Crosslinkable prepolymers for chemically stable polymer gels

Abstract

The present invention relates to water-soluble, cross-linkable prepolymers for preparing chemically stable cross-linked polymer gels, a process for their preparation, compositions containing them, and their use, such as medical or dental filling compositions.

Description

Technical Field

[0001] The present invention relates to water-soluble, cross-linkable prepolymers for preparing chemically stable cross-linked polymer gels, a process for their preparation, compositions containing them, and their use, such as medical or dental filling compositions. Background Art

[0002] Hydrogels have been investigated for many biomedical applications (tissue engineering, wound closure, tissue adhesives and sealants). They can be obtained by chemical crosslinking of water-soluble prepolymer solutions carrying crosslinkable groups. The prepolymer can be a difunctionalized, crosslinkable derivative of poly(ethylene glycol) (PEG), such as PEG-dimethacrylate (PEG-DMA, CAS: 25852-47-5).

[0003] A major advantage of hydrogels is that they are water-based, and therefore their precursors are water-soluble. This enables their use in a range of biomedical applications that require water as a solvent, which would otherwise be impossible. However, the inherent hydrophilicity required in the precursors results in hydrophilic materials that interact more strongly with water after crosslinking, and therefore have a higher potential for degradation or instability with water.

[0004] In most applications of hydrogels, degradation of the material needs to occur within days to weeks under physiological conditions. To achieve this, stable polyethers (e.g., PEG) are often combined with hydrolytically unstable polyesters (polylactic acid, polycaprolactone) in copolymers. Hydrolytic degradation of the polyester moiety renders the gel degradable [4].

[0005] However, even hydrogels based on pure polyethers (e.g., made from PEG-DMA) degrade over a period of weeks to months due to the hydrolytic instability of the ester bond between the PEG backbone and the crosslinkable end groups. PEG-diacrylamide (PEG-DAAm, CAS: 160556-48-9) has been proposed as a more hydrolytically stable alternative, having an amide bond instead of an ester bond [1, 2]. However, the applicants found that hydrogels based on PEG-DMA or PEG-DAAm degrade significantly over a period of months under physiological conditions. The ester and amide bonds in PEG-methacrylate and PEG-acrylamide degrade unexpectedly rapidly even at neutral pH. In addition, PEG derivatives with “trans-methacrylate” end groups have been proposed as hydrolytically stable alternatives to PEG-DMA [11-14]. These derivatives exhibit similar reaction rates to PEG-acrylates in Michael-type reactions with thiols

[11] and can also be crosslinked in free radical processes using redox initiator systems

[13] . However, the applicant has found that it is not possible to carry out rapid photopolymerization with such prepolymers within 1-2 minutes of irradiation. Therefore, crosslinkable prepolymers with improved hydrolytic stability are essential for applications requiring long-term stability over several years.

[0006] Furthermore, poly(ethylene glycol) itself is known to degrade under oxidative conditions, for example when used as a coating on archaeological artifacts, possibly through oxidation of terminal OH-groups and / or internal ether moieties [3, 8-10]. Therefore, the degradation of PEG-based hydrogels is expected to be a combination of hydrolysis of ester / amide bonds between the backbone and the terminal groups and oxidative degradation of ether groups in the backbone [1, 5-7]. Such hydrogels have been shown to degrade by oxidation of internal CO-bonds when stored in air, whereas this effect is reduced when stored in water due to lower oxygen concentrations [6]. Furthermore, the applicants were able to detect oxidative degradation products in accelerated aging experiments of hydrogels based on PEG-DMA and PEG-DAAm.

[0007] Therefore, in order to prepare long-term chemically stable hydrogels or polymer gels, suitable antioxidants are required in addition to hydrolytically stable prepolymers. Phenols are commonly used as antioxidants to inhibit oxidative degradation in polymers, cosmetics, pharmaceuticals, and foods. Furthermore, they are often used to improve the storability and shelf life of curable monomer and polymer compositions by inhibiting free radical polymerization. During the intended curing phase, this polymerization is inhibited or delayed because the free radicals generated by the initiator system are trapped by the stabilizer until these are consumed. This results in a cured formulation that contains no antioxidants and is therefore unable to protect against oxidative degradation, which also occurs through free radical processes.

[0008] Therefore, an antioxidant used to prepare a prepolymer formulation that can be converted into a chemically stable cross-linked polymer gel must sufficiently inhibit oxidative degradation while remaining inert to the free radicals generated during the curing step so as not to inhibit them and not be consumed in this reaction. In summary, it must meet the following properties:

[0009] Compatible with waterborne prepolymer formulations;

[0010] It does not inhibit any free radical-based polymerization / cross-linking process or is not consumed in the process, while effectively inhibiting degeneration based on oxygen free radicals;

[0011] Remains in the cross-linked polymer gel composition after curing to ensure long-term oxidative stability.

[0012] The most common phenolic-based antioxidants have been found to be insoluble in prepolymer formulations, unstable over the required product shelf life, or have a negative impact on free radical polymerization.

[0013] Based on this knowledge, the object of the present invention is to provide water-soluble, crosslinkable prepolymers for the preparation of chemically stable crosslinked polymer gels, as well as compositions comprising suitable antioxidants for the preparation of chemically stable crosslinked polymer gels; these are in particular resistant to oxidation and hydrolysis, and more generally to chemical degradation, thereby achieving unexpected long-term stability. Summary of the Invention

[0014] Compared to the reduced dry weight obtained with hydrogels based on PEG-DMA or PEG-DAAm, hydrogels based on functionalized PEG derivatives containing hydrophobic linking groups showed remarkable stability against hydrolytic degradation, as indicated by the constant dry weight after accelerated aging experiments. However, the aged solvents of these samples still showed trace amounts of oxidative degradation products. These degradation products were not observed when the prepolymer solution contained a suitable antioxidant.

[0015] An object of the present invention is to provide a water-soluble, cross-linkable prepolymer for preparing a chemically stable cross-linked polymer gel, said water-soluble, cross-linkable prepolymer having the formula I:

[0016] R 1 -LBLR 2 (I)

[0017] in:

[0018] B is a backbone selected from the group consisting of:

[0019] Poly(ethylene glycol) (PEG): wherein n comprises 1 to 450 repeating units,

[0020] Oligo(ethylene glycol) (EG): wherein m comprises 1 to 12 repeating units,

[0021] Poloxamer: wherein p, q, and s are independent of each other and comprise 1 to 200 repeating units,

[0022] Trans-Poloxamers: wherein x, y, and z are independent of each other and comprise 1 to 200 repeating units;

[0023] L is selected from C3 to C 18 a linking group of a straight or branched alkyl chain;

[0024] R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are selected from the group consisting of: H; OH; acrylate; methacrylate; acrylamide; methacrylamide; but-3-en-2-one; formula trans-methacrylate, wherein R is an alkyl group and X=O, NH; vinyl sulfone; ethylene urea; ethylene carbonate; vinyl carbamate; ethylene thioester; ethylene thiourea; provided that when R1 is H or OH, R2 is not H or OH;

[0025] And provided that when L=C3 (n-propyl, isopropyl), then the terminal groups R1 and R2 are not acrylamide.

[0026] Preferably, the water-soluble, cross-linkable prepolymer has formula I, with the proviso that when m=8, L is not C11 (undecyl).

[0027] In one embodiment, the water-soluble, cross-linkable prepolymer is a water-soluble, cross-linkable dental prepolymer having Formula I for preparing a chemically stable, cross-linked dental polymer gel.

[0028] Preferably, R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are selected from the group consisting of: H; OH; acrylate; methacrylate; but-3-en-2-one; trans-methacrylates wherein R is an alkyl group and X=O, NH; vinyl sulfone; ethylene urea; ethylene carbonate; vinyl carbamate; ethylene thioester; ethylene thiourea; provided that when R1 is H or OH, R2 is not H or OH.

[0029] Another object of the present invention is to provide a water-soluble, cross-linkable prepolymer for preparing a chemically stable cross-linked polymer gel, wherein the water-soluble, cross-linkable prepolymer has the formula II:

[0030] R1-B-R2 (II)

[0031] in,

[0032] B is a main chain consisting of:

[0033] Trans-Poloxamers: wherein x, y, and z are independent of each other and comprise 1 to 200 repeating units;

[0034] R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are selected from the group consisting of: H; OH; acrylate; methacrylate; acrylamide; methacrylamide; but-3-en-2-one; formula trans-methacrylate, wherein R is an alkyl group and X=O, NH; vinyl sulfone; ethylene urea; ethylene carbonate; vinyl carbamate; ethylene thioester; ethylene thiourea; provided that when R1 is H or OH, R2 is not H or OH;

[0035] In one embodiment, the water-soluble, cross-linkable prepolymer is a water-soluble, cross-linkable dental prepolymer for preparing a chemically stable, cross-linked dental polymer gel, the water-soluble, cross-linkable dental prepolymer having Formula II.

[0036] Preferably, R1 and R2 are selected from the group consisting of: H; OH; acrylate; methacrylate; but-3-en-2-one; trans-methacrylates wherein R is an alkyl group and X=O, NH; vinyl sulfone; ethylene urea; ethylene carbonate; vinyl carbamate; ethylene thioester; ethylene thiourea; provided that when R1 is H or OH, R2 is not H or OH.

[0037] Another object of the present invention is to provide a method for preparing a chemically stable cross-linked polymer gel composition, preferably a chemically stable cross-linked dental gel composition, comprising the steps of:

[0038] a) dissolving the water-soluble, cross-linkable prepolymer described herein in a suitable solvent;

[0039] b) adding a phenolic free radical stabilizer or an aminooxy free radical stabilizer;

[0040] c) adding a free radical polymerization initiator;

[0041] d) applying a polymerization or cross-linking step to form said chemically stable resistant polymer gel composition.

[0042] Preferably, the free radical polymerization initiator is provided either as a solution in a suitable solvent or as a fine suspension.

[0043] Another object of the present invention is to provide a precursor composition for a chemically stable crosslinked polymer gel composition, such as a dental precursor composition for a chemically stable crosslinked dental polymer gel composition. The precursor composition preferably comprises 5% to 95% by weight of a stable, water-soluble, crosslinkable prepolymer of the present invention, 5% to 95% by weight of a suitable solvent, 0.001% to 10% by weight of a phenolic free radical stabilizer or an aminooxy free radical stabilizer, and 0.001% to 10% by weight of a free radical polymerization initiator.

[0044] The present invention also provides a chemically stable cross-linked polymer gel composition obtainable by cross-linking a precursor composition according to the present invention, wherein the chemically stable cross-linked polymer gel composition retains at least 95% of its initial dry mass after being subjected to the following steps: storage in water at 57°C for 8 weeks, followed by a washing step and a vacuum drying step to remove any water or solvent.

[0045] Also included are precursor compositions for medical or dental fillers, preferably precursor compositions for dental fillers, comprising the precursor composition of the present invention.

[0046] Other objects and advantages of the present invention will become apparent to those skilled in the art from a reading of the following detailed description taken with reference to the following illustrative drawings and appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 : Photographs of hydrogel samples obtained from different prepolymers during the photopolymerization efficiency test according to Application Example 5.

[0048] Figure 2 : Schematic diagram of an apparatus for analyzing photopolymerization efficiency. The following reference numerals are given below:

[0049] 301 = 2 mL polystyrene cuvette; 302 = liquid prepolymer composition; 303 = cured hydrogel; 304 = laser beam. DETAILED DESCRIPTION

[0050] Although methods and materials similar or equivalent to those described herein can be used in the practice of the present invention or in testing, suitable methods and materials will be described below.All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety.The publications and applications discussed herein are only provided as disclosures for use before the filing date of the present application.Anything herein should not be construed as admitting that the present invention has no right to disclose earlier than described due to prior invention.In addition, materials, methods and embodiments are only illustrative and are not intended to be limiting.

[0051] In case of conflict, the present specification, including definitions, will control.

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. As used herein, the following definitions are provided to facilitate understanding of the present invention.

[0053] As used in the specification and claims, the singular indefinite articles ("a," "an," and "the") include plural referents unless the context clearly dictates otherwise.

[0054] In some cases, the presence of broad words and phrases such as "one or more," "at least," "but not limited to," or other similar phrases should not be understood to mean that a narrower context is intended or required where such broad phrases may be absent.

[0055] The terms "preferred" and "preferably" refer to embodiments of the present disclosure that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the present disclosure.

[0056] The term "predominantly" with respect to a feature or characteristic means that the feature or characteristic is present to a greater extent than the opposite aspect of the feature or characteristic.

[0057] Further, the use of "or" means "and / or" unless stated otherwise.

[0058] Similarly, "comprise / include," its third person singular form (comprises / includes) and present participle form (comprising / including) are interchangeable and not intended to be limiting. The term "comprise" is generally used in the sense of including, that is, allowing the presence of one or more features or components.

[0059] It should also be understood that where the term "comprising" is used in the description of various embodiments, those skilled in the art will understand that in some specific cases, the language "consisting essentially of" or "consisting of" may be used alternatively to describe the embodiment.

[0060] Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (eg, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0061] Unless otherwise indicated, all numerical values used in the specification and embodiments to represent quantities or components, measurements of features, etc. should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters listed in the accompanying lists of the foregoing specification and embodiments may vary according to the desired characteristics sought to be obtained by those skilled in the art using the teachings of the present disclosure. At a minimum, and without attempting to limit the application of the doctrine of equivalents to the scope of the claimed embodiments, each numerical parameter should at least be interpreted in light of the number of reported significant figures and by applying ordinary rounding techniques.

[0062] In the context of the present invention, the term "composition" is used interchangeably with the term "formulation." As used herein, a "composition" refers to a mixture of ingredients or compounds prepared in a certain manner and used for a specific purpose. This concept also clearly relates to methods in which different compounds are combined to produce a final product.

[0063] As used herein, the term "hydrogel" refers to a gel in which the swelling agent is an aqueous solution. A hydrogel is a macromolecular polymer gel composed of a network of cross-linked polymer chains. It is primarily, but not exclusively, synthesized from hydrophilic prepolymers and is sometimes a colloidal gel with water as the dispersion medium. Hydrogels are highly absorbent natural or synthetic polymer networks. Due to their properties, hydrogels typically possess strong yet resilient mechanical properties, with elastic moduli ranging from a few Pascals to several MPa, ultimate strengths ranging from a few Pascals up to tens or hundreds of MPa, and deformations ranging from less than 0.001% to several thousand times the original. Several physical properties of a hydrogel are concentration-dependent. Increasing the concentration of a hydrogel can alter its pore radius, morphology, or permeability to different molecules. Those skilled in the art will recognize that the volume or dimensions (length, width, and thickness) of a hydrogel can be selected based on the specific requirements, such as the area or environment in which the hydrogel will be implanted or whether it must be biodegradable.

[0064] In polymer chemistry, "crosslinking" generally refers to the use of crosslinking to promote changes in the physical properties of a polymer. The term "crosslink" refers to the bonds that connect one polymer chain to another. These connections can take the form of covalent bonds (chemical crosslinks) or through hydrogen bonds, hydrophobic interactions, or chain entanglements (physical crosslinks). The polymer can be synthetic or natural. Crosslinking is a general term for the process of forming relatively short sequences of bonds or chemical bonds to connect two polymer chains together. In polymer chemistry, when a synthetic polymer is referred to as "crosslinked," it generally means that the entire polymer has been exposed to a crosslinking process. The resulting changes in mechanical properties are strongly dependent on the crosslink density. Low crosslink density increases the viscosity of the polymer melt. Moderate crosslink density transforms a viscous polymer into a material with elasticity and potentially high strength. Very high crosslink density can make a material very hard or glassy, such as phenolic materials. Crosslinks can be formed by chemical reactions, which can be triggered by heat, pressure, changes in pH, or radiation. For example, mixing an unpolymerized or partially polymerized material with a specific chemical called a crosslinking agent results in a chemical reaction that forms crosslinks. Materials that are typically thermoplastics may also be induced to crosslink by exposure to a radiation source such as electron beam, gamma radiation, or UV light.

[0065] The term "cross-linkable" refers to materials which are also defined herein as prepolymers capable of being "cross-linked."

[0066] The term "pre-polymer" refers to a monomer or monomer system that has been reacted to a medium molecular weight state. This material can be further polymerized to a fully cured high molecular weight cross-linked state through reactive groups. Therefore, a mixture of reactive polymer and unreacted monomers can also be referred to as a prepolymer. The terms "prepolymer" and "polymer precursor" are interchangeable. A prepolymer is a stable, usually partially polymerized chemical intermediate that can be fully polymerized at a later time. The term "cure" refers to hardening or partially hardening a composition by any mechanism, such as by heat, light, radiation, electron beam, microwaves, chemical reaction, or a combination thereof.

[0067] The term "cured" refers to a material or composition that has been hardened or partially hardened (eg, (co)polymerized or cross-linked) by curing.

[0068] "Precursor," "precursor composition," or "polymer precursor" refers to a substance prior to chemical reaction (polymerization). The terms "prepolymer," "polymer precursor," or "polymer intermediate" are used interchangeably.

[0069] The terms "chemically stable cross-linked polymer gel" and "chemically stable cross-linked polymer gel composition" are used interchangeably.

[0070] A "polymer gel" is broadly defined as a cross-linked polymer network swollen in a solvent. Cross-linked polymer gels possess unique chemical and physical properties. Among these are dramatic volume changes in response to the application of an electric field and to changes in solvent composition, pH, and temperature. These properties of polymer gels depend on, among other factors, the chemical structure and composition of the monomer units, primary and higher-order structures, interactions between polymer chains and solvent, and molecular motion. In particular, their unique properties, in contrast to linear polymers, arise from the three-dimensional network structure formed by cross-linking.

[0071] "Chemical stability" or "chemically stable" refers to a compound's resistance to change due to chemical reactions. Some compounds are very stable and resistant to change; however, others are unstable and degrade in the presence of water, solvents, air, or other factors. In other words, it is a material's tendency to resist change or breakdown due to internal reactions or due to the effects of air, heat, light, pressure, etc. Chemically stable materials are less reactive and therefore more resistant to degradation. A chemical is considered stable if it is not particularly reactive in the environment or during normal use and if it retains its useful properties over the timescale expected to be useful. In particular, its usefulness is retained in the presence of air, moisture, or heat and under the conditions of its intended application.

[0072] In particular, the chemically stable cross-linked polymer gel of the present invention refers to a gel material that is stable to or resistant to hydrolysis and oxidation.

[0073] "Hydrolytic stability" is the property of a material, such as a cross-linked polymer gel, to resist chemical breakdown (hydrolysis) in the presence of water or moisture.

[0074] Hydrolysis is any chemical reaction in which water molecules break one or more chemical bonds. The term is broadly applied to substitution, elimination, and fragmentation reactions in which water acts as a nucleophile. This stability of polymer gels also extends to other solvents, such as ethanol.

[0075] Stability or resistance to "oxidation" is a process in which a chemical substance is not altered by the addition of molecular oxygen or oxygen radicals.

[0076] Oxidation is the loss of electrons from a molecule, atom, or ion during a reaction. Oxidation occurs when the oxidation state of a molecule, atom, or ion increases. The opposite process, called reduction, occurs when electrons are gained or the oxidation state of an atom, molecule, or ion decreases.

[0077] In polymer science, the "backbone" chain of a polymer is the longest series of atoms covalently bonded together to form a continuous chain of molecules. This science is subdivided into the study of organic polymers, which consist of a carbon backbone, and inorganic polymers, whose backbones consist only of main group elements.

[0078] "Linking group" refers to a chemical moiety comprising a covalent bond or chain of atoms that covalently links at least two compounds. A linking group can be attached to any synthetically feasible position of the compound, but is preferably attached in a manner that avoids blocking the desired activity of the compound. Linking groups are well known in the art.

[0079] "End groups" are an important aspect of polymer synthesis and characterization. In polymer chemistry, an end group is a functional group or structural unit located at the end of a macromolecule or oligomer (IUPAC). In polymer synthesis, such as polycondensation and free radical type polymerization, end groups are commonly used and can be analyzed, for example, by nuclear magnetic resonance (NMR) to determine the average length of the polymer. Other methods that use end groups to characterize polymers are mass spectrometry and vibrational spectroscopy, such as infrared and Raman spectroscopy. These groups are not only important for the analysis of polymers, but they can also be used to graft onto and off polymer chains to generate new copolymers. Finally, they can also be used to crosslink polymers.

[0080] As used herein, the term "substituted" when referring to a moiety means that one or more (specifically up to 5, more specifically 1, 2 or 3) hydrogen atoms in the moiety are independently replaced by a corresponding number of substituents. As used herein, the term "optionally substituted" refers to substituted or unsubstituted. Of course, it should be understood that substituents are only at their chemically possible positions, and those skilled in the art can easily determine (experimentally or theoretically) whether a specific substitution is possible.

[0081] When two or more moieties are described as being "each independently" selected from a series of atoms or groups, this means that the moieties may be the same or different. Thus, the characteristics of each moiety are independent of the characteristics of one or more other moieties.

[0082] As used herein, the term "alkyl" refers to saturated and unsaturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, which are optionally substituted with one or more groups. In some embodiments, a straight chain or branched chain alkyl group has about 30 or fewer carbon atoms in its backbone (e.g., C1-C2 for a straight chain). 30 , for the branched chain, it is C3-C 30), or about 20 or less carbon atoms, such as 1 to 6 carbon atoms (defined as lower alkyl). Preferably, the alkyl groups of the present invention have 1 to 30, more preferably 1 to 20, even more preferably 3 to 18, more preferably 3 to 8, more preferably 3 to 6, most preferably 4 to 6 carbon atoms, and are straight or branched. The term "C1-C6 alkyl" represents a straight or branched alkyl chain having 1 to 6 carbon atoms. Exemplary C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.

[0083] Poloxamers are nonionic triblock copolymers (PEG-PPG-PEG) consisting of a central hydrophobic chain of polyoxypropylene (PPO, PPG, poly(propylene oxide), poly(propylene glycol)) flanked by two hydrophilic chains of polyoxyethylene (PEO, PEG, poly(ethylene oxide), poly(ethylene glycol)) (Almeida et al., 2013a; From: Nanostructures for Novel Therapy, 2017). Poloxamers are also known under the trade name and Well known.

[0084] Inverse or reverse poloxamer refers to a reverse block type (PPG-PEG-PPG) with a central hydrophilic chain flanked by two hydrophobic chains, such as those known under the trade name 10R5.

[0085] “(Meth)acrylate” is an abbreviation for acrylate, methacrylate or a combination thereof; “(meth)acrylic” is an abbreviation for acrylic acid, methacrylic acid or a combination thereof; and “(meth)acryloyl” is an abbreviation for acryloyl, methacryloyl or a combination thereof.

[0086] "Trans-methacrylate" is short for 2-((X)meth)acrylate, where X is a covalently bonded variant as shown below:

[0087]

[0088] The measurements presented include a single standard deviation (68% confidence interval) for the sample data set followed by a ± sign.

[0089] An object of the present invention is to provide a water-soluble crosslinkable prepolymer, such as a water-soluble crosslinkable dental prepolymer, for preparing a chemically stable crosslinked polymer gel, preferably a chemically stable crosslinked dental polymer gel, wherein the water-soluble crosslinkable prepolymer has formula I:

[0090] R 1 -LBLR 2 (I)

[0091] in:

[0092] B is a backbone selected from the group consisting of:

[0093] Poly(ethylene glycol) (PEG): wherein n comprises 1 to 450 repeating units,

[0094] Oligo(ethylene glycol) (EG): wherein m comprises 1 to 12 repeating units,

[0095] Poloxamer: wherein p, q, and s are independent of each other and contain 1 to 200 repeating units,

[0096] Trans-Poloxamers: wherein x, y, and z are independent of each other and comprise 1 to 200 repeating units;

[0097] L is selected from C3 to C 18 a linking group of a straight or branched alkyl chain;

[0098] R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are selected from the group consisting of: H; OH; acrylate; methacrylate; acrylamide; methacrylamide; but-3-en-2-one; formula trans-methacrylate, wherein R is an alkyl group and X=O, NH; vinyl sulfone; ethylene urea; ethylene carbonate; vinyl carbamate; ethylene thioester; ethylene thiourea; provided that when R1 is H or OH, R2 is not H or OH;

[0099] And provided that when L=C3 (n-propyl, isopropyl), then the terminal groups R1 and R2 are not acrylamide.

[0100] Preferably, the water-soluble, cross-linkable prepolymer has formula I, with the proviso that when m=8, L is not C11 (undecyl).

[0101] Preferably, R1 and R2 are selected from the group consisting of: H; OH; acrylate; methacrylate; but-3-en-2-one; trans-methacrylate, wherein R is an alkyl group and X=O, NH; vinyl sulfone; ethylene urea; ethylene carbonate; vinyl carbamate; ethylene thioester; ethylene thiourea; provided that when R1 is H or OH, R2 is not H or OH;

[0102] It should be apparent to those skilled in the art that polymers such as poly(ethylene glycol) generally do not have a precise molecular weight, but rather a molecular weight distribution. The molecular weight M, and therefore the number of repeating units n, is given as an average value. In contrast, oligomers (e.g., di-, tri-, or tetra(ethylene glycol) etc.) have a precise molecular weight and number of repeating units m.

[0103] In this document, the number given after the name or abbreviation of the polymer refers to its number average molecular weight (M n ), for example: PEG2k refers to M n = 2000 g / mol of poly(ethylene glycol).

[0104] Another object of the present invention is to provide a water-soluble crosslinkable prepolymer, preferably a water-soluble crosslinkable dental prepolymer, for preparing a chemically stable crosslinked polymer gel, preferably a chemically stable crosslinked dental polymer gel, wherein the water-soluble crosslinkable prepolymer has formula II:

[0105] R1-B-R2 (II)

[0106] in:

[0107] B is a main chain consisting of:

[0108] Trans-Poloxamers: wherein x, y, and z are independent of each other and comprise 1 to 200 repeating units;

[0109] R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are selected from the group consisting of: H; OH; acrylate; methacrylate; acrylamide; methacrylamide; but-3-en-2-one; formula trans-methacrylates wherein R is an alkyl group and X=O, NH; vinyl sulfone; ethylene urea; ethylene carbonate; vinyl carbamate; ethylene thioester; ethylene thiourea; provided that when R1 is H or OH, R2 is not H or OH.

[0110] Preferably, R1 and R2 are selected from the group consisting of: acrylate; methacrylate; acrylamide; methacrylamide; but-3-en-2-one; Trans methacrylate, wherein R is an alkyl group, X=O, NH; vinyl sulfone.

[0111] Preferably, R1 and R2 are selected from the group consisting of: acrylate; methacrylate; but-3-en-2-one; Trans methacrylate, wherein R is an alkyl group, X=O, NH; vinyl sulfone.

[0112] More preferably, R1 and R2 are selected from the group consisting of acrylates and methacrylates.

[0113] Preferably, the linking group is a C4 to C6 straight or branched chain alkyl group.

[0114] In a preferred embodiment, the water-soluble, cross-linkable prepolymer to be used may, in some embodiments, comprise one or more compounds selected from a non-exhaustive list comprising: natural polymeric materials (i.e., non-synthetic polymers, polymers that can be found in nature), and / or polymers derived from the extracellular matrix (ECM), such as gelatin, elastin, collagen, agar / agarose, chitosan, fibrin, proteoglycans; polyamino acids or derivatives thereof, preferably polylysine or gelatin methylcellulose; carboxymethylcellulose; polysaccharides and derivatives thereof, preferably glycosaminoglycans, such as hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate or alginate; nucleotides; lipids; fatty acids; polylactic acid; lactic acid; cationic polyallyl ammonium chloride, and any derivatives, fragments and combinations thereof.

[0115] Water-soluble cross-linkable prepolymer can also comprise one or more synthetic or semi-synthetic biodegradable materials.According to the degradation rate of material, cells can migrate into wherein and may replace it.The example of such material is the polymer of hydroxyapatite, poly(lactic acid-co-glycolic acid), lactide and glycolide, caprolactone polymer, hydroxybutyric acid, polyanhydrides, polyester, polyphosphazene, polyphosphate, polycaprolactone (PCL) or the combination of PCL, caprolactone, urea-pyrimidone, poly-(N-isopropylacrylamide), polyvinylpyrrolidone and poly-(glycerol sebacate acrylate).

[0116] Other suitable prepolymers according to the present invention may comprise one or more compounds selected from the following non-exhaustive list: polypropylene, polypropylene oxide or derivatives thereof, polymethylenoxide or derivatives thereof, polyethylene, polyethylene oxide or derivatives thereof, polyacrylates or derivatives thereof, polyvinyl alcohol (PVA) or derivatives thereof, polyvinyl pyrrolidone (PVP) and derivatives thereof, and combinations thereof and copolymers containing any of these polymers.

[0117] In one embodiment, the water-soluble prepolymer composition comprises an antimicrobial, antibacterial, antifungal, or antiviral material, such as a quaternary ammonium compound (QAC), a cephalosporin, a penicillin, an aminoglycoside, gentamicin, vancomycin, or undecylenic acid, an antimicrobial peptide, poly (D, l-lactide) (PDLLA), silver nanoparticles, or chitlac.

[0118] In the most preferred embodiment, the water-soluble prepolymer material is not cross-linked or is minimally cross-linked to maintain the composition in a suitable needle injectable form. If desired, the cross-linking agent and its amount can be selected by the operator, and those skilled in the art can easily envision these parameters based on routine practice.

[0119] Another object of the present invention is to provide a method for preparing a chemically stable cross-linked polymer gel composition (e.g., a chemically stable cross-linked dental polymer gel), the method comprising the steps of:

[0120] a) dissolving the water-soluble, crosslinkable prepolymer of the invention as defined above in a suitable solvent;

[0121] b) adding a phenolic free radical stabilizer or an aminooxy free radical stabilizer;

[0122] c) adding a free-radical polymerization initiator as a solution in a suitable solvent or as a fine suspension;

[0123] d) applying a polymerization or cross-linking step to form said chemically stable resistant polymer gel composition.

[0124] It is worth noting that steps a) to c) are interchangeable and can be performed in any other order, provided that the last step comprises polymerization or cross-linking according to step d).

[0125] "Phenolic free radical" or phenolic antioxidants (AOs), also known as primary antioxidants, are highly effective, non-discoloring stabilizers for organic matrices susceptible to oxidation. They act as free radical scavengers, primarily protecting the finished product—namely, stable crosslinked polymer gel compositions. Additionally, they are often used to improve the storability and shelf life of curable monomer and polymer compositions by inhibiting free radical polymerization.

[0126] According to a preferred embodiment, the phenol-based free radical stabilizer is selected from the group consisting essentially of unsubstituted or methyl-, ethyl- or tert-butyl-substituted phenols or mixtures thereof.

[0127] "Aminoxy radicals" are chemical species containing an R2N–O· functional group. They are also known as nitroxyl radicals and nitrogen oxides, but IUPAC discourages the use of these terms because they incorrectly imply the presence of a nitro group. They are free radicals and are structurally related to hydroxylamine and N-oxoammonium salts, with which they can interconvert through a series of redox steps. Sterically hindered aminooxy radicals such as TEMPO and TEMPOL (4-hydroxy-TEMPO) are persistent (stable) free radicals. They are often used as free radical scavengers, inhibitors, or stabilizers. It should be apparent to those skilled in the art that other free radical scavengers or persistent (stable) free radicals, such as phenothiazines or galvinoxyl radicals, can be used instead.

[0128] The term "suitable solvent" refers to a non-reactive solvent, which is a solvent that does not (co)polymerize into the curable composition, in which the components of the composition can be dissolved homogeneously at the desired concentrations, and does not inhibit the polymerization reaction.

[0129] According to a preferred embodiment, the suitable solvent consists essentially of water (deionized water, or water containing ions or buffers), acetone, DMSO, or an alcohol or a mixture thereof. In another embodiment of the present invention, the suitable solvent may contain other agents or compounds. In another embodiment, these agents or compounds are NaOCl, EDTA, HEDP, chlorhexidine, NaOH, Ca(OH)2 or other agents commonly used for cleaning, disinfecting or rinsing root canals.

[0130] The term "free radical polymerization initiator", also referred to herein as a "curing agent", refers to a compound that generates free radicals to initiate a free radical polymerization reaction. The generation of free radicals can be triggered thermally by the decomposition of a thermally labile compound ("thermal initiator") or photochemically ("photoinitiator"). It is well understood by those skilled in the art that the thermal activation barrier of a thermal initiator can be lowered by adding other compounds, thereby producing a so-called "redox" or "two-component" initiator or initiation system.

[0131] In order to harden once or when injected into a structure, a free radical polymerization initiator is required, also referred to herein as a "crosslinker" or "curing agent." It will be understood that a curing agent can be used to chemically crosslink a water-soluble, crosslinkable prepolymer.

[0132] In a preferred embodiment, the curing agent is a photoinitiator.A "photoinitiator" is a molecule that generates reactive species (free radicals, cations, or anions) when exposed to electromagnetic radiation such as UV or visible light. Examples of suitable visible or UV light activated photoinitiators include ITX 4-isopropyl-9-thioxanthone, Lucirin TPO 2,4,6-trimethylbenzoyl-diphenyl-phosphine oxide, Irgacure 184 1-hydroxy-cyclohexyl-phenyl-ketone, Irgacure 2959 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one, Irgacure 819 phosphine oxide, phenyl bis(2,4,6-trimethylbenzoyl), LAP lithium phenyl-2,4,6-trimethylbenzoylphosphinate, Riboflavin 7,8-dimethyl-10-((2R,3R,4S)-2,3,4,5-tetrahydroxypentyl)benzo[g]pteridine-2,4(31-1,1OH)-dione, Rose Bengal 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein, PL-BDK biphenyl dimethyl ketal, PL-CPK 1-hydroxy-cyclohexylphenyl-ketone, PL-HMPP 2-hydroxy-2-methyl-1-phenyl-1-propanone, camphorquinone, 3-(4-Quantucure BPQ benzoylphenoxy)-2-hydroxy-N,N,N-trimethyl-1-propylammonium chloride, APi-180 hydroxyalkyl acetone, bis(acyl)phosphine oxide or mono(acyl)phosphine oxide-based initiators. In an embodiment, a bis(acyl)phosphine oxide (BAPO)-derived photoinitiator is used, such as bis(2,4,6-trimethylbenzoyl)phosphinic acid (BAPO-OH). Other examples of suitable BAPO photoinitiators are given in the following references, for example: K. Dietliker, A compilation of photoinitiators commercially available for UV today, SITA Technology Ltd, Edinbergh, London, 2002; J. V. Crivello, K. Dietliker, G. Bradley, Photoinitiators for free radical cationic & anionic photopolymerisation, John Wiley & Sons, Chichester, West Sussex, England, New York, 1998.; S. Benedikt, J. Wang, M. Markovic, N. Moszner, K. Dietliker, A. Ovsianikov, H.Grutzmacher, R. Liska, J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 473-479.; T. Majima, W. Schnabel, W. Weber, Makromol. Chem. 1991, 192, 2307-2315; S. Li, F. Wu, M. Li, E. Wang, Polymer 2005,46,1 1934-1 1939;MATasdelen,B.Karagoz,N.Bicak,Y.Yagci,Polymer Bulletin 2008,59,759-766;BDFairbanks,MPSchwartz,CNBowman,KSAnseth,Biomaterials 2009,30,6702-6707.;A.Huber,A.Kuschel,T.Ott,G.Santiso-Quinones,D.Stein,J.Brauer,R.Kissner,F.Krumeich,H.Schonberg,J.Levalois-Grutzmacher,H.Grut zmacher,Angew.Chem.2012,124,4726^1730.G.; Muller,M.Zalibera,G.Gescheidt,A.Rosenthal,G.Santiso-Quinones,K.Dietliker,H.Grutzmacher,Macromol.Rapid Commun.2015,36,553-557,WO 2006056541,WO2011003772,WO 2014053455,WO 2014095724,WO2019175112,WO2019175319. .

[0133] In a specific embodiment, the free radical polymerization initiator of step c) is a photoinitiator consisting of common UV, violet, blue or other visible light activated photoinitiators.

[0134] In another embodiment, the photoinitiator can be activated by a multiphoton process (eg, two-photon absorption) using UV, visible, or infrared light.

[0135] Preferably, the photoinitiator is selected from the group consisting of quinones, α-hydroxyketones, acylgermanium derivatives, bis(acyl)phosphine oxide derivatives and mono(acyl)phosphine oxide derivatives, or mixtures thereof.

[0136] Another object of the present invention is to provide a precursor composition for a chemically stable, crosslinked polymer gel composition, wherein the precursor composition comprises 5% to 95% by weight of a stable, water-soluble, crosslinkable prepolymer according to the present invention, 5% to 95% by weight of a suitable solvent, 0.001% to 10% by weight of a phenolic free radical stabilizer or an aminooxy free radical stabilizer, and 0.001% to 10% by weight of a free radical polymerization initiator. Preferably, the precursor composition is a dental precursor composition of a chemically stable, crosslinked dental polymer gel composition. The dental precursor composition preferably comprises 5% to 95% by weight of a stable, water-soluble, crosslinkable dental prepolymer according to the present invention, 5% to 95% by weight of a suitable solvent, 0.001% to 10% by weight of a phenolic free radical stabilizer or an aminooxy free radical stabilizer, and 0.001% to 10% by weight of a free radical polymerization initiator.

[0137] Another object of the present invention is to provide a precursor composition of a chemically stable cross-linked polymer gel composition, wherein the precursor composition comprises 5 wt% to 80 wt% of a stable water-soluble cross-linkable prepolymer according to the present invention, 20 wt% to 95 wt% of a suitable solvent, 0.001 wt% to 5 wt% of a phenolic free radical stabilizer or an aminooxy free radical stabilizer, and 0.001 wt% to 5 wt% of a free radical polymerization initiator.

[0138] Preferably, the precursor composition is a chemically stable crosslinked dental polymer gel composition. The dental precursor composition preferably comprises 5% to 80% by weight of a stable, water-soluble, crosslinkable dental prepolymer according to the present invention, 20% to 95% by weight of a suitable solvent, 0.001% to 5% by weight of a phenolic free radical stabilizer or an aminooxy free radical stabilizer, and 0.001% to 5% by weight of a free radical polymerization initiator.

[0139] Those skilled in the art will appreciate that the precursor compositions of the present invention as described herein are susceptible to variation and modification, and that the proportions of the precursor compositions may be adjusted above or below the amounts shown.

[0140] According to an embodiment, the precursor composition further comprises 1 wt% to 90 wt% of an inorganic filler (also referred to herein as an additive).Inorganic fillers may be included to adjust mechanical, physical or optical properties.

[0141] Preferably, the inorganic filler is a powder or a suspension and is selected from the group consisting of water-insoluble metal oxides or salts.

[0142] According to an embodiment, the precursor composition also contains other fillers (or additives) that are inorganic or organic, natural or synthetic, monomeric or polymeric, in order to modify and improve (primarily but not only) their mechanical properties. Reinforcement with organic fibers (e.g., Kevlar (poly-p-phenylene terephthalamide), cellulose fibers or carbon fibers) is also possible.

[0143] The term "powder" refers to a dry bulk material comprising a plurality of fine particles that flow freely when shaken or tilted.

[0144] The term "particle" or "microparticle" refers to a solid substance having a geometrically definable shape. The shape can be regular or irregular. Particles can generally be analyzed, for example, with respect to particle size and particle size distribution. A particle can comprise one or more crystallites. Thus, a particle can comprise one or more grains.

[0145] Fillers can be selected from one or more of a variety of materials suitable for incorporation into compositions for, for example, dental applications, such as fillers currently used in dental composites and dental (e.g., crown) products, etc. Fillers are typically non-toxic and suitable for use in the oral cavity. Fillers can be radiopaque, radiopaque, or non-radiopaque. In some embodiments, fillers typically have a refractive index of at least 1.25, 1.3, 1.33, 1.470, 1.480, 1.500, 1.510, 1.520, 1.530, or 1.540.

[0146] Also provided is a chemically stable cross-linked polymer gel composition obtainable by cross-linking a precursor composition of the present invention, wherein the chemically stable cross-linked polymer gel composition retains at least 95% of its initial dry mass after being subjected to the following steps: storage in water at 57°C for 8 weeks, followed by a washing step and a vacuum drying step to remove any water or solvent.

[0147] Also included is a chemically stable cross-linked polymer gel composition obtainable by the method according to the present invention, wherein the chemically stable cross-linked polymer gel composition retains at least 95% of its initial dry mass after being subjected to the following steps: storage in water at 57°C for 8 weeks, followed by a washing step and a vacuum step to remove any water or solvent.

[0148] The present invention also relates to a precursor composition for a medical or dental filler, preferably a precursor composition for a dental filler, comprising the precursor composition according to the present invention as described above.

[0149] As used herein, "medical or dental filling composition" refers to a material that is capable of filling a hollow structure in the human or animal body (such as, but not limited to, a vein, artery, bone, tooth, or any other natural tissue), for example, to treat, cure, or alleviate any medical condition in the dental, neurological, cardiovascular, or orthopedic fields, or any other human or veterinary fields. It can also be used to adhere to or bond to any natural tissue or surface. Dental filling compositions are used to fill and seal hollow structures in teeth, jawbone, or buccal mucosa. Curable dental filling compositions can also be used to bond dental articles to tooth structures, to form a coating (e.g., a sealant or varnish) on the tooth surface, can be used as a restorative that is placed directly in the oral cavity and cured in situ, or can be used to manufacture a prosthesis outside the oral cavity that is subsequently adhered to the oral cavity.

[0150] Curable dental filling compositions include, for example, adhesives (e.g., dental and / or orthodontic adhesives), cements (e.g., one-component cements), primers (e.g., orthodontic primers), liners (applied to the base of a cavity to reduce tooth sensitivity), coatings such as sealants (e.g., pit and fissure sealants) and varnishes, endodontic sealants (e.g., epoxy-based sealants); and resin restoratives (also known as direct composites) such as dental fillings, as well as crowns, bridges, and articles for dental implants. Highly filled dental compositions can also be used as mill blanks from which crowns can be milled.

[0151] Surprisingly, the applicant observed that the cross-linked polymer gel compositions of the present invention (functionalized PEG derivatives with hydrophobic linking groups) described above exhibited remarkable chemical stability, as shown by the constant dry weight after accelerated aging experiments, compared to the reduced dry weight obtained with cross-linked polymer gel compositions based on PEG-DMA or PEG-DAAm. As shown in Examples 1-11, the derivatives can be obtained from PEG in three to five synthetic steps. PEG is first converted to PEG-dimethylsulfonate (PEG-dimesylate), which is then reacted with a monoalcohol salt of a suitable diol and then esterified with acryloyl chloride or methacryloyl chloride to produce the corresponding (meth)acrylate. To obtain the corresponding (meth)acrylamide, the PEG containing the linking group is converted via dimethylsulfonate to the corresponding diamine and then amidated with acryloyl chloride or methacryloyl chloride, similar to the established process for converting PEG to PEG DAAm in the literature [Browning, MB; Cosgriff-Hernandez, E. Biomacromolecules 2012, 13(3), 779.].

[0152] As shown in Comparative Example 2, PEG-DMA-based and PEG-DAAm-based cross-linked polymer gel compositions degrade significantly in an aqueous environment and lose up to 18% of their dry content when aged at 57°C for 8 weeks. Unexpectedly, the extent of degradation of the PEG-DAAm-based cross-linked polymer gel composition samples (18.0%) was greater than that of the PEG-DMA-based samples (12.3%), even though the amide bonds in PEG-DAAm should be inherently more resistant to hydrolysis than the ester bonds in PEG-DMA. The efficiency of PEG-DAAm photopolymerization and cross-linking is much lower than that of PEG-DMA, as evidenced by the significantly lower polymerization mass (11%, compared to 53% in the case of PEG-DMA, Comparative Example 1). The reduced polymerization efficiency leads to a lower degree of cross-linking and, therefore, a more fragile gel network, which negatively affects the chemical stability of the PEG-DAAm-based cross-linked polymer gel compositions.

[0153] Due to this combination of disadvantages, PEG-DMA and PEG-DAAm cannot be used as precursors for cross-linked polymer gel compositions that require efficient polymerization and long-term chemical stability. In contrast, as described above, functionalized PEG derivatives with aliphatic linking groups can be efficiently polymerized and allow the preparation of hydrogels or cross-linked polymer gel compositions of the present invention that have significant chemical stability. Therefore, they are suitable precursors for cross-linked polymer gel compositions that must remain stable and not degrade under physiological conditions, for example.

[0154] As demonstrated in Comparative Examples 1 and 2, PEG-methacrylate derivatives with hydrophobic linking groups polymerized more efficiently than PEG-DMA (79% and 53% polymerized mass, respectively) and retained 100% of their dry weight even after treatment at elevated temperatures. In preferred embodiments, the aliphatic linking group increases the hydrophobicity of the derivative, which positively impacts polymerization efficiency and the resistance of the cross-linked polymer gel to chemical degradation and hydrophilic attack.

[0155] The stability-enhancing effect of the linking group is further demonstrated in Comparative Example 3, where the hydrolysis resistance of non-crosslinkable compounds with saturated ester rather than unsaturated methacrylate end groups is compared with and without the aliphatic linking group. After a short period of time, hydrolysis products can be clearly detected in the derivative without the linking group, while the derivative with the linking group remains stable.

[0156] However, cross-linked polymer gel compositions containing PEG can degrade not only through end group hydrolysis but also through oxidative degradation. To ensure long-term stability in an oxidative environment, suitable antioxidants or stabilizers are required to capture the denatured oxygen species.

[0157] In a preferred embodiment, suitable antioxidants meet the following properties:

[0158] Compatible with waterborne prepolymer formulations;

[0159] It does not inhibit any free radical-based polymerization / cross-linking process or is not consumed in the process, while effectively inhibiting denaturation based on oxygen free radicals;

[0160] Remains in the cross-linked polymer gel composition after curing to ensure long-term oxidative stability.

[0161] Most common phenolic antioxidants are either insoluble in prepolymer formulations or unstable over the desired product shelf life. Furthermore, many of these compounds inhibit free radical polymerization. Adding such antioxidants to crosslinkable prepolymer formulations reduces crosslinking efficiency. Furthermore, such antioxidants fail to protect crosslinked polymer gel compositions from oxidative degradation because the antioxidant is consumed during the free radical crosslinking process.

[0162] Thus, another embodiment of the present invention discloses suitable antioxidants that are soluble or miscible in aqueous prepolymer formulations, inhibit oxidative degradation of the crosslinked polymer gel composition, and are retained within the crosslinked polymer gel network. Yet another embodiment discloses antioxidants that unexpectedly inhibit oxidative degradation while not affecting the free radical polymerization process and not being consumed by the reaction (Comparative Example 4).

[0163] Another embodiment of the present invention describes a process wherein the chemically stable prepolymer of the present invention and an antioxidant are combined with a suitable free radical polymerization initiator and a polymerization or crosslinking step to form a chemically stable crosslinked polymer gel composition. In one embodiment of the present invention, crosslinking is accomplished by photopolymerization.

[0164] Another aspect of the present invention is the above-described precursor composition of a chemically stable cross-linked polymer gel composition. In embodiments, the composition further comprises an inorganic or other filler to adjust the mechanical, physical, or optical properties of the composition or the resulting cross-linked polymer gel composition, such as viscosity, adhesion, hydrophilicity or hydrophobicity, elastic modulus, maximum strain under deformation, compressive strength, equilibrium swelling ratio, expansion capacity, internal osmotic pressure, color, refractive index, or radiopacity.

[0165] Such compositions can be used as injectable, curable fillers in the medical or dental fields (preferably the dental field), or any other application requiring a stable water-based material to fill hollow structures or cover surfaces. In a preferred embodiment, the use of PEG-based prepolymers and the use of water as an inert, non-toxic solvent enables the preparation of formulations with excellent biocompatibility. In another embodiment, such formulations exhibit at least as high biocompatibility as formulations containing PEG-DMA instead of the prepolymers disclosed herein, as demonstrated by >70% cell viability in an in vitro cytotoxicity assay.

[0166] In another embodiment, the adjustable viscosity allows such formulations to have high surface wettability and hydrophilicity, enabling them to be injected through fine needles or cannulas (20 μm-1 mm inner diameter) and to completely fill thin, small, branched or complex hollow structures (5 μm-2 mm in diameter, 1 mm-20 cm in length), unlike existing high viscosity paste sealers, fillers or cements, which often result in incomplete filling of, for example, complex, branched tubular root canal systems.

[0167] In yet another embodiment, the formulation can also be used to fill larger, bulky structures. Thus, converting the formulation into a crosslinked polymer gel composition by crosslinking allows implants to be placed in all areas of the human or animal body with minimal invasiveness. In contrast, existing medical fillers for dental, orthopedic, ophthalmic, neurological, or cardiovascular applications typically require the use of toxic monomers or solvents, and their high viscosity hinders administration through fine needles or catheters.

[0168] In another preferred embodiment, polymerization shrinkage, which typically occurs upon crosslinking, is compensated by self-expansion resulting from the absorption of water or other liquids from the surrounding environment. Thus, such formulations can be used to tightly seal hollow structures within the human or animal body while avoiding shrinkage-based leakage and other treatment failures, such as in endodontic treatment, where shrinkage of the sealant can lead to bacterial leakage into the filled root canal and thereby reinfection of the root canal system.

[0169] Another aspect of the present invention describes chemically stable crosslinked polymer gel compositions obtained by the above-described methods or by crosslinking the above-described precursor compositions. These compositions offer the advantages common to hydrogels or other crosslinked polymer gel compositions, such as tissue-like mechanical properties, high biocompatibility, high elastic modulus, maximum strain under deformation, and compressive strength. These gels are chemically stable under physiological conditions. Therefore, they can be used in medical or dental applications to permanently seal cavities or other hollow structures.

[0170] In addition to the aforementioned advantages of hydrogel or other polymer gel compositions, applications as endodontic sealants preferably benefit from tunable mechanical properties. This allows for the preparation of endodontic sealants with mechanical properties similar to those of natural pulp tissue and also enables easy removal of the sealant, which may be desirable in the event of retreatment.

[0171] In another embodiment of the present invention, the chemically stable, cross-linked polymer gels of the present invention provide a seal against the migration of microorganisms, such as bacteria, or leakage that would not be achieved if the polymer gel degraded over time.

[0172] In yet another embodiment, the chemically stable cross-linked polymer gel of the present invention permanently resists mechanical stimulation, such as compression, traction or expansion of the gel. Preferably, in the case of deformation / strain, it is 0.001% and 10%. In another preferred embodiment, the deformation / strain is from 2 up to 10 9 cycles are cyclically applied to the material.

[0173] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It should be understood that the invention includes all such variations and modifications without departing from its spirit or essential characteristics. The invention also includes all steps, features, compositions and compounds mentioned or indicated in this specification, whether individually or collectively, and any and all combinations or any two or more of said steps or features. Therefore, this disclosure is to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and all variations that come within the meaning and range of equivalents are intended to be encompassed therein.

[0174] Various references are cited throughout this specification, each of which is incorporated herein by reference in its entirety.

[0175] The foregoing description will be more fully understood with reference to the following examples. However, such examples are illustrative of methods of practicing the invention and are not intended to limit the scope of the invention.

[0176] Example

[0177] Example 1

[0178] Poly (ethylene glycol) (1 equivalent) is loaded into a round-bottom flask equipped with a magnetic stirring bar. Dichloromethane (DCM, 0.17 M) and triethylamine (1.6 equivalents) are added and the solution is cooled to 0 ° C. Then methanesulfonyl chloride (1.25 equivalents) is slowly added, the reaction is stirred at 0 ° C for 45 minutes, and heated to room temperature overnight. Once completed, the reaction is quenched with water and extracted with DCM. The aqueous phase is washed with DCM. The combined organic layer is dried over magnesium sulfate. The mixture is filtered and the filtrate is concentrated to about 5% volume under reduced pressure. At room temperature, the obtained crude oil product is added to rapidly stirred ether and stirred for 30 minutes. The mixture is then cooled to 0 ° C and stirred for another 30 minutes. The precipitate is collected by vacuum filtration on a glass frit, washed with ether, and dried under high vacuum to obtain poly (ethylene glycol) dimethyl sulfonate (PEG DOM), which is a white solid. 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.34-4.27 (m, 4H, MsOCH2), 3.72-3.63 (m, 4H, CH2), 3.51 (br s, main chain), 3.17 (s, 6H, CH3).

[0179] Example 2

[0180] Under an argon atmosphere, anhydrous THF (0.15M relative to PEG DOM) and sodium hydride (2 equivalents, 60% dispersion in mineral oil) were charged into a round-bottom flask equipped with a magnetic stir bar. The solution was cooled in an ice bath and 1,3-propylene glycol (2.5 equivalents) was slowly added. The mixture was stirred for 6 hours while warming to room temperature. Poly(ethylene glycol) dimethyl sulfonate (1 equivalent) was then slowly added to the mixture. A reflux condenser was then connected and the reaction was heated to reflux overnight. When complete conversion was reached, the reaction mixture was cooled to room temperature. Once cooled, water and dichloromethane were added. The aqueous phase was further extracted with dichloromethane (2 / 3 times). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to approximately 5% volume. The remaining residue was vigorously stirred, and then diethyl ether was added until a large amount of precipitate was observed. The solution was further cooled in an ice bath to maximize the yield of the precipitate. The precipitate was collected by vacuum filtration on a glass frit, washed with ether, and further dried under high vacuum to afford the product as a white solid. PEG DP 2k (di-n-propyl): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.34 (t, J = 5.2 Hz, 2H, OH), 3.51 (br s, backbone), 1.63 (p, J = 6.5 Hz, 4H, CH2).

[0181] Example 3

[0182] Under an argon atmosphere, anhydrous THF (0.15M relative to PEG DOM) and sodium hydride (2 equivalents, 60% dispersion in mineral oil) were charged into a round-bottom flask equipped with a magnetic stir bar. The solution was cooled in an ice bath and 1,2-propylene glycol (2.5 equivalents) was slowly added. The mixture was stirred for 5 hours while warming to room temperature. Poly(ethylene glycol) dimethyl sulfonate (1 equivalent) was then slowly added to the mixture. A reflux condenser was then connected, and the reaction was heated to reflux overnight. When complete conversion was reached, the reaction mixture was cooled to room temperature. Once cooled, water and dichloromethane were added. The aqueous phase was further extracted with dichloromethane (2 / 3 times). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to about 5% volume. The remaining residue was vigorously stirred, and then diethyl ether was added until a large amount of precipitate was observed. The solution was further cooled in an ice bath to maximize the yield of the precipitate. The precipitate was collected by vacuum filtration on a glass frit, washed with ether, and further dried under high vacuum to afford the product as a white solid. PEG DiP 2k (diisopropyl from (S)-propane-1,2-diol): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.51 (d, J = 4.5 Hz, 2H, OH), 3.51 (br s, backbone), 3.43-3.33 (m, 2H, CH), 1.01 (d, J = 6.1 Hz, 6H, CH3).

[0183] Example 4

[0184] Other linking groups were introduced in a similar manner. PEG DBu 2k (di-n-butyl): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.34 (t, J = 5.0 Hz, 2H, OH), 3.51 (br s, backbone), 3.37 (t, J = 6.0 Hz, 4H, CH2), 1.58-1.34 (m, 8H, CH2). PEG DiBu2k (diisobutyl): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.36 (t, J = 5.3 Hz, 2H, OH), 3.51 (br s, backbone), 3.30-3.12 (m, 4H, CH2), 1.74 (h, J = 6.6 Hz, 2H, CH), 0.83 (d, J = 6.8 Hz, 6H, CH3). PEG DPe 2k (di-n-pentyl): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.32 (t, J = 5.0 Hz, 2H, OH), 3.51 (br s, main chain), 3.36 (t, J = 6.1 Hz, 4H), 1.56-1.22 (m, 12H, CH2). PEG DHe 2k (di-n-hexyl): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.30 (t, J = 5.0 Hz, 2H, OH), 3.51 (br s, main chain), 3.36 (t, J = 6.0 Hz, 4H, CH2), 1.53-1.21 (m, 16H, CH2).

[0185] Example 5

[0186] Poly (ethylene glycol) di (propan-3-ol) (PEG DP 2k, 1 equivalent) is loaded into a round-bottom flask equipped with a magnetic stirring bar and dissolved in anhydrous DCM (0.17 M). Triethylamine (1.5 equivalents) is added to the solution. Methacryloyl chloride (freshly distilled, 1.3 equivalents) is then added at 0 ° C and the reaction is stirred overnight at 25 ° C in the dark. Once completed, DCM is used as eluent to pass the mixture through a basic alumina column. The filtrate is concentrated to about 5% volume under reduced pressure. At room temperature, the obtained crude oily product is added to rapidly stirred ether and stirred for 30 minutes. The mixture is then cooled to 0 ° C and stirred for another 30 minutes. The precipitate is collected by vacuum filtration on a glass frit, washed with ether, and dried under high vacuum to obtain the product as a white solid. PEG DPMA2k (di-n-propyl methacrylate): 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.01 (dd, J = 0.8, 1.7 Hz, 2H, vinyl), 5.47 (t, J = 1.7 Hz, 2H, vinyl), 4.16 (t, J = 6.4 Hz, 4H, CO2CH2), 3.57 (br s, main chain), 3.49 (t, J = 6.4 Hz, 4H, CH2), 1.92–1.84 (m, 4H, CH2), 1.86 (s, 6H, CH3); 13C NMR (CDCl3, 300 MHz) δ (ppm): 167.3, 136.3, 125.2, 70.6, 70.5, 70.2, 67.7, 61.8, 28.9, 18.2.

[0187] Example 6

[0188] Poly(ethylene glycol) di(propan-2-ol) (PEG DiP 2k, 1 equivalent) was loaded into a round-bottom flask equipped with a magnetic stir bar and dissolved in anhydrous DCM (0.17 M). Triethylamine (1.5 equivalents) was added to the solution. Methacryloyl chloride (freshly distilled, 1.3 equivalents) was then added at 0°C and the reaction was stirred overnight in the dark at 25°C. Once complete, the mixture was passed through a basic alumina column using DCM as eluent. The filtrate was concentrated to approximately 5% volume under reduced pressure. At room temperature, the resulting crude oily product was added to rapidly stirred ether and stirred for 30 minutes. The mixture was then cooled to 0°C and stirred for an additional 30 minutes. The precipitate was collected by vacuum filtration on a glass frit, washed with ether, and dried under high vacuum to obtain the product as a white solid. PEG DiPMA2k (diisopropyl methacrylate): 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.08 (s, 1H), 5.52 (s, 1H), 5.17–5.01 (m, 1H), 4.31–4.22 (m, 1H), 4.13–4.04 (m, 1H), 3.62 (s, main chain), 1.91 (s, 3H), 1.23 (d, J=6.4 Hz, 3H); 13C NMR (CDCl3, 300 MHz) δ (ppm): 136.60, 125.38, 73.70, 70.55, 69.78, 18.35, 16.70.

[0189] Example 7

[0190] Other esterification reactions were carried out in a similar manner.

[0191] PEG DMA 2k (dimethacrylate): 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.10 (s, 2H, vinyl), 5.54 (s, 2H, vinyl), 4.35–4.17 (m, 4H, CO2CH2), 3.77–3.66 (m, 4H), 3.61 (br s, main chain), 1.92 (s, 6H, CH3); 13C NMR (CDCl3, 300 MHz) δ (ppm): 166.9, 135.8, 125.4, 70.3, 68.8, 63.6, 18.1. PEG DBuMA 2k (di-n-butyl methacrylate): 1H NMR (CDCl3, 200 MHz) δ (ppm): 6.07 (s, 2H, vinyl), 5.52 (s, 2H, vinyl), 4.14 (t, J = 6.1 Hz, 4H, CO2CH2), 3.62 (br s, main chain), 3.47 (t, J = 6.1 Hz, 4H, CH2), 1.91 (s, 6H, CH3), 1.81–1.55 (m, 8H); 13C NMR (CDCl3, 300 MHz) δ (ppm): 167.5, 136.5, 125.4, 70.9, 70.7, 70.7, 70.3, 64.6, 26.3, 25.5, 18.4. PEG DiBuMA 2k (diisobutyl methacrylate): 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.04 (s, 2H, vinyl), 5.50 (s, 2H, vinyl), 4.09 (dd, J = 10.8, 5.7 Hz, 2H, CH2), 4.00 (dd, J = 10.9, 6.1 Hz, 2H, CH2), 3.59 (s, main chain), 3.42–3.29 (m, 6H, CH3), 2.11 (h, J = 6.4 Hz, 2H, CH), 1.89 (s, 6H, CH3), 0.93 (d, J = 6.9 Hz, 6H, CH3); 13C NMR (CDCl3, 300MHz) δ (ppm): 167.4, 136.5, 125.3, 73.3, 70.6, 66.7, 33.3, 18.4, 14.1.PEG DPeMA 2k (di-n-pentyl methacrylate): 1H NMR (CDCl3, 200 MHz) δ (ppm): 6.09 (s, 2H, vinyl), 5.54 (s, 2H, vinyl), 4.14 (t, J = 6.5 Hz, 4H, CO2CH2), 3.64 (br s, main chain), 3.47 (t, J = 6.3 Hz, 4H, CH2), 1.94 (s, 6H, CH3), 1.80–1.54 (m, 8H), 1.52–1.36 (m, 4H); 13C NMR (CDCl3, 300 MHz) δ (ppm): 167.6, 136.6, 125.30, 71.2, 70.7, 70.2, 64.7, 29.3, 28.5, 22.7, 18.4. PEGDHeMA 2k (di-n-hexyl methacrylate): 1H NMR (CDCl3, 200 MHz) δ (ppm): 6.05 (s, 2H, vinyl), 5.51 (s, 2H, vinyl), 4.10 (t, J = 6.5 Hz, 4H, CO2CH2), 3.63-3.36 (br s, main chain), 1.90 (s, 6H, CH3), 1.76–1.45 (m, 8H), 1.44–1.27 (m, 8H); 13C NMR (CDCl3, 300 MHz) δ (ppm): 167.5, 136.5, 125.2, 71.3, 70.6, 70.1, 64.7, 29.6, 28.6, 25.9, 25.8, 18.4.

[0192] Example 8

[0193] Poly (ethylene glycol) dimethyl sulfonate is transferred to a round-bottom flask equipped with a magnetic stirring bar. 25% ammonia solution (about 5mL / mmol or until viscosity decreases) is added to the flask and clamped and sealed with a stopper and a metal clamp. The reaction is stirred vigorously for about 3 days. Once complete conversion is confirmed by H NMR, the water layer is extracted 3 / 4 times with dichloromethane, the combined organic extracts are dried over magnesium sulfate, and concentrated under reduced pressure, but only a viscous oil is obtained. The remaining residue is stirred vigorously, and then ether is added until a large amount of precipitate is observed. The solution is further cooled in an ice bath to maximize the yield of the precipitate. The precipitate is collected by vacuum filtration on a glass frit, washed with ether, and further dried under high vacuum to obtain the product as a white solid. PEG DAm 2k (diamine): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 3.51 (br s, main chain), 3.36 (t, J = 5.8 Hz, 4H, CH2), 2.66 (t, J = 5.7 Hz, 4H, CH2).

[0194] Example 9

[0195] Other amination reactions were carried out in a similar manner with their respective dimethylsulfonated compounds. PEG DPAm2k (di-n-propylamine): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.24 (t, J = 6.3 Hz, 4H, NH2), 3.51 (br s, backbone), 3.15 (s, 4H, CH2), 1.89 (p, J = 6.2 Hz, 4H, CH2). PEG DiPAm2k (diisopropylamine): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 4.51 (d, J = 4.6 Hz, 4H, NH2), 3.51 (br s, backbone), 1.01 (d, J = 6.2 Hz, 6H, CH3). PEG DBuAm 2k (di-n-butylamine): 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.54 (br s, main chain), 3.37 (t, J = 6.2 Hz, 4H, OCH2), 2.61 (t, J = 6.8 Hz, 4H, OCH2), 1.58-1.29 (m, 8H, CH2). PEGDiBuAm 2k (diisobutylamine): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 3.51 (br s, main chain), 1.63 (o, J = 6.7 Hz, 2H, CH), 0.82 (d, J = 6.7 Hz, 6H, CH3). PEG DPeAm 2k (di-n-pentylamine): 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.64 (br s, main chain), 3.50 (t, J = 5.8 Hz, 4H, OCH2), 2.96 (t, J = 7.0 Hz, 4H, OCH2), 1.82-1.41 (m, 12H, CH2). PEG DHeAm 2k (di-n-hexylamine): 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.64 (br s, main chain), 3.46 (t, J = 6.7 Hz, 4H, OCH2), 2.80 (t, J = 7.2 Hz, 4H, OCH2), 1.67–1.46 (m, 8H, CH2), 1.43-1.28 (m, 8H, CH2).

[0196] Example 10

[0197] Poly(ethylene glycol) diamine (1 equivalent) was loaded into a round-bottom flask equipped with a magnetic stirring bar and dissolved in dichloromethane (0.18 M). Acryloyl chloride (distilled, 1.65 equivalents) was added, followed by sodium hydroxide solution (1 M, 1.6 equivalents). The two-phase solution was stirred vigorously at 25 ° C for 1.5 hours (up to 5 hours). After the reaction was completed (assessed by H NMR), sodium hydroxide solution (1 M, 1.6 equivalents) was added and the mixture was stirred for 5 minutes. The mixture was transferred to a separatory funnel and the aqueous layer was extracted with DCM. The organic phase was passed through a basic alumina plug (the solution faded). The plug was washed with DCM as an eluent. The solvent was then removed under reduced pressure, but only a viscous oil was obtained. The remaining residue was stirred vigorously. Ether was then added until a more obvious precipitate was observed. The solution was further cooled in an ice bath to maximize the yield of the precipitate. The precipitate was collected by vacuum filtration on a glass frit and washed with ether. The white powder was dried under high vacuum to remove the ether and then freeze-dried to remove the water. PEG DAAm 2k (diacrylamide): 1H NMR (CDCl 3 , 300 MHz) δ (ppm): 6.54 (br s, 2H, NH), 6.28 (dd, J = 1.5, 17.0 Hz, 2H, vinyl), 6.14 (dd, J = 10.0, 17.0 Hz, 2H, vinyl), 5.61 (d, J = 10.0 Hz, 2H, vinyl), 3.63 (br s, backbone), 3.52 (dd, J = 5.0, 10.1 Hz, 4H, CH 2 ); 13C NMR (CDCl 3 , 300 MHz) δ (ppm): 165.7, 131.2, 126.2, 70.7, 70.4, 69.9, 39.4.

[0198] Example 11

[0199] Other amidation reactions were carried out in a similar manner with their respective diamino compounds. PEG DPAAm 2k (di-n-propylacrylamide): 1H NMR (CDCl 3 , 300 MHz) δ (ppm): 6.66 (br s, 2H, NH), 6.25 (d, J = 16.9 Hz, 2H, vinyl), 6.11 (dd, J = 17.0, 10.1 Hz, 2H, vinyl), 5.58 (d, J = 10.0 Hz, 2H, vinyl), 3.63 (br s, backbone), 1.86-1.76 (m, 4H, CH 2 ); 13C NMR (CDCl 3 , 300 MHz) δ (ppm): 165.8, 131.3, 126.0, 70.7, 70.3, 70.1, 38.4, 28.7. PEG DiPAAm 2k (diisopropylacrylamide): 1H NMR (D2O, 300 MHz) δ (ppm): 6.31 (dd, J = 17.1, 9.7 Hz, 2H, vinyl), 6.21 (dd, J = 17.1, 1.9 Hz, 2H, vinyl), 5.79 (dd, J = 9.6, 1.9 Hz, 2H, vinyl), 3.74 (br s, main chain), 3.32 (t, J = 5.9 Hz, 4H, NCH2), 1.68-1.54 (m, 6H, CH3); 13C NMR (D2O, 300 MHz) δ (ppm): 168.3, 130.2, 127.1, 70.5, 69.6, 69.2, 39.1, 26.1, 25.1. PEG DiBuAAm 2k (diisobutylacrylamide): 1H NMR (D2O, 300 MHz) δ (ppm): 6.33 (dd, J = 17.1, 9.8 Hz, 2H, vinyl), 6.22 (d, J = 16.3 Hz, 2H, vinyl), 5.81 (d, J = 10.5 Hz, 2H, vinyl), 3.74 (br s, main chain), 3.57-3.41 (m, 4H, CH2), 3.38-3.17 (m, 4H, CH2), 2.07 (o, J = 6.9 Hz, 2H, CH), 0.97 (d, J = 6.8 Hz, 6H, CH3); 13C NMR (D2O, 300MHz) δ (ppm): 168.4, 130.2, 127.2, 74.2, 69.6, 42.5, 33.1, 14.3.PEG DBuAAm 2k (di-n-butylacrylamide): 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 6.20 (dd, J = 17.1, 9.9 Hz, 1H), 6.05 (dd, J = 17.1, 2.5 Hz, 1H), 5.55 (dd, J = 9.9, 2.5 Hz, 1H), 3.51 (s, 131H), 3.42–3.34 (m, 2H), 3.17–3.07 (m, 2H), 1.55–1.42 (m, 6H); 13C NMR (DMSO-d6, 300 MHz) δ (ppm): 164.37, 131.86, 124.68, 69.75, 69.46, 38.28, 26.69, 25.83. PEG DPeAAm 2k (di-n-pentylacrylamide): 1H NMR (DMSO-d6, 300 MHz) δ8.03 (t, J = 5.6 Hz, 2H, NH2), 6.20 (dd, J = 17.1, 9.9 Hz, 2H, vinyl), 6.05 (dd, J = 17.1, 2.5 Hz, 2H, vinyl), 5.55 (dd, J = 9.9, 2.5 Hz, 2H, vinyl), 3.51 (s, main chain), 3.37 (t, J = 6.5 Hz, 6H, OCH2), 3.11 (q, J = 6.5 Hz, 4H, NCH2), 1.57–1.19 (m, 17H); 1H NMR (CDCl3, 300MHz) δ6.25 (dd, J = 17.0, 1.7Hz, 2H, vinyl), 6.08 (dd, J = 17.0, 10.1Hz, 2H, vinyl), 5.93 (s, 2H, NH2), 5.58 (dd, J = 10.1, 1.8Hz, 2H, vinyl), 3.62 (s, main chain), 3.44 (t, J = 6.2Hz, 8H, OCH2), 3.30 (q, J = 6.7Hz, 5H, NCH2), 1.55 (dq, J = 11.7, 7.2Hz, 11H), 1.38 (tt, J = 10.8, 5.9Hz, 6H); 13C NMR (DMSO-d6, 300MHz) δ164.4,131.9,124.6,69.8,38.5,29.0,28.9,28.9,23.2.PEG DHeAAm 2k (di-n-hexylacrylamide): 1H NMR (DMSO-d6, 300 MHz) δ8.02 (t, J = 5.6 Hz, 2H, NH2), 6.20 (dd, J = 17.1, 9.9 Hz, 2H, vinyl), 6.05 (dd, J = 17.1, 2.5 Hz, 2H, vinyl), 5.54 (dd, J = 9.9, 2.5 Hz, 2H, vinyl), 3.51 (s, main chain), 3.36 (t, J = 6.5 Hz, 9H, OCH2), 3.10 (q, J = 6.6 Hz, 5H, NCH2), 1.58–1.13 (m, 25H); 1H NMR (CDCl3, 300MHz) δ6.24 (dd, J = 17.0, 1.7Hz, 2H, vinyl), 6.07 (dd, J = 17.0, 10.1Hz, 2H, vinyl), 5.86 (s, 2H, NH2), 5.57 (dd, J = 10.1, 1.8Hz, 2H, vinyl), 3.61 (s, main chain), 3.46–3.34 (m, 9H, OCH2), 3.28 (td, J = 7.2, 5.9Hz, 5H, NCH2), 1.53 (dq, J = 14.1, 6.8, 5.2Hz, 13H), 1.33 (dd, J = 7.1, 3.7Hz, 13H); 13C NMR(DMSO-d6,300MHz) δ164.3,131.9,124.6,69.8,29.2,29.1,29.0,26.3,25.5,25.4.

[0200] Example 12

[0201] Will 10R5 (1 equivalent) was loaded into a round-bottom flask equipped with a magnetic stirring bar and dissolved in anhydrous DCM (0.1 M). Anhydrous triethylamine (2 equivalents) was added to the solution. Methacryloyl chloride (freshly distilled, 1.75 equivalents) was then added at 0°C and the reaction was stirred overnight at 25°C in the dark. After completion, the reaction was quenched with water and extracted with DCM. The combined organic extracts were passed through a basic alumina plug and eluted with DCM. The solvent was then removed under reduced pressure to obtain a viscous oil. The crude oily residue was dissolved in water and dialyzed against water in a Spectra / Por 6 membrane tube for 24 hours. The dialyzed solution was then lyophilized to dryness to obtain the product 10R5-DMA, which was a viscous colorless oil. 1H NMR (CDCl3, 300MHz) δ (ppm): 6.08 (dd, J = 1.0, 1.8Hz, 2H, vinyl), 5.53-5.52 (m, 2H, vinyl), 5.09-5.02 (m, 1H, CH), 3.63-3.36 (m, PEG and PPG CH backbone), 3.41 (t, J = 6.5Hz, 4H, CH2), 1.92 (m, 6H, CH3), 1.26-1.23 (m, 6H, CH3), 1.13-1.11 (m, PPG CH3 backbone); 13C NMR (CDCl3, 300MHz) δ (ppm): 167.1, 136.8, 125.3, 75.6, 75.5, 75.3, 75.3, 70.7, 70.7, 18.4, 17.5, 17.4, 16.9.

[0202] Application Example 1

[0203] The hydrogel samples were prepared by pipetting a solution of the prepolymer prepared according to Examples 5-7, 10 or 11 (30 wt%), photoinitiator (0.25 wt%) and deionized water (69.75 wt%) into a cylindrical sample mold (V = 250 μL, Height = 5 mm) and photopolymerized using a blue light source with a wavelength of 400-460 nm.

[0204] Application Example 2

[0205] The stability of the hydrogel samples prepared according to Application Example 1 was investigated in an accelerated aging experiment: the hydrogel samples were immersed in deionized water at 57°C for 8 weeks to accelerate the aging process. At the end of the aging period, the hydrogels were removed, dried in a vacuum oven, and then weighed. The dry content was compared with that of the unaged sample, and the loss in dry content was used as a measure of material degradation.

[0206] Application Example 3

[0207] The effects of various antioxidants on hydrogel stability were investigated by doping prepolymer formulations with the indicated antioxidants, followed by photopolymerization as described in Application Example 1, and then accelerated aging in deuterated water (DO). Decomposition was observed by NMR spectroscopy, with the formation of decomposition markers such as formic acid in the liquid. This was quantified by the addition of an internal standard.

[0208] Application Example 4

[0209] The antioxidant retention properties were tested by preparing and aging samples spiked with antioxidants according to Application Example 3. The deuterium hydroxide in which the hydrogel samples were aged was replaced weekly and then tested. Decomposition was detected by NMR spectroscopy, observing the formation of decomposition markers (e.g., formic acid) in the liquid. Quantification was performed by adding an internal standard.

[0210] Application Example 5

[0211] The photopolymerization efficiency was checked by gravimetric determination of the cured polymer mass: a solution containing the prepolymer prepared according to Examples 5-7, 10 or 11 (15 wt %) and a photoinitiator (0.1 wt %) was prepared in deionized water. 500 mg of the premixed solution was placed in a 2 mL polystyrene cuvette and irradiated from the side with a laser (λ = 405 nm, p = 10 mW) for 60 seconds. The solid hydrogel was removed, the residual liquid was wiped off, and then weighed. The ratio of solid cured material to liquid uncured material was calculated and used as a measure of the photopolymerization efficiency. Some results of this experiment are shown in FIG. Figure 1 The device used is as shown in Figure 2 As shown: 301 represents a polystyrene cuvette, 302 represents a liquid prepolymer composition, 303 represents a solidified hydrogel, and 304 represents a laser beam.

[0212] Comparative Example 1

[0213] The photopolymerization efficiencies of the prepolymer PEG-DMA (prepared according to Example 7), PEG-dimethacrylate containing a linker (Examples 5-7), PEG-DAAm (Example 10), PEG-diacrylamide containing a linker (Example 11), and 10R5-dimethacrylate (Example 12) were compared according to Application Example 5:

[0214] prepolymer Polymer quality prepolymer Polymer quality DMA 6k 43％ DAAm 2k 11％ DMA 2k 53％ DPAAm 2k 6％ DPMA 2k 43％ DiPAAm 2k 6％ DiPMA 2k 66％ DiBuAAm 2k 8％ DiBuMA 2k 83％ DBuAAm 2k 5％ DBuMA 2k 79％ DPeAAm 2k 4％ DPeMA 2k 79％ DHeAAm 2k 8％ DHeMA 2k 72％ 10R5-DMA 92％

[0215] Comparative Example 2

[0216] The stability of hydrogel samples prepared from prepolymer PEG-DMA (prepared according to Example 7), PEG-dimethacrylate containing a linker (Examples 5-7), PEG-DAAm (Example 10), PEG-DPAAm containing a linker (Example 11), and 10R5-dimethacrylate (Example 12) were compared according to Application Example 2:

[0217] prepolymer RDC DMA 2k 87.7±2.7％ DPMA 2k 100.2±0.7％ DBuMA 2k 99.0±0.6％ DiBuMA 2k 97.5±1.0％ DPeMA 2k 98.8±1.9％ DHeMA 2k 97.6±0.6％ DAAm 2k 82.0±2.5％ DPAAm 2k 67.1±2.7％ 10R5-DMA 103.3±1.9％

[0218] Comparative Example 3

[0219] A model comparative hydrolysis experiment was conducted using PEG diisobutyrate and PEG di(butane-1,4-diylisobutyrate) at a concentration of 30 wt% in deuterated water. After accelerated aging at 57°C for 10 days in the presence of MEHQ (0.5 wt%), hydrolysis products (isobutyric acid) were observed exclusively in PEG diisobutyrate by 1H NMR spectroscopy, while the derivative with a butyl linker (PEG di(butane-1,4-diylisobutyrate)) showed no hydrolysis products.

[0220] Comparative Example 4

[0221] The antioxidant test according to Application Example 3 showed that no decomposition was observed when BHT (containing 1% DMSO) or sodium 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate (sodium fenozan) was added to the prepolymer formulation, as confirmed by the absence of decomposition markers. In contrast, the hydrogel sample without antioxidants showed a large amount of markers (1.2 mM) after one week of accelerated aging. Furthermore, in the presence of these antioxidants, no reduction in polymer mass was observed in the photopolymerization efficiency test according to Application Example 5.

[0222] Comparative Example 5

[0223] The retention of BHT and sodium 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate was studied according to Application Example 5. The retention of BHT in the hydrogel samples was demonstrated by the lack of decomposition markers and antioxidants in the leaching solvent during a three-week leaching experiment, while the sample containing sodium 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate showed decomposition markers (1.4 mM) after 3 weeks.

[0224] References

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Claims

1. A method for preparing a chemically stable cross-linked polymer gel composition, comprising the steps of: a) Dissolve i) or ii) in a suitable solvent: i) a water-soluble, cross-linkable prepolymer for preparing a chemically stable cross-linked polymer gel, said water-soluble, cross-linkable prepolymer having the formula I: R 1 -L-B-L-R 2 (I) in: B is any backbone selected from the following: Polyethylene glycol: wherein n is 1 to 450 repeating units, Poloxamer: wherein p, q, and s are independent of each other and are 1 to 200 repeating units, wherein x, y, and z are independent of each other and are 1 to 200 repeating units; L is a linking group selected from a C3 to C8 linear or branched alkyl chain; R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are any group selected from the following: H; OH; acrylate; methacrylate; trans-methacrylate, wherein R is alkyl and X=O or NH; ethylene carbonate; vinyl carbamate; provided that when R1 is H or OH, R2 is not H or OH; or ii) a water-soluble, cross-linkable prepolymer for preparing a chemically stable cross-linked polymer gel, said water-soluble, cross-linkable prepolymer having the formula II: R 1 -BR 2 (II) in: B is a main chain consisting of: wherein x, y, and z are independent of each other and are 1 to 200 repeating units; R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are any group selected from the following: H; OH; acrylate; methacrylate; trans-methacrylate, wherein R is alkyl and X=O or NH; ethylene carbonate; vinyl carbamate; provided that when R1 is H or OH, R2 is not H or OH; b) adding a phenolic free radical stabilizer or an aminooxy free radical stabilizer; c) adding a free radical polymerization initiator; d) applying a polymerization or cross-linking step to form said chemically stable cross-linked polymer gel composition; The phenol-based free radical stabilizer is selected from the group consisting of unsubstituted or methyl-, ethyl-, isopropyl- or tert-butyl-substituted phenols or mixtures thereof.

2. The method according to claim 1, wherein The free radical polymerization initiator in step c) is a photoinitiator composed of common UV, violet, blue or other visible light activated photoinitiators.

3. The method according to claim 2, wherein: The photoinitiator is selected from the group consisting of quinones, α-hydroxyketones, acylgermanium derivatives, bis(acyl)phosphine oxide derivatives and mono(acyl)phosphine oxide derivatives, or a mixture thereof.

4. The method according to any one of claims 1 to 3, wherein The suitable solvent consists of water, acetone, DMSO, or alcohol or a mixture thereof.

5. A precursor composition of a chemically stable cross-linked polymer gel composition, wherein: The precursor composition comprises 5% to 95% by weight of i) or ii) : i) a stable water-soluble, cross-linkable prepolymer for preparing a chemically stable cross-linked polymer gel, said water-soluble, cross-linkable prepolymer having the formula I: R 1 -L-B-L-R 2 (I) in: B is any backbone selected from the following: Polyethylene glycol: wherein n is 1 to 450 repeating units, poloxamer: wherein p, q, and s are independent of each other and are 1 to 200 repeating units, wherein x, y, and z are independent of each other and are 1 to 200 repeating units; L is a linking group selected from a C3 to C8 linear or branched alkyl chain; R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are any group selected from the following: H; OH; acrylate; methacrylate; trans-methacrylate, wherein R is alkyl and X=O or NH; ethylene carbonate; vinyl carbamate; provided that when R1 is H or OH, R2 is not H or OH; or ii) a water-soluble, cross-linkable prepolymer for preparing a chemically stable cross-linked polymer gel, said water-soluble, cross-linkable prepolymer having the formula II: R 1 -BR 2 (II) in: B is a main chain consisting of: wherein x, y, and z are independent of each other and are 1 to 200 repeating units; R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are any group selected from the following: H; OH; acrylate; methacrylate; Trans methacrylate, wherein R is alkyl, X = O or NH; ethylene carbonate; vinyl carbamate; provided that when R1 is H or OH, R2 is not H or OH, 5 wt% to 95 wt% of a suitable solvent, 0.001 wt% to 10 wt% of a phenolic free radical stabilizer or an aminooxy free radical stabilizer, and 0.001 wt% to 10 wt% of a free radical polymerization initiator; The phenol-based free radical stabilizer is selected from the group consisting of unsubstituted or methyl-, ethyl-, isopropyl- or tert-butyl-substituted phenols or mixtures thereof. The precursor composition according to claim 5 , further comprising 1 wt % to 90 wt % of an inorganic filler.

7. The precursor composition according to claim 6, wherein The inorganic filler is in the form of powder or suspension and is selected from the group consisting of water-insoluble metal oxides or salts.

8. A chemically stable cross-linked polymer gel composition obtainable by cross-linking a precursor composition according to any one of claims 5 to 7, wherein the chemically stable cross-linked polymer gel composition retains at least 95% of its initial dry mass after being subjected to the following steps: storage in water at 57°C for 8 weeks, followed by a washing step and a vacuum drying step to remove any solvent.

9. A chemically stable cross-linked polymer gel composition obtainable by the method according to any one of claims 1 to 3, wherein the chemically stable cross-linked polymer gel composition retains at least 95% of its initial dry mass after being subjected to the following steps: storage in water at 57°C for 8 weeks, followed by a washing step and a vacuum drying step to remove any solvent.

10. A precursor composition for a medical or dental filler, comprising the precursor composition according to any one of claims 5 to 7.

11. A water-soluble, cross-linkable prepolymer for preparing a chemically stable, cross-linked dental polymer gel, the water-soluble, cross-linkable prepolymer having the formula I: R 1 -L-B-L-R 2 (I) in: B is any backbone selected from the following: Polyethylene glycol: wherein n is 1 to 450 repeating units, Poloxamer: wherein p, q, and s are independent of each other and are 1 to 200 repeating units, wherein x, y, and z are independent of each other and are 1 to 200 repeating units; L is a linking group selected from a C3 to C8 linear or branched alkyl chain; R1 and R2 are terminal groups, R1 and R2 are the same or different, wherein R1 and R2 are any group selected from the following: H; OH; acrylate; methacrylate; trans-methacrylate, wherein R is alkyl, X=O or NH; ethylene carbonate; vinyl carbamate; provided that when R1 is H or OH, R2 is not H or OH.

12. The water-soluble, cross-linkable prepolymer according to claim 11, wherein R1 and R2 are selected from the group consisting of acrylates and / or methacrylates.

13. The water-soluble cross-linkable prepolymer according to claim 11 or 12, wherein the linking group is a C4 to C6 linear or branched alkyl group.

14. The water-soluble, cross-linkable prepolymer according to claim 11 or 12, wherein the water-soluble, cross-linkable prepolymer is a water-soluble, cross-linkable dental prepolymer.

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