Coated implants

Abstract

An implant, usually a stent, has a coating of a cross-linked water swellable polymer matrix preferably having a dry thickness of at least 0.1 μm, and a pharmaceutically active compound, the polymer having pendant cationic and pendant zwitterionic groups. The active is usually an anionic compound such as a nucleic acid. The polymer is peferably formed from 2-methacyloy-loxyethyl-2′-trimethylammoniumethyl phosphate inner salt, trialkylammoniumalkyl(meth)acrylate and a cross-linkable monomer such as ω-(trialkoxysilyl)alkyl(meth)acrylate, optionally with a termonomer such as a higher alkyl (meth)acrylate. The stent is coated with polymer, cross-linked then contacted with a solution or dispersion of active compound in a solvent which swells the polymer whereby the active is absorbed into the polymer matrix. The stent is delivered by usual means into a body lumen and the actives released over an extended period of time into the wall of the lumen and/or fluid flowing therein.

1 - 38 . (canceled)  
     
     
         39 . A method of producing an implant loaded with a pharmaceutical active comprising the steps: 
 a) providing a coated implant having a coating of cross-linked water-swellable polymer matrix on its external surface, the cross-linked water-swellable polymer matrix comprising a polymer having pendant zwitterionic groups and pendant cationic groups, the coating having a dry thickness of at least 0.1 μm; and    b) contacting the coated implant with a solution or dispersion of a pharmaceutical active in a solvent whereby the pharmaceutical active is absorbed into or adsorbed onto the polymer matrix.    
     
     
         40 . A method according to  claim 39  in which the said solvent is selected for its ability to swell the polymer matrix and in step b) the solvent partially swells the said polymer matrix.  
     
     
         41 . A method according to  claim 39  in which the said solvent is aqueous.  
     
     
         42 . A method according to  claim 39  in which the solvent is organic and which additionally comprises, following step b) a step: 
 c) drying the treated implant to remove the solvent.  
 
     
     
         43 . A method according to  claim 42  in which the removal is by evaporation.  
     
     
         44 . A method according to  claim 39  in which the step b) of contacting the coated implant involves dipping the implant into a volume of the said solution or dispersion.  
     
     
         45 . A method according to  claim 39  in which the implant is a stent.  
     
     
         46 . A method according to  claim 45  in which the stent is mounted on a delivery device prior to said contacting step b).  
     
     
         47 . A method according to  claim 44  in which step b) lasts at least 30 s.  
     
     
         48 . A method according to  claim 39  in which step a) comprises the sub-steps: 
 a i) providing an uncoated implant;  
 a ii) coating the implant with a cross-linkable polymer; and  
 a iii) cross-linking the cross-linkable polymer to form the said cross-linked water-swellable polymer matrix.  
 
     
     
         49 . A method according to  claim 41  in which the pharmaceutical active is a nucleic acid.  
     
     
         50 . A method according to  claim 41  in which the pharmaceutical active is a protein which is anionically charged at physiological pH.  
     
     
         51 . A method according to  claim 50  in which the protein is an antibody or a fragment thereof.  
     
     
         52 . A method according to  claim 48  in which the cross-linkable polymer is 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 polymer.  
 
     
     
         53 . A method according to  claim 52  in which Q 3  is a group SiR 4   3  in which each R 4  is a C 1-4  alkoxy group or a halogen atom.  
     
     
         54 . A method according to  claim 52  in which X is a group of formula VI  
       
         
           
           
               
               
           
         
       
       where the groups R 8  are the same or different and each is hydrogen or C 1-4  alkyl, and e is from 1 to 6.  
     
     
         55 . A method according to  claim 52  in which Q 1  is selected from the group consisting of N + R 5   3 , P + R 5   3  and S + R 5   2  
 in which the groups R 5  are the same or different and are each selected from the group consisting of hydrogen, C 1-4 -alkyl and aryl, or two of the groups R 5  together with the heteroatom to which they are attached form a saturated or unsaturated heterocyclic ring containing from 5 to 7 atoms.  
 
     
     
         56 . A method according to  claim 52  in which the groups Y, Y 1  and y 3  all have the general formula CH 2 ═C(R)C(O)A— in which A is —O— or —NR 1  where R 1  is hydrogen or a C 1-4  alkyl group, and R is hydrogen or a C 1-4  alkyl group.  
     
     
         57 . A method of producing an implant loaded with a pharmaceutical active comprising the steps: 
 a) providing a coated implant having a coating of cross-linked water-swellable polymer matrix on its external surface, the cross-linked water-swellable polymer matrix comprising a polymer having pendant zwitterionic groups and pendant cationic groups; and    b) contacting the coated implant with a solution or dispersion of a pharmaceutical active which is a nucleic acid, in a solvent whereby the pharmaceutical active is absorbed into or adsorbed onto the polymer matrix.    
     
     
         58 . A method according to  claim 57  in which the said solvent is selected for its ability to swell the polymer matrix and in step b) the solvent partially swells the said polymer matrix.  
     
     
         59 . A method according to  claim 57  in which the said solvent is aqueous.  
     
     
         60 . A method according to  claim 57  in which the solvent is organic and which additionally comprises, following step b), a step: 
 c) drying the treated implant to remove the solvent.  
 
     
     
         61 . A method according to  claim 60  in which the removal is by evaporation.  
     
     
         62 . A method according to  claim 57  in which the implant is a stent.  
     
     
         63 . A method according to  claim 62  in which the stent is mounted on a delivery device prior to said contacting step b).  
     
     
         64 . A method according to  claim 57  in which step a) comprises the sub-steps: 
 a i) providing an uncoated implant;  
 a ii) coating the implant with a cross-linkable polymer; and  
 a iii) cross-linking the cross-linkable polymer to form the said cross-linked water-swellable polymer matrix.  
 
     
     
         65 . A method according to  claim 64  in which the cross-linkable polymer is 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 polymer.  
 
     
     
         66 . A method according to  claim 65  in which Q 3  is a group SiR 4   3  in which R 4  is a C 1-4  alkoxy group or a halogen atom.  
     
     
         67 . A method according to  claim 65  in which X is a group of formula VI  
       
         
           
           
               
               
           
         
       
       where the groups R 8  are the same or different and each is hydrogen or C 1-4  alkyl, and e is from 1 to 6.  
     
     
         68 . A method according to  claim 65  in which Q 1  is selected from the group consisting of N + R 5   3 , P + R 5   3  and S + R 5   2  
 in which the groups R 5  are the same or different and are each selected from the group consisting of hydrogen, C 1-4 -alkyl and aryl, or two of the groups R 5  together with the heteroatom to which they are attached form a saturated or unsaturated heterocyclic ring containing from 5 to 7 atoms.  
 
     
     
         69 . A method according to  claim 65  in which the groups Y, Y 1  and Y 3  all have the general formula CH 2 ═C(R)C(O)A— in which A is —O— or —NR 1  where R 1  is hydrogen or a C 1-4  alkyl group, and R is hydrogen or a C 1-4  alkyl group.  
     
     
         70 . A method of producing an implant loaded with a pharmaceutical active comprising the steps: 
 a) providing a coated implant having a coating of cross-linked water-swellable polymer matrix on its external surface, the cross-linked water-swellable polymer matrix comprising a polymer having pendant zwitterionic groups and pendant cationic groups; and    b) contacting the coated implant with a solution or dispersion of a pharmaceutical active which is a protein in a solvent, the protein being anionically charged at physiological pH, whereby the pharmaceutical active is absorbed into or adsorbed onto the polymer matrix.    
     
     
         71 . A method according to  claim 70  in which the said solvent is selected for its ability to swell the polymer matrix and in step b) the solvent partially swells the said polymer matrix.  
     
     
         72 . A method according to  claim 70  in which the said solvent is aqueous.  
     
     
         73 . A method according to  claim 70  in which the solvent is organic and which additionally comprises, following step b), a step: 
 c) drying the treated implant to remove the solvent.  
 
     
     
         74 . A method according to  claim 73  in which the removal is by evaporation.  
     
     
         75 . A method according to  claim 70  in which the implant is a stent.  
     
     
         76 . A method according to  claim 75  in which the stent is mounted on a delivery device prior to said contacting step b).  
     
     
         77 . A method according to  claim 70  in which step a) comprises the sub-steps: 
 a i) providing an uncoated implant;  
 a ii) coating the implant with a cross-linkable polymer; and  
 a iii) cross-linking the cross-linkable polymer to form the said cross-linked water-swellable polymer matrix.  
 
     
     
         78 . A method according to  claim 77  in which the cross-linkable polymer is 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 polymer.  
 
     
     
         79 . A method according to  claim 78  in which Q 3  is a group SiR 4   3  in which each R 4  is a C 1-4  alkoxy group or a halogen atom.  
     
     
         80 . A method according to  claim 78  in which X is a group of formula VI  
       
         
           
           
               
               
           
         
       
       where the groups R 8  are the same or different and each is hydrogen or C 1-4  alkyl, and e is from 1 to 6.  
     
     
         81 . A method according to  claim 78  in which Q 1  is selected from the group consisting of N + R 5   3 , P + R 5   3  and S + R 5   2  
 in which the groups R 5  are the same or different and are each selected from the group consisting of hydrogen, C 1-4 -alkyl and aryl, or two of the groups R 5  together with the heteroatom to which they are attached form a saturated or unsaturated heterocyclic ring containing from 5 to 7 atoms.  
 
     
     
         82 . A method according to  claim 78  in which the groups Y, Y 1  and Y 3  all have the general formula CH 2 ═C(R)C(O)A— in which A is —O— or —NR 1  where R 1  is hydrogen or a C 1-4  alkyl group, and R is hydrogen or a C 1-4  alkyl group.  
     
     
         83 . A method according to  claim 70  in which the protein is an antibody or a fragment thereof.  
     
     
         84 . A method according to  claim 39  in which the protein is an antibody or a fragment thereof.  
     
     
         85 . A method according to  claim 57  in which the nucleic acid is DNA or RNA.  
     
     
         86 . A method according to  claim 57  in which the nucleic acid has a molecular weight higher than 1 kD.  
     
     
         87 . A method according to  claim 86  in which the nucleic acid has a molecular weight higher than 1.2 kD.  
     
     
         88 . A method according to  claim 85  in which the nucleic acid is linear or circular and is single or double stranded.  
     
     
         89 . A method according to  claim 57  in which the step b) of contacting the coated implant involves dipping the implant into a volume of the said solution or dispersion.  
     
     
         90 . A method according to  claim 70  in which the step b) of contacting the coated implant involves dipping the implant into a volume of the said solution or dispersion.  
     
     
         91 . A method according to  claim 57  in which step b) lasts at least 30 s.  
     
     
         92 . A method according to  claim 70  in which step b) lasts at least 30 s.