Methods Of Drug Loading A Hollow Stent By Immersion

Abstract

A method of loading a composition into a structural element of a stent, where the structural element is defined by a lumen and at least one opening to access the lumen. The structural element, or a stent having such a structural element, is immersed in a solution or a composition, and the composition or solution is allowed to fill the lumen. The composition or solution may comprise a therapeutic agent.

1 . A method of loading a composition into a structural element of a stent, comprising:
 providing a stent having a structural element or providing a structural element that is to be used in forming a stent, the structural element defined by a lumen and at least one opening to access the lumen;   providing a container filled with a solution, the solution being in a liquid or a supercritical fluid state, and the solution comprising a solvent and a composition comprising a therapeutic agent,
 wherein the solvent has a boiling point of less than 20° C. at 1 atmosphere; and 
 wherein the solution is maintained under a condition of temperature and pressure that maintains the solution in a liquid or a supercritical fluid state. 
   immersing the structural element into the solution;   allowing the solution to fill the lumen; and   adjusting the condition to evaporate the solvent thereby leaving the composition comprising the therapeutic agent in a solid state, or a semi-solid state, or a fluid state having a viscosity of at least 100 cP, within the lumen.   
     
     
         2 . The method of  claim 1 , wherein after the solvent has evaporated, the composition remaining in the lumen is in a solid state, or a semi-solid state. 
     
     
         3 . The method of  claim 1 , further comprising, after allowing the solution to fill the lumen before adjusting the condition, removing the structural element from the solution. 
     
     
         4 . The method of  claim 3 , further comprising, sealing the access opening when the structural element is removed from the solution to prevent the solution from escaping out from the lumen. 
     
     
         5 . The method of  claim 4 , the method further comprising removing the seal after the solvent has evaporated. 
     
     
         6 . The method of  claim 1 , further comprising executing at least one additional time the cycle of immersing the structural element, allowing the solution to fill the lumen, and adjusting the condition. 
     
     
         7 . The method of  claim 1 , wherein adjusting the condition comprises increasing the temperature to about 20° C. or greater than 20° C. 
     
     
         8 . The method of  claim 1 , wherein adjusting the condition comprises decreasing the pressure to about one atmosphere or less than one atmosphere. 
     
     
         9 . The method of  claim 1 , wherein adjusting the condition comprises decreasing the pressure to about one atmosphere or less than one atmosphere, and increasing the temperature to about 20° C. or greater than 20° C. 
     
     
         10 . The method of  claim 1 , further comprising rinsing the structural element to at least partially remove the composition comprising the therapeutic agent on an exterior surface of the structural element such that the rinsing act does not remove the composition comprising the therapeutic agent from within the lumen. 
     
     
         11 . The method of  claim 1 , wherein the structural element is a tube such that the access opening is positioned at one end of the tube and the tube further comprises a plurality of discharge openings about a surface of the tube to allow discharge of the composition comprising the therapeutic agent from the structural element after implantation of the stent. 
     
     
         12 . The method of  claim 11 , additionally comprising, prior to the immersion, attaching a conduit to the access opening, and applying a vacuum through the access opening via the conduit when the structural element is immersed in the solution to draw the solution through the discharge openings into the lumen. 
     
     
         13 . The method of  claim 11 , wherein each of the discharge openings is at most 50% of the size of the access opening. 
     
     
         14 . The method of  claim 1 , further comprising cooling the structural element to a temperature of about 20° C. or less than 20° C. before immersion to assist with the solution penetration into the lumen. 
     
     
         15 . The method of  claim 1 , wherein the composition comprises an additive or an excipient and the additive or the excipient causes the solution to have a contact angle of less than 90 degrees on the surface of the structural element to allow the solution to penetrate into the lumen with greater ease than if the additive were not present. 
     
     
         16 . The method of  claim 1 , wherein the composition comprises a wetting enhancement fluid which allows the solution to have a contact angle of less than 90 degrees on the surface of the structural element to allow the solution to penetrate into the lumen with greater ease than if the wetting enhancement fluid were not present. 
     
     
         17 . The method of  claim 1 , wherein the solvent has a boiling point at one atmosphere of 0° C. or less than 0° C. 
     
     
         18 . The method of  claim 17 , wherein the solvent has a boiling point at one atmosphere of −10° C. or less than −10° C. 
     
     
         19 . The method of  claim 1 , wherein the solvent is selected from the group consisting of pentane, cyclopentane, butane, propane, dimethylether, trifluoromethane, dichlorodifluoromethane, chlorodifluoromethane, 1,2-dichloro-1,1,2,2-tetrafluoroethane, 1-chloro-1,1-difluoroethane, 1,1,1,2-tetrafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) freons, carbon dioxide, and all combinations thereof in all proportions. 
     
     
         20 . The method of  claim 1 , wherein the therapeutic agent is selected from the group consisting of paclitaxel, protaxel, clobetasol, dexamethasone, momentasone, dexamethasone acetate, zotarolimus, sirolimus, everolimus, biolimus, deforolimus, novolimus, myolimus, temsirolimus, and all combinations thereof in all proportions. 
     
     
         21 . A method of loading a composition into a structural element of a stent, comprising:
 providing a stent comprising a structural element or providing a structural element that is to be used in forming a stent, the structural element defined by a lumen and at least one opening to access the lumen;   providing a container filled with the composition, the composition comprising a therapeutic agent;
 wherein
 the composition is in a fluid state in the container, and the composition has characteristics such that when the composition is at a temperature of 30° C. and at one atmosphere, the composition is in a solid state or semi-solid state or in a fluid state with a viscosity of about 10 cP or greater than 10 cP; 
 
 or
 the composition has characteristics such that when the composition is at a temperature of 20° C. to 30° C. and a pressure of one atmosphere, the 
 
 viscosity of the composition is greater than 10 cP or about 10 cP; 
   immersing the structural element into the composition; and   allowing the composition to fill the lumen.   
     
     
         22 . The method of  claim 21 , further comprising, after allowing the composition to fill the lumen, removing the structural element from the composition. 
     
     
         23 . The method of  claim 21 , further comprising, sealing the access opening when the structural element is removed from the composition to prevent the composition from escaping out from the lumen. 
     
     
         24 . The method of  claim 21 , further comprising rinsing the structural element to at least partially remove the composition comprising the therapeutic agent on an outer surface of the structural element such that the rinsing act does not remove the composition comprising the therapeutic agent from within the lumen. 
     
     
         25 . The method of  claim 21 , wherein the structural element is a tube such that the access opening is positioned at one end of the tube and the tube further comprises a plurality of discharge openings about a surface of the tube to allow discharge of the composition comprising the therapeutic agent from the structural element after implantation of the stent in a patient. 
     
     
         26 . The method of  claim 25 , additionally comprising, prior to the immersion, attaching a conduit to the access opening, and applying a vacuum through the access opening via the conduit when the structural element is immersed in the composition to draw the composition through the discharge openings into the lumen. 
     
     
         27 . The method of  claim 25 , wherein each of the discharge openings is at most 50% of the size of the access opening. 
     
     
         28 . The method of  claim 21 , wherein the composition is free of, or essentially free of, solvents, and the composition is in a fluid state in the container, and the composition has characteristics such that when the composition is at a temperature of 30° C. and at one atmosphere, the composition is in a solid state or a semi-solid state or in a fluid state with a viscosity of not less than 10 cP. 
     
     
         29 . The method of  claim 21 , wherein the composition is free of, or essentially free of, solvents, and the composition is in a fluid state in the container, and the composition has characteristics such that when the composition is at a temperature of 30° C. and at one atmosphere, the composition is in a solid state or a semi-solid state or in a fluid state with a viscosity of not less than 100 cP. 
     
     
         30 . The method of  claim 21 , wherein the composition is free of, or essentially free of, solvents, and the composition is in a fluid state in the container, and the composition has characteristics such that when the composition is at a temperature of 30° C. and at one atmosphere, the composition is in a solid state or a semi-solid state. 
     
     
         31 . The method of  claim 28 , further comprising heating the structural element to a temperature of about 30° C. to about 60° C. prior to immersion into the composition. 
     
     
         32 . The method of  claim 31 , further comprising after allowing the composition to fill the lumen, cooling the structural element. 
     
     
         33 . The method of  claim 28 , wherein the composition consists essentially of the therapeutic agent. 
     
     
         34 . The method of  claim 33 , wherein the therapeutic agent is relatively stable or stable in the melt. 
     
     
         35 . The method of  claim 33 , wherein the therapeutic agent is selected from the group consisting of paclitaxel, protaxel, dexamethasone, momentasone, clobetasol, dexamethasone acetate, and all combinations thereof in all proportions. 
     
     
         36 . The method of  claim 28 , wherein the composition comprises an excipient. 
     
     
         37 . The method of  claim 36 , wherein the therapeutic agent is temperature sensitive. 
     
     
         38 . The method of  claim 36 , wherein the therapeutic agent is not stable at temperatures of about 60° C. and greater than 60° C. 
     
     
         39 . The method of  claim 36 , wherein the therapeutic agent is selected from the group consisting of zotarolimus, everolimus, sirolimus, biolimus, deforolimus, novolimus, myolimus, temsirolimus, and all combinations thereof in all proportions. 
     
     
         40 . The method of  claim 36 , wherein the excipient is selected from the group consisting of solid poloxamers, polysorbate 60, Vitamin E TGPS, di-block and tri-block polymers formed from ethylene oxide and propylene oxide, Poloxamer 188, Poloxamer 407, ascorbyl palmitate, lecithin, egg yolk phospholipid, phosphatidylcholine, polyethylene glycol-phosphatidyl ethanolamine conjugate (PEG-PE), polyethylene glycol, triglycerides, diglycerides, monoglycerides, fatty alcohols, and all combinations thereof in all proportions. 
     
     
         41 . The method of  claim 21 , wherein the composition is free of, or essentially free of, solvents, and the composition has characteristics such that when the composition is at a temperature of 20° C. to 30° C. and a pressure of one atmosphere, the viscosity of the composition is greater than 100 cP or about 100 cP. 
     
     
         42 . The method of  claim 41 , wherein the composition has characteristics such that that when the composition is at a temperature of 20° C. to 30° C. and a pressure of one atmosphere, the viscosity of the composition is equal to or greater than 5000 cP but not more than 5000 cP. 
     
     
         43 . The method of  claim 30 , wherein the composition comprises an excipient. 
     
     
         44 . The method of  claim 43 , wherein the therapeutic agent is dispersed in the excipient. 
     
     
         45 . The method of  claim 43 , wherein the composition comprises microspheres, nanoparticles, microparticles, and/or microshells which comprise the therapeutic agent.