US2017014553A1PendingUtilityA1

Implantable medical device

52
Assignee: GORE & ASSPriority: Mar 13, 2014Filed: Mar 13, 2015Published: Jan 19, 2017
Est. expiryMar 13, 2034(~7.6 yrs left)· nominal 20-yr term from priority
Inventors:Per AntoniKarin LeonteinLars VincentRobert L. CleekPaul D. DrumhellerTheresa A. HollandTodd J. JohnsonKrzysztof PietrzakBruce M. Steinhaus
A61P 9/00A61P 35/00A61P 7/02A61L 27/34A61L 31/048A61L 2300/602A61L 33/064A61L 2300/416A61L 2420/06A61K 31/727A61F 2002/91575A61L 27/28A61F 2/07A61K 31/337A61L 2300/216A61F 2/915A61L 2300/42A61L 2300/606A61L 29/08A61K 9/0024A61L 2300/608A61L 29/16A61L 33/08A61L 31/10A61K 45/06A61K 31/436A61L 29/085A61L 33/0035A61L 2420/02A61L 31/16A61L 27/54A61L 33/0076A61L 31/08A61L 33/04A61L 2300/61A61K 2300/00A61L 31/06
52
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Claims

Abstract

According to the invention there is provided inter alia an implantable medical device with coatings comprising an immobilized heparin moiety and elutable paclitaxel and to methods for making such devices.

Claims

exact text as granted — not AI-modified
1 . An implantable medical device with a surface having a coating comprising:
 a first coating layer comprising an immobilized heparin moiety and a second particulate coating layer comprising elutable paclitaxel and at least one organic additive, wherein at least a portion of the second particulate coating layer is in contact with at least a portion of the first coating layer.   
     
     
         2 . An implantable medical device according to  claim 1 , wherein the medical device is a tubular medical device. 
     
     
         3 . An implantable medical device according to  claim 1 , wherein the first coating layer comprises a polymer. 
     
     
         4 . An implantable medical device according to  claim 3 , wherein the heparin moiety is covalently attached to the polymer. 
     
     
         5 . An implantable medical device according to or  claim 4 , wherein the polymer is a cationic polymer. 
     
     
         6 . An implantable medical device according to  claim 5 , wherein the first coating layer comprises one or more coating bilayers of cationic polymer and anionic polymer, the innermost layer being a layer of cationic polymer and the outermost layer being the layer of cationic polymer to which the heparin moiety is covalently attached. 
     
     
         7 . An implantable medical device according to  claim 3 , wherein the heparin moiety is covalently end-point attached to the polymer and wherein the end-point attached heparin moiety is connected through its reducing end. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . An implantable medical device according to  claim 1 , wherein the or each organic additive is non-polymeric and hydrolytically stable. 
     
     
         11 . (canceled) 
     
     
         12 . An implantable medical device according to  claim 1 , wherein at least a proportion of the second particulate coating layer comprising paclitaxel and at least one organic additive melts as a single phase at a lower temperature than the melting point of paclitaxel and the at least one organic additive when in pure form. 
     
     
         13 . An implantable medical device according to  claim 1 , wherein the second particulate coating layer is surfactant-free. 
     
     
         14 . An implantable medical device according to  claim 1 , wherein the second particulate coating layer is polymer-free. 
     
     
         15 . An implantable medical device according to  claim 1 , wherein the paclitaxel and the or each organic additive are in crystalline form. 
     
     
         16 . An implantable medical device according to  claim 1 , wherein the second particulate coating layer comprises crystalline particles of the therapeutic agent and the at least one organic additive in a eutectic mixture or comprises crystalline particles of the therapeutic agent and the at least one organic additive in co-crystalline form. 
     
     
         17 . (canceled) 
     
     
         18 . An implantable medical device according to  claim 1 , wherein the each organic additive is independently selected from the list consisting of paminobenzoic acid, saccharin, ascorbic acid, methyl paraben, caffeine, calcium salicylate, pentetic acid, creatinine, ethylurea, acetaminophen, aspirin, theobromine, tryptophan, succinic acid, adipic acid, glutaric acid, theophylline, and saccharin sodium. 
     
     
         19 . An implantable medical device according to  claim 18 , wherein the or each organic additive is independently selected from the list consisting of p-aminobenzoic acid, methyl paraben, caffeine, calcium salicylate and succinic acid. 
     
     
         20 . An implantable medical device according to  claim 19 , wherein the or each organic additive is caffeine or succinic acid. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . An implantable medical device according to  claim 1 , wherein the second particulate coating layer consists of paclitaxel and one organic additive. 
     
     
         24 . An implantable medical device according to  claim 1 , wherein the implantable medical device is an implantable endoluminal medical device. 
     
     
         25 . An implantable medical device according to  claim 24 , wherein the implantable medical device is a stent. 
     
     
         26 . An implantable medical device according to  claim 24 , wherein the implantable medical device is a stent-graft, wherein the stent-graft comprises a stent member and a graft member. 
     
     
         27 . An implantable medical device according to  claim 26 , wherein the stent member is composed of a metal alloy. 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . An implantable medical device according to  claim 1 , wherein the implantable medical device comprises ePTFE. 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . An implantable medical device according to  claim 2 , wherein the first coating layer is applied to a portion of the luminal side and to a portion of the abluminal side of the medical device; and wherein, the second particulate coating layer is applied only to a portion of the abluminal side of the device. 
     
     
         34 . An implantable medical device according to  claim 33 , wherein the first coating layer is applied to the entire luminal side and abluminal side of the medical device. 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . An implantable medical device according to  claim 1 , wherein at least a portion of the second particulate coating layer is applied on top of at least a portion of the first coating layer. 
     
     
         38 . A stent or stent-graft having a coating comprising:
 a first coating layer comprising an immobilized heparin moiety; and   a second particulate coating layer comprising elutable paclitaxel and at least one organic additive;   wherein,   the first coating layer is applied to a portion of the luminal side and to a portion of the abluminal side of the stent or stent-graft; and   the second particulate coating layer is applied only to a portion of the abluminal side of the stent or stent-graft,   wherein at least a portion of the second particulate coating layer is in contact with at least a portion of the first coating layer.   
     
     
         39 . A stent or stent-graft according to  claim 38 , wherein the first coating layer is applied to the entire luminal side and abluminal side of the medical device. 
     
     
         40 . A stent or stent-graft according to  claim 38 , wherein the second particulate coating layer is applied only to one end of the abluminal side of the medical device. 
     
     
         41 . A stent or stent-graft according to  claim 38 , wherein at least a portion of the second particulate coating layer is applied on top of at least a portion of the first coating layer. 
     
     
         42 . A stent or stent-graft having a coating comprising:
 a first coating layer comprising an immobilized heparin moiety; and   a second particulate coating layer comprising elutable paclitaxel and at least one organic additive;   wherein at least a portion of the second particulate coating layer is in contact with at least a portion of the first coating layer,   and wherein the organic additive is independently selected from the list consisting of paminobenzoic acid, saccharin, ascorbic acid, methyl paraben, caffeine, calcium salicylate, pentetic acid, creatinine, ethylurea, acetaminophen, aspirin, theobromine, tryptophan, succinic acid, adipic acid, glutaric acid, theophylline, and saccharin sodium.   
     
     
         43 . A stent or stent-graft according to  claim 42 , wherein the or each organic additive is independently selected from the list consisting of p-aminobenzoic acid, methyl paraben, caffeine, calcium salicylate and succinic acid. 
     
     
         44 . A stent or stent-graft according to  claim 43 , wherein the organic additive is caffeine or succinic acid. 
     
     
         45 . An implantable medical device according to  claim 25 , wherein the second particulate coating layer has suitable adherence such that less than 40% of the paclitaxel (wt % as determined using Test Method C-I or C-II) is lost during manipulation using Test Method H-I followed by Test Method H-II, for example less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5%. 
     
     
         46 . An implantable medical device according to  claim 26 , wherein the second particulate coating layer has suitable adherence such that less than 40% of the paclitaxel (wt % as determined using Test Method C-I or C-II) is lost during manipulation using Test Method I-I followed by Test Method I-II, for example less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5%. 
     
     
         47 . An implantable medical device according to  claim 25 , wherein the second particulate coating layer has paclitaxel release and tissue transfer characteristics such that using Test Method A the measured drug concentration in the tissue at the 24 hr timepoint is at least 1 I-Ig drug per g tissue (I-Ig/g), for example at least 2.5 I-Ig/g, at least 5 I-Ig/g or at least 10 I-Ig/g. 
     
     
         48 . An implantable medical device according to  claim 26 , wherein the second particulate coating layer has paclitaxel release and tissue transfer characteristics such that using Test Method A the measured drug concentration in the tissue at the 24 hr timepoint is at least 1 I-Ig drug per g tissue (I-Ig/g), for example at least 10 I-Ig/g, at least 50 I-Ig/g or at least 100 I-Ig/g. 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . An implantable medical device according to  claim 1 , wherein the medical device has HCII binding activity of at least 1 pmol/cm 2  of surface according to Test Method J, following removal of the second particulate coating layer according to Test Method C-II, e.g. at least 5 pmol/cm 2  or wherein the medical device has ATII I binding activity of at least 1 pmol/cm 2  of surface according to Test Method K, following removal of the second particulate coating layer according to Test Method C-II, e.g. at least 5 pmol/cm 2 . 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . An implantable medical device according to  claim 1 , wherein at least 80%, such as at least 85%, 90% or 95% of the paclitaxel chemical content (determined using Test Method C-II) is retained following sterilization using Test Method D. 
     
     
         58 . An implantable medical device according to  claim 1 , wherein the first coating layer is applied to the medical device before the second particulate coating layer. 
     
     
         59 . An implantable medical device according to  claim 1 , wherein the second particulate coating layer is applied to the medical device by dissolving the paclitaxel and the at least one organic additive in a solvent to form a solution, applying the solution to the medical device and then evaporating the solvent. 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . A method for the prevention or treatment of stenosis or restenosis in a blood vessel which comprises implanting into said blood vessel in the human body a medical device according to  claim 1 . 
     
     
         63 . A process for preparing a coated implantable medical device comprising the steps of:
 i) treating the medical device to provide a first coating layer comprising an immobilized heparin moiety; and further   ii) treating the medical device to provide a second particulate coating layer comprising elutable paclitaxel and at least one organic additive,   wherein at least a portion of the second particulate coating layer is in contact with at least a portion of the first coating layer.   
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . (canceled)

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