RADIOPAQUE POLYMERS

Abstract

The present disclosure relates to radiopaque PVA polymers where the PVA has a first pendant group and a second pendant group, wherein the first pendant group comprises a first phenyl group bearing 1 to 5 iodine atoms, and the second pendant group comprises either (a) a second phenyl group bearing 1 to 3 substituents selected from the group W and optionally 1 to 4 iodine substituents, the group(s) W and the optional iodines being the sole substituents of the second phenyl group. Each W is selected from —OH, —COOH, —SO.sub.3H, —OPO.sub.3H.sub.2, —O—(C.sub.1-4alkyl), —O—(C.sub.1-4alkyl)OH, —O—(C.sub.1-4alkyl)R.sup.2, —O—(C.sub.2H.sub.5O).sub.qR.sup.1 —(C═O)—O— C.sub.1-4alkyl and —O—(C═O)C.sub.1-4alkyl; wherein R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is —COOH, —SO.sub.3H, or —OPO.sub.3H.sub.2; q is an integer from 1 to 4; wherein the group W may be in the form of a pharmaceutically acceptable salt; or (b) a pyridyl group; which is optionally in the form of a pyridinium ion.

Claims

1. An implantable medical device comprising a polymer that comprises polyvinyl alcohol (PVA), the PVA having a first pendant group and a second pendant group, wherein the first pendant group comprises a first phenyl group bearing 1 to 5 iodines as the sole substituent(s) of the first phenyl group, and wherein the second pendant group comprises a group selected from: (a) a second phenyl group bearing 1 to 3 substituents selected from the group W and optionally 1 to 4 iodine substituents, the group(s) W and the optional iodines being the sole substituents of the second phenyl group; wherein each W is independently selected from —OH, —COOH, —SO.sub.3H, —OPO.sub.3H.sub.2, —O—(C.sub.1-4alkyl), —O—(C.sub.1-4alkyl)OH, —O—(C.sub.1-4alkyl)R.sup.2, —O—(C.sub.2H.sub.sO).sub.qR.sup.1 —(C═O)—O—C.sub.1-4alkyl and O—(C═O)C.sub.1-4alkyl; wherein R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is —COOH, —SO.sub.3H, or —OPO.sub.3H.sub.2; wherein q is an integer from 1 to 4; and wherein the group W may be in the form of a pharmaceutically acceptable salt; and (b) a pyridyl group; which is optionally in the form of a pyridinium ion.

2. A medical device according to claim 1, wherein the first pendant group is coupled to the PVA through an ether, ester, amide or 1,3 dioxane group.

3. A medical device according to claim 1, wherein the second pendant group is coupled to the PVA through an ether, ester, amide or 1,3 dioxane group.

4. A medical device according to claim 1, wherein the first pendant group is a group according to formula 1A or 1B ##STR00073## ##STR00074## wherein X is independently either a bond or is a linking group having a chain of 1 to 6 atoms selected from C, N, S and O, directly between the phenyl group and the coupling group, provided that the chain contains no more than one atom selected from N, S and O; wherein C is optionally substituted by a group selected from C.sub.1-4 alkyl; wherein N is substituted by R.sup.3, wherein R.sup.3 is selected from H and C.sub.1-4 alkyl; and wherein S is either an —S(O)— or —S(O).sub.2— group; G is a coupling group through which the group of the formula 1A is coupled to the PVA and is selected from ether, ester and amide; and n is an integer from 1 to 5.

5. A medical device according to claim 1, wherein the second pendant group is of the formula 2A, 2B, 2C or 2D ##STR00075## ##STR00076## ##STR00077## ##STR00078## wherein X is independently either a bond or is a linking group having a chain of 1 to 6 atoms selected from C, N, S and O, directly between the phenyl group and the coupling group, provided that the chain contains no more than one atom selected from N, S and O; wherein C is optionally substituted by a group selected from C.sub.1-4 alkyl; wherein N is substituted by R.sup.3, wherein R.sup.3 is selected from H and C.sub.1-4 alkyl; and wherein S is either an —S(O)— or —S(O).sub.2— group; G is a coupling group through which the group of the formula 2A or 2C is coupled to the polyvinyl alcohol and is selected from ether, ester and amide; W is independently selected from —OH, —COOH, —SO.sub.3H, —OPO.sub.3H.sub.2, —O—(C.sub.1-4alkyl), —O—(C.sub.1-4alkyl)OH, —O—(C.sub.1-4alkyl)R.sup.2, —O—(C.sub.2H.sub.5O).sub.qR.sup.1 —(C═O)—O—C.sub.1-4alkyl and —O—(C═O)C.sub.1-4alkyl; wherein R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is —COOH, —SO.sub.3H, or —OPO.sub.3H.sub.2; wherein q is an integer from 1 to 4; and wherein the group W may be in the form of a pharmaceutically acceptable salt; and PYR is a pyridyl group; n2 is an integer from 0 to 4; p is an integer from 1 to 3; q is an integer from 1 to 4; and n2 + p is an integer from 1 to 5.

6. A medical device according to claim 4 wherein X is selected from the group consisting of a bond, C.sub.1-6alkylene groups; C.sub.1-5 alkoxylene groups, groups of the formula — (CH.sub.2)y—O—(CH.sub.2).sub.z— wherein y and z are, independently, 1, 2 or 3, and y + z is an integer from 2 to 5; and groups of the formula —N(R.sup.3)(CH.sub.2).sub.n3- wherein R.sup.3 is H or C.sub.1-4 alkyl.

7. A medical device according to claim 4 wherein X is selected from the group consisting of a bond, methylene, ethylene, oxymethylene and oxyethylene, —CH.sub.2—O—CH.sub.2— and —NH(CH.sub.2)—.

8. A polymer according claim 1 wherein W is, independently in each case, selected from —OH, —COOH, —SO.sub.3H, —O—(C.sub.1-4alkyl), —O—(C.sub.1-4alkyl)OH, —O—(C.sub.1-4alkyl)R.sup.2, —O—(C.sub.2H.sub.5O).sub.qR.sup.1 —(C═O)—O—C.sub.1-4alkyl and —O—(C═O)C.sub.1-4alkyl, wherein R.sup.1 is H or C.sub.1-4 alkyl; and R.sup.2 is —COOH, or —SO.sub.3H, and q is an integer from 1 to 4.

9. A medical device according to claim 1 wherein W is, independently in each case, selected from —OH, —COOH, —SO.sub.3H, —O—(C.sub.1-4alkyl)R.sup.2 and —O—(C.sub.2H.sub.5O).sub.qR.sup.1; wherein R.sup.1 is H or C.sub.1-4 alkyl; R.sup.2 is —COOH or —SO.sub.3H; and q is an integer from 1 to 4.

10. A medical device according to claim 1, wherein W is, independently in each case, selected from —SO.sub.3H and—O—(C.sub.1-4alkyl)R.sup.2; wherein R.sup.2 is —SO.sub.3H .

11. A medical device according to claim 1, wherein either the first pendant group is coupled to the PVA through an ether linkage and the second pendant group is coupled to the PVA through a 1,3 dioxane group or both the first pendant group and the second pendant group are coupled to the PVA through a 1,3 dioxane group.

12. A medical device according to claim 1, wherein the first pendant group is of the formula 4A and the second pendant group is of the formula 4B: ##STR00079## ##STR00080## wherein n is an integer from 1 to 4; n2 is an integer from 1 to 4; W is selected from SO.sub.3H, —O—(C.sub.1-4alkyl)SO.sub.3H and —COOH; p is 1 or 2.

13. A medical device according to claim 1, wherein the first pendant group is of the formula 4A and the second pendant group is of the formula 4D: ##STR00081## ##STR00082## wherein n is an integer from 1 to 4; W is selected from —SO.sub.3H and —COOH,; and p is 1 or 2.

14. A medical device according to claim 1, wherein the first pendant group is of the formula 4A and the second pendant group is of the formula 4E ##STR00083## ##STR00084## wherein n is an integer from 1 to 4; W is selected from —SO.sub.3H and —COOH; and p is 1 or 2. PYR is a pyridyl group.

15. A medical device according to claim 4 wherein n is 2 or 3.

16. A medical device according to claim 5 wherein p is one.

17. A medical device according to claim 1 wherein the PVA without the first and second pendant groups has a weight average molecular weight of 1 kDa to 250 kDa.

18. A medical device according to claim 1 wherein the PVA without the first and second pendant groups has a weight average molecular weight of 10 kDa to 100 kDa.

19. A medical device according to claim 1 having an iodine content of at least 10% dry weight.

20. A medical device according to claim 1, having a radiodensity of at least 500 HU.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0081] FIG. 1A shows a sample of a liquid embolic composition in PBS shortly after formation. FIG. 1B shows a second sample (PVA.sub.(146-186 kDa)-TIBA.sub.(0.4eq)-D-FSAS.sub.(0.2eq)) shortly after formation. FIG. 1C shows a mature plug of liquid embolic material following dissipation of DMSO.

[0082] FIGS. 2A-2B show an X-ray shadow graph (FIG. 2A), and a reconstructed and segmented 2D cross-section (FIG. 2B) of a sample of a liquid embolic composition with the following composition: 20% PVA(13 kDa)-TIBA(0.4eq)-FSAS(0.01eq).

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS

[0083] The present disclosure will now be described further by way of the following non-limiting examples with reference to the figures. These are provided for the purpose of illustration only and other examples falling within the scope of the claims will occur to those skilled in the art in the light of these. All references cited herein are incorporated by reference in their entirety. Any conflict between that reference and this application shall be governed by this application.

Example 1: Preparation of 2,3,5-triiodobenzaldehyde From 2,3,5-triiodobenzyl Alcohol

[0084] ##STR00054##

[0085] 2,3,5-triiodobenzaldehyde may be prepared according to example 1 of WO2015/033092.

Example 2: Preparation of 2-(2,3,5-triiodophenoxy)acetaldehyde

[0086] ##STR00055##

(A) Synthesis of 2-(2,4,6-triiodophenoxy)ethanol from 2,4,6-triiodophenol

[0087] This compound may be prepared according to example 2(a) of WO2015/033092.

(B) Oxidation of 2-(2,4,6-triiodophenoxy)ethanol to 2-(2,3,5-triiodophenoxy) acetaldehyde

[0088] This compound may be prepared according to example 2(b) of WO2015/033092.

Example 3: Preparation of 1-(2,2-dimethoxyethoxymethyl)-2,3,5-triiodo-benzene From 2,3,5-triiodobenzyl alcohol and 2-bromo-1,1-dimethoxy-ethane (Example of a radiopaque acetal/protected aldehyde)

[0089] ##STR00056##

[0090] This compound may be prepared according to example 3 of WO2015/033092.

Example 4: Synthesis of 3,5-diiodo-2-(2-(2-methoxyethoxy)ethoxy) benzaldehyde

[0091] ##STR00057##

[0092] To a HEL PolyBlock8 parallel synthesis 125 ml reactor fitted with a reflux condenser and suspended magnetic stirrer, was added 3,5-diiodosalicylaldehyde (13.9011 g, 37.72 mmol, 1.0 eq) and TBAI (2.7481 mg, 0.802 mmol, 0.2eq). To this was added water and the pH adjusted to 9.5 with 1 M NaOH (total aqueous volume 97 ml). The reactor was set to 500 rpm stirring until full dissolution to give a bright yellow solution and 1-bromo-2-(2-methoxyethoxy)ethane (5.00 ml, 37.17 mmol, 1.0eq) was added. The reactor zone was set to heat to 120° C.

[0093] The reaction was monitored by Thin Layer Chromatography (TLC) (30%EA in i-hex) and after 2 hours additional bromide was added (2.50 ml, 18.59 mmol, 0.5eq). After a further 0.5 hours, the pH was readjusted to 9.5 due to consumption of the bromide. After a further 2 hours additional bromide (1.25 ml, 9.29 mmol, 0.25eq) were added and the reactor temperature was lowered to 50° C. and left to stir overnight.

[0094] After 19 hours, the resulting suspension was reheated to reflux for 1 hour, cooled to room temperature and transferred to a separating funnel in ethyl acetate (400 ml). The organics were washed twice with saturated sodium bicarbonate, dried with magnesium sulfate, hot filtered from toluene, and recrystallised from toluene/isohexane to give, after filtration and hi-vacuum drying, the desired product as a yellow powder:

[0095] (15.2909 g, 86.4% yield); δ.sub.H (CDCl.sub.3, 500.1 MHz)/ppm; 10.31 (1H, s), 8.31 (1H, d, 2.2 Hz), 8.09 (1H, d, 2.2 Hz), 4.26 (2H, app. t, 4.5 Hz), 3.89 (2H, app. t, 4.5 Hz), 3.67 (2H, app. t, 4.6 Hz), 3.55 (2H, app. t, 4.6 Hz), 3.38 (3H, s); δ.sub.C NMR (CDCl.sub.3, 125.8 MHz)/ppm; 188.71 (CH), 161.55 (q), 152.43 (CH), 137.57 (CH), 131.75 (q), 94.07 (q), 89.19 (q), 75,56 (CH2), 71.90 (CH2), 70.79 (CH2), 70.06 (CH2), 59.13 (CH3).

Example 5: Synthesis of 3-Hydroxy-2,4,6-triiodobenzaldehyde

[0096] ##STR00058##

[0097] To a 2 L 3-necked round bottomed flask with large oval stirrer bar was added 3-hydroxybenzaldehyde (10.007 g, 81.89 mmol), sodium iodide (0.614 g, 4.09 mmol, 0.05 eq) and sodium carbonate (93.028 g, 877.44 mmol, 10.7 eq), rinsed in with a total of 750 ml of deionised water. When the benzaldehyde had dissolved to give a bright yellow stirred solution, iodine balls (70.008 g, 275.80 mmol, 3.37 eq) was added in 2 portions over 30 minutes and rinsed in with 225 ml of water each time. The reaction is followed by TLC (60%DCM in i-hex) and over 3 hours, the iodine almost completely dissolves resulting in a dark yellow/orange precipitate. The solid was isolated by Büchner filtration and washed with i-hexane to remove any residual iodine. The isolated solid was re-dissolved in warm water (2 L, 45° C.) to give a clear brown solution to which 100 ml of saturated sodium thiosulfate solution were added to reduce any remaining iodine. The pH of the solution was cautiously reduced from 10.2 to 3.26 using 1 M HCl (with care taken due to evolution of CO.sub.2). The solid was isolated by filtration, washed with water (2 × 500 ml) and dried in a high vacuum oven at 30° C. to give the desired compound as a yellow solid: (37.002 g, 90.3% yield, 97.2% HPLC purity); δ.sub.H (CDCl.sub.3, 500.1 MHz)/ppm; 9.65 (1H, s), 8.35 (1H, s), 6.42 (1H, s); δ.sub.C NMR (CDCl.sub.3, 125.8 MHz)/ppm; 194.90 (CH), 155.12 (q), 149.77 (CH), 135.69 (q), 88.78 (q), 87.66 (q), 85.70 (q).

Example 6: Synthesis of 2,4,6-triiodo-3-(2-(2-methoxyethoxy)ethoxy)benz aldehyde

[0098] ##STR00059##

[0099] To a flame dried 250 ml 3-necked round bottomed flask under a nitrogen atmosphere containing a stir bar and fitted with a reflux condenser, were added 3-hydroxy-2,4,6-triiodobenzaldehyde (15.627 g, 31.3 mmol, 1.0eq), sodium iodide (469 mg, 3.13 mmol, 0.1eq), anhydrous sodium carbonate (3.981 g, 37.6 mmol, 1.2eq) and anhydrous dimethylformamide (DMF) (160 ml).

[0100] The suspension was stirred until the aldehyde had completely dissolved, then 1-bromo-2-(2-methoxyethoxy)ethane (6.87 g, 37.5 mmol, 1.2eq) was added by syringe and the reaction heated to reflux. After 2 hours, TLC analysis (10%EA in i-hex) indicated the start material was consumed and the reaction was cooled to room temperature, transferred to a 250 ml round bottomed flask and evaporated to dryness under high vacuum. The resulting suspension was diluted with 500 ml of ethyl acetate, washed with 3 × 100 ml 1 M NaOH, 2 × 100 ml saturated brine, decolourised with activated charcoal and dried with magnesium sulfate. The resulting solution was concentrated to dryness, and purified by silica column chromatography (2-20% ethyl acetate in i-hexane) and dried under high vacuum to give the desired compound as a yellow powder:

[0101] (7.556 g, 40.1%); δ.sub.H (CDCl.sub.3, 500.1 MHz)/ppm; 9.65 (1H, s), 8.44 (1H, s), 4.20 (2H, t, 6.4 Hz), 4.01 (2H, t, 6.4 Hz), 3.79 (2H, app. t, 5.8 Hz), 3.60 (2H, app. t, 5.8H), 3.41 (3H, s); δ.sub.C NMR (CDCl.sub.3, 125.8 MHz)/ppm; 194.97 (CH), 159.10 (q), 150.83 (CH), 138.27 (q), 97.06 (q), 95.70 (q), 90.40 (q), 72.47 (CH2), 72.04 (CH2), 70.89 (CH2), 68.89 (CH2), 59.19 (CH3).

Example 7: Synthesis of 2,4,6-Triiodo-3-(2-(2-(2-methoxyethoxy)ethoxy) ethoxy)benz aldehyde

[0102] ##STR00060##

[0103] To a flame dried 100 ml 3-necked round bottomed flask containing a stirrer under a nitrogen blanket, was added triphenylphosphine (1.7216 g, 6.502 mmol, 1.3eq) and anhydrous tetrahydrofuran (THF) (35 ml). The stirring was started and, after full dissolution of the triphenylphosphine (PPh3), the reactor was cooled to ca 0° C. in an ice-bath. To the colourless solution was added to Diisopropyl azodicarboxylate (DIAD) (1.28 ml, 6.502 mmol, 1.3eq) dropwise via syringe resulting in a persistent yellow solution. After stirring for 5 minutes, triethylene glycol monomethyl ether (1.04 ml, 6.502 mmol, 1.3eq) was added dropwise by syringe. After stirring for a further 5 minutes, the 3-hydroxy-2,4,6-triiodobenzaldehyde (2.5077 g, 5.002 mmol, 1.0eq) was added in one portion resulting in an immediate colour change. The reaction was monitored by TLC (5%Et.sub.2O in toluene) and left to stir overnight. The solution was diluted with ether to precipitate triphenylphosphine oxide and then concentrated to dryness. The resulting thick oil was purified by column chromatography (2-10% Et.sub.2O in toluene) to give, after concentration and high vacuum drying, the desired product as a yellow powder: (3.2077 g, 99% yield, 94.4% HPLC purity); δ.sub.H (DMSO-D.sub.6, 500.1 MHz)/ppm; 9.58 (1H, s), 8.47 (1H, s), 4.08 (2H, t, 4.9 Hz), 3.57-3.53 (4H, m), 3.44 (2H, app. t, 4.8 Hz), 3.24 (3H, s).

Example 8: Synthesis of 3,4,5-Triiodosalicylaldehyde

[0104] ##STR00061##

[0105] To a 3-necked 2 L round bottomed flask containing a large oval stirrer was added 4-iodo-salicilaldehyde (25.01 g, 100.86 mmol, 1.0eq) and acetic acid (300 ml). After stirring for 5 minutes to allow the solid to dissolve, pre-warmed liquid iodine monochloride (39.11 g, 2.4eq) was diluted with AcOH (100 ml) and transferred to a dropping funnel on the round bottomed flask. This solution was added over 10 minutes.

[0106] The reactor was then placed in a large silicone oil batch a fitted with a 1 L dropping funnel, thermometer and condenser and set to heat to 80° C. During the heat up, water (700 ml) was slowly added to the solution causing a yellow/orange precipitation. After 20 mins at 80° C., the heating was turned off. After a further 30 minutes the heating bath was removed and the black solution/yellow suspension allowed to cool to room temperature and stirred for 65 hours; the reaction was analysed by TLC (20%EA in iHex). The solid was isolated by Büchner filtration and washed with water (2 × 500 ml). To remove residual iodine crystals, the solid was repeatedly re-slurried with i-hexane (200 ml) until the i-hexane supernatant was no longer purple. The isolated solid was dried in a high-vacuum oven overnight to give the desired product as a yellow crystalline solid (40.84 g, 81% yield, 93.2% pure by HPLC analysis).

[0107] The product could be further recrystallised to higher purity from acetone:water (9:1): δ.sub.H (CDCl.sub.3, 500.1 MHz)/ppm; 12.15 (1H, s), 9.67 (1H, s), 8.09 (1H, s); δ.sub.C NMR (CDCl.sub.3, 125.8 MHz)/ppm; 194.53 (CH), 159.58 (C), 142.24 (CH), 133.39 (C), 120.87 (C), 101.68 (C), 94.02 (C).

Example 9: Synthesis of 3,4,5-Triiodo-2-(2-(2-methoxyethoxy)ethoxy) benz-aldehyde

[0108] ##STR00062##

[0109] (5 g scale): To a flame dried 3-necked 250 ml round bottomed flask containing a small octagonal stirrer bar under a positive pressure of nitrogen, was added triphenylphosphine (2.76 g, 10.5 mmol, 1.05eq) and dry THF (70 ml) by syringe. The round bottomed flask was placed in a Dewer bath fitted with a low temperature thermometer and cooled to -68° C. with an ethanol/liquid nitrogen bath. Diethyl azodicarboxylate (1.65 ml, 10.5 mmol, 1.05eq) was added dropwise by syringe over 1 minute and left to stir for 5 minutes to give a yellow suspension. Diethyleneglycol mono-methyl ether (1.77 ml, 15 mmol, 1.5 eq) was then added dropwise and left to stir for 5 minutes. To this was added solid 3,4,5-triiodosalicylaldehyde (5.00 g, 10.0 mmol, 1.0 eq) in one portion. The initial dark orange/red suspension lightened to give a pale yellow solution which was allowed to stir for 2 hours, monitored by TLC analysis (20%ether in toluene) and left to warm up to room temperature overnight. TLC indicated complete consumption of aldehyde starting material with a clean reaction profile. The resulting solution was transferred to a 500 ml round bottomed flask, diluted with ether (200 ml) and cooled in the freezer. The resulting suspension was filtered through a short silica plug to remove triphenylphosphine oxide and flushed with further ether (200 ml). The resulting solution was concentrated to dryness, and purified by column chromatography eluting with ether in toluene (2-20%) with product fractions concentrated to dryness and dried under high vacuum to give the desired product as a yellow amorphous solid (4.91 g, 82% yield, 96% HPLC purity); δ.sub.H (CDCl.sub.3, 500.1 MHz)/ppm; 10.26 (1H, s), 8.34 (1H, s), 4.22 (2H, t, 4.5 Hz), 3.90 (2H, t, 4.5 Hz), 3.90 (2H, t, 4.6 Hz), 3.55 (2H, t, 4.6 Hz), 3.38 (3H, s); δ.sub.C NMR (CDCl.sub.3, 125.8 MHz)/ppm.

Example 10: Synthesis of 5-((2,2-Dimethoxyethyl)amino)-2,4,6-triiodoisophthalic acid

[0110] ##STR00063##

[0111] To a flame dried 500 ml round bottomed flask under nitrogen, was added solid 5-amino-2,4,6-triiodoisophthalic acid (46.95 g, 84.03 mmol, 1.0eq), sodium bicarbonate (28.21 g, 335.8 mmol, 4.0eq) and DMF (ca 400 ml) via cannula. To the resulting brown solution was added 2-bromo-1,1-dimethoxyethane (13 ml, 110.0 mmol, 1.3eq) dropwise and the resulting solution heated to reflux for 18 hours. After cooling to room temperature, the majority of DMF was removed by rotary evaporation under vacuum (9 mBar, 55° C.) and the resulting orange solid extracted with ethyl acetate (1 L).

[0112] This suspension was washed with saturated lithium chloride solution (7 × 400 ml) to remove residual DMF and salts, dried over magnesium sulfate, filtered and evaporated to dryness. The resulting solid was recrystallised from ethyl acetate, washed with i-hexane and filtered. This process was repeated a total of 3 times and the resulting orange solid dried under high vacuum to give the title compound (33.04 g, 61%, 91.7% HPLC purity).

[0113] The product could be further purified via silica gel column chromatography (MeOH in DCM, 0-15%) (4.91 g, 82% yield, 96% HPLC purity); δ.sub.H (CDCl.sub.3, 500.1 MHz)/ppm; 8.01 (1H, s), 4.86 (2H, br s), 4.76 (1H, t, 5.5 Hz), 4.37 (2H, d, 5.5 Hz), 3.44 (6H, s); δ.sub.C NMR (CDCl.sub.3, 125.8 MHz)/ppm.

Example 11: Synthesis of Potassium 3-(3-formyl-2,4,6-triiodophenoxy) propane-1-sulfonate and 3-(1-formyl-3,4,5-triiodophenoxy)propane-1-sulfonate, sodium salt

[0114] ##STR00064##

[0115] In a 150 mL three-neck round bottom flask, 3-hydroxy-2,4,6-triiodobenzaldehyde (10 g, 20 mmol, 1.0eq) was dissolved in anhydrous THF(50 ml) by magnetic stirrer. Potassium t-butoxide (2.47 g 22 mmol, 1.1eq) was mixed with 20 mL of THF and the suspension was added slowly into the flask under nitrogen atmosphere at room temperature, followed by increasing temperature to 40° C. to allow a full dissolution of product. Then sultone (15 g, 120 mmol, 6.0eq) of was dissolved in 15 mL of THF and the mixture was added slowly to the reaction flask. A precipitation appeared almost immediately. After 3 hours reaction at 40° C., the reaction mixture was poured into 500 mL of ethyl acetate to receive solid raw product. The filtered solid was washed with 100 mL of ethyl acetate, and recrystallized from ethanol. After vacuum drying over 24 hours, the desired product (10.7 g, 80%yield,) was isolated; δ.sub.H (D.sub.2O, 500.1 MHz)/ppm; 2.24-2.34 (m, 2H), 3.12-3.25 (t, 2H), 3.88-4.02 (t, 2H), 8.18-8.25 (s, 1H), 9.42-9.50 (s, 1H) δ.sub.C NMR (CDCl.sub.3, 125.8 MHz)/ppm; Element analysis result: C18.56, H 2.22, S 5.66, I 52.31, K 6.27. Cal: C 18.20, H 1.22, S 4.85, I 57.68, K 5.92.

[0116] 3-formyl-3,4,5-triiodophenoxy)propane-1-sulfonate, sodium salt was synthesized analogously from 3,4,5-triiodosalicylaldehyde (see example 8).

Example 12: General Coupling Conditions

[0117] To a pre-dried reactor under a nitrogen blanket is added PVA (typically 5-10 g) and anhydrous solvent (typically DMSO or NMP, 40 vol with respect to (w.r.t.) PVA mass) and catalyst (typically 2.2 vol w.r.t. PVA mass). The stirred suspension is heated to elevated temperature (ca 90° C.) to dissolve the PVA. When a homogeneous solution had been obtained, the mixture is cooled to the desired reaction temperature (typically 50-80° C.) the desired aldehyde substrate for the first and second pendant groups (typically 0.01 to 0.6eq w.r.t. PVA diol functionalities) are added. The actual ratio of first and second pendant group aldehyde substrate to PVA 1,3-diol groups, and the ratio of first to second pendant groups, will depend on the tuning of hydrophilic to hydrophobic nature of the polymer required, but typically the first pendant group will be at a higher ratio than the second.

[0118] The reaction is then stirred under an N.sub.2 blanket and the reaction conversion is monitored by HPLC for consumption of substrate. At a pre-determined time (typically when consumption of the substrate has ceased) an anti-solvent is added (typically, acetone, DCM, MeCN or TBME, ca 40vol) dropwise from a dropping funnel.

[0119] The supernatant fluid is removed by aspiration through a filter membrane and further reaction solvent (typically 40 vol) is charged and stirred until the solids had fully dissolved. This solvent washing stage is repeated up to 3 times. Then the solid is re-dissolved in reaction solvent, and precipitated by the slow addition of water (typically up to 100 vol).

[0120] The resulting aggregated solid is removed from the supernatant and homogenised in a blender in water. The suspension is filtered and re-suspended in water (typically 100 vol), slurried for up to 30 minutes and filtered. The water slurrying is repeated until pH neutral had been obtained, then the damp solids are slurried in acetone (100 vol, 30 mins stir, 2 repetitions), filtered and dried in a high vacuum oven at 30° C. for up to 24 hours.

Example 13: Preparation of PVA Polymers Having a First Iodinated Pendant Group and a Second Non Iodinated Pendant Group on the Same PVA Backbone

[0121] The following polymers were prepared:

[0122] First pendant group:

##STR00065##

TABLE-US-00002 (a) (b) (c) (d) Second Pendant Group [00066] [00067] [00068] [00069]

[0123] A dry 600 ml HEL Ltd PolyBLOCK® vessel (Borehamwood WD6 1GW, United Kingdom) was purged with nitrogen and provided with a nitrogen blanket. Dry DMSO (120 ml, 40.2 vol) was added with stirring at 500 rpm, followed by PVA (146-189 kDa, 99% hydrolysed, 5.0 g). The suspension was heated to 50° C. (internal probe) until all solids were completely dissolved. 1, 3, 5-triiodobenzaldehyde (TIBA) was then added (10.4 g, 0.4eq w.r.t. PVA-1,3-diol units) followed by 0.05eq of either: [0124] (a) 2-sulfobenzaldehyde sodium salt, (Sigma Aldrich UK) (FSAS) [0125] (b) 4-formylbenzene 1,3 disulfonic acid disodium-salt, (Sigma Aldrich UK) (D-FSAS) [0126] (c) 4-formylbenzoic acid (Sigma Aldrich UK) (FBAS); or [0127] (d) 4-pyridinecarboxyaldehyde (Sigma Aldrich UK) (Pyr)

[0128] After full dissolution, methanesulfonic acid (11 ml, 3.37 vol), diluted with ~20 mL of cold DMSO and added and stirring continued overnight at 50° C. The pale-yellow solution was cooled to room temperature and transferred into1 L glass breaker containing a large stirrer bar. Acetonitrile (250 mL) was then added from a dropping funnel to precipitate the product.

[0129] The yellow supernatant was removed by vacuum and the resulting white polymer slowly re-dissolved in a minimum amount of DMSO (~100 ml) at 50° C. and re-precipitated with acetonitrile. Excess solvent was removed by vacuum. The white polymer was suspended in NaOH 0.1N solution (100 mL) for 20 min, then gently blended to achieve a homogeneous suspension that was carefully neutralised with deionised water (100 ×3) until pH=7 after removal of the excess solvent. The obtained white polymer was suspended in acetone (100 mL ×3) after removing excess water by vacuum and the solid isolated by filtration, using a Büchner funnel. The solid was then dried in a vacuum oven at 28-32° C. overnight to give the desired product (white solid 11-13.0 g, ~75-80% w/w yield). Table 2 gives the elemental analysis of a selection of these polymers.

[0130] A 20% (w/w) solution in DMSO, of each polymer, was prepared. The solutions were injected into PBS and quickly gelled and solidified as the DMSO dissipated in the water. An example is shown in FIGS. 1A-1C.

TABLE-US-00003 Sample C H N S I Na PVA(146-186 KDa) TIBA(0.4) FBASS(0.2) 32.46 3.11 <0.1 <0.1 47.61 1.26 PVA(146-186 KDa) TIBA(0.4) Pyr (0.2) 30.72 3.02 0.68 <0.1 53.98 <0.01 PVA(146-186 KDa) TIBA(0.4) D-FSAS(0.2) 37.84 2.91 <0.1 3.34 46.23 2.02

Example 14: Preparation of PVA Polymers Having a First Iodinated Pendant Group and a Second Iodinated Pendant Group on the Same PVA Backbone

[0131] The following polymers were prepared:

[0132] First pendant group:

##STR00070##

TABLE-US-00004 (a) (b) Second pendant group: [00071] [00072]

[0133] To a dry 50 ml HEL Ltd PolyBLOCK® vessel degassed, purged with nitrogen and provided of a nitrogen blanket, dry DMSO (20 ml) was added stirring at 500 rpm. Then PVA (13-23 kDa, 99% hydrolysed, 1.0 g) was added heating to 65° C. (internal probe) stirring at 500 rpm until all the solids was completely dissolved. After this time, TIBA, 2.2 g, 0.4eq w.r.t. PVA-1,3-diol units) followed by either: [0134] a. 3-(3-formyl-2,4,6-triiodophenoxy)propane-1-sulfonate, sodium salt; or [0135] b. 3-(1-formyl-3,4,5-triiodophenoxy)propane-1-sulfonate, sodium salt,at (0.1 eq w.r.t PVA-1,3-diol units). After full dissolution, methanesulfonic acid (2.2 ml) was added dropwise stirring the reaction at 65° C. overnight. The orange solution was cooled to room temperature and poured dropwise in to 500 mL glass breaker containing acetone 200 mL. A white solid was recovered and re-dissolved in DMSO 50 mL and precipitated again in acetone 500 mL. The solid was collected on a Buchner funnel and the excess of acid neutralised with 0.1N NaOH solution (~100 mL) washing with deionised water until a neutral pH was achieved. The solid was then dried in a hi-vacuum oven at 28- 32° C. overnight to give the desired product as off-white solid (3.0 g, ~70% w/w yield). A 20% (w/w) solution in DMSO, of each polymer, was prepared.

Example 15: General Preparation of Liquid Embolic Prototypes

[0136] A sample prototype is prepared in the following fashion: iodinated PVA prepared according to the above examples, is weighed into a 10 ml vial, to which is added the desired solvent (typically DMSO or NMP) such that the overall concentration is in the range 4-20%w/w with a total volume being less than 10 ml. The vial containing the thick suspension is then sealed, placed in a sonicator and sonicated until complete dissolution had occurred (typically ca. 4 hours).

Example 16: Precipitation of Liquid Embolic Under Flow Conditions

[0137] A clear detachable tube was attached to a flow system through which PBS (Biosciences, UK) was pumped using a peristaltic pump to mimic blood flow conditions. A 2.4 Fr catheter was used to deliver the liquid embolic preparation into the detachable tube. As the liquid embolic leaves the catheter and comes into contact with PBS, it is precipitated or gelled inside the detachable tubing. Observations on the length, and other characteristics of the precipitated/gelled polymer where then recorded. Flow rate and rate reduction are also recorded. The “longest length of advancement” is recorded. If reflux of the embolus occurs, its length is also recorded as the “longest length of reflux” (cm).

TABLE-US-00005 Sample Conc. (%, w/w) Viscosity @ 24° C. (cP) Longest length of advance (cm) Longest length of reflux (cm) Embolization efficiency Observation PVA.sub.13 kDa-TIBA.sub.0.4eq- FSAS.sub.0.01eq 20.0% 103.0 7.1 3.2 96.2% Stringing at first, then lava like flow.sup.∗. Embolisation further away from catheter. Opaque plug. PVA.sub.31 kDa-TIBA.sub.0.6eq-FSAS.sub.0.1eq 27.5% 1517.0 4.9 1.0 100.0% Lava like flow, gel like plug. Injection resistance high. Transparent plug. PVA.sub.31 kDa-TIBA.sub.0.4eq-FSAS.sub.0.1eq 20.0% 297.0 5.5 1.7 >98% Stringing at first, then lava like Flow. Transparent gel plug. PVA.sub.13 kDa-TIBA.sub.0.6eq-FSAS.sub.0.1eq 20.0% 109.0 2.9 3.0 100.0% Weak gel, formed string. No lava like flow. Transparent gel plug. .sup.∗In lava-like flow, the embolic composition initially forms a slight crust on the surface, which inhibits stringing. The crust fractures as the embolic advances and the reforms on the advancing portion, and so on.

Example 17: X-Ray Analysis of Precipitated Liquid Embolic Samples

[0138] In order to obtain radiopacity measurements for the material, 1 cm sections of precipitated formulations are cut and embedded in warm (55° C.) 1% agarose in a polypropylene capped tube, (Nunc cryotube vials - Sigma-Aldrich product code V7634, 48 mm × 12.5 mm) and scanned using Micro-CT according to the following protocol:

[0139] Samples were tested for radiopacity using micro-Computer Tomography (Micro-CT) using a Bruker Skyscan 1172 Micro-CT scanner at the RSSL Laboratories, Reading, Berkshire, UK, fitted with a tungsten anode. Each sample was analysed using the same instrument configuration with a tungsten anode operating at a voltage of 64 kV and a current of 155 .Math.A. An aluminium filter (500 .Math.m) was used. A two part analysis method is used. Initially an interpolated region of interest is created coving the inner tube diameter to include the plug and any void structures then the image is segmented to isolate the polymer from the void structures so as to report only polymer radiodensity. The radiodensity in HU was then calculated using the water standard acquired on the same day. Table 4 gives the acquisition parameters.

TABLE-US-00006 Software: SkyScan1172 Version 1.5 (build 14) NRecon version 1.6.9.6 CT Analyser version 1.13.1.1 Source Type: 10 Mp Hamamatsu 100/250 Camera Resolution (pixel): 4000 × 2096 Camera Binning: 1 × 1 Source Voltage 65 kV Source Current uA 153 Image Pixel Size (um): 3.96 Filter Al 0.5 mm Rotation Step (deg) 0.280 Output Format 8 bit BMP Dynamic Range 0.000 - 0.140 Smoothing 0 Beam Hardening 0 Post Alignment corrected Ring Artefacts 16

[0140] A small amount of purified MilliQ® water was carefully decanted into each sample tube. Each sample was then analysed by X-Ray micro-computer tomography using a single scan, to include the water reference and the sample (one such scan is shown in FIG. 2A). The samples were then reconstructed using NRecon and calibrated against a volume of interest (VOI) of the purified water reference (see FIG. 2B). A region of interest (ROI) of air and water was analysed after calibration to verify the Hounsfield calibration.

[0141] Radiodensity was reported in Hounsfield units. Values used for dynamic range for all samples in NRecon (thresholding): -0.005, 0.13 (minimum and maximum attenuation coefficient).

[0142] A polymer having the following composition: PVA(13 kDa)-TIBA(0.4 eq)-FSAS(0.01 eq) was dissolved in DMSO (20% w/w) and sealed inside a 0.58 mm polyethylene tubing for by microCT test (the tubing was embedded in agarose gel). The measured radiodensity was 6752 HU and the calculated iodine content of the solution is around 140 mg I/mL. Radiodensity figures for samples of liquid embolic compositions are given in Table 5.

Example 18. Viscosity Measurement

[0143] The viscosity of liquid embolics compositions prepared according to the above examples was measured using an Anton-Paar MCR 302 rheometer with 60 mm cone geometry. The temperature sweep was in the range of 20- 40° C. and constant sear rate 5.0 s.sup.-1 was applied. Sample results at 24° C. are given in Table 5 below.

Example 19: Water Content

[0144] The water content of the polymer was measured by dropping 1 mL of polymer DMSO solution into PBS to form rough spheres of a size of about 3-5 mm in diameter. After equilibrating in 500 mL of fresh PBS for 24 hr, the spheres were wicked dry with tissue to remove surface water and the weights were measured. The spheres were then dried in a vacuum oven over night at 50° C. The water content is expressed as percent by weight water, see Table 5.

TABLE-US-00007 Iodine content in solid (w/w %) TIBA/FSAS Molar ratio, Actual (calculated) Conc. of DMSO solution (w/w) % Radiopacity (HU) Viscosity @ 24° C. (cP) Hydrogel water content at equilibrium (%) PVA.sub.13 kDa-TIBA.sub.0.4eq-FSAS.sub.0.05eq 53% 5.6 (8.0) 25.0% 7388 289.7 71.1±0.6 PVA.sub.31 kDa-TIBA.sub.0.6eq-FSAS.sub.0.1eq 57% 4.5 (6.0) 27.5% 8697 1517.0 62.2±0.2 PVA.sub.31 kDa-TIBA.sub.0.4eq-FSAS.sub.0.1eq 52% 2.7 (4.0) 20.0% 6597 297.0 73.9±0.2 PVA.sub.13 kDa-TIBA.sub.0.6eq-FSAS.sub.0.1eq 61% 3.6 (6.0) 20.0% 7011 109.0 68.8±1.8