Morphology profiles for control of agent release rates from polymer matrices

Abstract

The present disclosure teaches methods of controlling the release rate of agents from a polymeric matrix that include designing and creating a predetermined initial morphology (IM) profile in a polymeric matrix. The teachings indicate, inter alia, that control over the release rate of agents can provide for an improved control over the administration of agents as well as have an effect upon the mechanical integrity and absorption rate of the polymeric matrix.

1 . A method for creating a medical article comprising a polymeric matrix having a predetermined initial morphology (IM) profile and an agent; wherein, the method includes selecting a desired IM profile; forming a polymeric layer comprising the agent on a surface of the medical article; and subjecting the polymeric layer to a terminal process step comprising:
 exposing the polymeric layer to a fluid while forming the layer, wherein the composition of the fluid is preselected to be miscible or immiscible with a component in the polymeric layer;   applying a pressure to the polymeric layer;   applying a combination of heat and pressure to the polymeric layer; or   a combination thereof; wherein, the subjecting transforms the polymeric layer into a polymeric matrix having a predetermined IM profile.   
     
     
         2 . The method of  claim 1 , wherein the fluid is a gas phase, or a phase consisting essentially of a gas phase, during the exposing. 
     
     
         3 . The method of  claim 1 , wherein the fluid comprises a polar fluid, a non-polar fluid, or a combination thereof. 
     
     
         4 . The method of  claim 1 , wherein the fluid comprises a hydrophilic fluid, a hydrophobic fluid, an amphiphilic fluid, or a combination thereof. 
     
     
         5 . The method of  claim 1 , wherein the component in the polymeric layer is a polymer or an agent and is miscible with the fluid phase. 
     
     
         6 . The method of  claim 1 , wherein the component in the polymeric layer is a polymer or an agent and is soluble in the fluid phase. 
     
     
         7 . The method of  claim 1 , wherein the fluid phase comprises water to provide a desired humidity while forming the polymeric layer. 
     
     
         8 . The method of  claim 1 , wherein the fluid phase comprises a component that was a solvent used in the forming of the polymeric layer. 
     
     
         9 . The method of  claim 1 , wherein the pressure is applied to the polymeric layer using a pressure vessel. 
     
     
         10 . The method of  claim 1 , wherein the pressure is applied to the polymeric layer using a mechanical force. 
     
     
         11 . The method of  claim 1 , wherein the pressure is applied using a crimping device for collapsing an expandable stent onto a balloon catheter. 
     
     
         12 . The method of  claim 1 , wherein the pressure is applied using a pressing device for pressing a collapsed stent onto a balloon catheter while heating the stent and the balloon catheter. 
     
     
         13 . The method of  claim 1 , wherein the pressure is applied as a negative pressure. 
     
     
         14 . The method of  claim 1 , wherein the pressure is applied as a point pressure. 
     
     
         15 . The method of  claim 1 , wherein the pressure is applied to a select surface of a stent. 
     
     
         16 . The method of  claim 1 , wherein the pressure is applied to an abluminal surface of a stent. 
     
     
         17 . The method of  claim 1 , wherein the pressure is applied by inflation of the balloon on which the stent has been mounted against a sheath or other restraint. 
     
     
         18 . The method of  claim 1 , wherein the pressure is pulsed while drying the polymeric layer to produce a desired release rate profile of the agent from the polymeric matrix. 
     
     
         19 . The method of  claim 1 , wherein the predetermined IM profile provides a controlled rate of release of the agent from the polymeric matrix. 
     
     
         20 . The method of  claim 1 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired physical characteristic selected from a group consisting of an increased or decreased water uptake, a dispersed phase morphology, a percolated phase morphology, a solid solution morphology, and a porous morphology within the matrix. 
     
     
         21 . The method of  claim 1 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired mechanical characteristic selected from a group consisting of an increased or decreased toughness, an increased elasticity, an increased or decreased Young's modulus, an increased tensile strength, and an increased tear strength of the matrix. 
     
     
         22 . The method of  claim 1 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired chemical characteristic selected from a group consisting of an increased agent loading capacity, an increased durability, and an increased hydrophilicity of the matrix. 
     
     
         23 . The method of  claim 1 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired biological characteristic selected from a group consisting of an increased biocompatibility, a desired bioactivity, an increased biobeneficiality, and a controllable rate of biodegradation and elimination of the matrix from a subject. 
     
     
         24 . A medical article comprising a polymeric matrix created using the method of  claim 1 . 
     
     
         25 . The medical article of  claim 24  comprising a stent or a coating for a stent. 
     
     
         26 . A method of treating a disorder in a patient comprising implanting in the patient the stent of  claim 25 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof. 
     
     
         27 . A medical article comprising a polymeric matrix having a first component and a second component; wherein, the first component comprises a first polymer, the second component comprises an agent, and the polymeric matrix has a predetermined initial morphology (IM) profile. 
     
     
         28 . The medical article of  claim 27  comprising a biodegradable component. 
     
     
         29 . The medical article of  claim 27 , wherein the predetermined IM profile provides a controlled rate of release of the agent from the polymeric matrix. 
     
     
         30 . The medical article of  claim 27 , wherein the agent is in a dispersed phase. 
     
     
         31 . The medical article of  claim 27 , wherein the agent is in a percolated phase. 
     
     
         32 . The medical article of  claim 27 , wherein the agent is in a solid solution. 
     
     
         33 . The medical article of  claim 27 , wherein the agent is covalently bound to a polymer. 
     
     
         34 . The medical article of  claim 27 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired physical characteristic selected from a group consisting of an increased or decreased water uptake, a dispersed phase agent morphology, a percolated phase agent morphology, a solid solution agent morphology, and a porous morphology within the matrix. 
     
     
         35 . The medical article of  claim 27 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired mechanical characteristic selected from a group consisting of an increased or decreased toughness, an increased elasticity, an increased or decreased Young's modulus, an increased tensile strength, and an increased tear strength of the matrix. 
     
     
         36 . The medical article of  claim 27 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired chemical characteristic selected from a group consisting of an increased agent loading capacity, an increased durability, hydrophilicity, and hydrophobicity of the matrix. 
     
     
         37 . The medical article of  claim 28 , wherein the predetermined IM profile is selected to provide a polymeric matrix having a desired biological characteristic selected from a group consisting of an increased biocompatibility, a desired bioactivity, an increased biobeneficiality, and a controllable rate of biodegradation and elimination of the matrix from a subject. 
     
     
         38 . The medical article of  claim 27 , wherein the polymeric matrix comprises a polymer selected from a group consisting of poly(hydroxyalkanoates) (PHAs), poly(ester amides) (PEAs), poly(hydroxyalkanoate-co-ester amides), polyesters, polyacrylates, polymethacrylates, polycaprolactones, polyglycolides, poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO), poly(propylene fumarate) (PPF), poly(D-lactide), poly(L-lactide), poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-meso-lactide), poly(D-lactide-co-meso-lactide), poly(D,L-lactide-co-meso-lactide), poly(D,L-lactide-co-PEG), poly(D,L-lactide-co-trimethylene carbonate), poly(lactide-co-glycolide), poly(glycolic acid-co-trimethylene carbonate), poly(trimethylene carbonate), PHA-PEG, PBT-PEG (PolyActive®), PEG-PPO-PEG (Pluronic®), and PPF-co-PEG. 
     
     
         39 . The medical article of  claim 27 , wherein the polymeric matrix includes a copolymer comprising a monomer selected from a group consisting of methyl methacrylate, hydroxyethyl methacrylate, butyl methacrylate, lauryl methacrylate, glycidyl methacrylate, and PEG-methacrylate. 
     
     
         40 . The medical article of  claim 27 , wherein the agent comprises a component selected from a group consisting of poly(alkylene glycols), phosphorylcholine, poly(N-vinyl pyrrolidone), poly(ethylene oxide), poly(acrylamide methyl propane sulfonic acid), poly(styrene sulfonate), polysaccharides, poly(ester amides), peptides, non-thrombotics, antimicrobials, nitric oxide donors, free radical scavengers, and any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts, and combinations thereof. 
     
     
         41 . The medical article of  claim 40 , wherein the poly(alkylene glycol) comprises a component selected from a group consisting of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), a PEG-PPG copolymer, and any analogs, homologues, congeners, derivatives, and combinations thereof. 
     
     
         42 . The medical article of  claim 40 , wherein the polysaccharide comprises a component selected from a group consisting of carboxymethylcellulose, sulfonated dextran, sulfated dextran, dermatan sulfate, chondroitin sulfate, hyaluronic acid, heparin, hirudin, and any analogs, homologues, congeners, derivatives, and combinations thereof. 
     
     
         43 . The medical article of  claim 40 , wherein the peptide comprises a component selected from a group consisting of elastin, silk-elastin, collagen, atrial natriuretic peptide (ANP), Arg-Gly-Asp (RGD), and any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts, and combinations thereof. 
     
     
         44 . The medical article of  claim 40 , wherein the free radical scavenger comprises a component selected from a group consisting of 2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical; 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, free radical; 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimic; and any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts, and combinations thereof. 
     
     
         45 . The medical article of  claim 40 , wherein the nitric oxide donor comprises a component selected from the group consisting of S-nitrosothiols, nitrites, N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazenium diolates, and any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts, and combinations thereof. 
     
     
         46 . The medical article of  claim 27 , wherein the agent comprises a component selected from a group consisting of rapamycin, methyl rapamycin, everolimus, pimecrolimus, 42-Epi-(tetrazoylyl)rapamycin (ABT-578), tacrolimus, and any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts, and combinations thereof. 
     
     
         47 . The medical article of  claim 27 , wherein the agent comprises a component selected from a group consisting of imatinib mesylate, paclitaxel, docetaxel, midostaurin, and any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts, and combinations thereof. 
     
     
         48 . The medical article of  claim 27 , wherein the agent comprises a component selected from a group consisting of estradiol, clobetasol, idoxifen, tazarotene, and any prodrugs, codrugs, metabolites, analogs, homologues, congeners, derivatives, salts, and combinations thereof. 
     
     
         49 . The medical article of  claim 27 , wherein the polymeric matrix comprises a combination of agents selected from a group consisting of everolimus and clobetasol, tacrolimus and rapamycin, tacrolimus and everolimus, rapamycin and paclitaxel, and combinations thereof. 
     
     
         50 . The medical article of  claim 27  comprising a stent or a coating for a stent. 
     
     
         51 . A method of treating a disorder in a patient comprising implanting in the patient the stent of  claim 50 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof. 
     
     
         52 . A method of creating a medical article having a desired rate of release of an agent, wherein the method comprises:
 selecting a rate of release of an agent from a medical article having a polymeric matrix comprising the agent;   obtaining the agent in a desired form, or a combination of forms, that provides the selected rate of release through dissolution, diffusion, or a combination thereof; wherein, the form, or combination of forms, comprises a component selected from a group consisting of a polymorph, a solvate, a hydrate, and an amorphous form of the agent;   preparing a composition comprising a polymer and the agent;   applying the composition on the medical article to form a polymeric layer comprising the agent; and   forming the polymeric matrix from the polymeric layer, wherein the polymeric matrix has the selected rate of release of the agent.   
     
     
         53 . The method of  claim 52 , wherein the obtaining includes melting the agent to produce a melted form and quenching the melted form to produce the desired form, or combination of forms, to provide a selected rate of release of the agent. 
     
     
         54 . The method of  claim 52 , wherein the obtaining includes dissolving the agent in a solvent to produce a solution and boiling the solution to precipitate the agent into the desired form, or combination of forms, to provide a selected rate of release of the agent. 
     
     
         55 . The method of  claim 52 , wherein the agent comprises a combination of a polymorphic form and an amorphous form of the agent, wherein the polymorphic form is combined with the amorphous form in an amount that provides a predetermined dissolution rate of the agent into an aqueous transport medium to provide the desired rate of release of the agent. 
     
     
         56 . The method of  claim 52 , wherein the agent comprises a polymorphic form that is needle-shaped, rod-shaped, cubic, spherical, or a combination thereof, to provide a predetermined diffusion rate of the agent through the polymeric matrix and provide the desired rate of release of the agent. 
     
     
         57 . The method of  claim 52 , wherein the medical article comprises a stent or a coating for a stent. 
     
     
         58 . A medical article created using the method of  claim 52 . 
     
     
         59 . The medical article of  claim 58  comprising a stent or a coating for a stent. 
     
     
         60 . A method of treating a disorder in a patient comprising implanting in the patient the stent of  claim 59 , wherein the disorder is selected from the group consisting of atherosclerosis, thrombosis, restenosis, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, and combinations thereof.