Radioopaque, iodine functionalized phenylalanine-based poly(ester urea)s

Patent metadata

Field	Value
Publication number	US-10280261-B2
Application number	US-201515330815-A
Country	US
Kind code	B2
Filing date	May 7, 2015
Priority date	May 7, 2014
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

In one or more embodiments, the present invention provides iodine-functionalized phenylalanine-based poly(ester urea)s (PEUs) (and related methods for their synthesis and use) that are metal free, degradable, radiopaque and suitable for use in surgical implants and other medical devices used within a patient. In one or more embodiment of the present invention 4-Iodo-L-phenylalanine and L-phenylalanine are separately reacted with 1,6-hexanediol to produce two monomers, bis-4-I-L-phenylalanine-1,6-hexanediol-diester (1-IPHE-6 monomer) and bis-L-phenylalanine-1,6-hexanediol-diester (1-PHE-6 monomer). It has been found that by varying the feed ratio of the 1-IPHE-6 and 1-PHE-6 monomers, the copolymer composition may be modulated to predictably create phenylalanine-based PEUs having a wide variation in thermal, mechanical and radiopacity properties. As most medical device procedures require placement verification via fluoroscopic imaging, materials that possess inherent X-ray contrast are valuable for a number of applications.

First claim

What is claimed is:

1. A radiopaque poly(ester urea) polymer comprising two or more amino acid-based monomer segments containing at least one amino acid residue functionalized to include a radiopaque atom.

2. The radiopaque poly(ester urea) polymer of claim 1 , wherein said radiopaque atom is selected from the group consisting of iodine, boron, and combinations thereof.

3. The radiopaque poly(ester urea) polymer of claim 1 , wherein said radiopaque atom is iodine.

4. The radiopaque poly(ester urea) polymer of claim 1 , wherein said amino acid residue is an L-phenylalanine residue.

5. The radiopaque poly(ester urea) polymer of claim 1 having the formula:

wherein R is I or H with the proviso that at least one R in said radiopaque poly(ester urea) polymer is I, a is an integer from 2 to 20, and n is an integer from 10 to 1000.

6. A radiopaque poly(ester urea) polymer comprising:
one or more first amino acid-based monomer segments, wherein said first amino acid-based monomer segments further comprise two or more iodine functionalized amino acid residues separated by from about 2 to about 20 carbon atoms; and
one or more second amino acid-based monomer segments, wherein said second amino acid-based monomer segments further comprise two or more amino acid residues separated by from about 2 to about 20 carbon atoms.

7. The radiopaque poly(ester urea) polymer of claim 6 wherein said two or more iodine functionalized amino acid residues are iodine functionalized L-phenylalanine residues.

8. The radiopaque poly(ester urea) polymer of claim 6 wherein said two or more amino acid residues of said second amino acid-based monomer segments are residues of alanine (ala-A), arginine (arg-R), asparagine (asn-N), aspartic acid (asp-D), cysteine (cys-C), glutamine (gln-Q), glutamic acid (glu-E), glycine (gly-G), histidine (his-H), isoleucine (ile-I), leucine (leu-L), lysine (lys-K), methionine (met-M), phenylalanine (phe-F), serine (ser-S), threonine (thr-T), tryptophan (trp-W), tyrosine (tyr-Y), or valine (val-V).

9. The radiopaque poly(ester urea) polymer of claim 6 wherein said two or more iodine functionalized amino acid residues comprise 4-iodo-L-phenylalanine.

10. The radiopaque poly(ester urea) polymer of claim 6 wherein said one or more first amino acid-based monomer segments comprise the residue of bis-4-I-L-phenylalanine-1,6-hexanediol-diester.

11. The radiopaque poly(ester urea) polymer of claim 6 wherein said two or more iodine functionalized amino acid residues are separated by from about 2 to about 20 carbon atoms.

12. The radiopaque poly(ester urea) polymer of claim 6 wherein said two or more iodine functionalized amino acid residues are separated by six carbon atoms.

13. The radiopaque poly(ester urea) polymer of claim 6 wherein said two or more amino acid residues of said second amino acid-based monomer segments are separated by from about 2 to about 20 carbon atoms.

14. The radiopaque poly(ester urea) polymer of claim 6 wherein two or more amino acid residues of said second amino acid-based monomer segments are separated by six carbon atoms.

15. The radiopaque poly(ester urea) polymer of claim 6 having the formula:

wherein a and a′ are each integers from 2 to 20; n is a mole percentage from about 1 to about 100; and m is a mole percentage from about 0 to about 99.

16. The radiopaque poly(ester urea) polymer of claim 6 wherein said first amino acid-based monomer segments comprise from 1% to 100% of said radiopaque poly(ester urea) polymer.

17. A method for making a radiopaque poly(ester urea) polymer comprising:
A. dissolving L-phenylalanine, a linear or branched polyol having from about 2 to about 60 carbon atoms, and an acid in a suitable solvent;
B. refluxing the solution of Step A to form the acid salt of a first amino acid-based monomer having two or more L-phenylalanine residues separated by from about 2 to about 20 carbon atoms;
C. dissolving L-phenylalanine functionalized with a radiopaque moiety, a linear or branched polyol having from 2 to about 60 carbon atoms, and an acid in a suitable solvent;
D. refluxing the mixture of Step C to form the acid salt of a second amino acid-based monomer having two or more iodine functionalized L-phenylalanine residues separated by from about 2 to about 20 carbon atoms;
E. dissolving the acid salt of said first amino acid-based monomer, the acid salt of said second amino acid based monomer, and an organic water soluble base in distilled water;
F. cooling the mixture of Step E to a temperature of from about −10° C. to about 2° C.;
G. dissolving an additional quantity of an organic water soluble base in distilled water and adding it to the mixture of Step F;
H. dissolving a first fraction of triphosgene in distilled chloroform and adding it to the mixture of Step G; and
I. dissolving a second fraction of triphosgene in distilled chloroform and adding it dropwise to the mixture of Step H over a period of from about 5 minutes to about 72 hours to form a radiopaque poly(ester urea) polymer.

18. The method for making a radiopaque poly(ester urea) polymer of claim 17 wherein said acid is p-toluene sulfonic acid monohydrate.

19. The method for making a radiopaque poly(ester urea) polymer of claim 17 wherein said organic water soluble base is sodium carbonate.

20. The method for making a radiopaque poly(ester urea) polymer of claim 17 wherein the radiopaque moiety is iodine.

21. The method for making a radiopaque poly(ester urea) polymer of claim 17 further comprising:
J. collecting and purifying said radiopaque poly(ester urea) polymer of Step I by transferring the mixture of step I to a separatory funnel, thereby forming a aqueous layer and a organic layer containing the radiopaque poly(ester urea) polymer;
K. adding said organic layer dropwise into boiling water thereby causing the radiopaque poly(ester urea) polymer to precipitate;
L. collecting the radiopaque poly(ester urea) polymer by filtration, and drying.

22. The method for making a radiopaque poly(ester urea) polymer of claim 17 wherein the molar ratio of the acid salt of said first amino acid-based monomer to the acid salt of said second amino acid based monomer is from about 1% to about 99%.

23. The method for making a radiopaque poly(ester urea) polymer of claim 17 wherein the molar ratio of the acid salt of said first amino acid-based monomer to the acid salt of said second amino acid based monomer is 1% to 99%.

24. A medical device comprising the radiopaque poly(ester urea) polymer of claim 1 .

25. The medical device of claim 24 , wherein said medical device comprises a tissue scaffold, 3D printed material, drug eluting scaffold, thin film or coating.

26. The medical device of claim 24 , wherein said medical device as formed by a process selected from the group consisting of extrusion, three-dimensional (3D) printing, injection molding, melt spinning, and combinations thereof.

Assignees

• Becker Matthew L
• Li Shan
• Univ Akron

Inventors

• Becker Matthew L
• Li Shan

Classifications

• A61L27/18

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds · CPC title

• C08G71/02 Primary

  Polyureas · CPC title

• A61L27/56

  Porous materials, {e.g. foams or sponges} · CPC title