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WO2008008437A1 - Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables - Google Patents

Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables Download PDF

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Publication number
WO2008008437A1
WO2008008437A1 PCT/US2007/015902 US2007015902W WO2008008437A1 WO 2008008437 A1 WO2008008437 A1 WO 2008008437A1 US 2007015902 W US2007015902 W US 2007015902W WO 2008008437 A1 WO2008008437 A1 WO 2008008437A1
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WO
WIPO (PCT)
Prior art keywords
poly
amide
ester
group
medical device
Prior art date
Application number
PCT/US2007/015902
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English (en)
Inventor
Stephen Dirk Pacetti
Jessica Renee Desnoyer
Mikael O. Trollsas
Syed F. A. Hossainy
Original Assignee
Abbott Cardiovascular Systems Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/487,059 external-priority patent/US8030436B2/en
Priority claimed from US11/486,553 external-priority patent/US7731987B2/en
Application filed by Abbott Cardiovascular Systems Inc. filed Critical Abbott Cardiovascular Systems Inc.
Priority to JP2009519529A priority Critical patent/JP2009543897A/ja
Priority to EP07810387A priority patent/EP2069421A1/fr
Publication of WO2008008437A1 publication Critical patent/WO2008008437A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/44—Polyester-amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • This invention relates to the fields of organic chemistry, polymer chemistry, materials science, and medical devices.
  • PTCA percutaneous transluminal coronary angioplasty
  • DES drug-eluting stents or DESs were introduced.
  • the drugs initially employed with the DES were cytostatic compounds, compounds that curtailed the proliferation of cells that resulted in restenosis. The occurrence of restenosis was thereby reduced to about 5 — 7%, a relatively acceptable figure.
  • the DES is the default the industry standard to treatment of atherosclerosis and is rapidly gaining favor for treatment of stenoses of blood vessels other than coronary arteries such as peripheral angioplasty of the femoral artery.
  • DESs One of the key criteria of DESs is selection of a polymer or blend of polymers to be used in a drug reservoir layer, a rate-controlling layer, a protective topcoat layer, etc. If a biostable polymer is selected, i.e., a polymer that does not significantly decompose in a patient's body, their chemical composition is often not of significant concern since they are not intended to break down and enter the patient's system. On the other hand, currently biodegradable polymers are preferred for many applications because their ability to decompose in a biological environment confers on them a number of desirable characteristics.
  • the fact that a polymer will biodegrade and can eventually be essentially completely eliminated from a patient's body can avoid the need to invasively remove a DES after its job is done.
  • biodegradable polymer e.g., selecting one that bio-erodes by bulk erosion or one that bio-erodes by surface erosion, the properties of the polymer can be used as an added tool for the fine-tuning of the release rate of a drug.
  • poly(ester-amide)s tend generally to be rather soft and quite permeable to many if not most drugs, which limits their application in DESs to some extent. What is needed is poly(ester-amide)s that are stronger, tougher and less permeable than those currently in use while still maintaining the other beneficial characteristics of the class.
  • an implantable medical device that includes a pro-healing influence to counter the delayed healing due to the eluting drugs and therefore to reduce or eliminate the occurrence of late stent thrombosis. While this would be particularly useful with regard to coronary stents, it would also provide substantial benefit to any manner of implantable medical device. For instance, it has been stated that the occurrence of restenosis in the case of lower extremity percutaneous angioplasty is particularly unacceptable (Paul S. Teirstein, Circulation. 2000, 102:2674) and it would be expected that this situation would also be amenable to the effects of stents having pro-healing properties.
  • the current invention provides poly(ester-amide)s and methods of their use that address each of the above issues..
  • the current invention is directed to poly(ester amide)s and poly(ester amide) derivatives that are stronger, tougher and less permeable than those currently available exhibit and, in addition, that include prohealing characteristics to ameliorate the problem of late stent thrombosis.
  • the present invention relates to a poly(ester-amide) having the formula:
  • m is an integer from 0 to about 200;
  • n is an integer from 0 to about 200;
  • k is an integer from 1 to about 3000;
  • M n is from about 10,000 to about 1 ,000,000 Da.
  • r is a number from 0 to 1 , inclusive;
  • s is a number from 0 to 1 , inclusive;
  • r + s 1 ;
  • X has the chemical structure: R 2
  • Y has the chemical structure: wherein:
  • R 5 is selected from the group consisting of:
  • R 1 and R 4 are independently selected from the group consisting of (1C-12C)alkyl and (2C-12C)alkenyl;
  • R 2 , R?. R 2 " and R 2 - are independently selected from the group consisting of hydrogen and (1C-4C)alkyl, wherein: the alkyl group is optionally substituted with a moiety selected from the group consisting of -OH, -SH, -SeH, -C(O)OH, -NHC(NH)NH 2 ,
  • R 2 , R 2 -, R 2 - and R 2 - may form a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
  • R 3 and R ⁇ are independently selected from the group consisting of (1 C- 12C)alkyl, (2C-12C)alkenyl, (3C-8C)cycloalkyl and -(CH 2 CH 2 ⁇ ) q CH 2 CH2-, wherein q is an integer from 1 to 10, inclusive, wherein the poly(ester-amide) is from about 0.05 mol% to about 5 mol% cross- linked.
  • M n is from about 20,000 Da to about 500,000 Da;
  • the crosslink is a chemical crosslink.
  • the chemical crosslink comprises a reaction product of an -OH, -SH, -NH 2 or -C(O)OH substituent on R 2 , R 2 -, R 2 -, R 2 - or R 6 with a multifunctional OH-reactive, -SH-reactive, -NH 2 - reactive or -C(O)OH- reactive multifunctional crosslinking agent.
  • the OH-reactive, -SH-reactive, -NH 2 -reactive or -C(O)OH-reactive multifunctional crosslinking agent comprises a diisocyanate.
  • the diisocyanate is selected from the group consisting of 1 ,2-ethanediisocyanate, 1 ,3-propanediisocyanate, 1,4- butanediisocyanate, 1 ,5-pentanediisocyanate, lysine diisocyanate and 1,4- cyclohexanediisocyanate.
  • the —SH-reactive multifunctional crosslinking agent comprises a bismaleimide.
  • the -OH-reactive, -SH-reactive, NH 2 -reactive or -C(O)OH-reactive multifunctional crosslinking agent comprises a diepoxide.
  • the -OH-reactive, -SH-reactive, -NH 2 - reactive or -C(O)OH-reactive multifunctional crosslinking agent comprises a diisothiocyanate.
  • the -OH-reactive, -SH-reactive, -NH 2 - reactive or-C(O)OH-reactive multifunctional crosslinking agent comprises a diacid halide.
  • R 2 , R 2 -, R 2 - and R 2 - are independently selected from the group consisting of unsubstituted (1C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
  • R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CHz) 4 NH-, -(CH 2 ) 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
  • R 6 is -OH.
  • R 5 is -(CHa) 4 CH(COR 6 )NH-.
  • R 2 and R 2 - are -CH 2 CH(CHa) 2 .
  • the OH-reactive, SH-reactive, NH 2 reactive, C(O)O H-reactive multifunctional crosslinking agent is a multifunctional aziridine compound.
  • the multifunctional aziridine compound is pentaerythriol tris(3-aziridi ⁇ opropionate).
  • R 2 , R 2 -, R 2 - and R 2 - are independently selected from the group consisting of unsubstituted (1C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
  • R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
  • R 6 is -OH.
  • R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
  • R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 .
  • Ri and R 4 are -(CH 2 Je; and, R 3 is -(CH 2 J 6 -.
  • R 5 is selected from the group consisting of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-,
  • R 6 is selected from the group consisting of -O(1C-20C)alkenyl and -0(CH 2 CH 2 O) C CH 2 CH 2 OR 7 , wherein: q is an integer from 0 to 600, inclusive;
  • the chemical crosslink comprises UV or free-radical initiated reaction of the double bond.
  • Rs is -(CH 2 J 4 CH(COR 6 )NH-.
  • R 6 is selected from
  • R 4 are -(CH 2 ) ⁇ -; R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 J 6 .
  • n 0.25.
  • Rs is one of R 1 or R 4 is a (2C-12C)alkyenyl, the other is a (1C-12C)alkyl; or, Ri and R 4 are a (2C-12C)alkyenyl and the chemical crosslink comprises UV or free-radical initiated reaction of the alkenyl double bond.
  • R 2 and R 2 - are -(CH 2 )CH(CH 3 ) 2 ; and, R 3 is - (CHz) 6 -.
  • at least one of R2, Rz, R 2 ". R ? " and R 6 comprises a -C(O)OH group; and the chemical crosslink comprises an ionomer.
  • the ionomer comprises a monovalent cation.
  • the monovalent cation is selected from the group consisting of sodium, potassium, lithium and silver.
  • the ionomer comprises a polyvalent cation.
  • the polyvalent cation is selected from the group consisting of calcium(ll), magnesium(ll), zinc(ll), iron(ll) and aluminum(lll).
  • R 2 and R 2 ' are independently selected from the group consisting of hydrogen and (1C-4C)alkyl;
  • R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
  • R 6 is -OH.
  • R 2 and R 2 - are - CH 2 CH(CH 3 J 2 ; and R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
  • Ri and R 4 are - (CH 2 ) 8 -; R 3 is -(CH 2 Je-.
  • the ionomer herein comprises Zn(II).
  • the cross-link is a physical crosslink.
  • A is a soft segment
  • B is a hard segment
  • the physical crosslink comprises segregated domains of soft segments and paracrystalline hard segments.
  • A has a glass-transition temperature of 40 0 C of lower; and, B has a glass transition temperature of 45 0 C or higher.
  • R 5 is R 2" R 2-"
  • Ri is -(CHaJs-; R2 and R 2 - are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 J 6 -; Rr is -(CH 2 ) 4 -; R 2 - and R 2 - are -CH(CH 3 ) 2 and R 3 - is -(CH 2 ) 3 -.
  • Ri is -(CH 2 )4-; R 2 and R 2 - are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 )i 2 -; R 1 . is -(CHz) 4 -; R 2 - and R 2 - are -CH(CH 3 J 2 and R 3 - is -(CH 2 ) 3 -.
  • Ri is -(CH 2 ) 8 -;
  • R 2 , R 2 -, R 2 - and R 2 - are -(CH(CH 3 )CH 2 CH 3 ;
  • R 3 is -(CH 2 ) 6 -;
  • R r is -(CH 2 J 2 - and R 3 - is -(CH 2 ) 2 -.
  • A is amorphous; B is crystalline; and the crosslink comprises inter-chain crystallization.
  • Ri is -(CH 2 )S-; Rr is -(CH 2 ) 4 ; R 2 and R 2 ' are -CH 2 CH(CH 3 ) 2 ; R 2 - and R 2 - are CH 2 phenyl; R 3 is -(CH 2 J 6 -; and, R 3 - is -(CH 2 J 4 -.
  • An aspect of this invention is an implantable medical device, comprising: a device body; an optional primer layer; a drug reservoir layer comprising at least one therapeutic agent; an optional rate-controlling layer; and an optional topcoat layer; wherein at least one of the drug reservoir layer, the rate-controlling layer, if opted, and/or the topcoat layer, if opted, comprises a poly (ester-amide) of this invention wherein the poly(ester-amide) has the formula:
  • m is an integer from 0 to about 200;
  • n is an integer from 0 to about 200;
  • k is an integer from 1 to about 3000;
  • M w is from about 10,000 to about 1 ,000,000 Da.
  • r is a number from 0 to 1 , inclusive;
  • s is a number from 0 to 1 , inclusive;
  • r + s 1 ;
  • Y has the chemical structure: wherein:
  • R 5 is selected from the group consisting of:
  • Ri and R 4 are independently selected from the group consisting of (1C-12C)alkyl and (2C-12C)alkenyl;
  • R 2 , R 2 -, R 2 » and R 2 - are independently selected from the group consisting of hydrogen and (1C-4C)alkyl, wherein: the alkyl group is optionally substituted with a moiety selected from the group consisting of -OH, -SH, -SeH, -C(O)OH, -NHC(NH)NH 2 ,
  • phenyl and , or one or more of R 2 , R 2 -, R 2 - and R 2 - may form a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
  • F* 3 and Ry are independently selected from the group consisting of (1C-12C)alkyl, (2C-12C)alkenyl, (3C-8C)cycloalkyl and -(CH 2 CH2 ⁇ ) q CH 2 CH 2 -, wherein q is an integer from 1 to 10, inclusive, wherein the poly(ester-amide) is from about 0.05 mol% to about 5 mol% cross- linked.
  • M n is from about 20,000 Da to about 500,000 Da.
  • the crosslink is a chemical crosslink.
  • the chemical crosslink comprises a reaction product of an -OH, -SH, -NH 2 or -C(O)OH substituent on R 2 , Rz, R 2 ", R 2 " or R 6 with a multifunctional OH- reactive, -SH-reactive, -NH 2 - reactive or -C(O)OH-reactive multifunctional crosslinking agent.
  • the OH-reactive, -SH-reactive, -NH 2 -reactive or— C(O)OH-reactive multifunctional crosslinking agent comprises a diisocyanate.
  • the diisocyanate is selected from the group consisting of 1 ,2-ethanediisocyanate, 1,3- propanediisocyanate, 1 ,4-butanediisocyanate, 1 ,5-pentanediisocyanate, lysine diisocyanate and 1 ,4-cyclohexanediisocyanate.
  • R 2 , R 2' , R 2 « and R 2 - are independently selected from the group consisting of unsubstituted (1 C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
  • R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
  • R 6 is -OH.
  • R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
  • R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 .
  • the OH-reactive, SH-reactive, NH 2 reactive, C(O)OH-reactive multifunctional crosslinking agent is a multifunctional aziridine compound.
  • the multifunctional aziridine compound is pentaerythriol tris(3-aziridinopropionate).
  • R 2 , R 2 -, R2 " and R 2 - are independently selected from the group consisting of unsubstituted (1C-4C)alkyl and a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
  • R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 NH-, -(CH 2 J 4 CH(COR 6 )NH-, -CH(COR 6 )CH(CH 3 )O-,
  • R 6 is -OH.
  • R 5 is -(CH 2 J 4 CH(COR 6 )NH-.
  • R 2 and R 2 ' are -CH 2 CH(CH 3 ) 2 .
  • Ri and R 4 are -(CH 2 J 8 and R 3 is -(CH 2 )S--
  • R 5 is selected from the group consisting of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 )(CH 2 ) 4 N H-,
  • R 6 is selected from the group consisting of -O(1C-20C)aIkenyl and -O(CH 2 CH 2 O)qCH 2 CH 2 OR7, wherein: q is an integer from 0 to 600, inclusive;
  • the chemical crosslink comprises UV or free-radical initiated reaction of the double bond.
  • R 5 is -(CH 2 ⁇ CH(COR 6 )NH-.
  • R 6 is selected from the group consisting of
  • Ri and R 4 are -(CH 2 ) 8 -; R2 and R 2 - are -CH 2 CH(CH 3 ) 2 and R 3 is -(CH 2 )S-
  • R 1 or R 4 is a (2C-12C)alkyenyl, the other is a (1C-12C)alkyl; or,
  • Ri and R 4 are a (2C-12C)alkyenyl and the chemical crosslink comprises UV or free-radical initiated reaction of the alkenyl double bond.
  • R 2 and R 2 . are -(CH 2 )CH(CHa) 2 ; and, R 3 is -(CH 2 J 6 -.
  • At least one of R 2 , R 2 , R 2 -, R 2 - and Re comprises a -C(O)OH group; and the chemical crosslink comprises an ionomer.
  • the ionomer comprises a monovalent cation.
  • the monovalent cation is selected from the group consisting of sodium, potassium, lithium and silver.
  • the ionomer comprises a polyvalent cation.
  • the polyvalent cation is selected from the group consisting of calcium(ll), magnesium(ll), zinc(ll), iron(ll) and aluminum(lll).
  • R 2 and R. 2 - are independently selected from the group consisting of hydrogen and (1 C-4C)alkyl;
  • R 5 is selected from the group consisting of -CH(COR 6 )CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 XCH 2 )4NH-,
  • R 2 and R 2 - are -CH 2 CH(CH 3 ) 2 ; and R 5 is -(CHa) 4 CH(COR 6 )NH-.
  • Ri and R4 are -(CH 2 )S-; R3 is -(CH 2 J 6 -.
  • the ionomer herein comprises Zn(II).
  • the cross-link is a physical crosslink.
  • A is a soft segment; B is a hard segment; and, the physical crosslink comprises segregated domains of soft segments and paracrystalline hard segments.
  • A has a glass-transition temperature of 40 0 C of lower; and, B has a glass transition temperature of 45 0 C or higher.
  • Ri is -(CH 2 )S-; R 2 and R 2 ' are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 J 6 -; Rr is -(CH 2 )*-; R 2 - and R 2 - are -CH(CH 3 ) 2 and R 3 - is -(CH 2 J 3 -.
  • R 1 is -(CH 2 J 4 -; R 2 and R 2 - are -(CH(CH 3 )CH 2 CH 3 ; R 3 is -(CH 2 J 12 -; R 1 . is -(CH 2 ) 4 -; R 2 - and R 2 - are -CH(CH 3 J 2 and R 3 - is -(CH 2 J 3 -.
  • R 1 is -(CH 2 ) S -;
  • R 2 , R 2 -, R 2 - and R 2 - are -(CH(CH 3 )CH 2 CH 3 ;
  • R 3 is -(CH 2 )6-;
  • Rr is - (CH 2 ) 2 - and R 3 - is ⁇ (CH 2 ) 2 -.
  • A is amorphous; B is crystalline; and the crosslink comprises inter-chain crystallization.
  • Ri is -(CH 2 )S-;
  • Rr is -(CH 2 J 4 ;
  • R 2 and R 2 - are -CH 2 CH(CH 3 J 2 ;
  • R 2 - and R 2 - are CH 2 phenyl;
  • R 3 is -(CH 2 Je-; and,
  • R 3 - is - (CH 2 J 4 -.
  • At least the drug reservoir layer comprises a crosslinked poly(ester-amide) of this invention.
  • at least the rate-controlling layer comprises a crosslinked poly(ester-amide) of this invention.
  • At least the topcoat layer comprises a cross-linked poly(ester-amide) of this invention.
  • an implantable medical device comprising: a device body; an optional primer layer disposed over the device body; a drug reservoir layer disposed over the device body or the primer layer if opted, wherein the drug reservoir layer comprises one or more therapeutic agents; an optional rate-controlling layer disposed over at least a portion of the drug reservoir layer, if opted; and, an optional top-coat layer disposed as an outermost layer over the device body, the primer layer, if opted, the drug reservoir layer, if opted, or the rate-limiting layer, if opted, wherein: at least one of the layers comprises a poly(ester-amide) having the formula:
  • Mn is from about 10,000 Da to about 1 ,000,000 Da; s is a number from 0 to1 , inclusive; t is a number from 0 to 1 , inclusive; v is a number from 0 to 1 , inclusive; wherein s + 1 + v - 1 ;
  • X has the chemical structure: R 2 R .r C ft-(Rv)-C Sf- HN-C Hp-C I?-O-(R 3 O-O-C ff- ⁇ H-N
  • Y has the chemical structure: 1 V R2- ;
  • Ri, Rv and R 4 are independently selected from the group consisting of (1C-12C)alkyl and (2C-12C)alkenyl;
  • R2, Rz, R2 " and R ⁇ - are independently selected from the group consisting of hydrogen and (1C-4C)alkyI, wherein: the alkyl group is optionally substituted with a moiety selected from the group consisting of -OH, -O(1C-4C)alkyl, -SH, -S(1C-4C)alkyl, -SeH, -COR 6 , -NHC(NH)NH 2 , imidazol-2-yl, imidazole-5-yl, indol-3-yl, phenyl, 4-hydroxyphenyl and 4-[(1C-4C)alkylO]phenyl, wherein:
  • R 2 " and R 2 - may form a bridge between the carbon to which it is attached and the adjacent nitrogen, the bridge comprising -CH 2 CH 2 CH 2 -;
  • R 3 is selected from the group consisting of (1C-12C)alkyl and (2C- 12C)alkenyl, (3C-8C)cycloalkyl and -(CH 2 CH 2 O) q CH 2 CH 2 -;
  • R 5 is selected from the group consisting Of -CH(CORe)CH 2 S-, -CH(COR 6 )CH 2 O-, -CH(COR 6 XCH 2 )4NH-, -(CH 2 J 4 CH(COR 6 )NH-, q is an integer from 1 to 600, inclusive.
  • M n is from about 20,000 Da to about 500,000 Da.
  • At least an outermost layer comprises the poly(ester-amide).
  • the outermost layer is a topcoat layer.
  • R 4 are selected from the group consisting of -(CH 2 ) 4 -and -(CH 2 J 8 -.
  • R 2 is -CH 2 CH(CHa) 2 .
  • R 3 is -(CH 2 ) ⁇ - and Ry is
  • R 1 and R 4 are independently selected from the group consisting of -(CH 2 ) 4 - and -(CH 2 Ja-.
  • R 2 and R 2 ' are independently selected from the group consisting of — CH 3 , -CH 2 CH 2 NHC(NH)NH 2 , -CH 2 CONH 2 , -CH 2 COOH, -CH 2 SH, -CH 2 CH 2 COOH,
  • R 3 is selected from the group consisting of -(CH 2 J 3 -, -(CH 2 J 6 - and -(CH 2 CH 2 O JqCH 2 CH 2 -, wherein q is an integer from 1 to 10, inclusive.
  • Re is selected from the group consisting of a stable nitroxide
  • R 2 and R 2 - are identical.
  • R 2 and R 2 - are -CH 2 CH(CH 3 )2.
  • R 2 and R 2 - are selected from the group consisting of -CH 3 , -H 2 CH 2 NHC(NH)NH 2 , -CH 2 CONH 2 ,
  • R 2 and R 2 - are the same.
  • R 2 and R 2 - are CH 2 CH(CH 3 ) 2 .
  • R 3 is selected from the group consisting of (3C-8C) alkyl, -(CH 2 CH 2 O) q CH 2 CH 2 -, wherein q is an integer
  • R 2 and R ⁇ are benzyl.
  • the implantable medical device further comprises a drug reservoir layer and a rate-controlling layer, wherein the rate- controlling layer comprises a polymer selected from the group consisting of poly(l-lactide), poly(D-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L- lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(meso-lactide-co-glycolide) and an combination thereof.
  • the rate- controlling layer comprises a polymer selected from the group consisting of poly(l-lactide), poly(D-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L- lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(meso-lactide-co
  • the rate-controlling layer comprises poly(D,L-lactide).
  • the implantable medical device further comprises a drug reservoir layer, wherein the drug reservoir layer comprises one or more drugs disposed neat over the primer layer.
  • the implantable medical device further comprises a drug reservoir layer, wherein the drug reservoir layer comprises one or more polymers.
  • the therapeutic agent is everolimus.
  • the drug reservoir layer polymer is selected from the group consisting of poly(vinylidene fluoride) and poly(vinylidene fluoride- co-hexafluoropropylene).
  • the implantable medical device further comprises a primer layer, wherein the primer layer comprises poly(n-butyl methacrylate).
  • An aspect of this invention is a stent, comprising a poly(n-butyl methacrylate) primer, a poly(vinylidene fluoride-co-hexafluoropropylene) drug reservoir layer comprising everolimus and a topcoat layer comprising a poly(ester-amide).
  • the poly(ester-amide) in the aspect immediately above is selected from the group consisting of PEA-TEMPO and PEA-BZ.
  • an outermost layer comprises the polyester- amide).
  • the outermost layer is a topcoat layer.
  • nitroxide is selected from the group consisting of V r ,
  • q is 1 — 10, inclusive.
  • q is 300 - 600, inclusive.
  • the implantable medical device is a stent.
  • Figure 1 graphically depicts the inflammatory and cellular response elicited by Impra ® graft material, Hemashield ® graft material, PEA-TEMPO and PEA-BZ at 14 days post-implantation in rat epicardial tissue.
  • Figure 2 graphically depicts the inflammatory and cellular response elicited by Impra ® graft material, Hemashield ® graft material, PEA-TEMPO and PEA-BZ at 30 days post-implantation in rat epicardial tissue.
  • Figure 3 graphically depicts endothelial cell coverage of a PEA-coated stent, a BMS and a Solef ® (poly(vinylidene fluoride-co-hexafluoropropylene)- coated stent.
  • Figure 4 graphically depicts the percentage everolimus released by a stent without a topcoat, which establishes a target release rate, compared with a stent having a topcoat of a poly(ester-amide) of this invention. Discussion
  • any words of approximation such as without limitation, "about,” “essentially,” “substantially” and the like mean that the element so modified need not be exactly what is described but can vary from the description by as much as ⁇ 15% without exceeding the scope of this invention.
  • if opted means that the item being discussed is optional and if the option is exercised the condition that follows the phrase will pertain.
  • a device body (db) that has coated on it an "optional” primer layer(pl), an "optional” drug reservoir layer (dr), an “optional” rate-controlling layer (re) and a top-coat layer (tc) refers, without limitation, to any of the following devices: db + tc, db + dr + tc, db + dr + re + tc, db + pi + tc, db + pi + dr + tc and db + pi + dr + re + tc.
  • a poly(ester-amide) refers to a polymer that has in its backbone structure both ester and amide bonds.
  • the following formulae represent poly(ester-amide)s of this invention:
  • X, Y and Z refer to the constitutional units, i.e., the repeating units, of the polymer.
  • the polymer in the polymer
  • R 2 -C-COOH comprises the reaction of an amino acid, H , with a diol
  • a diacid, HO-C-(R 1 J-C-OH 5 to give the constitutional unit.
  • the amine group, the carboxylic acid group or the hydroxyl group may be "activated," i.e., rendered more chemically reactive, to facilitate the reactions if desired; such activating techniques are well-known in the art and the use of any such techniques is within the scope of this invention.
  • a non-limiting example of the synthesis of an exemplary but not limiting X constitution unit having the above general structure is the reaction of 1 ,6-hexane diol with l-leucine to give the diamino diester, which is then /eacted with sebacic acid to give X.
  • Constitutional unit Y can be obtained by the same reactions as those affording X but using one or more different reactants such that the resulting constitutional units X and Y are chemically different or Y may result from the reaction of a diacid with a tri- functional amino acid wherein two of the functional groups are capable of reacting with the diacid.
  • a diacid with a tri- functional amino acid wherein two of the functional groups are capable of reacting with the diacid.
  • two of the functional groups are capable of reacting with the diacid.
  • l-lysine i.e., 2,6- diaminohexanoic acid.
  • amino acids selected for the preparation of poly(ester-amide)s of this invention any may be use; however, at present it is preferred that the amino acids be selected from the group commonly known as the standard amino acids or sometimes the proteinogenic amino acids because they are encoded by the normal genetic code.
  • the amino acids There currently are 20 standard amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenyl alanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • m, p and n are integers that represent the average number of constitutional units X, Y and Z in an uninterrupted string or, if there is more than on, block; i.e., the number of X units before a Y unit is encountered, etc.
  • the integers m, p and n can be any number, including 0; when two of m, p and n are 0, the resulting poly(ester-amide) is a homopolymer.
  • k represents the total number of X and Y units in the polymer and r represents the total number of X, Y and Z units in the polymer.
  • the value of k and r can be any integer from 1 to about 2500, with the proviso that the combination of m, n, p and k should provide a poly(ester-amide) that has a molecular weight within the range discussed below.
  • M n represents the number average molecular weight of a poly(ester-amide) of this invention.
  • the number average molecular weight of a poly(ester- amide) of this invention is from about 10,000 Da (Daltons) to about 1 ,000,000 Da, preferably at present from about 20,000 Da to about 500,000 Da.
  • s, t and v represent the mole fraction of each of the constitutional units.
  • the mole fraction and the number of constitutional units are obviously related and it is understood that the designation of one will affect the other.
  • t and v may each be 0, 1 or any fraction between.
  • certain provisos (1 ) if an additional prohealing entity is present on one of the constitutional units, that constitutional unit must be at least .02 mol fraction of the polymer; and (2) m and p can both be 0 only if R5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(C(O)R 6 CH 2 O-,
  • any values of s, t and v that provides a polymer having desirable properties for the intended use, e.g., as a drug reservoir layer, a rate-controlling layer, etc., and those skilled in the art will be readily able to make such variations and determine if the resulting polymer as the requisite properties based on the disclosures herein without undue experimentation.
  • s and t may each be 0, 1 or any fraction between.
  • the only proviso is that m can be 0 only if R 5 is selected from the group consisting Of -CH(COR 6 )CH 2 S-, -CH(C(O)R 6 CH 2 O-, -CH(COR 6 )CH(CH 3 )O- and because otherwise the resulting homopolymer would not be a poly(ester-amide).
  • m and n can be any number in the given range and those skilled in the art will be able, based on the disclosures herein, vary m and n to impart on the final polymer any type of desired property that varying the mole fractions can achieve depending on which type of layer, as set forth herein, is being contemplated.
  • Constitutional unit Z is the result of the reaction of a diacid with a tri-functional amino acid wherein two of the functional groups are capable of reacting with the diacid.
  • two of the functional groups are capable of reacting with the diacid.
  • sebacic acid or an activated derivative thereof with l-lysine, 2, 6-diami ⁇ ohexanoic acid, the two amino groups being capable of reacting with the diacid carboxyl groups to form amides.
  • poly(ester-amides) of this invention may be used as is, that is, as the product of amino acids, diacids and diols as described above because it has been found that the poly(ester-amide)s of this invention exhibit pro-healing properties in their own right. It is an aspect of this invention, however, that a poly(ester-amide) of this invention may be further modified by the attachment of an additional pro-healing moiety to an appropriate pendant group attached to the polymer backbone.
  • pro-healing moiety is meant a substituent group that is biocompatible and that aids in the amelioration of inflammation and/or in the endothelialization of the implantable medical device.
  • the polymers of this invention may be regular alternating polymers, random alternating polymers, regular block polymers, random block polymers or purely random polymers unless expressly stated to be otherwise.
  • a regular alternating polymer has the general structure: ...x-y-z-x-y-z-x-y-z-...
  • a random alternating polymer has the general structure: ...x-y-x-z-x-y-z-y-z-x-y-..., it being understood that the exact juxtaposition of the various constitution units may vary.
  • a regular block polymer has the general structure: ...x-x-x-y-y-y-z-z-x-x...
  • a random block polymer has the general structure: ...x-x-x-z-z-x-x-y-y-y-y-z- Z-Z-X-X-Z-Z-Z-...
  • the juxtaposition of blocks, the number of constitutional units in each block and the number of blocks in a particular block polymer of this invention are not in any manner limited by the preceding illustrative generic structures.
  • alkyl refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon (carbon and hydrogen only) group.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopjppyl, cyclobutyl, cyclope ⁇ tyl, and cyclohexyl.
  • alkyl includes “alkylene” groups, which refer to straight or branched fully saturated hydrocarbon groups having two rather than one open valences for bonding to other groups.
  • alkylene groups include, but are not limited to methylene, -CH 2 -, ethylene, -CH 2 CH 2 -, propylene, -CH 2 CH 2 CH 2 -, n-butyle ⁇ e, - CH 2 CH 2 CH 2 CH 2 -, sec-butylene, -CH 2 CH 2 CH(CH 3 )- and the like.
  • mC to nC refers to the number of possible carbon atoms in the indicated group. That is, the group can contain from “m” to "n", inclusive, carbon atoms.
  • An alkyl group of this invention may comprise from 1 to 12 carbon atoms, that is, m is1 and n is 12. Of course, a particular alkyl group may be more limited. For instance without limitation, an alkyl group of this invention may consist of 3 to 8 carbon atoms, in which case it would be designated as a (3C-8C)alkyl group.
  • the numbers are inclusive and incorporate all straight or branched chain structures having the indicated number of carbon atoms.
  • a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, CH 3 CH(CH 3 )-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 CH-.
  • a cycloalkyl group refers to an alkyl group in which the end carbon atoms of the alkyl chain are covalently bonded to one another.
  • the numbers “m” and “n” refer to the number of carbon atoms in the ring formed.
  • a (3C-8C)cycloalkyl group refers to a three, four, five, six, seven or eight member ring, that is, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
  • bicycloalkyl refers to two cycloalkylgroups bonded together by a single covalent bond.
  • bicycloalkyl group is bicyclohexane
  • benzyl refers to a phenylmethylene, group.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • 0 refers to the structure — c-R as that is the only way the carbon can be tetravalent without the addition of hydrogen or other atoms no shown in the structure.
  • stick structure exemplified by represents the structure that is, each terminus is capped with a CH3 group and the apex of each angle is a carbon atom with the requisite number of hydrogens attached.
  • alkyl-i alkyl-i, alkyb, etc.
  • alkyl groups may be the same or different.
  • a “stable nitroxide” refers to an isolatable paramagnetic organic compound having the generic structure RR 1 N-O wherein R and R 1 may be aliphatic or may join to form a ring which may be acyclic or aromatic.
  • the stable nitroxide must also contain at least one functional group through which the nitroxide may be covalently bonded to a poly(ester-amide) of this invention.
  • 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl can be reacted with a pendant carboxylic acid group of, without limitation, lysine that comprises the backbone of a poly(ester-amide) of this invention, to form an amide.
  • a pendant carboxylic acid group of, without limitation, lysine that comprises the backbone of a poly(ester-amide) of this invention can be reacted with a pendant carboxylic acid group of, without limitation, lysine that comprises the backbone of a poly(ester-amide) of this invention.
  • Other such functional groups that will afford covalently bonded stable nitroxides will be evident to those skilled in the art based on the disclosures herein and are within the scope of this invention.
  • to dispose a layer of "neat" therapeutic agent simply means that the therapeutic agent, once it is has been applied to a surface and any solvent used during the application has been allowed to evaporate, the therapeutic agent is the only constituent of the layer, i.e., there is essentially no solvent, no polymers, no excipients or any other material in the layer other than the therapeutic agent in essentially the same purity as it had before being applied to the device.
  • the poly(ester-amides) of this invention have been found to have beneficial pro-healing properties in vivo, in particular with regard to inflammation and neovascularization.
  • neovascularization kinetics of a stent coated with PEA-TEMPO was compared to that of a bare metal stent (BMS) and a poly(vinylidene fluoride-co-hexafluoropropylene) (SOLEF ® ) coated stent (Example 2) when the stents were implanted in a bioengineered vessel.
  • BMS bare metal stent
  • SOLEF ® poly(vinylidene fluoride-co-hexafluoropropylene)
  • polyester- amide) polymers of this invention are quite biocompatible, it is expected that coating implantable medical devices with a topcoat of a poly(ester-amide) herein should have a substantial beneficial effect on healing in the vicinity of the implanted device and thereby reduce the occurrence of problems associated with slow healing such as late-stage thrombosis. This should be particularly valuable with regard to drug eluting stents (DESs), which were initially introduced to counter the high rate of restenosis among recipients of BMSs.
  • DESs drug eluting stents
  • BMSs while overcoming some of the shortfalls of percutaneous coronary angioplasty (PTCA), such as elastic recoil of the arterial wall resulting in dynamic re-narrowing of the vessel, BMSs were found to still be susceptible to restenosis, albeit at a substantially lower rate than unstented PTCAs (15 - 20% in stented patients versus 30 - 50% in previous unstented PTCAs).
  • PTCA percutaneous coronary angioplasty
  • the first DESs designed to address BMS restenosis were introduced. The stents were engineered to slowly releases cytostatic drug in the vicinity of the stent thereby slowing or preventing cell growth and resultant restenosis. DESs have reduced the incidence of restenosis to 5 - 7%.
  • poly(ester-amide) of this invention may be incorporated into any of, any combination of, or all of the layers disposed over an implantable medical device of this invention, in one embodiment of this invention it is presently preferred that the poly(ester-amide) be included in at least the outermost layer coated on the device.
  • outermost layer simply refers to that layer of material disposed over an implantable medical device of this invention that is in contact with bodily fluids and/or tissues of the patient in whom the device is implanted.
  • the outermost layer is preferably at present a separate topcoat layer as described elsewhere herein but it may be a rate-controlling layer, if a topcoat layer is not opted, or even a drug reservoir layer if neither the topcoat layer nor the rate-controlling layer is opted.
  • a poly(ester-amide) topcoat can be applied directly to the surface of a BMS.
  • the healing characteristics of the poly(ester-amide) coating alone is expected to have a salutary effect on restenosis even without added therapeutic agent.
  • polyester- amide in a drug reservoir layer with no further layers being applied. This may be the case if the release profile of the therapeutic agent is not deleteriously affected by the inclusion of the poly(ester-amide) in that layer. Techniques for determining if the release profile of a particular therapeutic agent is acceptable for a particular application is well within the knowledge of those skilled in the art and need not be further described herein.
  • primers there may be layers disposed between the poly(ester-amide) topcoat and the device body.
  • a common additional layer would be a primer as described above.
  • a primer may be used if it is found that the material of which the device body is constructed does not adhere well to the selected polyester- amide). While many primer polymers and polymer blends are known in the art and any of them can be used with the devices and methods herein, a currently preferred class of primers is the acrylate polymers, copolymers and blends thereof. Preferable at present, poly(n-butyl methacrylate) is a preferred primer for use with the devices and methods of this invention.
  • an implantable medical device of this invention may encompass a large array of devices
  • a presently preferred device is a coronary stent and a presently preferred therapeutic agent for use with the stent is everolimus.
  • an implantable medical device herein comprise a primer applied directly to the device body and then a drug reservoir layer comprising po!y(ethylidene fluoride) and everolimus, applied over the primer layer.
  • a pro-healing poly(ester-amide) topcoat is then applied over the drug reservoir layer.
  • a rate-controlling layer may be present but is not necessarily so in that it has been determined (data not shown) that certain formulations of poly(vinylidene fluoride-co-hexafluoropropylene)/everolimus drug reservoir layers exhibit desirable release profiles.
  • a more detailed description of this aspect of this invention is provided in Example 3.
  • a separate rate-controlling layer may be used.
  • different rate-controlling polymers or polymer blends useful with different therapeutic agents are known in the art and all are within the scope of this invention so long as a poly(ester-amide) topcoat layer is applied as the outermost layer on the implantable device.
  • everolimus is a presently preferred therapeutic agent for use herein.
  • the presently preferred pro-healing poly(ester- amide)s, PEA-TEMPO and PEA-BZ are quite permeable to everolimus and cannot alone provide achieve desirable sustained-release profiles.
  • a rate- controlling layer may be disposed atop the drug reservoir layer can be employed.
  • polymers useful for establishing desired everolimus release profiles are poly(L-lactide), poly(D-lactide), poly(D.L-lactide), poly(meso-lactide), poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co- glycolide), poly(meso-lactide-co-glycolide) or any combination thereof. Most preferred at present in poly(D.L-lactide).
  • a concrete, but in no way limiting, example of an implantable medical device that follows the above protocol would be: a 12 mm Vision ® stent;
  • a crosslink refers to a small region in a macromolecule involving at least two discrete polymer chains and from which at least 4 chains emanate. Crosslinking results in the motion of the individual chains involved to be restricted with respect to other chains involved in the crosslink.
  • a crosslink may comprise covalent or ionic links between the chains, which is referred to herein as a “chemical crosslink” or it may be the result of non-bonded interactions of regions of the individual chains, which are referred to herein as "physical crosslinks.”
  • Covalent bond chemical crosslinks are created using chemical reactions well-known to those of ordinary skilJ in organic chemistry.
  • covalent chemical crosslinks are of two types.
  • the first type involves the reaction of a functional group appended to a polymer backbone with a multifunctional crosslinking agent.
  • a "multifunctional crosslinking agent” is a compound having two or more functional groups that are capable of reacting with a functional group appended to the polymer backbone.
  • the functional group appended to the polymer backbone can be a hydroxyl, -OH, group and the multifunctional crosslinking agent can be a diisocyanate.
  • the cross-linking reaction is shown schematically in Scheme 1:
  • the crosslink comprises a thiocarbamate, -SC(O)NH-.
  • the crosslink comprises a urea, -NHC(O)NH-. If the hydroxyl is replaced by a carboxyl, -C(O)OH, group, the crosslink comprises an amide, -C(O)NH-, group.
  • a non-limiting example of a chemically crosslinked segment of a poly(ester-amide) of this invention involving the reaction of an isocyanate and a carboxyl group is the following:
  • Aziridines are known to react with active H + functional groups such as carboxyls as exemplified by the following non-limiting example (Scheme 3):
  • the remaining aziridine group in the above product may, of course, also react with a polymer chain to give a three-way crosslink.
  • Many other chemical crosslinking agents that can react with -OH, -SH, -Nhb and -C(O)OH groups are known to those skilled in the art and the use of any of them to crosslink poly(ester-amide)s is within the scope of this invention.
  • ethylenic groups may be incorporated into the backbone of the polymer (Scheme 4):
  • Scheme 5 shows a non-limiting example of a UV or free radical initiated crosslinked segment of a poly(ester-amide) of this invention:
  • the ethylenic group may be incorporated in a group appended to the polymer backbone as shown in the following non-limiting example of yet another crosslinked poly(ester-amide) segment of this invention (Scheme 6):
  • crosslinking reagent that itself has ethylenic groups.
  • one of the MA-PEG-MA ethylenic groups reacts with an ethylenic groups of one polymer chain and the other ethylenic group of the MA-PEG-MA reacts with an ethylenic group of a different chain.
  • the other type of chemical crosslink for the purposes of this invention is the formation of ionic bonds between metal cations (M +) and carboxyl anions, - C(O)O " , appended to the backbone of a poly(ester-amide) herein.
  • Polymers crosslinked in this manner are referred to as ionomers.
  • lonomers "cross-link" polymers by two mechanisms, although there is a great deal of overlap. The first mechanism occurs when a carboxylic acid, -C(O)OH 1 group appended to a polymer backbone is reacted with a divalent base, for example without limitation, Zn(OH) 2 .
  • the clustering of ionic groups results from the phase separation of the fundamentally hydrophobic polymer backbone and the hydrophilic ionic groups, lonomers, however, are not formally crosslinked, which requires the formation of covalent bonds between polymer chains.
  • the ionic clusters of ionomers can be relatively easily be disrupted by forces such as heating, which increases the both the degree and vigor of molecular motion in the polymer chains to the point that the clusters are dispersed.
  • the clusters are primarily responsible for the physical properties of ionomers, which physical properties can, in some instances, be quite remarkable.
  • ionomers can be extremely tough, so much so that they are often used to make products requiring great resiliency as the outer covering on golf balls.
  • chemically crosslinked polymers of this invention can be of any type: homopolymers, alternating polymers, random alternating polymers, alternating block polymers, random block polymers or completely random polymers, physically crosslinked polymers of this invention must be block copolymers.
  • the first kind of physically cross-linked poly(ester-amide) of this invention involves multi-block copolymers consisting of alternating hard and soft segments.
  • Hard segments and soft segments are differentiated primarily by their glass transition temperatures, T 9 .
  • T 9 is the temperature at which a polymer (or a segment of a polymer) changes mechanical properties from those of a rubber (i.e., elastic) to those of a glass (brittle).
  • the polymeric molecules have very little translational freedom, i.e., they are unable to move easily or very far in relation to one another. Rather than moving around to adapt to an applied stress, they tend to separate violently so that the polymer breaks or shatters similarly to a pane of glass that is stressed.
  • T 9 relatively facile segmental motion becomes possible and the polymer chains are able to move around and slip by one another such that when a stress is applied to the polymer it bends and flexes rather than breaks.
  • the T 9 of the soft segment must be at or below the temperature of the intended operating environment, which is the body of a living mammal. While the normal body temperature of mammals differs considerably, the primary mammal to which this invention is presently intended to apply is humans, which have a normal body temperature of approximately 37 0 C. Thus, it is presently preferred that the soft segment of poly(ester-amides) of this invention have a T 9 at or below about 37 0 C such that, when placed in a human body, the soft segments will, when they equilibrate to body temperature, be in an elastic rather than glass-like mode.
  • poly(ester-amide)s of this invention may be used with other mammals having quite different normal body temperatures from humans; those skilled in the art will be able to determine what the proper T g s should be for particular mammals based on the disclosure herein and all such polyester- amides) for use with any mammal are within the scope of this invention.
  • the hard segments of the poly(ester-amides) of this invention must be in a brittle glass-like rather than elastic mode when subjected to mammalian body temperature in order to create in their working environment the soft segment/hard segment morphology necessary to engage in this manner of crosslinking.
  • the hard segments have a T 9 that is above 37 0 C and, of course, above the T 9 of the soft segments. It is presently preferred that the hard segments of the poly(ester-amides) of this invention have a T 9 that is at least 5 0 C, preferably at least 15 °C and most preferably at present at least 25 0 C above the body temperature of the projected patients in whom the polymers are to be used.
  • the degree of polymerization within the hard and soft segments is such that n and m are both greater than or equal to about 10. Further, while there is no absolute upper limit, it is presently preferred that the hard and soft segments have a degree of polymerization from about 10 to about 100.
  • the block copolymer comprised of the foregoing hard and soft segments will preferably at present have a degree of polymerization at least an order of magnitude greater than the degree of polymerization within the segments.
  • a poly(ester-amide) of this invention When subject to a temperature of about 37 0 C or higher (but below the T 9 of the hard segment), a poly(ester-amide) of this invention that meets the above criteria will phase separate into a soft-segment phase and a hard-segment phase due to chemical and physical incompatibility of the segments.
  • the soft segments will remain in a random array of polymer chains and will retain their elastic properties.
  • the hard segments due to their rigid structure, will tend to align with one another, that is, hard segments of different polymer chains will come together into what can be described as a paracrystalline structure. Paracrystalline simply means that the aligned segments display some short range order when examined by x-ray diffraction but they do not exhibit the intricate long range order of true crystals.
  • the aligned hard segments held together by physical forces such as hydrogen bonding, van der Waals forces and the like, resist separation and act as multifunctional spacious crosslinked regions. It should be noted that the hard segments need not have any crystallinity whatsoever. Their T g s, which are above the operating temperature, together with the fact that they will phase separate into particular domains alone permits them to act as physical crosslinkers.
  • Non-limiting examples of soft segment/hard segment poly(ester-amides) of this invention, together with the T g s of the segments are:
  • a further type of physically crosslinked poly(ester-amide) of this invention comprises a unique subset of the preceding soft segment/hard segment polymer, namely, wherein the hard segment is crystalline.
  • crystalline regions of polymers are substantially more robust and will maintain in a crosslinked configuration until the melting point, T m , which is a determinable number, of the crystalline regions is reached at which time the crystal structures "melt" similarly to small molecules crystals and become amorphous.
  • T m 104 0 C
  • T 9 59 0 C
  • T 0 28 0 C
  • an "implantable medical device” refers to any type of appliance that is totally or partly introduced, surgically or medically, into a patient's body or by medical intervention into a natural orifice, and which is intended to remain there after the procedure.
  • the duration of implantation may be essentially permanent, i.e., intended to remain in place for the remaining lifespan of the patient; until the device biodegrades; or until it is physically removed.
  • implantable medical devices include, without limitation, implantable cardiac pacemakers and defibrillators; leads and electrodes for the preceding; implantable organ stimulators such as nerve, bladder, sphincter and diaphragm stimulators, cochlear implants; prostheses, vascular grafts, self- expandable stents, balloon-expandable stents, stent-grafts, grafts, artificial heart valves and cerebrospinal fluid-shunts.
  • An implantable medical device specifically designed and intended solely for the localized delivery of a therapeutic agent is within the scope of this invention.
  • device body refers to an implantable medical in a fully formed utilitarian state with an outer surface to which no coating or layer of material different from that of which the device is manufactured has been applied.
  • outer surface is meant any surface however spatially oriented that is in contact with bodily tissue or fluids.
  • a common example of a “device body” is a BMS, i.e., a bare metal stent, which, as the name implies, is a fully-formed usable stent that has not been coated with a layer of any material different from the metal of which it is made on any surface that is in contact with bodily tissue or fluids.
  • BMS i.e., a bare metal stent, which, as the name implies, is a fully-formed usable stent that has not been coated with a layer of any material different from the metal of which it is made on any surface that is in contact with bodily tissue or fluids.
  • device body refers not only to BMSs but to any uncoated device regardless of what it is made
  • Implantable medical devices made of virtually any material, i.e., materials presently known to be useful for the manufacture of implantable medical devices and materials that may be found to be so in the future, may be used with a coating of this invention.
  • an implantable medical device useful with this invention may be made of one or more biocompatible metals or alloys thereof including, but not limited to, cobalt-chromium alloy (ELGILOY, L-605), cobalt-nickel alloy (MP-35N), 316L stainless steel, high nitrogen stainless steel, e.g., BIODUR 108, nickel-titanium alloy (NITINOL), tantalum, platinum, platinum-iridium alloy, gold and combinations thereof.
  • cobalt-chromium alloy ELGILOY, L-605
  • MP-35N cobalt-nickel alloy
  • 316L stainless steel high nitrogen stainless steel, e.g., BIODUR 108, nickel-titanium alloy (NITINOL), tantalum, platinum, platinum-iridium alloy, gold
  • Implantable medical devices may also be made of polymers that are biocompatible and biostable or biodegradable, the latter term including bioabsorbable and/or bioerodable.
  • biocompatible refers to a polymer that both in its intact, that is, as synthesized, state and in its decomposed state, i.e., its degradation products, is not, or at least is minimally, toxic to living tissue; does not, or at least minimally and reparably, injure(s) living tissue; and/or does not, or at least minimally and/or controllably, cause(s) an immunological reaction in living tissue.
  • relatively biostable polymers are, without limitation polyacrylates, polymethacryates, polyureas, polyurethanes, polyolefins, polyvinylhalides, polyvinylidenehalides, polyvinylethers, polyvinylaromatics, polyvinylesters, polyacrylonitriles, alkyd resins, polysiloxanes and epoxy resins.
  • Biocompatible, biodegradable polymers include naturally-occurring polymers such as, without limitation, collagen, chitosan, alginate, fibrin, fibrinogen, cellulosics, starches, dextran, dextrin, hyaluronic acid, heparin, glycosaminoglycans, polysaccharides and elastin.
  • One or more synthetic or semi-synthetic biocompatible, biodegradable polymers may also be used to fabricate an implantable medical device useful with this invention.
  • a synthetic polymer refers to one that is created wholly in the laboratory while a semi-synthetic polymer refers to a naturally- occurring polymer than has been chemically modified in the laboratory.
  • synthetic polymers include, without limitation, polyphosphazines, polyphosphoesters, polyphosphoester urethane, polyhydroxyacids, polyhydroxyalkanoates, polyanhyd rides, polyesters, polyorthoesters, polycarbonates, polyiminocarbonates, polyamino acids, polyoxymethylenes, poly(ester-amides) and polyimides.
  • Blends and copolymers of the above polymers may also be used and are within the scope of this invention. Based on the disclosures herein, those skilled in the art will recognize those implantable medical devices and those materials from which they may be fabricated that will be useful with the coatings of this invention. At present, preferred implantable medical devices for use with the coatings of this invention are stents.
  • a stent refers generally to any device used to hold tissue in place in a patient's body. Particularly useful stents, however, are those used for the maintenance of the patency of a vessel in a patient's body when the vessel is narrowed or closed due to diseases or disorders including, without limitation, tumors (in, for example, bile ducts, the esophagus, the trachea/bronchi, etc.), benign pancreatic disease, coronary artery disease, carotid artery disease and peripheral arterial disease such as atherosclerosis, restenosis and vulnerable plaque.
  • Vulnerable plaque (VP) refers to a fatty build-up in an artery thought to be caused by inflammation.
  • the VP is covered by a thin fibrous cap that can rupture leading to blood clot formation.
  • a stent can be used to strengthen the wall of the vessel in the vicinity of the VP and act as a shield against such rupture.
  • a stent can be used in, without limitation, neuro, carotid, coronary, pulmonary, aorta, renal, biliary, iliac, femoral and popliteal as well as other peripheral vasculatures.
  • a stent can be used in the treatment or prevention of disorders such as, without limitation, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, chronic total occlusion, claudication, anastomotic proliferation, bile duct obstruction and ureter obstruction.
  • disorders such as, without limitation, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, chronic total occlusion, claudication, anastomotic proliferation, bile duct obstruction and ureter obstruction.
  • stents may also be employed for the localized delivery of therapeutic agents to specific treatment sites in a patient's body.
  • therapeutic agent delivery may be the sole purpose of the stent or the stent may be primarily intended for another use such as those discussed above with drug delivery providing an ancillary benefit.
  • a stent used for patency maintenance is usually delivered to the target site in a compressed state and then expanded to fit the vessel into which it has been inserted. Once at a target location, a stent may be self-expandable or balloon expandable. In any event, due to the expansion of the stent, any coating thereon must be flexible and capable of elongation.
  • a material that is described as a layer “disposed over" an indicated substrate refers to a relatively thin coating of the material applied, preferably at present, directly to essentially the entire exposed surface of the indicated substrate.
  • exposed surface is meant that surface of the substrate that, in use, would be in contact with bodily tissues or fluids.
  • “Disposed over” may, however, also refer to the application of the thin layer of material to an intervening layer that has been applied to the substrate, wherein the material is applied in such a manner that, were the intervening layer not present, the material would cover substantially the entire exposed surface of the substrate.
  • a primer layer refers to a coating consisting of a polymer or blend of polymers that exhibit good adhesion characteristics with regard to the material of which the device body is manufactured and good adhesion characteristic with regard to whatever material is to be coated on the device body.
  • a primer layer serves as an adhesive intermediary layer between a device body and materials to be carried by the device body and is, therefore, applied directly to the device body.
  • primers include silanes, titanates, zirconates, silicates, parylene, polyacrylates and polymethacrylates, with poly(n-butyl methacrylate) being a presently preferred primer.
  • drug reservoir layer refers either to a layer of one or more therapeutic agents applied neat or to a layer of polymer or blend of polymers that has dispersed within its three-dimensional structure one or more therapeutic agents.
  • a separate drug reservoir layer may be required if, without limitation, if is found that a desired therapeutic agent is not sufficiently compatible with the poly(ester-amide) to provide the desired agent concentration, if the desired release profile cannot be achieved, etc.
  • the drug reservoir layer may comprise simply the drug alone, that is, neat. This can be accomplished by dissolving the drug in a suitable solvent, applying the solution atop a primer that has been coated on the device body, and removing the solvent leaving a layer of drug alone. The poly(ester-amide) topcoat may then be applied directly over the neat drug layer.
  • the therapeutic agent may be formulated with a polymer or polymer blend.
  • therapeutic agent and polymer can be dissolved in a suitable solvent or the polymer can be dissolved and the therapeutic agent evenly dispersed in the polymer solution.
  • the solution or mixture can then be applied to either the device body or over a primer layer.
  • the solvent is removed the drug is left suspended in polymer.
  • the polymer or polymer blend is selected to provide the desired release profile.
  • a polymer that is compatible with the drug may not afford the desired release profile or a polymer that can provide the desired profile is not sufficiently compatible with the drug. This situation may be ameliorated by the inclusion of a rate-controlling layer over the drug reservoir layer.
  • therapeutic agent refers to any substance that, when administered in a therapeutically effective amount to a patient suffering from a disease, has a therapeutic beneficial effect on the health and well-being of the patient.
  • a therapeutic beneficial effect on the health and well-being of a patient includes, but it not limited to: (1) curing the disease; (2) slowing the progress of the disease; (3) causing the disease to retrogress; or, (4) alleviating one or more symptoms of the disease.
  • a therapeutic agent also includes any substance that when administered to a patient, known or suspected of being particularly susceptible to a disease, in a prophylactically effective amount, has a prophylactic beneficial effect on the health and well-being of the patient.
  • a prophylactic beneficial effect on the health and well-being of a patient includes, but is not limited to: (1) preventing or delaying on-set of the disease in the first place; (2) maintaining a disease at a retrogressed level once such level has been achieved by a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount; or, (3) preventing or delaying recurrence of the disease after a course of treatment with a therapeutically effective amount of a substance, which may be the same as or different from the substance used in a prophylactically effective amount, has concluded.
  • drug and “therapeutic agent” are used interchangeably.
  • rate-controlling layer refers to a polymeric layer that is applied over a drug reservoir layer to modify the rate of release into the environment of the therapeutic agents from the drug reservoir layer.
  • a rate- controlling layer may be used simply to "tune" the rate of release of a therapeutic agent to exactly that desired by the practitioner or it may be a necessary adjunct to the construct because the polymer or blend of polymers with which the therapeutic agent is compatible with regard to coating as a drug reservoir layer may be too permeable to the therapeutic substance resulting in too rapid release and delivery of the therapeutic substance into a patient's body.
  • a non-limiting example is an everolimus drug reservoir layer comprising PEA-TEMPO (a poly(ester-amide) to which 2,2,6,6-tetramethyl-4-aminopiperidineoxyl has been covalently appended).
  • PEA-TEMPO a poly(ester-amide) to which 2,2,6,6-tetramethyl-4-aminopiperidineoxyl has been covalently appended.
  • PEA-TEMPO has very desirable in vivo properties, it is quite permeable to everolimus.
  • sustained release i.e., release of a therapeutically effective amount of a drug over an extended period of time which may be a few days, a few months, or even longer
  • everolimus from a poly(ester-amide) polymer matrix is difficult and in some cases impossible to achieve.
  • a rate-controlling polymer or blend of polymers through which the everolimus must pass can be applied over the more PEA-TEMPO layer.
  • the layer can comprise a polymer that, due to its inherent properties or because it has been cross-linked, presents a more difficult to traverse barrier to an eluting drug.
  • the rate-controlling propensity of this layer will depend, without limitation, on such factors as the amount of this polymer in the layer, the thickness of the layer and the degree of cross-linking of the polymer.
  • a “topcoat layer” refers to an outermost layer, that is, a layer that is in contact with the external environment and that is coated over all other layers.
  • the topcoat layer may be applied to provide better hydrophilicity to the device, to better lubricate the device or merely as a device protectant.
  • the topcoat layer may also contain therapeutic agents, in particular if the treatment protocol being employed calls for essentially immediate release of one or more therapeutic agent (these being included in the topcoat layer) followed by the controlled release of another therapeutic agent or agents over a longer period of time.
  • the topcoat layer may contain one or more "biobeneficial agents.”
  • an implantable medical device of this invention comprises at least a topcoat layer and that the topcoat layer comprise a, poly(ester-amide) as described herein.
  • a "biobeneficial” agent is one that beneficially affects an implantable medical device by, for example, reducing the tendency of the device to protein foul, increasing the hemocompatibility of the device, and/or enhancing the non- thrombogenic, non-inflammatory, non-cytotoxic, non-hemolytic, etc. characteristics of the device.
  • biobeneficial materials include, but are not limited to, polyethers such as poly(ethylene glycol) (PEG) and poly(propylene glycol); copoly(ether-esters) such as poly(ethylene oxide-co-lactic acid); polyalkylene oxides such as poly(ethylene oxide) and poly(propylene oxide); polyphosphazenes, phosphoryl choline, choline, polymers and copolymers of hydroxyl bearing monomers such as hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxypropylmethacrylamide, poly (ethylene glycol) acrylate, 2-methacryloyloxyethylphosphorylcholine (MPC) and n-vinyl pyrrolidone (VP); carboxylic acid bearing monomers such as methacrylic acid, acrylic acid, alkoxymethacrylate, alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate; polystyrene-PEG, polyisobutylene
  • An implantable medical device of this invention may include one or more therapeutic agents.
  • Virtually any therapeutic agent found to be useful when incorporated on and implantable medical device may be used in the device and method of this invention.
  • therapeutic agents include, but are not limited to anti-proliferative, anti-inflammatory, antineoplastic, antiplatelet, anti- coagulant, anti-fibrin, antithror ⁇ bonic, antimitotic, antibiotic, antiallergic and antioxidant compounds.
  • the therapeutic agent may be, again without limitation, a synthetic inorganic or organic compound, a protein, a peptide, a polysaccharides and other sugars, a lipid, DNA and RNA nucleic acid sequences, an antisense oligonucleotide, an antibodies, a receptor ligands, an enzyme, an adhesion peptide, a blood clot agent such as streptokinase and tissue plasminogen activator, an antigen, a hormone, a growth factor, a ribozyme, a retroviral vector, an anti-proliferative agent such as rapamycin (sirolimus), 40-O- (2-hydroxyethyl)rapamycin (everolimus), 40-O-(3-hydroxypropyl)rapamycin, 40- O-(2-hydroxyethoxy)ethylrapamycin, 40-O-tetrazolylrapamycin, 40-epi(N1- tetrazolyl)
  • therapeutic agents which are currently available or that may be developed in the future for use with implantable medical devices may likewise be used and all are within the scope of this invention.
  • Presently preferred therapeutic agents for use with this invention are rapamycin (sirolimus), 40-O-(2-hydroxyethyl)rapamycin (everolimus), 40-O-(3- hydroxypropyl)rapamycin, 40-O-(2-hydroxyethoxy)ethylrapamcyin, 40-O- tetrazolylrapamycin and 40-epi(N1-tetrazolyl)rapamycin (zotarolimus, ABT-578).
  • rapamycin sirolimus
  • 40-O-(2-hydroxyethyl)rapamycin everolimus
  • 40-O-(3- hydroxypropyl)rapamycin 40-O-(2-hydroxyethoxy)ethylrapamcyin
  • the inflammatory response of PEA-TEMPO and PEA-BZ was evaluated using a rat epicardial model. Hemashield ® graft material was used as a highly inflammatory control and Impra ® ePTFE graft material was used as a minimally inflammatory control.
  • Four millimeter diameter 300 ⁇ m thick discs of each polymer were implanted onto rat epicardial surface and the inflammation level was measured at 14 days and at 30 days. The control discs exhibited inflammatory and cellular responses typical of those materials.
  • Both PEA- TEMPO and PEA-BZ exhibited cellular and inflammatory responses that were equal to or less than that of the Impra ® disc. The results are shown graphically in Figs. 1 and 2.
  • the re-endothelializatio,n kinetics of PEA-TEMPO coated on a stent were compared to those of a bare metal stent (BMS) and a stent coated with Solef ® (poly(vinylidene fluoride-co-hexafluoropropylene).
  • BMS bare metal stent
  • Solef ® poly(vinylidene fluoride-co-hexafluoropropylene
  • Medium Vision ® 4.0 X 18 mm stents were used bare, coated with 1494 /yg of PEA-TEMPO or coated with 767 ⁇ g of Solef ® .
  • the stents were implanted in a bioengineered vessel and evaluated after 7 days.
  • the stented vessels were stained with bisbenzimide (BBI), cut in half longitudinally and imaged with a 10X objective.
  • BBI bisbenzimide
  • a poly(ester-amide) topcoat was applied over a small 18 mm stent having a poly(n-butyl methacrylate) primer and a drug reservoir layer of poly(vinylidene fluoride-co-hexafluoropropylene) containing 190 ⁇ g of everolimus.
  • the poly(ester-amide) used was PEA-TEMPO and 89 ⁇ g were applied to the stent over the drug reservoir layer.
  • the release rate target of the stent absent the topcoat is shown on the right in Fig. 4.
  • the release rate obtained with the PEA- TEMPO is shown on the left. As can be seen, the permissible standard deviations overlap, indicating that the PEA-TEMPO topcoat did not detrimentally interfere with the target release rate.
  • a poly(ester-amide) topcoat layer on the mechanical integrity of the stent of Example 3 was examined.
  • a small 18 mm Vision ® stent was coated with a poly(n-butyl methacrylate) primer and a drug reservoir layer of poly(vinylidene fluoride-co-hexafluoropropylene) containing 190 ⁇ g of everolimus.
  • 89 ⁇ g of PEA-TEMPO was spray-coated from a 2 wt% solids absolute ethanol solution resulting in an approximately 0.92 ⁇ m thick coating of the poly(ester-amide).
  • the coating was then examined post-wet expansion from an overall, an outside diameter and an inside diameter perspective. It was found that the PEA-TEMPO coating did not introduce any observable coating integrity failures on wet expansion.

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Abstract

La présente invention concerne des dispositifs médicaux implantables comprenant des élastomères de poly(ester-amide) disposés en couches de revêtement sur le dispositif. La présente invention concerne également des dispositifs médicaux implantables au sein desquels les poly(ester-amides) présentent des propriétés favorisant la guérison.
PCT/US2007/015902 2006-07-13 2007-07-12 Poly(ester-amides), leurs dérivés et leur emploi dans des dispositifs médicaux implantables WO2008008437A1 (fr)

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US11/487,059 US8030436B2 (en) 2006-07-13 2006-07-13 Poly(ester-amide) elastomers and their use with implantable medical devices
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Cited By (3)

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WO2009114326A3 (fr) * 2008-03-11 2010-06-17 Abbott Cardiovascular Systems Inc. Dispositif médical implantable comprenant un poly(ester-amide) favorisant la cicatrisation
WO2010135739A3 (fr) * 2009-05-22 2011-03-03 Cornell Research Foundation, Inc. Poly(ester amide)s et poly(ester éther amide)s ayant des groupes fonctionnels latéraux réticulables
EP2784101A1 (fr) * 2013-03-28 2014-10-01 Nitto Europe N.V Poly(ester-amide) fonctionnalisés d'hydroxyphényl

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KR101317414B1 (ko) 2011-12-07 2013-10-10 현대자동차주식회사 핫 스탬핑 성형용 금형 및 그 제작방법
FR3010081B1 (fr) * 2013-09-05 2017-11-17 Centre Nat Rech Scient Procede de synthese sequentielle de poly(alcoxyamine amide)s, copolymeres obtenus et leurs utilisations

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WO2002018477A2 (fr) * 2000-08-30 2002-03-07 Cornell Research Foundation, Inc. Copolyester amides et copolyester urethannes fonctionnels biodegradables et elastomeres
US20050245637A1 (en) * 2004-04-30 2005-11-03 Hossainy Syed F A Methods for modulating thermal and mechanical properties of coatings on implantable devices
WO2005121250A2 (fr) * 2004-06-03 2005-12-22 Cornell Research Foundation, Inc. Biomatieres de poly(ester-amide) insaturees

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WO2002018477A2 (fr) * 2000-08-30 2002-03-07 Cornell Research Foundation, Inc. Copolyester amides et copolyester urethannes fonctionnels biodegradables et elastomeres
US20050245637A1 (en) * 2004-04-30 2005-11-03 Hossainy Syed F A Methods for modulating thermal and mechanical properties of coatings on implantable devices
WO2005121250A2 (fr) * 2004-06-03 2005-12-22 Cornell Research Foundation, Inc. Biomatieres de poly(ester-amide) insaturees

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009114326A3 (fr) * 2008-03-11 2010-06-17 Abbott Cardiovascular Systems Inc. Dispositif médical implantable comprenant un poly(ester-amide) favorisant la cicatrisation
WO2010135739A3 (fr) * 2009-05-22 2011-03-03 Cornell Research Foundation, Inc. Poly(ester amide)s et poly(ester éther amide)s ayant des groupes fonctionnels latéraux réticulables
EP2784101A1 (fr) * 2013-03-28 2014-10-01 Nitto Europe N.V Poly(ester-amide) fonctionnalisés d'hydroxyphényl

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