Thermoresponsive injectable hydrogels for intravascular administration

Abstract

Disclosed herein is a flowable polymer solution for intravascular (arterial and venous) administration comprising a polymer comprising a first monomer for binding water; a second monomer for imparting mechanical properties; optionally, a third monomer for binding a natural or synthetic peptide or protein (NSPP); and a fourth monomer for imparting a thermally responsive phase transition behavior; and at least one radiocontrast agent selected from the group consisting of: contrast media for digital subtraction angiography (DSA), computed tomography (CT), and fluoroscopy, such as iodinated contrast media, tantalum and bismuth-based materials (e.g., bismuth chelates); heavy metal chelate contrast media for MRI, including gadolinium agents (e.g., gadobutrol) or MRI nanoparticles.

Description

Related applications

[0001] This application claims priority to Australian Provisional Patent Application No. 2024901241, filed on 1 May 2024. The contents of AU'241 are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to biocompatible polymers and the inventors’ unexpected discovery that such polymers can flow through interventional vascular catheters and microcatheters (1F-6F). The solution transforms into an adhesive hydrogel network after being extruded from the catheter, thus possessing the potential to be used as a formulation for intravascular (arterial or venous) administration.

[0003] The present invention also relates to the discovery that, at concentrations of about 10 to 120 mg / mL and about 5 to 200 mg / mL, the applicant’s proprietary polymers PNPHO and PPHO, or combinations thereof, show potential as advanced thermoresponsive carrier biomaterials for a variety of drug classes, including therapeutic agents, drugs, radioisotopes, etc.

[0004] This invention relates to the discovery that radioactive intravenous contrast agents can be incorporated into formulations of PNPHO and PPHO solutions for effective endovascular embolization or as delivery carriers. This includes contrast media for digital subtraction angiography (DSA), computed tomography (CT), and fluoroscopy—examples of which include iodinated contrast media (e.g., iohexol), tantalum, and bismuth-based materials (e.g., bismuth chelates). Furthermore, heavy metal chelate contrast media for MRI can also be incorporated into PNPHO and PPHO, including gadolinium agents (e.g., gadobutrol) or MRI nanoparticles.

[0005] This invention also relates to the use of PNPHO and PPHO (advanced thermoresponsive biomaterials) for endovascular embolization and as carriers of radioisotopes. This includes all classes of clinically relevant medical radioisotopes, including therapeutic alpha emitters (e.g., lead-212, radium-223) and beta emitters (e.g., iodine-131, yttrium-90, rhenium-186). Furthermore, this invention is applicable to diagnostic radioisotopes, including gamma emitters (e.g., gallium-67, technetium-99m) and positron emitters (e.g., gallium-68, fluorine-18), as well as therapeutic pairs (e.g., lutetium-177 and gallium-68).

[0006] The present invention also relates to the application of PNPHO and PPHO (advanced thermoresponsive biomaterials) for intravascular delivery of different drug classes (as described above) or other reagents for in-situ cargo deposition / reservoir formation.

[0007] Therefore, it is anticipated that the present invention will be applied in medicine, and more particularly in interventional radiology, interventional oncology, vascular surgery, diagnostic radiology, nuclear medicine, radiation oncology and related fields.

[0008] Although the invention will be described below with reference to its preferred embodiments, those skilled in the art will understand that the spirit and scope of the invention may be embodied in many other forms. Background Technology

[0009] Any discussion of prior art throughout the specification should in no way be construed as an admission that such prior art is widely known or constitutes part of common general knowledge in the art.

[0010] Transcatheter arterial embolization (TAE) is a minimally invasive surgical technique that has been widely used since the 1970s [1,2]. Typical conditions targeted by arterial embolization include, but are not limited to, gastrointestinal bleeding, bleeding from vascular malformations, tumors, preoperative blood flow redistribution, varicocele or endoleak, and tumors, particularly hepatocellular carcinoma [2]. The selection and design of the embolic material plays a crucial role in the success of TAE and depends on clinical, anatomical, and local blood flow factors at the target site. Such materials should be fluid through anatomically / arterially compatible catheter sizes, exhibit rapid and effective gelation upon application to fill or block the target site, adhere for an adjustable duration, and, if containing a drug, control the release of such drugs (e.g., chemotherapeutic agents).

[0011] Injectable polymeric embolic agents can be introduced in controlled amounts to partially or completely fill target sites [3]. Common liquid embolic materials include Onyx. TM TRUfill TM And EmboGel TM Onyx TM It consists of a solution of ethylene-vinyl alcohol copolymer and tantalum powder (as a contrast agent) in dimethyl sulfoxide, and has low prothrombotic activity [4,5]. Onyx TM Embolization for aneurysms is generally impractical because there is a risk of leakage of the embolus into the parent artery, which could lead to a stroke [4]. TRUfill TM It is an adhesive with a fast injection rate and is composed of n-butyl cyanoacrylate, which acts as an embolic agent when polymerized via an exothermic reaction [6].

[0012] Injectable hydrogels have been developed and used in TAEs due to their low toxicity. For example, EmboGel... TMIt is a product of the polymerization of a mixture of iohexol (contrast agent) and alginate induced by calcium chloride. However, this mixture may partially reflux into the tumor-bearing artery [7-9]. Other examples of injectable hydrogels that have been reported for embolization applications include shear-thinning materials [10,11], pH-responsive hydrogels [12,13], and thermoresponsive hydrogels [14-20].

[0013] Matsumaru et al. reported on thermosensitive polymers in 1996. N -Isopropylacrylamide and N A copolymer of n-propylacrylamide) is used as an embolic material in endovascular neurosurgery

[21] . Vernon and colleagues developed a copolymer based on N A copolymer system of NIPAAm isopropylacrylamide (NIPAAm) consisting of poly(NIPAAm-co-HEMA-acrylate) functionalized with olefins and 3-mercaptopropionate was used for endovascular embolization

[14] . Later, they enhanced their system by adding thiol groups, in which poly(NIPAAm-co-cysteamine) (NC) reacted with poly(NIPAAm-co-HEMA-acrylate) or poly(NIPAAm-co-cysteamine-vinyl sulfone) to construct a gel

[15] . Zhao et al. also reported a temperature-sensitive endovascular embolization material for interventional therapy based on poly(NIPAAm-co-HEMA-acrylate) mixed with iohexol (a nonionic X-ray contrast agent). N (-Isopropylacrylamide-co-butyl methacrylate), which increased the volumetric phase transition temperature of their system and lowered the critical gelation concentration

[22] . Interestingly, they demonstrated that adding iohexol to pure PNIPAAm shifted the LCST from 32°C to 46°C, resulting in no gelation at body temperature

[22] . Later, they claimed that their poly(N-isopropylacrylamide-co-butyl methacrylate) with iohexol could be modified and potentially used as a bioactive embolic agent in endovascular therapy

[16] . Shi et al. overcame the LCST problem of PNIPAAm by introducing a supramolecular copolymer hydrogel poly(N-acryloylglycamide-co-acrylamide) (PNAGA-PAAm) in combination with iohexol. Their system was injected into the renal artery of rabbits via a microcatheter, and they reported successful embolization with no recanalization after 8 weeks

[17] .

[0014] In various branches of the biomedical field, the applicant, Trimph IP Pty Ltd (Sydney, Australia), has been actively patenting a suite of biocompatible polymers for medical applications over the past decade. Each patent and patent publication cited herein is incorporated herein by reference in its entirety.

[0015] WO 2013 / 091001 (PCT / AU2012 / 001566) relates to polymers, particularly polymers that can be used as hydrogels, and the use of hydrogels for tissue repair or restoration. Specifically, the polymers and hydrogels of WO'001 can be used for the repair or restoration of cartilage, particularly articular cartilage. The polymer comprises at least a monomer for binding water, a monomer for imparting mechanical properties, and a monomer for binding extracellular proteins. The hydrogel comprises a polymer that comprises at least a monomer for binding water and a monomer for binding extracellular proteins. The polymer is cross-linked by binding extracellular matrix proteins, thereby forming the hydrogel.

[0016] The preferred polymer disclosed in WO'001 is poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), or "PNPHO". The polymer PNPHO preferably comprises about 1 to about 15 mol% of OEGMA, about 5 to about 50 mol% of PLA / HEMA, up to 15 mol% of NAS, and the balance to bring the polymer composition to 100%, for example, about 50 to about 85 mol% of NIPAAm. For clarity, the percentages stated refer to the final polymer composition, not the amount of feed used to form the polymer.

[0017] A preferred form of the polymer PNPHO is a polymer of formula (I) shown below. Furthermore, x is 1-1000, y is 1-1000, and m, n, p, and q are 1-20. Those skilled in the art will recognize that monomers A, B, C, and D can be present in the polymer in any order, provided that the desired water-binding, reinforcing, and / or crosslinking capabilities are achieved.

[0018] (I) WO 2017 / 035587 (PCT / AU2016 / 050817) discloses biocompatible materials that can be used for tissue regeneration and repair, wherein the bioactive polymer can be in the form of a hydrogel, such as a thermoresponsive hydrogel. The bioactive polymer of WO'587 and the resulting hydrogel can be used for bone tissue regeneration. Therefore, this reference teaches a method for treating bone defects in mammals, comprising administering a therapeutically effective amount of a hydrogel formed from a bioactive polymer to the mammal to treat the bone defect.

[0019] WO 2017 / 015703 (PCT / AU2016 / 050653) discloses a polymer comprising at least one antiseptic / analgesic / anti-inflammatory monomer unit and at least three additional monomer units having properties selected from: temperature activation, water solubility, mechanical strength, protein / polysaccharide binding capacity, and combinations thereof. Specifically, WO'703 discloses a polymer wherein the water-soluble monomer unit is a hydrophilic ethylene glycol (OEGMA) moiety; the monomer unit imparting mechanical strength is polylactide-co-2-hydroxyethyl methacrylate (PLA / HEMA); the protein-reactive monomer unit is an N-acryloyloxysuccinimide (NAS) moiety; and the thermosetting monomer unit is an N-isopropylacrylamide (NIPAAm) moiety. The antiseptic / analgesic / anti-inflammatory monomer unit comprises a methacrylate derivative of salicylic acid (5-HMA or 4-HMA, or a combination thereof).

[0020] WO 2021 / 119727 (PCT / AU2020 / 051332) teaches a composition comprising a polymer and a natural or synthetic peptide or protein (NSPP), such as thymosin β-4. The polymer comprises a first monomer for binding water, a second monomer for imparting mechanical properties, a third monomer for binding the NSPP, and a fourth monomer for imparting phase transition behavior. Specifically, the composition forms an adhesive and flowable hydrogel upon application to the body or body surface, thereby facilitating tissue repair and regeneration. Therefore, WO'727 discloses a method for tissue repair and / or regeneration comprising applying the composition by injection or by administration of an aerosol, thereby forming a hydrogel at mammalian body temperature.

[0021] Finally, WO 2023 / 201397 (PCT / AU2023 / 050329) discloses a new polymer “PPHO”, namely poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric(ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA).

[0022] The polymer PPHO preferably comprises about 1 to 15 mol% of OEGMA, about 5 to 50 mol% of PLA / HEMA, and the balance to bring the polymer composition to 100%, for example, about 50 to 85 mol% of NIPAAm. In a preferred embodiment, PPHO comprises about 1 to 15 mol% of OEGMA and / or about 15 to 50 mol% of PLA / HEMA and / or about 50 to 85 mol% of NIPAAm. As mentioned above, the percentages referred to herein refer to the composition of the final polymer, not the amount of feed used to form the polymer. A representative polymer of PPHO (Formula (II)) is shown below.

[0023] (II) To date, all applications of PNPHO and PPHO polymers have involved direct application of the polymer solution, such as percutaneous injection, direct syringe extrusion, and / or intranasal spray application. Furthermore, all hydrogels formed after application exhibit low inherent radiopermeability, limiting their effective use for a wide range of intra-arterial applications. The clinical translation of polymer hydrogel embolic agents into clinical practice fundamentally requires clinicians (e.g., interventional / diagnostic radiologists, vascular surgeons, etc.) to dynamically visualize the material during application and delivery. Modern interventional radiology techniques rely on radiographic “angiography” and image-guided techniques. The primary angiographic media used in clinical practice are iodinated agents used for angiography, computed tomography (CT), and fluoroscopy. MRI angiographic media including gadolinium chelates provide alternative media for magnetic resonance imaging. Radioisotopes are widely used in nuclear medicine for diagnostic imaging and have also formed the basis for many emerging interventional imaging techniques and therapies.

[0024] The purpose of this invention is to overcome or improve at least one of the disadvantages of the prior art, or to provide a useful alternative.

[0025] There is a general need in the field for new methods to provide transcatheter arterial embolization (TAE) therapy. As mentioned above, although the technique is widely practiced and minimally invasive, many known TAE agents are suboptimal to some extent.

[0026] It is against this backdrop that the present invention was developed. Various embodiments of the present invention can be applied to aspects related to one or more general needs identified above. Summary of the Invention

[0027] The applicant has unexpectedly discovered that polymer solutions of PNPHO (10 mg / mL to 120 mg / mL) and PPHO (5 mg / mL to 200 mg / mL) are flowable through interventional vascular catheters and microcatheters (1F-6F). Contrast media may or may not be incorporated into the formulation. The resulting solution transforms into an adhesive hydrogel network after being extruded from the catheter within the blood vessel. For the intravascular application of these hydrogel systems, their visibility during imaging is essential for their safe and accurate application.

[0028] Chemical and / or ionic interactions between the PNPHO / PPHO polymers and the buffer / excipients used in commercially available iodine-based contrast agent formulations prevent the direct dissolution of the polymers within the contrast agent. Unexpectedly, the applicant discovered that the PNPHO and / or PPHO polymers, initially dissolved at high concentrations (e.g., 200 to 400 mg / mL) in phosphate-buffered saline (PBS), Hartmann's solution, or water, followed by dilution with iohexol solution, resulted in the formation of PNPHO and PPHO solutions with high contrast agent content. The resulting solutions are flowable through microcatheters (e.g., 3.3 French) and form hydrogels upon extrusion from the catheters.

[0029] It is believed that PNPHO and PPHO can be combined with any contrast agent, including but not limited to X-ray media for CT / angiography / fluorescence fluoroscopy and heavy metal chelates for MRI.

[0030] It is also believed that such combinations can facilitate the delivery of radioisotopes through catheters for radioisotope diagnostic imaging and targeted internal radioisotope therapy, including directed PRRT (peptide receptor radionuclide therapy). The thermoresponsive hydrogel-based combination is flowable (liquid) throughout the catheter in vivo and forms a cohesive and adhesive hydrogel once applied to the target site. The developed system allows for targeted, image-guided delivery of diagnostic and therapeutic radioisotopes in interventional radiology and nuclear medicine.

[0031] Therefore, PNPHO or PPHO-based systems can be used to treat diseases or conditions, including but not limited to gastrointestinal bleeding, bleeding from vascular malformations, tumors, preoperative blood flow redistribution, varicocele or endoleak, and tumors.

[0032] In a broad sense, the present invention relates to a flowable polymer solution for intra-arterial / intravascular administration. Preferably, the polymer is “PPHO”, i.e., poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA)) or “PNPHO”, i.e., poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA).

[0033] According to a first aspect of the invention, a flowable polymer solution for intravascular (arterial and venous) administration is provided, comprising a polymer and at least one solvent, said polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer is used to bind a natural or synthetic peptide or protein (NSPP); and A fourth monomer used to impart thermally responsive phase change behavior.

[0034] In one embodiment, the polymer solution further comprises at least one radioactive intravenous contrast agent.

[0035] In the embodiments, the at least one radioactive intravenous contrast agent is selected from: contrast media for digital subtraction angiography (DSA), computed tomography (CT) and fluorescence fluoroscopy, such as iodinated contrast media, tantalum and bismuth-based materials (e.g., bismuth chelates), heavy metal chelate contrast media for MRI, including gadolinium (e.g., gadobutrol) or MRI nanoparticles.

[0036] In the implementation scheme, the at least one contrast agent is an iodine-based contrast agent.

[0037] In the implementation scheme, the iodine-based contrast agent is iohexol (1-N,3-N-bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6-triiodophenyl-1,3-dicarboxamide).

[0038] In an embodiment, the at least one solvent comprises phosphate-buffered saline (PBS) and / or water.

[0039] In an embodiment, the polymer is poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), or "PNPHO". The polymer PNPHO preferably comprises about 1 to about 15 mol% of OEGMA, about 5 to about 50 mol% of PLA / HEMA, up to 15 mol% of NAS, and the balance of the polymer composition to 100%, for example, about 50 to about 85 mol% of NIPAAm.

[0040] In an embodiment, the polymer is poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), i.e., "PPHO". The polymer PPHO preferably comprises about 1 to about 15 mol% of OEGMA, about 5 to about 50 mol% of PLA / HEMA, and the balance of the polymer composition to 100%, for example, about 50 to about 85 mol% of NIPAAm.

[0041] In the implementation scheme, the first monomer is selected from: polyether, polyvinyl alcohol (PVA); poly(vinylpyrrolidone) (PVP); poly(amino acid) and dextran.

[0042] In the implementation scheme, the polyether is selected from: polyethylene glycol (PEG), oligomeric (ethylene glycol) (OEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), copolymerized ethylene oxide block copolymer, or copolymerized ethylene oxide random copolymer.

[0043] In the implementation scheme, the first monomer is oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA).

[0044] In an embodiment, the second monomer is a methacrylate, or a random copolymer containing a methacrylate.

[0045] In the implementation scheme, the second monomer is selected from: hydroxyethyl methacrylate (HEMA), hydroxyethyl methacrylate poly(lactic acid) copolymer (PLA / HEMA), poly(lactic acid), poly(caprolactone), poly(glycolic acid), poly(glycolic acid), poly(glycolic acid-co-glycolic acid), or poly(glycolic acid-co-caprolactone).

[0046] In the implementation scheme, the second monomer is hydroxyethyl methacrylate poly(lactic acid) (PLA / HEMA).

[0047] In the implementation, the third monomer has an electrophilic functional group for binding NSPP.

[0048] In the embodiments, the third monomer is selected from: N-hydroxysulfosuccinimide (SNHS), N-hydroxyethoxysuccinimide (ENHS), and N-acryloyloxysuccinimide (NAS).

[0049] In the implementation scheme, the third monomer is N-acryloyloxysuccinimide (NAS).

[0050] In the implementation scheme, the fourth monomer has a low critical solution temperature (LCST) below about 37°C.

[0051] In the embodiments, the fourth monomer is selected from: poly(ethylene oxide) / poly(propylene oxide) and poly(N-isopropylacrylamide) (PNIPAAm) homopolymers and copolymers.

[0052] In the implementation scheme, the fourth monomer is (N-isopropylacrylamide) (NIPAAm).

[0053] In an embodiment, the polymer comprises about 1 to about 15 mol% of the first monomer.

[0054] In an embodiment, the polymer contains about 5 to about 50 mol% of the second monomer.

[0055] In an embodiment, the polymer contains about 0 to about 15 mol% of the third monomer.

[0056] In an embodiment, the polymer contains about 50 to about 85 mol% of the fourth monomer.

[0057] In one embodiment, the polymer comprises: a first monomer in an amount of about 1 to about 15 mol%; a second monomer in an amount of about 5 to about 50 mol%; a third monomer in an amount of about 0 to about 15 mol%; and a fourth monomer in an amount that brings the polymer to a balance of 100%.

[0058] In this implementation, the first monomer is OEGMA; the second monomer is PLA / HEMA; the third monomer is NAS; and the fourth monomer is NIPAAm. The polymer comprises: about 1 to about 15 mol% of OEGMA; 5 to about 50 mol% of PLA / HEMA; 0 to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

[0059] In this embodiment, the third monomer is present. In this embodiment, the polymer is poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), i.e., "PNPHO". The polymer PNPHO preferably comprises about 1 to about 15 mol% of OEGMA, about 5 to about 50 mol% of PLA / HEMA, up to 15 mol% of NAS, and the balance of the polymer composition to 100%, for example, about 50 to about 85 mol% of NIPAAm.

[0060] In one embodiment, the polymer solution may be mixed in situ with one or more load compounds prior to application to dilute the polymer solution accordingly, the load compounds being selected from therapeutic agents, drugs, or isotopes or combinations thereof.

[0061] In one embodiment, the one or more loaded compounds are mixed with the polymer solution via direct syringe-syringe mixing.

[0062] In one embodiment, the syringe used for mixing cools the polymer solution and the one or more load compounds during mixing.

[0063] In the implementation, the syringe used for mixing protects the operator from radiation exposure.

[0064] In an embodiment, the polymer solution has a polymer concentration of about 10 mg / mL to about 120 mg / mL.

[0065] Preferably, the polymer solution has concentrations of about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, about 39 mg / mL, about 40 mg / mL, about 41 mg / mL, about 42 mg / mL, and about 43 mg / mL. mg / mL, approximately 44 mg / mL, approximately 45 mg / mL, approximately 46 mg / mL, approximately 47 mg / mL, approximately 48 mg / mL, approximately 49 mg / mL, approximately 50 mg / mL, approximately 51 mg / mL, approximately 52 mg / mL, approximately 53 mg / mL, approximately 54 mg / mL, approximately 55 mg / mL, approximately 56 mg / mL, approximately 57 mg / mL, approximately 58 mg / mL, approximately 59 mg / mL, approximately 60 mg / mL, approximately 61 mg / mL, approximately 62 mg / mL, approximately 63 mg / mL, approximately 64 mg / mL, approximately 65 mg / mL, approximately 66 mg / mL, approximately 67 mg / mL, approximately 68 mg / mL, approximately 69 mg / mL, approximately 70 mg / mL, approximately 71 mg / mL, approximately 72 mg / mL, approximately 73 mg / mL, approximately 74 mg / mL, approximately 75 mg / mL, approximately 76 mg / mL, approximately 77 mg / mL, approximately 78 mg / mL mg / mL, approximately 79 mg / mL, approximately 80 mg / mL, approximately 81 mg / mL, approximately 82 mg / mL, approximately 83 mg / mL, approximately 84 mg / mL, approximately 85 mg / mL, approximately 86 mg / mL, approximately 87 mg / mL, approximately 88 mg / mL, approximately 89 mg / mL, approximately 90 mg / mL, approximately 91 mg / mL, approximately 92 mg / mL, approximately 93 mg / mL, approximately 94 mg / mL, approximately 95 mg / mL, approximately 96 mg / mL, approximately 97 mg / mL, approximately 98 mg / mL, approximately 99 mg / mL, approximately 100 mg / mL, approximately 101 mg / mL, approximately 102 mg / mL, approximately 103 mg / mL, approximately 104 mg / mL, approximately 105 mg / mL, approximately 106 mg / mL, approximately 107 mg / mLPolymer concentrations of approximately 108 mg / mL, 109 mg / mL, 110 mg / mL, 111 mg / mL, 112 mg / mL, 113 mg / mL, 114 mg / mL, 115 mg / mL, 116 mg / mL, 117 mg / mL, 118 mg / mL, 119 mg / mL, or 120 mg / mL.

[0066] In this embodiment, the third monomer is absent. In this embodiment, the polymer is poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), i.e., "PPHO". The polymer PPHO preferably contains about 1 to about 15 mol% of OEGMA, about 5 to about 50 mol% of PLA / HEMA, and the balance to bring the polymer composition to 100%, for example, about 50 to about 85 mol% of NIPAAm.

[0067] In an embodiment, the polymer solution has a polymer concentration of about 5 mg / mL to about 200 mg / mL.

[0068] Preferably, the polymer solution has concentrations of about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, about 25 mg / mL, about 26 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 31 mg / mL, about 32 mg / mL, about 33 mg / mL, about 34 mg / mL, about 35 mg / mL, about 36 mg / mL, about 37 mg / mL, about 38 mg / mL, and about 39 mg / mL. mg / mL, approximately 40 mg / mL, approximately 41 mg / mL, approximately 42 mg / mL, approximately 43 mg / mL, approximately 44 mg / mL, approximately 45 mg / mL, approximately 46 mg / mL, approximately 47 mg / mL, approximately 48 mg / mL, approximately 49 mg / mL, approximately 50 mg / mL, approximately 51 mg / mL, approximately 52 mg / mL, approximately 53 mg / mL, approximately 54 mg / mL, approximately 55 mg / mL, approximately 56 mg / mL, approximately 57 mg / mL, approximately 58 mg / mL, approximately 59 mg / mL, approximately 60 mg / mL, approximately 61 mg / mL, approximately 62 mg / mL, approximately 63 mg / mL, approximately 64 mg / mL, approximately 65 mg / mL, approximately 66 mg / mL, approximately 67 mg / mL, approximately 68 mg / mL, approximately 69 mg / mL, approximately 70 mg / mL, approximately 71 mg / mL, approximately 72 mg / mL, approximately 73 mg / mL, approximately 74 mg / mL mg / mL, approximately 75 mg / mL, approximately 76 mg / mL, approximately 77 mg / mL, approximately 78 mg / mL, approximately 79 mg / mL, approximately 80 mg / mL, approximately 81 mg / mL, approximately 82 mg / mL, approximately 83 mg / mL, approximately 84 mg / mL, approximately 85 mg / mL, approximately 86 mg / mL, approximately 87 mg / mL, approximately 88 mg / mL, approximately 89 mg / mL, approximately 90 mg / mL, approximately 91 mg / mL, approximately 92 mg / mL, approximately 93 mg / mL, approximately 94 mg / mL, approximately 95 mg / mL, approximately 96 mg / mL, approximately 97 mg / mL, approximately 98 mg / mL, approximately 99 mg / mL, approximately 100 mg / mL, approximately 101 mg / mL, approximately 102 mg / mL, approximately 103 mg / mL, approximately 104 mg / mLmg / mL, approximately 105 mg / mL, approximately 106 mg / mL, approximately 107 mg / mL, approximately 108 mg / mL, approximately 109 mg / mL, approximately 110 mg / mL, approximately 111 mg / mL, approximately 112 mg / mL, approximately 113 mg / mL, approximately 114 mg / mL, approximately 115 mg / mL, approximately 116 mg / mL, approximately 117 mg / mL, approximately 118 mg / mL, approximately 119 mg / mL, approximately 120 mg / mL, approximately 121 mg / mL, approximately 122 mg / mL, approximately 123 mg / mL, approximately 124 mg / mL, approximately 125 mg / mL, approximately 126 mg / mL, approximately 127 mg / mL, approximately 128 mg / mL, approximately 129 mg / mL, approximately 130 mg / mL, approximately 131 mg / mL, approximately 132 mg / mL, approximately 133 mg / mL, approximately 134 mg / mL mg / mL, approximately 135 mg / mL, approximately 136 mg / mL, approximately 137 mg / mL, approximately 138 mg / mL, approximately 139 mg / mL, approximately 140 mg / mL, approximately 141 mg / mL, approximately 142 mg / mL, approximately 143 mg / mL, approximately 144 mg / mL, approximately 145 mg / mL, approximately 146 mg / mL, approximately 147 mg / mL, approximately 148 mg / mL, approximately 149 mg / mL, approximately 150 mg / mL, approximately 151 mg / mL, approximately 152 mg / mL, approximately 153 mg / mL, approximately 154 mg / mL, approximately 155 mg / mL, approximately 156 mg / mL, approximately 157 mg / mL, approximately 158 mg / mL, approximately 159 mg / mL, approximately 160 mg / mL, approximately 161 mg / mL, approximately 162 mg / mL, approximately 163 mg / mL, approximately 164 mg / mL mg / mL, approximately 165 mg / mL, approximately 166 mg / mL, approximately 167 mg / mL, approximately 168 mg / mL, approximately 169 mg / mL, approximately 170 mg / mL, approximately 171 mg / mL, approximately 172 mg / mL, approximately 173 mg / mL, approximately 174 mg / mL, approximately 175 mg / mL, approximately 176 mg / mL, approximately 177 mg / mL, approximately 178 mg / mL, approximately 179 mg / mL, approximately 180 mg / mL, approximately 181 mg / mL, approximately 182 mg / mL, approximately 183 mg / mL, approximately 184 mg / mL, approximately 185 mg / mL, approximately 186 mg / mL, approximately 187 mg / mL, approximately 188 mg / mL, approximately 189 mg / mL, approximately 190 mg / mL, approximately 191 mg / mL, approximately 192 mg / mL, approximately 193 mg / mL, approximately 194 mg / mLPolymer concentrations of approximately 195 mg / mL, approximately 196 mg / mL, approximately 197 mg / mL, approximately 198 mg / mL, approximately 199 mg / mL, or approximately 200 mg / mL.

[0069] In this embodiment, the polymer is PNPHO or PPHO. In this embodiment, the polymer is applied to the treatment site via injection through a catheter.

[0070] In the implementation, the catheter is a fine-gauge catheter, such as a French 3.3 mm catheter or a similar catheter.

[0071] In the implementation scheme, the intra-arterial / intravascular administration is part of a transcatheter arterial embolization (TAE) procedure.

[0072] In an embodiment, the polymer solution comprises both a polymer in which the third monomer is present (i.e., PNPHO) and a polymer in which the third monomer is absent (i.e., PPHO).

[0073] In this embodiment, the polymer solution contains approximately 10 mg / mL of PNPHO to ionize with the compound and approximately 50 mg / mL of PPHO to provide adhesion and flowability. It will be understood that varying the relative proportions of PNPHO and PPHO allows these properties to be tuned according to specific circumstances.

[0074] According to a second aspect of the invention, a method for performing a transcatheter arterial embolization (TAE) procedure is provided, the method comprising administering a polymer solution according to the first aspect of the invention to a subject requiring such treatment.

[0075] In the implementation scheme, the polymer solution is applied at body temperature.

[0076] In one embodiment, the thermoresponsive polymer solution forms an adhesive hydrogel network after being extruded from the conduit.

[0077] According to a third aspect of the invention, the use of a polymer solution according to the first aspect of the invention in the preparation of a medicament or delivery carrier for administration via a transcatheter arterial embolization (TAE) procedure is provided.

[0078] In the implementation scheme, the polymer solution is applied at body temperature.

[0079] In one embodiment, the thermoresponsive polymer solution forms an adhesive hydrogel network after being extruded from the conduit.

[0080] According to a fourth aspect of the invention, a kit is provided for forming a flowable polymer solution for intra-arterial / intravascular administration, the kit comprising a polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer is used to bind a natural or synthetic peptide or protein (NSPP); A fourth monomer used to impart thermally responsive phase change behavior; and At least one solvent for forming the polymer solution; and A device for applying the polymer solution; and Optionally, instructions for administering the polymer solution via a transcatheter arterial embolization (TAE) procedure.

[0081] Definitions and Terms In describing and claiming protection for this invention, the following terms will be used in accordance with the definitions set forth below. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0082] Unless the context explicitly requires otherwise, throughout the specification and claims, the words “comprising,” “including,” and similar terms shall be interpreted as inclusive rather than exclusive or exhaustive; that is, meaning “including but not limited to.”

[0083] The terms "preferred" and "ideally" refer to embodiments of the invention that may provide certain benefits under specific circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the recounting 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 invention.

[0084] As used herein, the terminology defining a range or length limit, such as "from 1 to 5," means any integer from 1 to 5, i.e., 1, 2, 3, 4, and 5. In other words, any range defined by two explicitly mentioned integers is intended to include and disclose any integer that defines the limit and any integer contained within that range.

[0085] Except as described in the operational examples or otherwise, all figures used herein to indicate the amount of an ingredient or reaction conditions should in all cases be understood to be modified by the term “about”. The examples are not intended to limit the scope of the invention. In the following, or as otherwise stated, “%” will mean “by weight %”, “ratio” will mean “by weight ratio”, and “parts” will mean “parts by weight”.

[0086] Although the numerical ranges and parameters described in this invention are approximate, the values ​​presented in the specific embodiments are reported as precisely as possible. However, any numerical value inherently contains some error due to the standard deviation found in its respective test measurements.

[0087] The following abbreviations are used in this instruction manual: SEHNS N-hydroxyethoxylated succinimide HEMA hydroxyethyl methacrylate LA lactic acid NAS N-Acryloyloxysuccinimide NIPAAm N-isopropylacrylamide NSPP (Natural or synthetic peptides or proteins) OEG (Oligomerized Glycol) OEGMA Oligomeric (ethylene glycol) Monomethyl ether methacrylate PBS (Phosphate Buffered Saline) PEG (Polyethylene Glycol) PEO (polyethylene oxide) PLA (poly(lactic acid)) PLA / HEMA hydroxyethyl methacrylate poly(lactic acid) PPO (Polyethylene Oxide-Co-propylene Oxide) PVA (Polyvinyl alcohol) PVP (Polyvinylpyrrolidone) PNPHO is poly(N-isopropylacrylamide-co-(N-acryloyloxysuccinimide)-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), for example, as defined in formula (I) above. PPHO is poly(N-isopropylacrylamide-co-(polylactide / 2-hydroxymethacrylate)-co-(oligomeric (ethylene glycol) / poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), for example, as defined above in formula (II). Attached Figure Description

[0088] Preferred embodiments of the invention will now be described by way of example only with reference to the accompanying drawings, in which: Figure 1 relates to Example 7 below. In this example, 22.5 mL of “TL200” (defined below) was diluted with 7.5 mL of 350 mg I / mL to achieve a PPHO concentration of 150 mg / mL and 90 mg I / mL. The resulting solution was then subcutaneously injected into a warm cadaveric pig model. A total of approximately 5 mL of product was injected. CT scans of the injection site were used after application to verify the presence of the hydrogel and its thermal responsiveness and radiopaque properties. Injection of 5 mL of TL150-IOP090 into a cadaveric subcutaneous model resulted in the formation of a hydrogel (white gel, indicated by black arrows) at the application site (Figure 1(a)). CT scans of the injection site showed the presence of a radiopaque white structure at the application site, indicated by white arrows (Figure 1(b)).

[0089] Figure 2 Referring to Example 8 below. Results confirmed that injectable / flowable formulations with different Hounsfield units can be formed to match desired clinical needs. R... 2 A linear regression of 0.973 allows for further product formulation.

[0090] Figure 3 This relates to Example 9 below. In this example, the flowability of the formulation through a medical catheter (Excelsior XT-27) was tested using a "TP050 / TL50-IOP45" solution. To simulate physiological conditions, the catheter was immersed in pre-warmed PBS for 5 minutes. Afterward, the catheter was rinsed with warm water for injection. The solution was delivered via the catheter using a standard syringe. Figure 3 It has been confirmed that when the solution flows through the catheter, it forms cohesive hydrogel lines once it reaches physiological temperature.

[0091] Figure 4 This relates to Example 11 below. In this example, the “TP100-IOP45” solution was used to test the flowability of the formulation through a medical catheter as described. To simulate physiological conditions, the catheter was immersed in pre-warmed PBS for 5 minutes. Afterward, the catheter was rinsed with warm water for injection. The solution was delivered via the catheter using a standard syringe. Figure 4 It has been confirmed that when the solution flows through the catheter, it forms cohesive hydrogel lines once it reaches physiological temperature.

[0092] Figure 5 relates to Example 12 below. In this example, the flowability of the formulation through a catheter and an in vitro vascular model under fluorescence fluoroscopy was tested using a "TP050 / TL50-IOP240" solution. Phosphate-buffered saline (PBS) was pumped into the simulated in vitro vascular model at 37°C. A 2F Trevo catheter was used for this study. The TP050 / TL50-IOP240 solution was delivered via the catheter using a standard syringe. The results, as shown in Figure 5(a), confirmed that the solution flowed through the catheter and formed a solid white coil-like gel at the catheter tip after entering the fluid within the vascular model. Furthermore, the gel formation was observed by real-time fluorescence fluoroscopy. Similar results were observed by passing TL050 / TP050-IOP225 through a 2.9F Maestro catheter, as shown in Figure 5(b).

[0093] Figure 6 relates to Example 13 below. In this example, the flowability of the formulation within microvessels of an isolated pig kidney model via a 2F Trevo catheter (as an example) was tested using a "TL050 / TP050-IOP240" solution. The results, shown in Figures 6(a) and 6(b), confirm that the formulation is flowable and can flow within the target microvessels, as visible under real-time fluorescence fluoroscopic imaging. Detailed Implementation

[0094] The invention will now be described more fully with reference to the accompanying embodiments and drawings. However, it should be understood that the following description is illustrative only and should not be construed in any way as limiting the general scope of the invention described above.

[0095] Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with these embodiments, it should be understood that it is not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims.

[0096] Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described herein can be used in the practice of this invention. This invention is by no means limited to the methods and materials described.

[0097] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more individual features mentioned or obvious in the text or drawings. All these different combinations constitute various alternative aspects of the invention.

[0098] This article broadly discloses the use of biocompatible polymers for application to treatment sites at or near target tissue (e.g., human prostate), whereby the polymer forms a hydrogel at body temperature to provide a physical spacer between the tissue and nearby cells / tissues / organs (e.g., human rectum). This physical spacer / isolation of the prostate and rectum allows radiotherapy to focus on the isolated target tissue without substantially affecting the cells / tissues / organs separated from it by the polymer hydrogel.

[0099] polymer As used herein, the term "polymer" refers to a macromolecule (high molecular weight polymer) composed of repeating structural units (monomers). These subunits are typically linked by covalent chemical bonds. The polymer can be linear or branched. Preferably, the polymer of the present invention is a copolymer comprising three or more different monomers. For example, in one embodiment, the polymer of the present invention comprises a first monomer that binds water, a second monomer that imparts mechanical properties to the polymer, and a third monomer having functional groups for binding NSPP.

[0100] As used herein, the term "monomer" refers to a structural unit that can be combined to form a polymer, but it can also be a polymer itself, or a derivative of a monomer or polymer. This type of monomer is also referred to herein as a "macromonomer." In this context, a "macromonomer" is a polymer or oligomer whose molecule has an end group that acts as a monomer molecule, such that each polymer or oligomer molecule contributes only one monomer unit to the chain of the product polymer.

[0101] The polymer of the present invention comprises: a first monomer for binding water; a second monomer for imparting mechanical properties to the polymer; optionally, a third monomer for binding natural or synthetic peptides or proteins (NSPPs); and a fourth monomer for imparting phase transition behavior.

[0102] First monomer: Water-bound monomer As described above, the advantages of the polymers of the present invention can be attributed at least in part to the specific components constituting the polymers of the present invention. A particularly advantageous property of the polymers of the present invention is their water-binding capacity. The presence of water in the polymers of the present invention provides an environment that is both similar to the natural environment of damaged tissue (which facilitates tissue regeneration) and similar to the compressive strength required by the polymer.

[0103] Therefore, the preferred polymers used herein should contain monomers or units capable of binding water so that a plastic structure can be formed when the polymer is hydrated. Furthermore, the resulting structure should possess the required compressive strength and resilience.

[0104] Those skilled in the art will understand that the water-binding monomers need to be present in the polymers of the present invention in proportions sufficient to produce polymers that meet these requirements. Typically, the molar ratio of water-binding monomers to mechanical strength monomers in the polymer is about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, or about 1:50. In fact, the water-binding monomers not only need to make the polymer hydrophilic, but also need to impart a more significant water-binding capacity to the polymer. Therefore, the polymers according to the present invention will have a water-binding capacity of about 70% to about 500%, about 80% to about 400%, about 90% to 300%, or about 100% to 200%. For example, the water binding capacity of the polymer of the present invention is about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, about 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 400%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, or about 500%.

[0105] Suitable examples of water-binding monomers include those that can be synthesized into polymers, such as polyethers (e.g., polyalkylene oxides such as polyethylene glycol (PEG), oligomeric (ethylene glycol) (OEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), copolymerized ethylene oxide block or random copolymers, polyvinyl alcohol (PVA)), polyvinylpyrrolidone (PVP), poly(amino acids), and dextran. Polyethers are particularly preferred, and more particularly oligomeric (oxidized olefins) (e.g., OEG), because they have the desired water-binding capacity, are readily synthesized and / or available, and are inert, i.e., they elicit minimal or no immune response in the tissues in which they are placed.

[0106] Furthermore, any of a variety of hydrophilic functional groups can be used to make monomers (and polymers formed from such monomers) water-soluble. For example, water-soluble functional groups such as phosphate / ester, sulfate / ester, quaternary ammonium, hydroxyl, amino, sulfonate / ester, and carboxylate / ester can be incorporated into monomers to make them water-soluble.

[0107] Monomers can also react with other compounds to form "macromonomers". Therefore, the first monomer can optionally be a macromonomer.

[0108] A preferred first monomer (which is a macromonomer) is oligomeric (ethylene glycol) monomethyl ether methacrylate (OEGMA), which is a hydrophilic monomer composed of two hydrophilic monomers: ethylene glycol and methacrylate.

[0109] Preferably, the polymer comprises a first monomer in an amount of about 1 to about 15 mol%. In various embodiments, the first monomer may be present in the form of about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. In various embodiments, the first monomer may be present in the form of about 1 mol% to about 15 mol%, about 2 mol% to about 14 mol%, about 3 mol% to about 13 mol%, about 4 mol% to about 12 mol%, about 5 mol% to about 11 mol%, about 6 mol% to about 10 mol%, about 7 mol% to about 9 mol%, or about 8 mol%.

[0110] Second monomer: The monomer that imparts mechanical properties As described above, the advantageous properties of the polymers of the present invention can be attributed in part to the specific components constituting the polymers of the present invention. In some embodiments, the polymers of the present invention are able to contribute additional mechanical properties and adhesiveness to the polymers of the present invention.

[0111] Those skilled in the art will understand that monomers capable of imparting mechanical properties to polymers need to be present in the polymers of the present invention in proportions sufficient to produce polymers with the desired mechanical properties. Typically, the molar ratio of "mechanical" monomers in the polymer is about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:10, about 1:20, about 1:30, about 1:40, or about 1:50 for the molar ratio of water-bound monomers to mechanical strength monomers. Suitable examples of monomers capable of imparting mechanical properties (e.g., compressive strength) to polymers include acrylates, such as hydroxyethyl methacrylate (HEMA); polyesters, such as poly(lactic acid), poly(caprolactone), poly(glycolic acid), and their random copolymers (e.g., poly(glycolic acid-co-lactide) and poly(glycolic acid-co-caprolactone)).

[0112] Monomers can also react with other compounds to form "macromonomers". A preferred second monomer (which is a macromonomer) is poly(lactic acid) hydroxyethyl methacrylate (PLA / HEMA).

[0113] Preferably, the polymer contains about 1 to about 50 mol% of a second monomer. In various embodiments, the second monomer can be in the form of about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 It exists in mol%, about 43 mol%, about 44 mol%, about 45 mol%, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, or about 50 mol%.

[0114] In various embodiments, the second monomer may be in the form of about 1 mol% to about 15 mol%, about 2 mol% to about 49 mol%, about 3 mol% to about 48 mol%, about 4 mol% to about 47 mol%, about 5 mol% to about 46 mol%, about 6 mol% to about 45 mol%, about 7 mol% to about 44 mol%, about 8 mol% to about 43 mol%, about 9 mol% to about 42 mol%, about 10 mol% to about 41 mol%, about 11 mol% to about 40 mol%, about 12 mol% to about 39 mol%, about 13 mol% to about 38 mol%, about 14 mol% to about 37 mol%, about 15 mol% to about 36 mol%, about 16 mol% to about 35 mol%, about 17 mol% to about 34 mol%, about 18 mol% to about 33 mol%, about 19 mol% to about 34 mol%, about 20 mol% to about 33 mol%, about 21 mol% to about 30 mol%. It exists in mol%, about 22 mol% to about 29 mol%, about 23 mol% to about 28 mol%, about 24 mol% to about 27 mol%, or about 25 mol% to about 26 mol%.

[0115] Those skilled in the art will understand that, since mechanical strength and adhesion are key factors in this invention, the amount of the second monomer occupies a wider range than that of other monomers.

[0116] Third monomer: NSPP-binding monomer As described above, the polymers used in this invention can optionally be formed by combining the polymer with NSPP. For efficient combination of the polymer with NSPP, it is preferable to include crosslinking-capable monomers or units in the polymer.

[0117] This crosslinking ability means that the polymer can bind to NSPP and crosslink NSPP in doing so to form an NSPP-containing polymer. Alternatively, through a similar mechanism, NSPP acts as a crosslinking agent, thereby crosslinking the polymer to form a polymer.

[0118] In order to prepare a polymer capable of binding NSPP, those skilled in the art will understand that the monomers capable of binding NSPP need to be present in the polymer of the present invention in a proportion sufficient to crosslink with NSPP, so that the polymer can be formed in the presence of water. Typically, the ratio of "crosslinked" monomers in the polymer is about 15:1, about 10:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:10, or about 1:15.

[0119] Monomers capable of binding NSPP typically possess electrophilic or nucleophilic functional groups, allowing, for example, nucleophilic functional groups on NSPP to react with electrophilic functional groups on monomers to form covalent bonds.

[0120] Therefore, for example, if NSPP has a nucleophilic functional group such as an amine, the polymer may have an electrophilic functional group such as N-hydroxysuccinimide (NHS). Other electrophilic functional groups suitable for the present invention are N-hydroxysulfosuccinimide (SNHS) and N-hydroxyethoxysuccinimide (ENHS). An example of this type of monomer is N-acryloyloxysuccinimide (NAS). On the other hand, if NSPP has an electrophilic functional group, the polymer may have a nucleophilic functional group such as an amine or a thiol.

[0121] Preferably, the polymer contains up to 15 mol% of a third monomer. In various embodiments, the third monomer may be present in amounts of about 0 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. In various embodiments, the third monomer may be present in amounts of about 0 mol% to about 1 mol%, about 1 mol% to about 15 mol%, about 2 mol% to about 14 mol%, about 3 mol% to about 13 mol%, about 4 mol% to about 12 mol%, about 5 mol% to about 11 mol%, about 6 mol% to about 10 mol%, about 7 mol% to about 9 mol%, or about 8 mol%.

[0122] Those skilled in the art will understand that the polymer can be formed from a hydrophobic composition, and therefore the third monomer is optional in the polymer.

[0123] Fourth monomer: Phase change monomer In another embodiment of the invention, the polymer may further comprise a fourth monomer capable of imparting phase change properties to the polymer, thereby ensuring the stability of the polymer after application. Furthermore, these phase change properties allow the polymers of the present invention to form polymers whose various properties (e.g., viscosity) can be varied by changing factors such as pH and temperature. The polymers are designed such that the low critical solution temperature (LCST) is below body temperature. Various thermoresponsive and injectable polymers, including poly(ethylene oxide) / poly(propylene oxide) and poly(N-isopropylacrylamide) (PNIPAAm) copolymers, are suitable for use in this invention.

[0124] Typically, the proportion of phase change monomers in a polymer is at least approximately 3:1 in molar ratio of phase change monomer to water-bound monomer. This ratio can be increased to, for example, approximately 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, and 85:1.

[0125] Preferably, the polymer comprises a fourth monomer in an amount sufficient to make up the polymer composition to 100%. In embodiments, the mol% of the fourth monomer can be up to about 85%, preferably about 50 mol%, 51 mol%, 52 mol%, 53 mol%, 54 mol%, 55 mol%, 56 mol%, 57 mol%, 58 mol%, 59 mol%, 60 mol%, 61 mol%, 62 mol%, 63 mol%, 64 mol%, 65 mol%, 66 mol%, 67 mol%, 68 mol%, 69 mol%, 70 mol%, 71 mol%, 72 mol%, 73 mol%, 74 mol%, 75 mol%, 76 mol%, 77 mol%, 78 mol%, 79 mol%, 80 mol%, 81 mol%, 82 mol%, 83 mol%, 84 mol%, or 85 mol%.

[0126] Other polymer properties Those skilled in the art will understand that polymers with a range of different properties can be produced by combining different types of monomers. Furthermore, the properties of a polymer can be altered by incorporating specific monomers or functional groups into a pre-existing polymer. For example, copolymerization of HEMA monomer with other monomers (e.g., methyl methacrylate) can be used to modify properties such as swelling properties and mechanical properties. Monomers can also react with other compounds to form macromonomers (as defined above), which are then included in the polymers of the present invention. For example, HEMA can react with lactide to form a HEMA-polylactic acid polymer (PLA / HEMA), which can itself be used as a monomer in the polymers of the present invention. Furthermore, the monomer itself can be a combination of monomer units that are then incorporated into the polymer. An example of this type of monomer is oligomeric (ethylene glycol) monomethyl ether methacrylate (OEGMA), which is a hydrophilic monomer composed of two hydrophilic monomers: ethylene glycol and methacrylate.

[0127] The preferred polymers of the present invention may also be modified with one or more moieties and / or functional groups. Any moieties or functional groups may be used according to the present invention. In some embodiments, the polymer may be modified with polyethylene glycol (PEG), with carbohydrates, and / or with acyclic polyacetals derived from polysaccharides. Furthermore, as described above, hydrophilic groups may be incorporated into the monomers (and the polymer) to increase the polymer's water-binding capacity.

[0128] In terms of sequence, the copolymer can be a block copolymer, graft copolymer, random copolymer, blend, mixture, and / or any of the foregoing types of adducts with other polymers. Typically, the polymers according to the invention are organic polymers. Preferably, the polymers of the invention are biocompatible. In some embodiments, the polymer is biodegradable. In other embodiments, the polymer is both biocompatible and biodegradable.

[0129] The preferred polymers of the present invention may also include other monomers in their structure. For example, the monomers may be polymers such as poly(vinyl alcohol) (PVA), polyesters, acrylic polymers and ionomers, or monomers thereof.

[0130] If it is desired that the polymer be biodegradable or absorbable, one or more monomers having a biodegradable linkage can be used. Alternatively or additionally, the monomers can be selected such that the products of their reaction produce a biodegradable linkage. For each method, the monomers and / or linkages can be selected such that the resulting biodegradable polymer will degrade or be absorbed within a desired time period, for example, from about 6 hours to about 6 months. Preferably, the monomers and / or linkages are selected such that the resulting product is non-toxic when the polymer degrades under physiological conditions.

[0131] Biodegradable linkages can be chemically or enzymatically hydrolyzable or absorbable. Exemplary chemically hydrolyzable biodegradable linkages include polymers, copolymers, and oligomers of glycolide, lactide, caprolactone, dioxane, and trimethylene carbonate. Exemplary enzymatically hydrolyzable biodegradable linkages include peptide linkages that can be cleaved by metalloproteinases and collagenases. Other exemplary biodegradable linkages include polymers and copolymers of poly(hydroxy acids), poly(orthocarbonates), poly(anhydrides), poly(lactones), poly(amino acids), poly(carbonates), and poly(phosphonates).

[0132] In this invention, the chemical hydrolysis of lactide leads to an increase in the lower critical solution temperature (LCST) of the polymer (by reducing the overall hydrophobicity of the polymer) and thus increases its bioreabsorption capacity.

[0133] Preferred polymers The polymer preferably contains a first monomer in an amount of about 1 to about 15 mol%. In various embodiments, the first monomer may be present in amounts of about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. Preferably, the first monomer is OEGMA.

[0134] The polymer preferably contains about 5 to about 50 mol% of a second monomer. In various embodiments, the second monomer can be in the form of about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%, about 41 mol%, about 42 It is present in mol%, about 43 mol%, about 44 mol%, about 45 mol%, about 46 mol%, about 47 mol%, about 48 mol%, about 49 mol%, or about 50 mol%. Preferably, the second monomer is PLA / HEMA.

[0135] The polymer preferably contains a third monomer in an amount of up to 15 mol%. In various embodiments, the third monomer may be present in amounts of about 0 mol%, about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol%. Preferably, the third monomer is NAS.

[0136] The polymer preferably comprises a fourth monomer in an amount that brings the polymer composition to 100%, for example, about 50 to about 85 mol%. In embodiments, the mol% of the fourth monomer can be up to about 85%, preferably about 50 mol%, 51 mol%, 52 mol%, 53 mol%, 54 mol%, 55 mol%, 56 mol%, 57 mol%, 58 mol%, 59 mol%, 60 mol%, 61 mol%, 62 mol%, 63 mol%, 64 mol%, 65 mol%, 66 mol%, 67 mol%, 68 mol%, 69 mol%, 70 mol%, 71 mol%, 72 mol%, 73 mol%, 74 mol%, 75 mol%, 76 mol%, 77 mol%, 78 mol%, 79 mol%, 80 mol%, 81 mol%, 82 mol%, 83 mol%, 84 mol%, or 85 mol%. Preferably, the fourth monomer is NIPAAm.

[0137] The percentages mentioned in this article refer to the composition of the final polymer, not the amount of feed used to form the polymer.

[0138] In an embodiment, the polymer preferably comprises: a first monomer in an amount of about 1 to about 15 mol%; a second monomer in an amount of about 5 to about 50 mol%; a third monomer in an amount of up to 15 mol%; and a fourth monomer in an amount of up to about 85 mol%.

[0139] Preferably, the first monomer is OEGMA, the second monomer is PLA / HEMA, the third monomer is NAS, and the fourth monomer is NIPAAm.

[0140] In another embodiment, the polymer preferably comprises: about 7 mol% of a first monomer; about 30 mol% of a second monomer; about 7 mol% of a third monomer; and about 53 mol% of a fourth monomer.

[0141] Preferably, the first monomer is OEGMA, the second monomer is PLA / HEMA, the third monomer is NAS, and the fourth monomer is NIPAAm.

[0142] In one embodiment, the polymer of the present invention is a polymer of formula (a) or formula (b): (a) (b) in A is the first monomer (water-bound monomer), for example, OEGMA; B is the second monomer (a monomer that can impart mechanical properties to the polymer), for example, PLA / HEMA; C, if present, is a third monomer (a monomer with a functional group for binding NSPP), for example, NAS; and D is the fourth monomer (a monomer that can impart phase change properties to the polymer), for example, NIPAAm.

[0143] In various implementations, m is an integer from 1 to 20; n is an integer from 1 to 20; p is an integer from 0 to 20; and q is an integer from 1 to 20.

[0144] The exemplary polymers of the present invention are represented by formula (a) and / or formula (b) as shown above, wherein A is the water-binding monomer OEGMA, B is the reinforcing monomer PLA / HEMA, C (if present) is the crosslinking agent NAS, D is the phase change monomer NIPAAm, and m, n, p, q, x, and y are as defined above.

[0145] Those skilled in the art will recognize that monomers A, B, C, and D can be present in the polymer in any order, provided that the desired water-binding, reinforcing, and / or crosslinking capabilities are achieved.

[0146] It has also been found that certain monomers, such as PLA / HEMA, polyesters such as poly(lactic acid), poly(caprolactone), poly(glycolic acid), and their random copolymers (e.g., poly(glycolic acid-co-lactide) and poly(glycolic acid-co-caprolactone)), and other biodegradable and biocompatible polymers, can enhance the LCST of preferred polymers used in this invention during the in vivo degradation of biodegradable segments (e.g., PLA), leading to bioreabsorption of the polymer. This provides the additional advantage that the polymers used in this invention can be designed to be biodegradable in vivo.

[0147] The overall size of the preferred polymers used in this invention can vary depending on factors such as the type of monomer incorporated into the polymer, the type of NSPP sought to form the polymer, and the conditions under which the protein is coupled to the polymer. However, generally speaking, the preferred polymers used in this invention can be molecules of about 1 to about 100 kDa, about 5 to about 60 kDa, or about 30 kDa. In various embodiments, the polymer of the present invention may be about 1 kDa, about 2 kDa, about 3 kDa, about 4 kDa, about 5 kDa, about 6 kDa, about 7 kDa, about 8 kDa, about 9 kDa, about 10 kDa, about 11 kDa, about 12 kDa, about 13 kDa, about 14 kDa, about 15 kDa, about 16 kDa, about 17 kDa, about 18 kDa, about 19 kDa, about 20 kDa, about 21 kDa, about 22 kDa, about 23 kDa, about 24 kDa, about 25 kDa, about 26 kDa, about 27 kDa, about 28 kDa, about 29 kDa, about 30 kDa, about 31 kDa, about 32 kDa, about 33 kDa, about 34 kDa, about 35 kDa, about 36 kDa, about 37 kDa, about 38 kDa, about 39 kDa, about 40 kDa, about 41 kDa. KDa, approximately 42 KDa, approximately 43 KDa, approximately 44 KDa, approximately 45 KDa, approximately 46 KDa, approximately 47 KDa, approximately 48 KDa, approximately 49 KDa, approximately 50 KDa, approximately 51 KDa, approximately 52 KDa, approximately 53 KDa, approximately 54 KDa, approximately 55 KDa, approximately 56 KDa, approximately 57 KDa, approximately 58 KDa, approximately 59 KDa, approximately 60 KDa, approximately 61 KDa, approximately 62 KDa, approximately 63 KDa, approximately 64 KDa, approximately 65 KDa, approximately 66 KDa, approximately 67 KDa, approximately 68 KDa, approximately 69 KDa, approximately 70 KDa, approximately 71 KDa, approximately 72 KDa, approximately 73 KDa, approximately 74 KDa, approximately 75 KDa, approximately 76 KDa, approximately 77 KDa, approximately 78 KDa, approximately 79 KDa, approximately 80 KDa, approximately 81 KDa, approximately 82 Molecules of approximately 83 kDa, 84 kDa, 85 kDa, 86 kDa, 87 kDa, 88 kDa, 89 kDa, 90 kDa, 91 kDa, 92 kDa, 93 kDa, 94 kDa, 95 kDa, 96 kDa, 97 kDa, 98 kDa, 99 kDa, or 100 kDa.

[0148] PNPHO-Form (I) A preferred polymer of the present invention is poly(NIPAAm-co-NAS-co-(PLA / HEMA)-co-OEGMA), or "PNPHO". The polymer PNPHO preferably comprises about 1 to about 15 mol% of OEGMA, about 5 to about 50 mol% of PLA / HEMA, up to 15 mol% of NAS, and the balance of the polymer composition to 100%, for example, about 50 to about 85 mol% of NIPAAm.

[0149] The percentages mentioned in this article refer to the composition of the final polymer, not the amount of feed used to form the polymer.

[0150] In one embodiment, the preferred polymer comprises: OEGMA in amounts of approximately 3 mol% to approximately 8 mol% (e.g., approximately 4 mol% to approximately 6 mol%); Amounts of HEMA-PLA ranging from approximately 5 mol% to approximately 9 mol% (e.g., approximately 6 mol% to approximately 8 mol%); At least approximately 7 mol% of NAS; and The amount of NIPAAm is up to about 85 mol% (e.g., up to about 81 mol%).

[0151] In another embodiment, the polymer comprises: Approximately 5 mol% of OEGMA; Approximately 7 mol% of HEMA-PLA; Approximately 7 mol% of NAS; and Approximately 81 mol% of NIPAAm.

[0152] A preferred form of the polymer PNPHO used in this application is a polymer of formula (I) as shown above.

[0153] Based on the previously defined equation I: A is oligo(ethylene glycol) monomethyl ether methacrylate OEGMA; B is hydroxyethyl methacrylate poly(lactic acid) (HEMA-PLA); C is N-acryloyloxysuccinimide (NAS); and D stands for N-isopropylacrylamide (NIPAAm).

[0154] A preferred form of the polymer PNPHO used in this application is a polymer of formula (I) as shown above. Furthermore, x is in the range of 1-1000, y is in the range of 1-1000, and m, n, p, and q are in the range of 1-20.

[0155] Those skilled in the art will recognize that monomers A, B, C, and D can be present in the polymer in any order, provided that the desired water-binding, reinforcing, and / or crosslinking capabilities are achieved.

[0156] PPHO-Form (II) Another preferred polymer of the present invention is poly(NIPAAm-co-(PLA / HEMA)-co-OEGMA), or "PPHO". The polymer PPHO preferably comprises about 1 to about 15 mol% of OEGMA, about 5 to about 50 mol% of PLA / HEMA, and the balance of the polymer composition to 100%, for example, about 50 to about 85 mol% of NIPAAm. In a preferred embodiment, PPHO comprises about 1 mol%, about 2 mol%, about 3 mol%, about 4 mol%, about 5 mol%, about 6 mol%, about 7 mol%, about 8 mol%, about 9 mol%, about 10 mol%, about 11 mol%, about 12 mol%, about 13 mol%, about 14 mol%, or about 15 mol% of OEGMA and / or about 15 mol%, about 16 mol%, about 17 mol%, about 18 mol%, about 19 mol%, about 20 mol%, about 21 mol%, about 22 mol%, about 23 mol%, about 24 mol%, about 25 mol%, about 26 mol%, about 27 mol%, about 28 mol%, about 29 mol%, about 30 mol%, about 31 mol%, about 32 mol%, about 33 mol%, about 34 mol%, about 35 mol%, about 36 mol%, about 37 mol%, about 38 mol%, about 39 mol%, about 40 mol%. PLA / HEMA of approximately 41 mol%, approximately 42 mol%, approximately 43 mol%, approximately 44 mol%, approximately 45 mol%, approximately 46 mol%, approximately 47 mol%, approximately 48 mol%, approximately 49 mol%, or approximately 50 mol% and / or approximately 50 mol%, approximately 51 mol%, approximately 52 mol%, approximately 53 mol%, approximately 54 mol%, approximately 55 mol%, approximately 56 mol%, approximately 57 mol%, approximately 58 mol%, approximately 59 mol%, approximately 60 mol%, approximately 61 mol%, approximately 62 mol%, approximately 63 mol%, approximately 64 mol%, approximately 65 mol%, approximately 66 mol%, approximately 67 mol%, approximately 68 mol%, approximately 69 mol%, approximately 70 mol%, approximately 71 mol%, approximately 72 mol%, approximately 73 mol%, approximately 74 mol%, approximately 75 mol%, approximately 76 mol%, approximately 77 mol%, approximately 78 ... NIPAAm in amounts of mol%, approximately 79 mol%, approximately 80 mol%, approximately 81 mol%, approximately 82 mol%, approximately 83 mol%, approximately 84 mol%, or approximately 85 mol%.

[0157] The percentages mentioned in this article refer to the composition of the final polymer, not the amount of feed used to form the polymer.

[0158] A preferred form of the polymer PPHO used in this application is the polymer of formula (II) shown below. Furthermore, x is in the range of 1-1000, y is in the range of 1-1000, and m, n, and q are in the range of 1-20.

[0159] Those skilled in the art will recognize that monomers A, B, and D can be present in the polymer in any order, provided that the desired water-binding, reinforcing, and / or crosslinking capabilities are achieved.

[0160] Polymer Synthesis Those skilled in the art will understand suitable methods for synthesizing the preferred polymers used in this invention. These methods include, for example, ring-opening polymerization, addition polymerization (including free radical polymerization), and polycondensation.

[0161] The formation of preferred polymers PNPHO and PPHO is described in the examples below.

[0162] Excipients and bioactive agents Pharmaceutically acceptable excipients may be included in the compositions and / or polymers of the present invention, and include any and all solvents, dispersion media, inert diluents or other liquid solvents, dispersants or suspending agents, granulators, surfactants, disintegrants, isotonic agents, thickeners or emulsifiers, preservatives, binders, lubricants, buffers, oils, etc., as suitable for the desired particular dosage form. Remington (Gennaro, AR, Remington: The Science and Practice of Pharmacy, 21st edition (2006) Lippincott Williams & Wilkins) discloses a variety of excipients for formulating pharmaceutical compositions and known preparation techniques. Unless any conventional excipient is incompatible with the substance or its derivatives, for example by producing any undesirable biological effects or interacting in other harmful ways with any other component of the pharmaceutical composition, its use is considered to be within the scope of the present invention.

[0163] Excipients such as colorants, coating agents, sweeteners, flavoring agents, and aromatizers may be present in the composition, depending on the formulator's judgment.

[0164] Bioactive agents or pharmaceutical compounds that can be added to the compositions and / or polymers of the present invention include proteins, glycosaminoglycans, carbohydrates, nucleic acids, and inorganic and organic bioactive compounds such as enzymes, antibiotics, antitumor agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors (e.g., insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-b (TGFb)), antibodies, neurotransmitters, psychoactive drugs, anticancer drugs, chemotherapeutic drugs, drugs affecting reproductive organs, genes, and oligonucleotides.

[0165] Compositions containing components such as excipients and / or bioactive agents can be produced by combining the polymer of the present invention with NSPP, combining it with one or more other components, and then freeze-drying the resulting composition. This produces a ready-to-use polymer.

[0166] The amounts of polymers, NSPP, and bioactive agents present in the composition will necessarily depend on the specific drug and the condition to be treated. Those skilled in the art will understand the appropriate reagents and dosages for treating the condition.

[0167] Composition for forming hydrogels The present invention also relates to a preferred composition which can be used to form a hydrogel for use in the present invention.

[0168] The compositions of the present invention comprise a polymer and optionally NSPP, the polymer comprising: Water-bound first monomer; and The second monomer that imparts mechanical properties; Optionally, as a third monomer of the NSPP binding monomer, it contains functional groups capable of binding NSPP. A fourth monomer capable of imparting phase transition properties to hydrogels; The natural or synthetic peptides or proteins (NSPPs) may be thymosin β-4 or its functional homologs; Furthermore, the combination of NSPP with the second monomer crosslinks the polymer, thereby enabling the formation of a hydrogel when the composition comes into contact with water.

[0169] As used herein, the term "composition" refers to a solid or liquid composition containing the components described above. In some embodiments, other components, such as pharmaceutically acceptable excipients and bioactive agents (e.g., drugs, vitamins, and minerals), may also be included in the preferred compositions used in this invention to aid in the repair and / or regeneration of target bone tissue, and / or to provide a method for targeted delivery of bioactive compounds.

[0170] Generally, the amount of polymer in the composition used in this invention is the amount that allows for the formation of a hydrogel.

[0171] In some embodiments, the amount of polymer in the composition is: about 1% w / w to about 90% w / w, about 2% w / w to about 80% w / w, about 4% w / w to about 70% w / w, about 5% w / w to about 60% w / w, about 5% w / w to about 50% w / w, about 6% w / w to about 40% w / w, about 7% w / w to about 30% w / w, or about 8% w / w to about 20% w / w.

[0172] In some embodiments, the amount of polymer is: about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, about 80% w / w, or more. In some embodiments, the amount of polymer is about 85% w / w.

[0173] As a general rule, the robustness of hydrogels increases with increasing polymer concentration in the composition.

[0174] Generally, the amount of NSPP in the compositions of the present invention is the amount that allows for the formation of a hydrogel.

[0175] In some embodiments, the amount of NSPP in the composition is: about 0.01% w / w to about 60% w / w, about 1% w / w to about 50% w / w, about 1% w / w to about 40% w / w, about 5% w / w to about 30% w / w, about 5% w / w to about 20% w / w, or about 5% w / w to about 10% w / w.

[0176] In some implementations, the percentage of NSPP is about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 20% w / w, about 30% w / w, about 40% w / w, about 50% w / w or more.

[0177] % w / w is based on the total weight of the composition before it comes into contact with water.

[0178] Detailed description of preferred embodiments Preferred embodiments of the invention will now be described by way of example only: Example 1 - Dissolution of PPHO in iohexol solution (Omnipaque 350) Lyophilized PPHO polymers were collected and added directly to iohexol solutions containing 350 mg iodine / mL to achieve final PPHO concentrations of 50 mg / mL, 100 mg / mL, and 200 mg / mL. The resulting solutions were stored at 2–8 °C and dissolved under continuous shaking. Results after nearly 4 days of mixing showed the formation of a two-phase mixture, comprising a swollen gel layer resembling organic matter and a separated aqueous supernatant.

[0179] The results showed that PPHO polymers are not directly soluble in Omnipaque 350.

[0180] Examples 2 to 4 - PPHO in iohexol solution (300 mg / mL (Example 2), 240 mg / mL (Example 3)). Dissolution in Example 3) and 175 mg I / mL (Example 4) Example 1 was repeated with a weaker / lower concentration of iohexol solution. It was assumed that by reducing the iohexol concentration, PPHO became soluble in this solution. The results were very similar to those obtained in Example 1.

[0181] Therefore, it can be concluded that PPHO polymers are not directly soluble in iohexol solutions.

[0182] Table 1. Summary of results from Examples 1 to 4 Example 5 - Dissolution of PPHO and its mixing with iohexol solution (350 mg I / mL) In this embodiment, PPHO was dissolved in distilled water or phosphate-buffered saline (PBS) to achieve a final polymer concentration of 200 mg / mL. Under continuous mixing, a homogeneous single-phase PPHO polymer solution was obtained over 24 hours. This stock solution was coded as TL200. The resulting solution was then mixed with iohexol 350 mg I / mL at different volume ratios, according to the details provided in Table 2.

[0183] The results showed that, unexpectedly, dissolving PPHO in an aqueous solution followed by adding iohexol solution to the dissolved polymer solution resulted in the formation of a single-phase final solution. The resulting solution was then placed in an incubator at 37°C, and the thermal response properties of the solution were verified by using the vial tilting method after 1 minute of incubation.

[0184] Table 2 Prepare by mixing a pre-prepared PPHO solution (200 mg / mL) with an iohexol solution (350 mg / mL). PPHO solutions with varying polymer concentrations and iohexol contents Example 6 - Dilution of Iohexol with Distilled Water and Dissolution of PPHO In this example, iohexol 350 mg I / mL was diluted with different volumes of distilled water. The resulting solution was then used to dissolve the PPHO polymer at a concentration of 200 mg / mL.

[0185] Table 3. By mixing the pre-prepared PPHO solution (200 mg / mL) with an iohexol 350 mg I / mL solution and water, Prepare PPHO solutions with varying polymer concentrations and iohexol contents. The results showed that a variety of formulations with 200 mg / mL PPHO and relatively high iodine content could be prepared. These single-phase solutions were thermoresponsive and formed hydrogels after incubation at 37°C.

[0186] Example 7 - Formulation of TL150-IOP90 and its radiopermeability test In this embodiment, 22.5 mL of TL200 was diluted with 7.5 mL of 350 mg I / mL to achieve a PPHO concentration of 150 mg / mL and 90 mg I / mL. The resulting solution was then subcutaneously injected into a warmed cadaveric pig model. A total of approximately 5 mL of product was injected. Following administration, a CT scan of the site was used to verify the presence of the hydrogel and its thermal responsiveness and radiopermeability.

[0187] Referring to Figure 1, it can be seen that 5 mL of TL150-IOP090 was injected into the subcutaneous cadaver model, and a hydrogel (white gel, indicated by black arrows) formed at the application site (a). CT scan of the injection site showed a radiopaque white structure at the application site, indicated by white arrows (b).

[0188] Example 8 - Product Heinz Units Four formulations were prepared, and their Heinz units were measured. The results are shown in Table 4.

[0189] The results confirmed that injectable / flowable formulations with different Henle units can be formed to match desired clinical needs. Furthermore, R... 2 Linear regression with a value of 0.973 (see [reference]). Figure 2 This allows for further product formulation.

[0190] Table 4. Heinz units of different TL formulations are formed using a wide range of iohexol contents. Example 9 - PNPHO / PPHO (1:1) formulation In this embodiment, 50 mg / mL of PNPHO polymer and 50 mg / mL of PPHO polymer were dissolved in 1 mL of a buffer solution containing approximately 100 µL of 350 mg I / mL and 900 µL of PBS. This buffer solution was prepared in advance by dissolving 350 mg I / mL in PBS at a volume ratio of 1:9. This configuration was designated "TP050 / TL50-IOP45". Results showed that a homogeneous single-phase solution was formed after dissolving the two polymers in the buffer solution at 2 to 8 °C. Subsequently, this solution was added to pre-warmed PBS at 37 °C to simulate the gelation process under physiological conditions. Results confirmed that the TP050 / TL50-IOP45 solution transformed into a cohesive and structurally stable hydrogel with increasing temperature.

[0191] TP050 / TL50-IOP45 administration via catheter The flowability of this formulation through a medical catheter was tested using the TP050 / TL50-IOP45 solution prepared above. For this study, a 150 cm × 6 cm 2.7F catheter (Excelsior XT-27) was used. To simulate physiological conditions, the catheter was immersed in pre-warmed PBS for 5 minutes. Afterward, the catheter was rinsed with pre-warmed water for injection. The TP050 / TL50-IOP45 solution was delivered via the catheter using a standard syringe. Results are as follows. Figure 3 As shown, this confirms that when the solution flows through the catheter, it forms cohesive hydrogel lines once it reaches physiological temperature.

[0192] Example 10 - PNPHO / PPHO (1:2) formulation In this embodiment, 25 mg / mL of PNPHO polymer and 50 mg / mL of PPHO polymer were dissolved in 1 mL of a buffer solution containing approximately 100 µL of 350 mg I / mL and 900 µL of PBS. This buffer solution was prepared in advance by dissolving 350 mg I / mL in PBS at a volume ratio of 1:9. The product configuration was designated "TP025 / TL50-IOP45". Results showed that a homogeneous single-phase solution was formed after dissolving the two polymers in the buffer solution at 2 to 8 °C. Subsequently, this solution was added to pre-warmed PBS at 37 °C to simulate the gelation process under physiological conditions. Results confirmed that the TP025 / TL50-IOP45 solution transformed into a cohesive and structurally stable hydrogel with increasing temperature.

[0193] Example 11 - PNPHO Formulation In this embodiment, 100 mg / mL of PNPHO polymer was dissolved in 1 mL of a buffer solution containing approximately 100 µL of 350 mg I / mL and 900 µL of PBS. This buffer solution was prepared in advance by dissolving 350 mg I / mL in PBS at a volume ratio of 1:9. This configuration was designated "TP100-IOP45". Results showed that a homogeneous single-phase solution was formed after dissolving the two polymers in the buffer solution at 2 to 8 °C. Subsequently, this solution was added to pre-warmed PBS at 37 °C to simulate the gelation process under physiological conditions. Results confirmed that the TP100-IOP45 solution transformed into a cohesive and structurally stable hydrogel as the temperature increased. Figure 4 ).

[0194] Example 12 - TL050 / TP050 with IOP240 and TL050 / TP050 with IOP225 in an in vitro vascular model Flowability and capacity through microcatheters In this embodiment, the flowability of the formulation through a catheter and an in vitro vascular model under fluorescence fluoroscopy was tested using the TP050 / TL50-IOP240 solution prepared above. Phosphate-buffered saline (PBS) was pumped into the simulated in vitro vascular model at 37°C. A 2F Trevo catheter was used for this study. The TP050 / TL50-IOP240 solution was delivered via the catheter using a standard syringe. The results, as shown in Figure 5(a), confirmed that the solution flowed through the catheter and formed a solid white coil-like gel at the catheter tip after entering the vascular model. Furthermore, the gel formation was observed by real-time fluorescence fluoroscopy. Similar results were observed by passing TL050 / TP050-IOP225 through a 2.9F Maestro catheter, as shown in Figure 5(b).

[0195] Example 13 - Flowability of TL050 / TP050 and IOP240 via microcatheter in an isolated pig model and ability In this embodiment, the TL050 / TP050-IOP240 solution formed above was used to test the flowability of the formulation within microvessels of an isolated pig kidney model via a 2F Trevo catheter (as an example). The results, shown in Figures 6(a) and 6(b), confirmed that the formulation is flowable and can flow within the target microvessels, as visible under real-time fluorescence fluoroscopic imaging.

[0196] Example 14 - Formation of TL050-IOP1000 In this embodiment, Histodesnz TMA nonionic X-ray imaging compound was dissolved at a concentration of 1000 mg / mL in phosphate-buffered saline. This solution was then used to dissolve PPHO polymers at different concentrations. The resulting final solution with 50 mg / mL PPHO was designated TL050-IOP1000. This solution was monophase and formed a hydrogel upon heating to 37°C. The Henle units measured from these hydrogels were 3,994.90.

[0197] Industrial applicability It should be understood that the present invention has readily applicable applications in the biomedical, surgical, and therapeutic fields. Aqueous solutions of biocompatible PNPHO or PPHO polymers provide advanced thermoresponsive biomaterials for intravascular embolization and as carriers of radioisotopes, administered via catheters.

[0198] Regarding this invention, the key findings of this study are as follows: i. The biomaterials of the present invention can be combined with any contrast agent, including but not limited to iodinated radioactive mediators and heavy metal MRI chelates.

[0199] ii. Iohexol solutions of PNPHO and PPHO at concentrations such as 225 mg / mL, 175 mg / mL and lower mg / mL have been prepared.

[0200] iii. The biomaterials of the present invention can be used for the delivery of radioisotopes via catheters for targeted therapeutic radioisotopes.

[0201] iv. The final hydrogel-based system is flowable (liquid) throughout the entire catheter / microcatheter in vivo and forms a gel once applied to the target site.

[0202] v. The solution of the present invention forms a stable hydrogel after being extruded from the catheter under simulated physiological conditions (i.e., immersing the catheter in preheated hot water at 37°C for at least 5 minutes to simulate physiological conditions) and in the clinical application of the catheter.

[0203] vi. Because it can be coupled with contrast agents, the developed system is radiopaque and can therefore be seen under X-rays.

[0204] vii. Systems based on PNPHO or PPHO can be used to treat diseases or conditions, including but not limited to gastrointestinal bleeding, bleeding from vascular malformations, tumors, preoperative blood flow redistribution, varicocele or endoleak, and tumors.

[0205] Although the invention has been described with reference to specific embodiments, those skilled in the art will understand that the invention may be embodied in many other forms.

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Claims

1. A flowable polymer solution for intravascular (arterial and venous) administration, comprising a polymer and at least one solvent, said polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer is used to bind a natural or synthetic peptide or protein (NSPP); and A fourth monomer used to impart thermally responsive phase change behavior.

2. The polymer solution according to claim 1 further comprises at least one radioactive intravenous contrast agent.

3. The polymer solution according to claim 2, wherein the at least one radioactive intravenous contrast agent is selected from: contrast media for digital subtraction angiography (DSA), computed tomography (CT) and fluorescence fluoroscopy, such as iodinated contrast media, tantalum and bismuth-based materials (e.g., bismuth chelates), heavy metal chelate contrast media for MRI, including gadolinium (e.g., gadobutrol) or MRI nanoparticles.

4. The polymer solution according to claim 3, wherein the at least one contrast agent is an iodine-based contrast agent.

5. The polymer solution according to claim 4, wherein the iodine-based contrast agent is iohexol (1-N,3-N-bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)acetamido]-2,4,6-triiodophenyl-1,3-dicarboxamide).

6. The polymer solution according to any one of the preceding claims, wherein the at least one solvent comprises phosphate-buffered saline (PBS) and / or water.

7. The polymer solution according to any one of the preceding claims, wherein the first monomer is selected from: polyether, polyvinyl alcohol (PVA); poly(vinylpyrrolidone) (PVP); poly(amino acid) and dextran.

8. The polymer solution according to claim 7, wherein the polyether is selected from: polyethylene glycol (PEG), oligomeric (ethylene glycol) (OEG), polyethylene oxide (PEO), polyethylene oxide-co-propylene oxide (PPO), copolymerized ethylene oxide block copolymer, or copolymerized ethylene oxide random copolymer, preferably the first monomer is oligomeric (ethylene glycol) monomethyl ether methacrylate (OEGMA).

9. The polymer solution according to any one of the preceding claims, wherein the second monomer is a methacrylate or a random copolymer containing a methacrylate.

10. The polymer solution according to claim 9, wherein the second monomer is selected from: hydroxyethyl methacrylate (HEMA), hydroxyethyl methacrylate poly(lactic acid) copolymer (PLA / HEMA), poly(lactic acid), poly(caprolactone), poly(glycolic acid), poly(glycolic acid), poly(glycolic acid-co-lactide), or poly(glycolic acid-co-caprolactone), preferably the second monomer is hydroxyethyl methacrylate poly(lactic acid) (PLA / HEMA).

11. The polymer solution according to any one of the preceding claims, wherein the third monomer has an electrophilic functional group for binding the NSPP.

12. The polymer solution according to claim 11, wherein the third monomer is selected from: N-hydroxysulfosuccinimide (SNHS), N-hydroxyethoxysuccinimide (ENHS), and N-acryloyloxysuccinimide (NAS), preferably the third monomer is N-acryloyloxysuccinimide (NAS).

13. The polymer solution according to any one of the preceding claims, wherein the fourth monomer has a low critical solution temperature (LCST) below about 37°C.

14. The polymer solution according to claim 13, wherein the fourth monomer is selected from: poly(ethylene oxide) / poly(propylene oxide) and poly(N-isopropylacrylamide) (PNIPAAm) homopolymers and copolymers, preferably the fourth monomer is (N-isopropylacrylamide) (NIPAAm).

15. The polymer solution according to any one of the preceding claims, wherein the polymer comprises: a first monomer in an amount of about 1 mol% to about 15 mol%; a second monomer in an amount of about 5 mol% to about 50 mol%; a third monomer in an amount of 0 mol% to about 15 mol%; and a fourth monomer in an amount to bring the polymer to a balance of 100%.

16. The polymer solution according to any one of the preceding claims, wherein: The first monomer is OEGMA; the second monomer is PLA / HEMA; the third monomer is NAS; and the fourth monomer is NIPAAm. The polymer comprises: about 1 mol% to about 15 mol% of OEGMA; 5 mol% to about 50 mol% of PLA / HEMA; 0 mol% to about 15 mol% of NAS; and up to about 85 mol% of NIPAAm.

17. The polymer solution according to any one of the preceding claims, wherein the polymer solution may be mixed in situ with one or more loading compounds prior to application to dilute the polymer solution accordingly, said loading compounds being selected from therapeutic agents, pharmaceuticals, or isotopes or combinations thereof.

18. The polymer solution of claim 17, wherein the one or more loaded compounds are mixed with the polymer solution by direct syringe-syringe mixing.

19. The polymer solution of claim 18, wherein the syringe used for mixing cools the polymer solution and the one or more loaded compounds during mixing.

20. The polymer solution of claim 18, wherein the syringe used for mixing protects the operator from radiation exposure.

21. A polymer solution according to any one of the preceding claims, wherein the third monomer is present, and the polymer solution has a polymer concentration of about 10 mg / mL to about 120 mg / mL.

22. The polymer solution according to any one of claims 1 to 20, wherein the third monomer is absent, and the polymer solution has a polymer concentration of about 5 mg / mL to about 200 mg / mL.

23. The polymer solution according to any one of the preceding claims, wherein the polymer is applied to the treatment site by injection via a catheter.

24. The polymer solution of claim 23, wherein the catheter is a fine-gauge interventional vascular catheter / microcatheter (1F-6F), such as a French 3.3 mm catheter.

25. The polymer solution according to any one of the preceding claims, wherein the intravascular administration is part of a transcatheter arterial embolization (TAE) procedure.

26. A method of performing a transcatheter arterial embolization (TAE) procedure, the method comprising administering a polymer solution according to any one of claims 1 to 25 to a subject in need of such treatment.

27. The method of claim 26, wherein the application is performed at or substantially at body temperature.

28. The method of claim 27, wherein the thermally responsive polymer solution forms an adhesive hydrogel network after being extruded from the conduit.

29. Use of the polymer solution according to any one of claims 1 to 25 in the preparation of a medicament or delivery carrier for administration via a transcatheter arterial embolization (TAE) procedure.

30. The use according to claim 29, wherein the application is performed at body temperature.

31. The use according to claim 30, wherein the thermally responsive polymer solution forms an adhesive hydrogel network after being extruded from the conduit.

32. A kit for forming a flowable polymer solution for intravascular (arterial and venous) administration, the kit comprising a polymer comprising: The first monomer used for binding water; The second monomer used to impart mechanical properties; Optionally, a third monomer is used to bind a natural or synthetic peptide or protein (NSPP); A fourth monomer used to impart thermally responsive phase change behavior; and At least one solvent used to form a solution of the polymer; and Apparatus for applying the polymer solution; and Optionally, instructions for administering the polymer solution via a transcatheter arterial embolization (TAE) procedure.

33. The kit of claim 32 further comprises at least one radioactive intravenous contrast agent selected from: contrast media for digital subtraction angiography (DSA), computed tomography (CT) and fluorescence fluoroscopy, such as iodinated contrast media, tantalum and bismuth-based materials (e.g., bismuth chelates), heavy metal chelate contrast media for MRI, including gadolinium (e.g., gadobutrol) or MRI nanoparticles.

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