# US 8,465,758 B2 · Drug delivery from stents

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- Number: US 8,465,758 B2
- Document ID: US8465758B2
- Status: Granted
- Kind: B2
- Application number: 12/773,677
- Filed: 2010-05-04
- Published: 2010-11-04
- Granted: 2013-06-18
- Earliest claimed: 2001-01-11
- Assignees: Abbott Laboratories
- Applicants: Andrew L. Lewis; Peter W. Stratford; Michael J. Driver
- Inventors: Andrew L. Lewis; Peter W. Stratford; Michael J. Driver
- Web page: https://patentgrep.com/patent/US8465758B2

## CPC

- A61F 2/82: Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents (stent-grafts for tubular structures of the body other than blood vessels A61F2/04; stent-grafts for blood vessels A61F2/07)
- A61L 31/10: Macromolecular materials
- A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)}
- A61L 33/0029: {using an intermediate layer of polymer}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61L 2300/416: Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
- A61L 2300/434: of enzymes
- A61L 2300/606: Coatings
- A61L 2420/02: Methods for coating medical devices
- Y10T 29/49885: with coating before or during assembling
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- 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 (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

A method of producing an intravascular stent has a coat comprising a crosslinked amphiphilic polymer and a sparingly water soluble matrix metalloproteinase inhibitor (MMPI). Preferably the polymer is formed from 2-methacryloyloxy-2′-ethyltrimethylammonium phosphate inner salt, C4-18 alkyl methacrylate and reactive and/or crosslinking monomer and the MMPI is a hydroxamic acid, more preferably batimastat. Preclinical and clinical results are reported, showing good luminal areas and reduced intimal thickening.

## Claims

### Claim 1

A method for producing a drug coated intravascular stent comprising the steps:
a) coating a metallic stent body on its inner and outer walls with a cross-linkable amphiphilic polymer;
b) subjecting the cross-linkable amphiphilic polymer to conditions under which cross-linking takes place to produce a polymer-coated stent;
c) contacting at least the outer coated wall of the polymer coated stent with a liquid drug composition comprising a sparingly water-soluble matrix metalloproteinase inhibitor (MMPI) and an organic solvent in which the MMPI is at least partially dissolved and which is capable of swelling the cross-linked polymer of the coating, for a time sufficient to swell the polymer coating on the outer wall, to produce a wet drug-coated stent; and
d) evaporating the organic solvent from the wet drug-coated stent to produce a dry drug-coated stent;
wherein the cross-linkable amphiphilic polymer is of formula:
wherein:
B is a straight or branched alkylene, alkyleneoxaalkylene or alkylene oligo-oxaalkylene chain optionally containing one or more fluorine atoms or, if X contains a terminal carbon atom bonded to B, a valence bond;
X is a zwitterionic group;
A is —O— or —NR1—;
A1 is —O— or —NR15—;
A2 is —O— or —NR22—;
B2 is a straight or branched alkylene, oxaalkylene or oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains, or B2 is a valence bond;
D is a non-ionic alkyl(alk)acrylate or hydroxyalkyl(alk)acrylate;
R is hydrogen or a C1-C4 alkyl group;
R1 is hydrogen or a C1-C4 alkyl group or R1 is —B—X;
R13 is a straight or branched alkyl, alkoxyalkyl or oligoalkoxyalkyl chain containing four or more carbon atoms unsubstituted or substituted by one or more fluorine atoms optionally containing one or more carbon double or triple bonds, or —(CR182)qq(SiR192)(OSiR182)ppR19;
R14 is hydrogen or a C1-C4 alkyl group;
R15 is hydrogen, a C1-C4 alkyl group or R13;
each R18 is the same or different and is hydrogen or alkyl of 1 to 4 carbon atoms, or aralkyl;
each R19 is alkyl of 1 to 4 carbon atoms;
R20 is selected from the group consisting of ethylenically and acetylenically unsaturated group containing radicals; aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C1-4-alkoxy groups; hydroxyl; amino; carboxyl; epoxy; —CHOHCH2Hal; succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; acetoxy; mesylate; carbonyl di(cyclo)alkyl carbodiimidoyl; isocyanate, acetoacetoxy; and oximino;
R21 is hydrogen or C1-4 alkyl;
R22 is hydrogen, a C1-C4 alkyl group, or B2R20;
Hal is selected from chlorine, bromine and iodine atoms;
qq is from 1 to 6;
pp is from 0 to 49;
l is 1 to 75;
m is 0 to 99;
n is 0 to 33;
i is about 15; and
n+m is 25 to 99.

### Claim 2 (depends on 1)

The method according to claim 1 in which, in step c), the MMPI is both absorbed into the polymer and adsorbed at the surface of the polymer coating, whereby, upon evaporation of the solvent in step d), crystals of the MMPI are formed which are adherent to the surface of the dry drug-coated stent.

### Claim 3 (depends on 1)

The method according to claim 1 in which, in step c) the contacting is by dipping the polymer coated stent in the liquid drug composition, optionally repeatedly dipping.

### Claim 4 (depends on 1)

The method according to claim 1 in which in step c) the contacting is by flowing, spraying or dripping the liquid drug composition onto the stent, and immediately allowing evaporation of the solvent from the wet drug-coated stent in step d).

### Claim 5 (depends on 1)

The method according to claim 1 in which the stent is, between steps b) and c), mounted onto the stent delivery section of a stent-delivery catheter, whereby the stent delivery section is also contacted with the liquid drug composition.

### Claim 6 (depends on 5)

The method according to claim 5 wherein the stent-delivery catheter is a balloon catheter in which the balloon is formed of polyamide, and wherein the organic solvent in the liquid drug composition is selected from dimethylsulphoxide, dichloromethane, C1-4 alcohol, and admixtures thereof.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the MMPI is present in an amount in the range 1 μg to 1000 μg per stent.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the MMPI is present in an amount in the range 10 μg to 150 μg per stent.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the MMPI is batimastat or marimastat.