps: step S1, dispersing prepolyethylene glycol, prepolypropylene glycol and prepolycaprolactone in a solvent to form a first dispersion; step S2, removing the first The water in the first dispersion forms a second dispersion system; in step S3, a binding agent and a catalyst are added to the second dispersion system to perform polymerization to obtain a polyurethane polymer.
  • step S1 dispersing prepolyethylene glycol, prepolypropylene glycol and prepolycaprolactone in a solvent to form a first dispersion
  • step S2 removing the first
  • the water in the first dispersion forms a second dispersion system
  • step S3 a binding agent and a catalyst are added to the second dispersion system to perform polymerization to obtain a polyurethane polymer.
  • the polymerization reaction has better stability, better forward progress, and a higher raw material conversion rate. , the product yield is higher and the polymerization reaction efficiency is better. Furthermore, the above-mentioned excellent properties of the polymer obtained therefrom are all One sex is better.
  • the above step S1 can be performed in an air-isolated environment.
  • the solvent in step S1 can be a conventional organic solvent in this field, preferably one or more of toluene, xylene, benzene or dioxane, and the amount of solvent is 25 to 50 mL.
  • the water in the first dispersion liquid can be removed by distillation under reduced pressure.
  • the preferred reaction time of the polymerization reaction is 0.4 to 4h, for example, it can be 0.4h, 1h, 1.5h, 2h, 2.5h, 3h or 4h; the reaction temperature is 110 to 140°C, for example, it can be 110°C, 120°C, 130°C or 140°C.
  • the catalyst is an organotin catalyst, and more preferably, the catalyst is stannous octoate.
  • stannous octoate as the catalyst in the above preparation method of the present invention can speed up the polymerization reaction efficiency and shorten the polymerization reaction time compared with dibutyltin dilaurate commonly used in the prior art. At the same time, it has better synergy with the binding agent of the specific structure of the present invention, which can further improve the reaction efficiency.
  • the amount of catalyst used is 5 to 7 ⁇ L per gram of prepolyethylene glycol.
  • the present invention unexpectedly found that the light transmittance of the product can be controlled by adding the catalyst, so that during the preparation process, the product performance is more controllable.
  • the preparation method includes the step of purifying the polymerized material.
  • the polymerized material is sequentially subjected to precipitation treatment, suction filtration and drying to obtain a polyurethane polymer.
  • the solvent for the precipitation treatment is one or more of diethyl ether, tert-butyl methyl ether or n-hexane.
  • the drying treatment time is 8 to 24 hours, for example, it can be 8 hours, 12 hours, 16 hours, 20 hours, or 24 hours; the treatment temperature is 20 to 30°C, for example, it can be 20°C, 25°C, or 30°C. Based on this, the excellent structural properties of the product can be more completely protected.
  • the invention also provides a polyurethane polymer hydrogel.
  • the polyurethane polymer hydrogel includes the aforementioned polyurethane polymer, or the polyurethane polymer prepared by the aforementioned preparation method. and swelling solvent.
  • the hydrogel of the present invention when used as a vitreous substitute, first of all, it has good biocompatibility and lower irritation and toxicity.
  • the above-mentioned polymer of the present invention also has good rheological properties, which can ensure that the substitute has a lower viscosity and exhibits shear thinning properties at room temperature, thereby making it possible to It has good fluidity when injected, and then has a certain elastic modulus (G') when injected into the human eye, which will provide the necessary conditions for its injection into the eye.
  • G' elastic modulus
  • the properties of the above-mentioned polymer will not change significantly after it is subjected to high external force and strain, thus ensuring its good needle-passing properties. Furthermore, it also has a certain elastic modulus under the physiological conditions of the human eye, which allows it to withstand rapid eye movements more effectively.
  • the vitreous substitute of the present invention has a high surface tension, and after entering the vitreous cavity, it can provide sufficient pressure on the retina to make it close to the wall of the eyeball.
  • the vitreous substitute of the present invention also has good light transmittance, a refractive index close to that of the human eye, and a slow swelling and dissolution rate. It is also proven to have very low organic solvent residues, low tissue toxicity, and no eye damage.
  • vitreous substitute of the present invention can more effectively overcome the problems of poor biocompatibility of existing commercial preparations, the need to be placed face down for a long time after use, the inability to fly or dive, and the short residence time.
  • the above-mentioned hydrogel of the present invention not only has better biocompatibility and lower toxicity, but also after subsequent swelling in the swelling solvent to form a hydrogel, its needle penetration, gelling temperature, elastic modulus at 37°C,
  • the kinematic viscosity, density, surface tension, light transmittance, refractive index and other characteristics are more suitable for the vitreous body (the gel temperature should be between 20 and 30°C, and the elastic modulus at 37°C should be between 100 and 300Pa.
  • the light transmittance should be above 85%), it is used as a vitreous substitute, it is more replaceable and has better use effect.
  • the swelling solvent can be selected from one or more of 0.005-0.05M phosphate buffer, artificial tears or water.
  • the polyurethane polymer hydrogel can be obtained by swelling the aforementioned polyurethane polymer in such a swelling solvent.
  • the mass concentration of the polyurethane polymer hydrogel can be 5 to 7%.
  • the hydrogel of the present invention has a lower gelling temperature at the same concentration.
  • its concentration is lower, and the lower polymer concentration results in a higher water content, which is closer to the natural vitreous body.
  • the vitreous body substitute obtained by the present invention has a slightly higher density than water and is close to the natural vitreous body, which solves the problem that some vitreous body substitutes already on the market have low density and require patients to keep their faces down after use. It takes a while for the retina to return to its normal position.
  • the vitreous substitute of the present invention has a high surface tension.
  • the present invention After entering the vitreous cavity, it can provide sufficient pressure on the retina to make it close to the wall of the eyeball.
  • the present invention also has good light transmittance and a refractive index close to that of the human eye. luminosity and slower swelling and dissolution rate.
  • the polyurethane polymer hydrogel has a pH value of 7.4 to 7.5 and a refractive index of 1.334 to 1.344, which is more suitable for the vitreous body. When used as a vitreous body substitute, it is more replaceable and has better use effects.
  • the invention also provides a kit, which contains the aforementioned polyurethane polymer hydrogel.
  • the kit of the present invention when used as the vitreous substitute, first of all, it has good biocompatibility and lower irritation and toxicity.
  • the above-mentioned polymer of the present invention also has good rheological properties, which can ensure that the substitute has a lower viscosity and exhibits shear thinning properties at room temperature, thereby making it possible to It has good fluidity when injected, and then has a certain elastic modulus (G') when injected into the human eye, which will provide the necessary conditions for its injection into the eye.
  • G' elastic modulus
  • the properties of the above-mentioned polymer will not change significantly after it is subjected to high external force and strain, thus ensuring its good needle-passing properties. Furthermore, it also has a certain elastic modulus under the physiological conditions of the human eye, which allows it to withstand rapid eye movements more effectively.
  • the vitreous substitute of the present invention has a high surface tension, and after entering the vitreous cavity, it can provide sufficient pressure on the retina to make it close to the wall of the eyeball.
  • the vitreous substitute of the present invention also has good light transmittance, a refractive index close to that of the human eye, and a slow swelling and dissolution rate. It is also proven to have very low organic solvent residues, low tissue toxicity, and no eye damage. Irritating.
  • the aforementioned polymer is added to the swelling solvent and placed at 2 to 5°C to fully swell for 20 to 30 hours to obtain a polyurethane polymer with a mass concentration in the range of 5 to 7%.
  • Hydrogels The hydrogel is then filled into a 5-10 mL pre-filled syringe or vial, and sterilized by autoclaving at a temperature of 100-130°C for 8-30 minutes to obtain the above-mentioned kit. Store at 2 to 5°C for subsequent use.
  • the invention also provides the aforementioned polyurethane polymer, or the polyurethane polymer prepared by the aforementioned preparation method, or the aforementioned polyurethane polymer hydrogel, or the aforementioned kit. Medical uses include use as a vitreous substitute.
  • the above-mentioned polymer of the present invention also has good rheological properties, which can ensure that the substitute has a lower viscosity and exhibits shear thinning properties at room temperature, thereby making it possible to It has good fluidity when injected, and then has a certain elastic modulus (G') when injected into the human eye, which will provide the necessary conditions for its injection into the eye.
  • G' elastic modulus
  • the vitreous substitute of the present invention has a certain elastic modulus under the physiological conditions of the human eye, which allows it to withstand rapid eye movements more effectively.
  • the vitreous substitute of the present invention has a high surface tension, and after entering the vitreous cavity, it can provide sufficient pressure on the retina to make it close to the wall of the eyeball.
  • the vitreous substitute of the present invention also has good light transmittance, a refractive index close to that of the human eye, and a slow swelling and dissolution rate. It is also proven to have very low organic solvent residues, low tissue toxicity, and no eye damage. Irritating. When using hydrogel as a vitreous substitute, its gel temperature should be between 20 and 30°C, its elastic modulus at 37°C should be between 100 and 300Pa, and its light transmittance should be above 85%.
  • PBS (0.01M) configuration Add 8gNacl, 0.2gKcl, 1.44gNa 2 HPO 4 , 0.24gKH 2 PO 4 to 800mL of purified water, adjust the pH of the solution to about 7.4, and add purified water to 1L after complete dissolution.
  • Preparation method of STF (artificial tears): Add 6.8gNacl, 1.4gKCl, 2.2gNaHCO 3 , 0.0635gCaCl 2 to 800mL of purified water, use HCl/NaOH to adjust the pH to about 7.4, and add purified water to 1L.
  • the above polymer was evenly sprinkled on the water surface of the above artificial tear solution isotonic PBS, and allowed to fully swell at 4°C for 24 hours to obtain a polymer hydrogel.
  • the hydrogel was filled into a 5 mL sealed vial, autoclaved at 121°C for 12 min, and stored at 4°C.
  • FIG. 1 shows the rheological properties of the polymer hydrogels of Examples 2 to 7.
  • G' is the elastic modulus
  • G" is the viscous modulus
  • the intersection of the elastic modulus and the viscous modulus represents gelation.
  • the appropriate amount of solvent is 30 to 35 mL. If the solvent amount is too small, the molecular weight of the product will be large, the gelling temperature will be too small, and the elastic modulus at 37°C will be too large. The amount of solvent is too much, the gelling temperature of the product is too high, and the elastic modulus at 37°C is too small.
  • PBS (0.01M) configuration Add 8gNacl, 0.2gKcl, 1.44gNa 2 HPO 4 , 0.24gKH 2 PO 4 to 800mL of purified water, adjust the pH of the solution to about 7.4, and add purified water to 1L after complete dissolution.
  • Preparation method of STF (artificial tears): Add 6.8gNacl, 1.4gKCl, 2.2gNaHCO 3 , 0.0635gCaCl 2 to 800mL of purified water, use HCl/NaOH to adjust the pH to about 7.4, and add purified water to 1L.
  • the above polymer (0.6g) was evenly sprinkled on the water surface (9.4g) of the above artificial tear isotonic PBS, and allowed to fully swell at 4°C for 24 hours to obtain a polymer hydrogel with a mass concentration of 6%.
  • the hydrogel was filled into a 5 mL sealed vial, autoclaved at 121°C for 12 min, and stored at 4°C.
  • Refractive index Under the conditions of measuring temperature of 35°C ⁇ 2°C and wavelength of 546 ⁇ 10nm, drop 0.5mL sample into the measuring cell of the refractometer to measure the refractive index of the sample.
  • the refractive index test results are shown in Table 7 below:
  • the added amount of each group of samples is 4 to 5g. Close to the actual weight of the vitreous body of the human eye, after gelation at 37°C, 2mL of artificial tears were added to each group at 20min, 40min, 60min, 80min, 4h, 12h, 1d, 2d, 3d, 5d, 7d, 10d, 14d, 21d, respectively.
  • the degradation amount of the sample was monitored for 28 days. During each monitoring period, the artificial tears in the EP tube were poured out, the artificial tears remaining on the inner and outer walls of the tube were wiped, the total weight of the sample and the EP tube was weighed, and the degradation amount of the sample was calculated.
  • the above-mentioned polymer of the present invention has good degradability and biocompatibility.
  • the degradation rate of hydrogel is almost proportional to the gelation temperature. The higher the gelation temperature, the faster the degradation rate.
  • the gelling temperature of hydrogel needs to be controlled within a certain range (20-30°C). Because the gelling temperature is too low, it is inconvenient for injection, and the G’ at 37°C will be too high. If the gelling temperature is too high, G’ after gelation will be too low and it will not be able to withstand high enough intraocular pressure. Therefore, the gelling temperature in the above range can not only give the polymer a certain expansion reaction force without being too high, but also prevent the polymer from degrading too quickly.
  • the degradation rate is also related to the molecular weight of the product and the ratio of PEG:PPG:PCL segments.
  • Vitreous filler degradation product cytotoxicity test investigated the cytotoxicity of the polymer hydrogel and its degradation products in Example 5 and Comparative Example 1.
  • Method To culture ARPE cells, use a 96-well plate. Each well contains approximately 8,000 cells. After the cells are cultured in the 96-well plate for 24 hours, they will degrade the hydrogel of Comparative Example 1 and Example 5 for 0, 10, 20, and 30 days respectively. The hydrogel was added at the concentrations of 10mg/mL, 5mg/mL, 1mg/mL, 0.5mg/mL and 0.1mg/mL. There were 5 groups for each concentration. After 24h of culture, CCK was used as the staining agent.
  • Figure 3 shows the infrared spectra of the degradation products of Example 5 of the present invention on 10 days, 20 days and 30 days.
  • the cell survival rates of polymer degradation products in Example 5 and Comparative Example 1 ( Figure 4) are shown in Table 9 below.
  • Example 5 group The degradation products of the Example 5 group can all make the cell survival rate close to 120%. In contrast, the value of the Comparative Example 1 group is difficult to reach 110%. This reflects that the Example 5 group of samples not only compares The samples in Ratio 1 group have better biocompatibility and can promote cell proliferation.
  • the toxicity of products synthesized by LDI as a binding agent is much less than that of HDI as a binding agent, and it is still not cytotoxic at high concentrations, but can promote cell proliferation at lower concentrations.
  • SEM scanning electron microscopy
  • Figure 6 shows the kinematic viscosity curve of the polymer hydrogel in Example 5 of the present invention, which reflects that the product has pseudoplastic fluid properties.
  • Figure 7 shows the strain scanning curve of the polymer hydrogel in Example 5 of the present invention, which reflects the stability of the product under high strain.
  • Figure 8 shows the investigation chart of the needle penetration of the polymer hydrogel in Example 5 of the present invention. After applying a pressure of 400 to 2000 Pa, the polymer hydrogel still maintains its original properties, indicating that it has good needle penetration. Targeted.
  • Figure 9 shows that the polymers in Example 4, Example 5, Example 6 and Example 20 of the present invention were prepared into hydrogels with mass concentrations of 3%, 7% and 9% respectively and were subcutaneously implanted into mice 7 Mouse subcutaneous muscle tissue section diagram after 2 days;
  • Figure 10 shows that the polymers in Example 4, Example 5, Example 6 and Example 20 of the present invention are prepared into water with mass concentrations of 3%, 7% and 9% respectively.
  • Figure 11 shows that the polymers in Example 4, Example 5, Example 6 and Example 20 of the present invention were prepared into hydrogels with mass concentrations of 3%, 7% and 9% respectively and were subcutaneously implanted into mice 14 Diagram of mouse subcutaneous muscle anatomy. It can be seen from this that the irritation of hydrogels with different molecular weights was investigated after subcutaneous implantation on the back of mice. Tissue sections and naked eye observations showed that hydrogels with a molecular weight greater than 60,000 showed slight irritation, and hydrogels with a molecular weight of 35,000-60,000 Non-irritating in scope.
  • Figure 12 shows the rabbit eye irritation observation diagram of the polymer hydrogel in Example 4, Example 11, Example 12, Example 16 and Example 23 of the present invention. The rabbit eye irritation test shows that molecular weights in the range of 35,000-60,000 are non-irritating, and molecular weights greater than 60,000 are irritating.
  • Figure 13 shows the local nuclear magnetic H spectrum of the polymer synthesized using HDI as the binding agent in Comparative Example 1.
  • Figure 14 shows the local nuclear magnetic H spectrum of the polymer synthesized using LDI as the binding agent in Example 5.
  • Figure 15 shows Figure 16 shows the local nuclear magnetic H spectrum of the polymer synthesized by using HDI as the binding agent in Comparative Example 1, and
  • Figure 16 shows the local nuclear magnetic H spectrum of the polymer synthesized by using LDI as the binding agent in Example 5.
  • the difference between the peak area ratios of chemical shifts of 3.15 and 1.14 is about two times. This is because when HDI is used as a binding agent, its symmetrical structure causes the polymer monomer to obtain two symmetrical aminomethyl groups.
  • the hydrogens on their adjacent ⁇ -displaced methylene groups have the same chemical shift (3.15), while the LDI structure is different. Only one carbamate is connected to the same ⁇ -displaced methylene group as the LDI structure ( 3.15), therefore, the ratio of the alpha-displaced methylene group adjacent to the urethane to the characteristic peak of polypropylene glycol (1.14) in Figure 14 is almost half that of Figure 13 (the amount of polyethylene glycol is the same in the two figures, but the cement Different, the reaction process is also different.
  • the real ratio of the two peak areas in Figure 14 can only be close to half of that in Figure 13.
  • the peak with a chemical shift of 4.31 is the ⁇ adjacent to -OCOR in L-lysine.
  • Methylene is a characteristic peak of L-lysine. There is no peak at this position in Figure 15.

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Abstract

La présente invention concerne un polymère de polyuréthane à poids moléculaire élevé et son procédé de préparation, un hydrogel de polymère de polyuréthane à poids moléculaire élevé, un kit, et son utilisation. Le polymère de polyuréthane à poids moléculaire élevé est obtenu par polymérisation de polyéthylène glycol prépolymérisé, de polypropylène glycol prépolymérisé, de polycaprolactone prépolymérisée et d'un agent de conjugaison, l'agent de conjugaison ayant une structure telle que représentée dans la formule (I). Dans la présente invention, le polymère présente une meilleure biocompatibilité et une toxicité inférieure ; et lorsque le polymère est ensuite préparé en un hydrogel destiné à être utilisé, les caractéristiques de seringabilité, de température de gélification, du module d'élasticité à 37 °C, de viscosité cinématique, de densité, de tension de surface, de transmittance de lumière, de dioptrie, etc., de l'hydrogel sont toutes plus proches de celles d'un corps vitreux. Par conséquent, lorsqu'il est utilisé en tant que substitut vitreux, l'hydrogel a une performance de substitution plus élevée et de meilleurs effets d'utilisation.
PCT/CN2023/093621 2022-05-17 2023-05-11 Polymère de polyuréthane à poids moléculaire élevé et son procédé de préparation, hydrogel de polymère de polyuréthane à poids moléculaire élevé, kit, et utilisation associée Ceased WO2023221870A1 (fr)

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