polymer

Abstract

The present invention provides, inter alia, temperature-sensitive block copolymers, compositions comprising the polymers, and methods for their preparation that can be used in medical procedures, including therapeutic embolization. The block copolymers comprise a first block comprising A monomers and optionally P monomers, and a second block consisting of N monomers, where the P monomers are more hydrophobic than the A monomers, and the second block is a thermoresponsive block.

Description

[Technical Field]

[0001] The present invention relates to new block copolymers and their uses, particularly in medical applications, especially in embolization therapy, drug delivery, and other interventions, such as medical and surgical interventions. [Background technology]

[0002] Embolic materials are widely used in vascular interventional radiology. Such materials are typically introduced into blood vessels to occlude or reduce blood flow, causing tissue necrosis or preventing blood loss. They are typically used to treat neurovascular or peripheral vascular diseases, such as aneurysms, arteriovenous malformations and fistulas, uterine fibroadenomas, hypervascular tumors, and to prevent traumatic hemorrhage.

[0003] In one approach, embolic agents are liquid-based materials that polymerize, coagulate, deposit, or change phase within the target vessel to form an occlusion. Early versions included solutions of polymers such as ethylene vinyl alcohol in solvents such as DMSO, which dissipated in the bloodstream, depositing the polymer and occluding the vessel. Intravascular delivery of solvents such as DMSO is problematic and can result in endothelial damage, vasospasm, and pain, among other things.

[0004] Aqueous embolic agents have recently been developed. One approach takes advantage of the properties of temperature-sensitive polymers, which undergo a phase transition above their lower critical solution temperature (LCST), going from a soluble, hydrated state to an insoluble, dehydrated state. Useful polymers have an LCST below 37°C, remaining soluble outside the body but rapidly becoming insoluble when exposed to body tissues at 37°C. This makes it difficult to deliver such polymers through tiny catheters and needles, as the small cross-sectional area of ​​these devices means that the polymer is likely to reach its LCST inside the vessel and therefore become a hydrogel, which hinders delivery.

[0005] NIPAAM-HEMA copolymers have been developed as embolic agents. These polymers are hydrogels at temperatures above the LCST, but these physical hydrogel systems exhibit reduced strength at low frequencies due to the high ratio of NIPAAM to HEMA and viscoelasticity. High concentrations of polymer are used to increase gel strength, but catheter blockage often occurs due to the low LCST and poor viscoelasticity. To overcome deliverability issues, the polymers are used at low concentrations. However, this results in weak, soft gels that tend to fragment and "creep," or migrate, distally when used in large vessels under high shear, occluding the distal end rather than the point of delivery. Furthermore, gel fragmentation can result in off-target embolization, posing a risk to patients. Therefore, effective proximal embolization in relatively large vessels is a challenge for these physical hydrogels. Furthermore, several characteristics of these responsive polymers are that, after a phase change, they tend to shrink and contract, accompanied by a loss of water from the gel, which can contribute to embolic migration. Summary of the Invention [Problem to be solved by the invention]

[0006] It would be desirable to develop aqueous liquid emboli that can be easily formulated at low temperatures around 20°C, exhibit good gel strength in situ, can be delivered through a catheter without occlusion, and rapidly assume a robust gel form upon contact with blood or other tissues that does not fragment or shrink. It would also be desirable to be able to easily visualize such polymers in the body by various means and to use the gel form for drug delivery, if desired. [Means for solving the problem]

[0007] The polymers, compositions and other embodiments of the invention described herein address one of several of the problems identified above. [Brief explanation of the drawings]

[0008] [Figure 1] NMR data for synthetic intermediates. Figure 1a provides the NMR spectrum of the tri-arm initiator, glycerol tris(2-bromoisobutyrate), from Example 1. Figure 1b provides the proton NMR spectrum of the tri-arm polyHEMA macroinitiator I-[HEMA100-Br10]3 from Example 3. Figure 1c provides the proton NMR spectrum of the tri-arm star-comb polymer I-[HEMA100-g-(NIPAAM20)10]3 from Example 4. [Figure 2] Illustrated are aqueous polymer solutions (10% w / w) delivered in PBS at 37° C. (A) is a polymer lacking the P moiety in the PA block, and (B) is a polymer in which P is 10 mol % relative to the moles of the AP block. The polymers are (I-((HEMA50)-b-NIPAAM200)2) and (I-((HEMA45-co-HPMA5)-b-NIPAAM200)2), respectively (see Example 12). [Figure 3] Figure 1 shows catheter delivery of a liquid sample of I-[HEMA100-g-(NIPAAM20)10]3 in a flow model, with tubing diameter of 5 mm, media temperature of 37°C, initial flow rate of 150 mL / min, PBS media, and a 2.4 Fr catheter, as described in Example 12. [Figure 4] Figure 1 shows the delivery of an aqueous solution of polymer and an oil emulsion containing Lipiodol® into PBS at 37°C. The polymer solution was a 10% solution of I-((HEMA45-co-HPMA5)-NIPAAM200)2 in water. (A) 1:0.5 v / v ratio, (B) 1:1 v / v ratio, (C) 1:2 v / v ratio (see Example 16). Individual photographs, from left to right, represent a time series separated by approximately 30 seconds. [Figure 5] Figure 1 shows the delivery of a suspension containing dry polymer particles and Lipiodol® into PBS at 37° C. The polymer was I-((HEMA49.5-co-HPMA0.5)-NIPAAM200)2. [Figure 6]1 is a graph showing the temperature rise profile of copolymer I-((HEMA44.5-co-HPMA0.5)-NIPAAM200)2 aqueous solution (15% w / w) according to Example 13. DETAILED DESCRIPTION OF THE INVENTION

[0009] In a first aspect, the present invention provides a copolymer comprising a first block comprising A monomers and a second block consisting of N monomers, the second block being a thermo-responsive block. The first block may comprise both A and P monomers, with the P monomers being more hydrophobic than the A monomers. When both A and P monomers are present, the first block may be an AP or PA block copolymer (i.e., the first block is an AP or PA diblock copolymer), or may be a statistical (i.e., mixed) copolymer of A and P (collectively referred to as A-co-P).

[0010] The polymer may include a first block that includes a pendant second block, or may include a first block that includes an extension of a second block. When A and P exist in the first block as a statistical copolymer, the second block is pendant from both the A and P monomers. When A and P exist in a block copolymer, the second block can be pendant from the A monomer, the P monomer, or both.

[0011] The polymer may be in a linear or star format. A linear format polymer contains either a single first block or two identical or different first blocks covalently linked in a linear, inverted arrangement around a central hub. A star polymer contains m identical or non-identical first blocks individually covalently linked to the central hub. Thus, as further described below, for linear polymers, m is 1 or 2, and for star polymers, m is 3 to 10.

[0012] In a second embodiment, the polymer comprises an initiator of polymerization, the residue of which forms the hub. The definitions and preferences for A, P, N, x, x', y, y', r and q described below for the second embodiment and elsewhere herein also apply to this first embodiment.

[0013] In a second embodiment, the present invention provides a compound of formula I:

[0014] [ka] [In the formula, * represents the site of attachment to the polymerization initiator residue, A is a hydrophilic or hydrophobic monomer containing at least one substituent selected from the group consisting of -OH, -NH, -SH and -COOH; P is a monomer that is more hydrophobic than A and optionally includes at least one substituent selected from the group consisting of -OH, -NH, -SH, -COOH, alkyl, and aryl groups; N is a monomer that forms a thermoresponsive block, and N q and N r is a terminal thermoresponsive block, The sum of x and x' is the number of A monomers in the block and is an integer of 20 to 600, more preferably 30 to 200, even more preferably 60 to 120, or 70 to 100.

[0015] the sum of y and y' is the number of P monomers in the block, and y and y' are both 0 when P is not present, and (y+y') is at least 1 when P is present, so that (y+y') is either 0 or an integer of 1 to 500, preferably (0, 1, or 2) to 100, more preferably 3 to 30; the sum of x' and y' is the total number of grafts in the AP (first) block, and is either 0 or an integer of 1 to 300, preferably 6 to 275, and more preferably 8 to 130; q is the number of N monomers in the extension block, and is 0 or an integer of 1 to 800, preferably 20 to 600, and more preferably 50 to 400; r is the number of N monomers in the pendant block and is 0 or an integer of 3 to 500, preferably 5 to 200, more preferably 5 to 50, and q and r cannot both be zero at the same time; If r>0, q is an integer equal to or less than 2×r, preferably equal to or less than r.

[0016] m is an integer from 1 to 10, preferably from 1 to 6, more preferably from 1 to 4, even more preferably 1, 2 or 3; The round brackets represent the integrated blocks with hydrophobic / hydrophilic functional groups formed in the synthetic sequence, the square brackets surround the arms of the branched structure, and the order of A and P can be reversed when AP is in the form of a block.

[0017] In one preferred arrangement, the block copolymer may have a first block that is an (AP) block containing both A and P, and an (AbP) block, a (PbA) block, or an (A-co-P) block, and the copolymer is (AP)-bN or (AP)-gN.

[0018] In a further preferred arrangement, the block copolymer may have a first block that is an (A) block consisting solely of A monomers, and the copolymer is (A)-bN or (A)-gN.

[0019] The numerical values ​​given for x, x', y, y', r and q are the numerical values ​​to be targeted for synthesis.Those skilled in the art should recognize that when m>1, it is possible to target the synthesis of polymers in which the number of A, P and N monomers present in each arm must not be the same.For example, when the total number of target units of A, P and N is not divisible by the number m of arms, the number of target units will be different in each arm.One example of this situation is the formula: N 100 -(A 49 -P1)-I-(A 50 )-N 100 In this case, the polymer may be (ideally) I-[(A 49.5 -P 0.5 )-N 100 ]2 It can be expressed as:

[0020] Here, on average, one arm of the polymer has 49.5 A units and 0.5 P units. Ignoring the polymerization initiator, this is N 100 -(A 99 -P1)-N 100 It can be expressed as:

[0021] For example, NIPAAM 100 -(HEMA 49 -HPMA1)-I-(HEMA 50 )-NIPAAM 100 can be synthetically targeted, and the polymer (ideally) I-[(HEMA 49.5 -HPMA 0.5 )-NIPAAM 100 ]2 or ignoring the polymerization initiator, NIPAAM 100 -(HEMA 99 -HPMA1)-NIPAAM 100 It can be expressed as:

[0022] Thus, in some embodiments, the values ​​of x, x', y, y', r and q may be considered to be ranges, rather than integers, as follows: In some embodiments, the sum of x and x' is in the range of 20-600, more preferably 30-200, even more preferably 60-120, or 70-100.

[0023] In some embodiments, the sum of y and y′ is in the range of 0 to 500, preferably 0, 1, or 2 to 100, more preferably 3 to 30, or greater than 0 and less than or equal to 10; In some embodiments, the sum of x' and y' is in the range of (0 or 1) to 300, preferably (5 or 6) to 275, and more preferably 8 to 130; In some embodiments, q is in the range of 0 to 800, preferably 20 to 600, and more preferably 50 to 400; In some embodiments, r is in the range of 0-500, preferably 3-500, preferably 5-200, and more preferably 5-50.

[0024] In some embodiments, r is in the range of (0 or 1) to 100, preferably 5 to 80, and more preferably 5 to 50. In addition to a specific target copolymer, the bulk polymer composition may include one or more additional polymer products, such as other polymers described herein, polymers of different molecular weights, and polymers with alternative block patterns. The target polymer may have values ​​of x, x', y, y', r, and / or q that are integers, but as noted above, target polymers may also have values ​​of x, x', y, y', r, and / or q that are not the same for each arm. Furthermore, the synthesis may target values ​​for x, x', y, y', r, and / or q in the bulk polymer, which may be integers or any fractional values ​​therebetween. Consequently, those skilled in the art will recognize that the values ​​given for x, x', y, y', r, and / or q for bulk polymers herein may be considered ranges, including all fractional values ​​between the upper and lower limits.

[0025] The inventors have shown that in (A)N polymers, the hydrophobicity of the (A) block can be adjusted by incorporating a second, more hydrophobic monomer (P), increasing the hydrophobicity of the block. Increasing the hydrophobicity of the block tends to, among other things, improve gel stiffness and reduce gel syneresis; therefore, polymers having both A and P (i.e., where (y+y')>0) are preferred. The AP block may exist as a block copolymer having an A block and a P block, or as a statistical copolymer of A and P. When the AP block exists as a block copolymer having an A block and a P block, the block may be inverted to form a (PA) block.

[0026] When both A and P are present, the N block may be present as an extension of the AP block, or as a graft, or in some embodiments, both as an extension and a graft. The graft may be pendant from the A monomer, the P monomer, or preferably both. When no P monomer is present, the N block is present either as an extension of the A block, or as a graft, or in some embodiments, both as an extension and a graft. Preferably, the N block is a graft. When a P monomer is present, the N block is present either as an extension of the AP block (i.e., the first block), or as a graft, or in some embodiments, both as an extension and a graft.

[0027] Thus, in some embodiments, (y+y')>0, the (AP) block is an (AbP) block, a (PbA) block, or an (A-co-P) block, and the copolymer is (AP)-bN or (AP)-gN.

[0028] Since N must always be present, r and q cannot be simultaneously zero. The additional P monomers in the AP block make the current physical hydrogels much stronger. The additional hydrophobic block is not heat-sensitive, making catheter delivery easier, even at higher concentrations. The gels formed have a high storage modulus and can withstand greater shear stress from the bloodstream, making these systems suitable for proximal delivery and safer to use. Contrary to some earlier polymers, there is no need to crosslink the polymer to tailor its properties.

[0029] To the extent that the polymer contains grafted N blocks or that N blocks are present as extensions of AP blocks, it may be the case that during the synthesis of the graft polymer, a small number of N monomers are linked to and extend the AP blocks. Thus, in some cases, when r>0, q may be greater than (other than) 0. Under these circumstances, q is typically expected to be less than or equal to 2×r, preferably less than or equal to r.

[0030] The sum of x and x' is the number of A monomers in the block (A or AP), and in some embodiments is an integer from 20 to 600, more preferably from 30 to 200, even more preferably from 60 to 120, or from 70 to 100.

[0031] The sum of y and y' is the number of P monomers in the block, and in some embodiments, y and y' are both 0 when P is not present, and (y+y') is at least 1 when P is present, and thus (y+y') is either 0 or an integer from 1 to 500, preferably (0, 1, or 2) to 100, and more preferably 3 to 30.

[0032] The sum of x′ and y′ is the total number of grafts in the AP (first) block, and is either 0 or an integer of 1 to 300, preferably 6 to 275, and more preferably 8 to 130.

[0033] q is the number of N monomers in the extension block, and in some embodiments is 0 or an integer of 1 to 800, preferably 20 to 600, and more preferably 50 to 400.

[0034] r is the number of N monomers in the pendant block, which in some embodiments is 0 or an integer from 3 to 500, preferably from 5 to 200, and more preferably from 5 to 50; q and r cannot both be zero simultaneously; If r>0, q is an integer equal to or less than 2×r, preferably equal to or less than r.

[0035] m is an integer from 1 to 10, preferably from 1 to 6, more preferably from 1 to 4, even more preferably 1, 2 or 3; x' is the number of grafts on the A monomer, which in some embodiments is 0 or an integer from 1 to 400, preferably from 5 to 200, and more preferably from 7 to 100; y' is the N connected to P r In some embodiments, y′ is 0 (when r is 0) or an integer of 1 to 100, preferably 1 to 75, and more preferably 1 to 30.

[0036] In some embodiments, a relatively high A:P ratio is preferred; therefore, in some embodiments, in addition to the above preferences, the following condition applies: A is 70% (98% or 99% or 99.9%) of the AP blocks on a mol / mol basis, in particular 80% (95% or 99.9%) on a mol / mol basis.

[0037] When P is present, the ratio (x'+y') / [(y+y')+(x+x')] is the ratio of graft-bearing monomers to total monomers in the (first) block, and in some embodiments, this ratio is 0.0001 to 1, preferably 0.01 to 1, and more preferably 0.1 to 1.

[0038] In some embodiments, and optionally, in addition to the above preferences, the following proviso applies: the ratio of (A) or (AP) to N on a mol / mol basis is from 1:0.1 to 1:8, preferably from 1:2 to 1:5, in particular from 1:2 to 1:4.

[0039] In some embodiments, either the A monomers, or the A and P monomers, form the first block, and the N monomers form the second block. In some embodiments, and optionally, in addition to the above preferences, the following condition applies: total A(x+x'):P(y+y'):total N is 30-500:(0 or 1)-200:100-600, preferably 30-500:5-200:100-600, preferably 30-500:5-200:100-600, more preferably 100-200:10-30:400-500.

[0040] In some embodiments where P is absent and m=1 or 2, A:N is between 0.2:1 and 2:1. The polymers of the present invention may be linear or star polymers. A linear polymer according to Formula I is considered herein to be any polymer where m is 1 or 2, regardless of the arrangement of the polymer arms on the initiator. The number of arms (m) can be 1 to 10, preferably 1 to 6, and more preferably 1, 2, or 3. Thus, in particularly preferred arrangements, the polymer can be either linear or three-armed. Most preferably, m is 2 or 3.

[0041] The initiator (I) for polymerization can be any suitable initiator known to those skilled in the art, and may be selected, for example, for its ability to support the initiation of a selected number of chains; in particular, the initiator is suitable for atom transfer radical polymerization (ATRP). For example, linear polymers require an initiator to support polymerization initiation from either one or two groups, while star polymers require an initiator to support polymerization initiation from three or more groups. The polymer typically retains the residue of the initiator, and in some instances, the polymer arms may be linked together with two, three, four, five, six, or more arms. In this specification, the residue of the initiator is represented by I, and the functional group (typically a halide) is lost from the initiator.

[0042] Polymer initiators typically include either alkyl bromides or alkyl chlorides, with the number of halides ranging from 1 to 10. Thus, for linear polymers where m is 1, I may be selected from the group consisting of alkyl α-bromoisobutyrate, benzyl α-bromoisobutyrate, alkyl 2-bromopropionate, 1-phenylethyl bromide, tosyl chloride, and 2-bromopropionitrile, where alkyl is C1 to C6. 18 , preferably C3 to C 12 When m is 2, the initiator may be selected from the group consisting of diethyl meso-2,5-dibromoadipate, ethylene bis(2-bromoisobutyrate), bis[2-(2'-bromoisobutyryloxy)ethyl]disulfide, bis[2-(2-bromoisobutyryloxy)undecyl]disulfide, 2-[2-[2-(2-bromo-2-methylpropanoyl)oxyethoxy]ethoxy]ethyl 2-bromo-2-methylpropanoate, 2-[2-(2-bromo-2-methylpropanoyl)oxyethoxy]ethyl 2-bromo-2-methylpropanoate, and [2-(2-bromopropanoyloxy)-2-methylpropyl]2-bromopropanoate.

[0043] For star polymers where m is 3, the initiator may be selected from the group consisting of 1,1,1-tris(2-bromoisobutyryloxymethyl)ethane, glycerol tris(2-bromoisobutyrate), tris(2-bromopropanoic acid) 1,2,3-propanetriyl ester, 2,2',2"-nitrilotri(ethanol 2-methyl-2-bromopropanoate), and 3,4-bis[(2-bromo-2-methylpropanoyl)oxy]butyl 2-bromo-2-methylpropanoate. When m is 4, the initiator may be pentaerythritol tetrakis(2-bromoisobutyrate), 3,3,4-tris[(2-bromo-2-methylpropanoyl)oxy]butyl 2-bromo-2-methylpropanoate, and [2,4,5,5-tetrakis[( When m is 5, the initiator may be selected from the group consisting of [3,4,5,6-tetrakis[(2-bromo-2-methylpropanoyl)oxy]oxan-2-yl]methyl 2-bromo-2-methylpropanoate, and dipentaerythritol hexakis(2-bromoisobutyrate). When m is 6, the initiator may be, for example, 1-O,2-O,3-O,6-O-tetrakis(2-bromo-2-methylpropanoyl)-4-O-[2-O,3-O,4-O,6-O-tetrakis(2-bromo-2-methylpropanoyl)-β-D-galactopyranosyl]-α-D-glucopyranose.

[0044] Monomer A can be selected from hydrophilic or hydrophobic monomers containing at least one substituent selected from the group consisting of -OH, -NH, -SH, and -COOH. However, in practice, such substituents may be present in the form of protected functional groups during the polymerization step, or may be present as residues of functional groups when used to link additional groups, such as graft or extension blocks. For example, -NH, -SH, and -COOH may be protected during synthesis. Monomer A is preferably selected from the group consisting of acrylates, methacrylates, acrylamides, and methacrylamides. More preferably, A is selected from the group consisting of acrylate esters, methacrylate esters, N-substituted acrylamides, and N-substituted methacrylamides. In some embodiments, the acrylate esters and methacrylate esters are independently esters of C1-C6 alcohols having at least one unesterified hydroxyl group. In some embodiments, they may be, for example, esters of polyethylene glycol having between 1 and 6 ethylene glycol units, preferably 1 to 3 units. In some embodiments, these can be esters of zwitterionic alcohols (e.g., 2-methacryloyloxyethyl phosphoryl chloride, 2-(N-3-sulfopropyl-N,N-dimethylammonium)ethyl methacrylate, carboxybetaine methacrylate).

[0045] In some embodiments, the N-substituted acrylamides and methacrylamides may be N-substituted with a C1-C6 hydroxyalkane group having at least one hydroxyl group, and in some embodiments, they may be esters having a non-zwitterionic charged group, such as 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt (AMPS).

[0046] In a non-limiting example, the A monomer may be selected from the group consisting of: Acrylates: 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, 2-hydroxypropyl acrylate, and 2-hydroxyisopropyl acrylate.

[0047] Methacrylates: 2-hydroxypropyl methacrylate, 1-hydroxy-2-propanyl methacrylate, 2-hydroxyisopropyl methacrylate, 2-hydroxy-2,2-dimethylethyl methacrylate, 1,3-dihydroxypropyl methacrylate (1,3DHPMA), 2,3-dihydroxypropyl methacrylate (2,3DHPMA) [glycerol monomethacrylate (GMA), mixtures of 1,3 and 2,3DHPMA may also be used], dihydroxyethyl methacrylate, hydroxyethylene glycol methacrylate, diethylene glycol mono-methacrylate, 2-hydroxyethyl methacrylate, (1-fluoro-2-hydroxyethyl) 2-methylpropional 2-enoate, 3-hydroxypropyl methacrylate, 3-(2-hydroxyethoxy)propyl 2-methylprop-2-enoate, triethylene glycol monomethacrylate, 2,3-butanediol 2-methacrylate, 2-(tert-butylamino)ethyl methacrylate, 2-aminoethyl methacrylate hydrochloride, methacrylic acid 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl ester, 2-methacryloyloxyethyl phosphoryl chlorine, 2-(N-3-sulfopropyl-N,N-dimethylammonium)ethyl methacrylate, carboxybetaine methacrylate, and 2-hydroxy-1-methylethyl methacrylate.

[0048] Acrylamide: N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide. Methacrylamides: N-(2-hydroxypropyl)methacrylamide, N-(2-hydroxyethyl)methacrylamide, hydroxypropylmethacrylamide, N-(1-hydroxybutan-2-yl)-2-methylprop-2-enamide, methacrylic acid dihydroxyethylamide, N-(2-hydroxy-1-methoxyethyl)-2-methylprop-2-enamide, N-(2-hydroxybutyl)-2-methylprop-2-enamide, N-(1-hydroxypropan-2-yl)-2-methylprop-2-enamide, N-(2-aminoethyl)methacrylamide hydrochloride, N-(3-aminopropyl)methacrylamide hydrochloride, and 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt.

[0049] The A monomer is preferably selected from the group consisting of 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, 2-hydroxypropyl acrylate, 2-hydroxyisopropyl acrylate. 2-Hydroxypropyl methacrylate, 2-hydroxy-2,2-dimethylethyl methacrylate, 1,3-dihydroxypropyl methacrylate (1,3DHPMA), 2,3-dihydroxypropyl methacrylate (2,3DHPMA), glycerol monomethacrylate (GMA), dihydroxyethyl methacrylate, hydroxyethylene glycol methacrylate, diethylene glycol monomethacrylate, 2-hydroxyethyl methacrylate, 3-hydroxypropyl methacrylate, 1-hydroxy-2-propanyl methacrylate, 2-hydroxyisopropyl methacrylate, 3-(2-hydroxyethoxy)propyl 2-methylprop-2-enoate, triethylene glycol monomethacrylate, 2,3-butanediol 2-methacrylate, 2-methacryloyloxyethyl phosphorylcholine, 2-(N-3-sulfopropyl-N,N-dimethylammonium)ethyl methacrylate. N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, N-(2-hydroxypropyl)methacrylamide, N-(2-hydroxyethyl)methacrylamide, methacrylic acid dihydroxyethylamide, 2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt.

[0050] The A monomer is preferably selected from 1,3DHPMA, 2,3DHPMA, GMA, HEMA, HEA and HEMAm, in particular 1,3DHPMA, 2,3DHPMA, GMA and HEMA, especially HEMA.

[0051] Glycerol monomethacrylate (GMA) may be substituted with 2,3HPMA and / or 1,3DHPA. GMA includes mixtures of 1,3DHPMA and 2,3DHPMA, with 2,3DHPMA typically comprising around 90% of such preparations.

[0052] The P monomer is a monomer selected to be more hydrophobic than the A monomer. The hydrophobicity of a monomer is conveniently calculated using the XLogP3 algorithm (Cheng, T.; Zhao, Y.; Li, X.; Lin, F.; Xu, Y.; Zhang, X.; Li, Y.; Wang, R.; Lai, L. "Computation of Octanol-Water Partition Coefficients by Guiding an Additive Model with Knowledge," J. Chem. Inf. Model. 2007, 47, 2140-2148), available at http: / / www.sioc-ccbg.ac.cn / skins / ccbgwebsite / software / xlogp3 / . "More hydrophobic than" in this context means having an XLogP3 value at least 0.10 higher than the A monomer, preferably at least 0.2, and more preferably at least 0.3 higher.

[0053] P is a monomer that is more hydrophobic than A and optionally contains at least one substituent selected from the group consisting of -OH, -NH, -SH, -COOH, alkyl, and aryl groups. However, in practice, the -OH, -NH, -SH, and -COOH groups may be present in the form of protected functional groups during the polymerization step, or may be present as residues of functional groups when used to link additional groups, such as grafting. For example, -NH, -SH, and -COOH may be protected during synthesis. In some embodiments, the monomer P is selected from the group consisting of acrylates, methacrylates, acrylamides, and methacrylamides; preferably, P is selected from the group consisting of acrylate esters, methacrylate esters, N-substituted acrylamides, and N-substituted methacrylamides.

[0054] Non-limiting examples of P monomers include those selected from the group consisting of: Acrylates: benzyl acrylate, 2-phenylethyl acrylate, 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, 2-hydroxypropyl acrylate, 2-hydroxyisopropyl acrylate, 1-phenylethyl acrylate, butyl acrylate, 2-phenylethyl acrylate, methyl acrylate, propyl acrylate, neopentyl acrylate, isooctyl acrylate, benzooxyethyl methacrylate, benzooxyethyl acrylate, 2-methylhexyl acrylate, octadecyl acrylate, and 2-ethylhexyl acrylate.

[0055] Methacrylates: 2-Methoxyethyl methacrylate, 2-hydroxy-1-methylethyl methacrylate, 2-ethoxyethyl 2-methylprop-2-enoate, isobutyl methacrylate, (3-fluoro-2-hydroxypropyl) 2-methylprop-2-enoate, 2-hydroxy-2,2-dimethylethyl methacrylate, methyl methacrylate, propyl methacrylate, neopentyl methacrylate, 2-acetoxyethyl methacrylate, butyl methacrylate, 2,3-butanediol 2-methacrylate, 3-hydroxypropyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 1-hydroxypropyl methacrylate hydroxy-2-propanyl methacrylate, benzyl methacrylate, 2-phenylethyl methacrylate, 1-phenylethyl methacrylate, 3-phenylpropyl methacrylate, phenyl methacrylate, 2-ethylhexyl methacrylate, 4-fluorobenzyl methacrylate, dodecyl methacrylate, fluorobenzyl methacrylate, fluorobenzyl acrylate, (4-methylphenyl)methyl methacrylate, hexyl methacrylate, 2-(4-fluorophenyl)ethyl prop-2-enoate, (2-fluorophenyl)methyl 2-methylprop-2-enoate, and (2-methyl-3-phenylpropyl)prop-2-enoate.

[0056] Acrylamide: 2-propenamide, N-(1,1-dimethyl-3-oxobutyl)acrylamide, N-(3-(dimethylamino)propyl)acrylamide, N-(2-(dimethylamino)ethyl)acrylamide, N-[2-(diethylamino)ethyl]acrylamide, N-((dimethylamino)methyl)acrylamide, N-(hydroxymethyl)acrylamide, N-(isobutoxymethyl)acrylamide, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide, N-(3-methyl N-((S)-1-phenylethyl)acrylamide, N-cyclohexylacrylamide, N-(methoxymethyl)acrylamide, N-(4-chlorophenyl)acrylamide, N-(3-(dimethylamino)-2,2-dimethylpropyl)acrylamide, N-(1,1-dimethylpropynyl)acrylamide, N-(2-fluorenyl)acrylamide, N-(4-methoxyphenyl)acrylamide, N-(4-nitrophenyl)acrylamide, N-(3-nitrophenyl)acrylamide.

[0057] Methacrylamides: N-(2-methoxyethyl)methacrylamide, N-(1,1-dimethyl-3-oxobutyl)methacrylamide, N-(3-(dimethylamino)propyl)methacrylamide, N-(2-(dimethylamino)ethyl)methacrylamide, N-[2-(diethylamino)ethyl]methacrylamide, N-((dimethylamino)methyl)methacrylamide, N-(hydroxymethyl)methacrylamide, N-(isobutoxymethyl)methacrylamide, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide, N- (3-methoxypropyl)methacrylamide, N-((S)-1-phenylethyl)methacrylamide, N-cyclohexylmethacrylamide, N-(methoxymethyl)methacrylamide, N-(4-chlorophenyl)methacrylamide, N-(3-(dimethylamino)-2,2-dimethylpropyl)methacrylamide, N-(1,1-dimethylpropynyl)methacrylamide, N-(2-fluorenyl)methacrylamide, N-(4-methoxyphenyl)methacrylamide, N-(4-nitrophenyl)methacrylamide, and N-(3-nitrophenyl)methacrylamide.

[0058] In a preferred embodiment, the P monomer is selected from the group consisting of benzyl acrylate, 2-phenylethyl acrylate, 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, 2-hydroxypropyl acrylate, 2-hydroxyisopropyl acrylate, 1-phenylethyl acrylate, butyl acrylate, 2-phenylethyl acrylate, methyl acrylate, propyl acrylate, 2-methoxyethyl methacrylate, 2-hydroxy-1-methylethyl methacrylate, 2-ethoxyethyl 2-methylprop-2-enoate, isobutyl methacrylate, methyl methacrylate, propyl methacrylate, neopentyl methacrylate, butyl methacrylate, 2,3-butanediol 2-methacrylate, 3-hydroxypropyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 1-hydroxy-2-propanyl methacrylate, benzyl methacrylate, 2-phenylethyl methacrylate, 1-phenylethyl methacrylate, 3-phenylpropyl methacrylate, phenyl methacrylate Acrylate, 2-ethylhexyl methacrylate, 2-propenamide, N-(1,1-dimethyl-3-oxobutyl)acrylamide, N-(3-(dimethylamino)propyl)acrylamide, N-(2-(dimethylamino)ethyl)acrylamide, N-[2-(diethylamino)ethyl]acrylamide, N-((dimethylamino)methyl)acrylamide, N-(hydroxymethyl)acrylamide, N-(isobutoxymethyl)acrylamide, N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide N-(3-methoxypropyl)acrylamide, N-((S)-1-phenylethyl)acrylamide, N-cyclohexylacrylamide, N-(methoxymethyl)acrylamide, N-(3-(dimethylamino)-2,2-dimethylpropyl)acrylamide, N-(1,1-dimethylpropynyl)acrylamide, N-(3-(dimethylamino)-2,2-dimethylpropyl)acrylamide, N-(1,1-dimethylpropynyl)acrylamide, N-(2-methoxyethyl)methacrylamide, N-(1,The compound may be selected from the group consisting of 1-dimethyl-3-oxobutyl)methacrylamide, N-(3-(dimethylamino)propyl)methacrylamide, N-(2-(dimethylamino)ethyl)methacrylamide, N-[2-(diethylamino)ethyl]methacrylamide, N-((dimethylamino)methyl)methacrylamide, N-(hydroxymethyl)methacrylamide, N-(isobutoxymethyl)methacrylamide, N-(2-hydroxyethyl)methacrylamide, N-(2-hydroxypropyl)methacrylamide, N-(3-methoxypropyl)methacrylamide, N-((S)-1-phenylethyl)methacrylamide, N-cyclohexylmethacrylamide, and N-(methoxymethyl)methacrylamide.

[0059] The P monomer is most preferably selected from 3-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 1-hydroxy-2-propanyl methacrylate, or 2-hydroxypropyl methacrylate, or may be a mixture of any two or more of these isomers, any of which, individually or as mixtures of two or more of said isomers, are referred to herein as HPMA; N-(2-hydroxypropyl)methacrylamide (HPMAm) or N-(3-hydroxypropyl)acrylamide (HPA), and butyl methacrylate (BMA).

[0060] Monomer N is a thermosensitive block N q or N r The block preferably has an LCST value in water of 25°C to 37°C, preferably 30°C to 37°C, more preferably 30°C to 35°C.

[0061] The N block may be selected from the group consisting of poly(N-isopropylacrylamide) (pNIPAAM), poly(N-isopropylmethacrylamide) (pNIPMAM), poly(N,N-diethylacrylamide), poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA), poly(PEG methacrylate) (pPEGMA), poly(N-vinylcaprolactam), poly(2-isopropyl-2-oxazoline), poly(vinyl methyl ether), poly(l-lactic acid)-poly(ethylene glycol)-poly(l-lactic acid) (PLLA-PEG-PLLA), hydroxypropyl cellulose, and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO).

[0062] The N monomer is preferably selected from NIPAAM, NIPMAM, DEA, DMAEMA, N-vinylcaprolactam, 2-isopropyl-2-oxazoline, vinyl methyl ether, l-lactic acid-poly(ethylene glycol)-poly(l-lactic acid) (PLLA-PEG-PLLA), N-vinylcaprolactam, and 2-isopropyl-2-oxazoline, vinyl methyl ether, most preferably NIPAAM, NIPMAM or DEA, especially NIPAAM or NIPMAM, especially NIPAAM.

[0063] In one preferred embodiment, A is selected from HEMA, HEA, 1,3DHPMA, 2,3DHPMA, GMA, and HEMAm, P is selected from HPMA, BMA, HPAm, and HPA, and N is selected from NIPMAM, DEA, and NIPAAM. In one preferred embodiment, A is HEMA, P is HPMA, and N is NIPAAM, in another embodiment, A is selected from 1,3DHPMA, 2,3DHPMA, and GMA, P is BMA, and N is NIPAAM, in another embodiment, A is selected from 1,3DHPMA, 2,3DHPMA, and GMA, P is BMA, and N is NIPMAM.

[0064] The block copolymer may have a first block that is an (AP) block containing both A and P, an (AbP) block, a (PbA) block, or an (A-co-P) block, and the copolymer is an (AP)-bN or (AP)-gN.

[0065] The linkage between the N block and the AP block is typically an ester, amide, or ether linkage, depending on the monomers involved, and in a preferred embodiment is an ester linkage.

[0066] In one preferred embodiment, the block copolymer comprises a first block comprising A monomers and optionally P monomers, where the P monomers are more hydrophobic than the A monomers, and a second block consisting of N monomers (i.e., an N homopolymer), where the second block is a thermo-responsive block, where the A monomers are selected from the group consisting of acrylates, methacrylates, acrylamides, and methacrylamides, and the P monomers, when present, are selected from the group consisting of acrylates, methacrylates, acrylamides, and methacrylamides.

[0067] In some embodiments, the N block can be selected from pNIPAAM, pNIPMAM, poly(N,N-diethylacrylamide), pDMAEMA, pPEGMA, poly(N-vinylcaprolactam), poly(2-isopropyl-2-oxazoline), poly(vinyl methyl ether), poly(l-lactic acid)-poly(ethylene glycol)-poly(l-lactic acid) (PLLA-PEG-PLLA), hydroxypropyl cellulose, and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO).

[0068] In some embodiments, the N monomer may be selected from NIPAAM, NIPMAM, DEA, DMAEMA, N-vinylcaprolactam, 2-isopropyl-2-oxazoline, vinyl methyl ether, PLLA-PEG-PLLA, N-vinylcaprolactam, and 2-isopropyl-2-oxazoline, vinyl methyl ether, preferably NIPAAM, NIPMAM, and DEA, particularly NIPAAM and NIPMAM; thus, preferably, the N polymer may be pNIPAAM, pNIPMAM, or pDEA.

[0069] In particular, the A monomer is selected from HEMA, HEA, HEMAm, 1,3HHPMA, 2,3DHPMA and GMA, in particular HEMA, 1,3DHPMA, 2,3DHPMA and GMA; the P monomer is selected from 3-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 1-hydroxy-2-propanyl methacrylate, or 2-hydroxypropyl methacrylate, or may be a mixture of any two or more of these isomers (HPMA), HPMAm, HPA and BMA; and the N monomer is selected from NIPAAM, NIPMAM and DEA.

[0070] The polymer may include a first block that includes a pendant second block, or may include a first block that includes an extension of a second block. In some embodiments, the ratio of [first block] (A) or (AP) monomers to [second block] (N) monomers on a mol / mol basis is 1:0.1 to 1:8. In some embodiments, the ratio of graft-bearing monomers to total monomers in the (first) block is 0.0001 to 1, and in some, the ratio of total A:total P:total N is 30-500:(0 or 1) to 200:100-600. In some embodiments, in the AP block, A is 70% to 98%, 70% to 99%, or 70% to 99.9% of the AP block on a mol / mol basis.

[0071] In particular, the ratio of the [first block] (A) or (AP) to the [second block] (N) on a mol / mol basis is 1:0.1 to 1:8, and / or in the AP block, A is 70% to 98%, or 70% to 99%, or 70% to 99.9% of the AP block on a mol / mol basis.

[0072] In some embodiments, the P monomer has an XLogP3 value that is at least 0.10 higher than the A monomer. In any of the above embodiments, the polymer may be in a linear or star format, as described above.

[0073] In bulk polymers, including polymers of this embodiment, x, x', y, y', r and q may be considered to be in the ranges as described above. Other features of this preferred embodiment are as described elsewhere herein.

[0074] In a further preferred embodiment, the polymer has the form (a) according to formula 2, where m is 1 or 2, in particular 2: *-[A (x) -co-(AgN r ) x’ ] m formula 2 [In the formula, (x) is 1 to 800, preferably 50 to 500, more preferably 60 to 400, x' is 0 to 400, preferably 1 to 200, more preferably 5 to 100, r is 1 to 500, preferably 5 to 200, more preferably 10 to 100. It is a linear polymer in

[0075] In one embodiment, the polymer has the form (b) according to formula 3, where m is 1 or 2, particularly 2: *-[(A (x) -bN q )] m formula 3 [In the formula, (x) is 1 to 800, preferably 50 to 500, more preferably 60 to 400, q is 1 to 800, preferably 50 to 500. It is a linear polymer in

[0076] In one embodiment, the polymer has the form (c) according to formula 4, where m is 1 or 2, preferably 2: *-[(A (x) -co-(AgN r ) x’ )-(P (y) -co-(PgN r ) y’ )] m formula 4 It is a linear polymer in

[0077] In one embodiment according to Formula 4, (x+x') is preferably 60 to 120 or 70 to 100, (y+y') is 1 to 100 or 2 to 100, more preferably 1 to 30, 2 to 30, or 3 to 30; (x'+y') is 1 to 50, preferably 2 to 30, more preferably 5 to 20, r is 1 to 500, preferably 10 to 200.

[0078] In a further embodiment of (c), (y+y') is greater than 0 and less than or equal to 100, preferably less than or equal to 50, and more preferably less than or equal to 30. In one embodiment, the polymer has the form (d) according to formula 5, where m is 1 or 2, particularly 2: *-[(A (x) -P (y) )-b-(N q )] m formula 5 [In the formula, (x) is 1 to 400, preferably 20 to 200; (y) is 1 to 400, preferably 2 to 100, q is 1 to 800, preferably 50 to 400; m is 2] It is a linear polymer in

[0079] In a further embodiment of (d), (y) is greater than 0 and less than or equal to 400, preferably less than or equal to 100, more preferably less than or equal to 50, especially less than or equal to 10. In one embodiment, the polymer has the form (e) according to formula 6, where m is 3, 4, 5 or 6, particularly 3 or 4, more particularly 3: *-[A (x) -co-(AgN r ) x’ ] m formula 6 [(x+x') is 1 to 800, preferably 50 to 500, more preferably 60 to 300, x' is 1 to 400, preferably 1 to 200, more preferably 5 to 100, r is 1 to 500, preferably 5 to 200, more preferably 10 to 100. It is a star polymer in

[0080] In one embodiment, the polymer has the form (f) according to formula 7, where m is 3, 4, 5 or 6, particularly 3 or 4, more particularly 3: *[(A (x) )-N q ] m formula 7 [In the formula, (x) is 1 to 400, preferably 20 to 200; q is 1 to 800, preferably 50 to 500. It is a star polymer in

[0081] In one embodiment, the polymer has the form (g) according to formula 8, where m is 3, 4, 5 or 6, particularly 3 or 4, more particularly 3: I-[(A x -co-(AgN r ) x’ )-(P y-co-(PgN r ) y’ )] m formula 8 It is a star polymer in

[0082] In one embodiment, (x+x') is preferably 60 to 120 or 70 to 100, (y+y') is (1 to 2) to 100, more preferably 3 to 30, (x'+y') is (1 or 2) to 50, preferably 2 to 30, more preferably 5 to 20, r is 1 to 500, preferably 10 to 200.

[0083] In a further embodiment of (g), (y+y') is greater than 0 and less than or equal to 100, preferably less than or equal to 50, and more preferably less than or equal to 30. In one embodiment, the polymer has the form (h) according to Formula 9: x -A x’ -P y -P y’ )-N q ] m [In the formula, N q is an extension of the (AP) block, m is 3, 4, 5 or 6, in particular 3 or 4, more particularly 3, and A and P have no grafts (r is 0)]. It is a star polymer in *[(A (x) -P (y) )-bN q ] m formula 9 [In the formula, (x) is 1 to 400, preferably 40 to 200, (y) is 1 to 400, preferably (1 or 5) to 100; and q is 1 to 800, preferably 50 to 500.

[0084] In a further embodiment of (h), (y) is greater than 0 and less than or equal to 400, preferably less than or equal to 100, more preferably less than or equal to 50, more preferably less than or equal to 10. In any of (a) to (f), when both A and P are present, the AP blocks may be in the form of individual A and P blocks (which may be reversed) or in the form of a statistical copolymer. A and P may be inverted as (PA).

[0085] Forms (c), (d), (g) and (h) are preferred. In one preferred embodiment, A is selected from HEMA, HEA, and HEMAm, P is selected from HPMA, HPAm, and HPA, and N is selected from DEA and NIPAAM. In one preferred embodiment, A is HEMA, P is HPMA, and N is NIPAAM.

[0086] Particularly preferred polymers include those of the formula: *[(HEMA 40-120 )-g-(NIPAAM 10-50 ) 5-50 ]2 *[(HEMA 40-120 -HPMA 5-50 )-b-NIPAAM 150-450 ]2 *[(HEMA 40-120 -HPMA 1-50 )-b-NIPAAM 150-450 ]2 *[(HEMA 40-120 -HPMA 5-50 )-g-(NIPAAM 10-50 ) 5-50 ]2 *[(HEMA 40-120 -HPMA 1-50 )-g-(NIPAAM 10-50 ) 5-50 ]2 a linear polymer of and formula: *[(HEMA 40-120 )-b-NIPAAM 150-450 ]3 *[(HEMA 40-120 )-g-NIPAAM 10-50 ) 5-50 ]3 *[(HEMA 40-120 -HPMA 5-50 )-b-NIPAAM 150-450 ]3 *[(HEMA 40-120 -HPMA 1-50 )-b-NIPAAM 150-450 ]3 *[(HEMA 40-120 -HPMA 5-50 )-g-(NIPAAM 10-50 ) 5-50 ]3 and *[(HEMA 40-120 -HPMA 1-50 )-g-(NIPAAM 10-50 ) 5-50 ]3 Examples of star polymers include:

[0087] Further particularly preferred polymers include: *[(HEMA 40-120 -HPMA)-b-NIPAAM 150-450 ]2 *[(HEMA 40-120 -HPMA)-g-(NIPAAM 10-50 ) 5-50 ]2 *[(HEMA 40-120 -HPMA)-b-NIPAAM 150-450 ]3 and *[(HEMA 40-120 -HPMA)-g-(NIPAAM 10-50 ) 5-50 ]3 wherein the values ​​for the number of HEMA, HPMA and NIPAAM monomers are ranges inclusive of all decimal values ​​therebetween, and the number of HPMA monomers in the AP block is greater than 0 and less than or equal to 50.

[0088] Particularly preferred polymers include: I-(HEMA 90 -co-HPMA 10 )-g-(NIPAAM 20 )10 I-(HEMA 80 -co-HPMA 20 )-g-(NIPAAM 20 ) 10 I-((HEMA 45 -co-HPMA5)-NIPAAM 100 )2 I-((HEMA 45 -co-HPMA5)-NIPAAM 200 )2 I-[HEMA 100 -g-(NIPAAM 20 ) 10 ]3 I-[(HEMA 90 -b-HPMA 10 )-g-(NIPAAM 20 ) 10 ]3 I-[(HEMA 80 -b-HPMA 20 )-g-(NIPAAM 20 ) 10 ]3 I-((HEMA 49.5 -co-HPMA 0.5 )-NIPAAM 200 )2 Other examples include:

[0089] In a further aspect, the present invention also provides compositions comprising the polymers described herein. Such compositions include, for example, bulk polymer compositions comprising the polymers described herein. Such bulk compositions retain desirable properties but may contain, in addition to the specific target copolymer, one or more additional polymeric products, such as other polymers described herein, polymers of different molecular weights, and polymers with alternative block patterns. In some embodiments, such bulk compositions may comprise at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% by weight of the target polymer. Such bulk compositions are further embodiments of the present invention.

[0090] Typically, such copolymers or compositions will be in a pharmaceutically acceptable form, and may for example be sterile and / or pyrogen-free. In one embodiment, the composition is an aqueous composition comprising the copolymer or polymer composition described herein. In such compositions, the polymer of the present invention can be in a sol form (e.g., soluble or micellar) at a temperature of 25°C. This provides improved handling, as polymers in gel form, such as hydrogel form, would not be easily delivered at this temperature. Such compositions are in gel form (typically as hydrogels) at 37°C. Hydrogels are water-swellable but water-insoluble polymers. The combination of these characteristics provides a composition that is easily delivered by various mechanisms, for example, by spraying or through a syringe or catheter, at or near room temperature (which may be 20°C, but can vary above and below it as practical). The polymer or bulk polymer is present in the aqueous composition at at least 1%, preferably at least 5%, and more preferably at least 10% w / w. The polymer may be present at up to 30%, up to 50%, or up to 90% w / w.

[0091] In addition to aqueous compositions, the present invention also provides dry compositions comprising the copolymer or polymer compositions herein, by which is meant a composition containing less than 0.1% w / w water or other solvents, preferably less than 0.01% w / w water or other solvents, which can be achieved, for example, by oven drying, spray drying or freeze drying.

[0092] Such compositions may contain anti-caking agents or dissolution enhancers, such as glycerol, ethanol, mannitol, glucose, sorbitol, xylitol, trehalose, arabitol, galactitol, fucitol, iditol, inositol, lactose, fructose, sucrose, ribitol, threitol, erythritol, sorbitan, volemitol, isomalt, maltitol, lactitol, citric acid, succinic acid, urea, cholic acid, cholesterol, polysorbates, monolauric acid, It may be formulated with sorbitan, sorbitan monostearate, sorbitan tristearate, decyl glucoside, lauryl glucoside, octyl glucoside, polyvinylpyrrolidone, low molecular weight polyethylene glycol, poloxamer, polyvinyl alcohol, poly(2-acrylamido-2-methylpropanesulfonic acid) or sodium salt, alginate, sodium dodecyl sulfate, sodium lauryl sulfate, ammonium lauryl sulfate, docusate, and Triton X-100.

[0093] In some cases, contrast agents such as iohexol, iopamidol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoic acid, iothalamic acid, and ioxaglate may be included in the formulation (or composition), which may also improve solubilization of the polymer below the LCST, as described in more detail below.

[0094] The compositions may also include various additional components, including pharmaceutically acceptable excipients such as small molecules or polymers, including, among others, ethanol, glycerol, DMSO, N-methylpyrrolidone, dimethylformamide, diethylformamide, glucose, lactose, mannitol, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), poly(2-acrylamido-2-methylpropanesulfonic acid) and salts thereof (e.g., the sodium salt), polyacrylic acid or a salt thereof (e.g., the sodium salt), polymethacrylic acid or a salt thereof (e.g., the sodium salt), microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch, croscarmellose sodium, magnesium stearate, polysorbate, poloxamer, sodium lauryl sulfate, hypromellose acetate succinate, alginate, collagen, fibrin, chitosan, gelatin, hyaluronic acid, and cyclodextrins.

[0095] The composition may comprise, for example, at least one imaging agent for fluoroscopy, CT / microCT, magnetic resonance imaging (MRI) or ultrasound imaging, and / or at least one therapeutic or diagnostic radioisotope.

[0096] Examples of contrast imaging agents used in X-ray imaging (X-ray fluorography or CT / microCT) include metal particles or powders such as tantalum, tungsten, rhenium, niobium, molybdenum, gold and their alloys, barium compounds such as barium sulfate, bismuth compounds such as bismuth subcarbonate, bismuth subsalicylate and bismuth oxychloride. The particles are either spherical or irregularly shaped.

[0097] Contrast agents also include radiopaque substances or iodinated contrast agents, which may be ionic or non-ionic (preferably non-ionic), including iodinated compounds such as iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, and those mentioned elsewhere herein, or iodized oils such as ethiosoybean poppy oil (e.g., Lipiodol™).

[0098] MRI contrast agents include gadolinium ion-containing agents, superparamagnetic iron oxide, ion-platinum particles, and manganese(II) chelates. Contrast agents used to enhance ultrasound imaging include, but are not limited to, sulfur hexafluoride microbubbles (SonoVue / Lumason™), octafluoropropane (Optison™), perflutren lipid microspheres, CO2, air, particularly with lipid / galactose shells, perflexane lipid microspheres (Imagent / Imavist™), and perfluorobutane (Sonazoid™).

[0099] The composition may contain at least one therapeutic or diagnostic radioisotope. Imaging or diagnostic radioisotopes include, but are not limited to, Ga-67, Ga-68, rubidium-82, molybdenum-99 (Mo-99), thallium-201 chloride, Tc-99, Tc-99m, fluorodeoxyglucose (FDG) incorporating F-18, In-111, Cu-64, Zr-89, Xe-133, I-131, Cr-51, Gd-153, and Fe-59. Therapeutic isotopes include, but are not limited to, Y-90, Ho-166, Lu-167, I-131, Sr-89, and Sm-153. In some embodiments, these may be in the form of a chelate.

[0100] In some embodiments, chemotherapeutic agents can be incorporated into the composition. While such agents are selected as needed, in one approach, the composition can be used for interventional oncology applications, particularly as a liquid chemoembolization agent. Such compositions comprise a polymer and a pharmaceutically active substance. In this case, possible pharmaceutically active substances include anthracycline class drugs, such as doxorubicin, daunorubicin, epirubicin, and idarubicin; camptothecin class drugs, such as irinotecan, topotecan, and exatecan; platins, such as cisplatin, oxaliplatin, carboplatin, and miriplatin; mitomycin C; nucleoside analogs, such as 5-fluorouracil, cytarabine, fludarabine, and gemcitabine; multi-tyrosine kinase inhibitors, such as sorafenib, sunitinib, regorafenib, bribinb; vinb), dasetanib, bosutinib, erlotinib, gefitinib, imatinib and vandetinib, rapamycin, and biologically active substances such as nivolumab (Opdivo), pembrolizumab (Keytruda), ipilimumab, atezolizumab, avelumab, durvalumab, cemiplimab, dostallimab, relatolimab, spartalizumab, aldesleukin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon alpha-2a, interferon alpha-2b (Intron A®), pegylated interferon alfa-2b (Sylatron® / PEG-Intron®), imiquimod, olaparib, poly-ICLC (Hiltonol®), pexidartinib, or any combination thereof.

[0101] In certain non-limiting examples, the copolymers and compositions of the present invention may be used as incision agents, adhesives, tissue bulking agents and void fillers (e.g., for packing the left atrial appendage), in the treatment of aneurysms, arteriovenous malformations, fistulas, hypervascular tumors, polyps, urinary and fecal incontinence, traumatic bleeding, tissue separation, tissue thickening, and for wound healing, wound care and wound dressing administration, and environmental protection of superficial tissues, such as injured skin, for example, in burns.

[0102] The compositions are suitable for embolization of proximal and distal locations in the vascular environment.The present invention also relates to the use of the compositions as drug delivery depots. In some approaches, the polymers described herein can be used to provide controlled-release formulations, for example, of chemotherapeutic agents. In one approach, this can be achieved by incorporating charged monomers, such as AMPS, into the polymer so that drug release is inhibited by ionic interactions.

[0103] In some embodiments, the compositions are provided in sterile form, which, if desired, can be achieved by, for example, heat or radiation sterilization, or may be achieved by reconstitution of a sterile dry composition with a sterile aqueous solution.

[0104] A further aspect of the present invention provides methods of medical treatment using the polymers described herein. The polymers and compositions of the present invention can be used as embolic agents. Therefore, a further embodiment provides a method for embolizing a blood vessel in a patient in need thereof, comprising delivering a composition comprising the polymer or polymer composition described herein to the lumen of the blood vessel. In one approach, the composition is an aqueous composition comprising the polymer (copolymer or bulk polymer) described herein, which may be in the form of a solution or micellar suspension, and the temperature of the composition is raised above the LCST, for example, to increase the viscosity of the composition, thereby embolizing the blood vessel. In another approach, the aqueous composition is in the form of an oil emulsion, as further described elsewhere herein, or a suspension of the polymer or polymer composition in ethiodized oil, as described elsewhere herein.

[0105] In some embodiments, the polymer forms a hydrogel above the LCST, hi some embodiments, the hydrogel forms as thread-like or spherical deposits. In some embodiments, the method is for the treatment of hypervascular tumors, such as hepatocellular carcinoma (HCC), colorectal cancer or metastases thereof, neuroblastoma and neuroendocrine tumors, aneurysms, arteriovenous malformations and fistulas, uterine fibroids, and the like.

[0106] In some embodiments, the method is for the treatment of benign prostatic hyperplasia by embolization of the prostate's blood vessels, particularly the prostatic arteries or blood vessels arising therefrom.

[0107] In some embodiments, the method is for the treatment of osteoarthritis by embolization of blood vessels in major joints, including the knee, particularly the arteries of the knee or blood vessels arising therefrom.

[0108] The polymers and compositions of the present invention can be used as tissue separation agents.Therefore, in a further embodiment, the present invention provides a method for separating a first tissue from a second tissue, comprising: delivering a volume of an aqueous composition comprising a polymer (copolymer or bulk polymer) described herein in the form of a solution or micellar suspension to a location between the first tissue and the second tissue, thereby at least partially separating the first tissue from the second tissue; and increasing the temperature of the composition to above the LCST, for example, to increase the viscosity of the composition, thereby stabilizing the polymer in place.

[0109] The polymer and composition can be delivered using a needle, catheter, or other tubular device.In one approach, this technique can be used to separate a first tissue from a second tissue.In one example, the first tissue that undergoes radiation treatment can be separated from the second tissue that should be protected from the radiation treatment, thereby reducing the level of radiation that the second tissue is exposed to.In one particular approach, this technique can be used to separate rectal tissue from prostate tissue that undergoes radiation treatment, thereby reducing the radiation dose that rectal tissue (e.g., rectal epithelium) is exposed to.

[0110] In a further approach, the polymers and compositions may be used to separate diseased tissue from surrounding tissue to facilitate treatment, for example, to provide a submucosal lift of gastrointestinal mucosal lesions (e.g., polyps, adenomas, early cancers) to facilitate surgical resection using a snare or other endoscopic device.

[0111] The polymers and compositions of the present invention can be used as tissue bulking or augmenting agents. Thus, in a further embodiment, the present invention provides a method for tissue augmentation or bulking, comprising delivering to a location within a tissue a volume of an aqueous composition comprising a polymer as described herein in the form of a solution or micellar suspension, and increasing the temperature of the composition to above the LCST, e.g., to increase the viscosity of the composition, thereby stabilizing the polymer in place.

[0112] The polymer can be delivered using a needle, catheter, or other tubular device. In one approach, this technique can be used to bulk the tissue in which the polyp occurs. This approach elevates the polyp above the tissue, making it easier to access for resection. This technique can also be used to treat urinary or fecal incontinence by delivering a volume of polymer solution to the sphincter or the area behind the sphincter to improve sphincter tightness.

[0113] As described above, the polymers described herein may be combined with a contrast agent. In one embodiment, such contrast agents include the group of iodinated contrast agents. These are typically polyhydroxylated and polyiodinated compounds. Contrast agents include ionic and non-ionic contrast agents. Non-ionic contrast agents are preferred. Contrast agents include iohexol, iopamidol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoic acid, iothalamic acid, and ioxaglate.

[0114] The inventors have demonstrated that temperature-sensitive polymers, such as those disclosed herein, dissolve in aqueous compositions containing contrast agents at temperatures below the LCST, e.g., 25°C, rather than forming micelles. This provides a molecular solution of the polymer. Such solutions have greatly reduced turbidity, are substantially clear, do not tend to form hydrogels during delivery, and are less viscous at room temperature (20°C) than micellar forms, resulting in easier delivery. Furthermore, for a given concentration of polymer, the lower viscosity allows for the use of higher concentrations of polymer without catheter blockage, resulting in a stronger gel. Such compositions still rapidly hydrogel at 37°C. Without wishing to be bound by any theory, it is believed that the iodinated contrast agent acts as a cosolvent for the polymer. This effect causes micelles present at low temperatures (below the LCST) to dissolve or not form.

[0115] Accordingly, a further embodiment of the present invention provides a composition comprising (i) a temperature sensitive polymer, preferably one having an LCST between 25° C. and 37° C., and (ii) an iodinated contrast agent.

[0116] Such compositions can be aqueous or dry compositions. The compositions preferably comprise 1 part by weight of polymer to at least 1 part by weight of contrast agent, preferably at least 2 parts by weight, more preferably at least 5 parts by weight, more preferably at least 10 parts by weight, and even more preferably at least 12 parts by weight of contrast agent.

[0117] The aqueous composition may be at least 5% polymer by w / w, more preferably at least 7% by w / w, at least 10% by w / w, at least 15% by w / w, at least 20% by w / w, or even higher. The composition may be up to 30%, up to 50%, or up to 80%, or up to 90% polymer by w / w.

[0118] In some embodiments, the ratio of contrast agent to copolymer or bulk polymer composition is from 0.1 to 10, preferably 1-10, more preferably 1.5-5 on a weight to weight basis.

[0119] At temperatures below the LCST, e.g., 25°C, the polymer may dissolve (or substantially dissolve) in the aqueous composition. The polymer may form a molecular solution in the aqueous composition. The polymer may be in the form of a micellar suspension in the aqueous composition. In some embodiments, the aqueous composition may be a clear solution. In some embodiments, the solution has substantially no turbidity below the LCST, e.g., 25°C.

[0120] In a further embodiment, the present invention provides a method of preparing an aqueous composition comprising a polymer described herein, the method comprising the steps of providing a dry composition comprising the polymer, and rehydrating the polymer in a sterile aqueous medium at a temperature below the LCST of the polymer.

[0121] The aqueous medium may be, for example, sterile water or saline. The composition may be suspended, for example, at temperatures below 25°C or below 10°C. In one embodiment, the dry composition comprises an iodinated contrast agent. Reconstitution may comprise preparing a micellar suspension of the polymer, but more preferably, the dry composition comprises an iodinated contrast agent, and reconstitution comprises dissolving the polymer (or substantially all of the polymer) and the contrast agent to prepare a solution of the polymer. In some embodiments, reconstitution comprises preparing a molecular solution or a clear molecular solution of the polymer.

[0122] Iodized oils, such as ethiodized poppy oil (e.g., Lipiodol™), are used in the form of oil emulsions containing an oil phase and an aqueous phase to provide embolic compositions for use in the treatment of (among other things) hypervascular tumors, such as hepatocellular carcinoma. The emulsions can be used without further formulation, but may also contain one or more pharmaceutically active substances, particularly anticancer drugs (e.g., doxorubicin, irinotecan, or platinum drugs), for use in pharmacoembolization procedures. While these approaches have been used for many years, the use of these emulsions has several drawbacks. One particular problem is that the emulsions are only stable for short periods of time and separate into oil and aqueous phases prior to initiation. This means that the emulsions cannot be prepared in advance but must be prepared immediately before use in the operating room. Furthermore, the lack of long-term stability of the emulsions contributes to their rapid dissipation in situ, resulting in only a temporary embolic effect. In drug embolization, emulsion dissipation can also result in a burst release of the active ingredient into the bloodstream, increasing off-target exposure to the active substance. The inventors have discovered that the polymers and polymer compositions of the present invention, such as oil-based compositions including bulk polymer compositions, particularly emulsion compositions, have significantly improved stability. Therefore, a further embodiment of the present invention provides a composition comprising the polymer or polymer composition described herein and an iodized oil. In particular, the iodized oil is ethiosoybean poppy oil. Examples of such oils are available under the trade names Lipiodol® (Guerbet, Paris, France) or Vividol™ (Vivere Imaging, Hyderabad, India).

[0123] In one approach, the composition is in the form of an emulsion comprising an aqueous phase and an oily phase, and the aqueous phase comprises the aqueous composition comprising the copolymer or bulk polymer described herein.The composition can also be in the form of an emulsion, with the oily phase and the aqueous phase being in the same container but separated, for example, to provide a "ready-to-prepare" emulsion.In other words, the components of the emulsion are present as a single liquid volume, with the oily phase and the aqueous phase being completely separated, and typically the aqueous phase floats on the oily phase (Lipiodol has a density of 1.28g / cm at 20°C).

[0124] The ratio of oil to aqueous phase can be selected to prepare water-in-oil (W / O) or oil-in-water (O / W) emulsions. Oil-in-water-in-oil or water-in-oil-in-water emulsions can also be prepared. In some embodiments, the ratio of aqueous polymer to oil can be 1:1 to 1:100 v / v, preferably 1:1 to 1:5 v / v, and more preferably 1:1 to 1:2 v / v, to form a water-in-oil emulsion.

[0125] In some embodiments, the ratio of aqueous polymer solution to oil can be 1:0.01 to 1:1 v / v, preferably 1:0.05 to 1:0.8 v / v, and more preferably 1:0.1 to 1:0.5 v / v to form an oil-in-water emulsion.

[0126] In some embodiments, the polymer concentration in the aqueous solution can be from 1% to 20%, preferably from 3% to 15%, and more preferably from 5% to 10%. The emulsion can be prepared by conventional pumping through two syringes connected by a two-way or three-way stopcock or similar connector, or by homogenization or other mechanical mixing device or method.

[0127] Without wishing to be bound by any theory, it is believed that at ambient temperatures, the structured hydrophobic-hydrophilic copolymer chains rearrange at the interface of the aqueous-oil emulsion, stabilizing the formulation by reducing the surface energy between the oil and water. This structure allows loading of different therapeutic agents based on their hydrophobic or hydrophilic properties.

[0128] When the emulsion is delivered to a target site at body temperature (37°C), the thermoresponsive block converts to a relatively more hydrophobic form, causing the original micellar or lamellar structure to collapse. The increased hydrophobicity results in the formation of a more rigid, porous gel that functions as an embolic barrier. Meanwhile, depending on the ratio of aqueous to oil and the level of polymer in the aqueous phase, the oil contained within the porous structure may provide significantly longer-lasting radiopacity than seen in traditional emulsions or may be released as a delivery carrier for hydrophobic drugs.

[0129] The emulsions disclosed herein have improved stability compared to the same composition lacking the polymer or composition. Stability can be determined by delivering the emulsion composition to a measuring cylinder or syringe and determining the time it takes for half of the liquid phase to precipitate. This is a simple measure of stability. Alternatively, when comparing two compositions of the same volume, it is simpler to determine the time it takes for a given volume of aqueous phase to separate from the same emulsion volume in the same measuring cylinder. The emulsions described herein are stable for between 10 minutes and 2 hours, depending on the formulation. Emulsions with more polymer tend to be stable for longer periods.

[0130] Emulsion formulations can be tailored to have a range of viscosities and thermal response properties by varying the ratio of aqueous solution to Lipiodol. Thus, in some embodiments, the formulation forms an oily fluid, while in others, it forms a hydrogel above the polymer's LCST. In some embodiments, the formulation forms as threadlike or spherical deposits. The formulation may be used to direct the formulation to more distal or more proximal embolization. In the case of water-in-oil formulations with a high oil volume fraction (high oil to water ratio greater than 1:0.9, preferably greater than 1:0.5), the emulsion tends toward an oily fluid form that can be delivered to small distal vasculature. Conversely, oil-in-water formulations with a low oil volume fraction (low oil to water ratio less than 1:1.1, preferably less than 1:1.5) may be more suitable for proximal embolization of relatively large vessels, including those found in vascular diseases such as aneurysms.

[0131] The iodized oil or emulsion formulation may contain one or more surfactants or emulsion stabilizers. Examples of such additives include, among others, glucose, lactose, mannitol, ribitol, threitol, erythritol, sorbitan, volemitol, isomalt, maltitol, lactitol, cholesterol, polysorbates, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, decyl glucoside, lauryl glucoside, octyl glucoside, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol, polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide-co-polyethylene oxide (PEO-PPO-PEO), ethylene vinyl alcohol (EVOH), polyacrylates, polymethacrylates, polyacrylamides, polymethacrylamides, acrylate polymers, polyamides, polysiloxanes, polyesters, polyurethanes, polyvinyl ethers. , polyvinyl esters, polyglycerol methacrylate, poly(2-acrylamido-2-methylpropanesulfonic acid) or sodium salt, poly(2-acrylamido-2-methylpropanesulfonic acid) and salts thereof (e.g., the sodium salt), poly(2-methacryloyloxyethylphosphorylcholine), polyacrylic acid or salts thereof (e.g., the sodium salt), polymethacrylic acid or salts thereof, (e.g., the sodium salt), microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch, croscarmellose sodium, magnesium stearate, polysorbate, poloxamer, sodium lauryl sulfate, hypromellose acetate succinate, alginate, collagen, fibrin, chitosan, gelatin, hyaluronic acid, cyclodextrin, laponite, sodium dodecyl sulfate, sodium lauryl sulfate, ammonium lauryl sulfate, docusate, and Triton X-100.

[0132] The emulsion formulation may include a formulating agent, an imaging agent, and / or additional components, as described elsewhere herein. In further embodiments, the emulsion formulation may include, or may further include, at least one therapeutic or diagnostic radioisotope, and / or at least one chemotherapeutic agent, each of which is described elsewhere herein.

[0133] Suitable chemotherapeutic agents for use with the emulsions include those described elsewhere herein, but due to the hydrophobic nature of the oil phase, the emulsions may also include more hydrophobic drugs, such as taxanes, e.g., paclitaxel, docetaxel, and cabazitaxel.

[0134] In addition to aqueous compositions, the present invention also provides formulations comprising a block copolymer or bulk polymer described herein and ethiosoybean poppy oil, e.g., Lipiodol®, in dry form. Such compositions may contain at least 5%, at least 10%, at least 15%, or at least 20% polymer or bulk polymer w / w. This can be achieved by combining the oil with a dry polymer powder, preferably having a size range between 1 μm and 500 μm, preferably between 40 μm and 300 μm.

[0135] Upon delivery of the formulation to the capillaries, for example, embolization occurs first as a function of the particle size of the polymer, absorbing water from the blood and / or tissue while the oil liquid phase continues to permeate through the capillary bed, thus forming an embolism at 37°C.

[0136] A further aspect of the present invention provides methods for the preparation of the thermo-responsive polymer compositions disclosed herein, and products of those methods. Thus, in a first embodiment, the present invention provides a method for the preparation of a block copolymer, comprising: polymerizing A monomers, and optionally P monomers, to provide a first block, which is either an A block or an AP block, wherein the polymerization is initiated by a polymerization initiator I having m polymerization initiation sites; and reacting N monomers with the first block to provide a block copolymer comprising a first A block or AP block and a second N block, wherein the A monomers are reacted in an I:A molar ratio of 1:(20-600)m, the P monomers are reacted in an I:P molar ratio of 1:(0-500)m, and the N monomers are reacted in an I:N ratio of 1:(1-800)m.

[0137] A, P and N are as described elsewhere herein. The A monomer may be reacted in an I:A ratio of 1:(20-600)m, preferably 1:(30-200)m, more preferably 1:(60-120)m, and even more preferably 1:(70-100)m mol / mol.

[0138] The P monomer may be reacted at an I:P ratio of 1:(0-500)m, preferably 1:(2-100)m, more preferably 1:(3-30)m mol / mol. The N monomers may be reacted in an I:N ratio of 1:(1-800)m, preferably 1:(3-600)m, more preferably 1:(5-400)m mol / mol.

[0139] In one embodiment, the second block may be grafted to the first block, where the total number of N monomers grafted to the first block is 1 to 800, preferably 20 to 600, more preferably 50 to 400.

[0140] In some embodiments, when the second block is present as an extension to the first block, the number of N monomers in the second block can be 3 to 500, preferably 5 to 200, more preferably 5 to 50.

[0141] The AP block can be an (AbP) block, a (PbA) block, or an (A-co-P) block. The polymer can be AP-bN or AP-gN.

[0142] In some embodiments, the individual monomer species are reacted in a molar ratio of A to N of 1:0.1 to 1:8, preferably 1:2 to 1:5, and especially 1:2 to 1:4, or, if P is present, a molar ratio of (A+P) to N.

[0143] In some embodiments, when P is present, of the reacted first block monomers, 70% to 99.9% are A monomers, preferably 80% to 99% or 80% to 99.9% are A monomers.

[0144] In some embodiments, the N block is provided as a graft to the first block, in some embodiments, the N block is provided as an extension of the first block, in some embodiments, the N block is provided as both a graft and an extension.

[0145] The initiator may be selected from those described elsewhere herein. In any of the above embodiments, m can be an integer from 1 to 10, preferably 1 to 6, more preferably 1 to 4 or 1 to 3, although particularly preferred embodiments are those in which m is either 2 or 3.

[0146] The polymerization can be carried out by RAFT, ATRP, or conventional free radical polymerization, but is preferably carried out by ATRP. In some embodiments, the first block that reacts with the N monomer is in the form of a macroinitiator.

[0147] In some embodiments, the method comprises polymerizing an A monomer or a combination of A and P monomers to form a compound of formula 10, for example: *-(A-co-P), for example, *-(A (x+x’) -co-P (y+y’) ) Equation 10a b forming a first block comprising A monomers and optionally P monomers of and (a) N blocks, for example, Nq blocks, are divided into a first block, for example, (A (x+x’) -co-P (y+y’) ) block to form a compound of general formula 11 *-(A-co-P)-N, e.g., *-(A (x+x’) -co-P (y+y’) )-Nq Equation 11a b forming a polymer of or (b) at least one N graft, e.g., N r The graft may be extended from the AP block to form a compound of formula 11c, e.g., formula d;

[0148] [ka] wherein * represents the residue of an optional initiator molecule configured to support initiation of polymerization from m functional groups, and m is an integer from 1 to 10; r forming a copolymer comprising at least one graft of Contains any of the following.

[0149] The polymerization can be carried out by a variety of approaches, including RAFT, ATRP, or traditional free radical polymerization. In a preferred approach, the polymerization is carried out by ATRP. In one approach for ATRP, the method comprises: (i) polymerizing A monomers, or a combination of A and P monomers, in the presence of an initiator configured to support ATRP polymerization from m functional groups to provide a halogenated macroinitiator comprising a polyA block or (A-co-P) block containing residues of the initiator covalently attached to either m A polymers or AP copolymers, each of which contains a terminal monomer containing a Hal group, e.g., one of formula 12: *[(A-co-P)Hal] m , for example *[(A (x+x’) -co-P (y+y’) )Hal] m Equation 12a b wherein Hal is a halogen selected from Cl and Br, preferably Br, and m is the number of polymer arms covalently attached to the initiator, preferably 1 or 2. Including steps (ii) reacting a halogenated initiator with the N monomer in a further ATRP reaction to provide a copolymer comprising a first block comprising A monomers and optionally P monomers, and a second block consisting of N monomers, the second block being an extension of the A block (or AP block). These are linear polymers, as opposed to star polymers.

[0150] In the second approach, the ATRP method (i) polymerizing A monomers, or a combination of A and P monomers, in the presence of an initiator configured to support ATRP polymerization from "m" functional groups to provide a star polymer comprising residues of the initiator covalently attached to m copies of either the A polymer or AP copolymer; (ii) reacting the star polymer with an activated halogen compound, such as α-haloisobutyryl bromide, to provide a halogenated macroinitiator in which the halogen is pendant from the A monomer (in the case of an A polymer) or pendant from both the A and P monomers (in the case of an A-co-P polymer); (iii) reacting the halogenated macroinitiator with N monomers in a further ATRP reaction to provide a copolymer comprising a first block comprising A monomers, and optionally P monomers, and a second block consisting of N monomers, wherein (in the case of an A polymer) the second block is pendant from the A monomers, or (in the case of an A-co-P polymer) the second block is pendant from both the A and P monomers.

[0151] Typically, in ATRP reactions such as those described above, the reaction is carried out in the presence of a transition metal halide, typically a copper(I) halide. The halogen is typically the same as that present as a functional group on the initiator, and is typically the same as that present on the macroinitiator. This can be chlorine or bromine, but is typically bromine. The reaction is typically carried out in the presence of a nitrogen-containing ligand bound to the transition metal. Typically, the reaction is carried out in a solution where oxygen is excluded.

[0152] In one example, a (HEMA-co-HPMA)-block NIPAAm polymer, e.g., (HEMA (x) -co-HPMA (y) )-Block NIPAAM q The method for the preparation of the polymer (i) Polymerization of a combination of HEMA and HPMA monomers in the presence of a bifunctional initiator, such as diethyl meso-2,5-dibromoadipate (DMDBA), Cu(I)Br, and a nitrogen-containing ligand, such as 2,2'-bipyridine, in a polar solvent, such as MeOH, to form a I-[(HEMA-co-HPMA)Br] macroinitiator, such as I-[(HEMA (x) -co-HPMA (y) )Br] macroinitiator, wherein the terminal monomer of each arm contains a bromine group (see Scheme 1); (ii) In a further ATRP reaction, the brominated macroinitiator is reacted with a NIPAAM monomer in the presence of a nitrogen-containing ligand, such as 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (Me4Cyclam), in the presence of Cu(I)Br to give I-[(HEMA)-co-HPMA ) -block NIPAAm] polymers, e.g., I-[(HEMA (x) -co-HPMA (y) )-Block NIPAAM q ]2 to provide a polymer (see Scheme 2). Includes.

[0153] [ka]

[0154] [ka] In a second example, a comb-like triarm poly(I-[(HEMA-co-HPMA)-graft-(NIPAAM)] polymer, e.g., I-[(HEMA (x) -co-HPMA (y) )-graft-(NIPAAM r ) (x’+y’) ]3 The method for the preparation of the polymer is (i) Polymerizing a combination of HEMA and HPMA monomers in the presence of a trifunctional initiator, such as glycerol tris(2-bromoisobutyrate), Cu(I)Br, and a nitrogen-containing ligand, such as 2,2'-bipyridine, to form a stellar I-[(HEMA-co-HPMA)] polymer, such as a stellar I-[(HEMA (x) -co-HPMA (y) )]3 to provide the polymer (Formula 15) (Scheme 3),

[0155] [ka] (ii) Reacting the star polymer with an activated alkyl bromine compound, such as α-bromoisobutyryl bromide, in the presence of a base, such as triethylamine, to form a brominated I-[(HEMA-co-HPMA)] macroinitiator, such as I-[(HEMA (x) -co-HPMA (y) )]3 macroinitiator (Formula 16) (Scheme 4),

[0156] [ka] (iii) In a further ATRP reaction, the brominated I-[(HEMA-co-HPMA)] macroinitiator is reacted with N-monomers in the presence of Cu(I)Br and a nitrogen-containing ligand, such as N,N,N',N",N"-pentamethyldiethylenetriamine (PMDETA), in a solvent such as NMP, to give I-[(HEMA-co-HPMA)-graft-(NIPAAM)] polymers, such as I-[(HEMA (x) -co-HPMA (y) )-graft-(NIPAAM r ) (x‘+y’) ]3 to provide the polymer (Formula 17) (Scheme 5). Includes.

[0157] [ka] In some embodiments, the method includes drying the resulting polymer to provide a dry polymer composition.

[0158] In some embodiments, the method includes formulating the polymer by combining it with one or more of the additional ingredients described elsewhere herein. Formulating can be accomplished before or after drying.

[0159] In some embodiments, formulation can be achieved by drying any of the compositions described elsewhere herein. In one embodiment, the method may include combining a polymer described herein with one or more imaging agents in a solution phase and drying the solution to provide a dry composition of the polymer containing the imaging agent.

[0160] Any of the above embodiments or preferred embodiments may be used in combination with any other embodiment or preferred embodiment, and any of the foregoing may be combined with any aspect of the present specification above.

[0161] The present invention will now be described with reference to non-limiting experimental examples and figures. Further embodiments of the invention will be apparent to those skilled in the art in light of these. [Example]

[0162] In the examples, the polymer and intermediate formulas are idealized, assuming the reaction has gone to completion. In the examples below, HPMA is a mixture of isomeric hydroxypropyl methacrylate and hydroxyisopropyl methacrylate, as further outlined above.

[0163] Example 1: Preparation of the tri-arm initiator, glycerol tris(2-bromoisobutyrate) 5 g (0.054 mol) of anhydrous glycerol was added to a 250 mL round-bottom flask, followed by 23 mL of triethylamine (0.168 mol) and 50 mL of anhydrous N-methylpyrrolidone. The flask was placed in an ice-water bath and stirred with a magnetic stirrer for 20 minutes. 38 g (0.165 mol) of α-bromoisobutyryl bromide was then added dropwise via a dropping funnel over a period of approximately 30 minutes. The reaction was stirred overnight at room temperature. The reaction mixture was then filtered to remove the triethylamine salt, and the solution was then thoroughly mixed with saturated aqueous NaCl solution. The aqueous solution was extracted three times using ethyl acetate, and the combined organic phases were dried overnight with MgSO4. The ethyl acetate solution was removed on a rotary evaporator, and the product was dried under vacuum for 24 hours to yield a pale yellow waxy solid. This product 1The 1 H NMR spectrum is shown in Figure 1.

[0164] Example 2: Synthesis of tri-arm polyHEMA homopolymer by ATRP Triarm poly(I-(HEMA) 100 A typical synthesis procedure for 3) is given below. 0.2 g (0.37 mmol) of the initiator prepared in Example 1 was mixed with 14.5 g (111 mmol) of 2-hydroxyethyl methacrylate and 15 mL of methanol in a 100 mL three-neck round-bottom flask. The mixture was degassed with nitrogen gas for 60 minutes under magnetic stirring. Then, 0.16 g (1.11 mmol) of CuBr and 0.35 g (2.22 mmol) of 2,2'-bipyridine were added to the flask to initiate polymerization under a nitrogen atmosphere. During the first hour, the temperature of the reaction mixture increased, accompanied by a gradual increase in the solution viscosity. After approximately 20 hours, the reaction was terminated by exposure to air and diluted with methanol. The mixture was passed through a silica gel column to remove the copper catalyst, and the methanol was removed by rotary evaporation. Subsequently, 10.6 g of solid was recovered by drying overnight at 40 °C under vacuum.

[0165] Example 3: Synthesis of a tri-arm polyHEMA homopolymer macroinitiator In a 250 mL round-bottom flask, 15 g of the triarm poly(I-(HEMA)) obtained from the reaction in Example 2 was added. 100 )3) was dissolved in 50 mL of anhydrous N-methylpyrrolidone under magnetic stirring. 1.74 mL of triethylamine was then added. The flask was placed in an ice-water bath, and 1.41 mL of α-bromoisobutyryl bromide was then added dropwise over approximately 10 minutes via syringe, targeting 10 units of bromide per arm. The reaction solution quickly became cloudy and was stirred overnight at room temperature. The reaction mixture was precipitated dropwise into 500 mL of deionized water to remove NMP and triethylamine salts. The collected solid was dissolved in 30 mL of NMP, and the precipitation was repeated. The solid was collected by dissolving in MeOH, followed by rotary evaporation, and dried overnight in vacuo at 40 °C. 12.0 g of polymer was produced (Formula 18).

[0166] [ka] Example 4: Synthesis of comb-like triarm poly(HEMA-g-NIPAAM) copolymer by ATRP Using ATRP, a series of triarm poly(I-(HEMA-g-NIPAAM)3) copolymers were synthesized with varying levels of HEMA and NIPAAM polymerization. A typical procedure is given below.

[0167] In a 100 mL three-neck round-bottom flask, 3.0 g of the polyHEMA macroinitiator prepared in Example 3 was dissolved in a mixture of 40 mL of NMP and 30 mL of deionized water. Then, 4.68 g of NIPAAM monomer and 0.36 g of the catalyst N,N,N',N",N"-pentamethyldiethylenetriamine (PMDETA) were added. The solution was degassed with nitrogen for 1 hour, and the flask was placed in an ice-water bath and left until the mixture reached 5 °C. The CuBr catalyst was added under a stream of nitrogen to initiate the polymerization. The solution viscosity increased over time. After approximately 18 hours, the reaction was stopped by exposure to air and diluted with 20 mL of NMP. The mixture was dialyzed against water in a dialysis bag for 4 days, with the water replaced every 12 hours. The resulting translucent solution was freeze-dried, and 6.9 g of a white polymer solid (Formula 19) was finally recovered. The proton NMR spectrum of this product is shown in Figure 1c.

[0168] [ka] Example 5: Synthesis of Triarm Poly(HEMA-NIPAAM) Copolymer by Chain Extension Using ATRP Triarm poly(I-(HEMA) 100 -NIPAAM 100 A typical synthesis procedure for 3) is given below.

[0169] In a 100 mL three-neck round-bottom flask, 2.1 g of the macroinitiator polyHEMA prepared in Example 2 and 1.81 g of NIPAAm monomer were dissolved in 5 mL of NMP. The mixture was degassed with nitrogen for 60 minutes, and CuBr catalyst (0.023 g) and 0.041 g of 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (Me4Cyclam) were added, and polymerization was allowed to proceed overnight. The reaction mixture was then dialyzed against deionized water for 4 days to remove unreacted monomer and catalyst. The solution was lyophilized, and 2.4 g of polymer was recovered.

[0170] Example 6: Linear Copolymer I-((HEMA 45 -co-HPMA5)-NIPAAM 100 Synthesis of 2 (a) Poly(I-(HEMA) 45 Preparation of HPMA-co-HPMA5)2 copolymer In a 100 mL three-neck flask, 0.3 g (0.83 mmol) of initiator, diethyl meso-2,5-dibromoadipate, was mixed with 9.76 g (75 mmol) of 2-hydroxyethyl methacrylate, 1.20 g (8.3 mmol) of hydroxypropyl methacrylate, and 12 mL of methanol. HPMA was supplied by Merck (Cat. No. 268542) and is a mixture of isomeric hydroxypropyl methacrylate and hydroxyisopropyl methacrylate. After degassing the mixture with nitrogen gas for 60 minutes under magnetic stirring, 0.24 g (1.67 mmol) of CuBr and 0.52 g (3.33 mmol) of 2,2'-bipyridine were added to the flask to initiate polymerization under a nitrogen atmosphere. The temperature of the reaction mixture increased slightly over time, and a gradual increase in solution viscosity was observed until the magnetic stir bar stopped moving. After approximately 18 hours, the reaction was quenched by exposure to air and dilution with methanol. The mixture was passed through a silica gel column to remove the copper catalyst, and the dry polymer solid was recovered by rotary evaporation to remove the methanol, followed by vacuum drying at 40° C. overnight.

[0171] (b) I-((HEMA45 -co-HPMA5)-NIPAAM 100 ) Preparation of 2 In a 100 mL three-necked round-bottom flask, 3.0 g of the macroinitiator poly(HEMA-co-HPMA) prepared above and 5.0 g of NIPAAM monomer were dissolved in 25 mL of MeOH. The mixture was degassed with nitrogen for 1 hour, and then 0.06 g of CuBr catalyst and 0.114 g of Me4Cyclam were added to initiate the polymerization. The reaction was carried out overnight. The mixture was then dialyzed against deionized water for 4 days to remove unreacted monomer and catalyst. The solution was lyophilized to recover the linear polymer solid. This polymer was synthesized using the NIPAAM copolymer. 100 -(HEMA 90 -co-HPMA 10 )-NIPAAM 100 It is sometimes written as follows.

[0172] Example 7 Linear copolymer poly(NIPAAM) 200 -HEMA 99 -HPMA1-NIPAAM 200 ) synthesis Linear poly(HEMA 99A typical synthesis procedure for -st-HPMA1) is given below. 1.5 g (4.17 mmol) of the initiator diethyl meso-2,5-dibromoadipate was mixed with 53.7 g (412.81 mmol) of 2-hydroxyethyl methacrylate and 0.6 g (4.17 mmol) of hydroxypropyl methacrylate in a 250 mL three-neck round-bottom flask, followed by the addition of 55 mL of methanol. The mixture was degassed with nitrogen gas for 60–120 min under magnetic stirring. Then, 1.20 g (8.34 mmol) of Cu(I)Br and 2.60 g (16.68 mmol) of 2,2'-bipyridine were added to the flask to initiate polymerization under a nitrogen atmosphere. Over the first hour, the temperature of the reaction mixture increased, accompanied by a gradual increase in the solution viscosity. After approximately 20 h, the reaction was quenched by exposure to air and diluted with methanol. The mixture was passed through a silica gel column to remove the copper catalyst, and the methanol was removed by rotary evaporation. After further drying under vacuum at 40° C. overnight, 45 g of solid was recovered.

[0173] [ka] Targeted Poly(NIPAAM) 200 -HEMA 99 -HPMA1-NIPAAM 200 To prepare the poly(HEMA) copolymer, 15 g of the poly(HEMA) copolymer obtained from the above reaction was added to a 250 mL three-neck round-bottom flask. 99 The (-st-HPMA1) macroinitiator was dissolved in 72 mL of methanol under magnetic stirring. Then, 50.7 g of N-isopropylacrylamide monomer was added to the flask and dissolved. After the mixture was degassed with nitrogen for 60-120 min, the flask was placed in an ice-water bath and 0.32 g (2.24 mmol) of Cu(I)Br and 0.58 g (2.24 mmol) of 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane were added to initiate the polymerization.

[0174] The reaction solution quickly became viscous and was stirred overnight under a nitrogen atmosphere. After approximately 20 hours, the reaction was stopped by exposure to air and the viscous solution was diluted by adding 100 mL of methanol. The polymer was purified against water by ultrafiltration, and the resulting solution was freeze-dried for 48 hours. Finally, approximately 54 g of solid was collected. This polymer was found to be I-((HEMA 45.5 -HPMA 0.5 )-NIPAAM 200 )2.

[0175] [ka] Example 8: Synthesis of comb copolymer poly(HEMA-HPMA-graft-NIPAAM) (a) Synthesis of poly(HEMA-HPMA) macroinitiator In a 250 mL round-bottom flask, 8 g of poly(I-HEMA) obtained from Example 6a was added. 45 -HPMA5)2 was dissolved in 50 mL of anhydrous N-methylpyrrolidone (NMP) under magnetic stirring, followed by the addition of 2.72 mL of triethylamine. The flask was placed in an ice-water bath, and then 2.20 mL of α-bromoisobutyryl bromide was added dropwise over approximately 20 minutes, targeting 10 units of bromide per chain. The reaction solution quickly became cloudy and was stirred overnight at room temperature. The reaction mixture was precipitated dropwise into 500 mL of deionized water to remove NMP and triethylamine salts. The collected solid was dissolved in 30 mL of NMP, and the precipitation was repeated. The solid was collected and dried under vacuum at 40 °C for 2 days.

[0176] (b) Comb copolymer I-[(HEMA 45 -HPMA5)-g-(NIPAAM 20 )5]2 Synthesis In a 100 mL three-neck round-bottom flask, 3.0 g of the macroinitiator poly(HEMA-HPMA) prepared above and 5.0 g of NIPAAM monomer were dissolved in 15 mL of NMP. The mixture was degassed with nitrogen for 60 minutes, and then 0.32 g of CuBr catalyst and 0.57 g of PMDETA were added to initiate the polymerization. The reaction was carried out overnight and then dialyzed against deionized water for 4 days to remove unreacted monomer and catalyst. The solution was lyophilized and the polymer solid was recovered. The formula is poly(HEMA 90 -HPMA 10 -g-(NIPAAM 20 ) 10 ) (Figure 20).

[0177] [ka] Example 9: Triarm Poly(HEMA 90 -co-HPMA 10 ) synthesis In a 250 mL three-neck flask, 0.3 g (0.56 mmol) of the initiator prepared in Example 1 was mixed with 19.6 g (151 mmol) of 2-hydroxyethyl methacrylate and 2.41 g (16.8 mmol) of hydroxypropyl methacrylate in 23 mL of methanol. The solution was degassed with nitrogen for 60 minutes, and then 0.24 g (1.68 mmol) of CuBr and 0.52 g (3.36 mmol) of 2,2'-bipyridine were added under a nitrogen stream to initiate polymerization. After approximately 20 hours, the reaction was stopped by exposure to air and diluted with methanol. The mixture was precipitated in deionized water to remove the copper catalyst, and the solid precipitate was collected. The solid was dissolved in MeOH and precipitated in water. The extraction was repeated three times. The recovered polymer was dried under vacuum at 40 °C overnight, and 18.8 g of solid was collected.

[0178] Example 10: Poly(I-(HEMA) 90 -co-HPMA 10 )3) Synthesis of macroinitiators In a 250 mL round-bottom flask, 10 g (0.25 mmol) of the tri-arm poly(I-(HEMA-HPMA)3) from Example 8 was dissolved in 50 mL of anhydrous N-methylpyrrolidone (NMP) under magnetic stirring, followed by the addition of 1.15 mL of triethylamine. The flask was placed in an ice-water bath, and then 0.93 mL of α-bromoisobutyryl bromide was added dropwise via syringe over approximately 10 minutes, targeting 10 units of bromide per arm. The reaction solution quickly became cloudy and was stirred overnight at room temperature. The reaction mixture was precipitated by adding dropwise to 500 mL of deionized water to remove the NMP and triethylamine salt. The collected solid was dissolved in 30 mL of NMP, and the precipitation was repeated. The solid was collected and dried under vacuum at 40 °C for 2 days.

[0179] Example 11: Comb-like triarm poly(I-(HEMA)) synthesized by ATRP 90 -co-HPMA 10 )-graft-(NIPAAM 20 ) 10 ) Synthesis of 3 In a 100 mL three-neck round-bottom flask, 3.0 g of the poly(HEMA-HPMA) macroinitiator prepared in Example 9 and 5.1 g of NIPAAM monomer were dissolved in 50 mL of NMP. The mixture was degassed with nitrogen for 60 minutes, and then 0.32 g of CuBr and 0.39 g of PMDETA were added to initiate the polymerization. The reaction was carried out overnight. The mixture was then dialyzed against deionized water for 4-5 days to remove unreacted monomer and catalyst. The solution was freeze-dried, and the polymer solid was recovered (Equation 17) (see also Scheme 5).

[0180] [ka] Example 12: Sample preparation and in vitro testing A sample of the polymer solid produced as described above was weighed into a 30 mL vial, and deionized water was added to provide a 10% w / w polymer solution. The vial was placed in a cold water bath and magnetically stirred until a uniform solution was obtained. The solution was translucent and had low viscosity. The gelation ability of the polymer solution was tested by injecting the solution through an 18G needle into phosphate-buffered saline solution at 37°C. As shown in Figure 1, the solution immediately became a white hydrogel. Gels formed from less hydrophobic polymers (e.g., those lacking HPMA) tended to form soft clumps, as shown in Figure 2A, while more hydrophobic polymers (in this case, with 10% HPMA mol / mol in the PA block) tended to be more rigid and threadlike, as shown in Figure 2B. Needle pressure tests indicated that the gel strength was sufficiently strong and not easily broken. Table 1 records the properties observed for example polymers delivered to PBS solution at 37°C. Polymer solutions were prepared either in Omnipaque™ 300 aqueous contrast medium, which was used undiluted, or in deionized water.

[0181] [Table 1] Example 13: Rheology I-((HEMA 44.5 -co-HPMA 0.5 )-NIPAAM 200 A sample of the 2 aqueous solution (15% w / w) was tested using an oscillatory method with a rheometer, and the results of increasing temperature are shown in Figure 6. The results show that the sol-gel transition temperature is around 29°C, and the gel has a storage modulus of approximately 20,000 Pa and a loss modulus of 4,000 Pa at 37°C, suggesting that a solid gel can be formed when the sample is placed at body temperature.

[0182] Example 14: Polymer delivery in a flow model To prepare the polymer solution containing the contrast medium, the polymer solid was weighed into a 30 mL vial and the contrast medium Omnipaque 300 (647 mg / mL iohexol) was added to achieve a polymer concentration of 10% w / w. The vial was placed in a cold water bath and magnetically stirred to dissolve the polymer. The resulting polymer solution was transferred to a syringe for delivery testing using a 2.4 Fr catheter.

[0183] In the flow model, a 5 mm diameter silicon tubing was immersed in a 37°C water bath. A sponge was placed in the center of the tubing to mimic a collection of small blood vessels, such as the rete mirabile. PBS medium was pumped through the sponge tubing. A bypass allowed the flow rate through the sponge to be controlled at 150 mL / min, and the actual flow rate was monitored by a flow meter. The open end of a 2.4 Fr catheter was placed in front of the sponge, and a polymer solution was injected into the tubing. Upon exiting the tip of the catheter, the polymer solution transformed into a hydrogel thin line in the flow medium, forming a plug and occluding the flow path. Within 1–2 min, the flow meter reading dropped to zero (Figure 3).

[0184] Example 15: Dry Polymer Formulation Polymer powder samples were prepared by either grinding freeze-dried solids or spray-drying from polymer solutions to provide particle size distributions between 10 and 600 microns. 0.05 g of powder, with or without glycerol (0.025 g), was weighed into a 1 mL syringe. 0.925 g of contrast solution was weighed into a second 1 mL syringe. The two syringes were connected together via a three-way stopcock, and air was carefully removed. The contrast solution was quickly mixed with the polymer solid by passing the composition back and forth between the two syringes. The syringes were placed in a refrigerator at 2-8°C for 5 minutes to cool the contents and allow for better dissolution. The solution was further mixed back and forth 20 times. A catheter was connected to the syringe to deliver the mixture to 37°C PBS, and a hydrogel thread formed in the PBS.

[0185] Example 16 Preparation and properties of oil emulsions I-((HEMA)) was mixed with iodized poppy seed oil (Lipiodol® Guerbet, Paris, France) in various ratios by repeatedly shuttling the mixture between two syringes through a three-way stopcock to obtain a uniform emulsion. 45 -co-HPMA5)-NIPAAM 200 ) a 10% aqueous solution of 2 (see Table 3). The emulsion was slowly injected into PBS buffer at 37°C, and the product characteristics were observed. Figures 4A-4C show the products formed.

[0186] Example 17 Catheter Delivery of Linear Polymer-Based Emulsions in a Flow Model A sample of the emulsion prepared according to Example 16 was delivered through a 2.7 Fr catheter in a flow model according to Example 14, which mimics vascular embolization in PBS at 37° C. Observations are recorded in Table 3.

[0187] [Table 2] Example 16 Catheter Delivery of Lipiodol® Oil Containing Polymer Particles in Dry Form into PBS As described above, I-((HEMA)) was prepared by directly mixing Lipiodol® oil and 200-500 μm polymer particles between two syringes. 49.5 -co-HPMA 0.5 )-NIPAAM 200 ) Lipiodol® oil sample containing 2 dry polymer powder. The formulation was delivered through a 2.7 Fr catheter into PBS buffer at 37°C (Figure 5). The polymer powder was observed suspended within the oil droplets.

[0188] Example 17. Release of drug mimetics from hydrogel oil emulsions The water-soluble dye Safronin O was added to the copolymer I-((HEMA 49.5 -co-HPMA 0.5 )-NIPAAM 200The red dye was dissolved in a 10% aqueous solution of 2. The solution was then mixed with Lipiodol® in a 1:1 (v / v) ratio to form a pinkish water-in-oil emulsion. When the emulsion was injected into PBS buffer at 37°C, it immediately formed a hydrogel fluid. It was observed that the red dye was gradually released from the hydrogel injected into PBS, and the dye was completely released after 48 hours.

[0189] Similarly, the oil-soluble dye Sudan IV was dissolved in Lipiodol® followed by I-((HEMA) in a 1:1 ratio. 49.5 -co-HPMA 0.5 )-NIPAAM 200 )2 was mixed with a 10% aqueous solution to obtain a pink water-in-oil emulsion. When the emulsion was injected into PBS buffer at 37°C, a hydrogel fluid was immediately formed. The red dye was not released from the hydrogel injected into PBS, and even after 48 hours, there was no obvious dye release into PBS.

[0190] Example 18: Synthesis of poly(NIPAAM-[GMA-st-BMA]-NIPAAM) and poly(NIPMAM-[GMA-st-BMA]-NIPMAM) copolymers A. Poly (GMA 95 Synthesis of -st-BMA5) 0.1 g (0.3 mmol) of the initiator diethyl meso-2,5-dibromoadipate was mixed with 4.7 g (29.3 mmol) of glycerol monomethacrylate and 0.2 g (1.4 mmol) of butyl methacrylate in a 50 mL three-neck round-bottom flask, followed by the addition of 5 mL of methanol. The mixture was degassed with nitrogen gas under magnetic stirring for 60 min, after which 0.08 g (0.6 mmol) of Cu(I)Br and 0.1 g (0.6 mmol) of N,N,N',N",N"-pentamethyldiethylentriamine were added to the flask to initiate the polymerization. An initial increase in the temperature of the reaction mixture was observed, accompanied by an increase in the solution viscosity.

[0191] After approximately 20 hours, the reaction was quenched by exposure to air and diluted with methanol. The mixture was passed through a silica gel column to remove the copper catalyst, and the methanol was removed by rotary evaporation. After further drying under vacuum at 40 °C overnight, 4.1 g of solid was recovered.

[0192] B. Poly (NIPAAM 200 -[GMA 95 -st-BMA5]-NIPAAM 200 ) Copolymer Synthesis In a 50 mL three-neck round-bottom flask, 1.9 g of the poly(GMA-st-BMA) macroinitiator from the above reaction was dissolved in 9 mL of methanol under magnetic stirring. 5.3 g of N-isopropylacrylamide monomer was then added to the flask and dissolved. After degassing the mixture with nitrogen for 60 minutes, the flask was placed in an ice-water bath and 0.03 g (0.23 mmol) of Cu(I)Br and 0.06 g (0.23 mmol) of 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane were added to initiate the polymerization. The reaction solution quickly became viscous and was stirred overnight under a nitrogen atmosphere.

[0193] After approximately 20 hours, the reaction was stopped by exposure to air, and the viscous solution was diluted by adding 100 mL of methanol. The polymer was purified against water by ultrafiltration, and the resulting solution was freeze-dried for 48 hours. Approximately 5.5 g of solid was collected.

[0194] C. Poly(NIPMAM 200 -[GMA 95 -st-BMA5]-NIPMAM 200 ) Copolymer Synthesis In a similar manner to the above preparation, the product was prepared by reacting the poly(GMA-st-BMA) macroinitiator prepared above with N-isopropylmethacrylamide monomer in the presence of the catalyst Cu(I)Br and the ligand 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane. After lyophilization, a yellowish polymer solid was obtained.

[0195] Both polymers were soluble in cold water and showed a phase change of polymer aggregation and gel formation at 37°C.

[0196] [ka]

Claims

1. A block copolymer comprising a first block comprising A monomers and optionally P monomers, and a second block consisting of N monomers, wherein the P monomers are more hydrophobic than the A monomers, and the second block is a thermo-responsive block; the A monomer is selected from acrylates, methacrylates, acrylamides and methacrylamides, preferably the A monomer is selected from the group consisting of acrylate esters, methacrylate esters, N-substituted acrylamides and N-substituted methacrylamides; the P monomer is selected from the group consisting of acrylates, methacrylates, acrylamides and methacrylamides, preferably the P monomer is selected from the group consisting of acrylate esters, methacrylate esters, N-substituted acrylamides and N-substituted methacrylamides; P is more hydrophobic than A, A block copolymer wherein the second block is selected from poly(N-isopropylacrylamide) (pNIPAAM), poly(N-isopropylmethacrylamide) (pNPMAM), poly(N,N-diethylacrylamide) (pDEA), poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA), poly(PEG methacrylate) (pPEGMA), poly(N-vinylcaprolactam), poly(2-isopropyl-2-oxazoline), poly(vinyl methyl ether), poly(l-lactic acid)-poly(ethylene glycol)-poly(l-lactic acid) (PLLA-PEG-PLLA), hydroxypropyl cellulose, and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), preferably poly(N-isopropylacrylamide) or poly(N,N-diethylacrylamide).

2. The A monomer is selected from the group consisting of 2-hydroxyethyl methacrylate (HEMA), N-(2-hydroxyethyl)acrylamide (HEA), 1,3-dihydroxypropyl methacrylate (1,3DHPMA), 2,3-dihydroxypropyl methacrylate (2,3DHPMA), glycerol monomethacrylate (GMA) and N-(2-hydroxyethyl)methacrylamide (HEMAm), in particular 1,3DHPMA, 2,3DHPMA, GMA and HEMA, in particular HEMA, and the P monomer is selected from the group consisting of 3-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, acrylate, 1-hydroxy-2-propanyl methacrylate and 2-hydroxypropyl methacrylate, or a mixture of any two or more of the foregoing isomers (HPMA), N-(2-hydroxypropyl) methacrylamide (HPMAm), N-(3-hydroxypropyl) acrylamide (HPA) and butyl methacrylate (BMA), the N monomer is selected from N-NIPAAM, NIPMAM and DEA, in particular the A monomer is HEMA and the P monomer is HPMA, and the second block is polyNIPAAM.

3. 3. The block copolymer according to claim 1 or 2, wherein the number of A monomers in the first block is from 20 to 600, preferably from 30 to 200, more preferably from 60 to 120 or from 70 to 100, and the number of P monomers in the first block is 0 or anywhere between 0 and 500, preferably from 1 or 2 to 100, more preferably from 3 to 30, more preferably more than 0 and not more than 10.

4. 4. The block copolymer according to any one of claims 1 to 3, wherein the number of N monomers present as the second block is from 1 to 800, preferably from 3 to 600, more preferably from 5 to 400.

5. 4. The block copolymer according to claim 1, wherein the second block is grafted to the first block, and the total number of N monomers grafted to the first block is 3 to 500, preferably 5 to 200, more preferably 5 to 50.

6. 4. The block copolymer according to claim 1, wherein the second block is present as an extension to the first block and the number of N monomers in the second block is from 1 to 800, preferably from 20 to 600, more preferably from 50 to 400.

7. 7. The block copolymer according to claim 1, wherein the first block comprises A monomers and P monomers, and the ratio of total A:total P:total N is 30-500:(0 or 1)-200:100-600 on a molar basis.

8. 8. The block copolymer of claim 1, wherein the first block comprises A and P monomers, and A is 70 to 99.9% of the first block on a molar basis.

9. 9. The block copolymer of claim 1, wherein the P monomer has an XLogP3 value that is at least 0.10 higher than the A monomer.

10. 10. The block copolymer of claim 1, wherein the ratio of the first block monomer to the second block monomer is from 1:0.1 to 1:8 mol / mol.

11. 11. The block copolymer of claim 1, wherein the second block is pendant from the first block.

12. 11. The block copolymer of claim 1, wherein the second block is an extension of the first block.

13. 13. The block copolymer according to claim 1, wherein the first block is an (AP) block containing both A and P, and is an (A-b-P) block, a (P-b-A) block, or an (A-co-P) block, and the copolymer is an (AP)-b-N or (AP)-g-N.

14. 14. The block copolymer of any one of claims 1 to 13, wherein the block copolymer is either in a linear format comprising a single first block, two identical first blocks covalently bonded in a linear inverted arrangement around a central hub, or in a star format comprising m identical first blocks individually covalently bonded to a central hub, where m is an integer from 3 to 10.

15. Formula I: 【Chemical 1】 [In the formula, * represents the site of attachment to the polymerization initiator residue; A is selected from the group consisting of acrylates, methacrylates, acrylamides, and methacrylamides; P is selected from the group consisting of acrylates, methacrylates, acrylamides, and methacrylamides, and P is more hydrophobic than A as measured by XLogP3; N is a monomer that forms a thermoresponsive block, and N ｑ and N ｒ is a terminal thermoresponsive block selected from the group consisting of poly(N-isopropylacrylamide) (NIPAAM), poly(N-isopropylmethacrylamide) (NIPMAM), poly(N,N-diethylacrylamide) (DEA), poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA), poly(PEG methacrylate) (PEGMA), poly(N-vinylcaprolactam), poly(2-isopropyl-2-oxazoline), poly(vinyl methyl ether), poly(l-lactic acid)-poly(ethylene glycol)-poly(l-lactic acid) (PLLA-PEG-PLLA), hydroxypropyl cellulose, and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), preferably poly(N-isopropylacrylamide) or poly(N,N-diethylacrylamide); where: the sum of x and x′ is the number of A monomers in the block and is an integer from 20 to 600, preferably from 30 to 200, even more preferably from 60 to 120, or from 70 to 100; the sum of y and y' is the number of P monomers in the block, and y and y' are both 0 when P is not present, and when P is present, (y+y') is either 0 or an integer from 1 to 500, preferably from 2 to 100, more preferably from 3 to 30; the sum of x' and y' is the total number of grafts of the AP block, and is either 0 or an integer from 2 to 500, preferably from 6 to 275, more preferably from 8 to 130; q is the number of N monomers in the extended block and is 0 or an integer from 1 to 800, preferably from 20 to 600, more preferably from 50 to 400; r is the number of N monomers in the pendant block and is 0 or an integer from 3 to 500, preferably from 5 to 200, more preferably from 5 to 50; q and r cannot both be zero simultaneously; if r>0, q is an integer less than or equal to 2×r, preferably less than or equal to r; m is an integer from 1 to 10, preferably from 1 to 6, more preferably from 1 to 4, even more preferably 1, 2 or 3; The round brackets represent integral blocks with hydrophobic / hydrophilic functional groups formed in the synthetic sequence, the square brackets surround the arms of the branched structure, and the order of A and P can be reversed when A-P is in the form of a block.

15. 15. The block copolymer of claim 14, wherein A is selected from the group consisting of 2-hydroxyethyl methacrylate (HEMA), N-(2-hydroxyethyl)acrylamide (HEA), 1,3-dihydroxypropyl methacrylate (1,3DHPMA), 2,3-dihydroxypropyl methacrylate (2,3DHPMA), glycerol monomethacrylate (GMA), and N-(2-hydroxyethyl)methacrylamide (HEMAm), preferably HEMA, 1,3DHPMA, 2,3DHPMA and GMA, preferably HEMA.

16. 16. The block copolymer of claim 14 or 15, wherein P is selected from the group consisting of 3-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 1-hydroxy-2-propanyl methacrylate, and 2-hydroxypropyl methacrylate, or a mixture of any two or more of the foregoing isomers (HPMA), N-(2-hydroxypropyl)methacrylamide (HPMAm), butyl methacrylate (BMA), and N-(3-hydroxypropyl)acrylamide (HPA).

17. 17. The block copolymer of any one of claims 14 to 16, wherein the N block is selected from the group consisting of poly(NIPAAM), polyNIPMAM and poly(DEA), preferably poly(NIPAAM) and polyNIPMAM.

18. 18. The block copolymer of any one of claims 14 to 17, wherein A is HEMA, P is HPMA, and N is NIPAAM, or A is selected from 1,3 DHPMA, 2,3 DHPMA, and GMA, P is BMA, and N is NIPAAM, or A is selected from 1,3 DHPMA, 2,3 DHPMA, and GMA, P is BMA, and N is NIPAAM.

19. 19. The block copolymer according to any one of claims 14 to 18, wherein (y+y')>0, the (AP) block is an (A-b-P) block, a (P-b-A) block or an (A-co-P) block, and the copolymer is an (AP)-b-N or (AP)-g-N.

20. *[(HEMA ４０－１２０ )-'-(NAAM １０－５０ ) ５－５０ ] ２ *[(HEMA ４０－１２０ )-A-NAAM １５０－４５０ ] ３ *[(HEMA ４０－１２０ )--N0AAM １０－５０ ) ５－５０ ] ３ *[(HEMA ４０－１２０ -HPMA １－５０ )-b-NIPAAM １５０－４５０ ] ２ *[(HEMA ４０－１２０ -HPMA １－５０ )-g-(NIPAAM １０－５０ ) ５－５０ ] ２ * [(HEMA ４０－１２０ -HPMA １－５０ )-b-NIPAAM １５０－４５０ ] ３ and *[(HEMA ４０－１２０ -HPMA １－５０ )-g-(NIPAAM １０－５０ ) ５－５０ ] ３ is selected from A block copolymer in which the values ​​for the number of HEMA, HPMA and NIPAAM monomers are integers.

21. *[(HEMA ４０－１２０ -HPMA------AAM １５０－４５０ ] ２ *[(HEMA ４０－１２０ -HPMA)-g-(NIPAAM １０－５０ ) ５－５０ ] ２ * [(HEMA ４０－１２０ -HPMA)-b-NIPAAM １５０－４５０ ] ３ and *[(HEMA ４０－１２０ -HPMA)-g-(NIPAAM １０－５０ ) ５－５０ ] ３ is selected from A block copolymer wherein the values ​​for the number of HEMA, HPMA and NIPAAM monomers are in the range including all decimal values ​​therebetween, and the number of HPMA monomers in the AP block is greater than 0 and less than or equal to 50.

22. --(HEMA ９０ -co-HPMA １０ )-g-(NIPAAM ２０ ) １０ --(HEMA ８０ -co-HPMA ２０ )-g-(NIPAAM ２０ ) １０ --((HEMA ４５ -co-HPMA ５ )-NIPAAM １００ ) ２ --((HEMA ４５ -co-HPMA ５ )-NIPAAM ２００ ) ２ --[(HEMA ９０ -b-HPMA １０ )-g-(NIPAAM ２０ ) １０ ] ３ I-[(HEMA ８０ -b-HPMA ２０ )-g-(NIPAAM ２０ ) １０ ] ３ and --((HEMA ４９．５ -co-HPMA ０．５ )-NIPAAM ２００ ) ２ A block copolymer selected from:

23. 1. A method for the preparation of a block copolymer, comprising: polymerizing A monomers, and optionally P monomers, to provide a first block, which is either an A block or an AP block, wherein the polymerization is initiated by a polymerization initiator I having m polymerization initiation sites; and reacting N monomers with the first block to provide a block copolymer comprising a first A block or AP block and a second N block; reacting A monomers in an I:A ratio of 1:(20-600) m, preferably 1:(30-200) m, more preferably 1:(60-120) m, even more preferably 1:(70-100) m mol / mol; P monomer, if present, is reacted in an I:P ratio of 1:(0-500) m, preferably 1:(2-100) m, more preferably 1:(3-30) m mol / mol; reacting N monomers in an I:N ratio of 1:(1-800) m, preferably 1:(3-600) m, more preferably 1:(5-400) m mol / mol; m is an integer from 1 to 10; where: the A monomer is selected from acrylates, methacrylates, acrylamides and methacrylamides, preferably the A monomer is selected from the group consisting of acrylate esters, methacrylate esters, N-substituted acrylamides and N-substituted methacrylamides; the P monomer is selected from the group consisting of acrylates, methacrylates, acrylamides and methacrylamides, preferably the P monomer is selected from the group consisting of acrylate esters, methacrylate esters, N-substituted acrylamides and N-substituted methacrylamides, and P is more hydrophobic than A; The method, wherein the N-monomer is selected from NIPAAM, NIPMAM, N,N-diethylacrylamide, 2-(dimethylamino)ethyl methacrylate (DMAEMA), N-vinylcaprolactam, 2-isopropyl-2-oxazoline, vinyl methyl ether, l-lactic acid-poly(ethylene glycol)-poly(l-lactic acid) (PLLA-PEG-PLLA), N-vinylcaprolactam, and 2-isopropyl-2-oxazoline, vinyl methyl ether, preferably (NIPAAM), NIPMAM, or N,N-diethylacrylamide (DEA), especially NIPAAM.

24. 1. A method for the preparation of a block copolymer, comprising: Polymerizing the A monomer or the A monomer and the P monomer to form a compound of formula 10 *-(A （ｘ＋ｘ’） -co-@ （ｙ＋ｙ’） ) Formula 10 forming a first block comprising A monomers of formula (I) and optionally P monomers; and (a) N ｑ Block, (A （ｘ＋ｘ’） -co-P （ｙ＋ｙ’） ) block to form a compound of general formula 11 *-(A) （ｘ＋ｘ’） -co-P （ｙ＋ｙ’） )-NL Formula 11 forming a polymer of or (b) at least one N ｒ The graft extends from the AP block to include at least one N ｒ forming a copolymer comprising the graft; 【Chemistry 2】 where * represents the residue of an optional initiator molecule configured to assist in the initiation of polymerization from m functional groups, and m is an integer from 1 to 10. A method comprising any one of the following:

25. 25. The method according to claim 23 or 24, wherein the polymerization is carried out by RAFT, ATRP or conventional free radical polymerization, preferably by ATRP.

26. 26. A block copolymer prepared by the method of any one of claims 23 to 25.

27. 27. A bulk polymer composition comprising the block copolymer of any one of claims 1 to 22 or 26.

28. 28. A dry composition comprising the block copolymer of any one of claims 1 to 22 or 26, or the bulk polymer composition of claim 27.

29. 30. The dry composition of claim 28, comprising less than 0.1% w / w water or other solvents.

30. 28. An aqueous composition comprising the block copolymer of any one of claims 1 to 22 or 26, or the bulk polymer composition of claim 27.

31. 31. The aqueous composition of claim 30, wherein the copolymer or bulk polymer composition is in a sol form at 25°C and in a gel form at 37°C.

32. 32. The composition of any one of claims 27 to 31, further comprising at least one imaging agent, at least one therapeutic or diagnostic radioisotope, and / or at least one chemotherapeutic agent.

33. 28. A composition comprising a block copolymer according to any one of claims 1 to 22 or 26, or a bulk polymer composition according to claim 27, and an iodinated contrast agent, wherein the ratio of contrast agent to copolymer or polymer composition is between 0.1 and 110, preferably 1-10, more preferably 1.5-5, on a weight to weight basis.

34. 26. A composition comprising the block copolymer of any one of claims 1 to 20 or 24, or the bulk polymer composition of claim 25, and ethiosoybean poppy oil.

35. 35. The composition of claim 34 in the form of an oil-in-water emulsion.

36. 35. The composition of claim 34, wherein the block copolymer or bulk polymer composition is in particulate form.

37. 37. An embolic agent comprising a block copolymer according to any one of claims 1 to 22 or 26, or a bulk polymer composition according to claim 27, or a composition according to any one of claims 27 to 36.

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