Hyaluronic acid based copolymers

• US 8,734,817 B2
• Filed: 09/28/2012
• Issued: 05/27/2014
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Advanced Cardiovascular Systems Incorporated
• Original Assignee: Advanced Cardiovascular Systems Incorporated
• Inventors: Hossainy, Syed Faiyaz Ahmed, Michal, Eugene, Glauser, Thierry, Pacetti, Stephen Dirk, Kwok, Connie
• Primary Examiner(s): Switzer, Juliet
• Assistant Examiner(s): HELM, CARALYNNE E
• Application Number:
  US13/631,399
• Publication Number:
  US 20130023509A1
• Time in Patent Office: 606 Days
• Field of Search: None
• US Class Current: 424/400
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/785 Polymers containing nitrogen
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 5/10 Heparin; Derivatives thereof

Abstract

Hyaluronic acid (HA) conjugates or crosslinked HAs compositions for coating an implantable device are provided. The implantable device can be used for treating a disorder such as atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.

Claims

1. A hyaluronic acid (HA) conjugate comprising the reaction product of a moiety derived from HA and a moiety derived from poly(ethylene glycol) (PEG);

wherein the moiety derived from HA is a HA functionalized to bear a terminal amine group, a terminal anhydride group, or a terminal aldehyde group, wherein the moiety derived from PEG is a PEG functionalized to bear a terminal aldehyde group, a succinamide group, or a terminal amine group;

wherein the resulting HA conjugate with PEG is end-capped with a species selected from the group consisting of fatty acid, fatty alcohol, poly(ester amide) that may optionally contain alkyl, amino acid, PEG or alcohol group, polycaprolactone, polylactide, polyglycolide, polyhydroxyalkanoate (PHA), polydioxanone (PDS), or PHA-PEG.

2. An implantable device comprising the HA conjugate of claim 1.

3. The implantable device of claim 2, further comprising a bioactive agent.

4. The implantable device of claim 3, wherein the bioactive agent is selected from the group consisting of ABT-578™

, paclitaxel, docetaxel, paclitaxel derivatives, tacrolimus, pimecrolimus, batimastat, mycophenolic acid, estradiol, clobetasol, dexamethasone, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-tetrazole-rapamycin, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), prodrugs thereof, co-drugs thereof, and combinations thereof.

5. A method of treating a disorder selected from the group consisting of atherosclerosis, thrombosis, restenosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof, comprising:

implanting in a human being an implantable device comprising the HA conjugate of claim 1 and optionally a bioactive agent.

6. The implantable device of claim 2, which is a stent.

7. The HA conjugate of claim 1, wherein the fatty acid is selected from the group consisting of stearate, laurate, palmitate, and oleate.

8. The HA conjugate of claim 1, wherein the fatty alcohol is selected from the group consisting of hexanol, dodecanol, stanol, sterol, cholesterol, and cetyl alcohol.

9. The HA conjugate of claim 1, wherein the PHA is selected from the group consisting of poly(α

-hydroxyacids), poly(β

-hydroxyacid), poly(3-hydroxybutyrate) (PHB), poly(3-hydroxybutyrate-co-valerate) (PHBV), poly(3-hydroxypropionate) (PHP, poly(3-hydroxyhexanoate) (PHH), poly(4-hydroxyacid), poly(4-hydroxybutyrate), poly(4-hydroxyvalerate), and poly(4-hydroxyhexanoate).

10. The HA conjugate of claim 1, The HA conjugate of claim 1, wherein the HA conjugate is a PEG-HA-(C12-C18 alkyl) conjugate.