Polymeric, degradable drug-eluting stents and coatings

ES 2 395 076 T3

DESCRIPTION

Drug-eluting polymeric degradable coatings and stents

Field of the invention

[0001] The present invention relates generally to absorbable polymer compositions that can be used to prepare absorbable stents and absorbable stent coatings.

Background of the invention

[0002] Stents are currently used in a wide range of medical applications typically to prevent reocclusion of a vessel following a procedure to dilate the vessel. Examples include cardiovascular, urology and gastroenterology stents, the former being by far the largest market. Generally, stents are made of durable materials, such as metallic alloys or nonabsorbable thermoplastics, and may additionally incorporate special coatings and drugs to improve their performance in vivo. These coatings, for example, include a number of polymeric coating materials for metal stents, as well as a variety of active agents, such as agents that are anti-inflammatory or immunomodulatory, antiproliferative agents, agents that affect migration and production of extracellular matrix, agents that affect platelet deposition or thrombus formation, and agents that promote vascular healing and re-endothelialization. Currently marketed stent coatings are primarily made of permanent materials.

[0003] While incorporation of certain active agents into coatings on the surfaces of metallic coronary stents has been shown to delay restenosis, it has been reported that polymeric coatings left after drug elution may present a serious risk of late thrombosis (Virmani, R et al, Coron Artery Dis 2004; 15 (6): 313-8). Polymeric drug-eluting stent coating materials have also been reported to cause hypersensitivity reactions in the patient treated with such coated stents (Nebeker, JR et al., J Am Coll Cardiol 2006: 47: 175-81). Therefore, there is a need to develop new stent coating materials that can be used to deliver drugs without the risk of late thrombosis and hypersensitivity reactions.

[0004] Furthermore, although permanent metal stents are widely used in coronary stent applications, and their use in peripheral stents is growing rapidly, there remain several drawbacks to the use of permanent materials to fabricate these stents (Colombo, A et al., Circulation. 2000 25: 102 (4): 371-3, Erne, P. et al, Cardiovasc Intervent Radiol. 2005). First, metal stents are not compatible with certain medical imaging methods, such as MRI and CT systems. Second, metal stents can cause complications if the patient later requires coronary bypass surgery, or other surgical intervention, that requires manipulation of a stented vessel. Third, the use of permanent stents can cause long-term mismatches between the metal stent and the vessel in which it has been implanted, and fourth, in certain peripheral applications, catastrophic failure of the metal stent struts has been reported.

[0005] It should also be noted that permanent stents used in urology applications to temporarily relieve obstruction in a variety of benign, malignant, and post-traumatic vessel conditions are prone to rapid encrustation (Shaw GL et al, Res. Urol 2005 Feb; .. 33 (1): 17-22). Such inlay often requires removal of the stent. Removal, however, requires an additional procedure, and can be difficult and painful due to the growing tissue. The use of a degradable implant would eliminate this clinical problem.

[0006] To address the disadvantages associated with the use of permanent materials in stents and stent coatings, there have been several reports describing the use of absorbable materials to make stents and stent coatings. US patents no. 5,059,211 and 5,306,286 to Stack et al. describe the use of absorbable materials to make stents. Stack, however, does not describe what specific absorbable materials a person skilled in the art would use to make an absorbable stent, or the properties necessary to make such stents.

[0007] US Patent No. 5,935,506 to Schmitz et al. describes a method for manufacturing an absorbable poly3-hydroxybutyrate (P3HB) stent.

[0008] US Patent No. 6,045,568 to Igaki et al. describes absorbable stents made of knitted yarns of polylactic acid (PLA), polyglycolic acid (PGA), polyglactin (P (GA-co-LA)), polydioxanone (PDS), polyglyonate (a block copolymer of glycolic acid and trimethylene carbonate , P (GA-co-TMC)), and a glycolic acid or lactic acid copolymer with. e-caprolactone (P (GA-co-Cl) or P (LA-co-Cl)).

[0009] Laaksovirta et al. describe a self-expanding, biodegradable, self-reinforced P (GA-co-LA) stent for use in urethral applications (J Urol 2003 Aug; 170 (2 Pt 1): 468-71)

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[0010] The potential use of polyanhydride and polyorthoester polymers for the manufacture of absorbable stents has also been described by Tanguay, JF et al. Current Status of Biodegradable stents, Cardiology Clinics, 12: 699-713 (1994). Current Status of Biodegradable Stents, Cardiology Clinics, 12: 699-713 (1994).

[0011] WO 98/51812 to Williams et al. describes methods for removing pyrogens from polyhydroxyalkanoates, and the fabrication of stents from these depyrogenated materials. WO 99/32536 to Martin et al. and WO 00/56376 to Williams et al. disclose methods for preparing polyhydroxyalkanoates with controlled degradation rates, and the fabrication of stents with these materials.

[0012] Van der Giessen et al. (Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries, Circulation, 94: 1690-1697 (1996)) evaluated coatings of a copolymer of glycolic acid and lactic acid (P (GA-co-LA)), polycaprolactone (PCL), poly-3-hydroxybutyrate-co-3-hydroxyvalerate (P (3HBco-3HV), a polyorthoester, and a polybutylene terephthalate-polyethylene oxide in metal stents, and reported that the coatings induced marked inflammatory reactions within the coronary artery.

US2005 / 137678 refers to a low profile resorbable stent comprising a resorbable oriented material, wherein said material is polyhydroxybutyric acid, polylactic acid.

[0014] WO02 / 059201 refers to a composition comprising a mixture of poly-4-hydroxybutyrate and polylactide.

[0015] Despite some advances toward the development of absorbable stents and stent coatings, there is currently no coronary or peripheral stent device comprising an absorbable material approved for general sale in the United States or Europe. This is in part due to the highly demanding requirements of an absorbable material used for medical stents and the inadequacies of currently available materials. Other enhancements to existing materials that are deemed desirable, or necessary, include the following items:

(i) a stent or an absorbable stent coating that is biocompatible, does not create a risk of late-stage thrombosis, and provides long-term vessel patency; (ii) an absorbable stent that has sufficient radial strength (or ring strength) to prevent collapse of the vessel wall or stent; (iii) an absorbable polymer composition that when processed into a stent or stent coating can expand in vivo, from a suitable low profile shape to the desired diameter without surface or mesh cracking or similar types of mechanical failure; (iv) an absorbable stent or a permanent stent coated with an absorbable polymer that can be rapidly sufficiently dilated in vivo to allow deployment of the stent without risk to the patient, and using reasonable inflation pressure, if the stent is delivered by a balloon catheter, (v) an absorbable stent that does not recede significantly after deployment; (vi) an absorbable stent that is sufficiently resistant to creep to be effective; (vii) an absorbable stent with mesh thicknesses that are relatively low in profile once the stent is implanted, and that have smooth edges, (viii) an absorbable stent coating that can be applied evenly, without such defects as forming a band between the struts, and a method for such application, (ix) an absorbable stent, and / or a stent coated with an absorbable material, where the struts are not susceptible to fracture after implantation, and the risk of perforation of the vessel is eliminated; (x) an absorbable stent that does not interfere with medical scanning systems, such as MRI and CT; (xi) an absorbable stent, and a stent coated with an absorbable material, that protects against an inflammatory response, limits smooth muscle cell proliferation, and neointimal hyperplasia after implantation, stimulates positive remodeling of the vessel wall, and eliminate long-term mismatches between the stent and the vessel wall; (xii) an absorbable stent, and / or a stent coated with an absorbable material, that is flexible enough to allow delivery to the desired location without fracture or mesh kink, that can conform to the shape of the affected body lumen; (xiii) an absorbable stent containing a contrast agent; radiopaque markers, or similar material that allows imaging of the stent using conventional scanning techniques; (xiv) an absorbable coating that adheres sufficiently strongly to a metal stent, maintains its integrity after expansion of the stent, and does not delamine; (xv) an absorbable stent and a permanent coated stent that can be loaded with one or more drugs or co-drugs (e.g., on the interior or surface of the stent or coating) to improve stent performance by controlled drug delivery (s ), including agents that are anti-inflammatory or immunomodulatory, antiproliferative agents, drugs that affect migration and production of extracellular matrix, drugs that affect platelet deposition or thrombus formation, and drugs that promote vascular healing and re-endothelialization, and also allow higher drug loads, (xvi) an absorbable stent and / or a stent coated with an absorbable material that it can be mounted on a catheter, and subsequently delivered in vivo without causing damage to the stent; (xvii) an absorbable stent, and an absorbable coating on a stent, that is absorbed in vivo for a period of time that allows positive remodeling of the vessel wall, does not fail prematurely due to fatigue, and results in permeability of the long-term glass; (xviii) an absorbable stent that does not shorten undesirably after expansion and deployment (xix) an absorbable stent or permanent stent coated with an absorbable material that can be sterilized without detrimental loss of properties, for example, by radiation or exposure to ethylene oxide; (xx) an absorbable stent and a coated metal stent that can be loaded with one or more drugs to improve stent performance by controlled delivery of the drug (s), where the method of polymer degradation (e.g., surface erosion or bulk degradation) allow delivery of large drugs, such as proteins; (xxi) an absorbable stent and a permanent coated stent that can be loaded with one or more drugs to improve the

ES 2 395 076 T3 stent performance by controlled delivery of drug (s), where low acid polymer degradation products (from stent or stent coating) allow delivery of large drugs, such as proteins without drug denaturation ; (xxii) an absorbable material for use in stents having a glass transition temperature below body temperature, a melting temperature above 50 °. C, and a shelf life of at least one to three years.

[0016] Therefore, it is an object of this invention to provide absorbable compositions that can be used to develop better absorbable stents, and absorbable stent coatings.

[0017] It is another object of this invention to provide better absorbable stents, and stents coated with absorbable materials.

[0018] It is a further object of this invention to provide methods for preparing absorbable stents and stents coated with improved absorbable materials.

It is still a further object of this invention to provide methods for the delivery of absorbable stents and stents coated with absorbable materials.

Summary of the Invention [

[0020] Absorbable stents and compositions, and absorbable stent coatings, have been developed with improved properties and performance and methods for making these materials and devices. These compositions and stents comprise a polymeric composition containing:

(a) one or more polymers selected from the group consisting of poly-4-hydroxybutyrate, 4-hydroxybutyrate copolymers, and mixtures thereof and (b) between 60 and 98% by weight of one or more polymers selected from the group consisting of polylactides, lactic acid copolymers, and mixtures thereof, where the stent is plastically expandable at normal body temperature, and has a first diameter sufficient to be retained in a balloon catheter for placement within a body lumen, and is expandable to a second diameter sufficient to be retained within the body lumen.

[0021] Different methods can be used to apply absorbable stent coatings. Most preferably, the coatings are applied from a spray solution. Different methods can be used to prepare absorbable stents. A preferred method comprises forming a tube by solution immersion or extrusion, injection molding or microinjection molding, and cutting the tube with a laser to form the stent. The stent can be used as fabricated or expanded in vivo, for example, using an expandable balloon catheter.

[0022] Absorbable stent coatings provide devices with thin coatings on the stent mesh, without the formation of sheet-like structures between the mesh, and stents that can expand rapidly without cracking of the coating, delamination, or loss of structural integrity . Absorbable stent coatings are biocompatible, they degrade to less acidic metabolites by mechanisms including surface erosion (minimizing the risk of particle breakage away from the stent surface), they elongate up to 1,000% of their original length, they adhere to the stent , they can be mounted on a catheter and deployed without damage to the coating, they degrade in a period of up to about one year, they can be sterilized by radiation or treatment with ethylene oxide, and they can be loaded or coated with drugs for controlled release. Stents are flexible, and more adaptable to the vessel wall; they have sufficient radial strength and strength retention to allow positive remodeling for long-term permeability, and have a radial setback of less than 10%, and more preferably less than 6%; can be rapidly expanded in vivo, without stirring or other mechanical failure, preferably in less than five minutes, and more preferably in less than a minute, using a balloon pressure of 4 to 16 bar, more preferably 8 bar, and can deliver to the desired location without fracture, curling, or damage to the vessel wall; they do not show any significant fluence at 100 mmHg for 7 days, they do not shorten significantly after expansion; They can be constructed with smooth mesh edges with mesh thicknesses of less than 300 µm, more preferably 160 µm or less for coronary applications, and 250-270 µm for peripheral applications; may contain contrast agents, radiopaque markers, or similar material to allow imaging of the stent in vivo, and may also be loaded and / or coated with therapeutic, prophylactic, or diagnostic agents, including, but not limited to, agents that are anti-inflammatory. or immunomodulators, antiproliferative agents, drugs that affect the migration and production of extracellular matrix, drugs that affect platelet deposition or thrombus formation, and drugs that promote vascular healing and re-endothelialization, at low or high drug loads; they can be sterilized, for example, by gamma radiation, electron beam radiation or ethylene oxide. In the specific case of coronary applications, the absorbable compositions can be used to prepare absorbable stents that can expand in vivo from an inner diameter of approximately 1-1.4 mm to 3-4 mm in about one minute. Larger absorbable stents can also be made for use, for example, in applications

ES 2 395 076 T3 peripheral and urology. A preferred internal diameter for peripheral applications is 2.0 to 2.8 mm with a wall thickness of 250-270 μιτι

Brief description of the drawings

[0023]

The figure. 1 is the chemical structure of poly-4-hydroxybutyrate (P4HB, TephaFLEX. ® biomaterial).

The figure. 2 shows some of the known biosynthetic pathways for P4HB production. The pathway enzymes are as follows: 1. succinic semialdehyde dehydrogenase, 2. 4-hydroxybutyrate dehydrogenase; 3. diol oxidoreductase; 4. aldehyde dehydrogenase, 5. Coenzyme A transferase, and 6. PHA synthetase.

Figure 3 is a graph showing the accelerated decrease in molecular weight (Mw) of a high molecular weight polymer blend material PLLA and P4HB with a mass ratio of 78: 22% compared to pure PLLA as a function of the In vitro incubation time in Sorensen buffer (pH = 7.4) at 37 °. C.

Figure 4 is a graph showing the in vitro drug release profiles of metal stents coated with the following different compositions of a P4HB matrix incorporated with the immunomodulator rapamycin as a base coat, and coated with a top coat of pure P4HB as diffusion barrier for delayed drug release :. stent 85: 15-1- polymer / drug ratio of 85:15 (w / w), base layer thickness = 20 μιι, without top coating; stent 85: 15-2- polymer / drug ratio 85:15 (w / w), base layer thickness = 20 μιι, upper layer thickness = 5 μιι; stent 85: 15-3- polymer / drug ratio of 85:15 (w / w), base layer thickness = 20 μιι, top layer thickness = 15 μιι; stent 85: 15-4- polymer / drug ratio of 85:15 (w / w), base layer thickness = 10 μιι thickness, top layer = 10 μιι.

The figure. 5 is a graph showing the in vitro drug release profiles of metal stents coated with the following different compositions of a P4HB matrix incorporated with the immunomodulator rapamycin as a base layer, and coated with a top layer of pure P4HB as a barrier of diffusion for delayed drug release: stent 40: 60-1- polymer / drug ratio of 40:60 (w / w), base layer thickness = 5 μιι, top layer thickness = 10 μιι; stent 70: 30-1-polymer / drug ratio 70:30 (w / w), base layer thickness = 5 μιι, upper layer thickness = 10 μιι; stent 85: 15-4- polymer / drug ratio of 85:15 (w / w), base layer thickness = 10 µm; thickness of the upper layer = 10 μιι.

Detailed description of the invention

[0024] Absorbable stents and stents coated with absorbable materials have been developed that have improved properties.

I. Definitions

[0025] Poly-4-hydroxybutyrate as generally used herein, means a homopolymer comprising 4-hydroxybutyrate units. It can be referred to here as P4HB or TephaFLEX.RTM biomaterial. (manufactured by Tepha, Inc., Cambridge, MA)

[0026] Poly-4-hydroxybutyrate copolymers as generally used herein, mean any polymer comprising 4-hydroxybutyrate with one or more other hydroxy acid units.

[0027] Lactic acid copolymers as generally used herein, mean any polymer comprising lactic acid with one or more other hydroxy acid units.

[0028] Molecular weight as used herein, unless otherwise specified, refers to weight average molecular weight (Mw) as opposed to number average relative molecular weight (Mn).

[0029] Mixture as generally used herein means a macroscopically homogeneous mixture of two or more different species of polymer.

[0030] Absorbable or degradable as generally used herein means that the material breaks down in the body and is eventually eliminated from the body.

[0031] Biocompatible, as generally used herein means that the biological response to the material or device is adequate for the intended application of the device in vivo. All metabolites of these materials must also be biocompatible.

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II. Compositions

A. Absorbable polymers.

[0032] Stents and stent coatings are formed of absorbable polymers, comprising one or more poly-4-hydroxybutyrate (P4HB) polymers, copolymers thereof, such as poly-4-hydroxybutyrate-co-3-hydroxybutyrate (P (4HB -co-3HB)) or mixtures thereof, and between 60 and 98% by weight of one or more polymers of polylactic acid (PLA), and even more preferably of poly-L-lactic acid (PLLA) (such as Resomer ® L214 available from Boehringer Ingelheim), copolymers of lactic acid, including copolymers with glycolic acid, or mixtures thereof.

[0033] Tepha, Inc. of Cambridge, Massachusetts produces poly-4-hydroxybutyrate (P4HB) and copolymers thereof using transgenic fermentation methods. Poly-4-hydroxybutyrate is a strong, flexible thermoplastic polyester that is produced by a fermentation process (see US Patent 6,548,569 to Williams et al.). Despite its biosynthetic pathway, the structure of polyester is relatively simple (figure 1). ). The polymer belongs to a broader class of materials called polyhydroxy alkanoates (PHAs) that are produced by numerous microorganisms (Steinbüchel, A. Polyhydroxyalkanoic acids. Biomaterials, 123-213 (1991); Steinbüchel A., et al. Diversity of Bacterial Polyhydroxyalkanoic Acids, FEMS Microbial. Lett. 128: 219-228 (1995); and Doi, Y. Microbial Polyesters (1990)). In nature, these polyesters are produced in the form of storage granules within cells, and they serve to regulate energy metabolism. They are also of commercial interest due to their thermoplastic properties, and relative ease of production. Several biosynthetic pathways are currently known for the production of P4HB, as shown in the figure. 2. Chemical synthesis of P4HB has been attempted, but it has not been possible to produce the polymer with a sufficiently high molecular weight necessary for most applications (Hori, Y., et al. Polymer 36: 4703-4705 (1995)).

[0034] Tepha, Inc. (Cambridge, MA) produces P4HB and related copolymers for medical use, and has filed a Device Master File with the United States Food and Drug Administration (FDA) for P4HB. Related copolymers include 4-hydroxybutyrate copolymerized with 3-hydroxybutyrate or glycolic acid (US patent application publication number uS 2003/0211131 by Martin and Skraly, US patent 6,316,262 to Huisman et al., And US patent 6,323,010 to Skraly et al.). Tepha has also submitted a Device Master File to the US FDA for copolymers containing 3-hydroxybutyrate and 4-hydroxybutyrate. Methods for controlling the molecular weight of PHA polymers are disclosed by US Patent 5,811,272 to Snell et al., And methods for purifying PHA polymers for medical use are disclosed by US Patent 6,245,537 to Williams et al. PHAs with in vivo degradation rates of less than one year are disclosed by US Patent 6,548,569 to Williams et al. and WO 99/32536 to Martin et al. Other applications of PHA are reviewed in Williams, SF, et al., Polyesters, III, 4: 91-127 (2002), and other specific applications for P4HB are reviewed in Martin et al. Medical Applications of Poly-4-hydroxybutyrate: A Strong Flexible Absorbable Biomaterial, Biochem. Eng. J. 16: 97-105 (2003).

B. Other Components of the stent.

I Plasticizers

[0035] The composition of the absorbable material used to produce stents and stent coatings may comprise other materials in addition to the polymers described above. In a preferred method of the invention, a plasticizer can be introduced into the absorbable material prior to forming the coating of the stent or stent. Preferred plasticizers are biocompatible. A particularly preferred plasticizer is triethyl citrate (CTE).

II. Therapeutic, prophylactic and diagnostic agents

[0036] In addition to incorporating plasticizers into the absorbable material, it may be advantageous to incorporate one or more therapeutic, prophylactic, or diagnostic agents (agents) into the stent, either by loading the agent (s) into the absorbable material prior to processing, and / or coating the surface of the stent with the agent (s). The release rate of the agent can be controlled by a number of methods, including varying the following: the ratio of absorbable material to agent, molecular weight of absorbable material, agent composition, absorbable polymer composition, coating thickness , the number of coating layers and their relative thicknesses, and / or the concentration of the agent. Polymeric and other top coatings, including absorbable polymers, can also be applied to active agent coatings to control the rate of release. For example, P4HB (TephaFLEX.RTM. Biomaterial from Tepha, Inc.) can be applied as a top coat over a P4HB-coated metal stent comprising an active agent, such as rapamycin, to retard the release of rapamycin.

Examples of therapeutic agents include, but are not limited to, anti-inflammatory or immunomodulatory agents, antiproliferative agents, agents that affect migration and extracellular matrix production, agents that affect platelet deposition or thrombus formation. , and agents that promote vascular healing and re-endothelialization, described in Tanguay et al. Current Status of Biodegradable Stents, Cardiology Clinics, 12: 699-713 (1994), JE Sousa, PW Serruys and MA Costa, Circulation 107 (2003) 2274 (Part I), 2283 (Part II), KJ Salu, JM Bosmans, H. Bult and CJ Vrints, Acta Cardiol 59 (2004). Agent examples

ES 2 395 076 T3 antithrombin include, but are not limited to, Heparin (including low molecular weight heparin), R-hirudin, Hirulog, Argatroban, Efegatran, Tick anticoagulant peptide and PPack.

[0038] Examples of antiproliferative agents include, but are not limited to, Paclitaxel (Taxol), QP-2, Vincristine, Methotrexate, Angiopeptin, Mitomycin, BCP 678, c-myc Antisense, ABT 578, Actinomycin-D, RestenASE, 1-chlorodeoxyadenosine , PCNA Ribozyme, and Celecoxib.

Examples of anti-restenosis agents include, but are not limited to, immunomodulators such as Sirolimus (rapamycin), Tacrolimus, Biorest, Mizoribin, Cyclosporin, Interferon. y1b, Leflunomid, Tranilast, Corticosteroid, Mycophenolic acid and Bisphosphonate.

[0040] Examples of anti-migratory agents and modulators of the extracellular matrix include, but are not limited to Halofuginone, Propyl-hydroxylase Inhibitors, C-Proteinase Inhibitors, mMp Inhibitors, Batimastat, Probucol.

Examples of antiplatelet agents include, but are not limited to, heparin. Examples of wound healing agents and endothelial promoters include vascular include Vascular Epithelial Growth Factor (VEGF), 17-p-estradiol, Tkase Inhibitors, BCP 671, Statins, Nitric Oxide Donors (NO), and Cell Antibodies. endothelial progenitors (EPC).

[0042] In addition to coronary applications, drugs and active agents can be incorporated into the stent or stent coating for other indications. For example, in urological applications, antibiotic agents can be incorporated into the stent coating or the stent for the prevention of infection. In gastroenterology and urology applications, the active agents can be incorporated into the stent or stent coating for the local treatment of carcinoma.

[0043] It may also be advantageous to incorporate in or on the stent a contrast agent, radiopaque markers, or other additives to allow imaging of the stent in vivo for tracking, positioning, and other purposes. Such additives can be added to the absorbable composition used to make the stent or stent coating, or absorbed into, cast onto, or sprayed onto the surface of part or all of the stent. Preferred additives for this purpose include silver, iodine, and iodine-labeled compounds, barium sulfate, gadolinium oxide, derivatives of bismuth, zirconium dioxide, cadmium, tungsten, gold, tantalum, bismuth, platinum, iridium, and rhodium. These additives can be, but are not limited to, micro- or nano-particles or nano-particles. Radiopacity can be determined by fluoroscopy or by X-ray analysis.

III. Methods of Manufacture of absorptive stents

[0044] The stents described herein can be manufactured from solution processes, such as dip coating and casting, melt processes such as extrusion and injection molding, and combinations thereof.

[0045] In a preferred method, an absorbable stent can be prepared as follows. A polymer, such as P4HB or its copolymer, is optionally mixed in a predetermined ratio with a second absorbable polymer, such as PLLA, and if desired, a plasticizer, such as triethyl citrate (TCE), and / or other additives, in a suitable solvent, to prepare a viscous solution of a predetermined concentration. A rod or mandrel of predetermined diameter is then repeatedly dipped into the viscous solution and removed so that layers of the absorbable material composition build up on the rod, by precipitation of the material while the solvent evaporates, with the previously deposited layer only partially. dissolved. Successive dipping of the rod is repeated until a desired thickness of material builds up on the rod, after which the rod is withdrawn to provide a circular tube, known as a raw stent, which can be trimmed or further coated as desired.

In an alternative method of preparing the raw stent, a tube of predefined dimensions can be melt extruded from a mixture of P4HB or copolymers thereof, optionally with a second absorbable polymer, such as PLLA, and if desired a plasticizer, and / or other additives.

[0047] In a further alternative method for preparing the raw stent, a tube of predefined dimensions can be injection molded or micro-molding injection system from a mixture or composition of P4HB or copolymer thereof with the second absorbable polymer, such as PLLA, and if desired a plasticizer, and / or other additives.

In a preferred method, the dimensions of the raw stent for coronary application are an external diameter of approximately 1.3 mm, and a wall thickness of approximately 150 µm.

[0049] The raw stent can then be cut to form the stent. In a preferred method, the stent is cut with a laser according to a predefined stent design. Examples of suitable stent designs are described by Grabow et al. (J. Biomech Ing. Claudia Feh 2005; 127 (1): 25-31) and Sternberge et al (Urologe A. 2004 Oct; 43 (10): 1200-7) In a preferred embodiment, a CO2 laser is used, Excimer laser or a femtosecond laser to cut the raw stent.

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[0050] Another alternative method of preparing the raw stent is to prepare a fiber by injection molding or extrusion of a P4HB composition or copolymer thereof, optionally with a second absorbable polymer, such as PLLA, and if desired, a / plasticizer or other additives. The fiber can be strengthened by solid state drawing. The stent can be manufactured from a single fiber or multiple fibers, which can be wound, knitted, braided, woven or welded to a tubular structure or to form a tubular structure.

[0051] If desired, additives can be added to the stent or raw stent at different stages of the manufacturing process. Such additives can include radiopaque materials and / or active agents.

In addition, stent coatings can be added to the stent after the stent is manufactured. Such coatings can include radiopaque materials and / or active agents.

[0053] Absorbable stents prepared according to these methods are characterized by the following properties: biocompatibility, potentially reduced risk of late thrombosis and restenosis, low profile; rapid implantation in vivo; maintenance of structural integrity after expansion; radial resistance and resistance retention; limited recoil after implantation; creep resistance; removal of struts that could potentially fracture in the long term; radio-opaque, if desired; a good adaptation between stent and vessel wall; flexibility and low profile to allow stent placement in small vessels and along restricted and tortuous pathways; ability to load drug of choice; ability to positively reshape the vessel wall for long-term patency; compatibility with imaging systems such as CT and MRI; length maintenance with expansion, compatibility with various sterilization options, including gamma radiation, electron beam radiation, and ethylene oxide treatment; degradation which may include, but is not limited to, surface erosion, in addition to mass degradation; lower acid degradation products and the ability to dilate the stent in vivo quickly enough to allow implantation of the stent without risk to the patient, and using only a reasonable amount of pressure.

It is notable, in particular, that absorbable stents and stent liners can be plastically deformed at normal body temperature, and in reasonable operating times (eg, less than 5 minutes and more preferably less than 1 minute). They do not require the use of thermo-mechanical expansion or stent designs that rely on the use of non-plastic deformation of the stent. For example, US Patent 5,670,161 to Healy et al. describes biodegradable stents made of L-lactide and caprolactone copolymers that are not plastically expandable at normal body temperature, but which can be expanded using thermo-mechanical expansion. Attempting to expand these stents (and other stents made of degradable material compositions that are not plastically expandable) in one minute or less causes the stents to rupture. Although not wishing to be bound by theory, this may be due to brittle or glassy characteristics of the stent composition. Tamai et al. Circulation, 2000; (102) 399-404 also describes the need to heat a PLLA stent (the Igaki-Tamai stent) to 50 °. C in order to expand the stent in 13 seconds. At normal body temperature, it is reported that expansion can take 20 minutes. Zeltinger et al. Biomaterials Forum, 2004 First Quarter, 8, 9 and 24 reported that the expansion of absorbable stents, prepared for example from polylactides (poly-L-lactic acid), with the use of a heated balloon, represented additional risks for the patient, and reported that these stents have therefore not been commercialized. In an approach to overcome the inability to plastically expand absorbable rigid polymers, this group employed a new stent design, based on a sliding and ratcheting mechanism. Therefore, prior approaches to developing absorbable stents have looked for ways that use heat to expand absorbable rigid polymers or polymer compositions, or to eliminate the need for plastic deformation of the polymer composition through the use of stent designs, such as slide and ratchet or self-expanding designs that do not require compositions that are plastically expandable. In contrast, stents made from the compositions described herein can be expanded without the use of heat.

The specific compositions described herein are highly advantageous in allowing stent deployment in vivo for coronary applications in about one minute, using reasonable inflation pressure at normal body temperature, yet still providing an absorbable stent with high radial strength. and retention of acceptable strength, recoil and creep, flexibility to conform to the vessel wall, ability to reshape the vessel wall and degrade over time, and all based on a low profile design. The specific compositions described herein can be designed to degrade more rapidly than polymer or copolymer stents having lactic acid. For example, Ormiston et al. (Catheter Cardiovasc. Interv. 2006; (69) 128-131) has reported that absorbable stents made of poly-L-lactic acid (PLLA) degrade very slowly over a period of 2-3 years. In contrast, a specific PLLA composition disclosed herein comprising 22% P4HB (TephaFLEX ® biomaterial from Tepha, Inc.) can be manufactured into an absorbable stent that degrades much faster. At 48 weeks, less than 20% of the original molecular weight of this mixture is maintained compared to almost 50% for a PLLA-derived stent. The rate of degradation can be further adjusted by manipulating the percentage of P4HB in the P4HB / PLLA mixture.

IV. Method of Coating a Stent with an Absorbable Polymer Composition

ES 2 395 076 T3

[0056] In a preferred method, a stent can be coated with an absorbable polymer as follows. A polymer, such as P4HB or copolymer thereof, which can optionally incorporate a second absorbable polymer and / or additives, is dissolved at a known concentration in a volatile solvent. The solution is then sprayed onto the stent to be coated evenly to provide a uniform surface coating of the stent. Evaporation of the solvent produces a film coating on the surface of the stent. The process can be repeated to build coating thickness. Solution concentration, application time, drying time, stent position and rotation, and number of applications can be adjusted to create the desired coating thickness, and also to give a coated stent where the coating only covers the struts evenly , and do not form sheet structures between the struts. In addition, dip coating or fluidized bed sintering methods can be used to apply the coating.

[0057] Stents coated according to these methods are characterized by the following properties: good biocompatibility; a uniform coating that remains after expansion of the stent, adheres well to the surface of the stent and does not delaminate or crack on expansion; a coating that partially degrades by surface erosion, in addition to general erosion, and is therefore less likely to cause thrombosis, as a result of the release of small coating fragments from the surface of the stent; a coating that is less likely to cause an inflammatory response; a coating that can be loaded with a drug or is compatible with a surface coating with a drug; and a stent coating that can be sterilized by radiation or ethylene oxide treatment

Due to the ductility and high elongation at break of P4HB, and copolymers thereof, stent coatings derived from these materials, and applied using the methods described herein, form exceptionally good coatings that maintain their structural integrity after expansion. of the stent, as evidenced by SEM (Scanning Electron Microscopy). This is advantageous compared to more brittle materials of limited ductility and low elongation at break.

V. Stent deployment,

The stents described herein can be deployed in vivo by any means suitable to their design, such as self-expansion, a combination of self-expansion and balloon expansion, or balloon expansion without self-expansion. A preferred method of administration is to mount the stent on a balloon catheter, insert the stent system into the body at the desired position for delivery, and expand the balloon over a pressure range of 4 to 16 bar, more preferably 8 bar, to position the stent against the luminal wall in the desired position.

Due to the greater flexibility, relatively low profile, and small diameter of the absorbable stents described herein, it may be possible to deploy these stents in positions that require navigation through difficult and narrow pathways. Stents can be used for coronary, peripheral, urological, neurological, gastroenterological, esophageal and tracheal applications.

[0061] The present invention will be better understood by reference to the following non-limiting examples.

EXAMPLES

Example 1. Absorbable Coronary Stent from a Dip-Coated Raw Stent

[0062] Polymer tubes with an inside diameter of 1.0 or 1.4 mm were manufactured by dip coating stainless steel male cores in a 2% w / w solution of a preferred composition of 70% PLLA (Resomer® L214 from Boehringer Ingelheim), 20% P4HB (TephaFLEX®. Biomaterial from Tepha Inc., Mw 300-600K) and 10% TEC in chloroform. The dip coating procedure was repeated until an average wall thickness of 160 ± 10 µm of the polymer tubes was achieved. The polymer tubes were then removed from the cores and washed twice in methanol and twice in water for 24 h each to remove the solvent.

[0063] The polymer tubes were then machined with a CO2 laser to manufacture balloon expandable coronary stents with nominal measures in dilated state of 3.0 and 3.5 mm in diameter and different lengths from 10-25 mm, depending on what is established by SEM.

[0064] The stents were deployed with a balloon catheter that was inflated to 8 bar in 1 minute. The stents showed a recoil of between 2-10% when deflating the balloon and a collapse pressure of 0.3-0.7 bar. In contrast to compositions of other materials, such as a composition of P3HB, P4HB and TEC, no mesh cracking was observed, as established by comparing detailed electron micrographs of struts of an absorbable polymeric stent made of a mixture of poly-3-hydroxybutyrate. (P3HB), poly-4-hydroxybutyrate (P4HB) and triethyl citrate (TEC) (70/20/10% w / w / w) and a mixture of PLLA, P4HB and TEC (70/20/10% w / p / p) after deployment. In contrast to the P3HB / P4HB / TEC stent, the PLLA / P4HB / TEC stent does not exhibit mesh cracking. SEM shows cracking of a stent composition of P3HB, P4HB and TEC dilated slowly over 7 minutes, compared to a composition P4HB, PLLA and TEC dilated much more rapidly (in 1 minute), and shows no cracking.

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Example 2. Absorbable Coronary Stent from Extruded Raw Stent

Polymer tubes with an internal diameter of 1.0 or 1.4 mm and a wall thickness of 150 pm were manufactured by extrusion of a preferred composition of 78% PLLA (Resomer® 1214 from Boehringer Ingelheim) and 22% P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw 300-600K).

The polymer tubes were then machined with a CO2 or excimer laser for the manufacture of balloon-expandable coronary stents with nominal dilated dimensions of 3.0 and 3.5 mm in diameter and different lengths of 10 -25 mm.

Comparative Example 1: Absorbable Polymeric Matrix for a Drug-eluting Stent Coating

[0067] A 0.3% w / w solution of P4HB (TephaFLEX® biomaterial from Tepha, Inc., Mw 300-600K) was prepared in chloroform. The metallic coronary stents were spray coated with this solution until a mean coating layer thickness of 15-20 microns was achieved. After 24 hours of vacuum storage to remove chloroform, the stents were mounted on standard balloon catheters and subsequently deployed to a nominal diameter of 3.5 mm. Detailed electron micrographs of metal struts of the P4HB-coated stent before and after stent dilation show the smoothness and integrity of the coating before and after balloon expansion.

Comparative Example 2: Permanent Drug-Eluting Stent with Absorbable Polymeric Coating Matrix and Built-in Antiproliferative Immunosuppressant (Low Dose)

[0068] A 0.3% w / w solution of P4HB (TephaFLEX® biomaterial from Tepha Mw, Inc. 300-600K) and rapamycin (70/30% w / w, polymer / drug) in chloroform was prepared. Coronary metallic stents were spray coated with this solution until a mean coating layer thickness of 15-20 microns was achieved. After 24 hours of vacuum storage to remove chloroform, the stents were mounted on standard balloon catheters and subsequently deployed to a nominal diameter of 3.5 mm. The active agent rapamycin was released from the coating.

Comparative Example 3: Permanent Drug-Eluting Stent with Absorbable Polymeric Coating Matrix and Built-in Antiproliferative Immunosuppressant (High Dose)

[0069] A 0.3% w / w solution of P4HB (TephaFLEX® biomaterial from Tepha Mw, Inc. 300-600K) and rapamycin (40/60% w / w, polymer / drug) in chloroform was prepared. . Coronary metallic stents were spray coated with this solution until a mean coating layer thickness of 15-20 microns was achieved. After 24 hours of vacuum storage to remove chloroform, the stents were mounted on standard balloon catheters and then deployed to a nominal diameter of 3.5 mm. The active agent rapamycin was released from the coating.

Example 3: Absorbable Drug-Eluting Stent with Built-in Antiproliferative Immunosuppressant (Low Dose)

[0070] Polymer tubes with an internal diameter of 2.8 mm were manufactured by dip coating stainless steel male cores in a 2% w / w solution of a preferred composition of 70% PLLA (Resomer® L214 from Boehringer Ingelheim), 20% P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw 300-600K) and 10% TEC in chloroform. The dip coating procedure was repeated until an average wall thickness of 250 ± 10 µm of the polymer tubes was achieved. The polymer tubes were then removed from the cores and washed twice in methanol and twice in water for 24 hrs each to remove solvent and TEC.

The polymer tubes were then machined with a CO2 laser to fabricate balloon-expandable peripheral vascular stents with nominal dilated dimensions of 6.0 mm in diameter and varying lengths from 15-25 mm.

The metal stents were then spray coated with a 0.3% w / w solution of P4HB and rapamycin (70: 30% w / w, polymer / drug) in chloroform. After 24 hours of vacuum storage to remove chloroform, the stents were mounted on balloon catheters. The stents were deployed to a nominal 6.0 mm ID with a balloon catheter that was inflated to 8 bar in 1 minute. The stents showed a recoil of approximately 5% when deflating the balloon and a collapse pressure greater than 0.6 bar. The active agent rapamycin was released from the coating.

Example 4: Absorbable Drug-Eluting Stent with Incorporated Antiproliferative Immunosuppressant (High Dose)

[0073] Polymer tubes with an internal diameter of 2.8 mm were manufactured by dip coating stainless steel male cores in a 2% w / w solution of a preferred composition of 70% PLLA (Resomer® L214 from Boehringer Ingelheim), 20% P4HB (TephaFLEX® biomaterial from Tepha Inc., Mw 300-600K) and 10% TEC in chloroform. The dip coating procedure was repeated until a wall thickness

ES 2 395 076 T3 average of 250 ± 20 pm of the polymer tubes. The polymer tubes were then removed from the cores and washed twice in methanol and twice in water for 24 hrs each to remove solvent and TEC.

The polymer tubes were then machined with a CO laser.₂ to fabricate balloon-expandable peripheral vascular stents with nominal dilated dimensions of 6.0 mm in diameter and varying lengths from 15-25 mm.

The stents were then spray coated with a 0.3% w / w solution of P4HB and rapamycin (40/60% w / w, polymer / drug) in chloroform. After 24 hours of vacuum storage to remove chloroform, the stents were mounted on balloon catheters. The stents were deployed to a nominal 6.0 mm ID with a balloon catheter that was inflated to 8 bar in 1 minute. The stents showed a recoil of approximately 5% when deflating the balloon and a collapse pressure greater than 0.6 bar. Rapamycin as an active agent was released from the coating by diffusion and also supported by polymer degradation.

Example 5: Accelerated in vitro degradation behavior of an absorbable peripheral stent of a high molecular weight polymer blend material PLLA and P4HB.

[0076] Peripheral balloon expandable absorbable stents with nominal dilated dimensions of 6.0 mm x 25 mm were manufactured from a blend of high molecular weight polymers PLLA (Resomer ® L214 from Boehringer Ingelheim), and P4HB (biomaterial TephaFLEX® from Tepha Inc., Mw 300-600K) with a 78/22% mass ratio or pure high molecular weight PLLA (Resomer® L214). The stents were deployed with balloon catheters and then incubated in vitro in Sorensen's buffer solution at 37 ° C to assess hydrolytic degradation in vitro.

[0077] After 0/2/4/8/12/24/48 weeks, the stents were removed from storage and analyzed by gel permeation chromatography (GPC) to determine molecular weight. Figure 3 shows the accelerated decrease in molecular weight of the high molecular weight polymer blend material PLLA and P4HB compared to pure PLLA.

Comparative Example 4: In vitro drug release kinetics of permanent drug-eluting stent with absorbable polymeric coating matrix and rapamycin as incorporated antiproliferative immunosuppressant showing the influence of base layer thickness, and top layer thickness on the release profile

[0078] A 0.3% w / w solution of P4HB (TephaFLEX® biomaterial from Tepha, Inc., 300 Mw-600K) and the immunomodulator rapamycin 85: 15% w / w in chloroform were prepared. The metallic coronary stents were spray coated with this solution as a base coat, until a coating layer thickness of 10-20 microns was achieved, which is equivalent to a drug content of 1-2 pg per mm.² surface area of ​​the stent. The metal stents were then spray-coated with a 0.3% w / w solution of P4HB until a top layer thickness of 5-15 microns was achieved in order to establish different diffusion barriers for delayed drug release. After 24 hours of vacuum storage to remove chloroform, the stents were mounted on standard balloon catheters and subsequently deployed to a nominal diameter of 3.5 mm. The stents were then stored in 2 ml of 0.9% sodium chloride solution and incubated at 37 ° C. Then, at different times, aliquots of the elution medium were taken for analysis of released drug, the elution medium was changed, and the stents were stored again. Aliquots were analyzed by HPLC.

[0079] FIG. 4 shows the in vitro drug release profiles of sample stents, showing the effect of top layer thickness and base layer on the drug release profile at constant drug concentration. The use of a top layer delayed drug release (stent 85: 15-1 compared to stent 85: 152). The use of a thicker top layer further delayed drug release (85: 15-1 and 85: 15-2 stents compared to 85: 15-3 stents). The use of a thinner base layer reduces the amount of drug released (stent 85: 15-1 compared to stent 85: 15-4).

Comparative Example 5: In vitro drug release kinetics of permanent drug-eluting stent with absorbable polymeric coating matrix and rapamycin as incorporated antiproliferative immunosuppressant showing the influence of drug content, and base layer thickness on the release profile

[0080] A 0.3% w / w solution of P4HB (TephaFLEX® biomaterial from Tepha, Inc., 300 Mw-600K) and the immunomodulator rapamycin 85: 15% w / w (polymer / drug) was prepared, or 70: 30% w / w, or 40: 60% w / w in chloroform. The metallic coronary stents were spray coated with any of these solutions as a base coat, until a coating layer thickness of 5-10 microns was achieved, which is equivalent to a drug content of 1-2 pg per mm.² surface area of ​​the stent. The stents were then spray coated with a 0.3% w / w solution of P4HB until a top layer thickness of 10 microns was achieved in order to establish a diffusion barrier to delay drug release. After 24 hours of vacuum storage to remove chloroform, the stents were mounted on standard balloon catheters and subsequently deployed to a nominal diameter of 3.5 mm. The stents were then stored in 2 ml of 0.9% sodium chloride solution and incubated at 37 ° C.

ES 2 395 076 T3

Then, at different times, aliquots of the elution medium were taken for analysis of released drug, the elution medium was changed, and the stents were stored again. Aliquots were analyzed by HPLC.

[0081] Figure 5 shows in vitro drug release profiles from sample stents, showing increased drug release at higher drug concentrations at constant top layer thickness. The elution rate and the total amount of drug released increases as the drug concentration in the base layer increases (stent 85: 15-4 compared to stent 70: 30-1 and stent 40: 60-1 ).

Example 6: Secure mounting of a coronary absorbed stent on a balloon catheter

[0082] Balloon expandable absorbable stents with an inner diameter of 1.4 mm in the unexpanded state and a length of 10 mm were manufactured from a mixture of high molecular weight polymers PLLA and P4HB (TephaFLEX® biomaterial from Tepha, Inc., Mw 300-600K) by melt extrusion followed by laser cutting. The polymeric stents were mounted without crimping in balloon catheter systems with a nominal dimension of 3.5 mm x 10 mm in the dilated state. The balloon catheter system contained an inner support tube in the balloon region below the stent to improve stent retention. The inner support tube was made of an elastomeric material and provided a press fit to hold the assembled stent in place. The diameter or durometer of the elastic support tube could be modified to adjust the strength of the press fit and modify the retention of the stent. The dislodging force of the stent systems was tested using a universal testing machine.

[0083] A mean stent dislodging force of 2 N was measured, and a maximum dislodging force greater than 5 N. Without the inner support tube, the dislodging force was less than 0.3 N and would not be suitable for intravascular deployment without some method of holding the stent in place.