Polymer

Abstract

The present invention provides temperature sensitive copolymers useful, inter alia, in medical procedures, including therapeutic embolism, compositions comprising the polymers, and methods for their preparation. The block copolymer comprises a first block containing a monomer A and an optional monomer P and a second block composed of a monomer N; wherein the hydrophobicity of the monomer P is greater than that of the monomer A; and wherein the second block is a thermally responsive block.

Description

Technical Field

[0001] The present invention relates to novel block copolymers and their use, in particular in medical applications such as embolization therapy, drug delivery and other interventions such as medical and surgical interventions. Background Art

[0002] Embolic materials are widely used in interventional radiology of blood vessels. These materials are typically introduced into blood vessels to block or reduce blood flow, to cause tissue necrosis or to prevent blood loss. They are commonly used to treat neurological or peripheral vascular diseases such as aneurysms, arteriovenous malformations and fistulas, uterine fibroids, hyper-vascular tumours and to prevent bleeding from trauma.

[0003] In one approach, the embolizing agent is a liquid-based material that polymerizes, solidifies or undergoes a phase change in the target blood vessel to form an occlusion. Early versions of embolizing agents included solutions of polymers (such as ethylene-vinyl alcohol) in solvents (such as DMSO), which dissipated in the bloodstream causing polymer deposition and occlusion of the blood vessel. Intravascular delivery of the solvent (such as DMSO) is problematic and can cause vascular endothelial damage, vasospasm and pain.

[0004] Recently, aqueous embolizing agents have been developed. In one approach, these aqueous embolizing agents utilize the properties of temperature-sensitive polymers that undergo a phase change from a soluble hydrated state to an insoluble dehydrated state when the temperature is above their lower critical solution temperature (LCST). The available polymers have an LCST below 37°C and remain in their soluble state in vitro, while becoming insoluble rapidly upon exposure to body tissue at 37°C. This makes delivery of such polymers through fine catheters and needles difficult because the low cross-sectional area of these devices means that the polymer may reach its LCST within the tube, thus becoming a hydrogel and hindering delivery.

[0005] NIPAAM-HEMA copolymers have been developed as embolization agents; these polymers are hydrogels above their LCST, but in these physical hydrogel systems, high ratios of NIPAAM to HEMA exhibit low-frequency strength loss due to viscoelasticity. To improve gel strength, high concentrations of polymers are used, which in turn often lead to catheter blockage due to low LCST and low elasticity. To overcome the deliverability problem, the polymers are used at low concentrations, however this results in weak and soft gels that rupture under high shear forces when used in large blood vessels, may "creep" or migrate distally, and tend to embolize distal to their delivery point. Additionally, gel fragmentation can lead to off-target embolization, which is dangerous to the patient. Thus, effective proximal embolization in relatively large blood vessels is challenging for these physical hydrogels. Further, a characteristic of some of these responsive polymers is that they tend to exhibit shrinkage of the polymer and concomitant with moisture in the gel after phase transition, and shrinkage that can cause embolus flow.

[0006] There is a desire to develop an aqueous liquid embolization agent that is easily formulated at low temperature (about 20 °C), that in situ exhibits good gel strength, can be delivered through a catheter without catheter blockage, and rapidly assumes a firm gel form upon contact with blood or other tissue without fragmentation or shrinkage. It is also desired to be able to easily observe these polymers in vivo via various routes and use the gel form for drug delivery when needed.

[0007] The polymers, compositions, and other aspects of the present invention described herein solve one or more of the problems pointed out above. SUMMARY OF THE INVENTION

[0008] 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, wherein the second block is a thermoresponsive block. The first block may comprise both A monomers and P monomers, where the P monomers are more hydrophobic than the A monomers. When both A monomers and P monomers are present, the first block may be an A-P or P-A block copolymer (i.e., the first block is an AP or PA diblock copolymer) or it may be a statistical (i.e., mixed) copolymer of A and P (which is commonly referred to by the term A-co-P).

[0009] The polymer may comprise a first block comprising pendant second blocks or it may comprise a first block comprising an extension of the second block. When both A and P are present as a statistical copolymer in the first block, the second block pendant from both A monomers and P monomers. When A and P are present as a block copolymer, the second block may pendant from the A monomer, from the P monomer, or from both.

[0010] The polymer can be in a linear form or a star form. The linear form polymer either comprises a single first block or two identical or different first blocks covalently coupled in a linear reflective arrangement around a central node. The star polymer comprises m identical or different first blocks individually covalently coupled to the central node. Thus, for the linear polymer, m is 1 or 2, and for the star polymer, m is from 3 to 10, as further described below.

[0011] In a second aspect, the polymer comprises a polymerization initiator, the residue of which forms the node.

[0012] The definitions and preferences for A, P, N, x, x’, y, y’, r and q for the second embodiment as described below also apply to this first embodiment.

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

[0014]

[0015] wherein

[0016] * represents the site of attachment to the residue of the polymerization initiator;

[0017] A is a hydrophilic or hydrophobic monomer comprising at least one substituent selected from the group consisting of: -OH, -NH, -SH and –COOH;

[0018] P is a monomer that is more hydrophobic than A and optionally comprises at least one substituent selected from the group consisting of: -OH, -NH, -SH, -COOH, alkyl and aryl groups;

[0019] N is a monomer that forms a thermoresponsive block, and N q and N r are the terminal thermoresponsive blocks; the sum of x and x’ is the number of A monomers in one block and is an integer from 20 to 600, more preferably from 30 - 200, more preferably from 60 to 120, or from 70 to 100.

[0020] The sum of y and y’ is the number of P monomers in one block; when P is absent, both y and y’ are 0; when P is present, (y + y’) is at least 1, so (y + y’) is either 0 or an integer from 1 to 500, preferably from (0, 1 or 2) to 100, more preferably from 3 - 30;

[0021] The sum of x’ and y’ is the total number of grafts in the AP (first) block and is either 0 or an integer from 1 to 300, preferably from 6 to 275, more preferably from 8 to 130;

[0022] q is the number of N monomers in an extended block and is an integer of 0 or 1 - 800, preferably 20 - 600, more preferably 50 - 400;

[0023] r is the number of N monomers in a 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 0 at the same time;

[0024] If r > 0, then q is an integer not greater than 2*r, preferably not greater than r.

[0025] m is an integer of 1 to 10, preferably 1 to 6, more preferably 1 to 4; even more preferably 1, 2 or 3; parentheses indicate an overall block with hydrophobic / hydrophilic functions formed in the synthesis order; brackets enclose the arms of the branched structure; and when A - P is in the form of a block, the order of A and P can be reversed

[0026] In a preferred arrangement, the block copolymer may have a first block, which is a (AP) block containing both A and P and is a (A - b - P) block, (P - b - A) block or (A - co - P) block, and the copolymer is (AP) - b - N or (AP) - g - N.

[0027] In a further preferred arrangement, the block copolymer may have a first block, which is an (A) block consisting only of A monomers, and the copolymer is (A) - b - N or (A) - g - N.

[0028] The numbers given by x, x’, y, y’, r and q are the target numbers for synthesis. Those skilled in the art will realize that when m > 1, the synthesis of the polymer can be targeted, and the number of A, P and N monomers present in each arm may be different. For example, in the case where the total target units are A, P and N, these units are numbers that cannot be divided evenly by the number of arms m, so they are different in each arm. An example of this situation may be a polymer of the following formula being the target for synthesis:

[0029] N 100 -(A 49 -P1)-I-(A 50 )-N 100

[0030] In this case, the polymer can be (theoretically) represented as

[0031] I - [(A 49.5 -P 0.5 )-N 100 2

[0032] Among them, one arm of the polymer on average has 49.5 A units and 0.5 P units. Ignoring the polymerization initiator, it can be expressed as:

[0033] N 100 -(A 99 -P1)-N 100

[0034] For example, NIPAAM 100 -(HEMA 49 -HPMA1)-I-(HEMA 50 )-NIPAAM 100 can be the synthesis target, and the polymer can be (theoretically) expressed as

[0035] I-[(HEMA 49.5 -HPMA 0.5 )-NIPAAM 100 2

[0036] Or ignoring the polymerization initiator:

[0037] NIPAAM 100 -(HEMA 99 -HPMA1)-NIPAAM 100

[0038] Therefore, in some embodiments, the values of x, x’, y, y’, r, and q can be regarded as ranges rather than integers. Thus:

[0039] In some embodiments, the total number of x and x’ is in the range of 20 to 600, more preferably 30 - 200, even more preferably 60 to 120, or 70 to 100.

[0040] In some embodiments, the total number of y and y’ is in the following range: 0 to 500, preferably 0, 1 or 2 to 100, more preferably 3 - 30, or >0 and less than or equal to 10;

[0041] In some embodiments, the total number of x’ and y’ is in the range of (0 or 1) to 300, preferably (5 or 6) to 275, more preferably 8 to 130;

[0042] In some embodiments, q is in the range of 0 - 800, preferably 20 - 600, more preferably 50 - 400;

[0043] In some embodiments, r is in the range of 0 to 500, preferably 3 to 500, preferably 5 to 200, more preferably 5 to 50.

[0044] In some embodiments, r ranges from (0 or 1) to 100, preferably from 5 to 80, more preferably from 5 to 50.

[0045] In addition to the specific target copolymer, the bulk polymer composition may include one or more additional polymer products such as other polymers described in the present application, polymers with different molecular weights, and copolymers with alternative block patterns. The target polymer may have x, x’, y, y’, r, and / or q values that are integers, but the following target polymers may be used as described above, where the x, x’, y, y’, r, and / or q values are different on each arm. Additionally, the synthesis may target the x, x’, y, y’, r, and / or q values within the bulk polymer, and these values may be integers or any fractional value therebetween. Thus, those skilled in the art will recognize that the present application for a given value of x, x’, y, y’, r, and / or q associated with the bulk polymer can be considered to include the range of all fractional values between the limiting values.

[0046] The inventors have recognized that in the (A)N polymer, the hydrophobicity of the (A) block can be adjusted by introducing a second, more hydrophobic monomer (P) to increase the hydrophobicity of the block. Increasing the hydrophobicity of the block tends to improve gel hardness and reduce gel syneresis, and thus gels having both A and P (i.e., where (y + y’) > 0) are preferred. The A-P block may exist as a block copolymer having A-blocks and P-blocks or it may exist as a statistical copolymer of A and P. When the A-P block exists as a block copolymer having A-blocks and P-blocks, the blocks may be inverted to (P-A) blocks.

[0047] When both A and P are present, the N-block may exist as an extension of the A-P block or as a graft, or in some embodiments as both an extension and a graft. The graft may dangle from the A monomer, the P monomer, or preferably both. When the P monomer is absent, the N-block may exist as an extension of the A-block or as a graft, or in some embodiments as both an extension and a graft. Preferably the N-block is a graft. When the P monomer is present, the N-block may exist as an extension of the AP-block (i.e., the first block) or as a graft, or in some embodiments as both an extension and a graft.

[0048] Thus, in some embodiments, (y + y’) > 0, and the (AP) block is an (A-b-P) block, a (P-b-A) block, or an (A-co-P) block, and the copolymer is (AP)-b-N or (AP)-g-N.

[0049] Since N must always be present, r and q cannot both be 0.

[0050] Additional P monomers in the AP block make the current physical hydrogel more robust. The additional hydrophobic block is thermally insensitive, so that even at higher concentrations, catheter delivery becomes easier. The resulting gel has a high storage modulus and can withstand higher shear stresses from the blood flow, thus making these systems suitable for proximal delivery and safer to use. Contrary to some earlier polymers, there is no need to crosslink the polymers to adjust their properties.

[0051] Although the polymer contains either grafted N blocks or N-blocks present as an extension of the AP block, during the synthesis of the grafted polymer, it is possible that a small amount of N monomers couple to the AP block and extend the AP block. Thus, in some cases, when r > 0, q can be > 0 (and not 0). In these cases, it is expected that q will generally not be greater than 2*r, preferably not greater than r.

[0052] The sum of x and x' is the number of A monomers in one block (A or AP), which is an integer from 20 to 600, more preferably 30 - 200, even more preferably 60 to 120, or 70 to 100 in some embodiments.

[0053] The sum of y and y' is the number of P monomers in one block. When P is absent, both y and y' are 0 in some embodiments; when P is present, (y + y') is at least 1, so (y + y') is either 0 or an integer from 1 to 500, preferably (0, 1 or 2) to 100, more preferably 3 - 30.

[0054] The sum of x' and y' is the total number of grafts in the AP (first) block, which is either 0 or an integer from 1 to 300, preferably 6 to 275, more preferably 8 to 130.

[0055] q is the number of N monomers in the extended block, which is 0 or an integer from 1 - 800, preferably 20 - 600, more preferably 50 - 400 in some embodiments.

[0056] r is the number of N monomers in one pendant block and is 0 in some embodiments, or an integer from 3 to 500, preferably 5 to 200, more preferably 5 to 50; and q and r cannot both be 0 at the same time;

[0057] If r > 0, then q is an integer not greater than 2*r, preferably not greater than r.

[0058] m is an integer from 1 to 10; preferably 1 to 6; more preferably 1 to 4; even more preferably 1, 2 or 3;

[0059] x' is the number of grafts on the A monomer, which is 0 in some embodiments; or an integer from 1 to 400, preferably 5 to 200, more preferably 7 to 100.

[0060] y’ is the number of grafts attached to P. r In some embodiments, y’ is 0 (when r is 0); or is an integer from 1 to 100, preferably from 1 to 75, more preferably from 1 to 30.

[0061] In some embodiments, a relatively high ratio of A:P is preferred. Thus, in some embodiments, in addition to the above preferred cases, the following limiting conditions also apply: A is 70%-(98% or 99% or 99.9%) of the AP block, on a mol / mol basis, particularly 80-(95% or 99.9%), on a mol / mol basis.

[0062] When P is present, the ratio (x’+y’) / [(y+y’)+(x+x’)] is the ratio of the monomer with grafts to the total monomers in the (first) block; in some embodiments, this ratio is 0.0001:1; preferably 0.01:1; more preferably 0.1:1.

[0063] In some embodiments, and optionally in addition to the above preferred cases, the following limiting conditions also apply: the ratio of (A) or (AP) to N is 1:0.1 to 1:8; preferably 1:2 to 1:5, particularly 1:2 to 1:4, on a mol / mol basis.

[0064] In some embodiments, either the A monomer, or the A monomer and the P monomer, form the first block; the N monomer forms the second block.

[0065] In some embodiments; and optionally in addition to the above preferred cases, the following limiting conditions also apply, 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.

[0066] In some embodiments, when P is absent and when m = 1 or 2; A:N is between 0.2:1 and 2:1.

[0067] The polymers of the present invention can be linear or they can be star polymers. The present application considers a linear polymer according to formula I to be any polymer in which m is 1 or 2, regardless of the arrangement of the polymer arms on the initiator. The number of arms (m) can be from 1 to 10, preferably from 1 to 6, more preferably 1, 2 or 3. Thus, in a particularly preferred arrangement, the polymer can be of linear structure or three-arm structure. Most preferably, m is 2 or 3.

[0068] The polymerization initiator (I) can be any suitable initiator known to those skilled in the art and can be selected according to, for example, its ability to support the initiation of the selected number of chains. In particular, the initiators are those suitable for atom transfer radical polymerization (ATRP). For example, linear polymers require the initiator to support the initiation of one or two groups, and star polymers require the initiator to support the initiation of 3 or more groups. The polymer usually retains the residue of the initiator, which in some cases can be connected to the arms of a polymer having 2, 3, 4, 5, 6 or more arms. The residue of the initiator described in this application is represented by I and the functional group (usually a halide) is lost from the initiator.

[0069] Polymer initiators generally include alkyl bromides or alkyl chlorides, where the number of halides is from 1 to 10. Thus for linear polymers, where m is 1, I can be selected from: alkyl α-bromoisobutyrates, benzyl α-bromoisobutyrates, alkyl 2-bromopropionates, 1-phenylethyl bromide, p-toluenesulfonyl chloride, and 2-bromopropionitrile, where the alkyl is C1-C 18 alkyl, preferably C3-C 12 alkyl. When m is 2, the initiator can be selected from: diethyl meso-2,5-dibromoadipate, bis(ethylene glycol 2-bromoisobutyrate), bis[2-(2'-bromoisobutyryloxy)ethyl] sulfide, bis[2-(2-bromoisobutyryloxy)undecyl] sulfide, 2-[2-[2-(2-bromo-2-methylpropanoyl)oxyethoxy]ethoxy]ethyl 2-bromo-2-methylpropionate, 2-[2-(2-bromo-2-methylpropanoyl)oxyethoxy]ethyl 2-bromo-2-methylpropionate, and [2-(2-bromopropenoyloxy)-2-methylpropyl] 2-bromopropionate.

[0070] For star polymers, when m is 3, the initiator can be selected from: 1,1,1-tris(2-bromoisobutyryloxymethyl)ethane, glycerol tris(2-bromoisobutyrate), 1,2,3-propanetriyl tris(2-bromopropionate), 2,2’,2”-aminotris(2-methyl-2-bromoethyl propionate), and 3,4-bis[(2-bromoisobutyryl)oxy]butyl 2-bromo-2-methylpropionate. When m is 4, the initiator can be selected from: pentaerythritol tetrakis(2-bromoisobutyrate), 3,3,4-tris[(2-bromoisobutyryl)oxy]butyl 2-bromo-2-methylpropionate, and [2,4,5,5-tetrakis[(2-bromoisobutyryl)oxy]-6-methyloxiran-3-yl] 2-bromo-2-methylpropionate. When m is 5, the initiator can be selected from: methyl [3,4,5,6-tetrakis[(2-bromoisobutyryl)oxy]oxiran-2-yl] 2-bromo-2-methylpropionate and dipentaerythritol hexakis(2-bromoisobutyrate). When m is 6, the initiator can be, for example, 1-O,2-O,3-O,6-O-tetrakis(2-bromo-2-methylpropionyl)-4-O-[2-O,3-O,4-O,6-O-tetrakis(2-bromo-2-methylpropionyl)-β-D-galactopyranosyl]-α-D-glucopyranose.

[0071] Monomer A can be selected from hydrophilic monomers or hydrophobic monomers, and contains at least one substituent selected from the following: -OH, -NH, -SH, and -COOH. However, in practice, the substituents may exist in the form of protected functional groups during the polymerization step or as residues of functional groups when used to couple other groups (such as grafts or extended blocks). For example, during synthesis, -NH, -SH, and -COOH can be protected. Monomer A is preferably selected from: acrylates, methacrylates, acrylamides, and methacrylamides; more preferably, A is selected from: acrylates, methacrylates, N-substituted acrylamides, and N-substituted methacrylamides. In some embodiments, the acrylate and the methacrylate are independently esters of C1 to C6 alcohols having at least one unesterified hydroxyl group. In some embodiments, they can also be esters of polyethylene glycol having, for example, 1 to 6 ethylene glycol units, preferably 1 to 3 ethylene glycol units. In some embodiments, they can be esters of zwitterionic alcohols (such as 2-methacryloyloxyethyl phosphorylcholine, 2-(N-3-sulfopropyl-N,N-dimethylammonium)ethyl methacrylate, carboxybetaine methacrylate).

[0072] In some embodiments, the N-substituted acrylamides and N-substituted methacrylamides may be N-substituted via a C1 to C6 hydroxyalkane group having at least one hydroxy group. In some embodiments, they may be esters having a zwitterionic charged group, such as sodium 2-acrylamido-2-methyl-1-propanesulfonate (AMPS).

[0073] In non-limiting examples, the A monomer may be selected from:

[0074] Acrylates: 2-hydroxyethyl acrylate, 3-hydroxypropyl acrylate, 2-hydroxypropyl acrylate, and 2-hydroxyisopropyl acrylate.

[0075] Methacrylates: 2-hydroxypropyl methacrylate, 1-hydroxy-2-propyl methacrylate, 2-hydroxyisopropyl methacrylate, 2-hydroxy-2,2-dimethylethyl methacrylate, 1,3-dihydroxypropyl methacrylate (1,3DHPMA), 2,3-dihydroxypropyl methacrylate (2,3DHPMA) [a mixture of glycerol monomethacrylate (GMA), 1,3DHPMA, and 2,3DHPMA may be used], dihydroxyethyl methacrylate, hydroxyethyleneglycol methacrylate, diethyleneglycol monomethacrylate, 2-hydroxyethyl methacrylate, (1-fluoro-2-hydroxyethyl) 2-methylprop-2-enoate, 3-hydroxypropyl methacrylate, 3-(2-hydroxyethoxy)propyl 2-methylprop-2-enoate, triethyleneglycol monomethacrylate, 2,3-butanediol 2-methylacrylate, 2-(tert-butylamino)ethyl methacrylate, 2-aminoethyl methacrylate hydrochloride, 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl methacrylate, 2-methacryloyloxyethyl phosphorylcholine, 2-(N-3-sulfopropyl-N,N-dimethylammonium)ethyl methacrylate, carboxybetaine methacrylate ester, and 2-hydroxy-1-methylethyl methacrylate.

[0076] Acrylamides: N-(2-hydroxyethyl)acrylamide, N-(2-hydroxypropyl)acrylamide.

[0077] Methacrylamides: N-(2-hydroxypropyl)methacrylamide, N-(2-hydroxyethyl)methacrylamide, hydroxypropyl methacrylamide, N-(1-hydroxybutan-2-yl)-2-methylprop-2-enamide, dihydroxyethyl methacrylamide, 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 sodium 2-acrylamido-2-methyl-1-propanesulfonate.

[0078] The A monomer is preferably selected from: 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 g(GMA), dihydroxyethyl methacrylate, hydroxyethyl 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-methylacrylate, 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, dihydroxyethyl methacrylamide, sodium 2-acrylamido-2-methyl-1-propanesulfonate.

[0079] The A monomer is preferably selected from: 1,3DHPMA, 2,3DHPMA, GMA, HEMA, HEA, and HEMA m; particularly 1,3DHPMA, 2,3DHPMA, GMA, and HEMA, particularly HEMA.

[0080] Glycerol monomethacrylate (GMA) can replace 2,3HPMA and / or 1,3DHPA. GMA contains a mixture of 1,3DHPMA and 2,3DHPMA, but 2,3DHPMA usually accounts for about 90% of such a formulation.

[0081] The P monomer is selected to be more hydrophobic than the A monomer. The hydrophobicity of the monomer is conveniently calculated using the XLogP3 algorithm available at http: / / www.sioc-ccbg.ac.cn / skins / ccbgwebsite / software / xlogp3 / (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). In this context, "more hydrophobic than" means having an XLogP3 value that is at least 0.10 higher, preferably at least 0.2 higher, and more preferably at least 0.3 higher than that of the A monomer.

[0082] P is a monomer that is more hydrophobic than A and optionally contains at least one substituent selected from: -OH, -NH, -SH, -COOH, alkyl, and aryl groups. However, in practice, the -OH, -NH, -SH, -COOH groups may be in the form of protected functional groups during the polymerization step or as residues of said functional groups when used to couple other groups (such as grafts). For example, -NH, -SH, and -COOH can be protected during synthesis. In some embodiments, the monomer P is selected from: acrylates, methacrylates, acrylamides, and methacrylamides; preferably, P is selected from: acrylates, methacrylates, N-substituted acrylamides, and N-substituted methacrylamides.

[0083] Non-limiting examples of the P monomer include those selected from:

[0084] 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, 2-benzyloxyethyl methacrylate, 2-benzyloxyethyl acrylate, 2-methylhexyl acrylate, octadecyl acrylate, and 2-ethylhexyl acrylate.

[0085] 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-methylacrylate, 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, 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.

[0086] Acrylamides: 2-acrylamide, 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-(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.

[0087] Methacrylamide: 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.

[0088] In a preferred embodiment, the P monomer may be selected from: 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-methylacrylate, 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, 2-ethylhexyl methacrylate, 2-acrylamide, 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-(1,1-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.

[0089] 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, wherein any one of these isomers alone or as a mixture of two or more of the isomers is referred to as HPMA in the present application; N-(2-hydroxypropyl)methacrylamide (HPMAm) or N-(3-hydroxypropyl)acrylamide (HPA) and butyl methacrylate (BMA).

[0090] The monomer N forms a temperature-sensitive 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.

[0091] The N block may be selected from: 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).

[0092] 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.

[0093] In a preferred embodiment, A is selected from HEMA, HEA, 1,3 - DHPMA, 2,3 - DHPMA, GMA, and HEMA m, P is selected from HPMA, BMA, HPAm, and HPA, and N is selected from NIPMAM, DEA, and NIPAAM. In a preferred embodiment, A is HEMA, P is HPMA, and N is NIPAAM. In another embodiment, A is selected from 1,3 - DHPMA, 2,3 - DHPMA, and GMA; P is BMA, and N is NIPAAM. In another embodiment, A is selected from 1,3 - DHPMA, 2,3 - DHPMA, and GMA, P is BMA, and N is NIPMAM.

[0094] The block copolymer can have a first segment which is a (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 (AP) - b - N or (AP) - g - N.

[0095] The linking group between the N block and the AP block is typically an ester, amide, or ether linking group, depending on the monomers involved. In a preferred embodiment, it is an ester linking group.

[0096] In a preferred embodiment, the block copolymer comprises: a first block containing 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 thermoresponsive block; wherein the A monomers are selected from: acrylates, methacrylates, acrylamides, and methacrylamides; and the P monomers (when present) are selected from: acrylates, methacrylates, acrylamides, and methacrylamides.

[0097] 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).

[0098] 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 monomer may be pNIPAAM, pNIPMAM or pDEA.

[0099] Particularly, the A monomer is selected from: HEMA, HEA, HEMA m, 1,3HHPMA, 2,3DHPMA and GMA; and particularly 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); HPMA m, HPA and BMA; and the N monomer is selected from: NIPAAM, NIPMAM and DEA.

[0100] The polymer may comprise a first block containing a pendant second block or it may comprise a first block containing an extended portion of a second block.

[0101] In some embodiments, the ratio of [first block] (A) or (AP) monomer to [second block] (N) monomer is from 1:0.1 to 1:8, on a mol / mol basis. In some embodiments, the ratio of the monomer with a graft to the total monomers in the (first) block is 0.0001:1; in some embodiments, the ratio of total A:total P:total N is 30 - 500:(0 or 1) - 200:100 - 600; in some embodiments, in the AP block, A is 70% to 98%, 70% - 99% or 70% to 99.9% of the AP block, on a mol / mol basis.

[0102] Particularly, the ratio of [first block] (A) or (AP) to [second block] (N) is from 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.

[0103] In some embodiments, the P monomer has an XLogP3 value that is at least 0.10 higher than that of the A monomer.

[0104] In any of the above embodiments, the polymer may be in the linear form or star form as described above.

[0105] In the bulk polymer containing the polymer of this embodiment, x, x', y, y', r, and q can be regarded as the ranges described above.

[0106] Other features of this preferred embodiment are described elsewhere in this application.

[0107] In a further preferred embodiment, the polymer is a linear polymer in the form of (a): according to Formula 2, where m is 1 or 2, particularly 2.

[0108] *-[A (x) -co-(A-g-N r ) x ’] m

[0109] Formula 2

[0110] where

[0111] (x) is from 1 to 800, preferably from 50 to 500, more preferably from 60 to 400;

[0112] x' is from 0 to 400, preferably from 1 to 200, more preferably from 5 to 100;

[0113] r is from 1 to 500, preferably from 5 to 200, more preferably from 10 to 100.

[0114] In one embodiment, the polymer is a linear polymer in the form of (b), according to Formula 3, where m is 1 or 2, particularly 2;

[0115] *-[(A (x) -b-N q )] m

[0116] Formula 3

[0117] where

[0118] (x) is from 1 to 800, preferably from 50 to 500, more preferably from 60 to 400; and

[0119] q is from 1 to 800, preferably from 50 to 500.

[0120] In one embodiment, the polymer is a linear polymer in the form of (c): according to Formula 4, where m is 1 or 2, preferably 2;

[0121] *-[(A (x) -co-(A-g-N r ) x ’)-(P (y) -co-(P-g-N r ) y’)]m

[0122] Formula 4

[0123] In one embodiment according to Formula 4

[0124] (x + x') is preferably from 60 to 120; or from 70 to 100;

[0125] (y + y') is from 1 to 100 or 2 - 100; more preferably from 1 to 30, 2 - 30 or 3 - 30;

[0126] (x' + y') is from 1 to 50, preferably from 2 to 30, more preferably from 5 to 20

[0127] r is from 1 to 500, preferably from 10 to 200.

[0128] In a further embodiment of (c), (y + y') is > 0 and <= 100, preferably <= 50, more preferably <= 30.

[0129] In one embodiment, the polymer is a linear polymer in the form of (d): according to Formula 5 and wherein m is 1 or 2, especially 2.

[0130] *-[(A (x) -P (y) )-b-(N q )] m

[0131] Formula 5

[0132] Wherein:

[0133] (x) is from 1 - 400, preferably from 20 - 200;

[0134] (y) is from 1 - 400, preferably from 2 - 100;

[0135] q is from 1 to 800, preferably from 50 to 400; and

[0136] m is 2.

[0137] In a further embodiment of (d), (y) is > 0 and <= 400, preferably <= 100, more preferably <= 50, especially less than or equal to 10.

[0138] In one embodiment, the polymer is a star polymer in the form of (e): according to Formula 6; wherein m is 3, 4, 5 or 6, especially 3 or 4, more especially 3.

[0139] *-[A (x) -co-(A-g-N r ) x ’]m

[0140] Formula 6

[0141] (x + x') is from 1 to 800, preferably from 50 to 500, more preferably from 60 to 300;

[0142] x' is from 1 to 400, preferably from 1 to 200, more preferably from 5 to 100; and

[0143] r is from 1 to 500, preferably from 5 to 200, more preferably from 10 to 100.

[0144] In one embodiment, the polymer is a star polymer in the form of (f): according to Formula 7, where m is 3, 4, 5 or 6, particularly 3 or 4, more particularly 3

[0145] *[(A (x) ) - N q m

[0146] Formula 7

[0147] Wherein:

[0148] (x) is from 1 to 400, preferably from 20 to 200; and

[0149] q is from 1 to 800, preferably from 50 to 500.

[0150] In one embodiment, the polymer is a star polymer in the form of (g): according to Formula 8, where m is 3, 4, 5 or 6, particularly 3 or 4, more particularly 3.

[0151] I - [(A x - co - (A - g - N r ) x ') - (P y - co - (P - g - N r ) y ')] m

[0152] Formula 8

[0153] In one embodiment

[0154] (x + x') is preferably from 60 to 120; or from 70 to 100;

[0155] (y + y') is from (1 or 2) to 100, more preferably from 3 to 30;

[0156] (x' + y') is from (1 or 2) to 50, preferably from 2 to 30, more preferably from 5 to 20 r is from 1 to 500, preferably from 10 to 200. ​

[0157] In a further embodiment of (g), (y + y') is > 0 and <= 100, preferably <= 50, more preferably <= 30.

[0158] In one embodiment, the polymer is a star polymer in the form of (h): *[(A x -A x’ -P y -P y’ )-N q m , where N q is an extension of the (A - P) block; where m is 3, 4, 5 or 6, especially 3 or 4, more especially 3; and according to formula 9, A and P do not carry grafts (r = 0).

[0159] *[(A (x) -P (y) )-b-N q m

[0160] Formula 9

[0161] where:

[0162] (x) is 1 - 400, preferably 40 - 200;

[0163] (y) is 1 - 400, preferably (1 or 5) - 100

[0164] q is 1 to 800, preferably 50 to 500

[0165] In a further embodiment of (h), (y) is > 0 and <= 400, preferably <= 100, more preferably <= 50, even more preferably less than or equal to 10.

[0166] In any one of (a) to (f), when both A and P are present, the A - P block can be in the form of separate A and P blocks (which can be reversed) or can be in the form of a statistical copolymer. A and P can be reversed to (P - A).

[0167] Forms (c), (d), (g) and (h) are preferred.

[0168] In a preferred embodiment, A is selected from HEMA, HEA and HEMA m; P is selected from HPMA, HPAm and HPA; and N is selected from DEA and NIPAAM. In a preferred embodiment, A is HEMA, P is HPMA and N is NIPAAM.

[0169] Particularly preferred polymers include linear polymers having the following formula:

[0170] ​​*[(HEMA 40-120 )-g-(NIPAAM 10-50 ) 5-50 2

[0171] *[(HEMA 40-120 -HPMA 5-50 )-b-NIPAAM 150-450 2

[0172] *[(HEMA 40-120 -HPMA 1-50 )-b-NIPAAM 150-450 2

[0173] *[(HEMA 40-120 -HPMA 5-50 )-g-(NIPAAM 10-50 ) 5-50 2;

[0174] *[(HEMA 40-120 -HPMA 1-50 )-g-(NIPAAM 10-50 ) 5-50 2

[0175] and

[0176] star polymers of the following formula:

[0177] *[(HEMA 40-120 )-b-NIPAAM 150-450 3

[0178] *[(HEMA 40-120 )-g-NIPAAM 10-50 ) 5-50 3

[0179] *[(HEMA 40-120 -HPMA 5-50 )-b-NIPAAM 150-450 3

[0180] *[(HEMA 40-120 -HPMA 1-50 )-b-NIPAAM 150-450 3

[0181] *[(HEMA 40-120 -HPMA 5-50 )-g-(NIPAAM 10-50 ) 5-50 3; and

[0182] *[(HEMA 40-120 -HPMA1-50 )-g-(NIPAAM 10-50 ) 5-50 3

[0183] Further particularly preferred polymers include:

[0184] *[(HEMA 40-120 -HPMA)-b-NIPAAM 150-450 2

[0185] *[(HEMA 40-120 -HPMA)-g-(NIPAAM 10-50 ) 5-50 2

[0186] *[(HEMA 40-120 -HPMA)-b-NIPAAM 150-450 3; and

[0187] *[(HEMA 40-120 -HPMA)-g-(NIPAAM 10-50 ) 5-50 3

[0188] wherein the values of the number of HEMA, HPMA and NIPAAM monomers are in the range of all fractional values included therein; and wherein the number of HPMA monomers in the AP block is >0 and <=50.

[0189] Particularly preferred polymers further include:

[0190] I-(HEMA 90 -co-HPMA 10 )-g-(NIPAAM 20 ) 10

[0191] I-(HEMA 80 -co-HPMA 20 )-g-(NIPAAM 20 ) 10

[0192] I-((HEMA 45 -co-HPMA5)-NIPAAM 100 )2

[0193] I-((HEMA 45 -co-HPMA5)-NIPAAM 200 )2

[0194] I-[HEMA 100 -g-(NIPAAM 20 )10 3

[0195] I-[(HEMA 90 -b-HPMA 10 )-g-(NIPAAM 20 ) 10 3

[0196] I-[(HEMA 80 -b-HPMA 20 )-g-(NIPAAM 20 ) 10 3

[0197] I-((HEMA 49.5 -co-HPMA 0.5 )-NIPAAM 200 )2

[0198] In a further aspect, the present invention also provides a composition comprising a polymer as described in the present application. The composition includes, for example, a bulk polymer composition comprising a polymer as described in the present application. The bulk composition retains the desired properties but may include one or more additional polymer products in addition to the specific target copolymer, such as other polymers described in the present application, polymers having different molecular weights, and copolymers having an alternating block pattern, etc. In some embodiments, the bulk composition may comprise at least 30%, 40%, 50%, 60%, 70%, 80% or 90% by weight of the target polymer. The bulk composition is a further embodiment of the present invention.

[0199] Typically, such copolymers or compositions are in a pharmaceutically acceptable form and may be, for example, sterile and / or pyrogen-free.

[0200] In one embodiment, the composition is an aqueous composition comprising a copolymer or polymer composition as described in the present application. In the composition, the polymer of the present invention may be in the sol form (e.g., solutes or micelles) at a temperature of 25 °C. This can result in improved processability because polymers in the gel form (e.g., hydrogel form) are less likely to be easily delivered at this temperature. The composition is in the gel form (usually as a hydrogel) at 37 °C. A hydrogel is a water-swellable but water-insoluble polymer. The combination of these features provides a composition that is easily deliverable (e.g., by spraying or by syringe or catheter) at room temperature or near room temperature, which may be 20 °C, but may fluctuate up and down from time to time in actual applications. The polymer or bulk polymer is present in the aqueous composition at at least 1% w / w, preferably at least 5% w / w, more preferably at least 10% w / w. The polymer may be present at up to 30% w / w, up to 50% w / w or up to 90% w / w.

[0201] In addition to the water-removing composition, the present invention also provides a dry composition comprising the copolymer or polymer of the present application, and the dry composition means a composition comprising less than 0.1% water or other solvents w / w, preferably less than 0.01% water or other solvents w / w. This can be achieved by, for example, oven drying, spray drying or freeze drying.

[0202] The composition can be admixed with an anti-caking agent or a dissolution enhancer, 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, bile acid, cholesterol, polysorbate, sorbitan monolaurate, 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 its sodium salt, alginate, sodium dodecyl sulfate, sodium lauryl sulfate, ammonium lauryl sulfate, docusate, and triton X-100.

[0203] In some cases, a contrast agent can be included in the formulation (or composition), such as iohexol, iopamidol, ioxilan, iopromide, iodixanol, iobitridol, ioflurane, diatrizoate, metrizoic acid, iotalamic acid, and ioxaglic acid. These can also improve the solubilization of the polymer below its LCST in a more detailed manner described below.

[0204] The composition can also include various additional components, including pharmaceutically acceptable excipients, such as small molecules or polymers, including ethanol, glycerol, DMSO, N-methylpyrrolidone, dimethylformamide, diethylformamide, glucose, lactose, mannitol, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), poly(2-acrylamido-2-methylpropanesulfonic acid) and its salts (such as sodium salt), polyacrylic acid or its salts (such as sodium salt), polymethacrylic acid or its salts (such as sodium salt), microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, magnesium stearate, polysorbate, poloxamer, sodium lauryl sulfate, hydroxypropylmethylcellulose acetate succinate, alginate, collagen, fibrin, chitosan, gelatin, hyaluronic acid, and cyclodextrin, etc.

[0205] The composition may comprise at least one contrast agent for X-ray fluorescence, CT / microCT, magnetic resonance imaging (MRI) or ultrasound imaging, and / or at least one therapeutic or diagnostic radioisotope.

[0206] Examples of contrast agents for X-ray imaging (X-ray fluorescence 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. These particles are spherical or irregular in shape.

[0207] Contrast agents also include radiopaque or iodine contrast agents, which may be ionic or non-ionic (preferably non-ionic) and include iodinated compounds such as iohexol, iodixanol, iopamidol, iopromide, ioxilan, iopamidol and those mentioned elsewhere in this application, or iodinated oil such as ethiodized poppyseed oil (e.g., Lipiodol TM )

[0208] MRI contrast agents include gadolinium ion-containing agents, superparamagnetic iron oxides, ionic platinum particles and manganese (II) chelators.

[0209] Contrast agents for enhancing ultrasound imaging include but are not limited to sulfur hexafluoride microbubbles (SonoVue / Lumason TM ), octafluoropropane (Optison TM ), octafluoropropane lipid microspheres, CO2, air, especially air with a lipid / galactose shell, perfluoroalkane lipid microspheres (Imagent / Imavist TM ) and perfluorobutane (Sonazoid TM )

[0210] The composition may include at least one therapeutic or diagnostic radioisotope. Imaging or diagnostic isotopes 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) labeled with 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 complexes.

[0211] In some embodiments, chemotherapeutic agents can be incorporated into the composition. These agents can be selected as needed, but in one approach, the composition can be used in interventional oncology applications, particularly as a liquid chemoembolization agent. These compositions comprise the polymer and a pharmaceutically active substance. In such cases, pharmaceutically active substances that can be used include anthracyclines such as doxorubicin, daunorubicin, epirubicin, and idarubicin; camptothecins such as irinotecan, topotecan, and exatecan; platinum-based agents such as cisplatin, oxaliplatin, carboplatin, and miriplatin; mitomycin C, nucleotide analogs such as 5-fluorouracil, cytarabine, fludarabine, and gemcitabine; multi-tyrosine kinase inhibitors such as sorafenib, sunitinib, regorafenib, brivinb, dasetanib, bosutinib, erlotinib, gefitinib, imatinib, and vandetinib, rapamycin; and bioactive substances such as nivolumab (Opdivo), pembrolizumab (Keytruda), ipilimumab, atezolizumab, avelumab, durvalumab, cemiplimab, dostarlimab, relatlimab, spartalizumab, aldesleukin, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon α-2a, interferon α-2b (Intron ), polyethylene glycol interferon α-2b imiquimod, olaparib, poly ICLC pexidartinib; or any combination thereof.

[0212] In certain non-limiting examples, the copolymers and compositions of the present invention can be used for treating aneurysms; arteriovenous malformations, fistulas, highly vascular tumors, polyps, urinary and fecal incontinence, traumatic bleeding, tissue separation, tissue expansion, and wound healing management including closure, wound care, and wound dressings (e.g., in burns), and protecting surface tissues such as damaged skin from environmental effects, as dissecting agents, adhesives, tissue fillers, and cavity fillers (e.g., for filling the left atrial appendage).

[0213] The composition is suitable for embolization proximal or distal in a vascular environment. The present invention also relates to the use of the composition as a drug delivery depot.

[0214] In some methods, the compositions described in the present application can be used to provide controlled release formulations of, for example, chemotherapeutic drugs. In one method, this can be achieved by incorporating charged monomers (such as AMPS) into the polymer such that the release of the drug is retarded by ionic interactions.

[0215] In some embodiments, the compositions are provided in a sterile form. This can be achieved, as needed, by, for example, heat or radiation sterilization, or by reconstituting a sterile dry composition with a sterile aqueous solution.

[0216] Another aspect of the invention provides a method of medical treatment using the polymers described in the present application.

[0217] The polymers and compositions of the invention can be used as embolizing agents. Thus, another embodiment provides a method for embolizing blood vessels in a patient in need thereof, which comprises delivering into the vascular lumen a composition comprising a polymer or polymer composition as described in the present application. In one method, the composition is an aqueous composition comprising a polymer (copolymer or bulk polymer) described in the present application, which can be in the form of a solution or a micellar suspension and the temperature of the composition is increased to a point above its LCST, for example, to increase the viscosity of the composition and thereby embolize the blood vessels. In another method, the aqueous composition is in the form of an oily emulsion described elsewhere in the present application or in the form of a suspension of a polymer or polymer composition in lipiodol as described elsewhere in the present application.

[0218] In some embodiments, the polymer forms a hydrogel above its LCST. In some embodiments, the hydrogel forms linear or spherical deposits.

[0219] In some embodiments, the method is used to treat highly vascular tumors, such as hepatocellular carcinoma (HCC), colorectal cancer or its metastases, neuroblastoma, and neuroendocrine tumors; aneurysms, arteriovenous malformations and fistulas, uterine fibroids, etc.

[0220] In some embodiments, the method is used to treat benign prostatic hyperplasia by embolizing the prostatic blood vessels, particularly the prostatic artery or the resulting blood vessels.

[0221] In some embodiments, the method is used to treat osteoarthritis by embolizing the blood vessels of major joints (including the knee joint), particularly the knee artery or the resulting blood vessels.

[0222] The polymers and compositions of the present invention can be used as tissue separating agents. Thus, in another embodiment, the present invention provides a method for separating a first tissue from a second tissue, which comprises delivering a volume of an aqueous composition to a location between the first and second tissues, the aqueous composition comprising a polymer (copolymer or homopolymer) as described herein in the form of a solution or micellar suspension, thereby at least partially separating the first tissue from the second tissue, and raising the temperature of the composition to a temperature above its LCST such that the viscosity of the composition is increased and thereby the polymer is stabilized in place.

[0223] The polymers and compositions can be delivered using needles, catheters, or other tubular devices. In one method, the technique can be used to separate a first tissue from a second tissue. In one example, a first tissue designated for radiotherapy can be separated from a second tissue to protect the second tissue from the radiotherapy, thereby reducing the level of radiation to which the second tissue is exposed. In a particular method, the technique can be used to separate rectal tissue from prostate tissue designated for radiotherapy and thereby reduce the radiation dose to which the rectal tissue (e.g., rectal epithelium) is exposed.

[0224] In another method, the polymers and compositions can 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 catheter or other endoscopic device.

[0225] The polymers and compositions of the present invention can be used as tissue expanders or bulking agents. Thus, in a further embodiment, the present invention provides a method for tissue bulking or expansion, which comprises delivering a volume of an aqueous composition to an internal location of the tissue, the aqueous composition comprising a polymer as described herein in the form of a solution or micellar suspension, and raising the temperature of the composition to a temperature above its LCST, for example to increase the viscosity of the composition and thereby stabilize the polymer in place.

[0226] The polymer can be delivered using needles, catheters, or other tubular devices. In one method, the technique can be used to fill the tissue opposite a polyp. The method can lift the polyp above the tissue, making it easier to excise. The technique can also be used to treat urinary and fecal incontinence by delivering a volume of the polymer solution to the sphincter area or the area behind the sphincter to improve sphincter closure.

[0227] As detailed above, the polymers described in the present application can be combined with contrast agents. In one embodiment, the contrast agents include a group of iodine contrast agents. These are generally polyhydroxylated compounds and polyiodinated compounds. The contrast agents include ionic contrast agents and non-ionic contrast agents. Non-ionic contrast agents are preferred. The contrast agents include iohexol, iopamidol, ioxilan, iopromide, iodixanol, iobitridol, ioflupane, diatrizoate, metrizoic acid, iotalamic acid, and ioxaglic acid.

[0228] The inventors have determined that temperature-sensitive polymers (such as those disclosed in the present application) do not form micelles, but dissolve in an aqueous composition containing a contrast agent at temperatures below their LCST (such as 25 °C). This provides a molecular solution of the polymer. These solutions have greatly reduced turbidity, are substantially clear, do not tend to form hydrogels during delivery, and have a lower viscosity at room temperature (20 °C) than in the micellar form, and are thus easier to deliver. In addition, since they have a lower viscosity for a given polymer concentration, higher concentrations of the polymer can be used without clogging the catheter, resulting in a stronger gel. These compositions can still rapidly turn into hydrogels at 37 °C. Without wishing to be bound by any theory, it is believed that the iodine contrast agent acts as a co-solvent for the polymer. This effect can cause the micelles present at lower temperatures (below the LCST) to dissolve or not form.

[0229] Accordingly, another embodiment of the present invention provides a composition comprising (i) a temperature-sensitive polymer; preferably those having an LCST of 25 to 37 °C; and (ii) an iodine contrast agent.

[0230] The polymer can be an aqueous composition or a dry composition. The composition preferably contains 1 part by weight of the polymer and at least 1 part by weight of the 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 the contrast agent.

[0231] The aqueous composition can be at least 5% w / w of the polymer, more preferably at least 7% w / w, at least 10% w / w, at least 15%, at least 20% or higher. The composition can be at most 30%, at most 50% or at most 80% or at most 90% w / w of the polymer.

[0232] In some embodiments, the ratio of the contrast agent to the copolymer or bulk polymer composition is from 0.1 to 10, preferably from 1 to 10, more preferably from 1.5 to 5, by weight to weight.

[0233] At temperatures below the LCST, such as at 25 °C, the polymer is soluble (or substantially soluble) 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 (such as at 25 °C).

[0234] In a further embodiment, the present invention provides a method of preparing an aqueous composition comprising a polymer as described in the present application, the method comprising 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.

[0235] The aqueous medium may be, for example, sterile water or saline. The composition may be resuspended, for example, below 25 °C or below 10 °C. In one embodiment, the dry composition comprises an iodine contrast agent. Reconstitution may comprise preparing a micellar suspension of the polymer, but more preferably, the dry composition comprises an iodine 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.

[0236] Iodized oil such as ethylioidosat (e.g., Lipiodol TM ) is used in the form of an oily emulsion comprising an oil phase and an aqueous phase to provide an embolization composition for treating (in particular) highly vascular tumors such as hepatocellular carcinoma. The emulsion may be used without further formulation, but may comprise one or more pharmaceutically active substances, particularly anticancer agents (such as doxorubicin, irinotecan or platinum drugs), which are used in the chemoembolization process. Although these methods have been used for many years, there are still a number of disadvantages in using these emulsions. A particular problem is that the emulsion is only stable for a short period of time before it begins to separate into an oil phase and an aqueous phase. This means that the emulsion cannot be prepared in advance and must be prepared on-site (in theatre) just prior to use. In addition, the lack of long-term stability of the emulsion can lead to rapid in situ dissipation of the emulsion, such that the embolization effect is only temporary. In chemoembolization, the dissipation of the emulsion can also lead to a burst release of the active ingredient into the bloodstream, which increases off-target exposure to the active ingredient. The inventors have determined that oily compositions, particularly emulsion compositions comprising the polymers and polymer compositions of the present invention (such as bulk polymer compositions), have greatly improved stability, and thus further embodiments of the present invention provide compositions comprising a polymer or polymer composition as described in the present application and iodized oil. In particular, the iodized oil is ethylioidosat. Examples of the oil may be available under the trade name (Guerbet, Paris, France) or VividolTM (Purchased from Vivere imaging, Hyderabad, India.)

[0237] In one method, the composition is in the form of an emulsion comprising an aqueous phase and an oil phase, wherein the aqueous phase comprises an aqueous composition comprising a copolymer or a bulk polymer as described in the present application. The composition may also be in the form of a separated oil phase and an aqueous phase of an emulsion in the same container, for example to provide a "ready-to-prepare" emulsion. In other words, the components of the emulsion exist as one liquid volume, where the complete oil phase and the aqueous phase are separated, and typically the aqueous phase floats on top of the oil phase (iodized oil has a density of 1.28 g / cm at 20 °C).

[0238] The ratio of the oil phase to the aqueous phase can be selected to allow the preparation of a water-in-oil (W / O) emulsion or an oil-in-water (O / W) emulsion. Water-in-oil-in-water or oil-in-water-in-oil emulsions can also be prepared. In some embodiments, the ratio of the aqueous polymer to the oil can be 1:1 - 1:100 v / v, preferably 1:1 - 1:5 v / v, more preferably 1:1 - 1:2 v / v, to form a water-in-oil emulsion.

[0239] In some embodiments, the ratio of the aqueous polymer solution to the oil can be 1:0.01 - 1:1 v / v, preferably 1:0.05 - 1:0.8 v / v, more preferably 1:0.1 - 1:0.5 v / v, to form an oil-in-water emulsion.

[0240] In some embodiments, the polymer concentration in the aqueous solution can be 1% - 20%, preferably 3% - 15%, more preferably 5% - 10%.

[0241] The emulsion can be prepared by conventional pumping methods through two syringes connected by a two-way or three-way stopcock or a similar connector, or by homogenization or other mechanical mixing devices or methods.

[0242] Without wishing to be bound by any theory, it is believed that at ambient temperature, the structured hydrophobic-hydrophilic copolymer chains rearrange at the interface of the water-oil emulsion and stabilize the formulation by reducing the surface energy between the oil and water. Based on their hydrophobic or hydrophilic properties, the structures can allow the loading of different therapeutic agents.

[0243] When the emulsion is delivered to the target site at body temperature (37 °C), the thermoresponsive block is converted into a relatively more hydrophobic form and the original micellar or lamellar structure disintegrates. The increased hydrophobicity results in the formation of a relatively rigid porous gel, which serves as an embolization barrier. At the same time, the radiopacity provided by the oil contained in the porous structure lasts significantly longer than that seen in traditional emulsions, or can be released as a delivery vehicle for hydrophobic drugs, depending on the ratio of the aqueous phase to the oil phase and the polymer content in the aqueous phase.

[0244] Compared with the same composition lacking the polymer or composition, the emulsion disclosed in the present application has improved stability. The stability can be determined by delivering the emulsion composition to a graduated cylinder or syringe and measuring the time required for half of the liquid phase to separate out. This is a simple way to measure stability. Alternatively, when comparing two compositions of the same volume, it is easier to determine the time required for a given volume of the aqueous phase to separate out from the same emulsion volume in the same graduated cylinder. The emulsions described in the present application are stable for 10 min to 2 h, depending on the formulation. Emulsions with a higher polymer content tend to be stable for a longer time.

[0245] The emulsion formulation is adjusted by varying the ratio of the aqueous solution to the lipiodol to have a certain range of viscosities and thermoresponsive properties. Thus in some embodiments, the formulation forms an oily fluid above the polymer LCST, while in other embodiments it forms a hydrogel. In some embodiments, the formulation forms linear or spherical deposits. The formulation can be used to direct the formulation directly to more distal and more proximal embolizations. In the case of a water-in-oil formulation with a high oil volume fraction (a high oil-to-water fraction being higher than 1:0.9, preferably higher than 1:0.5), the emulsion tends to form an oily fluid that can be delivered to a distally stenosed vessel. Conversely, a water-in-oil formulation with a low oil volume fraction (a low oil-to-water fraction being lower than 1:1.1, preferably lower than 1:1.5) may be more suitable for proximal embolization of relatively large-sized vessels, including those found in vascular diseases such as aneurysms.

[0246] Iodized oil or emulsion formulations may contain one or more surfactants or emulsion stabilizers. Examples of such additives may include glucose, lactose, mannitol, ribitol, threitol, erythritol, sorbitol, heptitol, isomalt, maltitol, lactitol, cholesterol, polysorbates, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, decyl glucoside, lauryl glucoside, octyl glucoside, hypromellose (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, polyglyceryl methacrylate, poly(2 - acrylamido - 2 - methylpropanesulfonic acid) or its sodium salt, poly(2 - acrylamido - 2 - methylpropanesulfonic acid) and its salts (e.g., sodium salt), poly(2 - methacryloyloxyethyl phosphorylcholine), polyacrylic acid or its salts (e.g., sodium salt), polymethacrylic acid or its salts (e.g., sodium salt), microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch, cross - linked sodium carboxymethyl cellulose, magnesium stearate, polysorbates, poloxamers, sodium lauryl sulfate, hypromellose acetate succinate, alginates, collagen, fibrin, chitosan, gelatin, hyaluronic acid and cyclodextrins, laponite, sodium dodecyl sulfate, sodium lauryl sulfate, ammonium lauryl sulfate, dioctyl sodium sulfosuccinate and Triton X - 100, etc.

[0247] The emulsion formulation may contain a compounding agent, imaging agent, and / or additional components as described elsewhere in this application. In a further embodiment, the emulsion formulation may contain or may further contain at least one therapeutic or diagnostic radioisotope and / or at least one chemotherapeutic agent, each as described elsewhere in this application.

[0248] While chemotherapeutic agents suitable for use in emulsions include those described elsewhere in this application, due to the hydrophobic nature of the oil phase, emulsions may also contain more hydrophobic drugs such as taxanes, for example paclitaxel, docetaxel, and cabazitaxel.

[0249] In addition to aqueous compositions, the present invention also provides compositions comprising a block copolymer or bulk polymer as described in this application in dry form and lipiodol, for example The preparation. The composition may comprise at least 5% w / w, at least 10% w / w, at least 15% w / w or at least 20% w / w of a polymer or bulk polymer. This can be achieved by combining an oil with a dry polymer powder, the size of which preferably ranges between 1 μm and 500 μm, preferably between 40 μm and 300 μm.

[0250] During delivery of the preparation to the capillaries, for example, embolization initially occurs as a function of the polymer particle size and subsequently water is absorbed from the blood and / or tissue as the oil phase continues to penetrate through the capillary bed, thereby forming an embolism at 37 °C.

[0251] Another aspect of the present invention provides methods for preparing thermoresponsive polymers as disclosed herein and the products of those methods; thus in a first embodiment, the present invention provides a method for preparing a block copolymer, which comprises polymerizing A monomers and optionally P monomers to provide a first block that is either an A block or an AP block, wherein the polymerization reaction is initiated with 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 react at an I:A molar ratio of 1:(20 to 600)m, the P monomers react at an I:P molar ratio of 1:(0 to 500)m, and the N monomers react at an I:N ratio of 1:(1 to 800)m.

[0252] A, P and N are as described elsewhere in this application.

[0253] The A monomers may react at an I:A ratio of 1:(20 - 600)m, preferably 1:(30 to 200)m, more preferably 1:(60 to 120)m, even more preferably at 1:(70 to 100)m, on a mol / mol basis.

[0254] The P monomers may react at an I:P ratio of 1:(0 - 500)m, preferably 1:(2 to 100)m, more preferably 1:(3 - 30)m, on a mol / mol basis.

[0255] The N monomers may proceed at an I:N ratio of 1:(1 to 800)m, preferably 1:(3 to 600)m, more preferably 1:(5 to 400)m, on a mol / mol basis.

[0256] In one embodiment, wherein the second block may be grafted to the first block, the total number of N monomers grafted to the first block is from 1 to 800; preferably from 20 to 600; more preferably from 50 to 400.

[0257] In some embodiments, where the second block exists as an extension of the first block, the number of N monomers in the second block can be from 3 to 500, preferably from 5 to 200, more preferably from 5 to 50.

[0258] The AP block can be an (A-b-P) block, a (P-b-A) block, or an (A-co-P) block. The polymer can be AP-b-N or AP-g-N.

[0259] In some embodiments, the respective monomer species react in an A or (A + P) (when P is present) to N molar ratio of 1:0.1 to 1:8, preferably 1:2 to 1:5, particularly 1:2 to 1:4.

[0260] In some embodiments, when P is present in the first block of the reaction, 70% to 99.9% is A monomer; preferably 80 - 99% or 80 - 99.9% is A monomer.

[0261] In some embodiments, the N block is provided as a graft of 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.

[0262] The initiator can be selected from those described elsewhere in this application.

[0263] In any of the above embodiments, m can be an integer from 1 to 10, preferably from 1 to 6, more preferably from 1 to 4 or 1 to 3, and particularly preferred embodiments are those where m is 2 or 3.

[0264] The polymerization reaction can be carried out by RAFT, ATRP, or conventional free radical polymerization, but is preferably carried out by ATRP.

[0265] In some embodiments, the first block reacting with the N monomer is in the form of a macroinitiator.

[0266] In some embodiments, the method includes polymerizing an A monomer or a combination of A and P monomers to form a first block comprising A monomers and optionally P monomers, such as a first block having formula 10

[0267] *-(A-co-P)eg*-(A (x+x’) -co-P (y+y’) )

[0268] Formula 10a b

[0269] and any of the following steps

[0270] (a) From the first block such as (A (x+x’) -co-P (y+y’)) Extend the block N block such as Nq block to form a polymer of general formula 11

[0271] *-(A-co-P)-N e.g.*-(A (x+x’) -co-P (y+y’) )-Nq

[0272] Formula 11a b

[0273] Or;

[0274] (b) Extend at least one N graft such as N r graft from the AP block to form a copolymer containing at least one N or N r graft, said copolymer being a copolymer according to formula 11c, for example according to formula d;

[0275]

[0276] where * represents the residue of an optional initiator molecule, which is constructed to support the initiation of polymerization from m functional groups; and m is an integer from 1 to 10.

[0277] The polymerization reaction can be carried out by various methods including RAFT, ATRP or conventional free radical polymerization. In a preferred method, the polymerization reaction is carried out by ATRP.

[0278] In one method of ATRP, the method comprises the following steps:

[0279] (i) Polymerize the A monomer or a combination of A and P monomers in the presence of an initiator constructed to support ATRP polymerization from m functional groups to provide a halogenated macroinitiator containing a poly A block or an (A-co-P) block, said block containing initiator residues covalently bound to m replicas in either the A polymer or the A-P copolymer, each replica including a terminal monomer containing a Hal group. For example, a macroinitiator of formula 12.

[0280] *[(A-co-P)Hal] m For example *[(A (x+x’) -co-P (y+y’) )Hal] m

[0281] Formula 12a b

[0282] where Hal is a halogen, selected from Cl and Br, preferably Br; m is the number of polymer arms covalently bound to the initiator, preferably 1 or 2.

[0283] (ii) React the halogenated initiator with the N monomer in a further ATRP reaction to provide a copolymer comprising a first block comprising the A monomer and optionally the P monomer and a second block consisting of the N monomer, wherein the second block is an extension of the A block (or AP block). These are linear polymers rather than star polymers.

[0284] In a second method, the ATRP method comprises:

[0285] (i) Polymerize the A monomer or a combination of the 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 initiator residues with m replicates covalently bound to either the A polymer or the A-P copolymer;

[0286] (ii) React the star polymer with an activated halogen compound (such as α-haloisobutyryl bromide) to provide a halogenated macroinitiator, where (in the case of the A polymer) the halogen hangs from the A monomer; or (in the case of the A-co-P polymer) where the halogen hangs from both the A monomer and the P monomer;

[0287] (iii) React the halogenated macroinitiator with the N monomer in a further ATRP reaction to provide a copolymer comprising a first block comprising the A monomer and optionally the P monomer and a second block consisting of the N monomer, where (in the case of the A polymer) the second block hangs from the A monomer; or where (in the case of the A-co-P polymer) the second block hangs from both the A monomer and the P monomer.

[0288] Typically in ATRP reactions such as those described above, the reaction occurs in the presence of a transition metal halide (usually cuprous (I) halide). The halogen will typically be the same as the halogen present as a functional group on the initiator and the same as the halogen present on the macroinitiator. It can be chlorine or bromine, but is usually bromine. The reaction typically occurs in the presence of a nitrogen-containing ligand that binds the transition metal. Typically, the reaction occurs in a solution from which oxygen has been excluded.

[0289] In one example, a method for preparing a (HEMA-co-HPMA)-block NIPAAM polymer (such as (HEMA (x) -co-HPMA (y) )-block NIPAAM q polymer) comprises:

[0290] (i) Polymerize a combination of HEMA monomer and HPMA monomer in the presence of a difunctional initiator such as meso-2,5-dibromohexanedioic acid diethyl ester (DMDBA), Cu(I)Br and a nitrogen-containing ligand such as 2,2'-bipyridine in a polar solvent such as MeOH to produce a macroinitiator I-[(HEMA-co-HPMA)Br]2 such as I-[(HEMA (x) -co-HPMA (y) )Br]2 macroinitiator, where the terminal monomer of each arm contains a bromine group (see Scheme 1).

[0291] (ii) React the brominated macroinitiator with NIPAAM monomer in a further ATRP reaction in the presence of Cu(I)Br and in the presence of a nitrogen-containing ligand such as 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (Me4Cyclam) to provide a polymer I-[(HEMA ) -co-HPMA)-block-NIPAAM]2 such as I-[(HEMA (x) -co-HPMA (y) )-block-NIPAAM q 2 polymer. (See Scheme 2)

[0292]

[0293] In a second example, a method for preparing a comb-shaped three-armed polycomb-shaped poly I-[(HEMA-co-HPMA)-graft-(NIPAAM)]3 polymer such as I-[(HEMA (x) -co-HPMA (y) )-graft-(NIPAAM r ) (x’+y’) 3 polymer includes:

[0294] (i) Polymerize a combination of HEMA and HPMA monomers in the presence of a trifunctional initiator such as glycerol tribromoisobutyrate, Cu(I)Br and a nitrogen-containing ligand such as 2,2'-bipyridine to provide a star-shaped I-[(HEMA-co-HPMA)]3 polymer such as star-shaped I-[(HEMA (x) -co-HPMA (y) )]3 polymer (Formula 15), (Scheme 3).

[0295]

[0296] (ii) React the star-shaped polymer with an activated alkyl bromide compound such as α-bromoisobutyryl bromide in the presence of a base such as triethylamine to provide a brominated I-[(HEMA-co-HPMA)]3 macroinitiator such as I-[(HEMA(x) -co-HPMA (y) )]3 macromolecular initiator (Formula 16), (Scheme 4);

[0297]

[0298] (iii) Reacting the brominated I-[(HEMA-co-HPMA)]3 macromolecular initiator with N monomer in a further ATRP reaction 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 provide an I-[(HEMA-co-HPMA)-graft-(NIPAAM)]3 polymer such as I-[(HEMA (x) -co-HPMA (y) )-graft-(NIPAAM r ) (x’+y’) 3 polymer (Formula 17), (Scheme 5).

[0299]

[0300] In some embodiments, the method includes the step of drying the resulting polymer thereby providing a dried polymer composition.

[0301] In some embodiments, the method includes the step of formulating the polymer by combining it with one or more additional components described elsewhere in this application. The formulation can be obtained before or after drying.

[0302] In some embodiments, the formulation can be obtained by drying any of the compositions described elsewhere in this application.

[0303] In one embodiment, the method includes the steps of: combining the polymer described in this application with one or more contrast agents in the solution phase and drying the solution to provide a dried composition of the polymer containing the contrast agent.

[0304] Any of the embodiments or preferred embodiments described above can be used in combination with any other embodiment or preferred embodiment, and any of the above-described embodiments can be combined with any aspect of the present invention described above.

[0305] The present invention will be described below with reference to non-limiting experimental examples and the drawings. In view of these, further embodiments of the present invention will be obvious to those skilled in the art. Description of the Drawings

[0306] Figure 1 shows the NMR data of the synthetic intermediates. Figure 1a presents the NMR spectrum of the three-arm initiator of Example 1: glycerol tris(2-bromoisobutyrate). Figure 1b presents the proton NMR spectrum of the three-arm poly-HEMA macroinitiator I-[HEMA 100 -Br 10 3. Figure 1c presents the proton NMR spectrum of the three-arm star-shaped comb polymer I-[HEMA 100 -g-(NIPAAM 20 ) 10 3.

[0307] Figure 2 Shows an aqueous polymer solution (10% w / w) delivered to PBS at 37 °C. (A) is a polymer lacking the P component in the PA block; (B) is a polymer in which P accounts for 10% of the A-P block, in molar ratio. The polymers are (I-((HEMA 50 )-b-NIPAAM 200 )2.) and (I-((HEMA 45 -co-HPMA5)-b-NIPAAM 200 )2) (see Example 12).

[0308] Figure 3 Shows the delivery of a liquid sample of I-[HEMA 100 -g-(NIPAAM 20 ) 10 3 in a fluid model. The tube diameter is 5 mm, the medium temperature is 37 °C; the initial flow rate is 150 mL / min, PBS medium, 2.4 Fr catheter as described in Example 12.

[0309] Figure 4 shows the delivery of an oily emulsion containing an aqueous polymer solution and to PBS at 37 °C. The polymer solution is a 10% solution of I-((HEMA 45 -co-HPMA5)-NIPAAM 200 )2 in water. (A) ratio is 1:0.5 v / v, (B) ratio is 1:1 v / v, (C) ratio is 1:2 v / v (see Example 16). Each photograph shows a time series spaced approximately 30 s from left to right.

[0310] Figure 5 shows the delivery of a suspension containing dry polymer particles and to PBS at 37 °C. The polymer is I-((HEMA 49.5 -co-HPMA 0.5 )-NIPAAM 200 )2.

[0311] Figure 6 Shows the temperature increase curve of an aqueous solution (15% w / w) of copolymer I-((HEMA 44.5 -co-HPMA 0.5 )-NIPAAM 200 )2. Example

[0312] In the examples, assuming complete reaction, the molecular formulas of the polymers and intermediates are idealized. In the following examples, HPMA is a mixture of the isomers hydroxypropyl methacrylate and hydroxyisopropyl methacrylate, as outlined further above.

[0313] Example 1: Preparation of the three-arm initiator glycerol tris(2-bromoisobutyrate)

[0314] 5 g (0.054 mol) of anhydrous glycerol was charged into a 250 mL round-bottom flask, then 23 mL of triethylamine (0.168 mol) and 50 mL of anhydrous N-methylpyrrolidone were added. The flask was placed in an ice-water bath and stirred with a magnetic stirrer for 20 min. Then 38 g (0.165 mol) of α-bromoisobutyryl bromide was added dropwise via a dropping funnel over a period of about 30 min. The reaction was stirred overnight at room temperature. The reaction mixture was then filtered to remove the triethylamine salt, and the solution was thoroughly mixed with saturated aqueous NaCl. The aqueous solution was extracted three times with ethyl acetate, and the combined organic layers were dried over MgSO4 overnight. The ethyl acetate solution was removed using a rotary evaporator, and the product was dried under vacuum for 24 h to give a pale yellow waxy solid. The 1 1H NMR spectrum of the product is shown in Figure 1.

[0315] Example 2: Synthesis of a three-arm poly-HEMA homopolymer by ATRP

[0316] A typical synthesis procedure for three-arm poly(I-(HEMA 100 )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-necked round-bottom flask. After the mixture was degassed with nitrogen under mechanical stirring for 60 min, 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 the polymerization reaction under a nitrogen atmosphere. It was observed that the temperature of the reaction mixture increased within the first hour, accompanied by a gradual increase in the solution viscosity. After about 20 h, the reaction was stopped by exposing it to air and diluted with methanol. The mixture was passed through a silica gel column to remove the copper catalyst, the methanol was removed by rotary evaporation, and then dried under vacuum at 40 °C overnight to give 10.6 g of a solid.

[0317] Example 3: Synthesis of a three-armed poly(HEMA) homopolymer macroinitiator

[0318] In a 250 mL round-bottom flask, 15 g of the three-armed poly(I-(HEMA 100 )3) obtained from the reaction of Example 2 was dissolved in 50 mL of anhydrous N-methylpyrrolidone under mechanical stirring. Then 1.74 mL of triethylamine was added. The flask was placed in an ice-water bath, and then 1.41 mL of α-bromoisobutyryl bromide was added dropwise via a syringe over a period of about 10 min to achieve the target of 10 units of bromide per arm. The reaction quickly became turbid 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 process was repeated. The solid was collected as follows: it was dissolved in MeOH, then rotary evaporated and dried under vacuum at 40 °C overnight. 12.0 g of polymer (Formula 18) was produced.

[0319]

[0320] Example 4: Synthesis of comb-shaped three-armed poly(HEMA-g-NIPAAM) copolymer by ATRP

[0321] A series of three-armed poly(I-(HEMA-g-NIPAAM)3) copolymers with various polymerization levels of HEMA and NIPAAM were synthesized by ATRP. A typical procedure is given below.

[0322] In a 100 mL three-neck round-bottom flask, 3.0 g of the macroinitiator poly(HEMA) 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 h, and the flask was placed in an ice-water bath to bring the mixture temperature to 5 °C. The polymerization reaction was initiated by adding CuBr catalyst under a nitrogen stream. The solution viscosity increased with time. After about 18 h, the reaction was stopped by exposing the reaction to air and it was diluted with 20 mL of NMP. The mixture was dialyzed against water in a dialysis bag for 4 days, changing the water every 12 h. The resulting translucent solution was lyophilized, and finally 6.9 g of white polymer solid (Formula 19) was obtained. The proton NMR spectrum of the product is given in Figure 1c.

[0323]

[0324] Example 5: Synthesis of three-armed poly(HEMA-NIPAAM) copolymer by chain extension using ATRP

[0325] The typical synthesis process of triblock poly(I-(HEMA 100 -NIPAAM 100 )3) is given below.

[0326] In a 100 mL three-necked round-bottom flask, 2.1 g of the macroinitiator poly-HEMA 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 min, and a CuBr catalyst (0.023 g) and 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane (Me4Cyclam) (0.041 g) were added, and the polymerization reaction was carried out overnight. Then, the reaction mixture was dialyzed against deionized water for four days to remove unreacted monomers and catalysts. The solution was lyophilized to obtain 2.4 g of the polymer.

[0327] Example 6: Synthesis of linear copolymer I-((HEMA 45 -co-HPMA5)-NIPAAM 100 )2

[0328] (a) Preparation of poly I-(HEMA 45 -co-HPMA5)2 copolymer.

[0329] In a 100 mL three-necked round-bottom flask, 0.3 g (0.83 mmol) of the initiator meso-2,5-dibromoadipic acid diethyl ester 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 provided by Merck (catalog number 268542) and was a mixture of the isomers hydroxypropyl methacrylate and hydroxyisopropyl methacrylate. After the mixture was degassed with nitrogen for 60 min under mechanical 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 the polymerization reaction under a nitrogen atmosphere. It was observed that the temperature of the reaction increased slightly with time, and the solution viscosity gradually increased until the magnetic stir bar stopped moving. After about 18 h, the reaction was stopped by exposing the reaction to air, and it was diluted with methanol. The mixture was passed through a silica gel column to remove the copper catalyst, the methanol was removed by rotary evaporation, and then it was dried in vacuo at 40 °C overnight to obtain a dry polymer solid.

[0330] (b) Preparation of I-((HEMA 45 -co-HPMA5)-NIPAAM 100 )2

[0331] In a 100 mL three-necked round-bottom flask, 3.0 g of the above-prepared macromolecular initiator poly(HEMA-co-HPMA) and 5.0 g of NIPAAM monomer were dissolved in 25 mL of MeOH. The mixture was degassed with nitrogen for 1 h, and then 0.06 g of CuBr catalyst and 0.114 g of Me4Cyclam were added to initiate the polymerization reaction. The reaction was allowed to proceed overnight. Then the mixture was dialyzed against deionized water for 4 days to remove unreacted monomers and catalysts. The solution was lyophilized and the linear polymer solid was recovered. The polymer can also be written as NIPAAM 100 -(HEMA 90 -co-HPMA 10 )-NIPAAM 100 。

[0332] Example 7. Synthesis of linear copolymer poly(NIPAAM 200 -HEMA 99 -HPMA1-NIPAAM 200 )

[0333] The following gives the standard synthesis method of linear poly(HEMA 99 -st-HPMA1). 1.5 g (4.17 mmol) of the initiator meso-2,5-dibromohexanedioic acid diethyl ester 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-necked round-bottom flask, and then 55 mL of methanol was added. After the mixture was degassed with nitrogen under mechanical stirring for 60 - 120 min, 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 the polymerization reaction under a nitrogen atmosphere. It was observed that the temperature of the reaction mixture increased within the first hour, accompanied by a gradual increase in the solution viscosity. After about 20 h, the reaction was stopped by exposing the reaction to air and it was 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 vacuum drying at 40 °C overnight, 45 g of solid was obtained.

[0334]

[0335] To prepare the target poly(NIPAAM 200 -HEMA 99 -HPMA1-NIPAAM 200 ) copolymer, in a 250 mL three-necked round-bottom flask, 15 g of poly(HEMA 99-st-HPMA1) The macroinitiator was dissolved in 72 mL of methanol. Then, 50.7 g of N-isopropylacrylamide monomer was added to the flask and dissolved. After degassing the mixture 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 reaction.

[0336] The reaction solution rapidly became viscous and was stirred overnight under a nitrogen atmosphere. After approximately 20 h, the reaction was stopped by exposing it to air, and 100 mL of methanol was added to dilute the viscous solution. The polymer was purified by ultrafiltration with water, and the resulting solution was freeze-dried for 48 h. Finally, approximately 54 g of solid was collected.

[0337] This polymer can also be referred to as I-((HEMA 45.5 -HPMA 0.5 )-NIPAAM 200 )2.

[0338]

[0339] Example 8: Synthesis of comb copolymer poly(HEMA-HPMA-graft-NIPAAM)

[0340] (a) Synthesis of poly(HEMA-HPMA) macroinitiator

[0341] In a 250 mL round-bottom flask, 8 g of poly I-(HEMA 45 -HPMA5)2 obtained from Example 6a was dissolved in 50 mL of anhydrous N-methylpyrrolidone (NMP) under mechanical stirring, and then 2.72 mL of triethylamine was added. The flask was placed in an ice-water bath, and then 2.20 mL of α-bromoisobutyryl bromide was added dropwise over a period of approximately 20 min to achieve a target of 10 units of bromide per chain. The reaction rapidly became turbid and was stirred at room temperature overnight. 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 process was repeated. The solid was collected and dried in vacuo at 40 °C for two days.

[0342] (b) Synthesis of comb copolymer I-[(HEMA 45 -HPMA5)-g-(NIPAAM 20 )5]2

[0343] In a 100 mL three-necked round-bottom flask, 3.0 g of the above-prepared macromolecular initiator poly(HEMA-HPMA) and 5.0 g of NIPAAM monomer were dissolved in 15 mL of NMP. The mixture was degassed with nitrogen for 60 min, and then 0.32 g of CuBr catalyst and 0.57 g of PMDETA were added to initiate the polymerization reaction. The reaction was allowed to proceed overnight, and then it was dialyzed against deionized water for 4 days to remove unreacted monomers and catalysts. The solution was freeze-dried and the polymer solid was recovered. This formula can also be expressed as poly(HEMA 90 -HPMA 10 -g-(NIPAAM 20 ) 10 )(Figure 20).

[0344]

[0345] Example 9: Synthesis of three-armed poly(HEMA 90 -co-HPMA 10 )

[0346] In a 250 mL three-necked round-bottom 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 min, 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 the polymerization reaction. After about 20 hours, the reaction was stopped by exposing it to air and it was diluted with methanol. The mixture was precipitated into deionized water to remove the copper catalyst, and a solid precipitate was obtained. The solid was dissolved in MeOH and precipitated into water. The extraction was repeated three times. The resulting polymer was dried in vacuo at 40 °C overnight to obtain 18.8 g of a solid.

[0347] Example 10: Synthesis of poly(I-(HEMA 90 -co-HPMA 10 )3) macromolecular initiator

[0348] In a 250 mL round-bottom flask, 10 g (0.25 mmol) of the three-armed poly(I-(HEMA-HPMA)3) obtained from Example 8 was dissolved in 50 mL of anhydrous N-methylpyrrolidone (NMP) under mechanical stirring, and then 1.15 mL of triethylamine was added. The flask was placed in an ice-water bath, and then 0.93 mL of α-bromoisobutyryl bromide was added dropwise over about 10 min via a syringe to achieve the target of 10 units of bromide per arm. The reaction solution quickly became turbid and was stirred at room temperature overnight. 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 process was repeated again. The solid was collected and dried in vacuo at 40 °C for two days.

[0349] Example 11: Synthesis of Comb-Type Three-Armed Poly(I-(HEMA 90 -co-HPMA 10 )-Grafted-(NIPAAM 20 ) 10 )3

[0350] 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 the NIPAAM monomer were dissolved in 50 mL of NMP. The mixture was degassed with nitrogen for 60 min, and then 0.32 g of CuBr and 0.39 g of PMDETA were added to initiate the polymerization reaction. The reaction was allowed to proceed overnight. Then the mixture was dialyzed against deionized water for 4 to 5 days to remove unreacted monomers and catalysts. The solution was lyophilized to obtain a polymer solid (Formula 17) (see also Scheme 5).

[0351]

[0352] Example 12: Sample Preparation and In Vitro Testing

[0353] Samples of the polymer solid produced as described above were weighed into 30 mL vials, and deionized water was added to provide a 10% w / w polymer solution. The vials were placed in a cold water bath and mechanically stirred until a homogeneous solution was obtained. The solution was translucent and had a low viscosity. The gelation ability of the polymer solution was tested by injecting the polymer solution into a phosphate buffer saline medium at 37 °C through an 18G needle. As shown in Figure 1, the solution immediately turned into a white hydrogel. Gels formed from polymers with lower hydrophobicity (such as those lacking HPMA) tended to form soft blocks as shown in Figure 2 A, while gels formed from more hydrophobic polymers (in this case, having 10% HPMA in the PA block, on a molar / molar basis) tended to be harder and linear, as shown in Figure 2As shown in Figure B. Pressure testing with a needle indicated that the gel strength was strong enough and not prone to rupture. Table 1 records the properties observed when the polymer of the example was delivered into PBS solution at 37°C. The polymer solution was prepared in Omnipaque TM 300 aqueous contrast agent (used at full strength) or in deionized water.

[0354] Table 1.

[0355]

[0356]

[0357] Example 13: Rheology

[0358] Samples of an aqueous solution of I-((HEMA 44.5 -co-HPMA 0.5 )-NIPAAM 200 )2 (15% w / w) were tested by a rheometer using the oscillatory method, and the results of the temperature increase are as Figure 6 shown. The results showed that the sol-gel transition temperature was approximately 29°C and the storage modulus of the gel at 37°C was approximately 20,000 Pa and the loss modulus was 4,000 Pa, indicating that a solid gel could be formed when the sample was placed at body temperature.

[0359] Example 14: Delivery of the polymer in a flow model

[0360] To prepare the polymer solution with the contrast agent, the polymer solid was weighed and placed in a 30 mL vial, and the contrast agent - Omnipaque 300 (647 mg / ml iohexol) was added to make the polymer concentration 10% w / w. The vial was placed in a cold water bath and mechanically stirred to dissolve the polymer. The resulting polymer solution was transferred to a syringe for delivery testing with a 2.4 Fr catheter.

[0361] In the flow model, a 5 mm diameter silicone tube was immersed in a 37°C water bath. A sponge was placed in the middle of the silicone tube to simulate the collection of some small blood vessels such as venules. PBS medium was pumped through the sponge tube. The bypass controlled the flow rate through the sponge at 150 mL / min, and the actual flow rate was monitored by a flow meter. The open end of the 2.4 Fr catheter was placed in front of the sponge and the polymer solution was injected into the tube. The polymer solution turned into a hydrogel thread when leaving the catheter tip in the flowing medium, piled up and formed a blockage, blocking the flow channel and causing the flow meter reading to drop to 0 within 1 - 2 min ( Figure 3 ).

[0362] Example 15: Preparation of the dried polymer

[0363] Samples of the polymer powder were prepared as follows: either grinding the lyophilized solid or spray drying from a polymer solution to provide a particle size distribution of 10 - 600 microns. The powder (0.05 g) was weighed with glycerol (0.025 g) or without glycerol (0.025 g) and placed in a 1 mL syringe. In a second 1 mL syringe, 0.925 g of the contrast agent solution was weighed. The two syringes were connected together via a three-way stopcock and air was carefully removed. The contrast agent solution was rapidly mixed with the polymer solid by passing the composition back and forth between the two syringes. The syringe was placed in a refrigerator at 2 - 8 °C for 5 min to cool the contents and dissolve them better. The solution was further mixed approximately 20 times. A catheter was connected to the syringe to deliver the mixture to PBS at 37 °C, and a linear hydrogel formed in the PBS.

[0364] Example 16 Preparation and properties of an oily emulsion

[0365] Prepare a 10% aqueous solution of I - ((HEMA 45 -co - HPMA5)-NIPAAM 200 )2, which was mixed with Lipiodol Ultra Fluide ([[]] Guerbet, Paris, France) at various ratios (see Table 3). Mixing was achieved by repeatedly passing the mixture back and forth between two syringes by means of a three-way stopcock. The emulsion was slowly injected into PBS at 37 °C, and the characteristics of the product were observed. Figures 4A through 4C The formed product is shown.

[0366] Example 17 Catheter delivery of a linear polymer-based emulsion in a flow model

[0367] According to Example 14, a sample of the emulsion prepared according to Example 16 was delivered through a 2.7 Fr catheter in a fluid model to simulate vascular embolization in PBS at 37 °C. The observed results are recorded in Table 3.

[0368] Table 3

[0369]

[0370] Example 16. Delivery of oil and polymer particles in dry form through a catheter into PBS.

[0371] Oil and a sample of the dry polymer powder of I - ((HEMA 49.5 -co - HPMA 0.5 ) - NIPAAM 200 )2 was prepared as follows: The oil and 200 - 500 μm polymer particles were directly mixed between two syringes as described above. The formulation was delivered through a 2.7Fr catheter at 37 °C and into PBS buffer (Figure 5). The polymer powder was observed to be suspended within the oil droplets.

[0372] Example 17. Release of a drug mimic from a hydrogel oil-in-water emulsion

[0373] The water-soluble dye Safronin O was dissolved in a 10% aqueous solution of the copolymer I - ((HEMA 49.5 -co-HPMA 0.5 )-NIPAAM 200 ). The solution was then mixed with in a 1:1 (v / v) ratio to form an oil-in-water emulsion with a light pink color. The emulsion was injected into PBS buffer at 37 °C and immediately formed a hydrogel liquid. The red dye was observed to gradually release from the injected hydrogel into the PBS, and the dye was completely released after 48 hours.

[0374] Similarly, the oil-soluble dye Sudan IV was dissolved in , and then mixed with a 10% aqueous solution of I - ((HEMA 49.5 -co-HPMA 0.5 )-NIPAAM 200 ) in a 1:1 ratio to obtain a pink oil-in-water emulsion. The emulsion was injected into PBS buffer at 37 °C and immediately formed a hydrogel liquid. No red dye was released from the injected hydrogel into the PBS, and even after 48 hours, no significant dye release into the PBS was observed.

[0375] Example 18: Synthesis of poly(NIPAAM-[GMA-st-BMA]-NIPAAM) and poly(NIPMAM-[GMA-st-BMA]-NIPMAM) copolymers.

[0376] A. Synthesis of poly(GMA 95 -st-BMA5)

[0377] 0.1 g (0.3 mmol) of the initiator meso-2,5-dibromohexanedioic acid diethyl ester 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-necked round-bottom flask, and then 5 mL of methanol was added. After degassing the mixture with nitrogen under mechanical stirring for 60 min, 0.08 g (0.6 mmol) of Cu(I)Br and 0.1 g (0.6 mmol) of N,N,N′,N″,N″-pentamethyldiethylenetriamine were added to the flask to initiate the polymerization reaction. The temperature of the reaction mixture was initially observed to increase, accompanied by an increase in the viscosity of the solution.

[0378] After approximately 20 hours, the reaction was stopped by exposing it 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 a solid was obtained.

[0379] B. Synthesis of poly(NIPAAM 200 -[GMA 95 -st-BMA5]-NIPAAM 200 ) copolymer.

[0380] In a 50 mL three-necked round-bottom flask, the poly(GMA-st-BMA) macroinitiator obtained from the above reaction was dissolved in 9 mL of methanol under mechanical stirring. Then, 5.3 g of N-isopropylacrylamide monomer was added to the flask and dissolved. After degassing the mixture with nitrogen for 60 min, 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 reaction. The reaction solution quickly became viscous and was stirred overnight under a nitrogen atmosphere.

[0381] After approximately 20 hours, the reaction was stopped by exposing it to air, and 100 mL of methanol was added to dilute the viscous solution. The polymer was purified by ultrafiltration with water, and the resulting solution was freeze-dried for 48 hours. Approximately 5.5 g of a solid was collected.

[0382] C. Synthesis of poly(NIPMAM 200 -[GMA 95 -st-BMA5]-NIPMAM 200 ) copolymer

[0383] The product was prepared as follows: The poly(GMA-st-BMA) macroinitiator prepared above was reacted 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 in a manner similar to that described above. A pale yellow polymer solid was obtained after freeze-drying.

[0384] Both polymers are soluble in cold water and exhibit a phase transition of polymer aggregation and gel formation at 37 °C.

[0385]

Claims

1. A block copolymer comprising a first block containing 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; wherein the second block is a thermoresponsive block; Among them The A monomer is selected from acrylate, methacrylate, acrylamide, and methacrylamide; preferably, the A monomer is selected from acrylate, methacrylate, N-substituted acrylamide, and N-substituted methacrylamide; The P monomer is selected from acrylate, methacrylate, acrylamide, and methacrylamide; preferably, the P monomer is selected from acrylate, methacrylate, N-substituted acrylamide, and N-substituted methacrylamide; wherein P is more hydrophobic than A; and 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 block copolymer according to claim 1, wherein the A monomer is selected from: 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); particularly 1,3DHPMA, 2,3DHPMA, GMA, and HEMA; especially HEMA; the P monomer is selected from: 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 above isomers (HPMA); N-(2-hydroxypropyl)methacrylamide (HPMAm), N-(3-hydroxypropyl)acrylamide (HPA), and butyl methacrylate (BMA); and the N monomer is selected from: N-NIPAAM, NIPMAM, and DEA; particularly, the A monomer is HEMA, the P monomer is HPMA, and the second block is poly NIPAAM.

3. The block copolymer according to claim 1 or 2, wherein the number of A monomers in the first block is 20 to 600; preferably 30 to 00; more preferably 60 to 120; or 70 to 100; and the number of P monomers in the first block is either 0 or 0 to 500; preferably 1 or 2 to 100, more preferably 3 - 30; more preferably >0 and less than or equal to 10.

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

6. The block copolymer according to any one of claims 1 to 3, wherein the second block is present as an extension of 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. The block copolymer according to any one of the preceding claims, 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, in moles.

8. The block copolymer according to any one of the preceding claims, wherein the first block comprises A monomers and P monomers, and wherein A accounts for 70 to 99.9% of the first block, in moles.

9. The block copolymer according to any one of the preceding claims, wherein the P monomer has an XLogP3 value that is at least 0.10 higher than the XLogP3 value of the A monomer.

10. The block copolymer according to any one of the preceding claims, wherein the ratio of the first block monomers to the second block monomers is from 1:0.1 to 1:8, on a mol / mol basis.

11. The block copolymer according to any one of the preceding claims, wherein the second block hangs from the first block.

12. The block copolymer according to any one of claims 1 to 10, wherein the second block is an extension of the first block.

13. The block copolymer according to any one of the preceding claims, wherein the first block is a (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 (AP) - b - N or (AP) - g - N.

14. The block copolymer according to any one of the preceding claims, which is either in a linear form, comprising a single first block, or two identical first blocks covalently coupled in a linear reflective arrangement around a central node; or in a star form, comprising m identical first blocks separately covalently coupled to a central node, where m is an integer from 3 - 10.

15. A block copolymer of formula I: Wherein: * represents the site of attachment to the residue of the polymerization initiator; A is selected from acrylate, methacrylate, acrylamide, methacrylamide; P is selected from acrylate, methacrylate, acrylamide, methacrylamide; wherein as measured by XLogP3, P is more hydrophobic than A; N is a monomer that forms a thermoresponsive block, and N q and N r is a thermoresponsive block having a terminal selected from 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); Wherein: The sum of x and x' is the total number of A monomers in the block, and is an integer from 20 to 600, preferably 30 - 200, more preferably 60 to 120, or 70 to 100; The sum of y and y’ is the total number of P monomers in the block; when P is absent, both y and y’ are 0; when P is present, (y + y’) is 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 in the AP block and is 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, and more preferably from 5 to 50; and q and r cannot both be 0 at the same time; If r > 0, then q is an integer not greater than 2*r, preferably not greater than 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; and wherein The parentheses indicate an integral block with hydrophobic / hydrophilic functions formed in the synthesis order; the brackets enclose the arms of the branched structure; and when A-P is in the form of a block, the order of A and P can be reversed.

16. The block copolymer according to claim 14, wherein A is selected from: 2-hydroxyethyl methacrylate (HEMA), N-(2-hydroxyethyl) acrylamide (HEA), 1,3-dihydroxypropyl methacrylate (1,3DHPMA), 2,3-dihydroxypropyl methacrylate (2,3DHPMA), glycidyl methacrylate (GMA), and N-(2-hydroxyethyl) methacrylamide (HEMAm); preferably HEMA, 1,3DHPMA, 2,3DHPMA, and GMA; more preferably HEMA.

17. The block copolymer according to claim 14 or 15, wherein P is selected from: 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 above isomers (HPMA); N-(2-hydroxypropyl) methacrylamide (HPMAm), butyl methacrylate (BMA), and N-(3-hydroxypropyl) acrylamide (HPA).

18. The block copolymer according to any one of claims 14 to 16, wherein the N-block is selected from poly(NIPAAM), polyNIPMAM, and poly(DEA); preferably poly(NIPAAM) and polyNIPMAM.

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

20. 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 (AP)-b-N or (AP)-g-N.

21. A block copolymer selected from: *[(HEMA 40-120 )-g-(NIPAAM 10-50 ) 5-50 2 *[(HEMA 40-120 )-b-NIPAAM 150-450 3 *[(HEMA 40-120 )-g-NIPAAM 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 wherein the values of the number of HEMA, HPMA and NIPAAM monomers are integers.

22. A block copolymer selected from: *[(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 of the number of HEMA, HPMA and NIPAAM monomers are in a range including all fractional values therebetween; and wherein the number of HPMA monomers in the AP block is > 0 and <= 50.

23. A block copolymer selected from: 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 90 -b-HPMA 10 )-g-(NIPAAM 20 ) 10 3 I-[(HEMA 80 -b-HPMA 20 )-g-(NIPAAM 20 ) 10 3; and I-((HEMA 49.5 -co-HPMA 0.5 )-NIPAAM 200 )2。 24. A method for preparing a block copolymer, comprising polymerizing an A monomer and optionally a P monomer to provide a first block which is either an A block or an AP block, wherein the polymerization reaction is initiated by a polymerization initiator I having m polymerization reaction initiation sites; and reacting an N monomer with the first block to provide a block copolymer comprising the first A block or the first AP block and a second N block; wherein: The A monomer reacts at an I:A ratio of 1:(20 - 600)m, preferably 1:(30 to 200)m, more preferably 1:(60 to 120)m, even more preferably 1:(70 to 100)m, on a mol / mol basis; The P monomer, when present, reacts at an I:P ratio of 1:(0 - 500)m, preferably 1:(2 to 100)m, more preferably 1:(3 - 30)m, on a mol / mol basis; and The N monomer reacts at an I:N ratio of 1:(1 to 800)m, preferably 1:(3 to 600)m, more preferably 1:(5 to 400)m, on a mol / mol basis; and m is an integer from 1 to 10; and wherein The A monomer is selected from acrylates, methacrylates, acrylamides and methacrylamides; preferably, the A monomer is selected from acrylates, methacrylates, N-substituted acrylamides and N-substituted methacrylamides; The P monomer is selected from acrylates, methacrylates, acrylamides and methacrylamides; preferably, the P monomer is selected from acrylates, methacrylates, N-substituted acrylamides and N-substituted methacrylamides; wherein P is more hydrophobic than A; and 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, poly(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.

25. A method for preparing a block copolymer, which comprises polymerizing A monomers or A and P monomers to form a first block having Formula 10, the first block comprising A monomers and optionally P monomers *-(A (x+x’) -co-P (y+y’) ) Formula 10 and one of the following (a) and (b): (a) Extend the Nq block from (A (x+x’) -co-P (y+y’) ) to form a polymer of general formula 11 *-(A (x+x’) -co-P (y+y’) )-Nq Formula 11 (b) Extend at least one N from the AP block r graft to form a copolymer comprising at least one N r graft; where * represents the residue of an optional initiator molecule, which is constructed to support the initiation of polymerization from m functional groups; and where m is an integer from 1 to 10.

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

27. A block copolymer prepared according to any one of claims 23 to 25.

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

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

30. The dry composition according to claim 28, which comprises less than 0.1% w / w of water or other solvents.

31. An aqueous composition comprising the block copolymer according to any one of claims 1 - 22 or 26 or the bulk polymer composition according to claim 27.

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

33. The composition according to any one of claims 27 to 31, which further comprises at least one imaging agent, at least one therapeutic or diagnostic radioisotope and / or at least one chemotherapeutic agent.

34. A composition comprising the block copolymer according to any one of claims 1 - 22 or 26 or the bulk polymer composition according to claim 27 and an iodine contrast agent, wherein the ratio of the contrast agent to the copolymer or polymer composition is from 0.1 to 110, preferably from 1 to 10, more preferably from 1.5 to 5, by weight to weight.

35. A composition comprising the block copolymer according to any one of claims 1 - 20 or 24 or the bulk polymer composition according to claim 25 and lipiodol.

36. The composition according to claim 34, which is in the form of an oil-in-water emulsion.

37. The composition according to claim 34, wherein the block copolymer or bulk polymer composition is in particulate form.

38. An embolization agent comprising the block copolymer according to any one of claims 1 - 22 or 26 or the bulk polymer composition according to claim 27, or the composition according to any one of claims 27 to 36.

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