Drug-eluting medical device

Abstract

The present invention relates to a drug-eluting medical device, in particular a balloon for angioplasty catheters with drug elution to prevent the restenosis of the vessel subjected to angioplasty. More particularly, the present invention relates to a catheter balloon completely or partially coated with paclitaxel in hydrated crystalline form or in hydrated solvated crystalline form, having an immediate release and bioavailability of a therapeutically effective amount of paclitaxel at the site of intervention. The balloon can be made of a polyether-polyamide block copolymer, or a polyester amide, or polyamide-12.

1 . A catheter balloon completely or partially coated with paclitaxel in crystalline hydrated form, having an immediate release and bioavailability of a therapeutically effective amount of paclitaxel at the site of intervention. 
     
     
         2 . The catheter balloon completely or partially coated with paclitaxel in crystalline hydrated solvated form, having an immediate release and bioavailability of a therapeutically effective amount of paclitaxel at the site of intervention. 
     
     
         3 . The catheter balloon according to  claim 1 , wherein said crystalline hydrated form comprises water of crystallization in a molar ratio expressed by an integer or a decimal ranging between 2 and 4 per molecule of paclitaxel. 
     
     
         4 . The catheter balloon according to  claim 2 , wherein said crystalline hydrated solvated form comprises water of crystallization in a molar ratio expressed by an integer or a decimal from 2 to 3, and solvating solvent in a molar ratio expressed by an integer or a decimal from 1 to 3 per molecule of paclitaxel. 
     
     
         5 . The catheter balloon according to any one of the  claims 1  to  4 , wherein said release of a therapeutically effective amount of paclitaxel occurs in a period of time ranging between 1 second and 1.5 minutes, preferably between 20 seconds and 1 minute. 
     
     
         6 . The catheter balloon according to any one of the  claims 1  to  5 , wherein said bioavailability of a therapeutically effective amount of paclitaxel occurs in periods of time ranging between 1 second and 25 minutes, preferably between 20 seconds and 25 minutes. 
     
     
         7 . The catheter balloon according to any one of the  claims 1  to  6 , wherein said paclitaxel in crystalline hydrated or crystalline solvated hydrated form can be obtained by means of a method comprising:
 i) dissolving paclitaxel in an aqueous solvent so as to form a paclitaxel solution; 
 ii) completely or partially wetting the balloon surface with such solution; and 
 iii) letting the solvent to evaporate. 
 
     
     
         8 . The catheter balloon according to  claim 7 , wherein said aqueous solvent is selected from acetone/ethanol/water, tetrahydrofuran/water, methanol/water, acetone/water, ethanol/water, acetonitrile/water, DMF/water mixtures for crystalline hydrated paclitaxel, and from dioxane/water, DMF/water, DMSO/water, N-methylpyrrolidone/water, acetonitrile/water, N,N-dimethylacetamide/water, 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone/water, 1,3-dimethyl-2-imidazolidinone/water mixtures, or mixtures thereof, for crystalline hydrated solvated paclitaxel. 
     
     
         9 . The catheter balloon according to  claim 8 , wherein said aqueous solvent for the formation of paclitaxel in crystalline hydrated form is selected from a 9:1 tetrahydrofuran/water mixture, or a tetrahydrofuran/water mixture with ratios ranging between 9.5:0.5 and 65:35, or an acetone/ethanol/water mixture, in which the organic solvent is present in an amount not less than 50% by volume relative to water. 
     
     
         10 . The catheter balloon according to any one of the  claims 7  to  9 , wherein said balloon can be obtained by depositing said paclitaxel solution on the folded balloon surface or on the surface of the balloon in inflated condition by means of a syringe, micropipette, or other similar dispensing means, and by making said dispensing means to slide on the surface from an end to the other one, and vice versa, while rotating the balloon around the longitudinal axis thereof, so as to establish a zigzag path. 
     
     
         11 . The catheter balloon according to any one of the  claims 7  to  10 , wherein said paclitaxel solution of the step i) comprises urea, preferably in amounts ranging between 1 and 100 mg/mL, or between 4 and 10 mg per mL solvent, or about 7 mg per mL solvent. 
     
     
         12 . The catheter balloon according to any one of  claims 7  to  11 , wherein the said paclitaxel has a concentration between 4 and 6 mg/ml in the said paclitaxel solution. 
     
     
         13 . The catheter balloon according to any one of the  claims 1  to  12 , wherein said balloon is made of a polyether-polyamide block copolymer, or compound thereof with a polyamide. 
     
     
         14 . The catheter balloon according to  claim 13 , wherein said polyether-polyamide block copolymer can be obtained by polymerization of a polyamide block-forming compound selected from the group consisting of an aminocarboxylic acid according to the formula (1), and a lactam according to the formula (2): 
       
         
           
           
               
               
           
         
         with a triblock polyetherdiamine compound of formula (3): 
       
       
         
           
           
               
               
           
         
         and with a dicarboxylic acid according to the formula (4):
   HOOC—(R3) m -COOH   (4)
 
 
       
       wherein each of the R1, R2, and R3 groups represents linking groups comprising a hydrocarbon chain therein, optionally interrupted by one or more amide groups. 
     
     
         15 . The catheter balloon according to  claim 14 , wherein: R1 and R2 independently comprise an alkylene group having 2 to 20 carbon atoms and amide bonds; R3 comprises an alkylene group having 1 to 20 carbon atoms; x can vary between 1 and 20, or between 1 and 18, or between 1 and 16; y can vary between 4 and 50, or between 5 and 45, or between 8 and 30; z can vary between 1 and 20, or between 1 and 18, or between 1 and 12; m is 0 or 1. 
     
     
         16 . The catheter balloon according to  claim 14  or  15 , wherein said polymerization is carried out by using 15 to 70% by weight of the compound of formula (1) and/or (2), and a mixture of compounds of formulae (3) and (4) in an overall weight percentage between 30 and 85%, at a temperature ranging between 150 and 300° C., or between 160 and 280° C., or between 180 and 250° C. 
     
     
         17 . The catheter balloon according to any one of the  claims 13  to  16 , wherein said compounds of the polyether-polyamide block copolymer with a polyamide can be obtained by mixing the copolymer in amounts from 10 to 90% by weight, or 75 to 25%, or 60 to 40% by weight, with an amount of polyamide to completion of 100%. 
     
     
         18 . The catheter balloon according to  claim 17 , wherein said polyamide is polyamide-12. 
     
     
         19 . The catheter balloon according to any one of the  claims 1  to  12 , wherein said balloon is made of polyamide-12. 
     
     
         20 . The catheter balloon according to any one of the  claims 1  to  12 , wherein said balloon is made of polyester amide. 
     
     
         21 . The catheter balloon according to  claim 20 , wherein said polyester amide can be described by the following general formula:
   H—(O—PF—OOC—PA—COO—PF—OOC—PA—CO) n —OH
   
       wherein PA is a polyamide segment, PF is a diol segment comprising OH-terminating dimer diol segments, and n is a number ranging between 5 and 20. 
     
     
         22 . The catheter balloon according to  claim 21 , wherein the content of the diol component within the polyester-amide copolymer is 5-50% by weight, or 10 to 30% by weight, or between 10 and 20% by weight of the total formulation. 
     
     
         23 . The catheter balloon according to any one of the  claims 1  to  22 , wherein said balloon has a surface which is hydrophilic or hydrophilized by suitable hydrophilizing treatment. 
     
     
         24 . The catheter balloon according to any one of the  claims 1  to  23 , wherein paclitaxel is present in the catheter balloon coating layer in amounts ranging between 1 and 20 μg/mm 2 , or between 2 and 7 μg/mm 2 , or between 3 and 5 μg/mm 2 . 
     
     
         25 . A method of coating a catheter balloon with a drug, the said method comprising the following steps:
 (a) Providing a balloon;   (b) Inflating the said balloon to a predetermined pressure;   (c) Coating the said inflated balloon of step (b) with a paclitaxel solution;   (d) Deflating the coated balloon of step (c);   (e) Folding the deflated balloon of step (d) when still wet;   (f) Optionally, applying to the said folded balloon a protective cover.   
     
     
         26 . A method of coating a catheter balloon with a drug, the said method comprising the following steps:
 (g) Providing a folded balloon, for example a balloon having 3 or 6 folds;   (h) Inflating the said folded balloon to a predetermined pressure;   (i) Coating the said inflated balloon of step (h) with a paclitaxel solution;   (j) Deflating the coated balloon of step (i);   (k) Re-folding the deflated balloon of step (j) when still wet;   (l) Optionally, applying to the said re-folded balloon a protective cover.   
     
     
         27 . The method of  claim 25  or  26 , wherein in step (b) or (h) the said predetermined pressure is a pressure below the RBP pressure of the catheter balloon. 
     
     
         28 . The method of  claim 25  or  26 , wherein the said predetermined pressure is between 5 and 9 bar. 
     
     
         29 . The method according to any one of  claims 25  to  28 , wherein the said catheter balloon is disconnected from the pressurised air source before coating. 
     
     
         30 . The method according to any one of  claims 25  to  29 , wherein the said inflating step (b) or (h) is prolonged for 20 to 40 seconds. 
     
     
         31 . The method according to any one of  claims 25  to  30 , wherein step (c) or (i) of coating is performed by delivering the drug solution over the inflated balloon surface, starting delivery of the solution from the mid of the balloon length and moving to an end of the balloon, then to the opposite end, while the balloon is rotated. 
     
     
         32 . The method according to  claim 31 , wherein the balloon catheter is rotated at a speed from about 5 rpm to about 30, preferably from about 10 rpm to about 20 rpm and the delivery time of the drug solution ranges from about 10 seconds to about 500 seconds. 
     
     
         33 . The method according to any one of  claims 25  to  32 , wherein step (d) or (j) of deflation of the coated balloon is accomplished by applying vacuum to the catheter balloon opening and/or by pressing the balloon from the exterior. 
     
     
         34 . The method according to any one of  claims 25  to  33 , wherein step (e) or (k) or folding or of re-folding, respectively, is performed within 20 minutes from the end of the coating step (c), or between 1 minute and 10 minutes, or between 1 minute and 5 minutes. 
     
     
         35 . The method according to any one of  claims 25  to  34 , wherein step (f) or (l) is accomplished by inserting over the re-folded balloon a protective cover, typically a sleeve that envelops the balloon surface that has been coated with the drug. 
     
     
         36 . The method according to  claim 35 , wherein the said sleeve is made of a low friction material having a friction coefficient below the friction coefficient of the material of which the balloon is made. 
     
     
         37 . The method according to  claim 36 , wherein the said low friction material is polytetrafluoroethylene (PTFE). 
     
     
         38 . A device ( 1 ) for rotating a catheter balloon ( 2 ) during the coating step with a drug, the said device ( 1 ) comprising a first motor unit ( 5 ) and a second motor unit ( 6 ) that rotate synchronously, the said first and second motor units ( 5 ,  6 ) comprising respective clamp means ( 8 ,  8 ′) to clamp opposite ends of a catheter balloon ( 2 ). 
     
     
         39 . The device of  claim 38 , comprising a command and control unit ( 7 ) that operates synchronously the said first and second motor units ( 5 ,  6 ). 
     
     
         40 . The device according to  claim 38  or  39 , wherein the said first and second motor units ( 5 ,  6 ) are brushless motors. 
     
     
         41 . The device according to any one of  claims 38  to  40 , comprising one or more supporting means ( 9 ) for the catheter balloon ( 2 ).