# US 7,744,644 B2 · Medical articles having regions with polyelectrolyte multilayer coatings for regulating drug release > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,744,644 B2 - Document ID: US7744644B2 - Status: Granted - Kind: B2 - Application number: 10/805,576 - Filed: 2004-03-19 - Published: 2005-09-22 - Granted: 2010-06-29 - Earliest claimed: 2004-03-19 - Assignees: Boston Scientific Scimed, Inc. - Inventors: Jan Weber; Rachel Neuendorf - Web page: https://patentgrep.com/patent/US7744644B2 ## CPC - A61L 31/16: Biologically active materials, e.g. therapeutic substances {(A61L31/047 takes precedence)} - A61L 27/34: Macromolecular materials - A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)} - A61L 29/085: {Macromolecular materials} - A61L 29/16: Biologically active materials, e.g. therapeutic substances {(A61L29/048 takes precedence)} - A61L 31/10: Macromolecular materials - A61L 2300/604: Biodegradation - A61L 2300/608: having two or more layers - A61L 2300/61: containing two or more active agents in different layers - A61L 2400/12: Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces - A61N 1/05: for implantation or insertion into the body, e.g. heart electrode (A61N1/06 takes precedence) - A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K) - A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B) ## Abstract The medical articles which including the following: (a) a ceramic or metallic region whose surface includes a plurality of depressions, (b) a multilayer coating region including multiple polyelectrolyte layers deposited over the surface of the ceramic or metallic region; and (c) a therapeutic agent disposed beneath or within the multilayer coating region. According to another aspect of the present invention, medical articles are provided, which include: (a) a ceramic or metallic region, (b) a multilayer coating region including multiple polyelectrolyte layers deposited over a surface of the ceramic or metallic region, the multilayer coating region including a plurality of protuberances; and (c) a therapeutic agent disposed within regions beneath the protuberances. Also described herein are methods of making such medical articles, and methods of administering a therapeutic agent to a patent using such medical articles. ## Claims ### Claim 1 A medical article comprising: (a) a ceramic or metallic region whose surface comprises a plurality of depressions; (b) a multilayer coating region comprising multiple polyelectrolyte layers deposited over said surface wherein each polyelectrolyte layer has a net charge opposite in sign from the adjacent layers; and (c) a therapeutic agent disposed within the depressions beneath said multilayer coating region, wherein the multilayer coating region extends over the therapeutic-agent-containing surface depressions to provide enclosed cavities which are occupied by the therapeutic agent. ### Claim 2 (depends on 1) The medical article of claim 1, wherein the multilayer coating region extends into the surface depressions of the ceramic or metallic region. ### Claim 3 (depends on 1) The medical article of claim 1, wherein said multilayer coating region is biodisintegrable. ### Claim 4 (depends on 1) The medical article of claim 1, wherein said multilayer coating comprises a polycation layer selected from polyallylamine, polyethyleneimine, poly(dimethyl diallyl ammonium chloride), protamine sulfate, chitosan, gelatin, spermidine, and albumin and a polyanion layer selected from poly(styrene sulfonic acid), poly(aniline sulfonic acid), polyacrylic acid, sodium alginate, polystyrene sulfonate, eudragit, gelatin, hyaluronic acid, carrageenan, chondroitin sulfate, carboxymethylcellulose. ### Claim 5 (depends on 1) The medical article of claim 1, wherein said multilayer coating contains from 2 to 100 polyelectrolyte layers. ### Claim 6 (depends on 1) The medical article of claim 1, wherein said medical article comprises a plurality of multilayer coating regions. ### Claim 7 (depends on 6) The medical article of claim 6, wherein said medical article comprises a first therapeutic agent disposed beneath or within a first multilayer coating region and a second therapeutic agent disposed beneath or within a second multilayer coating region. ### Claim 8 (depends on 1) The medical article of claim 1, wherein said medical article comprises first and second multilayer coating regions that differ from each other with respect to the number or the composition or both the number and composition of the polyelectrolyte layers contained therein. ### Claim 9 (depends on 1) The medical article of claim 1, wherein said ceramic or metallic region is a component of said medical article. ### Claim 10 (depends on 1) The medical article of claim 1, wherein said ceramic or metallic region is disposed as a layer over at least a portion of a medical article substrate. ### Claim 11 (depends on 1) The medical article of claim 1, wherein said medical article comprises a plurality of ceramic or metallic regions. ### Claim 12 (depends on 1) The medical article of claim 1, wherein said therapeutic agent is selected from anti-thrombotic agents, anti-proliferative agents, anti-inflammatory agents, anti-migratory agents, agents affecting extracellular matrix production and organization, antineoplastic agents, anti-mitotic agents, anesthetic agents, anti-coagulants, vascular cell growth promoters, vascular cell growth inhibitors, a cholesterol-lowering agents, vasodilating agents, and agents that interfere with endogenous vasoactive mechanisms. ### Claim 13 (depends on 1) The medical article of claim 1, wherein said medical article comprises a plurality of therapeutic agents. ### Claim 14 (depends on 1) The medical article of claim 1, wherein said medical article is an implantable or insertable medical device. ### Claim 15 (depends on 14) The medical article of claim 14, wherein said implantable or insertable medical device is a stent. ### Claim 16 (depends on 14) The medical article of claim 14, wherein said implantable or insertable medical device is selected from a catheter, a guide wire, a filter, a stent graft, a vascular graft, a vascular patch, a shunt, a vena cava filter, a pacemaker, a pacemaker lead, and an orthopedic implant. ### Claim 17 (depends on 14) The medical article of claim 14, wherein said implantable or insertable medical device is adapted for implantation or insertion into the vasculature. ### Claim 18 (depends on 14) The medical article of claim 14, wherein said implantable or insertable medical device is adapted for implantation or insertion into the esophagus, trachea, colon, biliary tract, ureter, urethra, urinary tract, prostate or brain. ### Claim 19 (depends on 14) The medical article of claim 14, wherein said multilayer coating region is biodisintegrable. ### Claim 20 (depends on 19) The medical article of claim 19, wherein said multilayer coating comprises a polycation layer selected from protamine sulfate, chitosan, gelatin, spermidine, and albumin and a polyanion layer selected from sodium alginate, gelatin, hyaluronic acid, carrageenan, and chondroitin sulfate. ### Claim 21 (depends on 1) The medical article of claim 1, wherein said multilayer coating comprises 3 or more polyelectrolyte layers. ### Claim 22 (depends on 21) A method of making the medical article of claim 21, comprising: depositing a first polyelectrolyte layer having a first net charge over the substrate, depositing a second polyelectrolyte layer having a second net charge that is opposite in sign to the first net charge over the first polyelectrolyte layer, and depositing additional polyelectrolyte layers, each having a net charge that is opposite in sign to the preceding layer. ### Claim 23 (depends on 1) The medical article of claim 1, wherein said depressions are pores having an average pore size ranging from 2-50 nanometers. ### Claim 24 (depends on 1) The medical article of claim 1, wherein said depressions are pores having an average pore size ranging from 50 nanometers to 5 microns. ### Claim 25 (depends on 1) The medical article of claim 1, wherein said substrate has a net surface charge, inherent or applied. ### Claim 26 (depends on 1) The medical article of claim 1, wherein each polyelectrolyte layer comprises a single polyelectrolyte species. ### Claim 27 A medical article comprising: (a) a ceramic region whose surface comprises a plurality of depressions; (b) a biodisintegrable polyelectrolyte multilayer coating region comprising multiple polyelectrolyte layers deposited over said surface wherein each layer has a net charge opposite in sign from the adjacent layers; and (c) a therapeutic agent disposed beneath or within said multilayer coating region. ### Claim 28 (depends on 27) The medical article of claim 27, wherein said ceramic region is a porous ceramic region. ### Claim 29 (depends on 28) The medical article of claim 28, wherein said medical article comprises a plurality of porous ceramic regions of different composition and porosity. ### Claim 30 (depends on 28) The medical article of claim 28, wherein said porous ceramic region has an average pore size ranging from 0.3 to 100 nm. ### Claim 31 (depends on 28) The medical article of claim 28, wherein said porous ceramic region comprises a ceramic material selected from aluminum oxide, titanium oxide, iridium oxide and calcium phosphate ceramics. ### Claim 32 (depends on 28) The medical article of claim 28, wherein said medical article is a stent. ### Claim 33 (depends on 1) The medical article of claim 1, wherein said medical article comprises a metallic region. ### Claim 34 (depends on 33) The medical article of claim 33, wherein said depressions are laser cut depressions. ### Claim 35 (depends on 33) The medical article of claim 33, wherein said medical article is a stent. ### Claim 36 A medical article comprising: (a) a metallic region whose surface comprises a plurality of depressions; (b) a biodisintegrable polyelectrolyte multilayer coating region comprising multiple polyelectrolyte layers deposited over said surface, wherein each layer has a net charge opposite in sign from the adjacent layers; and (c) a therapeutic agent disposed beneath or within said multilayer coating region, wherein said depressions are through-holes. ### Claim 37 A medical article comprising: (a) a ceramic or metallic region whose surface comprises a plurality of depressions; (b) a multilayer coating region comprising multiple polyelectrolyte layers deposited over said surface; and (c) a therapeutic agent disposed beneath or within said multilayer coating region, wherein said multilayer coating further comprises metal or metal oxide nanoparticles. ### Claim 38 A method of making a medical article that comprises: (a) a ceramic or metallic region whose surface comprises a plurality of depressions; (b) a multilayer coating region comprising 3 or more polyelectrolyte layers deposited over said surface wherein each polyelectrolyte layer has a net charge opposite in sign from the adjacent layers; and (c) a therapeutic agent disposed beneath or within said multilayer coating region, said method comprising (a) inserting a disintegrable material into said depressions to form filled depressions, (b) depositing said polyelectrolyte layers over the filled depressions by a method comprising depositing a first polyelectrolyte layer having a first net charge over the substrate, depositing a second polyelectrolyte layer having a second net charge that is opposite in sign to the first net charge over the first polyelectrolyte layer, and depositing additional polyelectrolyte layers, each having a net charge that is opposite in sign to the preceding layer, (c) subsequently removing the disintegrable material from the depressions and (d) subsequently introducing said therapeutic agent into the depressions.