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CA-3064294-C - VASCULAR GRAFTS HAVING A MODIFIED SURFACE

CA3064294CCA 3064294 CCA3064294 CCA 3064294CCA-3064294-C

Abstract

Disclosed are vascular grafts having a surface modified to reduce the risk of thrombi formation post implantation into a subject. The vascular graft can include a tubular structure comprising a base polymer admixed with an oligofluorinated additive.

Inventors

  • Jeannette Ho
  • J. Paul Santerre
  • Mark A. STEEDMAN
  • Jamie Robert SWENOR

Assignees

  • Evonik Canada Inc.

Dates

Publication Date
20260505
Application Date
20180530
Priority Date
20170530

Claims (9)

  1. What is claimed is: Claims 1. A vascular graft comprising a tubular body having an inner surface and a long axis wherein the inner surface comprises an oligofluorinated additive admixed with a base polymer comprising polyethylene terephthalate, wherein the tubular body has a first end and a second end adapted for an attachment to an artery or a vein.
  2. 2. A vascular graft comprising a tubular body having an inner surface and a long axis wherein the inner surface comprises an oligofluorinated additive admixed with a base polymer comprising polytetrafluoroethylene, wherein the tubular body has a first end and a second end adapted for an attachment to an artery or a vein.
  3. 3. A vascular graft comprising a tubular body having an inner surface and a long axis wherein the inner surface comprises an oligofluorinated additive admixed with a base polymer comprising a polyurethane, wherein the tubular body has a first end and a second end adapted for an attachment to an artery or a vein.
  4. 4. The vascular graft of claim 3, wherein the polyurethane is selected from the group consisting of polycarbonate urethanes, polyurethane with a poly(dimethylsiloxane) soft segment, a polytetramethylene glycol-based polyurethane elastomer, segmented polyurethanes, and polyetherurethanes.
  5. 5. The vascular graft of any one of claims 1-4, wherein the inner surface comprises from 0.05% (w/w) to 15% (w/w) of the oligofluorinated additive.
  6. 6. The vascular graft of any one of claims 1-5, wherein the oligofluorinated additive is any one of formulas (I)-(XVII): (1) Formula (I): where (i) Fr-[B-A]n-B-Fr (I) A is hydrogenated polybutadiene, poly((2,2-dimethyl)-1, 3-propylene carbonate), polybutadiene, poly(diethylene glycol)adipate, poly(hexamethylene carbonate), poly(ethylene-co-butylene), (neopentyl glycol-ortho phthalic anhydride) polyester, 49 Date Re9ue/Date Received 2024-02-16 (ii) (iii) (iv) (diethylene glycol-ortho phthalic anhydride) polyester, (1,6-hexanediol-ortho phthalic anhydride) polyester, or bisphenol A ethoxylate; B is a segment including a urethane; and FT is a polyfluoroorgano group, and n is an integer from 1 to 1 0; (2) Formula (II): where (i) (ii) (iii) (iv) B is a urethane; FT-[B-A]n-8-FT (11) A includes polypropylene oxide, polyethylene oxide, or polytetramethylene oxide; FT is a polyfluoroorgano group; and n is an integer from 1 to 1 O; (3) Formula (Ill) or Formula (IV): Fr ~r Fr s-A-(s-A):-S: Frl n Fr , (I II) where (IV) (i) A is an oligomeric segment containing an ether linkage, an ester linkage, a carbonate linkage, or a polyalkylene and having a theoretical molecular weight of from 500 to 3,500 Da (e.g., from 500 to 2,000 Da, from 1,000 to 2,000 Da, or from 1,000 to 3,000 Da); (ii) Bis a segment including a isocyanurate trimer or biuret trimer; B', when present, is a segment including a urethane; (iii) (iv) each FT is a polyfluoroorgano group; and n is an integer between O to 1 O; (4) Formula (V): where FT-[B-A]n-8-FT (V) (i) A is an oligomeric segment including polypropylene oxide, polyethylene oxide, or polytetramethylene oxide and having a theoretical molecular weight of from 500 to 3,000 Da(e.g., from 500 to 2,000 Da, from 1,000 to 2,000 Da, or from 1,000 to 3,000 Da); (ii) B is a segment formed from a diisocyanate; 50 Date Re9ue/Date Received 2024-02-16 (iii) (iv) (5) where (i) (ii) (iii) (iv) FT is a polyfluoroorgano group; and n is an integer from 1 to 1 0; Formula (VI): A is an oligomeric segment including polyethylene oxide, polypropylene oxide, polytetramethylene oxide, or a mixture thereof, and having a theoretical molecular weight of from 500 to 3,000 Da (e.g., from 500 to 2,000 Da, from 1,000 to 2,000 Da, or from 1,000 to 3,000 Da); B is a segment including an isocyanurate trimer or biuret trimer; FT is a polyfluoroorgano group; and n is an integer from 0 to 1 0; (6) Formula (VII): where (i) FT-[B-A]n-8-FT (VII) A is a polycarbonate polyol having a theoretical molecular weight of from 500 to 3,000 Da(e.g., from 500 to 2,000 Da, from 1,000 to 2,000 Da, or from 1,000 to 3,000 Da); (ii) B is a segment formed from a diisocyanate; (iii) FT is a polyfluoroorgano group; and (iv) n is an integer from 1 to 10; (7) Formula (VIII): where (i) A is an oligomeric segment including a polycarbonate polyol having a theoretical molecular weight of from 500 to 3,000 Da (e.g., from 500 to 2,000 Da, from 1,000 to 2,000 Da, or from 1,000 to 3,000 Da); (ii) B is a segment including an isocyanurate trimer or biuret trimer; (iii) FT is a polyfluoroorgano group; and 51 Date Re9ue/Date Received 2024-02-16 (iv) n is an integer from 0 to 1 0; (8) Formula (IX): where (i) A is a first block segment selected from polypropylene oxide, polyethylene oxide, polytetramethylene oxide, or a mixture thereof, and a second block segment including a polysiloxane or polydimethylsiloxane, where A has a theoretical molecular weight of from 1,000 to 5,000 Da (e.g., from 1,000 to 3,000 Da, from 2,000 to 5,000 Da, or from 2,500 to 5,000 Da); (ii) (iii) (iv) B is a segment including an isocyanurate trimer or biuret trimer; FT is a polyfluoroorgano group; and n is an integer from O to 1 O; (9) Formula (X): where (i) (ii) (iii) (iv) FT-[B-A]n-8-FT (X) A is a segment selected from the group consisting of hydrogenated polybutadiene (e.g., HLBH), polybutadiene (e.g., LBHP), hydrogenated polyisoprene (e.g., HHTPI), polysiloxane-polyethylene glycol block copolymer, and polystyrene and has a theoretical molecular weight of from 750 to 3,500 Da(e.g., from 750 to 2,000 Da, from 1,000 to 2,500 Da, or from 1,000 to 3,500 Da); B is a segment formed from a diisocyanate; FT is a polyfluoroorgano group; and n is an integer from 1 to 1 O; (10) Formula (XI): Fr ~r Fr 's-A-(s-A):-~ 30 F/ n Fr (XI) where (i) A is hydrogenated polybutadiene (e.g., HLBH), polybutadiene (e.g., LBHP), hydrogenated polyisoprene (e.g., HHTPI), or polystyrene and has a theoretical molecular 52 Date Re9ue/Date Received 2024-02-16 (ii) (iii) (iv) weight of from 750 to 3,500 Da (e.g., from 750 to 2,000 Da, from 1,000 to 2,500 Da, or from 1,000 to 3,500 Da); B is a segment including an isocyanurate trimer or biuret trimer; FT is a polyfluoroorgano group; and n is an integer from 0 to 1 0; (11) Formula(XII): where (i) A is a polyester having a theoretical molecular weight of from 500 to 3,500 Da(e.g., from 500 to 2,000 Da, from 1,000 to 2,000 Da, or from 1,000 to 3,000 Da); (ii) B is a segment including an isocyanurate trimer or biuret trimer; (iii) (iv) FT is a polyfluoroorgano group; and n is an integer from O to 1 O; (12) Formula (XIII): FT-A-FT (XIII) where FT is a polyfluoroorgano group and A is an oligomeric segment. (13) Formula (XIV): (FT) I C-A-[(LinkB)-A]a-C (XIV) where (i) FT is a polyfluoroorgano group covalently attached to LinkB; (ii) C is a chain terminating group; (iii) (iv) (v) A is an oligomeric segment; LinkB is a coupling segment; and a is an integer greater than 0; Date Re9ue/Date Received 2024-02-16 53 (14) Formula (XV): where (i) (ii) (iii) (iv) (v) where (XV) each FT is a polyfluoroorgano group; X1 is H, CH3, or CH2CH3; each of X2 and X3 is independently H, CH3, CH2CH3, or FT; each of L1 and L2 is independently a bond, an oligomeric linker, or a linker with two terminal carbonyls; and n is an integer from 5 to 50; (XVI) (i) each FT is a polyfluoroorgano; (ii) each of X1, X2, and X3 is independently H, CH3, CH2CH3, or FT; (iii) each of L1 and L2 is independently a bond, an oligomeric linker, a linker with two terminal carbonyls, or is formed from a diisocyanate; and (v) each of n1 and n2 is independently an integer from 5 to 50; and (16) Formula (XVII): 25 G - Am - [B - A]n - B - G (XVII) where (i) each A is hydrogenated polybutadiene, poly ((2,2-dimethyl)-1,3-propylene carbonate), polybutadiene, poly (diethylene glycol)adipate, poly (hexamethylene carbonate), poly (ethylene-co-butylene), (diethylene glycol-ortho phthalic anhydride) polyester, (1,6- 54 Date Re9ue/Date Received 2024-02-16 hexanediol-ortho phthalic anhydride) polyester, {neopentyl glycol--ortho phthalic anhydride) polyester, a polysiloxane, or bisphenol A ethoxylate; {ii) each B is independently a bond, an oligomeric linker, or a linker with two terminal carbonyls; {iii) {iv) {v) each G is H or a polyfluoroograno, provided that at least one G is a polyfluoroorgano; n is an integer from 1 to 1 0; and mis 0 or 1.
  7. 7. The vascular graft of claim 6, wherein the oligofluorinated additive is compound 11, compound 22, or compound 39: Compound 111 IPTMO = polytetramethylene oxide ,,c~c•~.-J.r •-tcH )e-1111r1L f \ U II r l' H • 2 o, ~lnfz =~n-(Cl+.!)11-NH_.Jil...,,__,OCHzCIH2(CF2)sCf, PTMO wherein the molecular weight is 800 to 1.200 gfmol; CHa wherein x, y, and z are integers; 55 Date Re9ue/Date Received 2024-02-16 Compound39 wherein x, y, and z are integers; and wherein Mw of the dial is 8000 g/mol, PEG is 80% and PPG is 20%.
  8. 8. The vascular graft any one of claims 1-7, wherein the vascular graft exhibits reduced thrombogenicity.
  9. 9. The vascular graft of any one of claims 1-8, wherein the first end and the second end adapted for an attachment to an artery or a vein comprise anchoring barbs or a material suitable for sewing onto a portion of an artery or of a vein. 56 Date Re9ue/Date Received 2024-02-16

Description

VASCULAR GRAFTS HAVING A MODIFIED SURFACE Related Application This is a Patent Cooperation Treaty Application based on the priority of U.S. Provisional Patent Application No. 62/512,230, filed May 30, 2017. Background of the Invention Grafts are tubular constructs used to replace, repair, or bypass occluded or damaged vessels in the cardiovascular system. In addition, vascular grafts are used as access points for medical procedures such as hemodialysis. Grafts can be natural or synthetic. Synthetic grafts are routinely used for large vessel replacement{> 7 mm), as they function well in these high-flow, low-resistance circuits. In small 10 diameter vessel replacement, natural grafts, such as autologous veins, are preferred as they have superior biocompatibility and mechanical properties more closely matching those of the native vessel, thus resulting in higher patency rates. However, autologous grafts (from the same human) are not always available (e.g., morbid condition, inappropriate length or diameter) and their harvesting may lead to donor site complications. Allografts (from another human donor) or heterografts (from animal donors) are also 15 used in some cases, but carry the risk of immunogenicity and are prone to degeneration over time. Often, synthetic or biosynthetic grafts remain the only alternative. However, some synthetic grafts perform well in a large, but not small, vessel repair or bypass. The most common causes of graft failure include inappropriate graft diameter. For example, a too large diameter can cause dilation, suture line failure, structural defects, bleeding, and infection. Small or medium diameters can cause thrombosis or 20 intimal hyperplasia. Summary of the Invention The invention features a vascular graft including a tubular body having an inner surface and a long axis wherein the inner surface includes an oligofluorinated additive admixed with a base polymer including polyethylene terephthalate, wherein the tubular body has a first end and a second end adapted 25 for an attachment to an artery or a vein. In a related aspect, the invention features a vascular graft including a tubular body having an inner surface and a long axis wherein the inner surface includes an oligofluorinated additive admixed with a base polymer including polytetrafluoroethylene, wherein the tubular body has a first end and a second end adapted for an attachment to an artery or a vein. 30 The invention further features a vascular graft including a tubular body having an inner surface and a long axis wherein the inner surface includes an oligofluorinated additive admixed with a base polymer including a polyurethane, wherein the tubular body has a first end and a second end adapted for an attachment to an artery or a vein. In particular embodiments, the polyurethane is selected from, without limitation, polycarbonate urethanes (e.g., BIONATE®), polyurethane with a poly(dimethylsiloxane) 35 soft segment (e.g., Elast-Eon™), a polytetramethylene glycol-based polyurethane elastomer (e.g., Pellethane® 2363-S0AE elastomer), segmented polyurethanes (e.g., BIOSPAN™) and polyetherurethanes (e.g., ELASTHANE™). 1 Date Re9ue/Date Received 2024-02-16 In particular embodiments of the above aspects, the inner surface can include from 0.05% (w/w) to 15% (w/w) (e.g., from 0.1% (w/w) to 15% (w/w), from 0.5% (w/w) to 15% (w/w), from 1% (w/w) to 15% (w/w), from 0.1% (w/w) to 5% (w/w), from 0.5% (w/w) to 5% (w/w), or from 1% (w/w) to 5 5% (w/w)) of the oligofluorinated additive. The oligofluorinated additives used in the prosthetic valves of the invention may be described by the structure of any one of formulae (I), (II), (Ill), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII) shown below. In certain embodiments, the oligofluorinated additive is selected from any one of compound 1-40. In particular embodiments, the oligofluorinated 1 0 additive is selected from compound 11, compound 22, and compound 39. In one particular embodiment, the vascular graft of the invention exhibits reduced thrombogenicity in comparison to the vascular graft in the absence of the oligofluorinated material. In some embodiments, the vascular graft includes a tubular body formed from polytetrafluoroethylene admixed with compound 11. In some embodiments, the vascular graft 15 includes a tubular body formed from polycarbonate urethanes (e.g., BIONATE®) admixed with compound 11. In some embodiments, the vascular graft includes a tubular body formed from polytetrafluoroethylene admixed with compound 11. In some embodiments, the vascular graft includes a tubular body formed from polyurethane with a poly(dimethylsiloxane) soft segment (e.g., Elast-Eon™) admixed with compound 11. In some embodiments, the vascular graft includes a 20 tubular body formed from a polytetramethylene glycol-based polyurethane elastomer (e.g., Pellethane® 2363-B0AE elastomer) admixed with compound 11. In some embodiments, the vascular g