Biodegradable hydrogel generation system

Abstract

The present invention relates to a system for generating a degradable hydrogel, a method for generating a degradable hydrogel, and a kit for generating a degradable hydrogel.

Description

[Technical Field]

[0001] The present invention relates to a system for generating a degradable hydrogel, a method for generating a degradable hydrogel, and a kit for generating a degradable hydrogel. [Background technology]

[0002] Prostate cancer is the most common cancer in men. Radiation therapy for prostate cancer aims to destroy malignant cancer cells. In this process, damage to healthy cells is unavoidable. Careful planning of radiation therapy can minimize damage. However, because the wall of the hindgut (rectum) is only a few millimeters away from the prostate, inflammatory disease (proctitis) frequently occurs here (about 36%), accompanied by diarrhea, painful hemorrhoids or bleeding (about 12%), and relatively rarely (1-3%) chronic bleeding, adhesions, or necrosis.

[0003] By using a temporary "spacer," the above side effects can be minimized while simultaneously reducing the number of radiation treatments. This spacer is placed between the prostate and rectum to increase the space between the two organs. This minimizes the radiation dose to the adjacent rectum, dramatically reducing the potential damage. At the same time, it may be possible to apply a higher radiation dose and significantly reduce the number of treatments, thereby improving the patient's quality of life. The spacer breaks down and is excreted from the body within a few months. This means that no further surgery is needed to remove the spacer.

[0004] A hydrogel is a network structure made of polymers with entropic elasticity, and depending on its crosslink density and chemical composition, it can absorb a large amount of water. Hydrogels are used in clinical fields such as contact lenses and bandages, as well as drug delivery systems. In special cases, hydrogels can be injected as liquids and crosslinked in situ, and their shape adapts to the local structure of the injection site. For example, hydrogels crosslinked in vivo have already been widely used as spacers, tissue adhesives, tissue markers, and hemostatic agents.

[0005] Patent Document 1 describes a biodegradable hydrogel implant containing a covalently bonded radiopaque substance, which is produced by the crosslinking reaction of a first precursor and a second precursor.

[0006] The patent application of Patent Document 2 describes a composition for producing a biodegradable polymer and the use of such a polymer for providing a solid biodegradable implant that is injectable and can be formed in situ.

[0007] Patent Document 3 describes biocompatible crosslinked polymers and methods and uses for their production. This biocompatible crosslinked polymer is formed from water-soluble precursors having electrophilic functional groups and nucleophilic functional groups that can react and crosslink in situ.

[0008] Patent Document 4 generally relates to biocompatible crosslinked polymers and methods and uses for their production.

[0009] Patent Document 5 relates to surgical treatments using hydrogels, particularly bioabsorbable covalently crosslinked hydrogels.

[0010] Patent Document 6 relates to a biocompatible covalently crosslinked polymer obtained by the reaction of a nucleophilic-activated polyoxazoline (NU-POX) with an electrophilic-activated crosslinking agent.

[0011] Patent document 7 describes the use of biomaterials as three-dimensional frames or matrices for wound treatment and tissue regeneration.

[0012] Patent document 8 relates to a PEG-based absorbent hydrogel useful for delayed release of proteins.

[0013] Patent document 9 provides a method for reducing the toxicity to adjacent organs of advanced resective cancer treatment. This method involves creating a space between individual or multiple tumor lesions and adjacent healthy organs. To create this space, a hyaluronic acid spacer based on a viscoelastic medium is used, which is viscous and injected at a concentration of 5-100 mg / mL.

[0014] Commercially available spacers are offered on the market. Three-component polyethylene glycol spacers (SpaceOAR® and SpaceOAR VUE® from Boston Scientific, USA) are available. In addition, hyaluronic acid spacers (Barrigel® from Palette Life Sciences, Inc., USA) are also available on the market.

[0015] In most clinical hydrogel systems, including the polyethylene glycol-based spacers SpaceOAR® and SpaceOAR VUE®, crosslinking between amino groups and N-hydroxysuccinimide esters (NHS esters) is carried out by substitution reactions. The main drawback here is, firstly, that the NHS ester groups are not stable in water over long periods.

[0016] Therefore, in the case of currently available spacers (SpaceOAR® and SpaceOAR VUE), the polymer must be stored as a powder. From this, it can be seen that the system needs to consist of a total of three components: the polymer as a powder (containing NHS ester groups), a liquid for dissolving the polymer, and another solution containing a crosslinking agent. As a result, the preparation of the original injection becomes more complex, as an additional polymer powder dissolution step is required.

[0017] A further drawback is that the low stability of the NHS ester group manifests as the polymer being stable for only a limited time after dissolution in the diluent. This reduces the therapeutic time frame before the precursor becomes unusable to a maximum of 30 minutes. Hydrogel formation occurs within a few seconds after complete mixing of the components. This extremely short time frame leaves little room to adequately address complications during injection. Precise positioning of the spacer by the treating physician is also difficult to achieve within this short time, placing a high demand on the physician's skill.

[0018] The aforementioned hyaluronic acid spacer (Barrigel®, manufactured by Palette Life Sciences, Inc., USA) is based on a viscoelastic medium that is injected at concentrations of 5–100 mg / mL. In the case of Barrigel®, hyaluronic acid (HA) is injected at a concentration of 20 mg / mL in phosphate-buffered saline. This HA gel is produced in advance in a separate synthesis process. Therefore, a pre-made viscoelastic medium is injected here, which can be administered using a large cannula. This gel is insoluble in water and organic solvents. A drawback is that a single disposable syringe can only hold 3 mL of Barrigel. Therefore, multiple syringes must be injected successively to create sufficient space. This may lead to a higher risk of undesirable perforation or bleeding of surrounding tissue.

[0019] Therefore, the object of the present invention is to overcome the shortcomings of the above system. One object of the present invention is to provide a composition, such as one for medical products, that can be used as is without the need for additional dissolution of polymer powder. Furthermore, a ready-to-use pharmaceutical product needs to be stable and able to be stored for a long period of time. Another object of the present invention is to enable the easy and single injection of a sufficient amount of the composition. At the same time, the spacer needs to have sufficient gelation rate, degradation rate, and rigidity. There is also potential to easily adapt this system to other treatments, such as breast cancer and cervical cancer. Furthermore, it may be advantageous to enable visualization of the spacer throughout the entire treatment period.

[0020] These problems can be solved by the following claims. [Prior art documents] [Patent Documents]

[0021] [Patent Document 1] U.S. Patent Application Publication No. 2011 / 0142936 [Patent Document 2] European Patent Application Publication No. 0436667 [Patent Document 3] U.S. Patent Application Publication No. 2008 / 0260802 [Patent Document 4] International Publication No. 00 / 33764 [Patent Document 5] European Patent Application Publication No. 2233160 [Patent Document 6] International Publication No. 2013 / 137736 [Patent Document 7] European Patent Application Publication No. 1446453 [Patent Document 8] U.S. Patent Application Publication No. 2012 / 0027775 [Patent Document 9] International Publication No. 2020 / 227107 [Overview of the project] [Means for solving the problem]

[0022] (Summary of the invention) The following description summarizes several aspects of the present invention.

[0023] A first aspect of the present invention relates to a system for producing a biodegradable hydrogel and includes: (a) a first composition; which is aqueous and contains a first precursor (ai) and a buffer system (a-ii), wherein the first precursor (ai) contains functional groups; and (b) a second composition; which is anhydrous and contains a second precursor (bi), wherein the second precursor (bi) is liquid and contains functional groups and at least one hydrolyzable bond; the functional groups of the first precursor (ai) react with the functional groups of the second precursor (bi); and the first precursor contains at least two functional groups and the second precursor contains at least three functional groups, or the first precursor contains at least three functional groups and the second precursor contains at least two functional groups.

[0024] A second aspect of the present invention relates to a system according to the first aspect, wherein the first precursor (ai) and the second precursor (bi) each contain at least three functional groups.

[0025] A third aspect of the present invention relates to a system according to the first or second aspect, wherein the reaction of the functional group of the first precursor (ai) with the functional group of the second precursor (bi) is a Michael-type reaction.

[0026] A fourth aspect of the present invention is that the functional group of the first precursor (ai) contains a conjugated unsaturated functional group selected from the group consisting of vinyl sulfone, (meth)acrylamide, maleimide, quinone, vinylpyridinium and combinations thereof, preferably vinyl sulfone, maleimide and combinations thereof, and the functional group of the second precursor (bi) contains a nucleophile selected from the group consisting of amine, thiol and combinations thereof, more preferably thiol; or The system relates to any one of the above embodiments, wherein the functional group of the first precursor (ai) contains a nucleophile selected from the group consisting of amines, thiols, and combinations thereof, preferably thiols, and the functional group of the second precursor (bi) contains a conjugated unsaturated functional group selected from the group consisting of (meth)acrylate, vinyl sulfone, vinyl sulfonate, (meth)acrylamide, maleimide, quinone, vinylpyridinium, and combinations thereof, preferably (meth)acrylate, vinyl sulfone, vinyl sulfonate, maleimide, and combinations thereof.

[0027] A fifth aspect of the present invention is that the functional group of the first precursor (ai) contains a conjugated unsaturated functional group selected from the group containing vinyl sulfone, and the functional group of the second precursor (bi) contains a nucleophile selected from the group containing thiol; or The present invention relates to a system according to any one of the above embodiments, wherein the functional group of the first precursor (ai) contains a nucleophile selected from the group containing thiols, and the functional group of the second precursor (bi) contains a conjugated unsaturated functional group selected from the group containing vinyl sulfones.

[0028] A sixth aspect of the present invention relates to a system according to any one of the above aspects, wherein the functional group of the first precursor (ai) is located at the end of the first precursor (ai).

[0029] A seventh aspect of the present invention relates to a system according to any one of the above aspects, wherein the functional group of the second precursor (bi) is located at the end of the second precursor (bi).

[0030] An eighth aspect of the present invention relates to a system according to any one of the above aspects, wherein the first precursor (ai) contains a polyether, polyacrylic acid, poly(ethylene-co-acrylic acid), polyvinyl acetate, polyvinyl alcohol, poly(ethylene-co-vinyl alcohol), polyvinyl acetal, polyvinyl ether, poly(oxazoline), polyvinylpyrrolidone, polyvinylamine, polyvinyl methyl ether, poly(meth)acrylate, polyacrylamide, poly(N-isopropylacrylamide), poly(N-ethylacrylamide), polyoxymethylene, polycarbonate, or copolymers thereof, preferably a polyether, polyacrylamide, poly(N-isopropylacrylamide), poly(N-ethylacrylamide), or copolymers thereof, more preferably a polyether.

[0031] A ninth aspect of the present invention relates to a system according to any one of the above aspects, wherein the first precursor (ai) contains a polyether, preferably polyethylene oxide, polyglycidol, poly(ethylene oxide-co-propylene oxide), and more preferably poly(ethylene oxide-co-propylene oxide).

[0032] A tenth aspect of the present invention relates to a system according to any one of the above aspects, wherein the first precursor (ai) contains random poly(ethylene oxide-co-propylene oxide).

[0033] An eleventh aspect of the present invention relates to a system according to any one of the above aspects, wherein the first precursor (ai) contains a linear, branched, dendrimeric, cyclic, or star-shaped polymer, preferably a dendrimeric or star-shaped polymer.

[0034] A twelfth aspect of the present invention relates to a system according to any one of the above aspects, wherein the first precursor (ai) contains a star-shaped polymer.

[0035] A thirteenth aspect of the present invention relates to a system according to the eleventh or twelfth aspect, wherein the star-shaped polymer has 3 to 12 arm portions, preferably 3 to 8 arm portions.

[0036] A fourteenth aspect of the present invention relates to a system according to any one of the above aspects, wherein the hydrolyzable bond of the second precursor (bi) includes an ester bond.

[0037] A fifteenth aspect of the present invention relates to a system according to any one of the above aspects, wherein the second precursor (bi) contains a polyether, preferably polyethylene oxide, polyglycidol, poly(ethylene oxide-co-propylene oxide), and more preferably poly(ethylene oxide-co-propylene oxide).

[0038] A sixteenth aspect of the present invention relates to a system according to any one of the above aspects, wherein the second precursor (bi) contains random poly(ethylene oxide-co-propylene oxide).

[0039] A seventeenth aspect of the present invention relates to a system according to any one of the above aspects, wherein the poly(ethylene oxide-co-propylene oxide) contains 50 to 90% by weight of ethylene oxide units and 10 to 50% by weight of propylene oxide units, more preferably 60 to 90% by weight of ethylene oxide units and 10 to 40% by weight of propylene oxide units, and even more preferably 70 to 90% by weight of ethylene oxide units and 10 to 30% by weight of propylene oxide units, the weight percentages being based on the total weight of the ethylene oxide units and propylene oxide units of the poly(ethylene oxide-co-propylene oxide).

[0040] An eighteenth aspect of the present invention relates to a system according to any one of the above aspects, wherein the second precursor (bi) contains a linear, branched, dendrimeric, cyclic, or star-shaped polymer, preferably a dendrimeric or star-shaped polymer.

[0041] A 19th aspect of the present invention relates to a system according to any one of the above aspects, wherein the second precursor (bi) contains a star-shaped polymer.

[0042] A 20th aspect of the present invention relates to a system according to the 18th or 19th aspect, wherein the star-shaped polymer has 3 to 12 arm portions, preferably 3 to 8 arm portions.

[0043] A 21st aspect of the present invention is the weight-average molecular weight (M) of the first precursor (ai). w This relates to a system according to any one of the above embodiments, where the frequency range is 100 Da to 40 kDa.

[0044] A 22nd aspect of the present invention is the weight-average molecular weight (M) of the first precursor (ai). w This relates to a system according to any one of the above embodiments, where the frequency range is 2.5kDa to 20kDa.

[0045] A 23rd aspect of the present invention is the weight-average molecular weight (M) of the second precursor (bi). w This relates to a system according to any one of the above embodiments, where the frequency range is 100 Da to 40 kDa.

[0046] A 24th aspect of the present invention is the weight-average molecular weight (M) of the second precursor (bi). w This relates to a system according to any one of the above embodiments, where the frequency range is 2.5kDa to 20kDa.

[0047] A 25th aspect of the present invention relates to a system according to any one of the above aspects, wherein the viscosity of the second precursor is up to 4,500 mPa·s at room temperature.

[0048] A 26th aspect of the present invention relates to a system according to any one of the above aspects, wherein the viscosity of the second precursor is 5 to 4,000 mPa·s at room temperature.

[0049] A 27th aspect of the present invention relates to a system according to any one of the above aspects, wherein the pH value of the first composition (a) is 7 to 10, more preferably 7.4 to 10, and even more preferably 7.4 to 9.

[0050] A 28th aspect of the present invention relates to a system according to any one of the above aspects, wherein the system is injectable.

[0051] A 29th aspect of the present invention relates to a system according to any one of the above aspects, wherein the first and / or second composition contains one or more visualization additives.

[0052] A 30th aspect of the present invention relates to a system according to any one of the above aspects, wherein the visualization additive comprises iohexol, metrizamide, iopamidol, triiodobenzoate, 2,3,5-triiodobenzoic acid, 2,3,5-triiodobenzoyl chloride, 3,4,5-triiodophenol, erythrosine, rose bengal, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, 3,5-diacetamido-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, ioversol, gadolinium, gadopentetate-modified zirconium particles, calcium hydroxyapatite, superparamagnetic iron oxide, the above residues, or a combination thereof.

[0053] A 31st aspect of the present invention relates to a system according to any one of the above aspects, wherein the second composition (b) contains a third precursor (b-ii), the third precursor (b-ii) is in liquid form and contains one functional group and at least one iodine-containing group, and the functional group of the third precursor (b-ii) reacts with the functional group of the first precursor (ai).

[0054] A 32nd aspect of the present invention relates to a method for producing a biodegradable hydrogel and comprises the following steps: (i) providing a system according to the first aspect; and (ii) mixing the first composition and the second composition.

[0055] A 33rd aspect of the present invention relates to a method according to the 32nd aspect, wherein the system of (i) is according to any one of the 2nd to 31st aspects.

[0056] A 34th aspect of the present invention relates to a kit for producing a biodegradable hydrogel, comprising (i) a system according to the first aspect; and (ii) a syringe.

[0057] A 35th aspect of the present invention relates to a kit according to the 34th aspect, wherein the syringe is a double syringe.

[0058] A 36th aspect of the present invention relates to a kit according to the 34th or 35th aspect, wherein the system of (i) is according to any one of the 2nd to 31st aspects. [Modes for carrying out the invention]

[0059] (Detailed description of the invention) The present invention relates to a system for producing a biodegradable hydrogel. The system comprises a first composition (a) and a second composition (b). The first composition (a) is aqueous and contains a first precursor (ai) and a buffer system (a-ii). The first precursor (ai) contains functional groups. The second composition (b) is anhydrous and contains a second precursor (bi). The second precursor (bi) is in liquid form. The second precursor (bi) contains functional groups and at least one hydrolyzable bond. The functional groups of the first precursor (ai) react with the functional groups of the second precursor (bi). The first precursor (ai) contains at least two functional groups, and the second precursor (bi) contains at least three functional groups. Alternatively, the first precursor (ai) contains at least three functional groups, and the second precursor (bi) contains at least two functional groups. The term "hydrogel" refers to a three-dimensional polymer network structure that can absorb large amounts of water. The term "degradability" refers to hydrogels that degrade through biologically supported mechanisms in a biological environment, such as enzyme-catalyzed reactions, or through chemical mechanisms that can occur in biomediums, such as hydrolysis. Degradation by hydrolysis usually occurs under physiological conditions (pH 7.4 and temperature 37°C).

[0060] Preferably, the first precursor (ai) and the second precursor (bi) each have at least three functional groups, and the functional groups of the first precursor (ai) react with the functional groups of the second precursor (bi). Reacting groups, in the sense of the present invention, are groups that are crosslinkable during the reaction and capable of forming covalent bonds. Preferably, the first precursor (ai) does not contain two different functional groups that react with each other. Preferably, the first precursor (ai) is not self-crosslinkable. Preferably, the second precursor (bi) does not contain two different functional groups that react with each other. Preferably, the second precursor (bi) is not self-crosslinkable.

[0061] The functional group of the first precursor (ai) can undergo addition or substitution reactions, including Michael-type reactions, with the functional group of the second precursor (bi). The functional group of the first precursor (ai) may be an electrophile and the functional group of the second precursor (bi) may be a nucleophile, or the functional group of the first precursor (ai) may be a nucleophile and the functional group of the second precursor (bi) may be an electrophile. The electrophile may be a conjugated unsaturated functional group selected from the group consisting of (meth)acrylates, vinyl sulfones, vinyl sulfonates, (meth)acrylamides, maleimides, quinones, vinylpyridiniums, oxiranes, oxazolines, aldehydes, carboxylic acids, carboxylic acid esters, carboxylic anhydrides, carboxylic acid halides, sulfonic acid halides, and combinations thereof. As an example of a carboxylic acid ester group, the so-called active ester group of formula -C(O)OX is particularly preferred, where X represents pentafluorophenyl, pyrrolidine-2,5-dione-1-yl, benzo-1,2,3-triazole-1-yl, or carboxamidine residue and N-hydroxysuccinimide ester (NHS ester). The nucleophile can be selected from the group including amines, thiols, and combinations thereof.

[0062] Preferably, the reaction between the functional group of the first precursor (ai) and the functional group of the second precursor (bi) is a Michael-type reaction. The term “Michael-type reaction” refers to the 1,4-addition reaction of a nucleophile to a conjugated unsaturated system. This addition mechanism may be exclusively polar or may proceed via a radical-like intermediate state; a Lewis acid or a well-designed hydrogen bond may act as a catalyst. Michael-type reactions are described in detail in US Pat. No. 6,958,212, particularly in column 29, line 36 to column 35, line 20.

[0063] The functional groups of the first precursor (ai) may contain conjugated unsaturated functional groups selected from the group consisting of vinyl sulfone, (meth)acrylamide, maleimide, quinone, vinylpyridinium, and combinations thereof, preferably vinyl sulfone, maleimide, and combinations thereof, and the functional groups of the second precursor (bi) may contain nucleophiles selected from the group consisting of amine, thiol, and combinations thereof, more preferably thiol. Alternatively, the functional groups of the first precursor (ai) may contain nucleophiles selected from the group consisting of amine, thiol, and combinations thereof, preferably thiol, and the functional groups of the second precursor (bi) may contain conjugated unsaturated functional groups selected from the group consisting of (meth)acrylate, vinyl sulfone, vinyl sulfonate, (meth)acrylamide, maleimide, quinone, vinylpyridinium, and combinations thereof, preferably (meth)acrylate, vinyl sulfone, vinyl sulfonate, maleimide, and combinations thereof.

[0064] Preferably, the functional group of the first precursor (ai) contains a conjugated unsaturated functional group selected from the group consisting of vinyl sulfones, and the functional group of the second precursor (bi) contains a nucleophile selected from the group consisting of thiols. Alternatively, the functional group of the first precursor (ai) may contain a nucleophile selected from the group consisting of thiols, and the functional group of the second precursor (bi) may contain a conjugated unsaturated functional group selected from the group consisting of vinyl sulfones. This combination of functional groups results in a faster reaction / gelation time and a good stiffness value for the resulting hydrogel. Furthermore, it does not release leaving groups compared to active ester groups such as N-hydroxysuccinimide esters (NHS esters).

[0065] The functional group of the first precursor (ai) may be located at the terminal end of the first precursor (ai). The functional group of the second precursor (bi) may be located at the terminal end of the second precursor (bi).

[0066] The reaction of the functional groups of the first precursor (ai) with the functional groups of the second precursor (bi) leads to the gelation of the system, and thus to the formation of a hydrogel. The reaction between the functional groups of the first precursor (ai) and the functional groups of the second precursor (bi) may be carried out at room temperature (23°C) and atmospheric pressure (101.3 kPa). The reaction between the functional groups of the first precursor (ai) and the functional groups of the second precursor (bi) may be carried out at a pH of 7 to 10. Preferably, the reaction between the functional groups of the first precursor (ai) and the functional groups of the second precursor (bi) is carried out in an aqueous composition in the presence of a buffer system.

[0067] This crosslinking reaction preferably does not release reaction heat and does not require an exogenous energy source to initiate or induce the reaction. The gelation time, i.e., the time required to form the hydrogel, may be 7 to 25 seconds, preferably 7 to 23 seconds, and more preferably 7 to 20 seconds.

[0068] According to the present invention, the first composition (a) is aqueous. The term "aqueous" means a composition that is liquid at room temperature (23°C) and atmospheric pressure (101.3 kPa) and contains water as the main component of the liquid carrier and less than 50% by weight of an organic solvent, for example less than 40% by weight, for example less than 30% by weight, for example less than 20% by weight, for example less than 10% by weight, for example less than 5% by weight, for example less than 2% by weight, for example less than 1% by weight, or for example less than 0.5% by weight of an organic solvent, based on the total weight of the liquid carrier, i.e., the total weight of a combination of water and one or more organic solvents (if any). The first composition (a) may be substantially free of organic solvents, i.e., the first composition may contain less than 0.5% by weight of an organic solvent, for example less than 0.2% by weight, or for example less than 0.1% by weight of an organic solvent, based on the total weight of the liquid carrier. The first composition (a) may contain no organic solvent at all; that is, the first composition (a) may contain 0% by weight of an organic solvent relative to the total weight of the liquid carrier.

[0069] A suitable organic solvent must be miscible with water and biocompatible. The term “miscible” should be interpreted as meaning that the solubility of the organic solvent can range from completely miscible to soluble in water and then to dispersible in water. Examples of suitable organic solvents can be selected from the group including N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethyl sulfoxide, oleic acid, and 1-dodecyl azacycloheptan-2-one, as well as combinations and mixtures thereof.

[0070] According to the present invention, the first composition (a) contains a buffer system (a-ii). The term "buffer system" or simply "buffer" refers to an acidic or basic aqueous solution comprising a mixture of a weak acid and its conjugate base or its corresponding base (or a salt thereof), or a mixture of a weak base and its conjugate acid or its corresponding acid (or a salt thereof). Preferably, the first composition (a) contains an alkaline buffer system (a-ii). The buffer system of the present invention may contain a phosphate buffer, a triethanolamine buffer, a borate buffer, a sodium bicarbonate buffer, a HEPES buffer, a HEPPS buffer, a glycine buffer, a glycine / NaOH buffer, a TRIS buffer, or a TRIS / glycine buffer.

[0071] The pH value of the first composition (a) may be at least 7, preferably at least 7.2, and more preferably at least 7.4. The pH value of the first composition (a) may be 10 or less, preferably 9.5 or less, and more preferably 9 or less. The pH value of the first composition (a) may be between 7 and 10, preferably 7.2 and 10, more preferably 7.4 and 10, and even more preferably 7.4 and 9.

[0072] According to the present invention, the second composition (b) is anhydrous. The term “anhydrous” refers to a composition in which no water has been added, or if any, only a trace amount of water, such as less than 0.05% by weight, preferably less than 0.01% by weight, where this weight percentage is relative to the total weight of the composition. Preferably, the second composition (b) contains 0% by weight of water, where this weight percentage is based on the total weight of the composition.

[0073] The second composition (b) may contain an organic solvent. The second composition (b) may contain up to 10% by weight, for example, up to 5% by weight, or up to 2% by weight, or up to 1% by weight of the total weight of the second composition (b). The second composition (b) may be substantially free of organic solvents, that is, the second composition (b) may contain less than 0.5% by weight of organic solvents, for example, less than 0.2% by weight, or for example, less than 0.1% by weight of organic solvents, based on the total weight of the second composition (b). The second composition (b) may be completely free of organic solvents, that is, the second composition may contain 0% by weight of organic solvents based on the total weight of the second composition. Suitable examples of organic solvents are the same as those described above for the first composition (a).

[0074] According to the present invention, the first precursor (ai) is preferably water-soluble. The term "water-soluble" refers to a substance whose solubility in water is preferably at least 1% by weight, and more preferably at least 5% by weight, at room temperature (23°C) and atmospheric pressure (101.3 kPa), where this weight percentage is based on the weight of water.

[0075] The first precursor may be a polyether, polyacrylic acid, poly(ethylene-co-acrylic acid), polyvinyl acetate, polyvinyl alcohol, poly(ethylene-co-vinyl alcohol), polyvinyl acetal, polyvinyl ether, poly(oxazoline), polyvinylpyrrolidone, polyvinylamine, polyvinyl methyl ether, poly(meth)acrylate, polyacrylamide, poly(N-isopropylacrylamide), poly(N-ethylacrylamide), polyoxymethylene, polycarbonate, or copolymers thereof. Preferably, the first precursor (ai) may contain a polyether, polyacrylamide, poly(N-isopropylacrylamide), poly(N-ethylacrylamide), or copolymers thereof.

[0076] In particular, the first precursor (ai) may contain a polyether. Suitable examples of polyethers include polyethylene oxide, polypropylene oxide, polyglycidol and copolymers thereof, preferably polyethylene oxide, polyglycidol and poly(ethylene oxide-co-propylene oxide), and more preferably poly(ethylene oxide-co-propylene oxide). Polyethers can be produced by oxyalkylation of polyols with alkylene oxides, e.g., ethylene oxide, propylene oxide and combinations thereof, in the presence of an acidic or basic catalyst. Suitable polyols include, in particular, bisphenol A, trimethylolpropane, pentaerythritol, glycerin, sugar alcohols, e.g., erythritol, xylitol, mannitol, sorbitol, maltitol, isomaltulose, isomaltite and trehalose, alkylene glycols, e.g., ethylene glycol, propylene glycol, butylene glycol and 1,6-hexylene glycol and combinations thereof.

[0077] The first precursor (ai) may contain polyethylene oxide, polyglycidol, and poly(ethylene oxide-co-propylene oxide), preferably poly(ethylene oxide-co-propylene oxide). Suitable examples of poly(ethylene oxide-co-propylene oxide) may include random poly(ethylene oxide-co-propylene oxide) or poly(ethylene oxide-block-propylene oxide). Preferably, the first precursor (ai) contains random poly(ethylene oxide-co-propylene oxide). Statistical poly(ethylene oxide-co-propylene oxide) can be produced by alkoxylation of a polyol with a monomer mixture containing ethylene oxide and propylene oxide in the presence of a base, for example, potassium hydroxide or sodium hydroxide.

[0078] The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the first precursor (ai), preferably contains 50% by weight or less of propylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the first precursor (ai), preferably contains a maximum of 50% by weight, preferably a maximum of 40% by weight, and more preferably a maximum of 30% by weight of propylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the first precursor (ai), preferably contains a minimum of 10% by weight of propylene oxide units. The first precursor (ai) may contain poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which contains 10-50% by weight, preferably 10-40% by weight, and more preferably 10-30% by weight of propylene oxide units. This weight percentage is based on the total weight of the ethylene oxide and propylene oxide units in the poly(ethylene oxide-co-propylene oxide).

[0079] The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the first precursor (ai), contains a minimum of 50% by weight, preferably a minimum of 60% by weight, and more preferably a minimum of 70% by weight, of ethylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the first precursor (ai), contains a maximum of 90% by weight, of ethylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the first precursor (ai), contains a minimum of 50-90% by weight, preferably a minimum of 60-90% by weight, and more preferably a minimum of 70-90% by weight, of ethylene oxide units. This weight percentage is based on the total weight of the ethylene oxide and propylene oxide units in the poly(ethylene oxide-co-propylene oxide).

[0080] The first precursor (ai) may contain poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which contains 50-90% by weight of ethylene oxide units and 10-50% by weight of propylene oxide units, preferably 60-90% by weight of ethylene oxide units and 10-40% by weight of propylene oxide units, and more preferably 70-90% by weight of ethylene oxide units and 10-30% by weight of propylene oxide units. These weight percentages are based on the total weight of the ethylene oxide and propylene oxide units in the poly(ethylene oxide-co-propylene oxide).

[0081] The functionalization of precursors can, in principle, be carried out in the same manner as known prior art functionalization methods. Starting materials having OH groups are suitable for functionalization. For example, OH groups can be converted to amino groups, for example, in the same manner as described by Skarzewski, J. et al. in Monatsh. Chem. 1983, 114, 1071-1077. Thiol groups can be converted to amino groups, for example, in the same manner as described by Houben-Weyl, Methoden der Organischen Chemie, Ed. E. Muller, 4th Aufl., Vol. 9, p. 749, G. Thieme, Stuttgart 1955, or in the same manner as described by T. Nie, A. Baldwin, N. Yamaguchi and KL Kiick, J Control Release, 2007, 122, 287-296.

[0082] The generation of precursors having (meth)acrylate or (meth)acrylamide groups is successful, for example, by esterification of a prepolymer precursor having an OH group or an NH2 group with (meth)acrylic acid, or by reaction with (meth)acryloyl chloride, or by reaction with (meth)acrylic anhydride in the same manner as known methods (e.g., Cruise et al. Biomaterials 1998, 19, 1287-1294 and Han et al. Macromolecules 1997, 30, 6077-6083). Precursors having a vinyl sulfone group can be prepared in the same manner as described in C. Adelow, T. Segura, JA Hubbell and P. Frey, Biomaterials, 2008, 29, 314-326, and precursors having a vinyl sulfonate group can be prepared in the same manner as described in V. Chudasama, RJ Fitzmaurice, JM Ahern and S. Caddick, Chemical Communications, 2010, 46, 133-135. Maleimide functional groups can be introduced into prepolymer precursors having an amino group according to Coleman et al. JOC, 1959, 24(1), 297-308 and Han et al. Biochem. Pharmacol., 2013, 86(2), 297-308.

[0083] The first precursor (ai) may contain linear, branched, dendrimeric, cyclic, or star-shaped polymers, preferably dendrimeric or star-shaped polymers. In particular, the first precursor (ai) may contain star-shaped polymers. The term "star-shaped polymer" refers to a polymer having multiple polymer chains bonded to a low molecular weight central unit, which typically has 4 to 100 skeletal atoms, e.g., C atoms, O atoms, and / or N atoms. This central unit may have both aliphatic and aromatic groups. The central unit may contain, for example, at least trivalent alcohols, e.g., 3 to 12valent alcohols, e.g., glycerin, pentaerythritol, dipentaerythritol, sugar alcohols, e.g., erythritol, xylitol, mannitol, sorbitol, maltitol, isomaltulose, isomaltite, and trehalose, or such derived groups. The polymer chains bonded to the low molecular weight central unit are typically referred to as the arms of the star-shaped polymer. The arm portion of the star-shaped polymer may contain the first precursor polymer described above.

[0084] The first precursor (ai) may contain a star-shaped polymer having at least three arms. The first precursor (ai) may contain a star-shaped polymer having 12 or fewer arms, particularly 8 or fewer. The first precursor (ai) may contain a star-shaped polymer having 3 to 12 arms, particularly 3 to 8 arms.

[0085] Star-shaped precursors are known in part from, for example, WO 98 / 20060; US 6,162,862; Gotz et al., Macromol. Mater. Eng. 2002, 287, S. 223; Bartelink et al. J. Polymer Science 2000, 38, p. 2555; DE 10216639 and DE 10203937 (polyether star polymers containing different functional groups); Chujo Y. et al., Polym. J. 1992, 24 (11), 1301-1306 (star-shaped polyoxazolines); WO 01 / 55360 (star-shaped polyvinyl alcohols, star-shaped vinylpyrrolidone-containing copolymers), or can be generated according to the methods described therein.

[0086] Weight-average molecular weight (M) of the first precursor (ai) w ) may be at least 100 Da, for example at least 200 Da, or at least 500 Da, or at least 1 kDa, or at least 1.5 kDa, or at least 2 kDa, or at least 2.5 kDa, or at least 2.8 kDa, or at least 3 kDa. The weight-average molecular weight (M) of the first precursor (ai) w The weight-average molecular weight (M) of the first precursor (ai) may be 40 kDa or less, for example, 35 kDa or less, or 30 kDa or less, or 25 kDa or less, or 20 kDa or less, or 18 kDa or less. w ) may be in the range of 100Da to 40kDa, preferably 1kDa to 40kDa, more preferably 1.5kDa to 30kDa, even more preferably 2kDa to 25kDa, and most preferably 2.5kDa to 20kDa. Molecular weight, especially weight-average molecular weight (M w This can be measured by gel permeation chromatography using polyethylene glycol standard material (PEG standard material).

[0087] According to the present invention, the second precursor (bi) is preferably water-soluble. The second precursor (bi) may contain a polyether. Suitable examples of polyethers include polyethylene oxide, polypropylene oxide, polyglycidol, and copolymers thereof, preferably polyethylene oxide, polyglycidol, and poly(ethylene oxide-co-propylene oxide), and more preferably poly(ethylene oxide-co-propylene oxide).

[0088] The second precursor (bi) may contain polyethylene oxide, polyglycidol, and poly(ethylene oxide-co-propylene oxide), preferably poly(ethylene oxide-co-propylene oxide). Suitable examples of poly(ethylene oxide-co-propylene oxide) may include random poly(ethylene oxide-co-propylene oxide) or poly(ethylene oxide-block-propylene oxide). Preferably, the second precursor (bi) contains random poly(ethylene oxide-co-propylene oxide).

[0089] A poly(ethylene oxide-co-propylene oxide), particularly a random poly(ethylene oxide-co-propylene oxide), which may contain the second precursor (bi), preferably contains 50% by weight or less of propylene oxide units. A poly(ethylene oxide-co-propylene oxide), particularly a random poly(ethylene oxide-co-propylene oxide), which may contain the second precursor (bi), preferably contains a maximum of 50% by weight, preferably a maximum of 40% by weight, and more preferably a maximum of 30% by weight of propylene oxide units. A poly(ethylene oxide-co-propylene oxide), particularly a random poly(ethylene oxide-co-propylene oxide), which may contain the second precursor (bi), preferably contains a minimum of 10% by weight of propylene oxide units. Poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), may contain a second precursor (bi) and contain 10-50% by weight, preferably 10-40% by weight, and more preferably 10-30% by weight of propylene oxide units. This weight percentage is based on the total weight of the ethylene oxide and propylene oxide units in the poly(ethylene oxide-co-propylene oxide).

[0090] Poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the second precursor (bi), contains a minimum of 50% by weight, preferably a minimum of 60% by weight, and more preferably a minimum of 70% by weight, of ethylene oxide units. Poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the second precursor (bi), contains a maximum of 90% by weight, of ethylene oxide units. Poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the second precursor (bi), contains a minimum of 50-90% by weight, preferably a minimum of 60-90% by weight, and more preferably a minimum of 70-90% by weight, of ethylene oxide units. This weight percentage is based on the total weight of the ethylene oxide and propylene oxide units in the poly(ethylene oxide-co-propylene oxide).

[0091] Poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain a second precursor (bi), contain 50-90% by weight of ethylene oxide units and 10-50% by weight of propylene oxide units, preferably 60-90% by weight of ethylene oxide units and 10-40% by weight of propylene oxide units, and more preferably 70-90% by weight of ethylene oxide units and 10-30% by weight of propylene oxide units. These weight percentages are based on the total weight of the ethylene oxide and propylene oxide units in the poly(ethylene oxide-co-propylene oxide).

[0092] According to the present invention, the second precursor (b-i) contains at least one hydrolyzable bond. The term "hydrolyzable bond" refers to a covalent bond that can be decomposed by reaction with water. The at least one hydrolyzable bond may include an ester bond, a carbonate bond, and combinations thereof. Preferably, the at least one hydrolyzable bond includes an ester bond. Preferably, the first precursor (a-i) does not contain a hydrolyzable bond, particularly an ester bond. The at least one hydrolyzable bond of the second precursor enables the degradability of the hydrogel. The hydrogel that can be produced by this system is degradable within 1 day to 1 year, and preferably within 2 months to 6 months.

[0093] The second precursor (b-i) may contain a linear, branched, dendrimer-shaped, cyclic, or star-shaped polymer, preferably a dendrimer-shaped or star-shaped polymer. In particular, the second precursor (b-i) may contain a star-shaped polymer.

[0094] The second precursor (b-i) may contain a star-shaped polymer having at least 3 arm portions. The second precursor (b-i) may contain a star-shaped polymer having 12 or fewer, particularly 8 or fewer arm portions. The second precursor (b-i) may contain a star-shaped polymer having 3 to 12 arm portions, particularly 3 to 8 arm portions.

[0095] The weight average molecular weight (M w ) of the second precursor (b-i) may be at least 100 Da, such as at least 200 Da, or at least 500 Da, or at least 1 kDa, or at least 1.5 kDa, or at least 2 kDa, or at least 2.5 kDa, or at least 2.8 kDa, or at least 3 kDa. The weight average molecular weight (M w ) of the second precursor (b-i) may be 40 kDa or less, such as 35 kDa or less, or 30 kDa or less, or 25 kDa or less, or 20 kDa or less, or 18 kDa or less. The weight average molecular weight (M w) may be in the range of 100Da to 40kDa, preferably 1kDa to 40kDa, more preferably 1.5kDa to 30kDa, even more preferably 2kDa to 25kDa, and most preferably 2.5kDa to 20kDa. Molecular weight, especially weight-average molecular weight (M w This can be measured by gel permeation chromatography using polyethylene glycol standard material (PEG standard material).

[0096] According to the present invention, the second precursor (bi) is in liquid form. The term "liquid" refers to a precursor that is liquid at room temperature (23°C) and atmospheric pressure (101.3 kPa). The viscosity of the second precursor may be up to 4,500 mPa·s, preferably up to 4,000 mPa·s, more preferably up to 3,500 mPa·s, and even more preferably up to 3,000 mPa·s at room temperature (23°C). The viscosity of the second precursor may be at least 1 mPa·s, preferably at least 2 mPa·s, and more preferably at least 5 mPa·s at room temperature (23°C). The viscosity of the second precursor may be 1–4,500 mPa·s, preferably 2–4,000 mPa·s, more preferably 5–4,000 mPa·s, even more preferably 5–3,500 mPa·s, and most preferably 5–3,000 mPa·s at room temperature (25°C). Viscosity can be measured using a rheometer. To measure viscosity (complex viscosity (Pa·s)), the precursor can be analyzed at 25°C using a DHR3 rheometer with a 40 mm cone-plate geometry from TA Instruments (USA). For this purpose, 581 μL of precursor is uniformly distributed onto the rheometer plate using a pipette. The geometry is adjusted to a "geometry gap" (height 57 μm). The "flow sweep" is then 0.1–1000 s. -1 The shear rate is measured over a period of 5 minutes.

[0097] The precursor concentration of the system of the present invention may be up to 500 mg per 1 mL of solution, for example, up to 450 mg per 1 mL of solution, or up to 400 mg per 1 mL of solution, or up to 350 mg per 1 mL of solution, or up to 300 mg per 1 mL of solution, or up to 250 mg per 1 mL of solution, or up to 200 mg per 1 mL of solution. The precursor concentration of the system of the present invention may be at least 10 mg per 1 mL of solution, for example, at least 30 mg per 1 mL of solution, or at least 50 mg per 1 mL of solution, or at least 60 mg per 1 mL of solution, or at least 65 mg per 1 mL of solution, or at least 70 mg per 1 mL of solution, or at least 75 mg per 1 mL of solution, or at least 80 mg per 1 mL of solution, or at least 90 mg per 1 mL of solution. The precursor concentration of the system according to the present invention may be in the range of 10 to 500 mg per mL of solution, for example, 50 to 500 mg per mL of solution, or 60 to 400 mg per mL of solution, or 70 to 300 mg per mL of solution, or 80 to 200 mg per mL of solution, or 90 to 200 mg per mL of solution. This precursor concentration is based on the total weight of the precursor required to produce the hydrogel per unit volume of the solution of this system.

[0098] The system of the present invention may be injectable. The term "injectable" refers to a system that can be injected into the human body using a syringe. Preferably, the system of the present invention is a two-component composition. The term "two-component composition" refers to a system in which both components are stored separately and are mixed only when used. According to the present invention, the first composition (a) and the second composition (b) can be stored separately. The first composition (a) and the second composition (b) can be mixed only immediately before the system is injected.

[0099] The first composition (a) may contain one or more visualization additives. The second composition (b) may contain one or more visualization additives. The first composition (a) and the second composition (b) may contain one or more visualization additives. The term "visualization additive" refers to a contrast agent for imaging techniques, such as magnetic resonance imaging (MRT), computed tomography (CT), ultrasound, or a combination thereof. The visualization agent may contain a radiopaque material. The visualization additive may be present free in the first and / or second composition, or covalently bonded to the first and / or second precursor. The visualization additive may be present covalently bonded to the third precursor.

[0100] The visualization additives may be iohexol, metrizamide, iopamidol, triiodobenzoate, 2,3,5-triiodobenzoic acid, 2,3,5-triiodobenzoyl chloride, 3,4,5-triiodophenol, erythrosine, rose bengal, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, 3,5-diacetamido-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, ioversol, gadolinium, gadopentate-modified zirconium particles, calcium hydroxyapatite, superparamagnetic iron oxide, the aforementioned residues, or combinations thereof.

[0101] According to the present invention, the first precursor (ai) and the second precursor (bi) may contain radiopaque groups, particularly iodine-containing groups. Preferably, the second precursor (bi) may contain radiopaque groups, particularly iodine-containing groups. Examples of radiopaque groups, particularly iodine-containing groups, that can be bonded to the first precursor (ai) and / or the second precursor (bi) include iohexol, metrizamide, iopamidol, triiodobenzoate, 2,3,5-triiodobenzoic acid, 2,3,5-triiodobenzoyl chloride, 3,4,5-triiodophenol, erythrosine, rose bengal, 3,5-bis(acetylamino)-2,4,6-triiodobenzoic acid, 3,5-diacetamido-2,4,6-triiodobenzoic acid, meglumine diatrizoate, iopentol, iopromide, ioversol, and combinations thereof. The radiopaque groups, particularly iodine-containing groups, can be bonded to the first precursor (ai) and / or second precursor (bi) of the present invention by a number of methods. Possible methods include the formation of ester, amide, or urethane bonds between the radiopaque groups, particularly iodine-containing groups, and the first precursor (ai) and / or second precursor (bi), particularly the second precursor (bi). Some of these methods are described in US 2005 / 0036946 A1, particularly in paragraphs

[0077] to

[0080] ,

[0093] to

[0173] , and

[0215] to

[0364] .

[0102] The first precursor (ai) and / or the second precursor (bi), particularly the second precursor (bi), may contain iodine in a minimum of 3.0% by weight, e.g., a minimum of 3.5% by weight, or a minimum of 4.0% by weight, or a minimum of 5.0% by weight, or a minimum of 6.0% by weight, or a minimum of 7.5% by weight. The first precursor (ai) and / or the second precursor (bi), particularly the second precursor (bi), may contain iodine in a maximum of 30.0% by weight, e.g., a maximum of 28.0% by weight, or a maximum of 27.5% by weight, or a maximum of 26.0% by weight, or a maximum of 25.0% by weight. The iodine content of the first precursor (ai) and / or the second precursor (bi), particularly the second precursor (bi), may be 3.0–30.0% by weight, preferably 3.0–27.5% by weight, more preferably 3.5–27.5% by weight, even more preferably 3.5–26.0% by weight, and most preferably 3.5–25.0% by weight. This iodine content is based on the total weight of each precursor.

[0103] According to the present invention, the second composition (b) may contain a third precursor. The third precursor (b-ii) is in liquid form and may contain one functional group and one radiopaque group, in particular an iodine-containing group, the functional group of the third precursor (b-ii) reacts with the functional group of the first precursor (ai). Examples of radiopaque groups, in particular iodine-containing groups, that can be bonded to the third precursor (b-ii) include the radiopaque groups, in particular iodine-containing groups, described for the first and / or second precursors. The third precursor (b-ii) may contain iodine in a content of at least 3.0% by weight, for example, at least 3.5% by weight, or at least 4.0% by weight, or at least 5.0% by weight, or at least 6.0% by weight, or at least 7.5% by weight. The third precursor (b-ii) may contain iodine in a maximum of 30.0% by weight, for example, a maximum of 28.0% by weight, or a maximum of 27.5% by weight, or a maximum of 26.0% by weight, or a maximum of 25.0% by weight. The third precursor (b-ii) may contain iodine in a maximum of 3.0 to 30.0% by weight, preferably 3.0 to 27.5% by weight, more preferably 3.5 to 27.5% by weight, even more preferably 3.5 to 26.0% by weight, and most preferably 3.5 to 25.0% by weight. This iodine content is based on the total weight of the third precursor (b-ii).

[0104] The functional group of the third precursor (b-ii) may contain a nucleophile selected from the group consisting of amines, thiols, and combinations thereof, preferably thiols. Alternatively, the functional group of the third precursor (b-ii) may contain a conjugated unsaturated functional group selected from the group consisting of (meth)acrylate, vinyl sulfone, vinyl sulfonate, (meth)acrylamide, maleimide, quinone, vinylpyridinium, and combinations thereof, preferably (meth)acrylate, vinyl sulfone, vinyl sulfonate, maleimide, and combinations thereof, more preferably vinyl sulfone. The functional group of the third precursor (b-ii) may be at the terminal end of the second precursor (b-ii).

[0105] According to the present invention, the third precursor (b-ii) is preferably water-soluble. The third precursor (b-ii) may contain a polyether. The third precursor (b-ii) may contain polyethylene oxide, polyglycidol, and poly(ethylene oxide-co-propylene oxide), preferably poly(ethylene oxide-co-propylene oxide). Preferably, the third precursor (b-ii) contains random poly(ethylene oxide-co-propylene oxide).

[0106] The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the third precursor (b-ii), preferably contains 50% by weight or less of propylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the third precursor (b-ii), contains a maximum of 50% by weight, preferably a maximum of 40% by weight, and more preferably a maximum of 30% by weight of propylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the third precursor (b-ii), contains a minimum of 10% by weight of propylene oxide units. The third precursor (b-ii) contains 10 to 50% by weight, preferably 10 to 40% by weight, and more preferably 10 to 30% by weight of propylene oxide units. This weight percentage is based on the total weight of the ethylene oxide and propylene oxide units in poly(ethylene oxide-co-propylene oxide).

[0107] The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the third precursor (b-ii), contains a minimum of 50% by weight, preferably a minimum of 60% by weight, and more preferably a minimum of 70% by weight, of ethylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the third precursor (b-ii), contains a maximum of 90% by weight, of ethylene oxide units. The poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the third precursor (b-ii), contains a minimum of 50-90% by weight, preferably a minimum of 60-90% by weight, and more preferably a minimum of 70-90% by weight, of ethylene oxide units. This weight percentage is based on the total weight of the ethylene oxide and propylene oxide units in poly(ethylene oxide-co-propylene oxide).

[0108] Poly(ethylene oxide-co-propylene oxide), particularly random poly(ethylene oxide-co-propylene oxide), which may contain the third precursor (b-ii), contain 50-90% by weight of ethylene oxide units and 10-50% by weight of propylene oxide units, preferably 60-90% by weight of ethylene oxide units and 10-40% by weight of propylene oxide units, and more preferably 70-90% by weight of ethylene oxide units and 10-30% by weight of propylene oxide units. These weight percentages are based on the total weight of the ethylene oxide and propylene oxide units in the poly(ethylene oxide-co-propylene oxide).

[0109] Weight-average molecular weight (M) of the third precursor (b-ii) w ) may be at least 100 Da, for example at least 200 Da, or at least 500 Da, or at least 1 kDa, or at least 1.5 kDa, or at least 2 kDa, or at least 2.5 kDa, or at least 2.8 kDa, or at least 3 kDa. The weight-average molecular weight (M) of the third precursor (b-ii) w ) may be 40 kDa or less, for example, 35 kDa or less, or 30 kDa or less, or 25 kDa or less, or 20 kDa or less, or 18 kDa or less. The weight-average molecular weight (M) of the third precursor (b-ii) w ) may be in the range of 100Da to 40kDa, preferably 1kDa to 40kDa, more preferably 1.5kDa to 30kDa, even more preferably 2kDa to 25kDa, and most preferably 2.5kDa to 20kDa. Molecular weight, especially weight-average molecular weight (M w This can be measured by gel permeation chromatography using polyethylene glycol standard material (PEG standard material).

[0110] The present invention also relates to a method for producing a biodegradable hydrogel. The method of the present invention comprises the steps of (i) providing the system of the present invention and (ii) mixing the first and second compositions. Thus, the method comprises the steps of (a) providing the first composition, (b) providing the second composition, and (ii) mixing the first and second compositions. The first composition (a) is aqueous and contains a first precursor (ai) and a buffer system (a-ii). The first precursor (ai) contains functional groups. The second composition (b) is anhydrous and contains a second precursor (bi) and optionally a third precursor (b-ii). The second precursor (bi) is liquid. The second precursor (bi) contains functional groups and at least one hydrolyzable bond. The functional groups of the first precursor (ai) react with the functional groups of the second precursor (bi). The first precursor (ai) contains at least two functional groups, and the second precursor (bi) contains at least three functional groups, or the first precursor (ai) contains at least three functional groups and the second precursor (bi) contains at least two functional groups. The third precursor (b-ii) is in liquid form and contains one functional group and one iodine-containing group, and the functional group of the third precursor (b-ii) reacts with the functional group of the first precursor (ai).

[0111] The first composition (a), the second composition (b), the first precursor (ai), the second precursor (bi), the third precursor (b-ii), and the buffer system (a-ii) may have the characteristics described above.

[0112] The first composition (a) may be provided in a syringe. The second composition (b) may be provided in a syringe. Preferably, the first composition (a) and the second composition (b) are provided separately in separate syringes.

[0113] For mixing (ii), a mixing adapter, a multi-lumen tube, or a Y-connector may be used. A suitable example of a mixing adapter is the adapter system from Medmix Switzerland AG (Switzerland).

[0114] The method of the present invention may include the step of mixing (ii) a first composition (a) and a second composition (b) and then injecting them at the injection site. A cannula may be used for injection.

[0115] Furthermore, the present invention relates to a kit for producing a degradable hydrogel. The kit comprises (i) a system according to the present invention and (ii) a syringe. Thus, the kit comprises (a) a first composition, (b) a second composition, and (ii) a syringe. The first composition (a) is aqueous and contains a first precursor (ai) and a buffer system (a-ii). The first precursor (ai) contains functional groups. The second composition (b) is anhydrous and contains a second precursor (bi) and optionally a third precursor (b-ii). The second precursor (bi) is liquid. The second precursor (bi) contains functional groups and at least one hydrolyzable bond. The functional groups of the first precursor (ai) react with the functional groups of the second precursor (bi). The first precursor (ai) contains at least two functional groups, and the second precursor (bi) contains at least three functional groups, or the first precursor (ai) contains at least three functional groups and the second precursor (bi) contains at least two functional groups. The third precursor (b-ii) is in liquid form and contains one functional group and one iodine-containing group, and the functional group of the third precursor (b-ii) reacts with the functional group of the first precursor (ai).

[0116] The first composition (a), the second composition (b), the first precursor (ai), the second precursor (bi), the third precursor (b-ii), and the buffer system (a-ii) may include the characteristics described above.

[0117] Syringe (ii) may be a double syringe or a syringe having multiple cylinders. The kit of the present invention preferably comprises two syringes. The kit may contain the first composition (a) in one syringe. The kit may contain the second composition (b) in one syringe. Preferably, the kit contains the first composition (a) and the second composition (b) separately in one syringe each, or in one cylinder each of a double syringe.

[0118] This kit may include a mixing adapter, a multi-lumen tube, or a Y-connector that can be used to mix the first composition (a) with the second composition (b).

[0119] The kit may include a cannula that can be used to inject the first composition (a) and the second composition (b) after mixing. According to the present invention, this may be a commercially available cannula, for example, an 18G to 25G cannula.

[0120] The following examples are intended to illustrate the present invention in detail and should not be understood as limiting the invention.

[0121] (drawing) Figure 1 shows sPEG-VS at 18 kDa, sPEG-SH at 18 kDa, and sPEG-TIB, an iodine-containing precursor without reactive functional groups, at 10 wt%, 20 wt%, and 50 wt%. 48 (Left side), and iodine-containing precursor sPEG-TIB having 3.8% by weight, 7.5% by weight, and 14.6% by weight of reactive functional groups. 48 -SH 15The image on the right shows computed tomography (CT) images of hydrogel sections prepared from (as in the example). This weight percentage is based on the total weight of the crosslinkable precursor. The upper image shows a CT image of the hydrogel section after being stored in PBS buffer (pH=7.4) at 37°C for 1 day. The lower image shows a CT image of the hydrogel section after being stored in PBS buffer (pH=7.4) at 37°C for 14 days.

[0122] (Examples) ( 1 H-NMR and 13 C-NMR measurement method) 1 H-NMR and 13 ¹¹C-NMR spectra were recorded at 400 MHz and room temperature using a Bruker Ultrashield 400 FTNMR spectrometer. Deuterated dimethyl sulfoxide (DMSO, Sigma Aldrich) or chloroform (CDCl3, Sigma Aldrich) were used as the solvent for the spectroscopic analysis.

[0123] (Gel Permeation Chromatography (GPC)) Gel permeation chromatography (GPC) was performed using dimethylformamide (DMF) as the eluent. All experiments were evaluated using PSS WinGPC UniChrom Software (Version 8.1.1). Measurements were performed using an Agilent 1100 system equipped with a dual RI / Visco detector (ETA-2020, WGE Dr.Bures GmbH&Co.KG (Germany)). The eluent contained 1 g / L lithium bromide. Distilled water was used as the internal standard in the solvent. One spare column (8 × 50 mm) and four GRAM gel columns (8 × 300 mm, Polymer Standards Service (Germany)) were used at a flow rate of 1.0 mL / min at 40°C. The gel particle diameter was 10 μm, and the nominal pore widths were 30, 100, 1000, and 3000 Å. A polyethylene glycol (PEG) standard with a narrow molecular weight distribution (Polymer Standards Service (Germany)) was used for calibration.

[0124] (Star-shaped polyether polyol (sPEG-OH)) First and second precursors were generated using a 6-arm star-shaped polyether polyol (sPEG-OH). This sPEG-OH is a random poly(ethylene oxide-co-propylene oxide) produced by anionic ring-opening polymerization of 80% by weight ethylene oxide and 20% by weight propylene oxide using sorbitol as an initiator and potassium hydroxide as a catalyst. This weight percentage is based on the total weight of the monomer mixture containing ethylene oxide and propylene oxide used. The weight-average molecular weight (M) of the sPEG-OH used is... w The pressures are 3 kPa, 12 kPa, and 18 kPa. Each sPEG-OH group was functionalized with a different group as described below.

[0125] (Synthesis of star-shaped polyethers (sPEG-SH) containing thiol groups) The reaction was carried out under an inert protective gas atmosphere. sPEG-OH was dried overnight at 75°C under high vacuum (HV). sPEG-OH (25 mmol of OH functional groups, 1 equivalent), 3-mercaptopropionic acid (20.0 equivalents), p-toluenesulfonic acid (0.2 equivalents), and dithiothreitol (0.5 equivalents) were dissolved in toluene (20 mL / g sPEG-OH) at room temperature (RT). This reaction mixture was refluxed under nitrogen at 110°C for 24 hours. All subsequent purification steps were performed to ensure the polymer was kept as cold as possible and exposure to air was minimized. Therefore, samples were kept cool at all times and processed under a nitrogen atmosphere whenever possible. A pale yellow, clear solution was concentrated at room temperature under high vacuum. The remaining solution was dissolved in cold DCM (5 mL) and precipitated from pentane (400 mL, technical quality) and diethyl ether (400 mL, technical quality) at 0°C. After storage at -80°C for 1.5 hours, the precipitant was removed by decantation, and the polymer was precipitated three more times in the same manner. This product was dissolved in 50 mL of DCM and cooled to 0°C. This solution was filtered four times through a silica gel-packed filter frit and once through a pleated filter. This product was dissolved in dichloromethane and dried at room temperature under high vacuum to obtain sPEG-SH in 86% yield and 100% functionalization (6-arm star polymer). Functionalization was measured by NMR spectroscopy. This polymer was stored under nitrogen at -20°C until further use. 1 ¹H-NMR (400MHz, CDCl3): δ = 5.07-4.88 (1H, m, CH3-CH-O), 4.20-4.05 (2H, m, O-CH2-CH2-O), 3.90-3.11 (m, polymer backbone), 2.72-2.44 (4H, m, -CH2CH2SH), 1.64-1.53 ​​(1H, m, -SH), 1.14-1.03 (m, polymer backbone -CH2CH(CH3)O-) ppm (Synthesis of star-shaped polyethers (sPEG-VS) containing vinyl sulfone groups) The reaction was carried out under an inert protective gas atmosphere. sPEG-OH was dried by azeotropic distillation with toluene at 80°C under high vacuum. sPEG-OH (0.45 mmol of OH functional groups, 1 equivalent) was dissolved in 33 mL of anhydrous DCM. Sodium hydride (7.5 equivalents) was suspended in 17 mL of anhydrous DCM in a Schlenk tube. This sPEG-OH solution was slowly added dropwise to the NaH solution through a dropping funnel. The mixture was stirred for 30 minutes. Subsequently, divinyl sulfone (DVS) (30 equivalents) was added all at once, and the mixture was stirred for 72 hours. Acetic acid (7.5 equivalents) was added to stop the reaction, and the solution was stirred again for 30 minutes. The solution was filtered, washed with THF, and concentrated in a rotary evaporator. The product was purified by dialysis. The crude product was dissolved in 5 mL of acetone (technical quality) and dialyzed in 500 mL of acetone (technical quality) (Spectra / Por6 dialysis membrane, MWCO: 1 kDa). The dialysis solvent was changed twice daily. This process was repeated until no more DVS residue was shown by NMR analysis. The product was dissolved in DCM and dried under reduced pressure at room temperature. A yellow viscous liquid polymer was obtained with a yield of 80% and a degree of functionalization of 100% (6-arm star polymer). 1 H-NMR (400MHz, CDCl3): δ=6.91-6.71(1H, m, SO2-CH=CH2), 6.41-6.28(1H, m, SO2-CH=CH2), 6.09-5.98(1H, m, SO2-C H=CH2), 3.91(2H, m, CH2-CH2-SO2), 3.78-3.27(m, polymer backbone), 3.21(2H, m, CH2-CH2-SO2), 1.11(3H, m, CH3-CH-O)ppm.

[0126] (Synthesis of star-shaped polyethers (sPEG-VS-at) having vinyl sulfonate groups) The reaction was carried out under an inert protective gas atmosphere. sPEG-OH (4.712 mmol of OH functional groups, 1 equivalent) was dried overnight under high vacuum (HV) at 75°C with stirring, and dissolved in dichloromethane at a ratio of 50 mL per gram of sPEG-OH. Triethylamine (4 equivalents) was added with stirring, and the solution was immediately cooled to 0°C. This solution was stirred for 30 minutes, and then 2-chloroethane-1-sulfonyl chloride (2 equivalents) was added to 10 mL of DCM over more than 2 hours using a dropping funnel (approximate dropping rate of 6 drops per minute). After stirring at room temperature for 24 hours, the solvent was removed, and the resulting product was dissolved in 50 mL of tetrahydrofuran (THF). This suspension was cooled in an ice bath and filtered through silica gel (approximately 0.5 cm thick). The product was washed with 150 mL of cold THF and concentrated under reduced pressure. This method was repeated until no salt residue was detectable using NMR analysis. After successive precipitation steps at -20°C in 400 mL of pentane and 600 mL of Et2O (technical quality), a yellow viscous liquid polymer was obtained in yield 71% and with a functionalization degree of 100% (6-arm star polymer). 1 H-NMR (400MHz, CDCl3): 6.71-6.49(1H, m, SO2-CH=CH2), 6.44-6.26(1H, m, SO2-CH=CH2), 6.12-5.97(1H, m, SO2-CH=CH2), 4.76-4.59(1H, m , CH3-CH-O), 4.31-4.16 (2H, m, O-CH2-CH2-O) 3.89-3.05 (m, polymer backbone), 1.40-1.27 (3H, m, CH3-CH-O-SO2), 1.24-1.01 (3H, m, CH3-CH-O) ppm.

[0127] (Synthesis of 1,4-dimethylpyridinium-p-toluenesulfonate (DPTS)) The reaction was carried out under an inert protective gas atmosphere. 4-dimethylaminopyridine (1.0 g, 8.19 mmol, 1 equivalent) was dissolved in 100 mL of anhydrous THF. 1.55 g of p-toluenesulfonic acid monohydrate (8.19 mmol, 1 equivalent) was added to the stirring solution and stirred at room temperature for 1 hour. The reaction mixture was filtered through a Buchner funnel and washed with analytical THF. The white powder was dried under reduced pressure at room temperature and stored at -20°C. 1 H-NMR (400MHz, CDCl3): δ=8.20(2H, d, -CH=NH + -CH=), 7.51(2H, d, =CH-SO3 - =CH-), 7.14 (2H, d, =CH—C-(CH3)-=CH-), 6.99 (2H, d, -CH=C-(N(CH3)2)-CH=), 3.17 (6H, s, -N-(CH3)2), 2.29 (3H, s, -C-CH3)ppm.

[0128] (Synthesis of 3-((2-vinylsulfonyl)ethyl)thio)propionic acid (Mercapto-VS)) The reaction was carried out under an inert protective gas atmosphere. DVS (2.40 g, 20.3 mmol, 20 equivalents) was dissolved in DMSO (anhydrous) (2.7 mL / 1 g DVS). 3-Mercaptopropionic acid (1.0 equivalent) was quickly added to the stirring solution and stirred at room temperature for 4 hours. 1 H-NMR (400MHz, CDCl3): δ=6.60-6.51(1H, q, SO2-CH=CH2), 6.36-6.30(1H, d, SO2-CH=CH2), 6.09-6.0(1H, d, SO2-CH=CH2), 2.72-2.55(8H, m, S-CH2-CH2-S)ppm. 13 C-NMR (400MHz, CDCl3): δ=136.84(1C, SO2-CH=CH2), 129.75(1C, SO2-CH=CH2), 37.88(1C, S-CH2-CH2-S), 19.41(1C, S-CH2-CH2-S)ppm.

[0129] (Synthesis of star-shaped polyethers (sPEG-mercapto-VS) containing mercaptovinylsulfone groups) Mercapto-VS was dried by azeotropic distillation from toluene at 80°C under high vacuum. sPEG-OH (0.51 mmol of OH functional groups, 0.5 equivalents) was dissolved in anhydrous DMSO (13.8 mL / 1 g N,N-dicyclohexylcarbodiimide (DCC)). DCC (1.5 equivalents) and DPTS (0.15 equivalents) were added to the stirred solution. This solution was slowly added to the Mercapto-VS solution. The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through silica gel. The DMSO was evaporated by high vacuum distillation at 60°C. The product was dialyzed five times in 800 mL of acetone (technical quality) (pre-wet RC tube MWCO: 1 kDa). Subsequently, the product was dissolved in 60 mL of cold (0°C) DCM (analytical grade) and filtered through silica gel. This process was repeated until no solid was detected in the solution. The product was dissolved in 5 mL of DCM (analytical grade) and precipitated in cold (-20°C) Et2O (100 mL) and pentane (100 mL) (technical quality). This process was repeated until no DVS residue was detectable. The product was dissolved in DCM and dried under reduced pressure at room temperature. A yellow viscous liquid polymer with a yield of 40% and a functionalization degree of 40% (6-arm star polymer) was obtained.

[0130] (Synthesis of linear polyethylene glycol (LPEG-VS) having vinyl sulfone groups) Linear 4kDa poly(ethylene glycol) (LPEG) (Sigma Aldrich) was dried overnight at 75°C under high vacuum. PEG (1.0 g, 0.5 mmol of OH functional groups, 1 equivalent) and sodium hydride (0.06 g, 2.5 mmol, 5 equivalents) were dissolved in anhydrous THF (65 mL, anhydrous) and stirred at room temperature (RT) for 30 minutes. DVS (1.77 g, 15.0 mmol, 30 equivalents) was added dropwise, and the reaction mixture was stirred at room temperature for 96 hours. The reaction was stopped by slowly adding acetic acid (0.15 g, 2.5 mmol, 5 equivalents), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, washed with THF, and concentrated. The polymer was precipitated from cold (-20°C) diethyl ether (100 mL, technical quality) to obtain a colorless solid. This procedure was repeated until no DVS residue was detectable. The mixture was filtered, the residue remaining on the filter was dissolved in DCM, and dried at room temperature under high vacuum. A white powder with a yield of 88% and a functionalization degree of 100% (two terminal groups) was obtained. 1 H-NMR (400MHz, CDCl3): δ=6.86-6.23(1H, m, -SO2CH=CH2), 6.39-6.29(1H, m, -SO2CH=CH2), 6.10-6.01(1H , m, -SO2CH=CH2), 3.85(2H, m, -CH2-CH2-SO2-), 3.79-3.48(m, polymer backbone), 3.27((2H, m, -CH2-CH2-SO2-)ppm.

[0131] (SpaceOAR (registered trademark)) Unless otherwise stated, SpaceOAR® (Boston Scientific Corp., USA) was prepared according to the accompanying instructions. For this purpose, the SpaceOAR® prepolymer was dissolved in the accompanying solution (5 mL) and mixed with the SpaceOAR® crosslinking agent (5 mL) for other tests.

[0132] (Buffer preparation) Preparation of the salt solution: 0.958 g of sodium tetraborate decahydrate was dissolved in a 100 mL volumetric flask.

[0133] Buffer preparation: 100 mL of salt solution was poured into a 200 mL volumetric measuring flask. To adjust the pH to the desired value, an equivalent amount of 0.1 M HCl solution was added, and the flask was filled with water to obtain 200 mL of buffer (Table 1).

[0134] [Table 1]

[0135] (Gellation test) Each sPEG polymer was weighed and placed in separate containers (e.g., 0.5 mL Eppendorf tubes). For this test, a total precursor concentration of 140 mg (total weight of the first and second precursors) was prepared in 1 mL of water for each precursor combination. A Michael acceptor (1 equivalent of functional group), e.g., 12 kDa sPEG-VS (3.18 mg, 1 equivalent of functional group), was dissolved in 50 μL of buffer (pH 9.0). A Michael donor (1 equivalent of functional group), e.g., 18 kDa sPEG-SH (3.82 mg, 1 equivalent of functional group), was used without a solvent. This buffer solution was pipetted into the undissolved sPEG-SH. Measurement was started as soon as the two compounds came into contact. The solution was continuously pipetted and the measurement was stopped when a gel formed (further pipetting was not possible). Each test was repeated at least three times.

[0136] Preliminary tests were conducted using the system according to the present invention and a system in which both precursors were dissolved in buffer to investigate whether different gelation times were obtained. For these tests, a concentration of 140 mg (total weight of the first and second precursors) was also adjusted to 1 mL of water. 12 kDa sPEG-VS and 12 kDa sPEG-SH were used. In the examples according to the present invention, as described above, only 12 kDa sPEG-VS was dissolved in 50 μL of buffer (pH=9.0), and this buffer solution was pipetteed into undissolved 12 kDa sPEG-SH. For comparison, 12 kDa sPEG-VS and 12 kDa sPEG-SH were each dissolved in 25 μL of buffer (pH=9.0), and the buffer solution containing 12 kDa sPEG-VS was pipetteed into the buffer solution containing 12 kDa sPEG-SH.

[0137] The gelation time of the system according to the present invention was 10.43 seconds (±1.01), while the gelation time of the comparative example was 10.89 seconds (±1.05). It is clear that both systems have comparable gelation times, which supports the idea that the precursor in the system according to the present invention mixes homogeneously and rapidly, thereby reacting quickly. Therefore, the swelling, rigidity, and decomposition properties are also likely to be comparable.

[0138] (Disassembly test) As an example, each combination of precursors was tested at a concentration of 140 mg (total weight of the first and second precursors) in 1 mL of water. Freshly prepared precursor solutions were used. A Michael donor (1 equivalent of functional groups), for example, 12 kDa sPEG-SH (66.63 mg, 1 equivalent of functional groups), was dissolved in 2 mL of buffer (pH=9). 2 mL of Michael acceptor solution was prepared with the same number of functional groups (1 equivalent of functional groups), for example, 12 kDa sPEG-VS (73.37 mg, 1 equivalent of functional groups). These solutions were pipetted into a double syringe (volume ratio 1:1, 2.5 mL per chamber, ADCHEM, K-System) and compressed with a mixing adapter (ADCHEM, K-System, MKH02-12S) to form a flexible shape (2.0 cm × 2.0 cm × 1.5 cm). After gelation, this hydrogel was removed and cut into four parts.

[0139] The hydrogel sections were stored in 4.0 mL of PBS buffer (AccuGENE PBS buffer, pH=7.4) at room temperature or 37°C (Mini-Incubator Cultura((c))M, 4 L). The medium was removed, and the weight of the sample was measured and compared to the original weight of the hydrogel to determine its degradability. After the measurement, fresh buffer was added to maintain consistent degradation conditions. This process was repeated at specific time intervals until the hydrogel was completely dissolved.

[0140] (Swelling test) The amount of each precursor (see Table 2) was measured and placed in separate containers. These polymers were dissolved in borax / HCl buffer at pH=9.0. These precursor solutions were mixed on a shaker for 10 minutes. This sPEG-SH solution was always used quickly. These solutions were pipetted into a double syringe (volume ratio 1:1, 2.5 mL per chamber, ADCHEM, K-System) and injected using a two-component mixing adapter (ADCHEM, K-System, MKH02-12S) to form a cylindrical shape (diameter = 1.7 cm).

[0141] [Table 2]

[0142] The hydrogel samples were removed from their molds and transferred to 20 mL containers. The mass of the empty containers was measured by the hydrogel. 4.0 mL of PBS buffer (pH=7.4) was added to the hydrogels. To ensure reproducibility, three of these samples were stored at 37°C and one at room temperature. The solvent (PBS buffer) was changed every 4 hours for the first 24 hours, and then daily thereafter. For each condition, the weight of the wet hydrogel was measured without buffer. The degree of swelling and the change in water content were measured.

[0143] The degree of swelling of the hydrogel was calculated using the following formula:

[0144]

number

[0145] (Measurement of the stiffness (storage modulus G') of hydrogels) To measure the mechanical properties (storage modulus G') of the hydrogels, both polymer components (total volume: 74 μL) were separately dissolved in borax / HCl buffer at a concentration of 140 mg per mL of solution (total weight of the first and second precursors) and measured at 37°C using a rheometer. Fresh precursor solutions were used. Michael donor (1 equivalent of functional group), e.g., 18 kDa sPEG-SH (6.07 mg, 1 equivalent of functional group), was dissolved in 37 μL of buffer (pH=9). 37 μL of Michael acceptor solution was prepared with the same number of functional groups (1 equivalent of functional group), e.g., 12 kDa sPEG-VS (4.29 mg, 1 equivalent of functional group).

[0146] Rheological characterization was performed using a TA Instruments (USA) DHR3 rheometer with a 20 mm cone plate geometry. All samples were prepared directly on the heated (37°C) plate of the rheometer. A 74 μL prepolymer solution, in which the volume ratio of sPEG-SH compound to sPEG-VS compound was 1:1 and both were dissolved in a pH 9 buffer solution, was poured into a punched PDMS film with a diameter of 20 mm, corresponding to the diameter of the geometry (diameter = 20 mm), ensuring that the punched-out part of the film was precisely positioned beneath the geometry. After the gel was formed, the PDMS film was removed and the geometry was adjusted to a "geometry gap" (height 51 μm). Subsequently, the following three measurements were initiated: a 300-second time sweep, which was always followed by a frequency sweep (0.1–100 Hz, strain 0.5%) and an amplitude sweep (strain 0.1–1000%, 1.0 Hz).

[0147] Table 3 shows the values ​​obtained from tests on the gelation, decomposition, swelling, and stiffness of the precursor combinations.

[0148] [Table 3]

[0149] (Star-shaped polyether functionalized with iodine-containing groups (sPEG-TIB) 48 (composition of) 3 kDa sPEG-OH (10.560 g, 21.12 mmol of OH functional groups, 1.0 equivalent) was dried overnight at 50°C under high vacuum and dissolved in anhydrous DCM (50 mL). Subsequently, anhydrous triethylamine (1.0 equivalent) was added, and the solution was cooled to 0°C in an ice bath. In a separate Schlenk tube, 2,3,5-triiodobenzoyl chloride (TIB-Cl) (0.67 equivalents) was dissolved in anhydrous dichloromethane (30 mL), and then slowly added dropwise to the sPEG-OH solution over 30 minutes at 0°C. After the addition was complete, the reaction was allowed to proceed with stirring at room temperature for 20 hours. The DCM was evaporated by rotary evaporation, and the crude product was placed in unstabilized THF (50 mL) and filtered through a glass frit with a thin silica layer (approximately 2 cm high) to separate the insoluble triethylamine hydrochloride. The solvent was then removed using a rotary evaporator. The product was dissolved in THF and further purified by precipitation at 0°C in a 1:1 mixture of diethyl ether and pentane. This process was repeated twice. A sPEG-TIB (3-arm star polymer) with a functionalization degree of 48% was obtained. Functionalization was measured using NMR spectroscopy. sPEG-TIB 48 The iodine content is 26% by weight, and this iodine content is sPEG-TIB 48 This is based on the total weight. 1 ¹H-NMR (400MHz, CDCl3): δ = 8.25-8.21 (1H, m, OC(O)-C-CH), 7.71-7.65 (CI-CH-CI), 4.45-4.32 (2H, m, O-CH2-CH2-OC(O)-C), 3.95-3.05 (m, polymer backbone), 2.72-2.44 (4H, m, -CH2CH2SH), 1.64-1.53 ​​(1H, m, -SH), 1.10-1.02 (m, polymer backbone -CH2CH(CH3)O-) ppm.

[0150] (A star-shaped polyether having a thiol group and functionalized with an iodine-containing group (sPEG-TIB 48 -SH 15 (composition of) sPEG-TIB 48(1.007 g, 0.674 mmol of OH functional groups, 1 equivalent) was dissolved in 20 mL of anhydrous toluene in a Schlenk tube, and dithiothreitol (0.5 equivalents) and p-toluenesulfonic acid (0.2 equivalents) were added. Subsequently, 3-mercaptopropionic acid (0.33 equivalents) was added, and the reaction mixture was refluxed under protective gas at 110°C for 24 hours. After the reaction time, the solvent was removed using a rotary evaporator, and the crude product was added back into dichloromethane and precipitated in a 1:1 mixture of diethyl ether and pentane. After storage at -80°C for 1.5 hours, the precipitant was removed by decantation, and the polymer was dried under vacuum. This step was repeated twice. The product was then dissolved in 50 mL of THF (unstabilized), cooled to 0°C, and subsequently filtered through silica gel to remove any remaining p-toluenesulfonic acid. Next, the polymer was precipitated in diethyl ether:pentane (1:1). One arm of sPEG-TIB48 could be modified with a thiol group, which corresponds to a degree of functionalization of 15%. Functionalization was measured using NMR spectroscopy. This sPEG-TIB 48 ―SH 15 The iodine content is 25% by weight, and this iodine content is sPEG-TIB 48 ―SH 15 This is based on the total weight. 1 H-NMR (400MHz, CDCl3): δ=8.27-8.20 (1H, m, OC(O)-C-CH), 7.72-7.65 (CI-CH-CI), 5.14- 4.96(1H, m, CH2-C(H)CH3-OC(O)-CH2), 4.45-4.32(2H, m, O-CH2-CH2-OC(O)-C), 4.24-4.1 4(2H, m, O-CH2-CH2-OC(O)-CH2-), 3.95-3.05(m, polymer skeleton), 2.77-2.51(4H, m, -CH2CH2SH), 1.67-1.58(1H, m, CH2-SH), 1.22-1.15(3H, m, CH2-CH(CH3)OC(O)-), 1.13-0.99(m, polymer skeleton -CH2CH(CH3)O-) ppm.

[0151] Iodine-containing star-shaped polyether sPEG-TIB 48 and sPEG-TIB 48 ―SH 15 A gelation test was performed. For this purpose, a total precursor concentration of 140 mg per 1 mL of water was used for each precursor combination. The same conditions as described above were used for the gelation test. 18 kDa sPEG-VS and 18 kDa sPEG-SH were used.

[0152] Additionally, 5% by weight, 10% by weight, 20% by weight, or 50% by weight of sPEG-TIB 48 , or 3.8% by weight, 7.5% by weight, or 14.6% by weight of sPEG-TIB 48 ―SH 15 Each of these was added, but the weight percentage of this iodine-containing component is based on the total weight of the crosslinkable precursor. In all examples, one equivalent of VS functional groups and one equivalent of SH functional groups of the precursor were used. 18 kDa sPEG-VS was dissolved in 50 μL of buffer (pH 9.0). 18 kDa sPEG-SH was dissolved in sPEG-TIB 48 or sPEG-TIB 48 ―SH 15 The mixture was used without a solvent. The net weights of each component were as follows (see Table 4).

[0153] [Table 4]

[0154] These solutions have the following gelation times, as shown in Table 5.

[0155] [Table 5]

[0156] (Visualization test using computed tomography (CT)) Hydrogel sections were prepared as described in the decomposition test. 18kDa sPEG-VS and 18kDa sPEG-SH were used. As described in the gelation test, 5% by weight, 10% by weight, 20% by weight, or 50% by weight of sPEG-TIB was used. 48 Alternatively, 3.8% by weight, 7.5% by weight, or 14.6% by weight of sPEG-TIB 48 ―SH 15 Each of these was added, but the weight percentage of this iodine-containing component is based on the total weight of the crosslinkable precursor.

[0157] For visualization testing, the hydrogel sections were stored in PBS buffer (pH=7.4) for 1 day and 14 days. CT scans were performed at both time points with scan parameters of 184 mAS, scan time of 13 seconds, and CTDIvol: 13 mGy (radiation intensity) (Philips (Netherlands) Brilliance Big). During CT scanning, the hydrogel sections were placed in water to obtain better contrast. The CT images are shown in Figure 1.

[0158] It has been shown that hydrogel sections with higher iodine concentrations provide better visualization on CT. (50% sPEG-TIB) 48 and 14.6% sPEG-TIB 48 -SH 15 Hydrogel sections containing sPEG-TIB still show sufficient visibility on CT even after 14 days. 48 -SH 15 Hydrogels containing this material exhibit the best visualization in CT scans over longer periods. [Brief explanation of the drawing]

[0159] [Figure 1]The images show computed tomography (CT) scans of hydrogel sections (as produced in the examples) prepared from 18kDa sPEG-VS, 18kDa sPEG-SH, and iodine-containing precursors sPEG-TIB48 (left) containing 10%, 20%, and 50% by weight of reactive functional groups, and iodine-containing precursors sPEG-TIB48-SH15 (right) containing 3.8%, 7.5%, and 14.6% by weight of reactive functional groups.

Claims

1. A system for producing a biodegradable hydrogel, which is as follows: (a) First composition; aqueous, containing a first precursor (a-i) and a buffer system (a-ii), wherein the first precursor (a-i) contains a functional group; and (b) Second composition; anhydrous and containing a second precursor (b-i), the second precursor (b-i) being liquid and containing a functional group and at least one hydrolyzable bond; It contains, A system wherein the functional groups of the first precursor (a-i) react with the functional groups of the second precursor (b-i); and the first precursor contains at least two functional groups and the second precursor contains at least three functional groups, or the first precursor contains at least three functional groups and the second precursor contains at least two functional groups.

2. The first and second precursors contain at least three functional groups; and / or The system according to claim 1, wherein the reaction of the functional group of the first precursor (a-i) with the functional group of the second precursor (b-i) is a Michael-type reaction.

3. The functional groups of the first precursor (a-i) contain conjugated unsaturated functional groups selected from the group consisting of vinylsulfone, (meth)acrylamide, maleimide, quinone, vinylpyridinium, and combinations thereof, preferably vinylsulfone, and the functional groups of the second precursor (b-i) contain nucleophiles selected from the group consisting of amine, thiol, and combinations thereof, preferably thiol; or The functional group of the first precursor (a-i) contains a nucleophile selected from the group consisting of amines, thiols, and combinations thereof, preferably thiols; and the functional group of the second precursor (b-i) contains a conjugated unsaturated functional group selected from the group consisting of (meth)acrylate, vinyl sulfone, vinyl sulfonate, (meth)acrylamide, maleimide, quinone, vinylpyridinium, and combinations thereof, preferably (meth)acrylate, vinyl sulfone, vinyl sulfonate, maleimide, and combinations thereof, more preferably vinyl sulfone; and / or The system according to claim 1 or 2, wherein the hydrolyzable bond of the second precursor (b-i) includes an ester bond.

4. The functional group of the first precursor (a-i) is located at the terminal end of the first precursor (a-i); and / or The system according to any one of claims 1 to 3, wherein the functional group of the second precursor (b-i) is located at the terminal end of the second precursor (b-i).

5. The system according to any one of claims 1 to 4, wherein the first precursor (a-i) is a polyether, polyacrylic acid, poly(ethylene-co-acrylic acid), polyvinyl acetate, polyvinyl alcohol, poly(ethylene-co-vinyl alcohol), polyvinyl acetal, polyvinyl ether, poly(oxazoline), polyvinylpyrrolidone, polyvinylamine, polyvinyl methyl ether, poly(meth)acrylate, polyacrylamide, poly(N-isopropylacrylamide), poly(N-ethylacrylamide), polyoxymethylene, polycarbonate, or copolymers thereof, preferably polyether, polyacrylamide, poly(N-isopropylacrylamide), poly(N-ethylacrylamide), or copolymers thereof, more preferably polyether.

6. The first precursor (a-i) contains a polyether, preferably polyethylene oxide, polyglycidol, poly(ethylene oxide-copropylene oxide), more preferably poly(ethylene oxide-copropylene oxide), even more preferably random poly(ethylene oxide-copropylene oxide); and / or The second precursor (b-i) contains a polyether, preferably polyethylene oxide, polyglycidol, poly(ethylene oxide-copropylene oxide), more preferably poly(ethylene oxide-copropylene oxide), and even more preferably random poly(ethylene oxide-copropylene oxide). The system according to any one of claims 1 to 5, wherein the poly(ethylene oxide-copropylene oxide) preferably contains 50 to 90% by weight of ethylene oxide units and 10 to 50% by weight of propylene oxide units, more preferably 60 to 90% by weight of ethylene oxide units and 10 to 40% by weight of propylene oxide units, and even more preferably 70 to 90% by weight of ethylene oxide units and 10 to 30% by weight of propylene oxide units, the weight percentages being based on the total weight of the ethylene oxide and propylene oxide units of the poly(ethylene oxide-copropylene oxide).

7. The first precursor (a-i) contains a linear, branched, dendrimeric, cyclic, or star-shaped polymer, preferably a dendrimeric or star-shaped polymer, more preferably a star-shaped polymer; and / or The second precursor (b-i) contains a linear, branched, dendrimeric, cyclic, or star-shaped polymer, preferably a dendrimeric or star-shaped polymer, and more preferably a star-shaped polymer; The system according to any one of claims 1 to 6, wherein the star-shaped polymer preferably has 3 to 12 arm portions, and more preferably 3 to 8 arm portions.

8. The molecular weight of the first precursor (a-i) is 100 Da to 40 kDa, preferably 2.5 kDa to 20 kDa; and / or The system according to any one of claims 1 to 7, wherein the molecular weight of the second precursor (b-i) is 100 Da to 40 kDa, preferably 2.5 kDa to 20 kDa.

9. The pH value of the first composition is 7 to 10, more preferably 7.4 to 10, even more preferably 7.4 to 9; and / or The viscosity of the second precursor is up to 4,500 mPa·s at room temperature; and / or The system is injectable, as described in any one of claims 1 to 8.

10. The system according to any one of claims 1 to 9, wherein the second composition (b) contains a third precursor (b-ii), the third precursor (b-ii) is in liquid form and contains one functional group and at least one iodine-containing group, and the functional group of the third precursor (b-ii) reacts with the functional group of the first precursor (a-i).

11. A method for producing a degradable hydrogel, comprising: (i) the step of providing the system according to claim 1; and (ii) The step of mixing the first and second compositions.

12. A kit for producing a biodegradable hydrogel, comprising the following: (i) The system according to claim 1; and (ii) Syringe, double syringe is advantageous.

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