Coated implants

Details Coated implants Coated implants

2001-09-24

2004-06-08

Azpuru, Carlos (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S423000, C424S424000

Reexamination Certificate

active

06746686

ABSTRACT:

The present invention relates to implants, especially stents, primarily for introduction into blood vessels, but which are also useful for introduction into other body lumens, which have a coating of a biocompatible hydrogel polymer, used as a reservoir from which drugs are delivered direct to the wall of the vessel in which the stent is positioned.
In our earlier WO-A-0101957 which was not published at the priority date hereof, we describe stents with coatings of biocompatible crosslinked polymers, which are swollen in drug containing solutions immediately before delivery into a patient. Drug is absorbed into the swollen hydrogel, and is released over extended periods of time from the implanted stent. The system described in those applications has been approved for marketing in Europe for use with drugs having molecular weights up to 1200D. Examples of such drugs include dipyridamole, dicloxacillin, vitamin B12 and angiopeptin.
In our earlier application number WO-A-9822516, we describe polymers formed from ethylenically unsaturated monomers including a cationic monomer and a zwitterionic monomer, useful for providing biocompatible coatings on various substrates. The cationic polymer attracts anionic mucopolysaccharide. A stent coated with the polymer may be used as a scavenging device to remove systemic heparin from the circulation of a patient. Alternatively, it is suggested that the device may be preloaded with, for instance, heparin to allow extended release of the drug into a circulation from an implanted stent.
In EP-A0809999, heparin is covalently bound to a stent using the Carmeda CH5 heparin coating system.
Angiogenic compounds have been delivered from stents to treat stenotic lesions. In WO-A-97/47253, for instance, angiogenic compounds are delivered following radiation treatment of the heart. Delivery may be from a stent coated with a polymer.
In U.S. Pat. No. 5,954,706 an anionic hydrogel is coated on to a stent, a monovalently cationic compound, such as a benzalkonium compound, is coated over the hydrogel and heparin is contacted and electrostatically bound to the cationic compound.
Sense and anti-sense DNA have been delivered from stents, for instance in WO-A-98/15575. The DNA may encode an angiogenic protein.
In U.S. Pat. No. 5,674,192 nucleic acids and monoclonal antibodies delivered by squeezing them from a swollen hydrogel coating on a balloon catheter. The nucleic acids may be antisense oligonucleotides or viral vectors. The hydrogel may be a polycarboxylic acid such as polyacrylic acid. Nucleic acid is delivered to cells of the vessel wall.
A new implant according to the invention has a coating on its external surface comprising:
a) a crosslinked, water swellable polymer matrix having a dry thickness of at least 0.1 &mgr;m, and
b) a pharmaceutically active compound
in which the polymer has pendant zwitterionic groups and pendant cationic groups.
The implant is preferably a stent.
The invention is of particular utility for delivering pharmaceutically active compounds which are anionic under physiological conditions. The invention is also of particular value for higher molecular weight active compounds, especially having molecular weights of more than 1000D, more preferably more than 1200D, for instance 5000D or more.
The pharmaceutical active may be a protein, for instance an antibody or fragment thereof. Such compounds are usually and preferably in this invention anionically charged in physiological environments. The invention is of particular value for active compounds comprised of nucleic acids. The nucleic acids may be DNA or RNA, and may be linear or circular, single or double stranded. The nucleic acid may encode a pharmaceutically useful polypeptide or protein, or it may be an anti-sense oligo-nucleotide, used to control the gene of interest in the cell to which the nucleic acid is delivered. A nucleic acid encoding a useful polypeptide or protein may include control regions, or other sequences to allow expression of the gene and/or its delivery into the cell and/or transport of the protein to its target. Oligo nucleotides conjugated to other actives eg for targeting purposes, are also usefully delivered by this invention.
One particularly interesting class of gene delivered by the invention encodes angiogenic factors, such as vascular endothelial growth factors or fibroblast growth factors, or platelet derived growth factors. Suitable control sequences may direct expression in smooth muscle cells, specifically. For instance the control sequences may be as described in WO-A-98/15575. Oligonucleotides which may be used in the present invention have, for instance, at least 5 bases, preferably at least 15 bases.
According to a second aspect of the invention, a new implant has a coating on its external surface comprising:
a) a crosslinked, biostable polymer matrix and
b) a pharmaceutically useful nucleic acid,
in which the polymer has pendant zwitterionic groups and pendant cationic groups.
According to a third aspect of the invention, a new implant having a coating on its external surface comprising:
a) a cross-linked, biostable polymer and
b) a pharmaceutically active compound which is a protein which is anionically charged at physiological pH in which the polymer has pendant zwitterionic groups and pendant cationic groups.
In the second and third aspects it is preferred, thought not essential for the polymer matrix to have a dry thickness of at least 0.1 &mgr;m. Furthermore it is preferred but not essential for the polymer matrix to be water swellable. We have found that anionic actives such as nucleic acid and proteins, especially those having molecular weights above 1 KD, primarily become adsorbed at the surface of a polymer having cationic groups and zwitterionic groups, with little being adsorbed into the body of the polymer. For this reason the swellability and the thickness are of lesser importance than in the first aspect.
The implant is preferably a stent. In the rest of this specification the device is described in terms of stents, but it will be understood other implants may be substituted for stents.
The crosslinking of the polymer matrix stabilises the coating on the stent, rendering it biostable. Adjustment of the crosslink density provides some control over the extent to which the polymer swells in a swelling solvent, generally aqueous in nature. The crosslink density furthermore effects the pore size of the polymer matrix. It is believed that the pore size, in turn, effects the maximum molecular size of pharmaceutically active compounds which may be absorbed into the matrix which is of particular relevance to the first aspect of the invention. It is preferred that the polymer be formed from ethylenically unsaturated monomers including less than 20% by mole of crosslinkable monomer.
The polymer used in the present invention is preferably formed from ethylenically unsaturated monomers including
a) a zwitterionic monomer of the formula I
YBX  I
 wherein B is a bond or a straight or branched alkylene, alkylene-oxa-alkylene or alkylene-oligooxa-alkylene group, any of which optionally include one or more fluorine substituents;
X is an organic group having a zwitterionic moiety; and
Y is an ethylenically unsaturated polymerisable group;
b) a cationic monomer of the formula II
Y
1
B
1
Q
1
  II
 wherein B
1
is a bond or a straight or branched alkylene, alkylene-oxa-alkylene or alkylene-oligooxa-alkylene group, any of which optionally includes one or more fluorine substituents;
Y
1
is an ethylenically unsaturated polymerisable group; and
Q is an organic group having a cationic or cationisable moiety and C a crosslinkable monomer having the general formula IV:
Y
3
B
3
Q
3
  IV
 wherein B
3
is a bond or a straight or branched alkylene, alkylene-oxa-alkylene or alkylene-oligooxa-alkylene group, any of which optionally includes one or more fluorine substituents;
Y
3
is an ethylenically unsaturated polymerisable group; and
Q
3
is an organic group having a reactive group capable of cross-linking the

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