Solvent methods for preparing crystalline macrolide particulates, compositions, and articles containing particulates

Abstract

The invention provides therapeutic particulates including a macrolide, such as rapamycin, in solid state crystalline form, having a size of 20 μm or less, or 10 μm or less. The particulates are formed in one method by preparing a composition with a macrolide and first (e.g., xylene) and second (e.g., an alcohol, acetone, or acetonitrile) solvents. In the composition a maximum solubility for the macrolide that is greater than a maximum solubility of the macrolide dissolved in either the first or second solvent individually. The first and second solvents are then evaporated from the composition to provide the macrolide particulates. In another method, the particulates can be formed by a method including sonication and stirring/evaporation steps, and the particulates can be obtained from a supersaturated solution, formed during the process. Particulates display desirable low polydispersity, and can be used in therapeutic compositions, or can be associated with an implantable or insertable medical device for the treatment of a subject.

What is claimed is: 
     
         1 . A particulate set comprising a plurality of macrolide particulates, wherein the majority of macrolide particulates in the set have a size of 10 μm or less, wherein particulates comprise macrolide in crystalline form. 
     
     
         2 . The particulate set of  claim 1  wherein the majority of macrolide particulates have a size in the range of 500 nm to 10 μm. 
     
     
         3 . The particulate set of  claim 1  wherein the majority of macrolide particulates have a size in the range of 0.4 μm to 4μm, wherein particulates comprise macrolide in crystalline form. 
     
     
         4 . The particulate set of  claim 1  having a degree of monodispersity of 5 or less. 
     
     
         5 . The particulate set of  claim 4  having a degree of monodispersity in the range of about 1 to about 5. 
     
     
         6 . The particulate set of  claim 5  having a degree of monodispersity in the range of about 1 to about 5. 
     
     
         7 . The particulate set of  claim 4  having a modal size in the range of 0.3 μm to 10 μm. 
     
     
         8 . The particulate set of  claim 1  wherein the macrolide is selected from the group consisting of rapamycin, everolimus, pimecrolimus, temsirolimus, fujimycin/tacrolimus, deforolimus, zotarolimus, and biolimus. 
     
     
         9 . The particulate set of  claim 8  wherein the macrolide is rapamycin. 
     
     
         10 . An implantable or insertable medical device comprising the particulate set of macrolide particulates according to  claim 1 . 
     
     
         11 . The implantable or insertable medical device of  claim 10  which is a balloon catheter. 
     
     
         12 . The implantable or insertable medical device of  claim 10  wherein the balloon catheter comprises a polymeric coating and the macrolide particulates are associated with a coating on the balloon catheter. 
     
     
         13 . The implantable or insertable medical device of  claim 12  wherein the coating is configured to release macrolide particulates from the coating upon expansion of the balloon. 
     
     
         14 . The implantable or insertable medical device of  claim 12  wherein the coating comprises a flexible hydrogel matrix. 
     
     
         15 . The implantable or insertable medical device of  claim 12  comprises poly(ethylenimine) or poly(vinyl amine) associated with the macrolide particulates. 
     
     
         16 . An injectable therapeutic composition comprising the particulate set of macrolide particulates according to  claim 1 .