EP3866869A1 - Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs - Google Patents

Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs

Info

Publication number
EP3866869A1
EP3866869A1 EP19797909.9A EP19797909A EP3866869A1 EP 3866869 A1 EP3866869 A1 EP 3866869A1 EP 19797909 A EP19797909 A EP 19797909A EP 3866869 A1 EP3866869 A1 EP 3866869A1
Authority
EP
European Patent Office
Prior art keywords
coating
catheter
reservoirs
micro
glycero
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19797909.9A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michael Thomas AHLERING
Ronald Kenichi Yamamoto
Robert John Elicker
Tien Thuy NGUYEN
John Edwin SHULZE
Jelle Jurjen ZOETHOUT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MA Med Alliance SA
Original Assignee
MA Med Alliance SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/160,888 external-priority patent/US11406742B2/en
Application filed by MA Med Alliance SA filed Critical MA Med Alliance SA
Publication of EP3866869A1 publication Critical patent/EP3866869A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M25/0045—Catheters; Hollow probes characterised by structural features multi-layered, e.g. coated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/104—Balloon catheters used for angioplasty
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222—Steroids, e.g. corticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/63—Crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
    • A61M2025/0024—Expandable catheters or sheaths
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M2025/0057—Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes

Definitions

  • This disclosure is related to the field of drug delivery via expandable catheters.
  • Balloon angioplasty is an established method for the treatment of vascular disease by physically dilating an area of atherosclerosis, stenosis or reduction in luminal diameter in a diseased blood vessel.
  • Angioplasty is typically performed with a catheter which may be advanced within the circulatory system to the diseased area.
  • the catheter has a balloon at the distal end that is inflated to dilate and expand the area of stenosis.
  • a stent is also mounted on the exterior of the balloon. The balloon is expanded at the area of atherosclerosis, and the stent is left in place after deflation and removal of the balloon to maintain the patency of the expanded lumen.
  • balloon angioplasty provides a much needed acute increase in blood flow in diseased vessels, restenosis is inherent due to the extent of associated mechanical injury.
  • One strategy for reducing the restenosis response is to release drugs into the vessel in combination with the balloon dilatation treatment to counteract the inflammation and healing response.
  • Approaches include the coating of the balloon with drugs, such as paclitaxel and sirolimus (rapamycin), which limit cellular proliferation. During contact of the balloon onto the luminal surface of the vessel it is believed that use of an excipient coating facilitates transfer of the drug to the vessel injury site.
  • drug delivery to the tissues of the vessel wall by drug coated balloons as described in the art is limited by the short period of time during which the balloon may be placed in contact with the vessel.
  • the balloon inflation during angioplasty is performed for approximately 30 to approximately 120 seconds to limit cardiac ischemia and potential patient complications and discomfort.
  • These short balloon inflation and drug delivery times may be sufficient for the antineoplastic drug paclitaxel which has demonstrated inhibition of neointimal formation in animals after a few minutes of exposure time.
  • drugs such as sirolimus and its analogues have both anti-proliferative and anti-inflammatory activity that may provide benefit beyond the acute period for restenosis if delivered over an extended time.
  • hydrophilic polymers and excipients or excipients that are liquid at body temperature.
  • Such hydrophilic coating formulations provide a hydrophilic matrix for the hydrophobic drug particles and may be effective at transferring the drug to the vessel wall.
  • such coatings do not provide significant resistance to wash off from blood either during maneuvering of the balloon to the treatment site or after transfer of the drug coating to the vessel surface.
  • Some embodiments provide a coating for an expandable portion of a catheter comprising a hydrophobic matrix and a dispersed phase, wherein the dispersed phase comprises a plurality of micro-reservoirs dispersed in the hydrophobic matrix, wherein the plurality of micro-reservoirs comprises a first active agent intermixed with or dispersed in a first biodegradable or bioerodable polymer.
  • Some embodiments provide a coating wherein the dispersed phase comprises a plurality of micro-reservoirs dispersed in the hydrophobic matrix wherein some of the plurality of micro-reservoirs comprises a first active agent and a first biodegradable or bioerodable polymer.
  • Some embodiments provide a catheter comprising an expandable portion on an elongated body and a coating over the expandable portion.
  • the coating comprises a lipophilic matrix, wherein the lipophilic matrix comprises at least one lipid, a plurality of micro-reservoirs dispersed in the lipophilic matrix, wherein the plurality of micro-reservoirs comprises an active agent, and wherein the lipophilic matrix is configured to adhere to a luminal surface when the expandable portion is expanded, and transfer at least a portion of the plurality of micro-reservoirs to the luminal surface.
  • Some embodiments provide a catheter comprising an expandable portion on an elongated body and a coating as described herein over the expandable portion.
  • the catheter further comprises a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion.
  • the catheter further comprises a protective coating over the coating.
  • Some embodiments provide a coating formulation for an expandable portion of a catheter comprising a solid portion and a fluid.
  • the solid portion comprises a plurality of micro-reservoirs and at least one hydrophobic compound.
  • the plurality of micro reservoirs comprises a first active agent and a first biodegradable or bioerodable polymer.
  • Some embodiments provide a coating formulation for an expandable portion of a catheter comprising a plurality of micro-reservoirs comprising an active agent and at least one lipid.
  • Some embodiments provide a method for coating an expandable portion of a catheter comprising disposing a coating formulation described herein over the surface of an expanded expandable portion of a catheter, evaporating the fluid, and collapsing the expandable portion.
  • Some embodiments provide a method for treating or preventing a condition at a treatment site comprising advancing a catheter comprising an expandable portion to the treatment site, wherein the expandable portion is coated with a coating described herein, expanding the expandable portion to allow contact between the coating and a tissue at the treatment site, collapsing the expandable portion, and removing the catheter.
  • FIG. 1 depicts one embodiment of a balloon catheter with a coating on the expandable portion of the catheter.
  • FIG. 2 depicts one embodiment of a balloon catheter with a release layer between the coating and the expandable portion of the catheter.
  • FIG. 3 depicts one embodiment of a balloon catheter with a protective layer over the coating.
  • FIG. 4 is a photomicrograph of the luminal surface of a vessel treated with one embodiment of the balloon catheter.
  • FIG. 5 is a photomicrograph of the luminal surface of a vessel treated with one embodiment of the balloon catheter.
  • FIG. 6 is a photomicrograph of the coated balloon surface at 100X magnification showing a coating containing a crystalline sirolimus micro-reservoir.
  • FIG. 7 is a photomicrograph of the artery surface at 50X magnification showing adhered material.
  • FIG. 8 is a photomicrograph of the artery surface at 1000X magnification showing adhered material.
  • the embodiments disclosed herein provide coatings for an expandable portion of a catheter that have time-release micro reservoirs of drug intermixed with or dispersed within a coating on a balloon that can be transferred to the luminal surface of the vessel during the 30 to about 120 seconds balloon inflation time.
  • This approach enables an extended and controlled release of drug over a longer period of time that may be tailored by the design of the micro-reservoirs for the characteristics of a particular drug or the pathology of the diseased vessel.
  • the coating disclosed herein can also resist blood wash off, which both increases drug transfer efficiency and patient safety from excessive particulate.
  • a coating for an expandable portion of a catheter or a catheter system is disclosed herein.
  • the catheter is designed for insertion into a living body for delivering at least one active agent locally.
  • the coating is formulated and constructed for minimal solubilization and dispersion into the blood stream while the catheter is being positioned into the target vessel for treatment, or after transfer of the coating to the tissues of the vessel wall.
  • the active agent or drug is delivered to the vessel for preventing or minimizing restenosis after balloon angioplasty.
  • the expandable portion may be a balloon of a balloon catheter.
  • the coating 12 for an expandable portion 11 of a catheter 10 includes two phases, a hydrophobic matrix 14 and a dispersed phase 13.
  • the dispersed phase 13 is dispersed in the hydrophobic matrix 14.
  • the dispersed phase 13 includes a plurality of micro-reservoirs, and the plurality of micro reservoirs include a first active agent and a first biodegradable or bioerodable polymer.
  • the first active agent is intermixed with or dispersed in the first biodegradable or bioerodable polymer.
  • some micro-reservoirs may comprise a first active agent and a biodegradable or bioerodable polymer.
  • the plurality of micro-reservoirs also include a second active agent.
  • the plurality of micro-reservoirs may further include a second biodegradable or bioerodable polymer.
  • the first and the second biodegradable or bioerodable polymer may be the same or different.
  • the plurality of micro-reservoirs may contain only one type of micro-reservoirs.
  • the coating 12 includes about 10% to about 75%, about 20% to about 65%, or about 30 % to about 55% by weight of the plurality of micro-reservoirs.
  • the coating 12 has a surface concentration of about 1 pg/mm 2 to about 10 pg/mm 2 , about 2 pg/mm 2 to about 9 pg/mm 2 , or about 3 pg/mm 2 to about 8 pg/mm 2 on the expendable portion of the catheter 10.
  • the hydrophobic matrix 14 comprises a combination of materials selected for its desired adhesive properties to the luminal surface.
  • Preferred hydrophobic matrix 14 includes a combination of hydrophobic compounds that are resistant to dissolution into blood but provide for uniform distribution of the formulation including the micro-reservoirs when applied to the surface of the balloon.
  • the hydrophobic matrix 14 includes at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and their derivatives. Particularly useful formulations are a combination of a sterol and a fatty acid or phospholipid.
  • the sterol may be a sterol which utilizes the body’s natural clearance mechanism such as by forming complexes with serum lipids or aggregates with serum apolipoproteins to provide transport to the liver for metabolic processing.
  • the sterol may be cholesterol. Due to the natural compatibility of cholesterol and fatty acids or phospholipids, such combinations may provide a homogenous mixture for coating 12 and a resulting homogenous coating on the balloon surface. The coating 12 formed by such combinations are homogenous without the formation of micelles or liposomes in the hydrophobic matrix 14.
  • the hydrophobic matrix 14 includes a cholesterol and a fatty acid.
  • the weight ratio of cholesterol to fatty acid is in the range of about 1:2 to about 3:1, about 1:1.5 to about 2.5:1, or about 1:1 to about 2:1.
  • the cholesterol component of the formulation may comprise cholesterol, chemically modified cholesterol or a cholesterol conjugate.
  • the cholesterol is dimethylaminoethane-carbamoyl cholesterol (DC-Cholesterol).
  • DC-Cholesterol dimethylaminoethane-carbamoyl cholesterol
  • preferred fatty acids are fatty acids normally found in serum or cell membranes.
  • the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradeadienoic acid, octanoic acid, myristic acid, myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachadonic acid, mead acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid.
  • the hydrophobic matrix 14 includes a cholesterol and a phospholipid.
  • the weight ratio of cholesterol to phospholipid is in the range of about 1:2 to about 3:1, about 1:1.5 to about 2.5:1, or about 1:1 to about 2:1.
  • the cholesterol component of the formulation may comprise cholesterol, chemically modified cholesterol or a cholesterol conjugate.
  • the cholesterol is DC-Cholesterol.
  • Preferred phospholipids are phospholipids normally found in serum or cell membranes.
  • the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol.
  • the phospholipid comprises an acyl chain length of about 20 to about 34 carbons.
  • the hydrophobic matrix 14 may further include a third active agent, which can be the same or different from the first active agent in the plurality of micro-reservoirs.
  • the hydrophobic matrix 14 comprises only hydrophobic components such as lipids, sterols and fatty acids. In other words, in some embodiments, the hydrophobic matrix contains no hydrophilic polymers or hydrophilic excipients. In some embodiments of the disclosure, the hydrophobic matrix 14 comprises only hydrophobic components such as lipids, sterols and fatty acids, and no amphiphilic constituents are present. Preferably, the coating 12 and its components have a limited solubility in blood or analogues such as plasma or phosphate buffered saline.
  • cationic cholesterol or a cationic phospholipid in the formulation may provide additional chemical attraction of the hydrophobic matrix 14 to the vessel surface and potentially to the surface of the micro-reservoirs to increase the transfer of the coating 12 and resistance to dissolution into blood after transfer.
  • Suitable cationic forms of cholesterol are modified at the 3 carbon position to attach a pendant tertiary or quaternary amine and include DC- Cholesterol.
  • Suitable cationic forms of phospholipids include naturally occurring phospholipids and synthetic modifications of phospholipids such as phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), and amine derivatives of phosphatidylcholine such as ethylphosphatidylcholine.
  • the acyl chain length and degree of unsaturation of the phospholipid component of the hydrophobic matrix 14 can be used for tailoring the physical and chemical properties of the hydrophobic matrix 14.
  • long acyl chain lengths are selected to increase hydrophobicity of the phospholipid for adhesion to the vessel surface and to decrease solubility and wash-off due to blood flow exposure.
  • the acyl chain length of fatty acids and fatty acid portion of phospholipids are described by shorthand notation with the number of carbons followed by a colon with the number of carbon-carbon double bonds. In the following description of phospholipids, both the generic or trivial name, the stereo specific numbering and shorthand notation is used for the first description of the compound.
  • Acyl chain lengths of 20 to 34 carbons are suitable for use as a coating 12 component, with acyl chain lengths of 20 to 24 carbons (C20 to C24) particularly preferred.
  • acyl chain lengths of 20 to 24 carbons particularly preferred.
  • the present invention will also work with saturated acyl chains, one or more sites of unsaturation may provide an increased chain flexibility.
  • Examples of preferred phospholipids include dieicosenoyl phosphatidylcholine (1,2- dieicosenoyl-sn-glycero-3-phosphocholine, C20:l PC), diarachidonoyl phosphatidylcholine (l,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:0 PC), dierucoyl phosphatidylcholine (l,2-dierucoyl-sn-glycero-3-phosphocholine, C22:l PC), didocosahexaenoyl phosphatidylcholine (l,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoyl phosphatidylcholine (l,2-heneicosenoyl-sn-glycero-3-phosphocholine, C2l:l PC) and dinervonyl
  • the plurality of micro-reservoirs comprises an active agent and a polymer.
  • the active agent may be referred to as a first active agent or a second active agent.
  • the active agent is associated with the polymer in a way to provide slow or extended release of the active agent from the micro-reservoirs.
  • the active agent is intermixed with or dispersed in the biodegradable or bioerodable polymer.
  • the active agent may be encapsulated by the biodegradable or bioerodable polymer.
  • the plurality of micro-reservoirs may include a first active agent.
  • the plurality of micro-reservoirs may further include a second active agent.
  • Suitable active agent may include antiproliferative or anti-inflammatory agents such as paclitaxel, sirolimus (rapamycin) and their chemical derivatives or analogues which are mTOR inhibitors, inhibitory RNA, inhibitory DNA, steroids and complement inhibitors.
  • the active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the active agent is about 10% to about 50%, about 15% to about 45%, about 20% to about 40%, or about 25% to about 35% by weight of the plurality of micro-reservoirs.
  • the micro-reservoirs may include microparticles or microspheres.
  • polylactic-co-glycolic acid (PLGA) microspheres are well suited for incorporation of the active agent for sustained release up to approximately 50% by weight of the active agent in the micro sphere.
  • the hydrophobic matrix 14 may be a lipophilic matrix, and the dispersed phase 13 is dispersed in the lipophilic matrix.
  • the lipophilic matrix may include at least one lipid.
  • the lipid may be a phospholipid, sphingolipids, ceramides, terpenes, terpenoids, monoglycerides, diglycerides, triglycerides, phytosterols, prostaglandins, vegetable oils (e.g., amaranth, apricot stone, argan, almond, avocado, coconut, grape seed, palm, safflower, sesame, soybean, sunflower, and wheat germ oils), vegetable waxes (e.g., beeswax, jojoba, and shea butter), paraffin wax, fat soluble vitamins and pro-vitamins (e.g., carotenes and vitamins A, D, E, K), steroids, squalene.
  • vegetable oils e.g., amaranth, apricot stone,
  • the phospholipid is a cationic phospholipid.
  • the lipophilic matrix may further include a sterol, such as cholesterol.
  • the lipophilic matrix as described is designed to adhere to a luminal surface when the expandable portion of the catheter is expanded in a lumen, such as blood vessel. When the expandable portion of the catheter is expanded in a lumen, at least a portion of the plurality of micro-reservoirs are transferred to the luminal surface along with at least a portion of the lipophilic matrix.
  • the dispersed phase 13 includes a plurality of micro-reservoirs.
  • the plurality of micro-reservoirs include a first active agent.
  • the plurality of micro-reservoirs include a first active agent and a first biodegradable or bioerodable polymer.
  • the first active agent is intermixed with or dispersed in the first biodegradable or bioerodable polymer.
  • some micro-reservoirs may include the first active agent alone, and some micro-reservoirs may include the first active agent intermixed with or dispersed in the first biodegradable or bioerodable polymer.
  • the first active agent may be crystalline.
  • the plurality of micro-reservoirs may contain only one type of micro-reservoirs.
  • the coating 12 includes about 10% to about 75%, about 20% to about 65%, or about 30 % to about 55% by weight of the plurality of micro reservoirs. In some embodiments, the coating 12 has a surface concentration of about 1 mg/mm 2 to about 10 mg/mm 2 , about 2 mg/mm 2 to about 9 mg/mm 2 , or about 3 mg/mm 2 to about 8 mg/mm 2 on the expendable portion of the catheter 10.
  • the micro-reservoirs comprise active agent microparticles.
  • the active agent such as sirolimus
  • the active agent can be crystalized powder from the manufacturer or recrystallized through a controlled process.
  • sirolimus microparticles may be prepared by grinding the crystalline powder for 2 hours in Novec 7100 hydrofluorcarbon solvent. Through selection of grinding ball size and hardness, as well as grinding speed and time, crystalline sirolimus can be reduced to micron sized particles or smaller. Grinding can be done dry or wet in an anti-solvent for sirolimus such as water, hexane, or hydroflurocarbons, which are then subsequently removed with drying or vacuum.
  • Alternative methods of mechanical size reduction include miniature hammer mills, automatic mortar and pestle, ultrasonic homogenization, electrohydraulic (arc cavitation) homogenization or any mechanical process which leaves the crystals intact without dissolving them in a solvent.
  • ground crystalline sirolimus can then be sieved to remove large particles.
  • an ASTM E-l l sieve number 100 (l50pm openings) could be used on this sirolimus sample and particles that did not pass through were returned to the planetary ball mill for additional grinding.
  • a specific size range microparticles can be selected using any particle size sorting techniques. For example, flowing the particles in an anti solvent through progressively smaller sieves. In some embodiments, optional further size reduction may be provided by an ultrasonic homogenization probe, electrohydraulic lithotripsy or other sources of high shear cavitation known in the art. In some embodiments, a recirculating loop can be constructed to continue to break particles down to sub- red blood cell sizing.
  • the uniformity of the particles can be further improved via flow sorting such as winnowing to remove finer particles that could give too much of a burst effect.
  • particles can be circulated in an anti- solvent (water, heptane, hydrofluorocarbon) and by controlling geometry and flow rate, particles of desired size can be collected via sedimentation.
  • the plurality of micro-reservoirs has an average diameter of about 0.5 microns to about 10 microns, about 1 micron to about 10 microns, about 0.5 microns to about 8 microns, about 1.8 micron to about 8 microns, about 2 microns to about 6 microns, or about 3 microns to about 5 microns.
  • the micro reservoirs are desired to have a size large enough to provide a sustained release of the active agent, approximately 1.5 micron or greater in diameter or average cross-sectional dimension for microparticles of non-uniform size. Smaller sizes of micro-reservoirs typically have an increased surface area to volume ratio and reduced diffusional pathway for the active agent that does not provide sufficient extended release.
  • the maximum size of the micro-reservoirs is approximately the size of a red blood cell, about 6 microns to about 8 microns, to prevent embolization into capillaries due to any micro-reservoirs released into the blood stream during or subsequent to treatment.
  • the plurality of micro-reservoirs does not contain nano-sized particles. In some embodiments, less than about 5%, less than about 8%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 40%, less than about 50% of the plurality of micro-reservoirs have a diameter of 1.5 micron or less.
  • the less than about 5%, less than about 8%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 40%, less than about 50% of the plurality of micro-reservoirs have a diameter of 1 micron or less. In some embodiments, the micro-reservoirs do not necessarily have affinity or adhesion to the vessel surface.
  • the biodegradable or bioerodable polymer can provide controlled and extended release of the active agent.
  • the biodegradable or bioerodable polymer may be referred to as a first biodegradable or bioerodable polymer or a second biodegradable or bioerodable polymer.
  • the polymer acts as a barrier to drug diffusion thereby providing a release profile tailored for the pharmacokinetics of the active agent acting on the treated vessel.
  • the active agent may be intermixed and distributed into a polymer in a solid solution.
  • the polymer may provide controlled release by reducing active agent diffusion or by coupling drug release to biodegradation, dissolution or bioerosion of the polymer.
  • the biodegradable or bioerodable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosoaminoglycans, and combination thereof.
  • the micro-reservoirs may also be microspheres or microparticles containing at least one active agent which treats the inflammation or healing response.
  • the plurality of micro reservoirs may include a first biodegradable or bioerodable polymer.
  • the plurality of micro-reservoirs may include a second biodegradable or bioerodable polymer.
  • the kinetics of active agent release is controlled by the release of active agent from the micro-reservoirs into the surrounding medium, thereby making available a sustained elution of active agent to penetrate into the vessel wall.
  • the active agent in the coating 12 be continuously released with a half-life release kinetics of about 2 weeks to about 6 weeks or greater.
  • the plurality of micro-reservoirs has active agent release kinetics with a half-life of at least 14 days.
  • the active agent release kinetics may be tailored by the characteristics of the micro-reservoirs. Two or more types of micro-reservoirs with different active agents or different release kinetics for the same active agent may be formulated into the coating 12 to tailor the treatment effect. In some embodiments, some active agent may be incorporated into the coating formulation outside of the micro-reservoirs to provide a rapid initial release of active agent to the vessel walls, allowing the micro-reservoirs to provide sufficient active agent to maintain effective tissue concentration of active agent for a prolonged period of time.
  • the active agent release kinetics also follows a power law of decreasing release rate, Korsmeyer-Peppas kinetic model, similar to the Higuchi equation.
  • Korsmeyer-Peppas kinetic model similar to the Higuchi equation.
  • the release kinetics of active agent from such micro reservoirs is well suited for treatment of the vessel wall post dilatation.
  • the design and selection of micro-reservoirs with the appropriate release constant provides for rapid initial release of active agent with sustained active agent release and extended active agent residence in the vessel wall over longer time periods compared to devices of the prior art.
  • the active agent release rate may be tailored by the solubility of the active agent in the micro-reservoir material and by adjusting microporosity of the micro-reservoir.
  • the length of effective active agent delivery may be tailored by the selection of micro-reservoir size, active agent solubility in the micro-reservoir material, and amount of active agent loaded in the micro-reservoirs.
  • the total amount of active agent to be delivered is determined by the amount of micro reservoirs in the coating formulation and their level of active agent loading.
  • the coating 12 is able to be formulated to have a concentration of active agent in the range of about 0.3 to about 3 pg per mm 2 of expandable portion 11 surface.
  • the desired kinetics of active agent release from the coating 12 may be provided by a single type of micro-reservoir or alternatively by a mixture of micro-reservoirs with different size or release characteristics to provide the desired release profile to the vessel wall.
  • the coating 12 further includes a PEG-lipid for increased hemocompatiblity. Since the coating 12 disclosed herein is designed to be transferred to the surface of a blood vessel and to remain there to release drug during the vessel healing period, hemocompatiblity of the coating 12 is desired. In addition to preventing dissolution of the coating 12 into the blood stream prior to healing of the vessel, it is desired to prevent initiation of significant clotting and the attachment of fibrin and platelets to the coating surface exposed to blood after transfer. The addition of a PEG-lipid to the composition of cholesterol and a phospholipid or fatty acid may be used to provide increased hemocompatiblity of the formulation.
  • PEG grafted polymer surfaces have shown improved blood contact characteristics primarily by lowering the interfacial free energy and by the steric hindrance of the hydrated PEG chains on the surface. While not wishing to be bound to a particular theory of operation, it is believed that a small amount of PEG-lipid conjugate added to the composition may migrate to the blood interface surface after transfer, especially for PEG-lipids of relatively low molecular weight. The PEG chains are thereby able to lower the interfacial free energy at the blood interfacing surface. Since the coating material at the blood interface is a small portion of the total coating, a relatively small amount of PEG-lipid is required.
  • the PEG-lipid is selected from the group consisting of 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine- methoxy(polyethylene glycol)-350 (DPPE-mPEG350), l,2-dioleoyl-sn-glycero-3- phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE- mPEG550), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550),
  • the PEG-lipid is about 1% to about 30% by weight of the hydrophobic matrix 14 consisting of the combination of the cholesterol, the fatty acid or phospholipid and the PEG-lipid. In other embodiments, the PEG-lipid is about 2% to about 25%, about 3% to about 20%, or about 5% to about 10% by weight of the hydrophobic matrix 14. In some embodiments, the amount of PEG-lipid is about 12% or less.
  • the coating 12 further includes one or more additives.
  • the one or more additives are independently selected from penetration enhancers and stabilizers.
  • the coating 12 may further include additives to enhance performance, such as penetration enhancers.
  • the penetration enhancer can aid diffusion of the active agent into the vessel wall and maximize tissue delivery of the active agent.
  • Suitable penetration enhancers may include surfactants, cationic excipients and cationic lipids.
  • the additive may be added to the hydrophobic matrix, the micro-reservoirs, or both.
  • stabilizers may be added to protect the drug during sterilization of the balloon catheter system and its subsequent storage before use.
  • Stabilizers may include antioxidants and free radical scavengers.
  • stabilizers include gallic acid, propylgallate, tocopherols and tocotrienols (Vitamin E), butylatedhydroxytoluene, butylatedhydroxyanisole, ascorbic acid, thioglycolic acid, ascorbyl palmitate, and EDTA.
  • the coating 12 further comprises a third active agent, wherein the third active agent is outside of the micro-reservoirs or in the hydrophobic matrix 14.
  • the third active agent may be the same or different from the first or the second active agent in the plurality of micro-reservoirs.
  • the active agent(s) are primarily contained in the micro-reservoirs and not in direct contact with the hydrophobic matrix 14, the need to solubilize or emulsify the active agent in the hydrophobic matrix 14 itself is obviated.
  • hydrophobic matrix 14 can therefore be optimized toward suitable properties for resistance to blood wash-off and adhesion to the vessel surface for coating 12 transfer.
  • a catheter 10 that includes an expandable portion 11 on an elongated body 17, a coating 12 as described above over the expandable portion 11, and a release layer 15 between the expandable portion 11 and the coating 12.
  • the release layer 15 is configured to release the coating 12 from the expandable portion 11.
  • a release layer 15 which is immiscible with the coating 12 is preferred to maintain distinct layers.
  • PEG conjugated lipids are used as a release layer 15 as the degree of hydrophilicity and miscibility with the active agent coating 12 may be tailored by the selection of the lipid and the PEG chain length.
  • the release layer 15 is l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- (methoxy(polyethylene glycol)-350) (DSPE-mPEG350) or l,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-(methoxy(polyethylene glycol)-550) (DSPE-mPEG550).
  • the release layer 15 has a surface concentration of about 0.1 mg/mm 2 to about 5 mg/mm 2 , 0.25 mg/mm 2 to about 3 mg/mm 2 , or 0.5 mg/mm 2 to about 2 mg/mm 2 .
  • the catheter 10 further includes a protective layer 16 over the coating 12 as a top coat.
  • the protective layer 16 includes a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer.
  • the protective layer 16 is a glycosaminoglycan or a crystalized sugar. Examples of glycosaminoglycans include dextran sulfate, chondroitin sulfate, heparan sulfate, and hyaluronic acid. Examples of crystalized sugars include mannitol, sorbitol, erythritol, and xylitol.
  • the crystalline nature of these sugars provides a hard surface that protects the underlying micro-reservoirs.
  • the thickness of the protective layer 16 can be adjusted such that the protective layer 16 washes away during the transit time required to advance the catheter 10 to the target site.
  • the protective layer 16 has a surface concentration of about 0.1 pg/mm 2 to about 5 pg/mm 2 , about 0.2 pg/mm 2 to about 4 pg/mm 2 , or about 0.3 pg/mm 2 to about 3 pg/mm 2 .
  • the expandable portion 11 of the catheter 10 may be a balloon, which acts as a substrate for the coating 12.
  • the balloon may be of a low pressure design using an elastomeric material such as polyisoprene, polystyrene copolymers, polysiloxane, or polyurethane.
  • the balloon may also be of a high pressure design using high tensile strength polymers such as polyvinylchloride, polyethylene, polyethylene terephthalate, or nylon.
  • the expandable portion 11 may be made of Nylon 12.
  • the coating 12 may be sufficiently adhered to the expandable portion 11, but is readily transferred to the tissues of the vessel lumen upon contact. In such cases, a release layer may be omitted.
  • Nylon 12 has sufficient strength such that the balloon may further act as a post-dilatation balloon (if needed) in a subsequent procedure after transfer of the coating 12.
  • the expandable portion 11 underneath the coating 12 may be used to dilate the target vessel.
  • the vessel may be pre dilated with another balloon catheter 10 prior to treatment with the coated balloon of the present embodiments.
  • Coating Formulation Disclosed herein is also a coating formulation for an expandable portion 11 of a catheter 10.
  • the formulation includes a solid portion and a fluid.
  • the solid portion includes a plurality of micro-reservoirs and at least one hydrophobic compound.
  • the fluid acts to disperse or solubilize the at least one hydrophobic compound.
  • the fluid may disperse some hydrophobic compounds and solubilize other hydrophobic compounds.
  • the micro-reservoirs are dispersed and suspended in the resultant fluid mixture to form the coating formulation.
  • the fluid mixture is formulated to form a homogenous mixture of the hydrophobic compounds that does not separate during drying to result in a uniform, conformal coating of the hydrophobic matrix 14.
  • the coating formulation is characterized by weight of the solid portion, which refers to all the non-volatile components of the coating formulation, but excludes the fluid that is subsequently evaporated during drying of the coating.
  • the micro-reservoirs include an active agent and a polymer.
  • the active agent may be referred to as a first active agent or a second active agent as described herein.
  • the polymer may be a first biodegradable or bioerodable polymer or a second biodegradable or bioerodable polymer described herein.
  • the active agent is intermixed with or dispersed in the biodegradable or bioerodable polymer described herein.
  • the formulation may include more than one type of micro-reservoirs.
  • the plurality of micro-reservoirs may include a first active agent and a first biodegradable or bioerodable polymer.
  • the plurality of micro reservoirs may further include a second active agent.
  • the plurality of micro-reservoirs may also include a second biodegradable or bioerodable polymer.
  • the micro-reservoirs may be fabricated by any of the known means for particle manufacture, including spray drying, coacervation, micromolding, and milling. All such processes begin by dissolving the active agent and the polymer together in a suitable solvent such as acetonitrile or dichloromethane, then removing the solvent in a controlled manner that creates uniform particles.
  • the particles may be further shaped by mechanical means. Processes that produce particles with size distributions with coefficients of variation of 10% or less are particularly useful for providing more consistent active agent release rates.
  • microspheres of uniform size are described by forming an emulsion of the microsphere material and extruding the emulsion through a substrate with through- holes of controlled size as described in US 7,972,543 and US 8,100,348.
  • microspheres may be produced by spray-drying solutions of polymers as described in US 6,560,897 and US 20080206349.
  • the fluid of the coating formulation may comprise water, organic solvent, perfluorocarbon fluids, or a mixture of such fluids.
  • the fluid is selected from the group consisting of pentane, hexane, heptane, heptane and fluorocarbon mixture, alcohol and fluorocarbon mixture, and alcohol and water mixture.
  • Fluids which readily solubilize the active agent or the polymer of the micro-reservoirs are not preferred since they may extract the active agent from the micro-reservoirs.
  • Such non-preferred fluids include acetic acid, acetonitrile, acetone, dichloromethane, ethyl formate, cyclohexanone, DMSO, and chloroform.
  • the fluid/fluid blend may be selected to saturate at the desired level of extracted active agent.
  • Additional active agent that is the same as the one in the micro-reservoirs may be added to the fluid in advance to pre-saturate the solution, thereby reducing extraction from the micro-reservoirs during processing of the coating.
  • the at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, and surfactants, and their derivatives.
  • the at least one hydrophobic compound comprises a cholesterol and a fatty acid as described herein.
  • the at least one hydrophobic compound comprises a cholesterol and a phospholipid as described herein.
  • the formulation can also include a PEG-lipid as described herein.
  • the formulation can further include additives like penetration enhancers and stabilizers.
  • the solid portion further includes a third active agent outside of the plurality of micro-reservoirs.
  • the coating formulation can lead to a hydrophobic matrix 14 that further comprises the third active agent.
  • the active agent outside of the micro-reservoirs may be the same or different from the active agent(s) in the micro-reservoirs.
  • the solid portion may further comprise a PEG-lipid.
  • the solid portion may also further comprise an additive described herein.
  • the concentration of the solid portion by percent weight in the coating formulation is approximately 1% to approximately 90%.
  • the solids content of the coating formulation has a concentration of about 2% to about 80% by weight, about 3% to about 70% by weight, or about 4% to about 60% by weight.
  • the solid portion of the coating formulation has a concentration of about 2% to about 7% by weight.
  • the solid portion of the coating formulation comprises about 10% to about 75%, about 20% to about 65%, or about 30 % to about 55% by weight of the plurality of micro-reservoirs.
  • Disclosed herein is also a method for coating an expandable portion 11 of a catheter 10.
  • the steps include, disposing a formulation described herein over the surface of an expanded expandable portion 11 of a catheter 10, evaporating the fluid constituents of the coating formulation, and collapsing the expandable portion 11.
  • Disposing a formulation over the surface of an expanded expandable portion 11 includes disposing the formulation on the surface of an expanded expandable portion 11.
  • the formulation can be disposed on or over the expanded expandable portion 11 by spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.
  • the coating formulation is prepared by mixing the coating components in a fluid as disclosed herein.
  • the micro-reservoirs are dispersed into the fluid formulation.
  • the coating formulation may be applied to the surface of the expanded expandable portion 11 such as a balloon and let dry to form the coating 12.
  • the application of the coating formulation may be repeated as necessary to deposit the desired amount of coating 12, usually in the range of about 5 mg to about 9 mg of coating 12 per mm 2 of the balloon surface.
  • the coating 12 is allowed to dry and the balloon deflated and folded to allow introduction into the vascular system.
  • the method may further comprise disposing a release layer on the surface of an expanded expandable portion 11.
  • the coating formulation would be disposed on the release layer, while the release layer is disposed onto the surface of the expanded expandable portion 11.
  • the release layer is described above.
  • Method for Treating or Preventing a Condition Disclosed herein is also a method for treating or preventing a condition at a treatment site. The method involves the steps of advancing a catheter 10 comprising an expandable portion 11 to the treatment site, expanding the expandable portion 11 to allow contact between the coating 12 and a tissue at the treatment site, collapsing the expandable portion 11, and removing the catheter 10.
  • the expandable portion 11 is coated with a coating described herein.
  • the contact between the tissue and the coating 12 results in a transfer of at least a portion of a coating on the expandable portion 11 to the treatment site during contact for a period of from about 30 to about 120 seconds.
  • a catheter 10 with expandable portion 11 such as a coated balloon catheter is used here to demonstrate the concept of delivering an active agent or a combination of active agents to a vessel.
  • the coated balloon catheter is introduced into a vessel with the expandable portion 11 folded to provide a small cross-sectional profile and to facilitate percutaneous insertion of the catheter 10, for example by the well-known Seldinger technique.
  • the balloon is inflated, and the coating 12 makes firm contact with the vessel lumen.
  • the coating is formulated to have affinity to the luminal tissue surface, resulting in adhesion of a layer of the coating on the vessel lumen.
  • the expandable portion 11 may be inflated or expanded for a period of 30 seconds up to 2 minutes to promote adhesion and provide for initial active agent penetration into the vessel.
  • the expandable portion 11 may be deflated and inflation repeated as desired for treatment to manage the time period and risks of vessel occlusion or tissue ischemia.
  • the coating is adhesively transferred to the lumen of the vessel upon balloon inflation and firm contact of the balloon surface to the vessel luminal surface. The adhesion of the coating to the vessel surface thereby carries the micro-reservoirs and transfers them to the vessel surface.
  • the condition is selected from the group consisting of atherosclerosis, stenosis or reduction in luminal diameter in a diseased blood vessel, restenosis, and in-stent restenosis.
  • an additional release layer as described herein is disposed between the expandable portion 11 and the coating 12.
  • the present disclosure is directed at the treatment of restenosis associated with balloon dilatation of blood vessels
  • the invention may be used to deliver drugs to various other lumens and hollow structures of the body such as the structures of the respiratory system, gastrointestinal system, urinary system, reproductive system, and lymphatic system.
  • the coated device may be an inflatable balloon or other inflatable device.
  • the device delivering the coating of the present invention may be a non- inflatable device or any other type of expandable device that is used for treatment of a living body.
  • Microspheres fabricated by coacervation of polylactic-co-glycolic acid copolymer incorporating sirolimus (rapamycin) were obtained.
  • Microsphere sample 1 50% DL-lactide / 50% glycolide copolymer, average diameter 3.1 pm, SD 0.44 pm, 39% rapamycin by weight
  • Microsphere sample 2 75% DL-lactide / 25% glycolide copolymer, average diameter 3.2 pm, SD 0.76 pm, 40% rapamycin by weight
  • Microsphere sample 3 50% DL-lactide / 50% glycolide copolymer, average diameter 2.7 pm, SD 0.8 pm, 45% rapamycin by weight
  • Microsphere sample 4 75% DL-lactide / 25% glycolide copolymer, average diameter 3.3 pm, SD 1.2 pm, 46% rapamycin by weight
  • Microsphere sample 5 75% DL-lactide / 25% glycolide copolymer, average diameter 4.1 pm, SD 0.61 pm, 25% rapamycin by weight
  • Microsphere sample 6 75% DL-lactide / 25% glycolide copolymer, average diameter 3.78 pm, SD 0.44 pm, 28.8% rapamycin by weight
  • Microsphere sample 7 75% DL-lactide / 25% glycolide copolymer, average diameter 3.8 pm, SD 0.34 pm, 27.7% rapamycin by weight
  • Microsphere sample 8 75% DL-lactide / 25% glycolide copolymer, average diameter 3.79 pm, SD 0.39 pm, 29.4% rapamycin by weight
  • micro-reservoirs were weighed and dissolved in 1 ml acetonitrile, agitated gently at room temperature for several hours or 37°C for 1 hour, and diluted 50- to 200-fold with acetonitrile. Absorbance at 278 nm was monitored, and content was determined from linear calibration curves.
  • Example 2 Sustained drug release from micro-reservoirs under physiological conditions
  • Micro-reservoirs from Example 1 were tested for sustained release of drug.
  • Micro-reservoir samples of 2 to 5 mg weight were placed in 1.6 ml Eppendorf tubes with 1.2 ml of phosphate buffered saline (PBS) to simulate a physiological environment. After an initial wash to remove any drug not incorporated in the micro-reservoirs, the tubes were incubated at 37°C with gentle mixing at 250 rpm. The PBS was sampled at time intervals and the released drug quantitated by reverse phase HPLC using a C18 column.
  • PBS phosphate buffered saline
  • K h is the Higuchi constant incorporating the area, diffusion coefficient and drug concentration coefficients.
  • microsphere Sample 4 was assayed for drug release over 8 weeks using the methods previously described. Due to the relatively long time intervals between sampling as compared to the previous release experiments, the micro reservoirs may not have released into sink conditions at later time points, potentially slowing effective release rate. The resultant drug release is listed in Table 4.
  • Micro-reservoirs may be tailored or selected with a half-life to provide drug through the healing period of the dilated vessel.
  • Example 3 Formulations of micro-reservoirs in coating formulation of cholesterol and fatty acid with PEG-lipid
  • a coating formulation was prepared with 107 mg of stearic acid, 105 mg of cholesterol, and 50 mg of DPPE-mPEG350 mixed with 14 mL of heptane and heated to 60°C such that a clear solution was obtained. The solution was then vortex mixed for 30 seconds and allowed to cool. Next, 200 mg of sirolimus loaded microspheres of sample #6 was added, and the formulation was placed in an ultrasonic bath for 4 minutes to disperse and suspend the microspheres. [Formulation 1023E]
  • a coating formulation was prepared with 58 mg of erucic acid, 43 mg of DC-Cholesterol, and 6.25 mg of DOPE-mPEG350 mixed with 7 mL of heptane and heated to 60°C such that a clear solution was obtained. The solution was then vortex mixed for 30 seconds and allowed to cool. Next, 100 mg of sirolimus loaded microspheres of sample #8 was added, and the formulation was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0424 A]
  • a coating formulation was prepared with 25 mg of nervonic acid, 75 mg of DC-Cholesterol, and 6.25 mg of DOPE-mPEG350 mixed with 7 mL of heptane and heated to 60°C such that a clear solution was obtained. The solution was then vortex mixed for 30 seconds and allowed to cool. Next, 97 mg of sirolimus loaded microspheres of sample #8 was added, and the formulation was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0422E]
  • Example 4 Formulation of micro-reservoirs in coating formulation of cholesterol, fatty acid, PEG-lipid and stabilizing additive
  • a coating formulation was prepared with 77 mg of stearic acid, 40 mg cholesterol, 50 mg DPPE-mPEG350, and 58 mg of alpha-tocopherol mixed with 7 mL of heptane and heated to 60°C until a clear solution was obtained. The solution was vortex mixed for 1 minute and allowed to cool to room temperature. Next, 100 mg of sirolimus loaded microspheres of sample #5 was added. The formulation was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 1009 A]
  • Example 5 Formulation of micro-reservoirs in coating formulation of cholesterol and phospholipid
  • a coating formulation was prepared with 43 mg cholesterol and 42 mg L- alpha-phosphatidylcholine mixed with 7 mL of heptane and heated to 60°C. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 100 mg of sirolimus loaded microspheres from sample #5 were added to the vial which was then placed in an ultrasonic bath for 8 minutes to disperse and suspend the microspheres.
  • Example 6 Formulation of micro-reservoirs in coating formulation of cholesterol and long acyl chain phospholipid with and without PEG-lipid
  • a coating formulation was prepared with 51 mg DC-Cholesterol, 6.25 mg DOPE-mPEG350 and 51 mg dierucoyl phosphatidylcholine (DEPC) mixed with 7 mL of heptane and heated to 60°C. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 100 mg of sirolimus loaded microspheres from sample #7 were added to the vial which was then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0410A]
  • a coating formulation was prepared with 20 mg DC-Cholesterol, 26 mg cholesterol, 6.25 mg DOPE-mPEG350 and 75 mg dinervonyl phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C.
  • the formulation had a weight ratio of DNPC to DC-Cholesterol of 1.6:1.
  • the solution was allowed to cool to room temperature.
  • 97 mg of sirolimus loaded microspheres from sample #7 were added to the vial which was then vortex mixed for 30 seconds and then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres.
  • a coating formulation was prepared with 28 mg DC-Cholesterol, 26 mg cholesterol, 6.25 mg DOPE-mPEG350 and 50 mg dinervonyl phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 97 mg of sirolimus loaded microspheres from sample #7 were added to the vial which was then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres.
  • DNPC dinervonyl phosphatidylcholine
  • a coating formulation was prepared with 50 mg DC-Cholesterol and 50 mg dinervonyl phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C.
  • the formulation had a weight ratio of DNPC to DC-Cholesterol of 1:1.
  • the solution was vortex mixed for 30 seconds and then allowed to cool to room temperature.
  • 100 mg of sirolimus loaded microspheres from sample #7 were added to the vial which was then placed in an ultrasonic bath for 4 minutes to disperse and suspend the microspheres.
  • a coating formulation was prepared with 49 mg DC-Cholesterol, 6.25 mg DOPE-mPEG350 and 50 mg dinervonyl phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C.
  • the formulation had a weight ratio of DNPC to DC-Cholesterol of 1:1.
  • the solution was vortex mixed for 30 seconds and then allowed to cool to room temperature.
  • 100 mg of sirolimus loaded microspheres from sample #7 were added to the vial which was then placed in an ultrasonic bath for 2 minutes to disperse and suspend the microspheres.
  • a coating formulation was prepared with 76 mg DC-Cholesterol, 6.25 mg DOPE-mPEG350 and 25 mg dinervonyl phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C.
  • the formulation had a weight ratio of DNPC to DC-Cholesterol of 1:3. The solution was allowed to cool to room temperature.
  • 100.7 mg of sirolimus loaded microspheres from sample #8 were added to the vial, vortex mixed for 30 seconds and then then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres.
  • Example 7 Formulation of micro-reservoirs in coating formulation of DC-Cholesterol with varying PEG-lipid content
  • a coating formulation was prepared with 12.5 mg of DOPE-mPEG350, 44 mg of DC-Cholesterol and 44 mg of dinervonoyl phosphatidylcholine (DNPC) mixed with 7 mL of heptane heated to 60°C. The clear solution was allowed to cool to room temperature, then 97 mg of sirolimus loaded microspheres from microsphere from sample #8 were added. The formulation was then placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [Formulation 0422A]
  • a coating formulation was prepared with 25 mg of DOPE-mPEG350, 37.5 mg of DC-Cholesterol and 37.5 mg of dinervonoyl phosphatidylcholine (DNPC) mixed with 7 mL of heptane heated to 60°C. The clear solution was allowed to cool to room temperature then 97 mg of sirolimus loaded microspheres from microsphere sample #8 were added. The formulation was then placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [Formulation 0422B]
  • a coating formulation was prepared with 72.9 mg DC-cholesterol in 7 mL of heptane and heated to 60C until the DC-cholesterol was solubilized to produce a clear solution.
  • To the solution was added 15.5 mg of sirolimus and vortex mixed for 30 seconds. The solution was heated for 40 minutes, vortexing 10 seconds every 10 minutes and sonicated for 5 minutes while cooling to room temperature.
  • To the solution was added 50 mg of DNPC. When at room temperature, the solution was filtered through a 0.2 micron PTFE filter to remove large drug particles. The solution was left overnight with no observed particulates formed overnight. The solution was assayed, and the sirolimus content was found to be 0.96 mg per ml.
  • Example 3 The stearic acid coating formulation of Example 3 (Formulation 1023E) was sprayed onto the balloon surface of 5.0 mm diameter X 20 mm length Nylon angioplasty balloons. Seven ml of the coating formulation was loaded into a 25 mL gas-tight syringe with an integrated magnetic stir bar system. The formulation was continuously stirred during spraying to keep the drug micro-reservoirs well suspended. A syringe pump delivered the coating formulation at a rate of 0.11 mL/min through a 120 kHz ultrasonic nozzle being activated with 5.5 watts of power [Sonotek DES1000].
  • a 5.0 mm diameter x 20 mm length cylinder of balloon material was cut, weighed and placed over the same size balloon. This sleeve of balloon material was then coated and weighed to verify approximately 2.2 mg total coating was applied, corresponding to 7 mg/mm 2 of coating density.
  • stearic acid comprised approximately 1.6 mg/mm 2
  • cholesterol comprised 1.6 mg/mm 2
  • DPPE-mPEG350 0.8 mg/mm 2
  • sirolimus loaded microspheres from microsphere sample #5 at 3 mg/mm 2 resulting in a drug density of 0.87 mg /mm 2 .
  • Example 6 A 5.0 mm diameter x 20mm length balloon was inflated, positioned underneath the spray and then rotated constantly while moving back and forth 5 times. The balloon was then removed and allowed to dry. The process was repeated until 6 balloons were coated. This same process was repeated to spray the coating formulation of Example 6 (Formulation 0513A) on 3.0mm diameter x 20mm length balloons.
  • the sleeve coating target weight for a 3.0mm diameter x 20mm length balloon with the formulation of Example 6 (Formulation 0513 A) was 1.4 mg to achieve a coating density of 7.6 mg/mm 2 .
  • dinervonoyl phosphatidylcholine comprised 0.9 mg/mm 2
  • DC-cholesterol 2.7 mg/mm 2 DC-cholesterol 2.7 mg/mm 2
  • DOPE-mPEG350 0.23 mg/mm 2 the sirolimus loaded microspheres of sample #5 comprised 3.7 mg/mm 2 resulting in a drug density of 1.08 mg /mm 2 .
  • the coating formulations of Examples 4, 5, 6, 7 and 8 were also sprayed onto the surface of 20 mm length balloons in the manner of spraying the formulation of Example 3 previously described. The resultant coating weights and coating densities are presented in Table 6.
  • each balloon was sprayed with an additional top coat formulation (1010D) consisting of 1 mg of cholesterol and cholesterol-PEG600 coating to cover the micro-reservoir layer.
  • top coat formulation 1010D
  • 23 mg of cholesterol-PEG600 and 224 mg of cholesterol were dissolved in 7 mL of isopropanol.
  • the target coating weight of 1 mg on a 5.0 mm diameter x 20 mm long balloon corresponds to 3.2 mg/mm 2 of total top coating comprised of 0.3 mg/mm 2 cholesterol- PEG600 and 2.9 mg/mm 2 cholesterol.
  • Ex-vivo porcine arteries were flushed with 37°C Lactated Ringer’s solution at 50 mL/min pulsatile flow (approximately 72 BPM) for 5 minutes.
  • the balloons coated with the formulation of Example 3 were inflated in the lumen of ex-vivo porcine arteries to an approximate overstretch of 1:1.2 to transfer the drug containing coating to the vessel lumen.
  • the solution that passed through the arteries prior to and after inflation (pre and post flush), the balloon used for the arteries, and the section of artery contacting the inflated balloon were subsequently assayed for drug after 5 minutes of post inflation flush.
  • the vessels treated with formulations 1205A and 1209A were flushed for a total of 60 minutes to evaluate extended stability of the transferred coating.
  • the amount of drug measured from all sources in the assay was totaled and compared to the estimated drug content of the balloon based on coating weight.
  • the proportion of drug transferred to the artery based on the estimated drug content of the balloon by coating weight was used as a measure of transfer efficiency.
  • Example 4 The balloons coated with the formulation of Example 4 were also tested in ex- vivo porcine arteries.
  • Example 5 The balloons coated with the formulation of Example 5 were also tested in ex- vivo porcine arteries.
  • Example 6 The balloons coated with the formulation of Example 6 were also tested in ex- vivo porcine arteries.
  • Fig. 4 is a photomicrograph of the luminal surface at 200X magnification showing adhered material.
  • Fig. 5 is a photomicrograph of the surface at 1000X magnification showing the adhered material to be a layer of spherical micro-reservoirs surrounded by coating material.
  • Example 11 Adhesion of Coatings to Vessel Luminal Surface of Formulations with Varying PEG-lipid Content
  • Example 7 The samples from Example 7 were tested for coating transfer and resistance to wash-off using the methods of Example 10. The results have been tabulated to compare the coatings with DNPC and DC-Cholesterol in equal weight proportion with varying amounts of DOPE-mPEG350. [Formulations 1205 A, 1209A, 0422A, 0422B]
  • Example 12 Adhesion of coating with additional rapamycin to vessel luminal surface
  • Example 8 The formulation of Example 8 was tested for coating transfer and resistance to wash-off using the methods of Example 10.
  • the iliofemoral artery of rabbits was used to assess the in-vivo transfer of the drug coating to an arterial vessel.
  • the iliofermoral artery segment for treatment was first denuded of endothelium to reproduce post-angioplasty tissue damage.
  • a dissection was made to the common carotid artery, and a size 5F balloon wedge catheter was inserted into the artery and directed under fluoroscopic guidance to the treatment site of the iliofemoral artery. Contrast agent was injected through the catheter and angiograms of the iliofemoral arteries recorded.
  • the balloon wedge catheter was exchanged for a 3.0 mm diameter x 8 mm length standard angioplasty balloon catheter under fluoroscopic guidance, inflated, and withdrawn proximally in its inflated state approximately to the level of the iliac bifurcation to denude the section of the artery.
  • the angioplasty balloon catheter was exchanged for a drug coated balloon catheter.
  • the catheter was advanced to the denuded vessel segment and inflated for 120 seconds.
  • the balloon was deflated and withdrawn. Both the right and left iliac arteries of each animal were treated. [0115] A total of eleven animals were treated.
  • One animal (2 iliac arteries treated) was euthanized 1 hour after treatment and vessel segments recovered for microscopic examination.
  • Another animal (2 iliac arteries treated) was euthanized 24 hours after treatment and vessel segments recovered for microscopic examination. Three animals (6 iliac arteries) were recovered at each time point of 1 hour, 7 days and 28 days. Blood samples were taken from these animals prior to surgery, at 0.5, 1, 4 hours post treatment and at sacrifice. The vessel segments were recovered and assayed for drug content by HPLC/MS quantitation.
  • Assay of the blood samples showed a rapid decline of drug in circulating blood with a concentration of 4.75 ng/ml at 30 minutes, 2.63 ng/ml at 1 hour and 0.82 ng/ml at 4 hours.
  • the blood concentration of drug collected at sacrifice for the 7 day and 28 day time points were below the limit of detection for the quantitation assay.
  • the blood levels were fit to an exponential decay curve with a half-life of 0.77 hours, indicating rapid dilution and clearance of drug from the bloodstream
  • Assay of the treated vessel segments demonstrated tissue drug levels of 261 pg/g ⁇ 116.5 pg/g at 1 hour after treatment, 43.8 pg/g ⁇ 34.2 pg/g at 7 days after treatment and 21.5 pg/g ⁇ 17.3 pg/g at 28 days after treatment.
  • the results indicate adhesion of the drug containing micro-reservoir coating to the luminal surface of an artery with sustained presence of drug associated with the tissues of the treated vessel through 28 days.
  • the tissue associated levels of drug demonstrated a rapid initial decline which slowed between 7 to 28 days.
  • the tissue associated drug levels from 7 and 28 days were fit to an exponential decay, indicating a half-life of approximately 20.4 days.
  • Example 14 Adhesion of coatings to vessel luminal surface for coating formulation comprising sirolimus microparticles
  • Crystalline sirolimus powder was ground, and lOOmgwas selected and added to about 75mg of phospholipid excipient formulation (about 15% DOPE-mPEG350, 35% DNPC, 50% DC-Chol).
  • Ground Sirolimus microparticles were dispersed and suspended in the formulation via magnetic stirring and then sprayed on 4x30mm balloon catheters using the Sonotek PSI Ultrasonic spray system.
  • Ultrasonic spraying formulation flow rate was set at 0.210 ml/min and used 4 passes to build up to a target coating weight of 2 milligrams corresponding to approximately 3pg of Sirolimus per mm 2 of balloon surface area.
  • Fig. 6 is a photomicrograph of the coated balloon surface at 100X magnification showing the coating containing crystalline sironlimus micro-reservoirs.
  • Fig. 7 is a photomicrograph of the artery surface at 50X magnification showing adhered material
  • Fig. 8 is a photomicrograph of the artery surface at 1000X magnification showing adhered material.
  • Conditional language such as, among others,“could,”“might,” or“may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include while other embodiments do not include, certain features or elements. Thus, such conditional language is not generally intended to imply that features or elements are in any way required for one or more embodiments.
  • a coating for an expandable portion of a catheter comprising a hydrophobic matrix and a dispersed phase comprising a plurality of micro-reservoirs dispersed in the hydrophobic matrix, wherein the plurality of micro-reservoirs comprises a first active agent and a first biodegradable or bioerodable polymer.
  • the first active agent is intermixed with or dispersed in the first biodegradable or bioerodable polymer.
  • the plurality of micro reservoirs further comprises a second active agent.
  • the second active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the plurality of micro reservoirs further comprises a second biodegradable or bioerodable polymer.
  • the second biodegradable or bioerodable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosoaminoglycans, and combination thereof.
  • the hydrophobic matrix comprises at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and their derivatives.
  • the hydrophobic matrix comprises a cholesterol and a fatty acid.
  • the weight ratio of cholesterol to fatty acid is in the range of about 1:2 to about 3:1.
  • the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradeadienoic acid, octanoic acid, myristic acid, myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachadonic acid, mead acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid.
  • the hydrophobic matrix comprises a cholesterol and a phospholipid.
  • the weight ratio of cholesterol to phospholipid is in the range of about 1:2 to about 3:1.
  • the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and pho sphatidylino sitol .
  • the phospholipid is a cationic phospholipid.
  • the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine.
  • the phospholipid comprises an acyl chain length of about 20 to about 34 carbons.
  • the phospholipid is selected from the group consisting of dieicosenoyl phosphatidylcholine (l,2-dieicosenoyl-sn-glycero-3- phosphocholine, C20:l PC), diarachidonoyl phosphatidylcholine (l,2-diarachidoyl-sn- glycero-3-phosphocholine, C20:0 PC), dierucoyl phosphatidylcholine (l,2-dierucoyl-sn- glycero-3-phosphocholine, C22:l PC), didocosahexaenoyl phosphatidylcholine (1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoyl phosphatidylcholine (l,2-dieicosenoy
  • the cholesterol is DC- Cholesterol.
  • the plurality of micro reservoirs is about 10% to about 75% by weight of the coating.
  • the plurality of micro reservoirs has an average diameter of about 1.5 microns to about 8 microns. In some embodiments, the plurality of micro-reservoirs has an average diameter of about 2 microns to about 6 microns. In some embodiments, the plurality of micro-reservoirs has an average diameter of about 3 microns to about 5 microns.
  • the plurality of micro reservoirs has an active ingredient release kinetics with a half-life of at least 14 days.
  • the first biodegradable or bioerodable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosoaminoglycans, and combination thereof.
  • the first active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the first active agent is about 10% to about 50% by weight of the plurality of micro-reservoirs.
  • the coating further comprises a third active agent outside of the plurality of micro-reservoirs.
  • the third active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the third active agent is the same as the first active agent.
  • the hydrophobic matrix further comprises a PEG-lipid.
  • the PEG-lipid is selected from the group consisting of l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- methoxy(polyethylene glycol)-350 (DSPE-mPEG350), l,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), l,2-dioleoyl- sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE- mPEG350), l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol
  • the coating further comprises one or more additives independently selected from penetrating enhancers and stabilizers.
  • the coating has a surface concentration of about 1 pg/mm 2 to about 10 pg/mm 2 .
  • a catheter comprising an expandable portion on an elongated body, and any embodiment of the coating described above over the expandable portion.
  • the catheter further comprises a release layer between the expandable portion and the coating, wherein the release layer is configure to release the coating from the expandable portion.
  • the release layer comprises DSPE-mPEG350 or DSPE-mPEG500.
  • the release layer has a surface concentration of about 0.1 pg/mm 2 to about 5 pg/mm 2 .
  • the catheter further comprises a protective coating over the coating.
  • the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer.
  • the protective coating is a glycosaminoglycan or a crystalized sugar.
  • the protective coating has a surface concentration of about 0.1 pg/mm 2 to about 5 pg/mm 2 .
  • a coating formulation for an expandable portion of a catheter comprising a solid portion and a fluid.
  • the solid portion comprises a plurality of micro-reservoirs and at least one hydrophobic compound, wherein the plurality of micro-reservoirs comprises a first active agent and a first biodegradable or bioerodable polymer.
  • the first active agent is intermixed with or dispersed in the first biodegradable or bioerodable polymer.
  • the plurality of micro-reservoirs further comprises a second active agent.
  • the second active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the plurality of micro-reservoirs further comprises a second biodegradable or bioerodable polymer.
  • the second biodegradable or bioerodable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosoaminoglycans, and combination thereof.
  • the fluid is selected from the group consisting of pentane, hexane, heptane, heptane and fluorocarbon mixture, alcohol and fluorocarbon mixture, and alcohol and water mixture.
  • the solid portion further comprises a third active agent outside of the plurality of micro reservoirs.
  • the third active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the first active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and their derivatives.
  • the at least one hydrophobic compound comprises a cholesterol and a fatty acid.
  • the weight ratio of cholesterol to fatty acid is in the range of about 1:2 to about 3:1.
  • the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradeadienoic acid, octanoic acid, myristic acid, myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachadonic acid, mead acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docos
  • the at least one hydrophobic compound comprises a cholesterol and a phospholipid.
  • the weight ratio of cholesterol to phospholipid is in the range of about 1:2 to about 3:1.
  • the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and pho sphatidylino sitol .
  • the phospholipid is a cationic phospholipid.
  • the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine.
  • the phospholipid comprises an acyl chain length of about 20 to about 34 carbons.
  • the phospholipid is selected from the group consisting of dieicosenoyl phosphatidylcholine (l,2-dieicosenoyl-sn-glycero-3- phosphocholine, C20:l PC), diarachidonoyl phosphatidylcholine (l,2-diarachidoyl-sn- glycero-3-phosphocholine, C20:0 PC), dierucoyl phosphatidylcholine (l,2-dierucoyl-sn- glycero-3-phosphocholine, C22:l PC), didocosahexaenoyl phosphatidylcholine (1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoyl phosphatidylcholine (l,2-dieicosenoy
  • the cholesterol is DC-Cholesterol.
  • the solid portion further comprising a PEG-lipid, and/or an additive.
  • the PEG-lipid is selected from the group consisting of l,2-distearoyl-sn-glycero-3- phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2- dipalmitoyl-sn-glycero-3-phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE- mPEG350), l,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- methoxy(polyethylene glycol)-550 (DSPE-mPEG550), l,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N- methoxy(polyethylene
  • the plurality of micro-reservoirs is about 10% to about 75% by weight of the solid portion.
  • the solid portion is about 2 to about 7% by weight of the coating formulation.
  • a method for coating an expandable portion of a catheter comprising disposing a coating formulation of any embodiments described above over the surface of an expanded expandable portion of a catheter, evaporating the fluid, and collapsing the expandable portion.
  • disposing the coating formulation comprises spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.
  • the method further comprises disposing a release layer on the expandable portion.
  • the release layer comprises DSPE-mPEG350 or DSPE-mPEG500.
  • a method for treating or preventing a condition at a treatment site comprising advancing a catheter comprising an expandable portion to the treatment site, wherein the expandable portion is coated with a coating of any embodiments described above, expanding the expandable portion to allow contact between the coating and a tissue at the treatment site, collapsing the expandable portion, and removing the catheter.
  • the contact between the tissue and the coating results in a transfer of at least a portion of a coating on the expandable portion to the treatment site.
  • the method further comprises maintaining the contact between the coating and the tissue for a period of from about 30 to about 120 seconds.
  • the condition is selected from the group consisting of atherosclerosis, stenosis or reduction in luminal diameter in a diseased blood vessel, restenosis, in-stent restenosis, and combinations thereof.
  • a catheter comprising an expandable portion on an elongated body; and a coating over an outer surface of the expandable portion, wherein the coating comprises: a lipophilic matrix, wherein the lipophilic matrix comprises at least one lipid; a plurality of micro-reservoirs dispersed in the lipophilic matrix, wherein the plurality of micro-reservoirs comprises an active agent; and wherein the lipophilic matrix is configured to adhere to a luminal surface when the expandable portion is expanded, and transfer at least a portion of the plurality of micro-reservoirs to the luminal surface.
  • the plurality of micro-reservoirs further comprises a biodegradable or bioerodable polymer.
  • the biodegradable or bioerodable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycarpolactone, polyphosphazine, collagen, gelatin, chitosan, and glycosoaminoglycans.
  • the active agent is about 10% to about 50% by weight of the micro reservoirs.
  • the at least one lipid comprises phospholipid.
  • the phospholipid comprises an acyl chain length of about 20 to about 34 carbons.
  • the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.
  • the phospholipid is selected from the group consisting of dieicosenoyl phosphatidylcholine (l,2-dieicosenoyl-sn- glycero-3-phosphocholine, C20:l PC), diarachidonoyl phosphatidylcholine (l,2-diarachidoyl- sn-glycero-3-phosphocholine, C20:0 PC), dierucoyl phosphatidylcholine (l,2-dierucoyl-sn- glycero-3-phosphocholine, C22:l PC), didocosahexaenoyl phosphatidylcholine (1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoyl phosphatidylcholine (l,2-heneicosenoyl-sn-glycero-3-phosphocholine, C2
  • the phospholipid comprises cationic phospholipid.
  • the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amine derivative of phosphatidylcholine.
  • the lipophilic matrix further comprises a sterol.
  • the sterol is selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-Cholesteryl-Spermine, Guanidium-Cholesterol/BGTC, and DC-Cholesterol.
  • the coating has a melting point between room temperature and body temperature. In some embodiments of the catheter, the coating comprises about 10% to about 75% by weight of the plurality of micro-reservoirs.
  • the plurality of micro-reservoirs has an average diameter of about 1.5 microns to about 8 microns. In some embodiments, the plurality of micro-reservoirs has an average diameter of about 2.0 microns to about 6 microns.
  • the active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the coating further comprising a polyethylene glycol-lipid (PEG-lipid).
  • PEG-lipid is selected from the group consisting of l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- methoxy(polyethylene glycol)-350 (DSPE-mPEG350), l,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), l,2-dioleoyl- sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE- mPEG350), l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), l,2-dipalmitoyl-sn-
  • the coating further comprising one or more additives independently selected from penetrating enhancers and stabilizers.
  • the coating has a surface concentration of about 1 pg/mm 2 to about 10 pg/mm 2 .
  • a catheter comprising: an expandable portion on an elongated body; a coating over an outer surface of the expandable portion, wherein the coating comprises: a lipophilic matrix, wherein the lipophilic matrix comprises at least one lipid; a plurality of micro-reservoirs dispersed in the lipophilic matrix, wherein the plurality of micro-reservoirs comprises an active agent; and wherein the lipophilic matrix is configured to adhere to a luminal surface when the expandable portion is expanded, and transfer at least a portion of the plurality of micro-reservoirs to the luminal surface; and a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion.
  • the release layer comprises DSPE-mPEG350 or DSPE-mPEG500. In some embodiments, the release layer has a surface concentration of about 0.1 pg/mm 2 to about 5 pg/mm 2 .
  • the catheter further comprises a protective coating over the first coating.
  • the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer.
  • the protective coating is a glycosaminoglycan or a crystalized sugar.
  • the protective coating has a surface concentration of about 0.1 pg/mm 2 to about 5 pg/mm 2 .
  • a method for coating an expandable portion of a catheter comprising: disposing a coating formulation over the surface of an expanded expandable portion of a catheter wherein the coating formulation comprises: a plurality of micro-reservoirs comprising an active agent; at least one lipid; and a fluid, wherein the fluid is selected from the group consisting of pentane, hexane, heptane, heptane, and fluorocarbon mixture, alcohol and fluorocarbon mixture, and alcohol and water mixture; evaporating the fluid; and collapsing the expandable portion.
  • the coating formulation has a solid content comprising the plurality of micro-reservoirs and at least one lipid, and the plurality of micro-reservoirs is about 10% to about 75% by weight of the solid content.
  • the plurality of micro-reservoirs further comprises a biodegradable or bioerodable polymer.
  • the active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivative, sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.
  • the active agent is crystalline.
  • the at least one lipid comprises phospholipid.
  • the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and pho sphatidylino sitol .
  • the phospholipid comprises a phospholipid with an acyl chain length of about 20 to about 34 carbons.
  • the phospholipid is selected from the group consisting of dieicosenoyl phosphatidylcholine (l,2-dieicosenoyl-sn- glycero-3-phosphocholine, C20:l PC), diarachidonoyl phosphatidylcholine (l,2-diarachidoyl- sn-glycero-3-phosphocholine, C20:0 PC), dierucoyl phosphatidylcholine (l,2-dierucoyl-sn- glycero-3-phosphocholine, C22:l PC), didocosahexaenoyl phosphatidylcholine (1,2- didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoyl
  • the phospholipid comprises cationic phospholipid.
  • the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amine derivative of pho sphatidylcholine .
  • the coating formulation further comprises a sterol.
  • the sterol is selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-Cholesteryl- Spermine, Guanidium-Cholesterol/BGTC, and DC-Cholesterol.
  • the coating formulation has a solid content of about 2% to about 7% by weight, wherein the solid content comprises a plurality of micro-reservoirs and at least one lipid.
  • the coating formulation further comprising a polyethylene glycol-lipid (PEG-lipid).
  • disposing the coating formulation comprises spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.
  • a method for treating or preventing a condition at a treatment site comprising advancing a catheter of Claim 1 to the treatment site; expanding the expandable portion to allow contact between the coating and a tissue at the treatment site; collapsing the expandable portion; and removing the catheter is described.
  • the contact between the tissue and the coating results in a transfer of at least a portion of a coating on the expandable portion to the treatment site.
  • the condition is selected from the group consisting of atherosclerosis, stenosis or reduction in luminal diameter in a diseased blood vessel, restenosis, and in-stent restenosis.

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  • Materials For Medical Uses (AREA)
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EP19797909.9A 2018-10-15 2019-10-14 Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs Pending EP3866869A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16/160,888 US11406742B2 (en) 2014-07-18 2018-10-15 Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs
PCT/US2019/056127 WO2020081455A1 (en) 2018-10-15 2019-10-14 Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs

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EP3866869A1 true EP3866869A1 (en) 2021-08-25

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JP (2) JP7449298B2 (ko)
KR (1) KR20210077697A (ko)
CN (1) CN112867514A (ko)
AU (1) AU2019362775A1 (ko)
BR (1) BR112021007192A2 (ko)
CA (1) CA3114461A1 (ko)
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WO (1) WO2020081455A1 (ko)

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CN116271254B (zh) * 2022-07-08 2024-04-02 上海申淇医疗科技有限公司 球囊导管涂层及其制备方法、球囊导管
CN117442789B (zh) * 2022-11-11 2024-07-19 凯诺威医疗科技(武汉)有限公司 一种药涂球囊涂覆液、涂层材料、药涂球囊、制备方法及应用
CN116492513B (zh) * 2023-05-30 2023-11-03 武汉天楚生物科技有限公司 一种母猪受孕自动输精管用温敏蜡材料及其制备方法

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JP2024026639A (ja) 2024-02-28
KR20210077697A (ko) 2021-06-25
CN112867514A (zh) 2021-05-28
JP2022512006A (ja) 2022-02-01
MX2021004238A (es) 2021-05-27
AU2019362775A1 (en) 2021-04-15
BR112021007192A2 (pt) 2021-07-20
WO2020081455A1 (en) 2020-04-23
JP7449298B2 (ja) 2024-03-13
CA3114461A1 (en) 2020-04-23

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