Endoprosthesis structures having supporting features

(54) Title: ENDOPROTESE (30) Unionist Priority: 19/01/2007 us 60/885700 (73) Owner (s): Elixir Medicai Corporation (72) Inventor (s): BrettCryer, Howard Huang, John Yan, Sirhan Motasim , Vinayak Bhat (74) Attorney (s): Momsen, Leonardos & CIA.

(86) International Order: pct 11S2008051497 of 18/01/2008 (87) International Publication: wo 2008 / 089446of 24/07/2008 (57) Abstract: ENDOPROTESE. An endoprosthesis includes a plurality of serpentine rings having support characteristics that increase the strength of the rim, inhibit recoil, and provide an increased surface area. The support characteristics can be formed between adjacent axial reinforcements of serpentine rings or they can be positioned between axial lengths joining the serpentine rings together.

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• 18 “ENDOPROSTHESIS”

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to stent designs, in particular biodegradable and non-biodegradable stents and grafts, which are adapted to be implanted in the lumen of the patient's body, such as coronary artery or other blood vessel or body lumen. Stents are particularly useful in the treatment of atherosclerotic stenosis in arteries and veins.

Stents are usually tubular-shaped devices that work to keep open or strengthen a segment of a blood vessel or other lumen in the body such as a coronary artery, carotid artery, saphenous vein graft, or femoral artery. They are also suitable for supporting and maintaining a dissected arterial lining that can occlude the passage of fluid, to stabilize plaque, or to support bioprosthetic valves. Stents can be formed from various materials, particularly polymeric and / or metallic materials, and can be non-degradable, biodegradable, or be formed from both degradable and non-degradable components. Stents are typically delivered to the target area within the body's lumen using a catheter. With expandable balloon stents, the stent is mounted to a balloon catheter, navigated to the appropriate area, and the expanded stent inflating the balloon. A self-expanding stent is delivered to the target area and released, expanding to the required diameter in order to treat the disease. Stents can also elute various drugs and pharmacological agents.

Referring to Fig. 1, a common model employed in the present cardiovascular stents comprises a plurality of serpentine rings 12 joined by short axial connections 14. The serpentine rings comprise axial reinforcements 16, where circumferentially adjacent reinforcements are connected by crowns 18 that act as joints to allow circumferential expansion of individual rings 12. These models can be used for both degradable and non-degradable stents and other endoprostheses.

In the design of stents and other endoprostheses, several competing objectives must be addressed. For coronary artery stents, it is generally desirable to be able to collapse the stent to minimize the cross-sectional area for delivery while maximizing the surface area of ​​the stent after expansion. A maximized surface area provides both increased barrier support to reduce vessel retraction and a greater ability to release drugs when using drug-coated stents. Another design objective is to allow the stent to be compressed with minimal force while still maintaining good rim strength after expansion to still resist retraction of the vessel.

Thus, a stent design or stent material is needed that increases radial or rim strength, reduces vessel retraction after implantation, provides an increased surface area while maintaining or reducing the size and mass of the stent. The present invention meets at least some of these requirements.

2. Description of the Background Art

US patent 6,773,455 describes a stent having serpentine rings axially connected through internal expansion elements. US 2003/0093143 describes a stent comprising box structures circumferentially joined by U-shaped connectors. US 2003/0144729 describes a stent comprising axially spaced streamer bands connected by furcula-shaped connectors. See also US 7,291,166 and US 6,896,695.

SUMMARY OF THE INVENTION

The present invention provides an endoprosthesis, such as a stent, graft or other luminal prosthesis, of the scaffold type, which is used to treat vascular and other luminal conditions. The endoprosthesis includes support features or elements added to a base structure. The base structure of the stent is formed by a series of circumferential serpentine rings connected directly to each other or with at least one connection or support, usually as shown in Fig. 1 discussed above, where each ring comprises multiple expansion segments constructed of crowns and supports. In accordance with the present invention, the base structure is reinforced with support features that can increase radial strength and / or reduce the expanding retraction of the stent compared to the structure without the support features. Supporting features can contain varying types of shapes such as an I shape, C shape, V shape, U shape, S shape, Y shape, M shape, W shape, Z shape, Z shape, spiral or other types. In a first embodiment, the support features connect at least some of the adjacent reinforcements. In another embodiment, at least one support functionality connects to at least one axial connection connection.

Thus, in accordance with the present invention, an endoprosthesis comprises a plurality of circumferentially expandable serpentine rings, axial connections joining adjacent rings, and support features. Circumferentially expandable serpentine rings each include axial reinforcements joined by crowns, where the crowns act as joints allowing the reinforcements to spread as the ring opens circumferentially. The axial connections connect the adjacent rings in a serpentine connecting at least some of the crowns to the rings. The support features extend between at least some of the adjacent reinforcements of at least some of the serpentine rings, where the support features lengthen and the reinforcements remain substantially undeformed as the ring expands circumferentially.

The stent can be constructed from a variety of conventional stent materials and can be either balloon expandable, self-expanding, or a combination of both. The serpentine rings of the self-expanding endoprostheses will be sufficiently elastic so that they can be limited in a small cross-sectional area during delivery and released into the vasculature or other lumens of the body to assume a circumferentially expanded configuration. In contrast, the serpentine rings of the balloon-expandable endoprostheses will be sufficiently malleable so that they can be expanded circumferentially by applying a radially outer force from within the rings, typically using an inflatable balloon or other expandable structure. Particularly preferred stent materials include metals and alloys such as iron, zinc, steel, cobalt-chromium, nickel-titanium, as well as polymers such as polylactides, polycaprolactone, polyethylene carbonate, polylactide-glycolide, polylactide-trimethylenecarbonate copolymers, and similar. Particular materials and manufacturing methods are described in a jointly owned order 11 / _ (Agent Reference No. 022265000520US), filed on the same day as this order.

Supporting features may have a variety of specific configurations or shapes that are selected to elongate or otherwise expand as the endoprosthesis serpentine rings are expanded. Exemplary support feature configurations include U-shaped connectors, V-shaped connectors, S-shaped connectors, spiral-shaped connectors, W-shaped connectors, N-shaped connectors, Z-shaped connectors, and similar. In order to increase or control the exposed surface area of ​​the endoprosthesis, the support structures can have variable widths, for example the spiral-shaped connectors can include disk or ring-shaped cores to improve or control the surface area. While the width and cross-sectional area of ​​a support feature will generally be less than the width and cross-sectional area of ​​the serpentine rings so that the expansion of the support features will not deform or flex the main ring structure, it will be It is possible to increase the area of ​​a support functionality by providing deflection points that allow the support functionality to deform yielding preferably with respect to the serpentine rings. For example, portions of a support feature can be notched so that they sag first as the stent is expanded.

In some embodiments, one or more support features can be arranged between at least some of the adjacent reinforcements. When a single support feature is employed, it will usually extend between the half-points in the adjacent reinforcements, but in other cases, it could be arranged closer to the ends of the reinforcements that are not connected together with a crown. In cases where two or more support features are provided between adjacent pairs of reinforcements, they can be located at any point along the length of the reinforcement, typically with one being located close to the midpoint and another being located close to the free ends (ie ie, ends that are not connected together with the crown).

Axial connections will generally comprise short linear beams, where the linear beams are axially aligned with the stent axis. In other cases, linear beams can be aligned at an acute angle relative to the axis, typically from zero degrees to 45 degrees.

Endoprostheses in accordance with the present invention may comprise a plurality of circumferentially expandable serpentine rings joined by axial connections, where the support features extend between at least some adjacent axial connections between adjacent serpentine rings. These support features between adjacent axial connections stretch as the rings expand circumferentially. Exemplary support features that are connected between adjacent axial connections include serpentine connectors, usually where folded portions of the connectors extend within the region between adjacent axial reinforcements. Alternatively, the connectors could comprise "box" connectors having lengths extending symmetrically that project in the regions between axial reinforcements.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates a conventional serpentine ring stent.

Figs. 2 A and 2B illustrate a first embodiment of the endoprostheses of the present invention having U-shaped connectors between adjacent axial reinforcements in a serpentine ring.

Fig. 3 illustrates the stent structure of Figs. 2A and 2B after expansion.

Figs. 4 and 5 illustrate an exemplary V-shaped connector as a support feature where the connector can be oriented towards the crown (Fig. 4) or away from the crown (Fig. 5).

Fig. 6 illustrates an exemplary S-shaped connector as the support structure.

Figs. 7-9 illustrate exemplary spiral-shaped support structures, where Fig. 7 illustrates an overturned spiral, Fig. 8 illustrates a spiral having a ring core, and Fig. 9 illustrates a spiral having a disk core.

Fig. 10 illustrates an exemplary stent structure having U-shaped connectors located near the opening end of the serpentine structure.

Figs. 11 and 12 illustrate exemplary stent structures having pairs of support features between adjacent axial reinforcements.

Fig. 13 illustrates a complex support feature having elongation portions aligned both radially and axially.

Figs. 14, 15A and 15B illustrate a U-shaped support feature having notch-like elastic points that control a two-stage expansion, as shown in Figs. 15A and 15B.

Figs. 16 and 17 illustrate exemplary stent designs where adjacent serpentine rings are connected by angled axial connections. Fig. 16 further illustrates an M-shaped connector as a support functionality, while Fig. 17 illustrates an N-shaped connector as a support functionality.

Figs. 18 and 19 illustrate support features connecting adjacent axial connections, where Fig. 18 illustrates a serpentine model, Fig. 19 illustrates a box model connector.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an endoprosthesis, such as a stent, which is used to treat vascular or other luminal conditions with supporting features or elements added to a stent-based structure. The base structure of the stent is formed from one or more serpentine rings. The rings can be interconnected directly or with at least one connection. Each ring is made up of multiple expansion segments constructed of crowns and supports. The stent is then reinforced by support features that increase radial strength (for example, rim strength), increase surface area, and / or reduce shrinkage compared to the stent without support features. At least one support feature usually connects opposite sides of axial reinforcements that expand (move away) around crowns (joints). Alternatively, the support functionality can connect axial connections that join the serpentine rings. In the segment expansion, the support functionality increases the radial resistance and / or reduces the shrinkage. Stents can be non-degradable or degradable, where degradation includes biodegradation, bioerosion, bioabsorption, corrosion, and disintegration completely or partially in a physiological medium. A support feature may undergo expanding plastic deformation to reinforce the base structure of the stent or alternatively it may elastically expand to provide reinforcement.

In one embodiment, at least one support functionality undergoes expanding deformation and reinforces the base structure of the stent. Generally, at least one support feature increases the radial strength of the expanded stent by at least 15%, preferably by at least 50%, more preferably by at least 100% compared to the stent without at least one support feature. In other embodiments, at least one support feature provides a stent that retracts after expansion by less than 15%, preferably by less than 7%, more preferably by less than 4%. In one example, the at least one support feature provides a stent with retraction at least 28 days after expansion in a mammal of less than 20%, preferably less than 10%, more preferably less than 6%.

The support features will generally connect from reinforcement to reinforcement, but may alternatively or additionally reinforce the crown, reinforce the connection, link to link, from crown to crown, from crown to link, or from crown to the same crown. Exemplary support features may contain varying types of shapes such as C shape, V shape, U shape, S shape, Y shape, M shape, W shape, Z shape, spiral shape or other types . These formats can be continuous or discontinuous. At least one type of ring support functionality may be present.

A thickness of support functionality and / or width can be greater than, less than or approximately equal to the thickness of the adjacent expansion segment. In one embodiment, the thickness of support functionality is in the range of 0.125 mm (0.0005 in) to 2.5 mm (0.010 in), preferably 0.25 mm (0.001 in) to 1.25 mm (0.005) in), more preferably 0.5 mm (0.002 in) to 1 mm (0.004 in). In one embodiment, the support functionality width is in the range of 0.125 mm (0.0005 in) to 2.5 mm (0.010 in), preferably 0.25 mm (0.001 in) to 1.25 mm (0.005 in) , more preferably 0.5 mm (0.002 in) to 1 mm (0.004 in). In one embodiment, the extension length of the support functionality is in the range of 1.25 mm (0.005 in) to 25 mm (1 in), preferably 0.25 mm (0.010 in) to 0.75 mm (0.250) in), more preferably 0.5 mm (0.020 in) to 2.5 mm (0.100 in).

In one embodiment the angle at which the support functionality connects to the expansion or connection segment is approximately 90 degrees, but the angle may alternatively be less than 90 degrees or greater than 90 degrees. Generally, the angle at which the support functionality connects to the axial reinforcement or connection is in the range of 30 degrees to 150 degrees, preferably 45 to 135 degrees, more preferably 60 to 120 degrees.

The material of the support functionality may be metallic, metallic alloy, polymeric, composite, ceramic, or a combination thereof, or other type of material, and may be of a similar type as the expansion or bonding segment, or different type.

The increase in radial resistance and / or reduction of shrinkage provided by these projects may be of particular benefit for biodegradable stents. The stent designs and models are applicable to both biodegradable and non-biodegradable materials to provide increased strength and / or increased elasticity. Exemplary biodegradable endoprosthesis materials include metallic materials, metallic alloy, polymeric, ceramic, composite, as well as others in combinations thereof. The deformation resistance for the biodegradable material (s) will generally be at least 50% final strength, preferably at least 75% final strength, and most preferably at least 90% final strength. For biodegradable polymeric stent materials, the resistance to deformation can be measured in water at 37 ° C. The elastic module for biodegradable metal stents will generally be at least 50 GPa, preferably at least 100 GPa, and more preferably at least 150 GPa. The elastic module of biodegradable polymeric stents, in contrast, will be at least 0.5 GPa, preferably being at least 0.75 GPa, and more preferably being at least 1 GPa, measured in water at 37 ° C. Higher resistance to deformation can contribute to greater stent retraction. The deformation resistance for biodegradable polymeric stent materials will preferably not be greater than 10% when measured in water at 37 ° C, preferably not more than 5%, and more preferably not more than 3%. The plastic deformation for biodegradable polymeric stent materials will preferably be at least 20%, more preferably at least 30%, and even more preferably at least 40% when measured in water at 37 ° C, while the elastic recovery of the material of biodegradable polymeric stent under deformation is at most 15%, preferably at most 10%, and most preferably at most 5%, when measured in water at 37 ° C.

Biodegradable stent materials can vary widely in persistence. Generally, the material will substantially degrade within three years after implantation, more generally within one year, and even more generally within six months. When degrading under physiological conditions, such as vascular conditions, after one month, the biodegradable stent will preferably retain at least 25% of the rim strength, preferably maintaining at least 40%, and more preferably maintaining at least 70%.

Biodegradable polymeric stent materials can degrade by any of several known mechanisms, including volume erosion, surface erosion, and combinations thereof. Biodegradable polymeric stent material generally degrades by at least one of hydrolytic degradation, enzymatic degradation, oxidative degradation, photodegradation, degradation under a physiological environment or combination thereof.

The appropriate biodegradable polymeric stent material includes, but is not limited to, polyesters, polyanhydrides, polyamides, polyurethanes, poly (urethane ester), polyureas, polyethers, polyalkylene carbonates, polyacrylic acids, polyamines, polyester amides, polyester amines, polyvinylacetate, imine polyethylene, polyanocrylates, polyphosphazenes, polyphosphates, polyphosphonates, polyurethanes, polyureas, polysulfonates, polysulfonamides, polylactides, polyglycolides, regenerated cellulose, or biopolymers or mixtures, block polymers, copolymers or combinations thereof. Examples of such polymers include but are not limited to poly (L-lactic acid), poly (L / D-lactic acid), poly (L / DL-lactic acid), poly (glycolic acid), poly (lactide-co-glycolide ), and copolymers and isomers, polydioxanone, poly- (ethyl glutamate), poly- (hydroxybutyrate), polyhydroxyvalerate and copolymer poly (3-hydroxy butyrate-co-hydroxy valerate), polycaprolactone, polyanhydride, poly (orthoesters); poly (ether esters), poly (trimethyl carbonate), poly (trimethylene L-lactic acid-co-carbonate), poly- (trimethylene L / D-lactic acid-co-carbonate), poly- (L-acid / DL-lactic coco-trimethylene carbonate), poly- (trimethylene caprolactone-co-carbonate), poly- (trimethylene glycolic-co-carbonate), poly- (trimethylene glycolic-carbonate-co-dioxanone), polyethylene carbonate, copolymers of polyethylene and poly (trimethylene carbonate), polypropylene carbonate, modified poly (iminocarbonates), poly (malic acid), poly (ethylene terephthalate), poly (butylene succinate), poly (butylene succinate adipate), poly (butylene succinate terephthalate), poly (butylene adipate) -co-terephthalate), starch-based polymers, hilaronic acid, oxidized and unoxidized regenerated cellulose copolymers and other aliphatic polyesters, or appropriate copolymers thereof. The biodegradable polymeric stent material in this invention can include homopolymers, copolymers, graft polymer, block polymers, polymers with special functional groups or end groups such as acidic or hydrophilic type or a mixture of two or more homopolymers or copolymers.

The biodegradable polymeric stent material may have a varying molecular architecture such as linear, branched, cross-linked, hyper-branched or dendritic. The biodegradable polymeric stent material in this invention can range from 10 KDa to 10,000 KDa in molecular weight, preferably from 100 KDa to 1000 KDa, more preferably 300 KDa to 600 KDa.

In some embodiments, the biodegradable polymeric stent material incorporates at least one additive. Additives can affect the rate of resistance, shrinkage, or degradation or combination thereof. Additives can also affect the processing of biodegradable stent material, radiopacity or surface roughness or others. Additives can be biodegradable or non-biodegradable. Additives can be incorporated into the biodegradable stent material by mixing, extrusion, injection molding, coating, surface treatment, chemical treatment, mechanical treatment, stamping, or others or combinations thereof. Additives can be chemically modified prior to incorporation into the biodegradable stent material.

In one embodiment, the weight percentage of the additives can vary from 0.01% to 25%, preferably 0.1% to 10%, more preferably 1% to 5%. In one embodiment, the additive includes at least nano-clay, nanotubes, nanoparticles, exfoliated, fibers, whisker threads, platelets, nanopowders, fuller earth, nanospheres, zeolites, polymers or others or a combination thereof. Examples of nano-clay include, montmorillonite, smectites, talc, or particles in the form of platelets or the like or a combination thereof. Clays can be intercalated or exfoliated. Examples of clays include Cloisite NA, 93 A, 30B, 25A, 15A, 10A or others or a combination thereof. Examples of fibers include cellulose fibers such as linen, cotton, artificial silk, acetate; protein fibers such as wool or silk; plant fiber; fiberglass; carbon fiber; metallic fibers; ceramic fibers; absorbable fibers such as polyglycolic acid, polylactic acid, polyglycolate or others. Examples of whisker yarns include hydroxyapatite whisker yarns, tricalcium phosphate whisker yarns or the like.

In another embodiment, the additives include at least modified starch, soy, hyaluronic acid, hydroxyapatite, tricarbonate phosphate, anionic and cationic surfactants such as sodium dodecyl sulfate, benzylammonium triethyl chloride, degraders such as D2W (from Symphony Plastic Technologies), photodegradative additives such as UV-H (by Willow Ridge Plastics), oxidative additives such as PDQ (by Willow Ridge Plastics), TDPA, family of polylactic acid and its random or block or other copolymers.

In another embodiment, the additive can induce degradation of non-degradable polymeric stent material. For example, degradable additives such as D2W (from Symphony Plastic Technologies), photodegradative additives such as UV-H (from Willow Ridge Plastics), oxidative additives such as PDQ (from Willow Ridge Plastics), TDPA or others or a combination thereof can initiate degradation non-degradable stent materials, such as polyethylene, polypropylene, polyethylene terephthalate or others. In yet other embodiments, the additives include electroactive polymers or electrolytes, hygroscopic polymers, desiccants, or the like. The additive can include an oxidant such as acids, perchlorates, nitrates, permanganates, salts or the like or a combination thereof. The additive may include a monomer of the biodegradable polymeric stent material. For example glycolic acid is an additive for polyglycolic acid or its copolymer stent material. The additive can include water-repellent monomers, oligomers or polymers such as beeswax, low MW polyethylene or the like. In other embodiments, the additive can include attractive water monomers, oligomers or polymers such as polyvinyl alcohol, polyethylene oxide, glycerol, caffeine, lidocaine or the like. In other embodiments, the additive can affect the crystallinity of the biodegradable polymeric stent material. Example of a nano-clay additive for PLLA affects its crystallinity. In still other embodiments, the biodegradable polymeric stent material may have its crystallinity increased upon exposure to radiation such as e-beam or gamma. The cumulative radiation dose can vary from 1 Mrad to 100 Mrad, preferably 5 to 50 Mrad, more preferably 10 to 30 Mrad. The biodegradable stent material has increased crystallinity, by increasing the orientation of polymer chains in the biodegradable stent material in radial and / or longitudinal direction by stretching, pressurizing and / or heating the stent material. In another embodiment, the stretching, pressurization and / or heating of the stent material occurs simultaneously or sequentially.

Specific methods for preparing biodegradable polymeric stents having the models described here are given in copending order no. 11 / _ (Agent Reference No. 022265-000520US), deposited on the same day as the present application, the description of which is incorporated herein by reference.

In the present invention, the stent material may include pharmacological agents, such as immunomodulators, anti-cancer, anti-proliferatives, anti-inflammatories, antithrombotics, antiplatelets, antifungals, antidiabetics, anti-hyperlipidimia, antiangiogenic, angiogenic, antihypertensive, drugs promoting cure , or other classes of therapeutic drugs or a combination thereof. Illustrative immunomodulatory agents include but are not limited to paramycin, everolimus, ABT 578, AP20840, AP23841, AP23573, CCI-779, deuterated paramycin, TAFA93, tacrolimus, cyclosporine, TKB662, myocardine, its analogs, prodrugs, metabolites, slats, or or combination of them.

Illustrative anti-cancer agents include acivicin, aclarubicin, acodazole, acronicin, adozelesin, alanosine, aldesleukin, sodium allopurinol, altretamine, aminoglutetimide, amonafide, ampligen, amsacrine, androgens, anguidine, azidine, acidinoline, asidine, asparagine, asparagine; Guerin (BCG), Baker Antifol (soluble), beta-2'-deoxythioguanosine, hcl bisanthrene, bleomycin sulfate, busulfan, butoxin sulfoximine, BWA 773U82, BW 502U83.HC1, BW 7U85 mesylate, ceracemide, carbetimer, carboplatin, carmustine, chlorambucil, chloroquinoxaline-sulfonamide, chlorozotocin, chromomycin A3, cisplatin, cladribine, corticosteroids, Corynebacterium parvum, CPT-11, chrysantine, cyclamide, cyclamide, cyclamide, cyclocyte , dacarbazine, dactinomycin, daunorubicin HCL, deazauridine, dexrazoxan, dianhydrogalactitol, diaziquone, dibromodulcitol, didemnin B, diethyldithiocarbamate, diglicoaldehyde, dihydro-5-azacytidine, doxorubicin, echinomycin, edatrexate, edelfosine, eflomitine, Elliott's solution, elsamitrucine, epirubicin, esorubicin, estramustine phosphate, estrogens, etanidazole, ethiophos, etoposide, etoposide, phenrazolide, phenrazolide flavone, floxuridine, fludarabine phosphate, 516 fluorouracil, Fluosol.RTM., flutamide, gallium nitrate, gemcitabine, goserein acetate, hepsulfam, hexamethylene bisacetamide, homoharringtonine, hydrazine sulfate, 4-hydroxyandrostenedione, hydrozurea, idarubicin HCI, ifosfamide, alpha interferon, interferon beta, gamma interferon, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, 4ipomeanol, iproplatin, isotretinoin, isotretinoin calcium leucovorin, leuprolide acetate, levamisole, liposomal daunorubicin, liposomal encapsulated doxorubicin, lomustine, lonidamine, podetansin, mecloretamine hydrochloride, melphalan, menogaryl, merbarone, 6-mercaptopurine, mesna, methanol extraction residue from Bacilo Calmette-Guerin, methotrexate, Nmethylformamide, mifepristone, mitoguazone, mitomycin-C, mitotane, mitoxantrone hydrochloride, monocyte / macrophage colony stimulating factor, nabilone, nafoxidine, acetone ormaplatin, oxaliplatin, paclitaxel, pala, pentostatin, piperazinedione, pipobroman, pyrarubicin, piritrexima, pyroxantrone hydrochloride, PIXY-321, plicamycin, porfimer sodium, prednimustine, procarbazine, progestins, pyrazofurin, razoxan, sargramostime, semustine, spirogermanium, spiromustine, streptozine, streptozocin, sulofenur, sodium suramine, tamoxifen, taxotere, tegafur, teniposide, terefthalamidine, teroxirone, thiopyrone, thiopyrone, thioguine, thioguanine , tretinoin, trifluoperazine hydrochloride, trifluridine, trimetrexate, tumor necrosis factor, uracil mustard, vinblastine sulfate, vincristine sulfate, vindesine, vinorelbine, vinzolidine, Yoshi 864, zorubicin, QP2, epothilone D, epothilone C Taxol, such as paclitaxel, docetaxel, ABJ879, patupilone, MN-029, BMS247550, ecteinascidines such as ET-743, tetrahydroxyquinone, alkaline hydroxyquinoline, actin hydroxyquinoline, alkaline hydroxymethylamine. , antiopeptin, vincristine, mitomycin, 2-chlorodeoxyadenosine or others, antifungal agents such as caspofungin, famesylated dibenzodiazepinone, ECO-4601, fluconazole, or others, angiogenesis drugs such as folistatin, leptin, midquine, angiogenin, angiopoietin-1, becaplermin, Regranex, angiogenesis anti-drugs such as canstatin, angiostatin, endostatin, retinoids, tumistatin, vasculostatin, angioarrestine, vasostatin, bevacizumab, prinomastat, or other, antidiabetic drugs such as metformin drugs, hypertension such as candesartan, diovan, diltiazem, atenolol, adalat or others, anti-ischemic drugs such as ranolazine, isosorbide dinitrate, or others.

Illustrative anti-inflammatory agents include classic non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmetin, ketorolac, oxaprosin, fenprofen, nefenfamenamine, fenprofen, nefenfamine, fenprofen, nefen, fenprofen, acid. , acetaminophen (Tylenol. RTM.), And mixtures thereof; COX-2 inhibitors, such as nimesulide, NS-398, flossulide, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, sodium parecoxib, JTE-522, valdecoxib, SC-58125, etoricoxib, RS-57067 , L748780, L-761066, APHS, etodolac, meloxicam, S-2474, and mixtures thereof; glucocorticoids, such as hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, triamcinolone, paramethasone, fluprednisolone, betamethasone, dexamethasone, fludrocortisone, methoxydexamide, piroxyamine, piroxyamine, piroxamide, piroxicam, poxy or others, hypercalcemia drugs such as zoledronic acid, alendronate or others, antithrombotic drugs such as plavix, heparin, Arixtra and Fraxiparina or others or mixtures thereof.

Use of analogs, prodrugs, derivatives, precursors, fragments, salts, or other modifications or variations of pharmaceutical agents are all included.

Analogs, derivatives, prodrugs, salts, synthetic or biological equivalents of these pharmaceutical agents can be released from stents depending on the type of treatment needed, such as hyperproliferative diseases, stenosis, healing, cancer, aneurysm, diabetic disease, abdominal aortic aneurysm, angiogenesis , hypercalcemia, ischemia, fibrillation, arrhythmia or others.

The agents can be released from the implant using non-degradable, partially degradable, completely degradable coatings or a combination as described in the previous patent application which is referred to and incorporated in this application in its entirety. The agents can be incorporated as a matrix with the coating or applied to the stent and covered with the coating as a rate limiting barrier, or the drug agent directly coated on the stent surface.

The solvent used to incorporate the agent and the coating into a stent can be an organic solvent such as dichloromethane, tetrahydrofuran, ethanol, or other solvents. In one embodiment, the solvent used to coat the agent and / or agent-polymer matrix does not affect the chemical or mechanical properties of the polymeric stent material.

In one embodiment, supercritical fluids such as supercritical carbon dioxide are used as a carrier solvent for the agent and / or the polymer and coat the stent with agent and / or agent-polymer matrix. The use of non-reactive gas such as carbon dioxide removes the need to use other organic solvents that can alter the chemical and physical properties of the pharmacological agent.

In one embodiment, the crystallinity of the pharmaceutical agent in the stent material is greater than 90%, preferably greater than 93%, more preferably greater than 95%.

In one embodiment, the pharmacological agent can be incorporated into the biodegradable polymeric stent material and extruded into the stent tubing prior to laser cutting the stent from the tubes. In another embodiment, the agent is incorporated into a protective coating to prevent degradation of the agents during extrusion or laser cutting.

In one embodiment, the agent release rate can be configured to be released at certain times and for certain durations corresponding to the rate of degradation of the stent material or biological response events within the ambient stent material. For example, an anti-inflammatory, antiproliferative, or immunomodulatory drug or a combination thereof can be made to release during the entire period of degradation. Multiple drugs can be released to match the rate of degradation of the coating and / or rate of degradation of the implant. Antiplatelet or antithrombotic agents can be released in the early stage and anti-inflammatory or antiproliferative or immunosuppressive agents can be released concurrently or in the later stage.

Referring now to Figs. 2A and 2B, a stent 10 according to the present invention has the same basic modeling as the stent illustrated in Fig. 1, including a plurality of adjacent serpentine rings 12 joined by axial connections 14. As illustrated, stent 10 includes six adjacent serpentine rings 12, where each ring includes six serpentine segments comprising a pair of axial reinforcements 16 joined by a joint-type crown 18 at one end. The number of rings and segments can vary widely depending on the size of the desired size of the stent. According to the present invention, a support feature 20 is arranged between adjacent axial reinforcements 16 and connected so that it will expand, generally extend, circumferentially with the reinforcements, as shown in Fig. 3. The support features 20 are in one generally closed U-shaped configuration before expansion, as shown in Figs. 2A and 2B, and open in a shallow V shape together with the opening of the axial reinforcements 16 around the crowns 18 during the radial expansion of the serpentine rings 12, as shown in Fig. 3. Support features 20 increase the resistance of stent rim after radial expansion, help resist retraction after expansion is complete, and provide an additional area to support the vascular or other luminal wall and optionally to deliver drugs to the luminal wall.

As a U-shaped support feature 20 is illustrated in Figs. 2A and 2B, a variety of other configurations can be used, as illustrated in Figs. 4-17. In Fig. 4, the V-shaped features and support 22 are arranged between adjacent axial reinforcements 16. The support features 24 of Fig. 5 are generally the same as those in Fig. 4, except that they are pointed in the direction opposite, that is, better away from crowns 18 than towards crowns. S-shaped connectors 26 are illustrated in Fig. 6, while spiral-shaped connectors 28 are shown in Fig. 7. Fig. 8 shows an alternative spiral-shaped connector 30 having an open ring in its center, while Fig. 9 shows similar support functionality 32 having a disk at its center.

As shown so far, support features 20-32 have been connected to adjacent axial reinforcements 16 close to the midpoints of said supports. Support features 34 can also be connected close to the open ends of the axial reinforcements 16, as shown in Fig. 10, or can be connected in pairs or in greater numbers, as shown in Fig. 11. Fig. 12 illustrates a pair of connectors 34 united close to the midpoint, while Fig. 13 illustrates a complex support feature 40 joined between adjacent axial reinforcements 16 at three points, two near the open end of the reinforcements and a third on the inner side of the crown 18.

Referring now to Figs. 14, 15A and 15B, support features 42 may have deflection points 44 formed along their lengths in order to control expansion. For example, by placing notches in the middle of the U-shaped connector 42, the support features can be programmed for first opening at deflection points 44, as shown in Fig. 15A, and for further opening at the connector crown, as shown in Fig. 15B. Such programmed opening helps to ensure that the axial reinforcements 16 can expand without being significantly impeded by the forces necessary to expand the support features 42.

Still other variations in the structure and positioning of the support features and axial connections can be provided. As shown in Fig. 16, support features 50 can comprise N-shaped connectors while axial connections 52 can be angled with respect to the axial direction of the stent. Similarly, as shown in Fig. 17, N-shaped support features 60 can be provided to join serpentine rings held together by angled axial connections 62.

Referring now to Figs. 18 and 19, the support functionalities can also be connected between axial connections 14 in the stents of the present invention. The support feature 70 has a generally serpentine configuration with a curved or bent portion extending in the region between adjacent axial reinforcements 16. The support feature 72 in the endoprosthesis of Fig. 19 is similar to 70, except that a support feature includes a housing region having a pair of projections 74 extending into the regions between adjacent axial reinforcements 16. In both cases, the support features 70 and 72 will increase both the strength of serpentine ring rim after radial expansion, inhibit shrinkage, and provide an increased surface area to support active release agents and tissue.

Although the above is a complete description of the preferred embodiments of the invention, several alternatives, modifications, and equivalents can be used. Therefore, the above description should not be taken to limit the scope of the invention as defined by the appended claims.