Apparatus and Methods for Loading a Drug Eluting Medical Device

Abstract

Methods and apparatus are disclosed for loading a therapeutic substance or drug within a lumenal space of a hollow wire having a plurality of side openings along a length thereof that forms a hollow drug-eluting stent with a plurality of side drug delivery openings. Loading a drug within the lumenal space of the hollow stent includes a drug filling step, in which the drug is mixed with a solvent or dispersion medium. The lumenal space may be filled with the drug solution or suspension in a reverse fill process and/or a forward fill process. After the drug filling step, a solvent or dispersion medium extracting step is performed to extract the solvent or dispersion medium from within the lumenal space such that only the drug remains within the hollow stent. A stent cleaning step may be performed to an exterior surface of the hollow stent.

What is claimed is: 
     
         1 . A method of loading a therapeutic substance within a lumenal space of a hollow wire having a plurality of side openings that forms a hollow stent, the method comprising the steps of:
 submerging the hollow stent within a solution of a therapeutic substance and a solvent;   vibrating the hollow stent and the solution to assist in moving the solution through the plurality of side openings into the lumenal space of the hollow stent;   removing the hollow stent from the solution when the lumenal space is substantially full of the solution and thereby creating a filled hollow stent; and   utilizing supercritical carbon dioxide extraction to extract substantially all residual solvent from the lumenal space of the filled hollow stent while the therapeutic substance remains within the hollow stent such that the hollow stent is thereby loaded with the therapeutic substance for subsequent delivery within a body lumen.   
     
     
         2 . The method of  claim 1 , wherein the step of utilizing supercritical carbon dioxide extraction further comprises:
 placing the filled hollow stent within an extraction vessel;   filling the extraction vessel with pressurized carbon dioxide above the critical pressure; and   heating the extraction vessel with the filled hollow stent to a temperature above the critical pressure for carbon dioxide to produce supercritical carbon dioxide; and   holding the supercritical carbon dioxide and the filled hollow stent at supercritical conditions for a period of time that is sufficient for the supercritical carbon dioxide to penetrate the lumenal space of the hollow stent and solubilize the residual solvent within the lumenal space of the hollow stent.   
     
     
         3 . The method of  claim 2 , wherein the step of utilizing supercritical carbon dioxide extraction further comprises:
 extracting solubilized residual solvent and supercritical carbon dioxide from the lumenal space of the filled hollow stent by depressurizing the extraction vessel to ambient.   
     
     
         4 . The method of  claim 3 , wherein the steps of heating, adding pressurized carbon dioxide, holding and depressurizing are repeated to extract substantially all residual solvent from the lumenal space of the filled hollow stent. 
     
     
         5 . The method of  claim 2 , wherein the step of utilizing supercritical carbon dioxide extraction further comprises:
 extracting the solubilized residual solvent and supercritical carbon dioxide from the lumenal space of the filled hollow stent by throttling an expansion valve of the extraction vessel while maintaining the pressure within the extraction vessel with a continuous inflow of supercritical carbon dioxide.   
     
     
         6 . The method of  claim 1 , wherein the solvent of the solution is a high-capacity solvent and the solution also includes an excipient to assist in elution of the therapeutic substance, wherein the excipient and therapeutic substance remain within the hollow stent after extraction of residual solvent therefrom. 
     
     
         7 . The method of  claim 6 , wherein the excipient is a hydrophilic agent. 
     
     
         8 . The method of  claim 7 , wherein the high capacity solvent is tetrahydrofuran, the therapeutic substance is sirolimus and the excipient is urea. 
     
     
         9 . The method of  claim 6 , wherein the excipient is a surfactant. 
     
     
         10 . The method of  claim 9 , wherein the high capacity solvent is di-chloromethane, the therapeutic substance is sirolimus and the excipient is a cyclodextrin. 
     
     
         11 . The method of  claim 6 , further comprising:
 cleaning an exterior surface of the hollow stent loaded with the therapeutic substance by using a carbon dioxide spray cleaning system.   
     
     
         12 . The method of  claim 1 , wherein the solvent of the solution is a low-capacity solvent and the solution also includes an excipient to assist in elution of the therapeutic substance, wherein the excipient and therapeutic substance remain within the hollow stent after extraction of residual solvent therefrom. 
     
     
         13 . The method of  claim 12 , wherein the excipient is a surfactant. 
     
     
         14 . The method of  claim 13 , wherein the low capacity solvent is methanol, the therapeutic substance is sirolimus and the excipient is a cyclodextrin. 
     
     
         15 . The method of  claim 12 , wherein the excipient is a hydrophilic agent. 
     
     
         16 . The method of  claim 15 , wherein the low capacity solvent is methanol, the therapeutic substance is sirolimus and the excipient is urea. 
     
     
         17 . A method of loading a therapeutic substance within a lumenal space of a hollow wire having a plurality of side openings that forms a hollow stent, the method comprising the steps of:
 submerging the hollow stent within a suspension of a therapeutic substance and a dispersion medium;   vibrating the hollow stent and the suspension to assist in moving the suspension through the plurality of side openings into the lumenal space of the hollow stent;   removing the hollow stent from the suspension when the lumenal space is substantially full of the suspension and thereby creating a filled hollow stent; and   utilizing supercritical carbon dioxide extraction to extract substantially all residual dispersion medium from the lumenal space of the filled hollow stent while the therapeutic substance remains within the hollow stent such that the hollow stent is thereby loaded with the therapeutic substance for subsequent delivery within a body lumen.   
     
     
         18 . The method of  claim 17 , wherein the step of utilizing supercritical carbon dioxide extraction further comprises:
 placing the filled hollow stent within an extraction vessel;   filling the extraction vessel with pressurized carbon dioxide above the critical pressure; and   heating the extraction vessel with the filled hollow stent to a temperature above the critical temperature for carbon dioxide to produce supercritical carbon dioxide; and   holding the supercritical carbon dioxide and the filled hollow stent at supercritical conditions for a period of time that is sufficient for the supercritical carbon dioxide to penetrate the lumenal space of the hollow stent and solubilize the residual dispersion medium within the lumenal space of the hollow stent.   
     
     
         19 . The method of  claim 18 , wherein the step of utilizing supercritical carbon dioxide extraction further comprises:
 extracting the solubilized residual dispersion medium and supercritical carbon dioxide from the lumenal space of the filled hollow stent by depressurizing the extraction vessel to ambient.   
     
     
         20 . The method of  claim 19 , wherein the steps of heating, holding and extracting are repeated to extract substantially all residual dispersion medium from the lumenal space of the filled hollow stent. 
     
     
         21 . The method of  claim 18 , wherein the step of utilizing supercritical carbon dioxide extraction further comprises:
 extracting the solubilized residual dispersion medium and supercritical carbon dioxide from the lumenal space of the filled hollow stent by throttling an expansion valve of the extraction vessel while maintaining the pressure within the extraction vessel with a continuous inflow of supercritical carbon dioxide.   
     
     
         22 . The method of  claim 17 , wherein the dispersion medium of the suspension is selected from the group consisting of water and C5-C10 alkanes and the suspension also includes surfactants to stabilize dispersion of the therapeutic substance within the suspension. 
     
     
         23 . The method of  claim 22 , wherein the dispersion medium is water, the therapeutic substance is sirolimus and the surfactant is a polysorbate. 
     
     
         24 . The method of  claim 22 , wherein the dispersion medium is hexane, the therapeutic substance is sirolimus and the surfactant is a sorbitan fatty acid ester. 
     
     
         25 . The method of  claim 17 , further comprising:
 cleaning an exterior surface of the hollow stent loaded with the therapeutic substance by using a carbon dioxide spray cleaning system.   
     
     
         26 . A method of loading a therapeutic substance within a lumenal space of a hollow wire having a plurality of side openings that forms a hollow stent, the method comprising the steps of:
 submerging the hollow stent within a suspension of small particles of a therapeutic substance in a dispersion medium;   vibrating the hollow stent and the suspension to assist in moving the suspension through the plurality of side openings into the lumenal space of the hollow stent;   removing the hollow stent from the suspension when the lumenal space is substantially full of the suspension and thereby creating a filled hollow stent; and   utilizing vacuum oven drying to extract substantially all residual dispersion medium from the lumenal space of the filled hollow stent while the small particles of the therapeutic substance remain within the hollow stent such that the hollow stent is thereby loaded with the therapeutic substance for subsequent delivery within a body lumen.   
     
     
         27 . The method of  claim 26 , further comprising:
 cleaning an exterior surface of the hollow stent loaded with the therapeutic substance by using a carbon dioxide spray cleaning system.   
     
     
         28 . The method of  claim 26 , wherein the suspension also includes surfactants to stabilize dispersion of the therapeutic substance within the suspension and wherein the dispersion medium is water, the therapeutic substance is sirolimus and the surfactant is a polysorbate. 
     
     
         29 . The method of  claim 26 , wherein the suspension also includes surfactants to stabilize dispersion of the therapeutic substance within the suspension and wherein the dispersion medium is hexane, the therapeutic substance is sirolimus and the surfactant is a sorbitan fatty acid ester. 
     
     
         30 . The method of  claim 26 , wherein homogenization of the suspension is utilized to create nanoparticles of the therapeutic substance therein. 
     
     
         31 . The method of  claim 26 , wherein the diameter of the small particles is less than 1 um. 
     
     
         32 . The method of  claim 26 , wherein the diameter of small particles is less than 100 nm.