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WO2013023051A1 - Procédés et compositions pour améliorer la biocompatibilité d'implants biomédicaux - Google Patents

Procédés et compositions pour améliorer la biocompatibilité d'implants biomédicaux Download PDF

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Publication number
WO2013023051A1
WO2013023051A1 PCT/US2012/050133 US2012050133W WO2013023051A1 WO 2013023051 A1 WO2013023051 A1 WO 2013023051A1 US 2012050133 W US2012050133 W US 2012050133W WO 2013023051 A1 WO2013023051 A1 WO 2013023051A1
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Prior art keywords
masitinib
composition
tissue
tyrosine kinase
kinase inhibitor
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PCT/US2012/050133
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English (en)
Inventor
Mahender Nath AVULA
Archana Nagaraja RAO
Florian Solzbacher
David W. Grainger
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University Of Utah Research Foundation
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Publication of WO2013023051A1 publication Critical patent/WO2013023051A1/fr

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    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—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
    • 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
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/04—Coatings containing a composite material such as inorganic/organic, i.e. material comprising different phases

Definitions

  • biomedical implants such as continuous glucose monitoring (CGM) sensors
  • CGM continuous glucose monitoring
  • FBR foreign body response
  • sensors, electrodes, pumps and structural implants this can compromise their function enough to require device removal and replacement, at substantial cost and patient morbidity.
  • Biomaterial surface properties play an important role in modulating the FBR in the first two to four weeks after medical device implantation. The FBR at the
  • tissue/material interface is sustained over the in vivo lifetime of implantation, leading to variability in device lifetime prediction.
  • host reactions following device implantation occur in a sequential fashion involving diverse cell types and associated cytokines.
  • the fibrous encapsulation associated with the FBR isolates and then hinders implant function, eventually leading to device failure.
  • This general host response is controlled by the extent of injury during implantation, the tissue or organ into which the device is implanted, and the extent of provisional matrix formed as a result.
  • Mast cell degranulation with histamine release, and fibrinogen adsorption are both known to mediate acute inflammatory responses to implanted biomaterials.
  • Cytokines such as interleukin-4 (IL-4) and interleukin-13 (IL-13), also are released from mast cells during degranulation to play significant roles in the extent and degree of the subsequent FBR development.
  • Surface modifications of implants, use of anti-inflammatory agents, angiogenesis promoters, and anti-thrombotic agents are used separately or in combination to arrest the FBR problem with highly variable results and limited clinical success.
  • compositions for reducing the foreign body response of a tissue adjacent to an implantable device include a tyrosine kinase inhibitor and a matrix.
  • the matrix is adapted to release the tyrosine kinase inhibitor directly into the tissue at a controlled rate.
  • Apparatuses according to embodiments of this disclosure include an apparatus body.
  • the apparatus body is at least partially coated with a composition including a tyrosine kinase inhibitor dispersed within a matrix adapted to release the tyrosine kinase inhibitor directly into the tissue at a controlled rate.
  • Methods according to embodiments of this disclosure include providing an apparatus including an apparatus body and coating the apparatus body with a
  • composition includes a tyrosine kinase inhibitor dispersed within a matrix adapted to release the tyrosine kinase inhibitor directly into the tissue at a controlled rate.
  • FIG. 1 is a flow chart showing the progression of the host foreign body response following medical device implantation into tissue, and identifying key cells and cytokines involved in the foreign body response.
  • FIG. 2 is a series of images showing TKI-loaded PLGA microspheres and a porous scaffold loaded with TKI-loaded PLGA microspheres, as follows: (A) an SEM micrograph of a TKI-loaded PLGA microsphere; (B) an SEM micrograph of TKI-loaded microspheres indicating substantial microspheres varying in size from about 5 microns to about 15 microns; and (C) a porous scaffold loaded with TKI-loaded PLGA microspheres.
  • FIG. 3 is a graph showing release kinetics of TKI from a drug loaded porous scaffold.
  • FIG. 4 is a pair of photographs showing diagonal subcutaneous implant sites of porous scaffolds in the dorsal regions of: (A) a normal/mast cell sufficient (C57BL/6) wild- type mouse; and (B) a mast cell deficient W-Sash mouse.
  • one implant site corresponds to a porous scaffold implant that is not loaded with TKI-loaded microspheres (i.e., a negative control), and the other implant site corresponds to a porous scaffold implant that is loaded with TKI-loaded microspheres (either a high dose (10 ⁇ ) or a lose dose (10nM)).
  • FIG. 5 is a series of optical microscope images of explants comparing the thickness of the fibrous capsule in tissues adjacent the tissue-implant interface two weeks after implantation of: (A) an implant not loaded with drug (i.e., a negative control implant); (B) an implant loaded with 10 nM of drug (i.e., a low dose implant); and (C) an implant loaded with 10 ⁇ of drug (i.e., a high dose implant). Localization of the fibrous capsule in each photograph is marked by white arrows.
  • FIG. 6 is a bar chart showing the thickness of the fibrous capsule in tissue adjacent the tissue-implant interface two weeks following implantation of negative control implants, high dose implants, and low dose implants.
  • FIG. 7 is a pair of optical microscope images of explants comparing the thickness of the fibrous capsule in tissues adjacent the tissue-implant interface two weeks after implantation, in mast cell deficient mice (i.e., knock-out mice), of (A) a low dose implant, and (B) a high dose implant. Localization of the fibrous capsule in each image is marked by white arrows.
  • FIG. 8 is a series of scanning electron microscope (SEM) micrographs of polymer coatings on 22-gauge needles, as follows: (left panel) a coating having a polymer mixture composition ID (P is percent polymer and N is percent non-solvent) of P10N0, (middle panel) a coating having a polymer mixture composition ID of P20N0, and (right panel) a coating having a polymer mixture composition ID of P30N0.
  • the magnification for P10N0 is 178*
  • P20N0 is 82x
  • P30N0 is 143* (i.e., the images from left to right).
  • FIG. 9 is a series of SEM micrographs of a porous coating having a polymer mixture composition ID of P20N20 on the surface of a 30-gauge needle.
  • magnification increases from left to right. Magnification from left to right: 83x, 107x, and 138x.
  • FIG. 10 is a graph depicting the release kinetics of a TKI from microspheres comprising PLGA 1A, 2A, or 4A (intended to release TKI for 1 week, 2 weeks, and a month, respectively) at pH 7.4 and 37 degrees Celsius.
  • FIG. 1 1 is a series of photographs showing the dissolution of a PEG scaffold in water, as follows: (left panel) at 0 minutes, (middle panel) at 2 minutes, and (right panel) at 15 minutes.
  • FIG. 12 is a pair of photographs showing (A) an implant coated with a PEG scaffold including PLGA microspheres and (B) a C57BL/6 mouse having a subcutaneous implant site with a control implant (square outline) coated with a PEG scaffold including PLGA microspheres and a test implant (circle outline) coated with a PEG scaffold including masitinib-loaded PLGA microspheres.
  • FIG. 13 is a series of optical microscope images depicting representative stained tissue samples from mice, in which the tissue sample was stained with (left panel of four images) H&E and (right panel of four images) Masson's trichrome.
  • upper left image is 14 days with a control implant
  • lower left image is 21 days with a control implant
  • upper right image is 14 days with a masitinib-loaded implant
  • lower right image is 21 days with a masitinib-loaded implant.
  • FIG. 14 is a bar chart showing the thickness of the fibrous capsule in tissue adjacent the tissue-implant interface 14 days and 21 days following implantation of the negative control implants and masitinib-loaded implants.
  • tyrosine kinase inhibitor refers to a variety of therapeutic agents or drugs that act as selective or non-selective inhibitors of receptor and/or non-receptor tyrosine kinases. Without being bound to any particular theory, tyrosine kinase inhibitors generally inhibit target tyrosine kinases by binding to the ATP- binding site of the enzyme.
  • implantable medical device refers to any device that may be positioned at a location within a body of an organism for any suitable period of time.
  • implantable class II medical device refers to any implantable medical device for which general controls (e.g., good manufacturing practices) are insufficient to assure safety and effectiveness, as set forth in 21 C.F.R. ⁇ 860.
  • implantable class II medical devices are subject to special controls as dictated by the U.S. Federal Drug Administration (FDA), e.g., special labeling requirements, mandatory performance standards, and postmarket surveillance.
  • FDA Federal Drug Administration
  • implantable class III medical device refers to any implantable medical device for which insufficient information exists to assure safety and effectiveness solely through general and/or special controls, as set forth in 21 C.F.R. ⁇ 860. As such, implantable class III medical devices require premarket approval and scientific review to ensure the device's safety and effectiveness.
  • providing refers to any means of obtaining a subject item, such as apparatuses or biomedical implants having improved
  • Mast cells normally are present in all tissues and are essential to normal wound healing and immune responses. Mast cells play a key role in the host inflammatory processes, activating to rapidly release their characteristic granules and various chemotactic stimulatory inflammatory mediators into tissue to trigger inflammatory cascades. Mast cells are stimulated to degranulate and activate by direct injury (e.g., physical wounding, or chemical injury by opioids, alcohols, and certain antibiotics such as polymyxins), by cross-linking of immunoglobulin E (IgE) receptors through FCeRI receptor, or by activated complement proteins. Chemicals from their degranulation are responsible for redness and swelling associated with inflammation and other innate immunity pathway signals in host tissues.
  • direct injury e.g., physical wounding, or chemical injury by opioids, alcohols, and certain antibiotics such as polymyxins
  • IgE immunoglobulin E
  • Mast cell inhibiting compounds, or drugs may limit these reactions and attenuate aspects of the acute inflammatory pathways and subsequent immune responses.
  • masitinib is a selective orally-dosed tyrosine kinase inhibitor (TKI) that effectively inhibits the survival, migration, and activity of mast cells.
  • TKI tyrosine kinase inhibitor
  • This disclosure demonstrates that the controlled release of TKIs from drug- releasing matrices bound to or associated with implantable medical devices delays the onset of and/or reduces the foreign body response (FBR) in tissues surrounding the implanted medical device. This effect prolongs the performance of the implant in tissue beyond that currently experienced without such drug release. Moreover, this approach provides the advantage of using miniscule amounts of drug compared to typical oral drug delivery (micrograms as opposed to milligrams), thereby minimizing the risks of adverse drug responses, and providing most intense drug dosing only at the intended site of action, i.e., immediately adjacent to the implant.
  • FBR foreign body response
  • this disclosure provides methods, compositions, and apparatuses for improving the biocompatibility of biomedical implants by delaying the onset of the foreign body response (FBR).
  • this disclosure provides compositions for reducing the foreign body response of a tissue adjacent to an implantable device, the composition comprising a TKI and a matrix adapted to release the TKI directly into the tissue at a controlled rate.
  • this disclosure provides an apparatus configured to be implanted within a tissue of a host and including an apparatus body at least partially coated with a composition. The composition includes a TKI dispersed within a matrix to release the TKI directly into the tissue at a controlled rate.
  • this disclosure provides methods of making an apparatus configured to be implanted within a tissue of a host, the method including providing an apparatus having an apparatus body and coating the apparatus body with a composition including a TKI dispersed within a matrix adapted to release the TKI directly into the tissue at a controlled rate.
  • Suitable TKIs for use with these compositions may include, but are not limited to, afatinib, axitinib, cediranib, erlotinib, gefitinib, grandinin, lapatinib, lestaurtinib, neratinib, pazopanib, quizartinib, regorafenib, semaxanib, sorafenb, sunitinib, tivozanib, toceranib, vandetanib, Bcr-Abl tyrosine-kinase inhibitor, bosutinib, crizotinib, CYT387, dasatinib, imatinib, Janus kinase inhibitor, lestaurtinib, nilotinib, ponatinib, ruxolitinib, tofacitinib, masitinib, imatinib, gefit
  • Any drug eluting matrix may be used within the scope of the disclosure to release TKIs into a host tissue surrounding or adjacent to an implantable medical device.
  • suitable coatings are described in U.S. Patent Nos. 6,042,875; 7,947,302; 5,879,697; 7,462,165; 6,364,856; 6,316,018; 7,691 ,400; 7,941 ,212; 7,945,319; 7,442,721 ; 7,572,625; 7,438,925; 7,862,835; 7,758,909; 8,017,142; 8,048,442; 6,702,850; 5,562,922; 7,279,175; and 7,892,221 ; and U.S. Patent Application Publication Nos. 2006/0088566; 2008/0071355; 2007/0190103; 2008/0255510; 2005/0004663; 2007/0244284;
  • Suitable matrices for use with these compositions may include water-soluble polymers, water-degradable polymers, resorbable polymers, water-swellable polymers, degradable polymers, and/or non-degradable polymers that can be coated on,
  • TKIs may be contained, dispersed, or embedded within the bulk of the matrix, may be contained or loaded within a microsphere that encapsulates at least some of the TKIs, and/or may be associated with a nanoparticle, nanosphere, nanocarrier, or wire (e.g., a microwire or a nanowire).
  • a microsphere that encapsulates at least some of the TKIs
  • a nanoparticle, nanosphere, nanocarrier, or wire e.g., a microwire or a nanowire.
  • the spheres, carriers, and/or wires may be of different sizes and structures. For instance, microspheres and nanospheres may have different surface area to volume ratios, which may alter the drug-release characteristics and dosage profiles of a TKI encapsulated therewithin.
  • a TKI encapsulated by a microsphere may have a release profile that is different from that of a TKI encapsulated by a nanosphere. While a particular amount of nanospheres and microspheres may encapsulate the same amount of a TKI, the nanospheres as compared to the microspheres may have an increased surface area to interact with cells in a host tissue adjacent to an implantable device coated with the composition. Additionally, nanospheres may have the risk of being internalized by cells in a host tissue by phagocytosis and/or pinocytosis.
  • the polymers may be fabricated or molded into a sleeve, scaffold, mold, and/or mesh to hold or contain TKI- containing microspheres, TKI-associated nanoparticles, TKI-associated nanospheres, TKI- associated nanocarriers, and TKI-associated nanowires/nanofibres.
  • Suitable polymers may include, but are not limited to, resorbable, degradable, erodible, and non-degradable polymers such as poly hydroxy ethyl methacrylate
  • PHEMA polymethy methacrylate
  • PMMA polyethylene terephthalate
  • PET polyethylene terephthalate
  • silicone porous PP
  • polysulfones polytetrafluoroethylene
  • PTFE polytetrafluoroethylene
  • PE polyethylene
  • PP poly(propylene)
  • PVC poly(vinyl)chloride
  • PEEK polyetheretherketone
  • polyvinylpyrollidones polyacrylates
  • PLGA poly(lactic-co-glycolic acid)
  • copolymers of PLGA e.g., PEO-PLGA-PEO
  • PEG poly(ethylene glycol)
  • PEO poly(ethylene oxide)
  • PGA polylactide-polyglycolide homo- or co-polymers
  • PCL polycaprolactone
  • the matrices may include inorganic salts including, but not limited to, calcium sulfate, calcium phosphate, and calcium salts with low solubility.
  • TKIs may be encapsulated within a polymer (e.g., a polymer microsphere, nanosphere, nanoparticle, etc.) which in turn may be dispersed within or on a matrix or scaffold.
  • the encapsulating polymer may be, for instance, a water soluble or resorbable polymer, including, but not limited to a poly(lactic-co-glycolic acid) (PLGA) 1 A, PLGA 2A, PLGA 4A, other molecular weights of PLGA, and any combination thereof.
  • PLGA poly(lactic-co-glycolic acid)
  • Encapsulating polymers may have diameters of about 0.5 microns to about 40 microns, such as diameters of about 1 micron to about 35 microns, about 3 microns to about 30 microns, about 5 microns to about 25 microns, or about 10 microns to about 20 microns.
  • Various methods may be used to encapsulate TKIs in polymers, including, but not limited to, forming the microspheres in the presence of a solution comprising the TKI.
  • the matrix or scaffold within which the encapsulating polymer is dispersed also may be, for instance, a water soluble or resorbable polymer, including, but not limited to PEG, (also known as poly(ethylene oxide) (“PEO”) at high molecular weights).
  • PEG also known as poly(ethylene oxide) (“PEO”) at high molecular weights.
  • the polymer may be provided at a concentration of at least about 50 mg/mL, at least about 100 mg/mL, at least about 150 mg/mL, at least about 200 mg/mL, at least about 250 mg/mL, at least about 300 mg/mL, at least about 350 mg/mL, at least about 400 mg/mL, at least about 450 mg/mL, at least about 500 mg/mL, at least about 550 mg/mL, and at least about 600 mg/mL. Additionally, the polymer may be a blend or mixture of different molecular weight polymers.
  • the blend may comprise one or more of 8,000 Dalton PEG, 20, 000 Dalton PEG, 80,000 Dalton PEG, and 100,000 Dalton PEG, such as a blend comprising 20,000 Dalton PEG and 100,000 Dalton PEG.
  • the blend may include any desired ratio of polymers to effectuate the desired mechanical properties, such as strength properties, rates of dissolution in water, and porosity, among others.
  • the blend may include two different molecular weight PEGs in ratios of about 10:90, 25:75, 50:50, 75:25, and 90:10 (w/w).
  • the matrices may be porous or non-porous, depending on the identity and functional requirements of the implantable medical device.
  • a non-porous matrix may not allow for the diffusion of fluids, salts, small molecules, proteins, nucleic acids, etc. between the implantable medical device and a tissue surrounding or adjacent to the implantable device.
  • Implantable medical devices that may be used with a non-porous matrix may include, but are not limited to, pacemakers, hernia meshes, and other devices not requiring access to fluids in a host tissue.
  • a porous matrix may allow for the diffusion of fluids, salts, small molecules, proteins, nucleic acids, etc. between the implantable medical device and the tissue surrounding or adjacent to the implantable device.
  • the diffusion across the porous matrices may be dependent upon the size or diameter of the pores or openings within the matrix. Additionally, the porosity of the matrix may depend upon the molecular weight, identity, and/or concentration of the polymer(s) comprising the matrix. Implantable medical devices that may be used with a porous matrix include, but are not limited to, continuous glucose monitor sensors and other devices requiring access to fluids in a host tissue.
  • compositions may be in the form of a gel, a liquid, or a solid.
  • some compositions may include a hydrogel, such as a hydrogel that is a liquid at room temperature and then cross-links at or around body temperature (i.e., 37 degrees Celsius).
  • the composition of the drug solution may be pure form/salt form of drug mixed in its solvent or a suspension of drug-loaded degradable microspheres for long term release.
  • compositions and the apparatus formed with the compositions may be adapted to locally release the drug rapidly into the tissue, followed either by prolonged or drawn out release of additional drug, or by little or no subsequent release of drug.
  • the compositions may be adapted to locally release the drug over extended periods, such as time periods of greater than about 10 days, greater than about 15 days, greater than about 20 days, greater than about 25 days, and greater than about 30 days.
  • the release rates may be adjusted by using differing matrices, including matrices having one or more different polymers and/or polymer concentrations, by encapsulating the TKI in
  • microspheres, nanospheres, etc. and/or by using different concentrations of drug.
  • compositions disclosed herein may be applied to, or otherwise associated with, an implantable device in any suitable manner to form an implantable apparatus adapted to release the TKI into an adjacent tissue of the host at a controlled rate.
  • the compositions also may be injected (e.g., continuously or periodically) into a tissue proximate to an implantation site for an implantable apparatus.
  • the composition may be injected into a tissue proximate to the implantation site to precondition the tissue proximate the implantation site.
  • variable amounts of the composition also may be injected using a syringe at desired time intervals into or near the site of implantation as required.
  • a medical grade polyvinyl chloride (PVC) tubing may be inserted into the implantation site at any desired distance from the implant itself.
  • the PVC tubing may be connected to a reservoir (outside the body, similar to insulin pumps) containing the composition, which may be pumped through the polymer tubing with an infusion pump at a controlled continuous or periodic flow rate.
  • composition disclosed herein further may comprise one or more additional drugs for reducing or mitigating the effects of the foreign body response, including, but not limited to an anti-inflammatory drug (e.g., dexamethasone, etc.), an anti-fibrotic drug (e.g., quinazolinone, etc.), an antibiotic (e.g., tobramycin, etc.), a tissue and angiogenesis promoter (e.g., VEGF, etc.), and a nucleic acid or other biomolecule (e.g., a cDNA, an siRNA, a transgene, an apatamer, a protein, etc.).
  • an anti-inflammatory drug e.g., dexamethasone, etc.
  • an anti-fibrotic drug e.g., quinazolinone, etc.
  • an antibiotic e.g., tobramycin, etc.
  • tissue and angiogenesis promoter e.g., VEGF, etc.
  • a nucleic acid or other biomolecule
  • compositions disclosed herein may be used to improve the biocompatibility of an apparatus that is at least partially implanted within a tissue of a host.
  • Methods of making apparatuses having improved biocompatibility comprise applying a composition to the apparatus, the composition comprising a tyrosine kinase inhibitor embedded, dispersed, or contained within a matrix adapted to release the tyrosine kinase inhibitor into an adjacent tissue of the host at a controlled rate.
  • the compositions and apparatuses disclosed herein also may be used in methods for treating various diseases, including but not limited to diabetes.
  • Apparatuses configured to be implanted within a tissue of a host may be at least partially coated with the compositions by any number of methods, including, but not limited to, phase inversion, physical vapor deposition, chemical vapor deposition, freeze condensation, surface condensation, polymerization on the surface of the implantable device, monolith coating, cast coating, electrospinning, spray coating, electrospray coating, dip coating, phase separation/inversion coating, mold coating, scaffold fabrication, e-beam polymerization, ink jet placement, drug-polymer blending and extrusion, nano or microfibrous mesh fabrication, nano or microfibrous (i.e., open cell) coatings, casting or injection molding processes to form a sleeve for the implantable device, and/or
  • compositions may be applied to the apparatuses in a bulk layer, or may be applied to a film, sheet, sleeve, or scaffold that is wrapped around or coats the
  • the thicknesses of coatings applied to the implantable devices may vary depending on the identity of the drug, the concentration of the drug, the components of the matrix, the identity of the implantable device, the desired application, the duration of implantation of the implantable device, and the method of application.
  • the thickness of the coating may be at least about 50 microns, at least about 100 microns, at least about 150 microns, at least about 200 microns, at least about 250 microns, at least about 300 microns, at least about 350 microns, at least about 400 microns, at least about 450 microns, at least about 500 microns, at least about 750 microns, at least about 1.00 mm, at least about 1.25 mm, and least about 1.50 mm, or any other suitable thickness depending on the application.
  • a coating may be applied using a spray coating method.
  • Spray coating may involve spraying or applying an atomized or aerosolized form of the composition to a body of the apparatus to form a sheet, film, or coating of the composition about the body of the apparatus.
  • the coatings created by spraying may have a thickness of about 20 microns.
  • the coatings may have a thickness of at least about 5 microns, at least about 10 microns, at least about 15 microns, at least about 25 microns, at least about 30 microns, at least about 35 microns, at least about 50 microns, at least about 75 microns, at least about 100 microns, at least about 125 microns, at least about 150 microns, at least about 175 microns, or at least about 200 microns. Any other thickness suitable with the coating's function may also be used.
  • the porosity and stability of the sprayed coating may vary as a function of the concentration of an alcohol(s) (e.g., ethanol) in the composition. For instance, the porosity may increase, and the stability may decrease (e.g., increased fragility and brittleness of the coating or sheet) as the alcohol concentration increases. Stability may be measured as a function of sheet or coating integrity.
  • a coating may be applied using a dip coating method.
  • Dip coating may involve dipping or immersing the body of the apparatus into a particular volume of the composition such that the body of the apparatus is coated or covered by the composition.
  • Dip coating further may include the steps of flash-freezing and then air- drying the coated apparatus body.
  • the porosity of the resulting coating may vary as a function of the concentration of an alcohol(s) (e.g., ethanol) in the composition. For instance, in the absence of alcohol, no pores may be formed in the coating, but in the presence of alcohol, pores may be formed in the coating.
  • the pores may have a diameter of about 5 microns to about 20 microns.
  • the pores may have a diameter of about 1 micron to about 25 microns, of about 1 micron to about 10 microns, of about 3 microns to about 7 microns, about 8 microns to about 15 microns, about 12 to about 18 microns, about 15 microns to about 25 microns, about 17 microns to about 25 microns, or about 20 to about 25 microns.
  • a coating may be applied using a mold coating method.
  • Mold coating may involve applying a matrix to the body of the apparatus, in which a scaffold, mold, or coating capable of holding or supporting one or more TKIs is formed or fabricated around the body of the apparatus.
  • the apparatus body may be at least partially inserted into a space defined by a mold, in which a solution or suspension is applied to the apparatus body.
  • the solution or suspension may include a polymer microsphere encapsulating a TKI(s) and a water soluble or degradable polymer.
  • the coated apparatus body may be removed from the mold space after freezing and lyophilizing of the solution or suspension.
  • the scaffold, mold, or coating on the apparatus body may have sufficient structural integrity (e.g., not crumble, not brittle, not shear off the apparatus body, etc.) to remain intact during implantation of the apparatus into a host tissue.
  • the scaffold, mold, or coating may be dissolvable or soluble in water such that after implantation of the apparatus into a tissue of a host, the scaffold dissolves due to the water present in the tissue of the host, allowing for dispersion or release of the TKI-containing polymer microspheres at the site of implantation.
  • the scaffold, mold, or coating may dissolve in water in less than about 15 minutes.
  • the scaffold, mold, or coating may dissolve in water in less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, and less than about 25 minutes.
  • Apparatuses coated with the composition when implanted into a host tissue, may decrease or reduce the density of inflammatory cells and the thickness of fibrous capsules in the tissue adjacent to the apparatus via the release of TKIs into the host tissue adjacent to or surrounding the apparatus. This reduction in inflammatory cell density and fibrous capsule thickness may in turn delay the onset of the foreign body response, thus increasing the in vivo lifetime of the apparatus.
  • Apparatuses made with the compositions disclosed herein may include any suitable implantable class II or class III medical device or implantable biomaterial.
  • Suitable medical devices may include, but are not limited to, devices requiring two-way diffusion or transport of fluids (e.g., glucose sensor), devices requiring one-way diffusion or transport of fluids (e.g., hernia mesh), sensors (e.g., glucose or lactate sensors), shunts, contact lens, bone and dental cement, drug delivery implants, catheters, lead insulations, tissue filling, adhesives, intraocular lens, pace maker leads, blood pumps, joint
  • fluids e.g., glucose sensor
  • sensors e.g., glucose or lactate sensors
  • shunts e.g., contact lens, bone and dental cement
  • drug delivery implants e.g., catheters, lead insulations, tissue filling, adhesives, intraocular lens, pace maker leads, blood pumps, joint
  • tissue filling tissue engineering scaffolds
  • stents electrodes
  • pacemakers catheters
  • in-dwelling pump infusion canulae insulin infusion devices
  • surgical or hernial repair meshes surgical weaves, tissue scaffolds, defect fillers, breast implants, and grafts (e.g., vascular).
  • the methods, compositions, and apparatuses disclosed herein have numerous advantages.
  • the drug acts in the local environment and is highly effective in low dosage as opposed to large dosage of drug of which only a small quantity may reach the target site, in case of oral delivery.
  • long-term sustained release for single dose possible - drug release kinetics with initial burst release and a control release for a longer duration of time period (e.g., greater than about 30 days).
  • Example 1 Fabrication and characterization of compositions comprising a TKI in a time-release matrix
  • PLGA microspheres were prepared using oil-in-water (o/w) emulsion/solvent evaporation techniques, as described in O'Donnell and McGinity, Advanced Drug Delivery Reviews, vol. 28, pp. 25-42, 1997, and Hickey, et al., Biomaterials, vol. 23, pp. 1649-1656, 2002.
  • the PLGA polymer granules (2.5% w/v) were allowed to stand in DCM for 30 minutes. 10 ⁇ masitinib was prepared in DCM
  • the resultant mixture was then centrifuged at 10,000 rpm at -4°C for 10 minutes, twice discarding the supernatant fluid in between the cycles, to obtain the "high dose” and "low dose” PLGA microspheres.
  • PLGA microspheres were lyophilized to obtain dry solid PLGA particles for storage at -80°C.
  • PLGA microspheres without drug were similarly made for a blank negative and coumarin positive control to study the release profiles in vitro.
  • the amount of masitinib encapsulated by the PLGA microspheres was determined to evaluate the efficiency of loading of masitnib into the PLGA microspheres. Particularly, the amount of drug encapsulated by the PLGA microspheres was measured by dissolving the PLGA microspheres in chloroform, which had been loaded with a known amount of masitinib. The UV absorbance of the resulting solution was then measured to determine the amount of masitnib released from the PLGA microspheres (i.e., via the dissolution of the PLGA microspheres), thus allowing for calculation of the efficiency of loading of masitnib into the PLGA microspheres.
  • FIGS. 2A and 2B show electron micrographs of the drug-loaded PLGA microspheres.
  • FIG. 2C is an image of a porous scaffold loaded with drug-loaded PLGA microspheres.
  • Example 2 In vitro release of TKIs from the compositions and
  • Porous non-degrading biomedical polyurethane (PU) polymer scaffold discs measuring 8mmx3mm were loaded (i.e., impregnated with) with the drug-loaded PLGA microspheres.
  • lyophilized masitinib-loaded PLGA microspheres were dispersed in water (2mL) to obtain a 10 ⁇ concentration and the resulting dispersion was incorporated into the porous PU polymer scaffold disc by vacuum pressure.
  • the scaffold discs with masitinib were allowed to stand overnight for complete drying.
  • hyaluronic acid was coated on to another set of masitinib-loaded PU polymer scaffold discs to enable the integration of the PLGA microspheres into the scaffold disc.
  • FIG. 3 is a graph showing the cumulative masitinib released from PLGA microspheres embedded within the PU scaffold discs over time.
  • Total amounts of masitinib released into the RPMI media as a percentage of the total amount of drug encapsulated into the PLGA microsphere system are plotted as a function of the elapsed time from the beginning of the release studies.
  • the initial burst of masitinib released may be due to the masitinib associated with the surface of the PLGA microspheres.
  • the plateau which follows, reflects the delay needed for PLGA hydrolysis to erode the microspheres sufficiently to allow drug egress from the microspheres.
  • the decrease in the release rate may be due to the depletion of masitinib from the microspheres.
  • the drug would be released successfully for a period of a month or more, depending on the molecular weight of the PLGA used in the synthesis of the microspheres. Additionally, altering the dosage of the drug and the polymer matrix (i.e., PLGA microsphere and/or PU scaffold disc) could be used to modulate the release of the drug for a stipulated period of time.
  • Porous scaffolds made according to the method described in Example 2 were implanted into subcutaneous pockets in two different strains of mice - mast cell deficient (w-sash) and normal mice (C57BL/6), purchased from Jackson
  • mice 8 week old female mast cell sufficient (C57BL/6) and mast cell deficient mice were utilized. Both strains of mice were maintained in a pathogen- free facility at the University of Utah. Mice were anesthetized using isofluorine and sterile procedures were used during surgery. Dorsal incisions about 1 cm long were made perpendicularly to the longitudinal axis at the same level as the diaphragm with sterilized surgical scissors. Subcutaneous pockets on both sides of incision were created by blunt curved forceps and the PU implants were implanted subcutaneously into the dorsal region of mice, as described in Kyriakides, ef a/., American Journal of Pathology, vol. 165, p.
  • mice received buprenex injections before and after the surgery for two days to relieve them of pain. All subjects were euthanized after 2 weeks and surrounding tissues with implants were harvested after necropsy and fixed in 10% neutralized formalin for histological analysis.
  • Capsule thickness for each section was estimated microscopically as the average thickness at six different random locations and was determined per implant as the average thickness of 3 sections per explant. Microscopic analysis of the fibrous capsule was performed independently by two investigators who were not aware of the identity of the samples. The mast cells were stained with toluidine and analyzed for intact mast cells. Additionally, inflammatory cells like neutrophils and macrophages around the implant were quantified.
  • Tissue harvests surrounding implants were stained with masson's trichrome staining to identify collagen capsules. All of the explants shown in FIG. 5 are from normal/mast cell sufficient mice (C57BL/6).
  • the collagen capsule thicknesses in FIGS. 5 and 6 were calculated and compared among the negative control-A (blank without drug 133 ⁇ 1 1 ⁇ ) and the positive controls: B - drug-loaded low dose is 88 ⁇ 8 ⁇ and C (drug- loaded high dose is 44 ⁇ 9 ⁇ ). Fibrous capsule structure and thickness were evaluated from microscopic histology images (see FIG. 5, fibrous capsules are demarcated with arrows).
  • Both the wild type and knockout mice i.e., mast cell deficient showed similar FBR, but the extent of fibrosis was higher in the wild-type mice as compared to the knockout mice when similar implants were employed in both mice. Fibrosis is known to affect glucose sensor function of implants as shown by Klueh, et al. in Biomaterials, vol. 31 , pp. 4540-51 , Jun 2010.
  • the knockout mice also had fibrous capsule tissue formation, which indicated that irrespective of the presence of mast cells, fibrous tissue was formed.
  • the glucose sensors in the knockout mice continued to function normally despite the presence of a fibrous capsule (Klueh, et al. in Biomaterials, vol. 31 , pp. 4540-51 , Jun 2010).
  • Example 4 Conclusions from in vitro and in vivo studies of drug release from implants (i.e.. Examples 1 -3)
  • the porous scaffold loaded with the drug masitinib had an initial burst release of masitinib and a continuous release of masitinib for a month. This was validated by the in vivo data (i.e., the mouse studies in Example 3), which indicated a reduction in the FBR response around the implant for 14 days. Drug dosing levels also impacted the extent of fibrous capsule reduction. The reduction in fibrous capsule thickness and the density of inflammatory cells validated the importance of tissue mast cells in mediating the FBR, supporting the conclusion that mast cells play a critical role in mediating the FBR.
  • the above data support using the coating i.e., masitinib-loaded PLGA microspheres loaded into the PU scaffold
  • implantable biomedical devices to extend the performance lifetime of the implants in a host tissue.
  • Example 5 Spray coating of apparatuses with a composition including PLGA and masitinib
  • Spray coating experiments were performed with a custom-built in-house set up using a computer controlled milling machine head equipped with an interfaced pneumatic liquid atomization head/sprayer as previously used in Kennedy et al. Solutions 1 and 2 separately filled two 60 mL syringes, which were loaded onto a dual syringe pump. The syringes containing these solutions were connected to pneumatic spray brushes via medical-grade polyvinyl chloride (PVC) tubing. The spray brushes were mounted on the head of a tabletop milling machine and connected to an air compressor via pneumatic tubing.
  • PVC polyvinyl chloride
  • the syringe pump was programmed to a pre-calculated feed rate of 1.962 mL/min to achieve an areal dried solids coverage of 0.2 gm/in 2 after 1.5 minutes of spraying.
  • the pneumatic lines were maintained at 10 psi while an area of 2"*2" was coated with a mixture of solutions 1 and 2 to form a polymer film or coating on a silicone tubing template.
  • Solutions 1 and 2 were simultaneously sprayed such that the two solutions mixed and adhered onto the surface of the silicone tubing template. After completion of the spraying process, the resulting polymer coating was then allowed to air-dry overnight.
  • the stability of the coatings resulting from mixing Solutions 1 and 2 was measured as a function of the integrity of the sheet or coating during handling.
  • the most stable coatings contained less than 20% ethanol with higher concentrations of ethanol resulting in brittle and fragile coatings.
  • porosity increased as a function of the ethanol concentration.
  • concentration of ethanol in Solution 2 e.g., 10% and 20% ethanol in 4% PVA-water solution
  • a permeability test using the coated polyester template examined diffusion across the coating. The fluorescein equilibrated between the two chambers of the Franz cell apparatus in 3 minutes.
  • Solutions 1 and 2 were immiscible with each other, thus forming a 2- phase mixture when combined during the spray coating process. Specifically, there was a DMSO phase and an ethanol phase.
  • the PVA in Solution 2 acted as a surfactant between the DMSO and ethanol phases to allow for the formation of highly porous polymer films, sheets, or coatings when spraying the mixture of Solutions 1 and 2 onto the tested templates.
  • the coatings on the tested templates were non-uniform and the concentration of masitinib loaded onto the template was not well controlled.
  • the separation between the DMSO and ethanol phases was observable and limited the thickness of the coating that could be achieved via spraying the mixture of Solutions 1 and 2 onto the tested templates.
  • Example 6 Dip coating of needle implants into a composition including PLGA and masitinib
  • Dip coating involves submersion of an oxygen plasma-treated implant in a mixture of solvent and non-solvent for a pre-determined amount of time. The implant is then flash frozen and air-dried to complete the process.
  • PLGA was dissolved in acetone (i.e., solvent) at 10% and 20% (w/v) to form a solution and 100% ethanol was used as the non-solvent for the dip coating studies.
  • acetone i.e., solvent
  • 100% ethanol non-solvent fraction or phase
  • Standard 30-gauge stainless steel needles were cleaned with acetone to remove any residual silicone oil from the manufacturing process.
  • the needle was plasma treated for 5 minutes at 0.1 bar pressure and 100 watts power.
  • the needle was then immediately submerged into a 1.5 ml vial containing 600 ⁇ _ of one of the polymer mixture solutions described in Table 1 above.
  • the needle was immersed in the polymer mixture solution for 1 minute to coat the needle with the polymer mixture solution and then the needle was immediately removed from the polymer mixture solution for flash freezing in a cold dry-ice chamber for 5 minutes. Flash freezing enabled the resulting coating of the polymer mixture solution on the needle to maintain its porous structure.
  • the porous structure is formed due to the polymer mixture solution having two phases, an acetone phase and an ethanol phase. After flash freezing, the acetone and ethanol were vaporized, leaving behind a coating including PLGA and masitinib.
  • a custom-developed high performance liquid chromatography (HPLC) analytical method using a C18 column was used to examine the loading of masitinib in the coatings on the 30-gauge needles resulting from the above-described dip coating method.
  • HPLC high performance liquid chromatography
  • needles with the PLGA/masitinib coating were immersed in a 200 ⁇ _ vial having 150 ⁇ _ PBS (pH 7.4) and located within a 37°C incubator. At regular intervals, the needles were moved to new vials in the 37°C incubator, the vials each having 150 ⁇ _ PBS (pH 7.4).
  • the 150 ⁇ _ PBS (pH 7.4) samples were stored at -20°C after removal of the needles until analyzed in the HPLC. HPLC analysis was used to determine the amount of masitinib released into the PBS sample, thus allowing for the determination of the amount of masitinib loaded into the coatings on the needles.
  • Solvent i.e., acetone
  • 20% PLGA produced appropriate solution viscosity for dip coating and was thus used with all other concentrations of non-solvent (i.e., ethanol) for further experiments.
  • a polymer mixture solution having the non-solvent at a concentration of 20% resulted in a porous coating having pore diameters in the range of 5- 20 ⁇ as shown in FIG. 9 at different magnifications.
  • magnifications for FIGS. 9A, 9B, and 9C were 83x, 107x, and 138, respectively (i.e., magnification from left to right in FIG. 9 is 83x, 107x and 138x).
  • Example 7 Fabrication and characterization of masitinib-loaded PLGA 1A microspheres, masitinib-loaded PLGA 2A microspheres, and masitinib-loaded PLGA 4A microspheres
  • PLGA 1A, PLGA 2A, and PLGA 4A are PLGA polymers having different molecular weights and as such, three different types of PLGA microspheres were synthesized using a solvent-evaporation technique (P.B. O'Donnell, J.W. McGinity , Advanced Drug Delivery Reviews 28 (1997) 25 -42).
  • a solution of 500 ⁇ g/mL masitinib in dichloromethane (DCM) was prepared and sonicated for 30 minutes to allow for complete dissolution of masitinib in DCM.
  • PLGA 1A, 2A, or 4A 100 mg of either PLGA 1A, 2A, or 4A was mixed into 2 mL of the masitinib-DCM solution, mixing occurring for 30 minutes to allow for the formation of a PLGA-masitinib solution.
  • 10 mL of 5% PVA (w/v) in water was stirred in a 100 mL beaker at 800 rpm while the PLGA- masitinib solution was slowly added into the PVA solution via a separating funnel to create an oil-in-water emulsion.
  • the resulting oil-in-water emulsion was stirred at 800 rpm for 4 hours to allow the DCM to evaporate and then was collected via centrifugation at 10,000 rpm for 10 minutes.
  • masitinib-loaded PLGA microspheres were suspended in 2 mL water and stored at -80°C. The frozen, suspended masitinib-loaded PLGA microspheres were then lyophilized for 24 hours at -50°C and 0.02 bar pressure.
  • masitinib-loaded PLGA microspheres had 2.50 - 6.50 ⁇ g masitinib per 1 mg of PLGA microspheres.
  • Higher molecular weight PLGA had lower loading (1 A - 6.5 g/ml, 2A - 4.9 ⁇ g/ml, 4A - 2.5 ⁇ g/ml).
  • Average of 4.66 ⁇ g/ml of masitinib per 1 mg of PLGA microspheres when the microspheres are mixed in equal ratios, i.e, 1A:2A:4A 1 :1 :1.
  • Example 8 In vitro release of masitinib from masitinib-loaded PLGA 1A microspheres, masitinib-loaded PLGA 2A microspheres, and masitinib-loaded PLGA 4A microspheres
  • the 1 mL aliquots were collected at regular time intervals for 30 days and were stored at -20°C after collection.
  • UV-HPLC at 281 nm was used to analyze the 1 mL aliquots to quantify the amount of masitinib that had been released from the masitinib-loaded PLGA microspheres into the PBS solution at the time of collecting the particular 1 mL aliquot.
  • the area under curve for the characteristic peak of masitinib was calculated for each 1 mL aliquot and accordingly, the masitinib loading was quantified using a standard curve.
  • Matrices used with compositions comprising TKIs may include polymers that may be fabricated or molded into a scaffold to hold or contain TKI-loaded PLGA microspheres.
  • scaffolds were made from Poly(ethylene glycol) (PEG), otherwise known as poly(ethylene oxide) (PEO) at high molecular weights (e.g., 80,000 and 100,000 Daltons), with the intent that the resulting scaffolds would be able to contain or hold TKI- loaded microspheres around an implant until after completion of implanting the implant into a host tissue.
  • PEG Poly(ethylene glycol)
  • PEO poly(ethylene oxide)
  • the polymer PEG is advantageous as it is non-toxic, highly hydrophilic, and can be used without solvents that may be harmful to the host tissue.
  • the resulting PEG scaffolds were mechanically assessed in a qualitative fashion to determine the strength properties of the PEG scaffolds. Scaffolds made from PEG solutions having a concentration of 50 mg/mL, irrespective of the molecular weight of the PEG used in the solution, lacked sufficient density and thus crumbled. As such, scaffolds made from 50 mg/mL PEG solutions are not appropriate for use with an implant or implantable medical device as the PEG scaffold could come off the implant or device during handling in an implantation procedure. On the other hand, scaffolds made from PEG solutions having a concentration of 600 mg/mL, irrespective of the molecular weight of the PEG used in the solution, were too dense and rigid such that the scaffolds could not be indented.
  • the blend of 20,000 Daltons PEG:100,000 Daltons PEG was prepared in different ratios, as follows: 10:90 (w/w); 25:75 (w/w); 50:50 (w/w); 75:25 (w/w); and 90:10 (w/w).
  • the resulting PEG scaffolds were mechanically assessed in a qualitative fashion to determine the strength properties of the PEG scaffolds. It was determined that blends having lower molecular weight PEG (i.e., 8000 Daltons) were too brittle for use with implants or implantable medical devices because scaffolds derived from lower molecular weight blends of PEG may possibly shear or come off of the implant or device during implantation of the device into a host tissue. It was determined that scaffolds comprising 10% of 20,000 Da PEG and 90% of 100,000 Da PEG mixed in water at 200 mg/ml concentration provided mechanical properties (e.g., rigidity or density) compatible with the implantation of an implant or device into a host tissue.
  • mechanical properties e.g., rigidity or density
  • the scaffolds comprising PEG are held together by the entanglement of the PEG polymer chains and not by chemical cross- linking. As such, this could enable the PEG scaffolds to disintegrate quickly in water and thus a host tissue.
  • the dissolution rate of the PEG scaffolds in water was measured by placing a PEG scaffold into a beaker containing about 7 ml of water to determine the length of time it took for the PEG scaffold to dissolve in the water. The volume of water was selected to allow for complete submersion of the PEG scaffold in the water. Time points and images of the dissolving PEG scaffolds were taken at 0 minutes, 2 minutes, and 15 minutes.
  • a matrix coating or covering an implant or implantable medical device such as a continuous glucose sensor could include a soluble PEG scaffold that functions as a carrier for PLGA microspheres, in which the microspheres are loaded with a composition comprising a TKI such as masitinib. The matrix would not impede CGS function as the PEG scaffold is porous and dissolved or disintegrated upon exposure to water.
  • Example 10 Preparation of a matrix on an implant.
  • masitinib-loaded PLGA microspheres 6 mg (i.e., about 28 ⁇ g of masitinib loaded into the PLGA microspheres) of masitinib-loaded PLGA microspheres (i.e., 2 mg each of PLGA 1A, 2A, and 4A microspheres loaded with masitinib) were mixed into a 200 mg/mL solution of 10:90 (w/w) 20kDa:100kDa PEG in water to form a dispersion of PEG and masitinib-loaded PLGA microspheres, in which the masitinib-loaded PLGA microspheres comprised equal parts of masitinib-loaded PLGA 1A microspheres, masitinib-loaded PLGA 2A microspheres, and masitinib-loaded PLGA 4A microspheres.
  • the PEG/masitinib-loaded PLGA microsphere dispersion had a final concentration of 200 mg/mL of masitinib-loaded PLGA microspheres.
  • 30 ⁇ of the PEG/masitinib-loaded PLGA microsphere dispersion was dispensed into a mold around a polyester wire and the 2-piece mold was screwed together tightly before placing the mold in liquid nitrogen for flash freezing. The frozen mold was then opened using a release mechanism built into the mold and the 2 halves of the mold were placed in glass jars and lyophilized for 8 hours at -50°C and 0.02 bar pressure to yield a PEG scaffold containing masitinib-loaded PLGA microspheres surrounding or coating the wire.
  • the wires within the PEG-PLGA scaffolds were gently released from the molds to yield the wire (i.e., mimic of implant) coated with the matrix (i.e., PEG scaffold containing the masitinib-loaded PLGA microspheres).
  • FIG. 12A A representative coated wire is shown in FIG. 12A.
  • the wire protrudes from the right end, i.e., at the 1 cm mark on the depicted ruler.
  • These coated wires could be used with drug-loaded and control (i.e., no drug) microspheres in in vivo experiments with wild-type C57BL/6 mice as subcutaneous implants as shown in FIG. 12B.
  • Drug loading efficiency of masitinib in the PEG-PLGA scaffold The above described coated wires were characterized with regards to masitinib loading.
  • Example 11 In vivo characterization of a model implant coated with a PEG scaffold including masitinib-loaded PLGA microspheres
  • Polyester wires coated with a PEG scaffold containing equal amounts of masitinib-loaded PLGA 1A microspheres, masitinib-loaded PLGA 2A microspheres, and masitinib-loaded PLGA 4A microspheres were prepared as described above in Example 10.
  • Polyester wires were also coated with a PEG scaffold containing equal amounts of PLGA 1 A microspheres, PLGA 2A microspheres, and PLGA 4A microspheres as described above in Example 10 except that the PLGA microspheres were not loaded with masitinib.
  • a representative example of a coated polyester wire is shown in FIG. 12A.
  • aseptic techniques were used during the fabrication of the coated polyester wires to minimize bacterial and/or lipopolysaccharide (LPS) contamination of the coated polyester wires as the coated polyester wires were implanted in mice.
  • a blood agar smear test was used to confirm whether the coated polyester wires were contaminated with bacteria during the fabrication process. Specifically, coated polyester wires were gently rolled over the surface of blood agar gel, which was then incubated in an incubator at 37 degrees Celsius for 24 hours. After 24 hours, the blood agar gel was examined for any bacterial growth to ensure no bacterial growth during fabrication of the polymer implant from the coated polyester wires. No bacterial growth was observed after the incubation period.
  • Betadine antiseptic solution was applied to the shaved area before making a small incision with autoclaved (steam sterilized) scissors to create an entry point for the model implant.
  • a 16 gage needle was used to inject about 150 ⁇ _ of sterile, pyrogen free, 0.9% NaCI solution to create a subcutaneous pocket for the implant.
  • the implant was then inserted into the pocket and the open wound was sealed with a liquid bandage (3M Nexcare skin crack care).
  • Each mouse was implanted with one control model implant (i.e., polyester wire coated with a PEG scaffold containing PLGA microspheres) and one masitinib-loaded model implant (i.e., polyester wire coated with a PEG scaffold containing masitinib-loaded PLGA microspheres) on either side of the spinal cord (FIG. 12B, square marks
  • one control model implant i.e., polyester wire coated with a PEG scaffold containing PLGA microspheres
  • masitinib-loaded model implant i.e., polyester wire coated with a PEG scaffold containing masitinib-loaded PLGA microspheres
  • control implant and circle marks the implantation site for the masitinib-loaded implant.
  • the control and masitinib-loaded implants were randomized as to which side of the spinal cord they were implanted to avoid location-specific effects. As noted above, the control implants were similar to the masitinib-loaded implants except that the PLGA microspheres used in the control implants were not loaded with masitinib.
  • mice having the control and masitinib-loaded implants were divided into four groups for the four time points, 7, 14, 21 , and 28 days.
  • the mice were euthanized at the end of their respective time point and the tissue surrounding (i.e., adjacent to) the implant was harvested for histological analysis.
  • the harvested tissue was fixed in 10% neutral buffered formalin for 24 hours before being submitted to ARUP (Associated Regional and University Pathologists) laboratories for sectioning and staining of the slides. Slides from each sample were stained with H&E, Masson's trichrome, and Toluidine blue to quantify inflammatory cell density, fibrous capsule thickness, and mast cell integrity, respectively.
  • Inflammatory cell densities in H&E stained tissues that surrounded (i.e., adjacent to) the implants at the 14-day and 21 -day time points are depicted in the left panel of four images in FIG. 13, in which the implantation site is marked by an asterisk, * .
  • Inflammatory cell densities around the control implants were found to be significantly higher than those around the masitinib-loaded implants for both the 14-day and 21-day time points.
  • Minimal numbers of inflammatory cells were present around the masitinib- loaded implants at the 14-day and 21-day time points, indicating that the masitinib was released from the PLGA microspheres in sufficient amounts to alter the density of inflammatory cells at the site of implantation.
  • compositions such as the PEG scaffold containing the masitinib-loaded microspheres may be a suitable coating for an implantable medical device, e.g., continuous glucose sensor, in which the composition reduces the inflammatory response (e.g., increased density of inflammatory cells, fibrous capsules, and mast cell activity at the site of implantation) of a host tissue to implantation and thus increases the duration of time that the medical device is implanted in the host tissue.
  • an implantable medical device e.g., continuous glucose sensor
  • the capsule thickness in Masson's trichrome stained tissues that surrounded (i.e., adjacent to) the implants at the 14-day and 21-day time points are depicted in the right panel of four images in FIG. 13, in which the implantation site is marked by an asterisk, * , and the capsule thickness is shown between the arrows.
  • the capsule thickness indicated the amount of fibrous encapsulation around the control and masitinib- loaded implants.
  • the capsule thicknesses in microns ( ⁇ ) for the control implants and the masitinib-loaded implants at the 14-day and 21-day time points are shown in FIG. 14.
  • the capsule thickness measured around the control implant was 42.2 ⁇ 4 ⁇ (mean ⁇ standard deviation) while the capsule thickness around the masitinib- loaded implant was 12 ⁇ 1.2 ⁇ .
  • the capsule thickness of the fibrous encapsulation around the control implant was 83.1 ⁇ 3.4 ⁇ while the capsule thickness around the drug-loaded implant was 8.4 ⁇ 3.2 ⁇ .
  • a significant reduction in the capsule thickness around the masitinib-loaded implants was observed as compared to the control implant (i.e., without masitinib) for both 14-day and 21-day time points.
  • masitinib-loaded implant showed a similar efficacy of masitinib in both the 14-day and 21- day time points.
  • the systems, compositions and methods disclosed herein are not limited in their applications to the details described herein, and are capable of other embodiments and of being practiced or of being carried out in various ways.
  • the phraseology and terminology used herein is for the purpose of description only, and should not be regarded as limiting.
  • Ordinal indicators, such as first, second, and third, as used in the description and the claims to refer to various structures are not meant to be construed to indicate any specific structures, or any particular order or configuration to such structures. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

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Abstract

L'invention concerne une composition pour réduire la réponse à un corps étranger d'un tissu adjacent à un dispositif implantable, laquelle composition comprend un inhibiteur de tyrosine kinase et une matrice. La matrice est conçue pour libérer l'inhibiteur de tyrosine kinase directement dans le tissu à une vitesse régulée.
PCT/US2012/050133 2011-08-09 2012-08-09 Procédés et compositions pour améliorer la biocompatibilité d'implants biomédicaux WO2013023051A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014160060A1 (fr) * 2013-03-14 2014-10-02 Cell and Molecular Tissue Engineering, LLC Capteurs, canules, collerettes et treillis chirurgical revêtu, et systèmes et procédés correspondants
US9717583B2 (en) 2014-03-13 2017-08-01 Cell and Molecular Tissue Engineering, LLC Sensors, cannulas, collars and coated surgical mesh, and corresponding systems and methods
US10130288B2 (en) 2013-03-14 2018-11-20 Cell and Molecular Tissue Engineering, LLC Coated sensors, and corresponding systems and methods
US10405961B2 (en) 2013-03-14 2019-09-10 Cell and Molecular Tissue Engineering, LLC Coated surgical mesh, and corresponding systems and methods
CN111407744A (zh) * 2020-01-19 2020-07-14 绍兴文理学院元培学院 一种枸橼酸托法替布长效缓释微球的制备方法
WO2023129438A1 (fr) * 2021-12-28 2023-07-06 Wisconsin Alumni Research Foundation Compositions d'hydrogel destinées à être utilisées dans le cadre de la déplétion de macrophages associés à une tumeur
WO2023137263A1 (fr) * 2022-01-13 2023-07-20 Verily Life Sciences Llc Véhicules d'administration de médicament, procédés de production de véhicules d'administration de médicament, et procédés d'utilisation de véhicules d'administration de médicament

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6497729B1 (en) * 1998-11-20 2002-12-24 The University Of Connecticut Implant coating for control of tissue/implant interactions
US6551355B1 (en) * 1998-08-14 2003-04-22 Cambridge Scientific, Inc. Tissue transplant coated with biocompatible biodegradable polymer
US20100226943A1 (en) * 2004-02-17 2010-09-09 University Of Florida Surface topographies for non-toxic bioadhesion control

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6551355B1 (en) * 1998-08-14 2003-04-22 Cambridge Scientific, Inc. Tissue transplant coated with biocompatible biodegradable polymer
US6497729B1 (en) * 1998-11-20 2002-12-24 The University Of Connecticut Implant coating for control of tissue/implant interactions
US20100226943A1 (en) * 2004-02-17 2010-09-09 University Of Florida Surface topographies for non-toxic bioadhesion control

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014160060A1 (fr) * 2013-03-14 2014-10-02 Cell and Molecular Tissue Engineering, LLC Capteurs, canules, collerettes et treillis chirurgical revêtu, et systèmes et procédés correspondants
US10130288B2 (en) 2013-03-14 2018-11-20 Cell and Molecular Tissue Engineering, LLC Coated sensors, and corresponding systems and methods
US10405961B2 (en) 2013-03-14 2019-09-10 Cell and Molecular Tissue Engineering, LLC Coated surgical mesh, and corresponding systems and methods
US11491001B2 (en) 2013-03-14 2022-11-08 Cell and Molecular Tissue Engineering, LLC Implantable devices coated with extracellular matrix
US9717583B2 (en) 2014-03-13 2017-08-01 Cell and Molecular Tissue Engineering, LLC Sensors, cannulas, collars and coated surgical mesh, and corresponding systems and methods
CN111407744A (zh) * 2020-01-19 2020-07-14 绍兴文理学院元培学院 一种枸橼酸托法替布长效缓释微球的制备方法
WO2023129438A1 (fr) * 2021-12-28 2023-07-06 Wisconsin Alumni Research Foundation Compositions d'hydrogel destinées à être utilisées dans le cadre de la déplétion de macrophages associés à une tumeur
WO2023137263A1 (fr) * 2022-01-13 2023-07-20 Verily Life Sciences Llc Véhicules d'administration de médicament, procédés de production de véhicules d'administration de médicament, et procédés d'utilisation de véhicules d'administration de médicament

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