Bioerodible cross-linked hydrogels based on multi-arm polyoxazolines with caged silica core

Abstract

In some aspects, the disclosure relates to reactive multi-arm polymers having a cage silica core and a plurality of polyoxazoline-containing arms extending from the core wherein the polyoxazoline-containing arms comprise a first end covalently attached to the cage silica core and a second end comprising a moiety comprising a reactive end group. In other aspects, the disclosure relates to systems comprising such reactive multi-arm polymers and multifunctional compounds comprising functional groups that react with reactive end groups of the reactive multi-arm polymers. Other aspects relate to medical hydrogels formed by cross-linking such reactive multi-arm polymers with such multifunctional compounds, and methods of treatment comprising administering to a subject a mixture comprising such reactive multi-arm polymers and such multifunctional compounds.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 399,122, filed on August 18, 2022, the disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to multi-arm polyoxazolines with caged silicon cores, biodegradable cross-linked compositions containing such multi-arm polymers, methods for preparing such multi-arm polymers, methods for using such multi-arm polymers, etc. The multi-arm polyoxazolines with caged silicon cores of the present disclosure can be used, for example, in various biomedical applications. Background Art

[0004] Bioerodible injectable hydrogels are an emerging class of materials with a variety of medical applications.

[0005] As a specific example, For example, a multi-arm PEG-based long-term bioerodible injectable hydrogel is used to create or maintain space between tissues to reduce off-target radiation therapy side effects. See “Augmenix Announces Positive Three-year SpaceOAR Clinical Trial Results,” Imaging Technology News, October 27, 2016. As another specific example, Augmenix has developed A hydrogel, a bioerodible, injectable synthetic hydrogel composed primarily of water and iodinated cross-linked polyethylene glycol (PEG), is visible under CT, cone beam, ultrasound, and MR imaging and can be used as a tissue marker (e.g., for targeted radiation therapy). See “Augmenix Receives FDA Clearance to Market its TraceIT TM Tissue Marker,” BusinessWire, January 28, 2013. The hydrogel remained stable and visible in tissue for three months, long enough for radiation therapy, after which it was absorbed and cleared from the body. Id.

[0006] There is a continuing need in the biomedical arts for additional hydrogels, including bioerodible injectable hydrogels, precursors to such hydrogels, methods of making such hydrogels and precursors, methods of using such hydrogels and precursors, and systems for forming such hydrogels. Summary of the invention

[0007] In some aspects, the present disclosure relates to a reactive multi-arm polymer having a caged silica core and a plurality of polyoxazoline-containing arms extending from the core, wherein the polyoxazoline-containing arms comprise a first end covalently attached to the caged silica core and a second end comprising a moiety comprising a reactive end group.

[0008] In some embodiments, the caged silicon core is selected from the group consisting of a T6 caged silicon core, a T8 caged silicon core, a T 10 Cage-like silicon oxygen core and T 12 The caged silicon oxygen core and / or the polyoxazoline-containing arm comprises a moiety selected from oxazoline, 2-(C1-C 10 -alkyl)-2-oxazoline and combinations thereof.

[0009] In some embodiments that may be used in conjunction with any of the above aspects and embodiments, the reactive end group is an electrophilic group. Examples of electrophilic groups may be selected from, for example, N-hydroxysuccinimide esters, imidazole esters, imidazole carboxylates, and benzotriazole esters, and the like.

[0010] In some embodiments that may be used in combination with any of the above aspects and embodiments, the moiety comprising a reactive end group may also comprise a hydrolyzable ester group.

[0011] In some embodiments that may be used in combination with any of the above aspects and embodiments, the reactive end group-containing moiety comprises a diester selected from the group consisting of a malonic acid-based diester, a succinic acid-based diester, a glutaric acid-based diester, and an adipic acid-based diester.

[0012] In some aspects, the present disclosure relates to a system comprising: (a) a reactive multi-arm polymer according to any of the above aspects and embodiments, and (b) a multifunctional compound comprising functional groups that react with reactive end groups of the reactive multi-arm polymer.

[0013] In some embodiments that may be used in combination with any of the above aspects, the reactive groups of the reactive multi-arm polymer are electrophilic groups and the functional groups of the multifunctional compound are nucleophilic groups.

[0014] In some embodiments, which may be used in combination with any of the above aspects and embodiments, the polyfunctional compound can be a polyamine compound.

[0015] In some embodiments that may be used in combination with any of the above aspects and embodiments, the polyfunctional compound can be a polyamine compound comprising 2 to 10 basic amino acid residues.

[0016] In some embodiments that may be used in combination with any of the above aspects and embodiments, the polyfunctional compound may be a compound comprising multiple -(CH2) x -NH2 group polyamine compounds, wherein x is 0, 1, 2, 3, 4, 5 or 6.

[0017] In some embodiments that may be used in combination with any of the above aspects and embodiments, the multifunctional compound can be a polyamine compound comprising two or more amino acid residues selected from the group consisting of lysine residues, ornithine residues, and combinations thereof.

[0018] In some embodiments that may be used in combination with any of the above aspects and embodiments, the system can include a first precursor composition comprising a multifunctional compound and a second precursor composition comprising a reactive multi-arm polymer.

[0019] In some embodiments that may be used in conjunction with any of the above aspects and embodiments, the system may further include an enhancer composition. For example, the enhancer composition may include a buffer solution having a pH range of about 9 to about 11.

[0020] In some embodiments that may be used in combination with any of the above aspects and embodiments, the first precursor composition can be provided in a syringe barrel, the second precursor composition can be provided in a vial, and the accelerator composition can be provided in a syringe barrel.

[0021] In some embodiments that may be used in combination with any of the above aspects and embodiments, the system may further comprise a delivery device.

[0022] In some aspects, the present disclosure relates to a medical hydrogel formed by crosslinking a reactive multi-arm polymer according to any of the above aspects and embodiments with a multifunctional compound according to any of the above aspects and embodiments, the multifunctional compound comprising a functional group that reacts with a reactive end group of the reactive multi-arm polymer.

[0023] In some aspects, the present disclosure relates to a treatment method comprising administering to a subject a mixture comprising a reactive multi-arm polymer according to any of the above aspects and embodiments, and a multifunctional compound according to any of the above aspects and embodiments, the multifunctional compound comprising a functional group that reacts with a reactive end group of the reactive multi-arm polymer.

[0024] In addition to the above, other aspects and embodiments of the present disclosure will become apparent by reading the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1A A method according to an embodiment of the present disclosure is schematically illustrated wherein a hydroxyalkyl silsesquioxane is formed using a silsesquioxane hydride.

[0026] Figure 1B A method according to an embodiment of the present disclosure is schematically shown, wherein the Figure 1A The hydroxyalkyl silsesquioxane forms a haloalkyl silsesquioxane.

[0027] Figure 1C A method according to an embodiment of the present disclosure is schematically shown, wherein the Figure 1B The haloalkylsilsesquioxane was used as an initiator for the ring-opening polymerization to form a multi-arm polyoxazoline with terminal hydroxyl groups.

[0028] Figure 1D The method according to an embodiment of the present disclosure is schematically shown, wherein Figure 1C The multi-arm polyoxazoline is then converted into a multi-arm polyoxazoline terminated with a reactive succinimidyl glutarate group.

[0029] Figure 2 is a schematic diagram of a method for preparing reactive multi-arm polyoxazolines according to an embodiment of the present disclosure.

[0030] Figure 3 is a schematic diagram of a method for cross-linking a reactive multi-arm polyoxazoline using a multifunctional cross-linking agent according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0031] In some aspects, the present disclosure relates to a multi-arm polymer having a caged silica core and having a plurality of polyoxazoline-containing arms.

[0032] In various embodiments, multi-arm polymer is a silsesquioxane compound with multiple arms containing polyoxazoline. Silsesquioxane is a compound with a caged silicon oxygen core, which is composed of Si-O-Si bonds and tetrahedral Si vertices. -H groups or external organic groups can be covalently attached to the caged silicon oxygen core. In the present disclosure, the organic group includes the arm containing polyoxazoline. Silsesquioxane used for the present disclosure includes silsesquioxane with 6 Si vertices, silsesquioxane with 8 Si vertices, silsesquioxane with 10 Si vertices and silsesquioxane with 12 Si vertices. The silicon oxygen core is sometimes referred to as T6, T8, T9, T10, T11, T12, T13, T14, T15, T16, T17, T18, T19, T20, T21, T22, T23, T24, T25, T26, T27, T28, T29, T30, T31, T32, T33, T34, T35, T36, T37, T38, T39, T40, T41, T42, T43, T44, T45, T46, T47, T48, T49, T50, T51, T52, T53, T54, T55, T56, T57, T58, T59, T6 10 and T 12 Cage-like silicon-oxygen core (where T = number of tetrahedral Si vertices). In all cases, each Si atom is bonded to three O atoms, which in turn are linked to other Si atoms.

[0033] Silsesquioxanes include those having the chemical formula [RSiO 3 / 2 ] n wherein n is an integer of at least 6, typically 6, 8, 10 or 12 (thus having T6, T8, T 10 or T 12 The caged silicon oxygen core) wherein R can be selected from a series of organic functional groups, such as alkyl, aryl, alkoxy and polymeric groups. The T8 caged silicon oxygen core has been widely studied and its formula is [RSiO 3 / 2 ]8, or equivalently R8Si8O12 . Such a structure would look like this: In the present disclosure, at least one R group is a polyoxazoline-containing arm, and typically all R groups are polyoxazoline-containing arms.

[0034] In various embodiments, the polyoxazoline-containing arms (e.g., the R groups in the above-described silsesquioxane formulas and structures, as well as many other possibilities) include one or more polymerized monomers selected from oxazoline and 2-alkyl-2-oxazoline, such as 2-(C1-C 10 2-alkyl)-2-oxazoline, including 2-methyl-2-oxazoline, 2-ethyl-2-oxazoline, 2-propyl-2-oxazoline, 2-butyl-2-oxazoline (including 2-n-butyl-2-oxazoline and 2-sec-butyl-2-oxazoline isomers), 2-pentyl-2-oxazoline (including various isomers), 2-hexyl-2-oxazoline (including various isomers), and the like.

[0035] In various embodiments, the polyoxazoline-containing arms comprise covalently attached to a caged silicon-oxygen core (e.g., T6, T8, T 10 or T 12 In some embodiments, the reactive end group may be a first end of a polyoxazoline (e.g., a cage-like silicon oxygen core) and a second end containing a portion comprising a reactive end group. (Such a molecule is also referred to herein as a reactive multi-arm polyoxazoline.) In some of these embodiments, the reactive end group may be an electrophile, for example, selected from N-hydroxysuccinimide esters, imidazole esters, imidazole carboxylates, and benzotriazole esters, etc. In some of these embodiments, the reactive end group may be a nucleophile, for example, selected from an amine group or a thiol group, etc.

[0036] In some embodiments, the portion comprising the reactive end group may also comprise a hydrolyzable ester group. For example, the portion comprising the reactive end group may comprise a diester. In a specific example, the diester may be selected from a diester based on malonic acid, a diester based on succinic acid, a diester based on glutaric acid, and a diester based on adipic acid.

[0037] The formation of the above and other multi-arm polyoxazolines is schematically shown in Figure 2In, wherein use the molecule with cage-like silicon oxygen core 110 (for example, silsesquioxane core) to form multifunctional initiator molecule 120, specifically, there is the molecule of the part 120 of cage-like silicon oxygen core 110 and a plurality of polymerization initiator groups, oxazoline polymerization can be carried out from this polymerization initiator group.Then, the polymerization of oxazoline monomer 125 is carried out from multifunctional initiator molecule 120, forms multi-arm polyoxazoline, this multi-arm polyoxazoline comprises cage-like silicon oxygen core 110 and a plurality of arms 130 containing polyoxazoline extending therefrom, each arm has a first end and a second end, and wherein the first end is connected to core 110.Subsequently, reactive group 140 can be provided at each second end of the arm 130 containing polyoxazoline.In certain embodiments, reactive group 140 is connected to the arm 130 containing polyoxazoline by hydrolyzable ester group.

[0038] In certain embodiments, the caged silicon core (e.g., T6, T8, T 10 or T 12 silsesquioxane precursor molecules (e.g., chemical formula [RSiO 3 / 2 ] n silsesquioxane hydride, wherein n is an integer of at least 6 and wherein R=H) and vinyl-substituted C3-C 10 alcohols (such as 2-propene-1-ol (also known as allyl alcohol), 3-butene-1-ol, 4-pentene-1-ol or 5-hexene-1-ol, etc.) to form C3-C 10 -Hydroxyalkyl substituted silsesquioxanes, for example, ω-hydroxyalkyl substituted silsesquioxanes, such as those having the formula [RSiO 3 / 2 ] n A compound wherein n is an integer of at least 6, and R is —(CH2) m OH and m ranges from 3 to 10, such as 3-hydroxypropyl substituted silsesquioxane (e.g., wherein R = —CH2CH2CH2OH), 4-hydroxybutyl substituted silsesquioxane (e.g., wherein R = —CH2CH2CH2CH2OH), 5-hydroxypentyl substituted silsesquioxane (e.g., wherein R = —CH2CH2CH2CH2CH2OH), 6-hydroxyhexyl substituted silsesquioxane (e.g., wherein R = —CH2CH2CH2CH2CH2OH), and the like. Figure 1A A specific example of such a reaction step is shown, which schematically illustrates a method in which a reaction of the formula [RSiO 3 / 2 ]8 (wherein R is H) T8 silsesquioxane hydride formation formula is [RSiO 3 / 2 ]8 (wherein R is -CH2CH2CH2OH) hydroxyalkyl T8 silsesquioxane.

[0039] Then, C3-C 10The hydroxyl group of the hydroxyalkyl-substituted silsesquioxane is converted into a halogen group by reaction with a halogen (e.g., Cl2, Br2, I2) to form a C3-C 10 A haloalkyl substituted silsesquioxane, for example, an ω-haloalkyl substituted silsesquioxane, such as a silsesquioxane having the formula [RSiO 3 / 2 ] n A compound wherein n is an integer of at least 6, and R is —(CH2) m X, m ranges from 3 to 10 and X = Cl, Br or I, for example, 3-halopropyl substituted silsesquioxane (for example, wherein R = —CH2CH2CH2X), 4-halobutyl substituted silsesquioxane (for example, wherein R = —CH2CH2CH2CH2X), 5-halopentyl substituted silsesquioxane (for example, wherein R = —CH2CH2CH2CH2CH2X), 6-halohexyl substituted silsesquioxane (for example, wherein R = —CH2CH2CH2CH2CH2CH2X), and the like. Figure 1B A specific example of such a reaction step is shown, which schematically illustrates a method in which Figure 1A The hydroxyalkyl silsesquioxane formation formula is [RSiO 3 / 2 ]8 (wherein R is -CH2CH2CH2I) of a halogenated alkyl T8 silsesquioxane.

[0040] Then use C3-C 10 The silsesquioxane substituted with a haloalkyl group is used as an initiator for the ring-opening polymerization of an oxazoline monomer (e.g., an oxazoline or 2-alkyl-2-oxazoline as described above), followed by termination / quenching of the ring-opening polymerization, so that a polyoxazoline arm is formed at each halogen atom, producing a silsesquioxane having a plurality of hydroxyl-terminated polyoxazoline arms, for example, comprising a caged silicon oxygen core (e.g., a caged silicon oxygen core such as T6, T8, T9, T10, T11, T12, T13, T14, T15, T16, T17, T18, T19, T20, T21, T22, T23, T24, T25, T26, T27, T28, T29, T30, T31, T32, T33, T34, T35, T36, T37, T38, T39, T40, T41, T42, T43, T44, T45, T46, T47, T48, T49, T50, T51, T52, T53, T54, T55, T56, T57, T58, T59, T6 10 or T 12 A polyoxazoline having a core, etc.) and a plurality of polyoxazoline-containing arms (formed from at least one type of oxazoline monomer), each arm having a first end and a second end, wherein the first end is connected to the core and the second end comprises a hydroxyl group. Figure 1C A specific example of such a reaction step is shown, which schematically illustrates a method in which Figure 1B The haloalkylsilsesquioxane is used as an initiator for the ring-opening polymerization of 2-methyl-2-oxazoline, through which a core having a T8 cage-like silicon oxygen core form is formed (in Figure 1C The multi-arm polyoxazoline represented by POSS in the formula is [RSiO 3 / 2 ]8, where R is n ranges from 10 to 25. Note that although halogen-based groups are exemplified in the above reaction steps, other leaving groups including mesylate / mesylate and tosylate groups may also be used.

[0041] The terminal hydroxyl groups of the polyoxazoline arms of the resulting silsesquioxanes can be used for subsequent reactions, for example, reactive end groups such as reactive electrophilic groups (e.g., N-hydroxysuccinimide ester groups, such as succinimide glutarate groups, succinimide succinate groups, succinimide carbonate groups or succinimide adipate groups, imidazole ester groups, imidazole carboxylate groups and / or benzotriazole ester groups, etc.) or reactive nucleophilic groups (e.g., amine groups and / or thiol groups, etc.) can be provided for reaction.

[0042] In a specific embodiment, the terminal hydroxyl group of the polyoxazoline arm of the obtained silsesquioxane is reacted with a cyclic anhydride (e.g., glutaric anhydride, succinic anhydride, malonic anhydride, etc.) to form a reaction product in the form of a silsesquioxane having a caged silicon oxygen core, comprising a plurality of arms containing polyoxazoline, the first end of the arm being connected to the core, the second end of the arm containing a carboxylic acid group, the carboxylic acid group being connected to the arm containing polyoxazoline via a hydrolyzable ester group, and then the silsesquioxane is catalyzed by a coupling agent (e.g., a carbodiimide coupling agent, such as N,N'-dicyclohexylcarbodiimide). (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N-hydroxybenzotriazole (HOBt), BOP reagent and / or other coupling agents) and N-hydroxysuccinimide (NHS) are treated to obtain a reactive multi-arm polyoxazoline containing a succinimidyl end group, in particular a hydrolyzable ester group and a reactive succinimidyl ester end group (such as succinimidyl glutarate, succinimidyl succinate, succinimidyl carbonate or succinimidyl adipate). Figure 1D A specific example of such a reaction step is shown, which schematically illustrates a method in which Figure 1C The hydroxyl groups of the multi-arm polyoxazoline are reacted with glutaric anhydride, followed by carbodiimide coupling with N-hydroxysuccinimide (NHS) to produce a multi-arm polyoxazoline terminated with reactive succinimidylglutarate groups.

[0043] Using the above and other techniques, reactive multi-arm polyoxazolines can be formed that contain a caged silicon oxygen core (e.g., a caged silicon oxygen core such as T6, T8, T 10 or T 12 core, etc.) and a plurality of arms containing polyoxazoline, each arm having a first end and a second end, and each arm is formed by polymerization of at least one type of oxazoline monomer, wherein the first end is connected to the cage-like silicon oxygen core and the second end comprises a reactive group.

[0044] In some embodiments, at least a portion of the polyoxazoline arm can comprise one or more covalently attached radiopaque parts, for example bromo or iodo.For example, the iodine-containing part can be connected to at least a portion of the polyoxazoline arm by suitable covalent bond (such as ester bond or amide bond etc.).The example of such iodine-containing part comprises the aromatic part that comprises monocyclic or polycyclic aromatic structure (such as phenyl or naphthyl), and it is replaced by the following: one or more radiopaque functional groups, for example one or more iodo, and optional multiple hydrophilic functional groups, for example be selected from hydroxyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl or C1-C4-carboxyalkyl one or more hydrophilic functional groups.

[0045] The reactive multi-arm polyoxazolines described herein can be cross-linked in vivo or in vitro with a suitable cross-linking agent to form a cross-linked product. When hydrated, the cross-linked product can be in the form of a hydrogel.

[0046] In some embodiments, the reactive multi-arm polyoxazoline can be cross-linked with a multifunctional compound having a functional group that reacts with the reactive group of the multi-arm polyoxazoline. Figure 3 As schematically shown, the reactive multi-arm polyoxazoline 210 as described above is cross-linked with the multi-functional compound 220 including a functional group that reacts with the reactive group of the multi-arm polyoxazoline 210 to form a cross-linked product 230 .

[0047] In some embodiments, the reactive group of the reactive multi-arm polyoxazoline is a nucleophilic group, and the functional group of the multifunctional compound group is an electrophilic group. In some embodiments, the reactive group of the reactive multi-arm polyoxazoline is an electrophilic group, and the functional group of the multifunctional compound is a nucleophilic group.

[0048] For example, the functional group of the multifunctional compound can be a nucleophilic group selected from an amine group and / or a thiol group. As another example, the functional group of the multifunctional compound can be an electrophilic group selected from imidazole esters, imidazole carboxylates, benzotriazole esters, imide esters (including N-hydroxysuccinimide esters).

[0049] In various aspects, the present disclosure relates to a cross-linkable system comprising a reactive multi-arm polyoxazoline as described herein and a multifunctional compound as described herein.

[0050] In various fields, the disclosure relates to a cross-linked product of a reactive multi-arm polyoxazoline as described herein and a multifunctional compound as described herein. Such a cross-linked product can be formed in vivo, or such a cross-linked product can be formed in vitro and then applied to a subject. Such a cross-linked product can be applied to various biomedical applications, including implants, lubricating coatings and pharmaceutical compositions.

[0051] In various embodiments, the reaction of the functional groups of the multifunctional compound with the reactive end groups of the reactive multi-arm polyoxazoline produces an amide bond.

[0052] In certain beneficial embodiments, the multifunctional compound used in the present disclosure can be a polyamine compound. Generally, the polyamine compounds suitable for use in the present disclosure include, for example, small molecule polyamines (e.g., containing at least two amine groups, for example, in certain embodiments, 3 to 20 amine groups or more), polymers having amine side groups, and branched polymers having amine end groups, including dendrimers having amine end groups. The polyamine compounds suitable for use in the present disclosure include polyamines containing multiple –(CH2) x -NH2 group, wherein x is 0, 1, 2, 3, 4, 5 or 6. Suitable polyamine compounds for use in the present disclosure include polyamine compounds containing basic amino acid residues (including amino acid residues having two or more primary amine groups, such as lysine and ornithine), for example, polyamines containing 2 to 10 lysine and / or ornithine amino acid residues (e.g., dilysine, trilysine, tetralysine, pentalysine, diornithine, triornithine, tetraornithine, pentaornithine, etc.).

[0053] Specific examples of polyamine compounds that can be used as the polyfunctional compound include ethylenetriamine, diethylenetriamine, hexamethylenetriamine, di(heptamethylene)triamine, di(trimethylene)triamine, bis(hexamethylene)triamine, triethylenetetramine, tripropylenetetramine, tetraethylenepentamine, hexamethyleneheptamine, pentaethylenehexamine, dimethyloctylamine, dimethyldecylamine, and JEFFAMINE polyetheramine available from Huntsman Corporation, chitosan and its derivatives, and poly(allylamine), etc.

[0054] In certain beneficial embodiments, the polyfunctional compound comprises one or more covalently linked radiopaque moieties, such as bromo or iodo groups. For example, polyamine compounds (such as those described above, etc.) can be linked to the iodine-containing moiety via a suitable covalent bond (such as an ester bond or an amide bond, etc.). Examples of such iodine-containing moieties include aromatic moieties comprising monocyclic or polycyclic aromatic structures (such as phenyl or naphthyl) substituted with one or more radiopaque functional groups, such as one or more iodo groups, and optionally multiple hydrophilic functional groups, such as one or more hydrophilic functional groups selected from hydroxyl, C1-C4-hydroxyalkyl, C1-C4-aminoalkyl or C1-C4-carboxyalkyl.

[0055] In the embodiment of reactive multi-arm polyoxazoline and / or the polyfunctional compound of the radiopaque part that comprises one or more covalent attachments, the cross-linked product of such reactive multi-arm polyoxazoline and / or polyfunctional compound is visible under fluoroscopy.In various embodiments, such cross-linked product has and is greater than 250 Hounsfield units (HU), advantageously in 250HU to 500HU to 750HU to 1000HU or higher any scope (in other words, in the scope between any two aforementioned numerical values) radiopacity.

[0056] As previously mentioned, in various fields, the present disclosure relates to a crosslinkable system comprising reactive multi-arm polyoxazolines as described herein and polyfunctional compounds as described herein. In certain embodiments, a system is provided, which is configured to deliver polyamine compounds and reactive multi-arm polyoxazolines comprising a plurality of reactive end groups reacting with the amino group of polyamine compounds under conditions such that polyamine compounds and reactive multi-arm polyoxazolines are crosslinked to each other. Such conditions include alkaline conditions, such as pH ranges from about 9 to about 11, typically ranges from about 9.5 to about 10.5, and more typically ranges from about 9.8 to about 10.2 those.

[0057] In some embodiments, a system can be provided that includes a first composition that includes a polyamine compound as described herein and a second composition that includes a reactive multi-arm polyoxazoline as described herein.

[0058] The first composition can be a first fluid composition comprising a polyamine compound, or a first dry composition comprising a polyamine compound, to which a suitable fluid such as water for injection, saline solution, etc. can be added to form a first fluid composition. In addition to the polyamine compound, the first composition can also include additives, including those described below.

[0059] The second composition can be the second fluid composition comprising reactive multi-arm polyoxazoline, or the second dry composition comprising reactive multi-arm polyoxazoline, suitable fluids such as water for injection, saline solution etc. can be added in the second dry composition to form the second fluid composition.Except reactive multi-arm polyoxazoline, the second composition can also include additives, including those described below.

[0060] In some embodiments, the polyamine compound is initially combined with the reactive multi-arm polyoxazoline at an acidic pH, at which the crosslinking between the reactive groups of the reactive multi-arm polyoxazoline and the amino groups of the polyamine compound is inhibited (e.g., the pH range is, for example, about 3 to about 5, typically ranging from about 3.5 to about 4.5, and more typically ranging from about 3.8 to about 4.2). Then, when crosslinking is required, the pH of the mixture of the polyamine compound and the reactive multi-arm polyoxazoline is changed from an acidic pH to an alkaline pH (e.g., a pH range of about 9 to about 11, typically ranging from about 9.5 to about 10.5, and more typically ranging from about 9.8 to about 10.2), resulting in crosslinking between the polyamine compound and the reactive multi-arm polyoxazoline.

[0061] In certain embodiments, the system comprises (a) a first precursor composition comprising a polyamine compound as described herein, (b) a second precursor composition comprising a reactive multi-arm polyoxazoline as described herein, and (c)

[0062] The third composition, specifically an accelerator composition, contains an accelerator configured to accelerate the cross-linking reaction between the polyamine compound and the reactive multi-arm polyoxazoline.

[0063] The first precursor composition can be the first fluid composition comprising the polyamine compound buffered to an acidic pH, or the first dry composition comprising the polyamine compound and an acidic buffer composition, suitable fluids such as water for injection, saline solution, etc. can be added to the first dry composition to form the first fluid composition comprising the polyamine compound buffered to an acidic pH. In some embodiments, for example, the acidic buffer composition can include sodium dihydrogen phosphate or the like. The pH range of the first fluid composition comprising the polyamine compound can be, for example, approximately 3 to approximately 5, typically ranging from approximately 3.5 to approximately 4.5, and more typically ranging from approximately 3.8 to approximately 4.2 values. In addition to the polyamine compound, the first precursor composition can also include additives, such as therapeutic agents and / or imaging agents.

[0064] The second precursor composition can be the second fluid composition comprising reactive multi-arm polyoxazoline, or the second dry composition comprising reactive multi-arm polyoxazoline, this fluid composition is formed by the second dry composition, for example by adding suitable fluid such as water for injection, saline solution or comprising the first fluid composition of the polyamine compounds that are buffered to acidic pH.Except reactive multi-arm polyoxazoline, the second precursor composition can also include additive, such as therapeutic agent and / or imaging agent.

[0065] In one embodiment, the first precursor composition is the first fluid composition comprising the polyamine compounds that are buffered to acidic pH, and the second precursor composition comprises the dry composition containing reactive multi-arm polyoxazoline.Then the first precursor composition can be mixed with the second precursor composition, to provide the fluid composition prepared that is buffered to acidic pH and comprises polyamine compounds and reactive multi-arm polyoxazoline.In a specific example, the syringe containing the first fluid composition can be provided, this first fluid composition comprises the polyamine compounds that are buffered to acidic pH, and the bottle comprising dry composition (for example powder) can be provided, and this dry composition comprises reactive multi-arm polyoxazoline.Then the first fluid composition can be injected into the bottle containing reactive multi-arm polyoxazoline using a syringe, to form the fluid composition prepared that contains polyamine compounds and reactive multi-arm polyoxazoline, it can be withdrawn in the syringe and used.

[0066] The promoter composition can be a fluid promoter composition buffered to an alkaline pH, or a dry composition comprising an alkaline buffer composition, to which a suitable fluid such as water for injection, saline solution, etc. can be added to form a fluid promoter composition buffered to an alkaline pH. For example, the alkaline buffer composition can include sodium borate and disodium hydrogen phosphate, etc. The pH range of the fluid promoter composition can be, for example, from about 9 to about 11, typically ranging from about 9.5 to about 10.5, and more typically ranging from about 9.8 to about 10.2. In addition to the above, the fluid promoter composition can also include additives such as therapeutic agents and / or imaging agents.

[0067] Examples of imaging agents include (a) fluorescent dyes, such as fluorescein, indocyanine green, or fluorescent proteins (e.g., green, blue, cyan fluorescent protein), (b) contrast agents used in conjunction with magnetic resonance imaging (MRI), including contrast agents containing elements that form paramagnetic ions, such as Gd (III) , Mn (II) , Fe (III) and compounds containing them (including chelates), such as gadolinium ions chelated with diethylenetriaminepentaacetic acid, (c) contrast agents used in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that cause an increase in reflected ultrasound energy) or organic and inorganic echolucent particles (i.e., particles that cause a decrease in reflected ultrasound energy), (d) radiocontrast agents used in conjunction with X-ray fluoroscopy, including metals and metal compounds (e.g., metal salts, metal oxides, etc.), such as barium compounds, bismuth compounds, and tungsten compounds, etc., and iodine compounds, etc., as well as clinically important isotope-based contrast agents 99m Tc radiocontrast agents, as well as other gamma emitters, such as 123 I. 125I. 131 I. 111 In, 57 Co. 153 Sm, 133 Xe, 51 Cr, 81m Kr, 201 Tl, 67 Ga and 75 Se, etc.; (e) positron emitters, such as 18 F. 11 C. 13 N. 15 O and 68 Ga, etc., which can be used to produce functionalized radiotracer coatings; and (f) contrast agents used in conjunction with near-infrared (NIR) imaging, which can be selected to impart near-infrared fluorescence to the coating of the present disclosure, thereby allowing deep tissue imaging and device labeling, such as NIR-sensitive nanoparticles, such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxyl or carboxyl groups, such as partially oxidized carbon nanotubes), dye-containing nanoparticles (such as dye-doped nanofibers and dye-encapsulated nanoparticles), and semiconductor quantum dots, etc. NIR-sensitive dyes include cyanine dyes, squarylium cyanines, phthalocyanines, porphyrin derivatives, and boron bipyrrolmethane (BODIPY) analogs, etc.

[0068] The prepared fluid composition buffered to an acidic pH as described above and comprising a polyamine compound and a reactive multi-arm polyoxazoline, and the fluidity enhancer composition buffered to an alkaline pH as described above, can be combined in vivo or in vitro to form a cross-linked hydrogel.

[0069] In various embodiments, a system is provided that includes one or more delivery devices for delivering a first composition and a second composition to a subject.

[0070] In some embodiments, system may include a delivery device, and this delivery device includes the first reservoir and the second reservoir, and this first reservoir contains the first composition comprising polyamine compounds as described above, and this second reservoir contains the second composition comprising reactive multi-arm polyoxazoline as described above.In some embodiments, system may include a delivery device, and this delivery device includes the first reservoir and the second reservoir, and this first reservoir contains the first composition comprising polyamine compounds and reactive multi-arm polyoxazoline and is buffered to acidic pH, such as the above-mentioned fluid composition prepared, and this second reservoir contains the second composition, such as the above-mentioned fluid promoter composition.In either case, in operating procedure, the first composition and the second composition are distributed and combined from the first reservoir and the second reservoir, and thus polyamine compounds and reactive multi-arm polyoxazoline are cross-linked to form hydrogel.

[0071] Regardless of the particular first and second compositions selected, in certain embodiments, the system can include a delivery device comprising a double-barreled syringe comprising a first barrel having a first barrel outlet (the first barrel containing the first composition, a first plunger movable in the first barrel), a second barrel having a second barrel outlet (the second barrel containing the second composition and a second plunger movable in the second barrel).

[0072] In some embodiments, device can also include a mixing part, and this mixing part has a first mixing part inlet that is communicated with the first pipe outlet fluid, a second mixing part inlet that is communicated with the second pipe outlet fluid, and a mixing part outlet. In some embodiments, device can also include sleeve pipe or conduit, which is configured to receive the first fluid composition and the second fluid composition from the first pipe and the second pipe. For example, sleeve pipe or conduit can be configured to be connected with the outlet of mixing part by sleeve pipe or conduit being attached to the outlet (for example, via suitable fluid connector such as Luer connector) to form fluid with mixing part.

[0073] As another example, the catheter can be a multi-lumen catheter including a first lumen and a second lumen, the proximal end of the first lumen being configured to form a fluid connection with the first tube outlet, and the proximal end of the second lumen being configured to form a fluid connection with the second tube outlet. In some embodiments, the multi-lumen catheter can include a mixing section having a first mixing section inlet in fluid communication with the distal end of the first lumen, a second mixing section inlet in fluid communication with the distal end of the second lumen, and a mixing section outlet.

[0074] During operation, when the first and second plungers are depressed, the first fluid composition and the second fluid composition are distributed from the first pipe and the second pipe, whereby the first fluid composition and the second fluid composition interact and finally crosslink to form a hydrogel, which is applied to the tissue of the subject or in the tissue. For example, the first fluid composition and the second fluid composition can enter the mixing part via the first mixing part inlet and the second mixing part inlet from the first pipe and the second pipe, whereby the first fluid composition and the second fluid composition mix to form a mixture, and the mixture leaves the mixing part via the mixing part outlet. In some embodiments, a sleeve tube or a conduit is attached to the mixing part outlet, thereby allowing the mixture to be applied to the subject after passing through a sleeve tube or a conduit.

[0075] As another example, the first fluid composition can enter the first lumen of the multi-lumen catheter from the first tube outlet, and the second fluid composition can enter the second lumen of the multi-lumen catheter from the second tube outlet. In some embodiments, the first fluid composition and the second fluid composition can enter the mixing part at the far end of the multi-lumen catheter from the first lumen and the second lumen via the first mixing part inlet and the second mixing part inlet, respectively, whereby the first fluid composition and the second fluid composition are mixed in the mixing part to form a mixture, which leaves the mixing part via the mixing part outlet.

[0076] No matter how the type of the device for mixing the first fluid composition and the second fluid composition or the first fluid composition and the second fluid composition are mixed, after the mixture of the first fluid composition and the second fluid composition is formed, the mixture is initially a fluid state, and can be applied to a subject (for example, mammal, particularly people) by various technologies. Or, the first fluid composition and the second fluid composition can be applied to a subject independently, and the fluid mixture of the first fluid composition and the second fluid composition is formed in the subject or on the body surface. In either method, the fluid mixture of the first fluid composition and the second fluid composition is formed, and is used for various medical procedures.

[0077] For example, in the treatment of diseases and cancers, and in the repair and regeneration of tissues, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected to provide spacing between tissues, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected (for example, in the form of blisters) to provide reference markers, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected for tissue augmentation or regeneration, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a filler or replacement for soft tissue, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected to provide mechanical support for damaged tissue, the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a scaffold, and / or the first fluid composition and the second fluid composition or a fluid mixture thereof can be injected as a carrier for therapeutic agents.

[0078] Upon administration of the disclosed composition (either alone as a first fluid composition and a second fluid composition that are mixed in vivo, or as a fluid mixture of the first fluid composition and the second fluid composition), a cross-linked hydrogel is ultimately formed at the site of administration.

[0079] As described above, the compositions of the present disclosure can be used in various medical procedures, including the following, among others: a procedure for implanting a tissue regeneration scaffold comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue support comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a tissue expander comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for implanting a therapeutic agent-containing depot comprising a cross-linked product of a first fluid composition and a second fluid composition, a procedure for tissue augmentation comprising implanting a cross-linked product of a first fluid composition and a second fluid composition, a procedure for introducing a cross-linked product of a first fluid composition and a second fluid composition between a first tissue and a second tissue to separate the first tissue from the second tissue, or a procedure for implanting a fiducial marker comprising a cross-linked product of a first fluid composition and a second fluid composition.

[0080] The first fluid composition and the second fluid composition, the fluid mixture of the first fluid composition and the second fluid composition, or the cross-linked product of the first fluid composition and the second fluid composition can be injected in conjunction with various medical procedures including: injection for spacing between the prostate or vagina and rectum in radiation therapy for rectal cancer, injection for spacing between the rectum and prostate in radiation therapy for prostate cancer, subcutaneous injection for palliative treatment of prostate cancer, transurethral or submucosal injection for female stress urinary incontinence, intravesical injection for urinary incontinence, intrauterine cavity injection for Asherman's syndrome, submucosal injection for anal incontinence, percutaneous injection for heart failure, intramyocardial injection for heart failure and dilated cardiomyopathy, transendocardial injection for myocardial infarction, intra-articular injection for osteoarthritis, for spinal fusion and spinal, oral maxillofacial and orthopedic surgery. Spinal injections for invasive surgery, Spinal injections for posterolateral lumbar fusion, Intradiscal injections for degenerative disc disease, Injections between the pancreas and duodenum for imaging of pancreatic cancer, Injections in the resection bed for imaging of oropharyngeal cancer, Injections around the tumor bed for imaging of bladder cancer, Submucosal injections for gastrointestinal tumors and polyps, Visceral pleural injections for lung biopsy, Renal injections for type 2 diabetes and chronic kidney disease, Renal cortical injections for chronic kidney disease from congenital anomalies of the kidney and urinary tract, Intravitreal injections for neovascular age-related macular degeneration, Intratympanic injections for sensorineural hearing loss, Dermal injections for correction of wrinkles, creases and folds, signs of facial fat loss, volume loss, contour defects from superficial to deep, correction of depressed skin scars, Perioral wrinkles, Lip augmentation, Facial lipoatrophy, Stimulation of natural collagen production.

Claims

1. a reactive multi-arm polymer, it has a cage-like silicon oxygen core and a plurality of arms containing polyoxazoline extending from the core, wherein the arm containing polyoxazoline comprises a first end that is covalently connected to the cage-like silicon oxygen core and a second end that contains the part that comprises a reactive end group.

2. The reactive multi-arm polymer according to claim 1, wherein the cage-like silicon oxygen core is selected from the group consisting of T6 cage-like silicon oxygen core, T8 cage-like silicon oxygen core, T 10 Cage-like silicon oxygen core and T 12 Cage-like silicon oxygen core.

3. according to the reactive multi-arm polymer described in any one of claims 1-2, the arm containing polyoxazoline comprises and is selected from oxazoline, 2-(C1-C 10 -alkyl)-2-oxazoline and a combination thereof.

4. The reactive multi-arm polymer according to any one of claims 1 to 3, wherein the reactive end groups are electrophilic groups.

5. according to the reactive multi-arm polymer described in any one of claims 1-4, the part that wherein said comprises reactive end group can further comprise hydrolyzable ester group, or the part that wherein said comprises reactive end group comprises diester, and the diester is selected from the diester based on malonic acid, the diester based on succinic acid, the diester based on glutaric acid and the diester based on adipic acid.

6. A system comprising: (a) a reactive multi-arm polymer according to any one of claims 1 to 5, and (b) a multifunctional compound comprising a functional group reactive with a reactive end group of the reactive multi-arm polymer.

7. The system according to claim 6, wherein the reactive groups of the reactive multi-arm polymer are electrophilic groups, and the functional groups of the multifunctional compound are nucleophilic groups.

8. The system of claim 7, wherein the polyfunctional compound is a polyamine compound.

9. The system of claim 8, wherein the polyamine compound comprises 2 to 10 basic amino acid residues, wherein the polyamine compound comprises a plurality of -(CH2) x -NH2 group, wherein x is 0, 1, 2, 3, 4, 5 or 6, or wherein the polyamine compound comprises two or more amino acid residues selected from lysine residues, ornithine residues and combinations thereof.

10. The system of any one of claims 6-9, wherein the system comprises a first precursor composition comprising the multifunctional compound and a second precursor composition comprising the reactive multi-arm polymer.

11. The system of claim 10, further comprising an accelerator composition.

12. The system of claim 11, wherein the enhancer composition comprises a buffer solution having a pH ranging from about 9 to about 11.

13. The system of any one of claims 11-12, wherein the first precursor composition is provided in a syringe tube, the second precursor composition is provided in a vial, and the accelerator composition is provided in a syringe tube.

14. The system of any one of claims 6-13, further comprising a delivery device.

15. A medical hydrogel formed by cross-linking the reactive multi-arm polymer according to any one of claims 1 to 5 and a multifunctional compound comprising a functional group reactive with a reactive end group of the reactive multi-arm polymer.

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