WO2016178251A2 - Dispositif implantable de protection embolique recouvert d'une maille polymère biorésorbable à élution de médicament - Google Patents

Dispositif implantable de protection embolique recouvert d'une maille polymère biorésorbable à élution de médicament Download PDF

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Publication number
WO2016178251A2
WO2016178251A2 PCT/IN2016/050130 IN2016050130W WO2016178251A2 WO 2016178251 A2 WO2016178251 A2 WO 2016178251A2 IN 2016050130 W IN2016050130 W IN 2016050130W WO 2016178251 A2 WO2016178251 A2 WO 2016178251A2
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bioresorbable
mesh
drug
embolic
mesh according
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PCT/IN2016/050130
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WO2016178251A3 (fr
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Rajesh VAISHNAV
Rohit BHANDERI
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Nano Therapeutics Pvt. Ltd.
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Publication of WO2016178251A2 publication Critical patent/WO2016178251A2/fr
Publication of WO2016178251A3 publication Critical patent/WO2016178251A3/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
    • 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
    • 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
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
    • 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
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment

Definitions

  • This invention relates to embolic protection device. More particularly, the invention relates to drug eluting bioresorbable polymer mesh covered embolic protection stents that are suitable for implantation into a patient's body lumen, such as a blood vessel or coronary artery, to maintain the patency thereof.
  • Vascular stents are particularly useful in the treatment of atherosclerotic stenosis in arteries and blood vessels. Stenting is a routine procedure for the patients suffering with ischemic heart disease or coronary heart disease, to open up the clogged artery that caused the attack.
  • Standard stents are not engineered for patients with acute coronary syndrome which is also known as myocardial infarction (MI) or acute heart attack patients. They are designed for treating stable angina patients whose occlusion is different from that of an occlusion in a heart attack patient.
  • MI myocardial infarction
  • the plaque or thrombus is unstable and often breaks up causing downstream blockages, some of which can be fatal in a significant portion of heart attack patients.
  • Thrombus embolization during percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), continues to be a major drawback leading to micro vascular obstruction and diminishing myocardial perfusion, leading to increase infarct size, reduces the recovery of ventricular function, and thus increases mortality.
  • PCI percutaneous coronary intervention
  • EPDs carotid artery stenting
  • CAS carotid artery stenting
  • a variety of embolic protection devices have been developed to address this issue, which includes a) a distal occlusion balloon; b) distal filter devices; and c) proximal protection devices with and without flow reversal.
  • EPDs embolic protection devices
  • proximal protection devices and distal protection devices has been introduced in the last decade to address this clinical problem.
  • PCI percutaneous coronary intervention
  • distal protection devices are requirement of distal "landing zone,” imperfect deliverability, suboptimal protection, lack of adjacent (between the target lesion and the EPD) side branch protection, device clogging, impaired flow, and device-related vessel spasm or injury.
  • Filters although, easier to use by less experienced operators, are only "partially" protective, allowing particles smaller than their pore sizes to pass through them and to the brain. Further, these filters can occasionally be difficult to retrieve, and also, if the filter becomes full, the overflowing debris must be removed or aspirated separately to avoid spilling the contents of the filter during retrieval.
  • proximal protection devices require a proximal "landing zone,” which results in a "working area” that is neither perfuse nor visualized, and can potentially cause proximal injury or proximal embolization involving side branches emerging between the EPD and the target lesion.
  • the efficacy of proximal EPDs is dependent on the absence of such side branches or collateral vessels between the EPD and the target lesion, which is often not the case.
  • Embolic protective mesh device comprises small apertures, which is often deployed with a stent to prevent restenosis through the larger metal stent apertures. While often preventing restenosis, mesh covered stents cause a significant increase in other life-threatening hazards.
  • Critical blood component such as platelets are sticky, irregularly shaped, that promote blood clotting and readily sense, aggregate around, and stick to, clumps of free floating endothelial cells.
  • An embolism of aggregated platelets and endothelial cells presents a health threat that can form at any time following mesh covered stent implantation (nondrug implant), causing an estimated 10 % of all mesh covered stent recipients to eventually develop necrosis of vital organs and lead to the death of the recipient.
  • Embolic protective filter implant device causes neo-intimal hyperplasia due to vessel wall injury and also the absence of anti-proliferative drug causes restenosis same as a bare metal vascular implant. Even with drug eluting vascular implant, the problem of late thrombosis in the absence of longer anti-platelet drug therapy still exists.
  • the drug-eluting bioresorbable polymer mesh covered stent although reduces restenosis more than the non- eluting mesh covered stents, however, may pose even greater threat of embolic death than the nondrug-eluting stents.
  • bioresorbable/Bioabsorbable vascular implants are invented in the prior art, however, with restrictive radial strength.
  • the objective of the invention is to develop drug eluting bioresorbable polymer mesh Covered Embolic Protection Stent that will eliminate the disadvantages associated with the current embolic protection devices in the market.
  • the instant invention provides drug eluting bioresorbable polymer mesh covered embolic protective Stent that has the potential of serving as a "built-in” and temporary EPD till the revascularization with enhanced bioavailability of therapeutic agents and bio absorption of Embolic protective mesh.
  • the biocompatible/bioresorbable/biodegradable materials as referred herein means and include the materials that dissolve in the body once their purpose has been served.
  • the invention provides a drug eluting embolic protection device which comprises;
  • a metallic stent configured to be positioned in body lumen
  • bioresorbable polymer mesh cover to be placed over the stent co-axially, fabricated from an oriented bioresorbable polymeric monofilament of diameter in the range of 15 to 50 ⁇ , knitted into expandable mesh structure having longitudinal aperture from 100 to 300 ⁇ with transverse aperture from 100 to 250 ⁇ ,
  • the polymeric mesh cover is coated abluminmusly with at least one drug selected from the group consisting of antiproliferative drug; antithrombin and antiplatelet dispersed in polymeric matrix to provide sustained release and to prevent plaque dislodgement and blocks debris (Emboli shower) from entering the bloodstream during and post stenting procedure.
  • at least one drug selected from the group consisting of antiproliferative drug; antithrombin and antiplatelet dispersed in polymeric matrix to provide sustained release and to prevent plaque dislodgement and blocks debris (Emboli shower) from entering the bloodstream during and post stenting procedure.
  • a new strategy has been developed in with respect to current invention to reduce the risk of distal embolization, restenosis & late thrombosis during percutaneous intervention.
  • We designed the system using a hybrid shell design cobalt chromium-metal stent covered with an ultrathin flexible drug eluting bioresorbable polymeric mesh that is anchored to the external surface of the struts. During stent deployment, the mesh stretches and slides over the expanded stent struts, traps the thromboembolic debris underneath the fiber net and isolates the plaque/prothrombotic intimal components from the blood stream.
  • the bioresorbable polymer mesh having capability to sustain the elute of antiproliferative drug used to prevent restenosis and elute antiplatelet drug to eliminate late thrombosis.
  • the platform of the therapeutic agent is designed to degrade as and when revascularisation occurs. These characteristics make this device very attractive for any intervention where thromboembolic complications might affect procedural success.
  • Figure 1 depicts hybrid design of the stent
  • FIG. 2 shows the flowchart depicting construction of bioresorbable mesh fiber monofilament using the combination of PLA and PCL polymers
  • FIG. 3 shows proprietary dedicated mandrel
  • Figures 4 and 5 depicts SEM images of drug eluting mesh covered stent
  • Figure 6 depicts in vitro analysis of drug eluting bioresorbable polymer mesh covered stent which includes drug release study of antiproliferative drug and antiplatelet drugs along with in-vitro degradation of bioresorbable polymer mesh and radial strength of device.
  • the invention describes drug eluting bioresorbable polymer mesh covered embolic protective Stent that has the potential of serving as a "built-in” and temporary EPD till the revascularization with enhanced bioavailability of therapeutic agents and bio absorption of Embolic protective mesh.
  • the invention provides a drug eluting embolic protection device which comprises;
  • a metallic stent configured to be positioned in body lumen
  • bioresorbable polymer mesh cover to be placed over the stent co-axially, fabricated from an oriented bioresorbable polymeric monofilament of diameter in the range of 15 to 50 ⁇ , knitted into expandable mesh structure having longitudinal aperture from 100 to 300 ⁇ with transverse aperture from 100 to 250 ⁇ ,
  • the polymeric mesh cover is coated abluminmusly with at least one drug selected from the group consisting of antiproliferative drug; antithrombin and antiplatelet dispersed in polymeric matrix to provide sustained release and to prevent plaque dislodgement and blocks debris (Emboli shower) from entering the bloodstream during and post stenting procedure.
  • at least one drug selected from the group consisting of antiproliferative drug; antithrombin and antiplatelet dispersed in polymeric matrix to provide sustained release and to prevent plaque dislodgement and blocks debris (Emboli shower) from entering the bloodstream during and post stenting procedure.
  • the invention provides unique dual mechanism that comprises sustained delivery of anti-proliferative drug, anti-thrombic and antiplatelet drug coupled with trapping the embolic debris beneath the micro level bioresorbable mesh.
  • the drug eluting embolic protective mesh minimizes body response; promote revascularization and eliminates the prothrombotic intima or embolic components from the blood stream makes it an attractive device for any intervention where embolic complications can affect procedural and clinical success.
  • Drug Eluting Bioresorbable Polymer mesh covered stent system comprises a novel combination of a drug eluting Bioresorbable polymer mesh covered coronary stent which is designed to prevent plaque dislodgement and blocks debris (Emboli shower) from entering the bloodstream during and post procedure.
  • a drug eluting Bioresorbable polymer mesh covered coronary stent which is designed to prevent plaque dislodgement and blocks debris (Emboli shower) from entering the bloodstream during and post procedure.
  • the stent material can be selected from the group consisting of Stainless Steel, CoCr, Nitinol or Bioresorbable polymer.
  • the stent with a hybrid design having partial closed cells at top and bottom has been provided to facilitate ease in attaching a drug eluting polymeric mesh.
  • Normally stent design comprises either open cell or closed cell.
  • a metal stent having partial closed cells design with multiple connectors is provided for uniform expansion of the stent.
  • optimum cell size and shape are provided to minimize the vessel wall injury which normally occurs due to intracellular balloon protrusion; better vessel wall coverage, lower strut thickness to minimize local mechanical injury to endothelium.
  • the hybrid design of the stent according to the invention is shown in figure 1.
  • the stents with other designs can also be used to attach the drug eluting polymeric mesh provided according to the invention.
  • the bioresorbable and bio-compatible polymer materials used in the preparation of micro mesh may be one or more polymers from selected from the group consisting of PLA or any other degradable co-polymeric combination, such as poly lactic-co-polyglycolic ("PLGA”), polycaprolactone (“PCL”), polygluconate, polylactic acid-polyethylene oxide copolymers, poly(hydroxybutyrate), polyanhydride, poly-phosphoester, poly(amino acids), poly-L-lactide, poly-D- lactide, polyglycolide, poly(alpha-hydroxy acid) and combinations thereof.
  • PLA poly lactic-co-polyglycolic
  • PCL polycaprolactone
  • PLA polygluconate
  • polylactic acid-polyethylene oxide copolymers poly(hydroxybutyrate)
  • polyanhydride poly-phosphoester
  • poly(amino acids) poly-L-lactide
  • poly-D- lactide polyglycolide
  • micro mesh as provided in the present invention can also be of other biodegradable and non-biodegradable polymers.
  • a bioresorbable mesh covered stent in accordance with present invention comprises either natural fiber monofilaments or an injection moulded or extruded fenestrated tube formed from the blends of at least two bioresorbable, biocompatible polymers.
  • These polymers may include, but are not limited to poly-L- lactide (PLLA), poly-D, L-lactide (PDLA) and poly-8-caprolactone (PCL).
  • the Drug Eluting Bioresorbable Polymer mesh covered stent system comprises an ultra-thin bioresorbable polymer mesh (emboli protective mesh), wrapped around the Cobalt Chromium (Co-Cr) L605 stent.
  • the Embolic protective mesh is composed of a micron-level -fiber knitted mesh of Bioresorbable oriented polymer "PLA”, engineered in an optimal geometric configuration and designed for utmost flexibility while retaining strength characteristics of the fiber material.
  • the mesh is designed to expand seamlessly & uniformly when the stent is deployed radially, without affecting the structural integrity of the stent; thereby prevents plaque detachment during and post procedure of stenting.
  • the Embolic Protective mesh is fabricated from an oriented PLA monofilament as a pre patterned micro knit fabric by circular micro knitting technology.
  • the oriented PLA monofilament has diameter in the range from 15 to 50 ⁇ .
  • the tolerance diameter of monofilament will be +/- 2 ⁇ (0.002 mm).
  • the PLA monofilament is fabricated from medical grade PLA polymer granule through micro extrusion system and orientation is performed by heating under oven, stretching & heating process.
  • An expansible stent operatively associated with the stent mesh, wherein, the diameter of bioresorbable fiber has a property of forming a substantially stable layer covering endothelial cells, thus reducing platelet aggregation.
  • the construction of bioresorbable mesh fiber monofilament using the combination of PLA and PCL polymers is described in figure 2.
  • the PLA and PCL polymers are first dry blended under an inert atmosphere, then extruded in a rod form.
  • granules of PLA and PCL are dry -blended with a PLA/PCL ratio of 90: 10 to 99.1 :0.9.
  • the blended PLA and PCL polymer rod is pelletized and then dried.
  • the dried polymer pellets are then extruded to form a coarse monofilament which is quenched into a final monofilament with an average diameter from approximately 0.05 mm to 1 mm which is further proceed to make high tensile monofilament fiber having the diameter of 0.015 to 0.050 mm (+/- 0.002).
  • the invention provides a method of fabricating monofilament using oriented monofilament fabrication accessory in conjunction with 20mm extruder.
  • Monofilament head & die mounted onto extruder output flange for downward extrusion through die assembly with one hole of suitable diameter to produce 30- 35 ⁇ thickness monofilaments.
  • the formed monofilament is passed through quench tank made of SS, having the measurements 250 mm wide x 250 mm deep x 500 mm long.
  • Monofilament moves to the first godet (taken up) set up comprise 3 godet rolls with one rubberized pressure roll (pneumatically operated) provided for conveying monofilament at a constant speed. The rolls are driven by 0.37 kW AC geared motor, 3 phase, 50 cycles with frequency inverter control to reduce the diameter of monofilament.
  • the monofilament is then entered into first orientation oven having the measurements 1000 mm long x 200 mm wide, fully insulated hot air oven mounted on steel frame having steel sheathed electrical resistance air heaters, and 1 No. high-velocity blower fitted with 0.18 kW AC motor, 2880 rpm, 3 phase, 50 cycles to assist stretching of the monofilament.
  • the monofilament is then entered into second godet (stretching) which comprises 5 godet rolls with pneumatically controlled pressure rolls on 1st and the 5th roll of godet assembly, driven by 0.75 kW AC geared motor, 3 phase, 50 cycles with frequency inverter control.
  • the monofilament is then entered into second orientation Oven which is having measurements 1000 mm long x 200 mm wide, fully insulated hot air oven mounted on steel frame having steel sheathed electrical resistance air heaters, and 1 No. high-velocity blower fitted with 0.18 kW AC motor, 2880 rpm, 3 phase, 50 cycles to assist stretching of the monofilament.
  • the monofilament is then finally entered into third Godet (Take-Off) which comprises 3 godet rolls with one rubberized pressure roll (pneumatically operated) provided for conveying monofilament at a constant speed.
  • the rolls are driven by 0.75 kW AC geared motor, 3 phase, 50 cycles with frequency inverter control.
  • Winder which is Single station bobbin, driven by 0.09 kW torque motor to wind oriented monofilament on a spool.
  • the blends of PCL, PL A, PLLA, and PDLLA used for the preparation of the mesh in accordance with the present invention have been found to provide improved process ability and stability when compared to co-polymerization process. Without intending to be bound by this theory, one possible explanation for the improvements in process ability and stability can be attributed to the difference in physical states in which the individual polymers exist once combined.
  • co-polymers are mostly amorphous compositions, but blends of PLA and PCL may exist as different size and shape of semi-crystalline domains of each polymer with a greater percentage of PCL at the surface. Morphology of both domains may be manipulated by thermal treatments. This increased concentration of PCL at the surface is believed to contribute to the blended composition's increased resistance to hydrolytic attack. Control over the morphology of the final polymer blend is an advantage in providing the improved physical and biological properties of the mesh.
  • Circular Knit structures come in two general forms; wefts knit and warp knit. Mesh construction can be dramatically different between the two structures, but the concept of using intermeshing loops of yarn is the same for both.
  • the properties of a weft knitted structure are largely dependent on the interaction of each stitch with its neighbouring stitches in the course and wale directions. The course is the cross direction to the fabric production, while the wale is the parallel direction to the fabric production.
  • the simple weft knit structure is formed by loops created by needles knitting fiber across the width of the fabric with each loop being created by pulling it through the previous loop in the same direction bellow figure. Needle movements are simply up and down and are controlled by a camera. When the needles are in the up position, each weft fiber is fed at an angle to the direction of fabric formation, solitary or multiple ends of fiber can be fed into the mesh at one time but each end knits has the same pattern with no overlap or variation. At a cross-sectional view of the structure, all the loops are bent into the third dimension due to the manner in which loops are pulled through each other.
  • Edge disruption can be prevented through trimming process which is removal of unwanted fiber thread generated after cutting the micro knitted mesh in to required length of pieces. It can be done by plastic welding or soldering to fuse the extended thread after cutting.
  • the proprietary manual trimming process is developed that can prevent disruption from mesh edges at the time of cutting weft knitted bioresorbable mesh.
  • the mesh is cut with sharp knife, screened the monofilament from which whole mesh is formed.
  • the unwanted fiber filament is flushed using medical grade nitrogen or inert gases. Identical end of both meshes is fixed through notch.
  • the whole trimming process is carried out under stereo-microscope beneath laminar air flow environment.
  • Weft knitting of micro-porous mesh structure is performed by circular knitting machine head having 15 to 40 needles, preferably 22 and 30 needles.
  • the aperture size of mesh depends on configuration of knitting head speed (RPM), mesh traction speed (frequency) &fiber initial tension.
  • the single oriented monofilament having a diameter of 15 to 50 ⁇ is knitted into expandable mesh structure with longitudinal aperture from 100 to 300 ⁇ while transverse aperture from 100 to 250 ⁇ , to be mounted on a stent frame structure to prevent embolic debris dislodgment as well as reducing a chance of endothelial cells breaking free as a result of natural pulsatile blood flow.
  • the bioresorbable fiber is treated by means of plasma surface modification to promote bio-absorption and sustained release of therapeutics substance. Tailoring the interface interactions between a Bioabsorbable embolic protective mesh and the surrounding tissue is a capital aspect to consider for the design of medical devices.
  • Bioabsorbable polymer fiber presents suitable mechanical properties for various biological substitutes; however the lack of cell adhesion on their surface is often a problem.
  • the common approach is to incorporate bio-molecules, either by blending or by coupling. But these modifications disrupt polymer intra- and intermolecular interactions leading therefore to a loss of its original mechanical properties.
  • surface modification by glow discharge plasma technique which is known to modify only the surface without altering the bulk properties.
  • This technique has been investigated to promote cell attachment on PLA substrates.
  • N2/H2 microwave plasma treatment has been performed, and the chemical composition of PLA surface has been investigated for the wettability.
  • Plasma modification of the oriented monofilament by amination as above induces an increase in the PLA surface wettability with no significant change in surface roughness.
  • plasma amination of PLA is a promising approach to improve cell behaviour on contact with bioresorbable fiber for vessel implant.
  • monofilaments of other bioresorbable polymers can also be subjected to plasma amination to improve the surface wettability.
  • the polymer fiber is elastic, biocompatible and hemocompatible
  • micro mesh as provided in the present invention can also be of other biodegradable and non-biodegradable polymers.
  • the pharmaceutical agent is eluted from the bioresorbable mesh.
  • the active pharmaceutical agent is eluted from a bioresorbable mesh.
  • the bioresorbable mesh is coated using dip coating, micro spray coating techniques through drug polymer matrix comprising biodegradable polymers.
  • dip coating porous structure is coated using a biocompatible, hemocompatible, bio-stable and/or biodegradable polymer dissolved in an organic solvent to create stable uniform therapeutic layer over the bioresorbable polymer mesh.
  • the bioresorbable polymer mesh is coated abluminusly with proprietary formulation of drug/polymer matrix.
  • the abluminus coating provides batter safety than fully coated bioresorbable mesh.
  • porous structure is mounted on mandrel and micro droplet of therapeutic agent is sprayed upon the porous structure using a biocompatible, hemocompatible, bio-stable and/or biodegradable polymer dissolved in an organic solvent to create stable uniform therapeutic agent layer on bioresorbable mesh.
  • the dose of therapeutic agents are reduced in contrast to normal drug eluting stent because the 'drug eluting mesh' provides more surface area in contact to vessel wall thereby enabling more tissue uptake and thus increases bioavailability with reduced therapeutic dose.
  • the thickness of the drug loaded bioresorbable polymer mesh ranges from about 15 to 50 ⁇ .
  • the invention provides sustained delivery of anti-proliferative drug (Sirolimus), anti-thrombic (Argatroban) & anti-platelet drug (sarpogralate) formulated with biodegradable polymer matrix to target site using bioresorbable mesh cover to be placed on a stent as a drug delivery platform.
  • the sustained drug release is obtained in such a way to inhibit vascular intimal hyperplasia, platelet deposition & platelet aggregation.
  • the pharmaceutical agents such as anti-proliferative Drug (Sirolimus) as well anti-thrombic& anti-platelet drug (Argatroban & sarpogralate) along with polymer matrix are coated only on abluminus surface of bioresorbable mesh which is stent expansible and in contact with vessel lumen to give better bioavailability.
  • the bioresorbable mesh is coated on abluminus surface with proprietary drug polymer matrix layer by layer to achieve endothelial coverage, target drug release and reduced systemic exposer of therapeutic agents.
  • the drug polymer matrix comprises biodegradable polymer, therapeutic agent and vaporizable solvent.
  • the following example illustrates a method for forming different layers of bioresorbable polymeric mesh.
  • a bioresorbable mesh is coated abluminiously in three different layers.
  • the method for formulation of bioresorbable mesh will now be described in detail herein below.
  • Layer l(base layer) is made up of PLLA, Argatroban and Sarpogrelate hydrochloride, which were weighed in mentioned amount in table 1 and dissolved in 70 ml HFIP + 30 ml DCM by blending at inert atmosphere then extruded in a rod form.
  • the polymer v/s drug ratio is 69:31.
  • PLLA as carrier polymer
  • Argatroban act as anticoagulant (thrombin inhibitor)
  • Sarpogrelate Hydrochloride avoid platelet aggregation).
  • Layer 2 (top layer) made up of PLLA and 50:50 PLGA polymers mixture (49:21); Argatroban which act as an anticoagulant (thrombin inhibitor), Sarpogrelate Hydrochloride (avoid platelet aggregation) and limus family drug (antiproliferative agent). Dissolving it in 70 ml Hexafluoro-isopropanol HFIP + 30 ml DCM. Here polymer v/s drug ratio is 70:30.
  • Layer 3 is made up of Shellac polymer which is coated on a mesh by dissolving it in 100 ml of DCM. Formulation content:
  • the Embolic Protective mesh is coated with anti-proliferative Drug (Sirolimus) as well anti-thrombic& anti-platelet drug (Argatroban& sarpogralate) dispersed in a polymer matrix.
  • the anti-proliferative drug selectively stops cell growth, by blocking cell-cycle progression and eventually inhibits Cell Proliferation and the restenosis.
  • the antithrombotic drug prevents deposition, aggregation, activation of platelet at the site of treatment and thrombin formation.
  • the synergistic effects of the drugs along with embolic protective mesh minimize Restenosis and thrombosis compared to any other DES currently available in the market.
  • the drug eluting bioresorbable embolic protective mesh is designed to prevent distal embolization by reducing thrombus and plaque fragments released during and post percutaneous coronary intervention (PCI).
  • PCI percutaneous coronary intervention
  • the objective of this invention is to establish the clinical feasibility, safety and performance during primary PCI for ST-segment elevation myocardial infarction (STEMI), saphenous vein graft (SVG) and coronary artery bypass graft surgery (CABG).
  • the main advantage of this invention lies in coating of micron thickness mesh with therapeutic agents.
  • the present inventors have designed proprietary dedicated mandrel as shown in figure 3 that can hold the knitted mesh with ease and mountable on the coating machine. Accordingly, the bioresorbable polymer mesh mounted on a mandrel using the hypodermic needle. The mandrel is inflated with inflation device so that mesh can hold on the mandrel at the time of coating. The mandrel pressure is locked and mounted the mandrel on the coating machine stage and adjusted nitrogen pressure, flow rate and angle of the micro-spray gun. Once coating process completed the mesh is removed carefully from the mandrel by applying negative pressure to the mandrel. The coating surface integrity is checked under a stereoscopic microscope and the coated mesh is stored in a vial and the vial is placed in a vacuum oven for the removal of residual solvent. The therapeutic agent content is determined by HPLC loading method with respect to loading requirement.
  • the micro spray coating technique is used to coat the drug dissolved in polymer matrix, layer by layer.
  • the base layer comprises anti-platelet &anti-thrombic drug polymer matrix having capability to prevent platelet deposition and promote healing of vessel endothelial cell.
  • the top layer comprises combination of drugs such as anti-proliferative, anti-thrombic as well as antiplatelet category.
  • the drug dose for base layer is from 0.4 to 0.7 ⁇ g /mm2 & top layer dose 0.5 to 0.8 ⁇ g /mm2.
  • the formulation of drug polymer matrix is designed to give sustained drug release in such a way that prevents vascular intimal hyperplasia, platelet deposition & aggregation.
  • the Drug eluting bioresorbable mesh is in coaxial association with the stent by wrapped around the stent structure and attached to an outside of the stent structure by bioresorbable micro fiber threading technique.
  • the coaxial association includes the knitted stent jacket being sewed, adhered, glued, folded, or sutured to the stent.
  • the combination of PLA and PCL polymeric mesh wrapped around cobalt chromium stent according to the invention which helps to diffuse the stent pressure and reduces injury to the vessel wall and lower the likelihood of restenosis.
  • the Embolic Protective mesh as provided in the present invention starts hydrolytic degradation after endothelialisation of lumen and generates soluble monomer (e.g., L-lactate), which is converted into pyruvate and eventually enters the Krebs cycle and is further converted into carbon dioxide and water. These final products are excreted from the body through the kidneys or lungs, which results in complete bioresorption of the drug coated mesh.
  • soluble monomer e.g., L-lactate
  • the metal stent as used in the invention has circumferential closed cells design with multiple connectors for uniform expansion; Optimum cell size and shape result in minimum vessel wall injury due to intra cellular balloon protrusion, better vessel wall coverage, and lower strut thickness to minimize local mechanical injury to endothelium.
  • the drug coated Bioresorbable Polymer mesh covered stent provided according to the invention is crimped onto the PTCA or PTA Balloon Delivery catheter. It provides the means for carrying the stent through the coronary vasculature and for proper positioning of the stent at site of intervention.
  • the drug coated Bioresorbable Polymer mesh covered stent according to the invention can be delivered using rapid exchange delivery system or over the wire delivery system.
  • the anti-proliferative drugs used for coating the mesh can be selected from Sirolimus, Everolimus, Paclitaxel, actinomycin D (ActD), taxol, 5-FU, daunomycin, mitomycin and dexamethasone.
  • the anti-platelet and anti-thrombic drugs can be direct acting drugs like Argatroban, sarpogrlate.
  • the other anti-platelet and anti-thrombic drugs which include sodium heparin, low molecular weight heparin, hirudin, recombinant hirudin, forskolin, vapiprost, prostacyclin and prostacyclin analogs, dextran, D- phe-pro-argchloromethylketone, dipyridamole, glycoprotein Ilb/IIIa platelet membrane receptor antagonist and thrombin inhibitor.
  • the anti-proliferative drug (Sirolimus), anti-thrombic (Argatroban) & anti-platelet drug (sarpogralate) are formulated in biodegradable polymer matrix as a drug delivery platform, coated on bioresorbable mesh placed over the stent, so as to deliver the drugs in sustained manner at target site.
  • the sustained drug release is obtained in such a way to inhibit vascular intimal hyperplasia, platelet deposition & platelet aggregation.
  • the drug eluting bioresorbable mesh covered stent according to the invention is provided with an anti-proliferative agent to minimize restenosis as well as risk of target lesion revascularization (TLR) and anti-platelet as well as anti-thrombic agents which are released in a sustained manner for a time period of not less than 3 month.
  • TLR target lesion revascularization
  • the sustained drug release is purely based on nature of therapeutic substance and carrier polymer.
  • the encapsulation capacity of anti-thrombin& anti platelet drug is poor due to hydrophilic nature; however, the release of both the drugs is very fast.
  • the polymers like PVB [poly (vinyl acetyl-co-vinyl alcohol-co vinyl acetate)] alone or with PLLA, PLGA, PCL, PDLLA polymer matrix can be used.
  • the optional primer layer of PVB can be applied on the mesh surface to improve the adhesion of the drug-polymer layer on the mesh surface.
  • the additional topcoat layer of PVB, PVA, PVP or Shellac can be applied which may serve as a release rate limiting membrane which further controls the rate of release of the drug.
  • the anti-proliferative drug can be released up to 25-30 days from the biodegradable mesh coated with drug polymer layer by layer formulation which prevents restenosis as well target lesion revascularization while anti-platelet &anti-thrombic agent can release at a slow rate to prevent sub- acute thrombosis up to 1-3 months.
  • the degradation of PLA starts after complete endothalisation of target site.
  • the mesh is completely degraded within 4 to 6 month after implantation.
  • the current Bioresorbable mesh is composed of either a polymer or bioresorbable metal alloy. Numerous different polymers are available, each with different chemical compositions, mechanical properties, and subsequently bio absorption times (table 1). The most frequently used polymer in the current generation of Bio Resorbable mesh is PLLA. PLLA is already in widespread clinical use with applications such as resorbable sutures, soft-tissue implants, orthopaedic implants, and dialysis media. The key mechanical traits for candidate material in coronary indications include high-elastic module to impart radial stiffness, large-break strains to impart the ability to withstand tensile strength from the crimped to expanded states of metal platform. Bioresorbable Stent developers look to increase stent strut dimensions to compensate for mechanical shortcomings of bioresorbable materials. As bioresorbable mesh is good alternative compare to bioresorbable stent having lower crossing profile and superior radial strength same as metal platform.
  • the coated mesh is secured on the outer surface of metal or polymeric stent scaffold which keep lumen open at site of atherosclerosis or blockage artery.
  • the securing of mesh on stent is achieved at proximal and distal end through the separate filament threading with same material as of mesh.
  • the thickness of drug eluting bioresorbable polymer mesh covered stent including strut with mesh cover ranges from about 75 to 150 ⁇ .
  • the drug coated Bioresorbable Polymer mesh covered stent provided according to the invention is indicated for improving luminal diameter in vessels with reference diameter greater than 2.50mm having lesion length greater than 8 mm and for providing embolic protection in the patients such as:
  • Symptomatic coronary artery disease due to culprit lesion in saphenous vein graft Treatment of coronary lesion in patients undergoing primary or rescue PCI for acute ST-segment elevation myocardial infarction (STEMI);
  • Symptomatic peripheral artery disease due to discrete de novo or restenosis lesion in native coronary artery; and also indicated for the improvement of the lumen diameter of carotid arteries in patients considered at high risk for adverse events from carotid endarterectomise who require percutaneous carotid angioplasty and stenting for occlusive artery disease.
  • Crimping the stent for insertion is relatively simple; 2. Profile of the crimped stent is small;
  • Mesh covered stent substantially has a minimal influence on the mechanical properties of the stent during the delivery and expansion
  • Mesh does not require folding during crimping when the coverage area of the stent is about 9%, or about 10%, or about 11%, or about 12% in balloon expanding stent. In general the coverage area is less than 15%.
  • the table 2 provides support that the above noted parameters of bioresorbable mesh coverage on a stent can be easily attained in the present invention using a fiber diameter of about 20 micrometers.
  • the present invention provides bioresorbable polymeric mesh covered stent configured to be positioned in a vessel, and a knitted stent mesh including an expansible mesh structure having a coverage area of less than 15%, having approximate aperture diameters greater than 20 micrometers.
  • the drug eluting bioresorbable polymer mesh covered stent structure involves a retracted state and an expanded state, and further wherein in the sent expanded state, the expansible cross section "mesh" structure characterizes gaps, having a base focus measurement, which is more prominent than around 150 ⁇ , hence minimizing events of a solitary endothelial cell holding fast to more than one fiber, crosswise over one of the gaps, and diminishing a possibility of endothelial cells breaking free as an after effect of common stent throb with blood stream.
  • embolic shower protection gadget which is situated only at during the stenting procedure downstream or upstream from the treatment area, the thought being that the protection gadget will trap debris which tumbles from the blood vessel walls amid the stenting system.
  • the anti-proliferative medication discharges from a bioresorbable cross section which forestalls neo- intimal hyperplasia in light of vessel harm amid a standard implantation system.
  • the coated mesh cover in accordance with the invention reduces platelet aggregation at the site of embolic trap because of the sustained release of the antiplatelet drug.
  • An additional advantage of using implanted bioresorbable mesh structure instead of a conventional embolic shower protection device is that it remains in place for up to 4 months after the implanting procedure.
  • the absorption process of bioresorbable mesh is different from other drug eluting stent; it starts with nourishing the vessels by which it prevents the late thrombosis.
  • the bioresorbable mesh according to the invention effectively works through unique dual mechanism which comprises a) sustaining the delivery of antiproliferative drug (Sirolimus), anti-thrombic (Argatroban), anti-platelet drug (sarpogralate) and b) trapping the embolic debris beneath the micro level bioresorbable mesh.
  • the mesh cover further minimizes body response; promotes revascularization and isolates the pro-thrombotic intima or embolic components from the blood stream and thus makes it an attractive device for any intervention where embolic complications can affect procedural and clinical success.

Abstract

L'invention concerne des stents de protection embolique recouverts d'une maille polymère biorésorbable à élution de médicament qui sont appropriés pour être implantés dans une lumière corporelle d'un patient, de type vaisseau sanguin ou artère coronaire, pour maintenir la perméabilité de ceux-ci.
PCT/IN2016/050130 2015-05-06 2016-05-06 Dispositif implantable de protection embolique recouvert d'une maille polymère biorésorbable à élution de médicament WO2016178251A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108641074A (zh) * 2018-05-23 2018-10-12 重庆大学 生物可降解材料及其制备方法和应用
WO2019138416A1 (fr) * 2018-01-12 2019-07-18 Meril Life Sciences Pvt Ltd Endoprothèse bi-stratifiée à maillage biodégradable et son procédé de fabrication
WO2021135057A1 (fr) * 2019-12-31 2021-07-08 元心科技(深圳)有限公司 Stent périphérique résorbable et son procédé de préparation
WO2022172891A1 (fr) * 2021-02-10 2022-08-18 テルモ株式会社 Élément à demeure in vivo et son procédé de fabrication

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105018B1 (en) * 2002-12-30 2006-09-12 Advanced Cardiovascular Systems, Inc. Drug-eluting stent cover and method of use
US10070977B2 (en) * 2005-05-24 2018-09-11 Inspire M.D. Ltd Stent apparatuses for treatment via body lumens and methods of use
CA2744906A1 (fr) * 2007-11-29 2009-06-04 Gregg A. Jackson Dispositifs et compositions contenant de la progesterone

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019138416A1 (fr) * 2018-01-12 2019-07-18 Meril Life Sciences Pvt Ltd Endoprothèse bi-stratifiée à maillage biodégradable et son procédé de fabrication
CN108641074A (zh) * 2018-05-23 2018-10-12 重庆大学 生物可降解材料及其制备方法和应用
CN108641074B (zh) * 2018-05-23 2021-01-29 重庆大学 生物可降解材料及其制备方法和应用
WO2021135057A1 (fr) * 2019-12-31 2021-07-08 元心科技(深圳)有限公司 Stent périphérique résorbable et son procédé de préparation
WO2022172891A1 (fr) * 2021-02-10 2022-08-18 テルモ株式会社 Élément à demeure in vivo et son procédé de fabrication

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