Drug composition and coating

Abstract

According to the invention there is provided inter alfa a medical device for delivering a therapeutic agent to a tissue, the device having a solid surfactant-free particulate coating layer applied to a surface of the device, the coating layer comprising a therapeutic agent and at least one non-polymeric organic additive which is hydrolytically stable; wherein at least a proportion of the particulate coating layer comprising the therapeutic agent and the at least one organic additive melts as a single phase at a lower temperature than the melting point of the therapeutic agent and the at least one organic additive when in pure form; wherein the therapeutic agent is paclitaxel; and wherein the therapeutic agent, when formulated in the coating layer, is stable to sterilization.

1 . A medical device for delivering a therapeutic agent to a tissue, the device having a solid surfactant-free particulate coating layer applied to a surface of the device, the coating layer comprising a therapeutic agent and at least one non-polymeric organic additive which is hydrolytically stable; wherein at least a proportion of the particulate coating layer comprising the therapeutic agent and the at least one organic additive melts as a single phase at a lower temperature than the melting point of the therapeutic agent and the at least one organic additive when in pure form; wherein the therapeutic agent is paclitaxel; and wherein the therapeutic agent, when formulated in the coating layer, is stable to sterilization. 
     
     
         2 . A medical device according to  claim 1  wherein the particulate coating layer is formed by evaporation of a solution of the therapeutic agent and the at least one organic additive applied to the device to form a solid particulate composition. 
     
     
         3 . (canceled) 
     
     
         4 . A medical device according to  claim 2  wherein the solution of the therapeutic agent and the at least one organic additive is a solution in a solvent selected from water, acetone and mixtures thereof. 
     
     
         5 . A medical device according to  claim 1 , wherein the therapeutic agent and the at least one organic additive in the particulate coating are in crystalline form. 
     
     
         6 . A medical device according to  claim 1 , wherein each at least one organic additive melts at a temperature of greater than about 80° C. when in pure form. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A medical device according to  claim 1 , wherein the coating layer comprises crystalline particles of the therapeutic agent and the at least one organic additive in a eutectic mixture. 
     
     
         10 . A medical device according to  claim 1 , wherein the coating layer comprises crystalline particles of the therapeutic agent and the at least one organic additive in co-crystalline form. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A medical device according to  claim 1 , wherein each at least one organic additive is independently selected from the list consisting of p-aminobenzoic 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. 
     
     
         17 . A medical device according to  claim 16 , wherein each at least one organic additive is independently selected from the list consisting of p-aminobenzoic acid, methyl paraben, caffeine, calcium salicylate and succinic acid. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . A medical device according to  claim 1 , wherein the coating layer consists of the therapeutic agent and one organic additive. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . A medical device according to  claim 1 , wherein the solid coating layer is applied to a surface of the device which is composed of nylon or ePTFE. 
     
     
         27 . (canceled) 
     
     
         28 . A medical device for delivering a therapeutic agent to a tissue, the device having a solid particulate coating layer applied to an exterior surface of the device, said surface being composed of a material selected from nylon and ePTFE, the coating layer comprising a therapeutic agent and at least one organic additive; wherein at least a proportion of the particulate coating layer comprising the therapeutic agent and the at least one organic additive melts as a single phase at a lower temperature than the melting point of the therapeutic agent and the at least one organic additive when in pure form; wherein the therapeutic agent is paclitaxel and wherein the at least one organic additive is independently selected from the list consisting of calcium salicylate, caffeine, methyl paraben, p-aminobenzoic acid and succinic acid. 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . A medical device according to  claim 28 , wherein the coating layer comprises one organic additive and wherein the coating layer consists of the therapeutic agent and one organic additive. 
     
     
         38 . (canceled) 
     
     
         39 . A medical device according to  claim 37 , wherein the organic additive is succinic acid. 
     
     
         40 . A medical device according to  claim 39 , wherein the succinic acid is present in the coating layer in the form of its alpha crystalline polymorph. 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . A medical device according to  claim 1 , which is a balloon catheter, a stent, a stent-graft or a graft. 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . A medical device according to  claim 1 , which coating layer comprising the therapeutic agent and the at least one organic additive has suitable adherence such that less than 40% of the paclitaxel is lost during shaking, for example less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5% using Test Method C. 
     
     
         53 . A medical device according to  claim 48 , wherein the device is a balloon catheter and wherein the coating has suitable paclitaxel release and tissue transfer characteristics such that the measured drug concentration in the tissue at the 1 hr timepoint is at least 50 μg drug per g tissue (μg/g), for example at least 60 μg/g, at least 70 μg/g or at least 80 μg/g using Test Method A. 
     
     
         54 . A medical device according to  claim 48 , wherein the device is a stent and wherein the coating has paclitaxel release and tissue transfer characteristics such that the measured drug concentration in the tissue at the 24 hr timepoint is at least 1 μg drug per g tissue (μ/g), for example at least 2.5 μg/g, at least 5 μg/g or at least 10 μg/g using Test Method B. 
     
     
         55 . (canceled) 
     
     
         56 . A medical device according to  claim 1 , wherein at least 80%, such as at least 85%, 90% or 95% of the therapeutic agent chemical content is retained following sterilization using Test Method D. 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . A method for the prevention or treatment of stenosis or restenosis which comprises inserting transiently or permanently into said blood vessel in the human body a medical device according to  claim 1 . 
     
     
         62 . A solid particulate composition comprising a therapeutic agent and at least one organic additive, wherein at least a proportion of the particulate composition comprising the therapeutic agent and at least one organic additive melts as a single phase at a lower temperature than the melting point of the therapeutic agent and the at least one organic additive when in pure form;
 wherein the therapeutic agent is paclitaxel and wherein the at least one organic additive is selected from the list consisting of p-aminobenzoic 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.   
     
     
         63 . (canceled) 
     
     
         64 . A solid particulate composition according to  claim 62 , wherein the at least one organic additive is selected from the list consisting of calcium salicylate, caffeine, methyl paraben, p-aminobenzoic acid and succinic acid. 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . A solid particulate composition according to  claim 62 , which consists of the therapeutic agent and at least one organic additive. 
     
     
         68 . (canceled) 
     
     
         69 . (canceled) 
     
     
         70 . (canceled) 
     
     
         71 . (canceled) 
     
     
         72 . A solid particulate composition according to  claim 62  in the form of a coating applied to a surface. 
     
     
         73 . (canceled) 
     
     
         74 . (canceled) 
     
     
         75 . (canceled) 
     
     
         76 . (canceled) 
     
     
         77 . (canceled) 
     
     
         78 . (canceled) 
     
     
         79 . (canceled) 
     
     
         80 . (canceled) 
     
     
         81 . (canceled) 
     
     
         82 . (canceled) 
     
     
         83 . (canceled) 
     
     
         84 . (canceled) 
     
     
         85 . (canceled)