IODINATED COMPOUNDS HAVING RADIOCONTRAST PROPERTIES

Abstract

The present disclosure pertains to iodinated compounds that comprise at least one 2,4,6-triiodobenzene moiety in which at least one of the hydrogens at 1-, 3- and 5-positions of the 2,4,6-triiodobenzene moiety is substituted by an iodinated substituent that comprises one or more iodophenyl-containing groups. The present disclosure also pertains to compositions containing such iodinated compounds and methods of making such iodinated compounds.

Claims

1. A composition comprising one or more iodinated compounds that comprise at least one 2,4,6-triiodobenzene moiety in which at least one of the hydrogens at 1-, 3- and 5-positions of the 2,4,6-triiodobenzene moiety is substituted by an iodinated substituent that comprises one or more iodophenyl-containing groups.

2. The composition of claim 1, wherein the iodinated compounds comprise one or two 2,4,6-triiodobenzene moieties in which at least one of the hydrogens at 1-, 3- and 5-positions of each of the 2,4,6-triiodobenzene moieties is substituted by an iodinated substituent that comprises one or more iodophenyl-containing groups.

3. The composition of claim 1, wherein the one or more iodophenyl-containing groups are selected from one or more of mono-iodophenyl-containing groups, di-iodophenyl-containing groups, tri-iodophenyl-containing groups, tetra-iodophenyl-containing groups or penta-iodophenyl-containing groups.

4. The composition of claim 1, wherein the one or more iodophenyl-containing groups are selected from iodophenyloxy groups, iodophenylcarbonyloxy groups, or iodophenyl groups coupled via a cyclic acetal group or a carbamate group.

5. The composition of claim 1, wherein the iodinated substituent comprises a C.sub.2-C.sub.6-alkyl-amino group in which C.sub.2-C.sub.6-alkyl hydrogens are substituted by (a) the one or more iodophenyl-containing groups and (b) zero, one or a plurality of hydroxyl groups.

6. The composition of claim 1, wherein the iodinated substituent is a C.sub.2-C.sub.6-alkyl-aminocarbonyl group or a C.sub.2-C.sub.6-alkyl-carbonylamino group in which C.sub.2-C.sub.6-alkyl hydrogens are substituted by (a) the one or more iodophenyl-containing groups and (b) zero, one or a plurality of hydroxyl groups.

7. The composition of claim 1, wherein the C.sub.2-C.sub.6-alkyl-aminocarbonyl group is a C.sub.3-alkyl-aminocarbonyl group.

8. The composition of any of claim 1, wherein a molar ratio of hydroxyl groups to iodophenyl-containing groups ranges from 0:1 to 10:1.

9. A composition of claim 1, further comprising a polymer.

10. The composition of claim 9 having a radiopacity ranging from 10-1000 Hounsfield Units (HU).

11. The composition of claim 9 having an amount of iodine ranging from 5 to 40 wt % or an amount of iodine ranging from 50-900 mg I/cm.sup.3.

12. A medical supply comprising (a) a composition comprising one or more iodinated compounds that comprise at least one 2,4,6-triiodobenzene moiety in which at least one of the hydrogens at 1-, 3- and 5-positions of the 2,4,6-triiodobenzene moiety is substituted by an iodinated substituent that comprises one or more iodophenyl-containing groups and (b) a polymer.

13. The medical supply of claim 12, wherein the medical supply is an embolic composition.

14. The medical supply of claim 13, wherein the embolic composition is a liquid embolic composition.

15. The medical supply of claim 12, wherein the medical supply is a medical device.

16. The medical supply of claim 15, wherein the composition is in the form of a medical device coating.

17. A method comprising reacting (a) at least one compound that comprises at least one 2,4,6-triiodobenzene moiety in which at least one of the hydrogens at 1-, 3- and 5-positions of the 2,4,6-triiodobenzene moiety is substituted by a polyhydroxylated substituent with (b) a compound of the formula XI, formula XII, or formula XIX ##STR00021## wherein n is 1, 2, 3, 4 or 5, wherein R.sup.81 is selected from —H, —F, —Cl, —Br, —I, anhydride, —OH, an imidazolide, or an O-acylisourea, wherein R.sup.70 is —H or C.sub.1-C.sub.6 alkyl, wherein m is 0, 1, 2, 3, 4 or 5, wherein X is —O.sup.−Na.sup.+ when m is 0, and wherein X is —F, —Cl, —Br, or —I when m is 1, 2, 3, 4 or 5, under conditions such a linkage comprising a moiety selected from an ether, an ester, a cyclic acetal or a hemiacetal, is formed.

18. The method of claim 17, wherein an ester-containing linkage is formed by carbodiimide coupling, wherein an ether-containing linkage is formed by Williamson synthesis, or wherein a cyclic-acetal-containing linkage or hemiacetal is formed by acetalization of aldehyde or ketone.

19. The method of claim 18, wherein the polyhydroxylated substituent comprises a polyhydroxylated C.sub.2-C.sub.6-alkyl group.

20. The method of claim 17, wherein the at least one compound is selected from the following: ##STR00022##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIGS. 1A and 1B show the FTIR spectra of two iodinated compounds, in accordance with the present disclosure.

[0042] FIGS. 2A and 2B show proton NMR spectra of two iodinated compounds, in accordance with the present disclosure.

[0043] FIG. 3 shows micro-CT images of strands of a liquid embolic material in accordance with the present disclosure, within an agar phantom. The insets are micro-CT images of the dissection of the liquid embolic material.

[0044] FIG. 4 is an optical image of an embolization created by delivery of a liquid embolic material in accordance with the present disclosure to a 5 mm silicone tube perfused a constant flow of phosphate buffered saline (PBS) at 400 ml/min of flow rate (at 37° C.).

[0045] FIG. 5 is an optical image of a balloon that has been coated with a coating of PVA and an iodinated compound, in accordance with the present disclosure.

[0046] FIG. 6 is an illustration of pCT analysis of the coated balloon of FIG. 5 and a cross-sectional analysis of the same (insets).

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS

[0047] Iodinated compounds have been synthesized from hydrophilic contrast media, specifically, 5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N′-bis(2,3-dihydroxypropyl) isophthalamide (iohexol) (Formula XII) and 5-[acetyl-[3-[acetyl-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodo-phenyl]amino]-2-hydroxy-propyl]amino]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-benzene-1,3-dicarboxamide (iodixanol) (Formula XVII), by reaction of the available hydroxyl groups with further iodinated groups. The obtained compounds contain a high level of iodine, which may be further tuned by controlling the level of hydroxyl groups reacted. By changing the ratio of hydrophobic iodinated moieties to hydrophilic OH groups, the interaction between the additives and the media may be regulated to achieve desired viscosity fluid and solidification properties.

[0048] In addition to iodinated compounds synthesis, a liquid embolic formulation prepared from iodinated PVA with hydrophilic functional groups and an iodinated compound in accordance with the present disclosure is also described. Injectability and radiopacity were demonstrated. Embolization ability was also demonstrated by delivery of the liquid embolic material to a 5 mm silicone tube perfused a constant flow of phosphate buffered saline (PBS) at 400 ml/min of flow rate (at 37° C.).

[0049] Also described is a coating composition prepared from PVA and an iodinated compound in accordance with the present disclosure. The composition is used to coat a catheter balloon. The coating is cohesive, flexible and is stable upon repeated balloon inflation/deflation cycles and exhibits radiopacity as described more fully below. Radiopaque coatings are desirable for balloon catheter coatings since the location of the edges of the balloon and balloon surface can be tracked in real time within the body under fluoroscopy. In the current clinical practice, a balloon filled with a contrast medium to enable radiopacity; however, a radiopaque polymer coating on the outside of the balloon is an alternative to the need for contrast and allow for use of saline to inflate the balloon. Thus, by providing a radiopaque polymer coating on the outside of the balloon, balloon catheters can be improved. Because the radiopaque polymer coating can be dipped, sprayed and pad printed onto the balloon, it is possible to create different patterns of the radiopaque coating on the balloon. These patterns could also be designed in order to provide useful information to a medical profession during an interventional procedure.

Example 1: Preparation of Iohexol and Iodixanol Derivatives

[0050] Iohexol (see Formula XII) powder (2.5 grams) was charged into a 250 mL of flask and dissolved in 10 mL of anhydrous DMSO by heating to 50° C. under magnetic stirring. 2,3,5-triiodobenzoic acid (TIBA) (9.9 grams) was dissolved in 15 mL of anhydrous DMSO in a 100 mL round bottom flask, followed by adding carbonyl diimidazole (CDI) powder (3.21 grams) very slowly at room temperature with constant agitation to allow the release of generated carbon dioxide. The addition/agitation took about 30 min, and CDI-activated TIBA was generated. This reaction mixture was then added into the flask containing the Iohexol solution, and reaction was carried out under magnetic stirring at 60° C. for 20 hr. After reaction, the mixture was poured into 500 mL of sodium carbonate water solution (2.5 w/w %) with vigorous magnetic stirring. White precipitates were received and filtered through a Buchner funnel. The white powder was further washed with deionised water to remove residual Na.sub.2CO.sub.3 salt and solvent until neutral pH reached in the washing solution. The white powder was then extracted three times with 500 mL of acetonitrile at 60° C. under magnetic stirring. The final product was collected and dried in vacuum at 40° C. overnight, and 5.5 grams of powder was yielded.

[0051] Iodixanol (see Formula XVII) powder (3.0 gram) was charged into a 250 mL of flask and dissolved in 10 mL of anhydrous DMSO by heating to 50° C. under magnetic stirring. 2,3,5-triiodobenzoic acid (TIBA) (9.2 grams) was dissolved in 15 mL of anhydrous DMSO in a 100 mL round bottom flask, followed by adding carbonyl diimidazole (CDI) powder (2.98 grams) very slowly at room temperature with constant agitation to allow the release of generated carbon dioxide. The addition/agitation took about 30 min, and CDI activated TIBA was generated. This reaction mixture was then added into the flask of Iodixanol solution, and reaction was carried out under magnetic stirring at 60° C. for 20 hr. After reaction, the mixture was poured into 500 mL of sodium carbonate water solution (2.5 w/w %) with vigorous magnetic stirring. White precipitates were received and filtered through a Buchner funnel. The white powder was further washed with deionised water to remove residual Na.sub.2CO.sub.3 salt and solvent until neutral pH reached in the washing solution. The white powder was then extracted three times with 500 mL of acetonitrile at 60° C. under magnetic stirring. The final product was collected and dried in vacuum at 40° C. overnight, and 6.2 grams of powder was yielded.

[0052] Table 1 lists the theoretical iodine content and element analysis results of Iohexol and Iodixanol derivatives obtained using the reaction processes described above. The products were targeted to achieve either 100% reacted —OH groups (referred to as Iohexol derivative (I) and Iodixanol derivative (III)) or 50% reacted —OH groups (referred to as Iohexol derivative (II) and Iodixanol derivative (IV)) on these two compounds. Only about 65% to 68% iodine content were obtained, which could be explained as the effect of steric hinderance from activated intermediate 2,3,5-triiodobenzoic acid imidazolide.

TABLE-US-00001 TABLE 1 Experimental Target molecular Iodine content iodine content Compound weight in theory (%) (%) Iohexol 821.14 46.36 — Iohexol derivative (I) 3711.18 71.80 68.70 Iohexol derivative (II) 2748.33 69.26 67.40 Iodixanol 1550.19 49.12 — Iodixanol derivative 5885.16 71.14 66.66 (III) Iodixanol derivative 3958.29 67.31 65.65 (IV)

[0053] FIGS. 1A and 1B show the FTIR spectra of two of the Iohexol and Iodixanol derivatives, specifically, Iohexol derivative (I) and Iodixanol derivative (III). FIGS. 2A and 2B show proton NMR spectra of the two Iohexol and Iodixanol derivatives (in DMSO-d6 as solvent). The NMR spectra show some unreacted starting material residues, which should disappear upon further purification.

Example 2: Preparation of iodinated PVA polymer

[0054] To a dry 50 ml HEL Ltd PolyBLOCK® vessel (Borehamwood WD6 1GW, United Kingdom) degassed, purged with nitrogen and provided of a nitrogen blanket, dry DMSO (20 ml) was added stirring at 500 rpm. Then PVA (31-50 kDa, 99% hydrolysed); 5.0 g was added heating to 65° C. (internal probe) stirring at 500 rpm until all the solids was completely dissolved. After this time, 2,3,5-triiodobenzaldehyde 0.4 eq with respect to PVA-1,3-diol units (TIBA—prepared according to example 1 of WO2015/033092), followed by 2-sulfobenzaldehyde sodium salt, (FSAS, Sigma Aldrich UK) 0.075 eq.

[0055] 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 was prepared.

Example 3: Preparation of Liquid Embolic Formulation

[0056] A liquid embolic formulation was prepared from iodinated PVA polymer (I-PVA) with hydrophilic functional groups and an iodinated compound in accordance with the present disclosure, dissolved in DMSO solvent. In particular, a solution containing I-PVA (18 wt %), Iodixanol derivative (III) from Example 1 (9.5 wt %) and DMSO (72.5% wt) was prepared by adding 3.6 g of I-PVA and 1.9 g of Iodixanol derivative (III) to a vial and gently mixing the powder together. 14.5 g of DMSO was then added to make a total 20 g solution. The vial was sealed and roller-mixed for at least 4 hours until both powders are fully solubilized in the solvent (DMSO). The vial was sterilized using dry-heat (121° C. for 0.5 hour).

[0057] Injectability was characterized by a dynamic viscosity (p) measurement using an Anton-Paar MCR 302 rheometer with a temperature sweep from 15° C. to 40° C. at 2.5° C./min, yielding a viscosity value at 20° C. of p=400 mPa s. Radiopacity (R) was characterized by micro-CT analysis to calculate the radiopacity in Hounsfield Unit (HU) of the liquid formulation, yielding a radiopacity value of R=7052 HU. Micro-CT images are presented in FIG. 3, which of shows strands of the liquid embolic material within an agar phantom. The insets of FIG. 3 are CT images of the dissection of the liquid embolic material. Embolization efficiency was shown by delivery of the liquid embolic material to a 5 mm silicone tube perfused to a constant flow of phosphate buffered saline (PBS) at 400 ml/min of flow rate (at 37° C.). Flow reduction greater than 99% was observed. FIG. 4 is an optical image of the resultant embolization.

Example 4: Radiopaque Coating on Balloon Catheter

[0058] PVA coating solutions were prepared in DMSO solvent at various concentrations with the radiopaque additive. In a specific case, PVA polymer (MW 31-50 kDa, 98% hydrolysed, available from Sigma-Aldrich) at 7% (w/w) was mixed with 8% to 23% (w/w) of iodixanol derivative in DMSO. A balloon catheter (Abbott Vascular Fox sv PTA Catheter (2-6 mm×120 mm), Abbott Laboratories, Chicago, Ill., USA) was inflated and the balloon was dip coated in the aforementioned DMSO solution for 5 to 10 seconds, followed by placing the balloon into deionised water to allow exchange of water and DMSO. The resulting coating, shown in FIG. 5, was cohesive, flexible and was stable to repeated balloon inflation/deflation cycles. The coated balloon was analysed by pCT, as shown in FIG. 6 (the lower images correspond to a cross-sectional analysis of the of the balloon). A radiopacity of 4700 Hounsfield Units (HU) was measured.