Covered stents for localized drug delivery

Abstract

The present invention generally relates to an endoprosthesis, such as a stent, for maintaining patency of a body vessel, having a generally tubular shape and including a lattice structure with a mesh covering capable of retaining one or more drugs and allowing them to be released and penetrate the surrounding tissue.

Description

[Technical field]

[0001] The present invention relates generally to an endoprosthesis, such as a stent, for maintaining patency of a body vessel, which has a basically tubular shape and includes a lattice structure with a mesh covering that can retain one or more drugs and allow them to be released and permeated into the surrounding tissue.

[0002] 2. Background of the Invention Stents are tubular devices made of plastic or metal that are used to secure or maintain the patency of animal or human vessels. Stents can be placed endoscopically or percutaneously to treat and relieve blockages in the common bile duct or main pancreatic duct. The devices are effectively used to drain fluids that accumulate in the gallbladder and pancreas. A less expensive option available is a plastic stent, but its diameter is limited to 12 French (0.156 inches), the maximum allowable diameter that can be accommodated by a standard endoscope. For drainage of larger vessels, some plastic stents or expandable metal stents may be used. Metal stents may be balloon expandable or may be composed of a material that self-expands when deployed from a delivery catheter. Both types of metal stents are available with a cover made of polymer or silicone. This cover prevents the ingress of tissue from the surrounding vessel lumen.

[0003] Obstruction of the bile duct or pancreatic duct can occur due to benign hyperplasia resulting from inflammation or malignant tumors of the pancreas or bile duct and surrounding tissues. The development of such obstruction can lead to poor clinical outcomes including pain and delays in subsequent treatment. Bile duct obstruction correlates with decreased survival time in cancer patients. Pancreatic cancer is diagnosed in over 50,000 people in the United States and over 400,000 people worldwide each year, with as many as 70% of patients having some degree of bile duct obstruction at the time of diagnosis. Pancreatitis affects 9 million people worldwide. The role of biliary stents in achieving patency in bile duct obstructions or strictures is well established, and more recent studies have demonstrated the increasing role of self-expanding metallic stents. In cases of resectable or surgically treatable pancreatic cancer, an increasing number of patients are receiving neoadjuvant chemoradiotherapy or chemotherapy prior to surgery to enhance the potential benefits of the procedure. With neoadjuvant approaches, surgery is likely to be delayed for many months, making effective and permanent biliary drainage necessary, especially given the fact that many chemotherapy drugs require adequate liver function.

[0004] Maintaining the patency of the bile duct with a stent is a requirement for further treatment of the disease and to facilitate subsequent surgical procedures. However, available literature reveals that the failure rate of stents used to treat malignant obstructions ranges from 19% to 46%. The primary cause of stent failure is hyperplasia or tumor growth into or around the implanted stent. Clogging of the stent lumen by bile salts or food debris is a secondary cause of stent failure. Adding a covering to the stent reduces but does not eliminate tissue ingrowth. The surface of the prosthesis may be entirely covered or may be bare and uncovered at the portions defined as the ends of the device.

[0005] Previous attempts have been made to release drugs from covered prostheses. A membrane containing a polymer and the drug paclitaxel was wrapped around a conventional self-expanding stent and deployed in the main bile duct of 36 patients with pancreatic cancer to maintain patency throughout neoadjuvant therapy or while waiting for surgery. The duration of main bile duct patency in these patients was not significantly different from that of pancreatic cancer patients treated traditionally with covered stents without drug. There may be several possible explanations for this outcome. The paclitaxel drug may not have been stable or effective in the high pH environment found in the main bile duct. There may have been insufficient amounts of drug or availability of drug to the surrounding tissues. It may also be that the physical shape of the stent used in this study was susceptible to interference from food or bile contents. The present invention is directed to overcoming either of the two possible shortcomings of the previously studied devices.

[0006] Thus, it is an object of the present invention to provide a drug-eluting stent system for drug delivery in the bile or pancreatic duct that is capable of preventing hyperplasia and invasion or abnormal growth of tumor material by providing an effective dose of a suitable therapeutic agent.

[0007] Summary of the Invention The present invention provides a drug-eluting stent system comprising a coating layer, the coating being comprised of a porous surface covering and at least one therapeutic agent comprising an antiproliferative agent, preferably a macrocyclic triene immunosuppressant compound, applied to a radial expansion stent such that the stent is encapsulated by the coating.

[0008] In one aspect, there is provided a drug eluting stent system for use in the delivery of at least one therapeutic agent to a target, preferably a bile duct or pancreatic duct, comprising: (a) a radially expandable stent; and (b) a coating comprising a porous surface covering and at least one therapeutic agent that is an antiproliferative agent; wherein the stent is encapsulated by the coating.

[0009] The porous surface covering may be in the form of a mesh, and ideally will be biocompatible with the surrounding tissue and maintain the flexibility and radial strength of the original uncovered stent. At least a portion of the porous surface covering has sufficient porosity to contain enough therapeutic agent to provide therapeutic benefit over the entire treatment period. The porous surface covering is provided with an inner surface on the luminal side of the drug-eluting stent system and an outer surface on the abluminal side of the drug-eluting stent system. Both the inner and outer surfaces may have the same properties and may belong to the same material of the surface covering. The drug-eluting stent system of the present invention may also be provided with the inner and outer surfaces of the surface covering having different properties, especially when the surface covering encapsulating the stent is made of two different porous material sheets.

[0010] The drug-eluting stent system of the present invention is preferably provided with a smooth, continuous inner surface that prevents clogging by fluids and food materials, and also with an effective means of preventing invasion or overgrowth of hyperplasia and tumor parenchyma. The morphology of the inner stent surface may be less porous than the outer surface. The drug-eluting stent system of the present invention minimizes or inhibits tissue ingrowth by delivering drugs over a period of time while maintaining vascular patency.

[0011] Drugs to be administered into the bile or pancreatic duct are required to have good efficacy and stability. It is desirable for the drug to have both anti-proliferative and anti-inflammatory properties to allow for the inhibition of tumor and endothelial proliferation. In living tissue, such drugs will inhibit benign or malignant hyperplasia in the particular vascular environment in which they are deployed. The drug should be non-covalently bound to the porous surface covering to ensure that a constant release of the drug is delivered at the target site. Special consideration is given to the pH of bile duct fluid, which differs from the pH found in venous or arterial blood. Thus, the drug needs to be stable in a basic pH environment. It is also desirable for the drug to be lipid soluble to facilitate absorption into the surrounding tissue. Furthermore, it is also desirable for the drug to have a wide dosing window of therapy. Specifically, the drug should exert therapeutic effects over low to high dose levels without concerns of local toxicity. The lack of efficacy of paclitaxel-embedded biliary stents may be due to poor compatibility with one or more of the aforementioned attributes.

[0012] Thus, in one aspect, the present invention provides a macrocyclic triene immunosuppressant compound that meets all of the aforementioned requirements and has the following structure: [ka] [Wherein, R is C(O)-(CH2) n -X, n is 0, 1 or 2, and X is a cyclic hydrocarbon having 3 to 9 carbons, optionally containing one or more unsaturated bonds. As a coating material for medical implants, in particular for vascular stents, there is provided a drug-eluting stent system comprising the compound C(O)-(CH2) n -X has one of the following structures: [ka]

[0013] In another aspect, the present invention provides a method for producing a composition comprising: (a) providing a sheet having a surface made of a porous material; (b) placing the sheet on at least one of the luminal or abluminal surface of a stent; (c) applying high temperature and pressure to encapsulate the stent with the porous material, thereby providing the stent with a porous surface covering; (d) applying a therapeutic agent formulation to the porous surface covering; and (e) drying the porous surface covering with the therapeutic agent formulation applied thereto. The present invention is directed to a method for preparing a drug eluting stent system, comprising:

[0014] The therapeutic agent formulation applied to the covered stent must meet the requirements of manufacturability and efficacy. The therapeutic agent formulation must contain at least one therapeutic agent as defined herein and must be dissolved in a suitable solvent and applied as a liquid formulation by spraying, capillary application, or dip coating. The drug formulation will be maintained within the porous surface covering (e.g., in a mesh lattice), as a solid mass, or as captive microparticles or microspheres. Selected areas of the stent's surface features may be coated with the drug, if desired. Once dried, the drug must remain stable at room temperature throughout the usable lifetime of the product. The therapeutic agent formulation containing at least one therapeutic agent may be applied to the inner surface, the outer surface, or both the inner and outer surfaces. [Brief description of the drawings]

[0015] [Figure 1] Photograph of a self-expanding stent encapsulated with two layers of porous electrosprayed PTFE film. [Diagram 2] A close-up image of the encapsulated stent showing the membrane covering the struts. [Diagram 3] 1 is a scanning electron microscope image of a cross section of the encapsulated device showing the stent struts surrounded by a porous mesh material. [Figure 4] A scanning electron microscope image of a cross section of the encapsulated device showing a single stent strut surrounded by a porous mesh material. [Diagram 5] 1 is a scanning electron microscope image of a porous mesh material showing a cut cross-section. [Figure 6] Top view of the porous mesh, with scaled scanning electron microscope image, showing approximate pore size of 2.0-5.0 microns. [Figure 7] A scanning electron microscope image of the porous mesh viewed from above at high magnification. [Figure 8] FIG. 13 is a scanning electron microscope image showing a top view of a drug formulation applied to the inner surface of a porous mesh. [Figure 9A] FIG. 13 is a rendering of a cross-section of a design shape created by encapsulating two PTFE sheets. [Figure 9B] FIG. 13 is a rendering of a cross-section of a design feature created by a single electrospray application on a stent. [Figure 10] FIG. 1 is a graph showing the incremental measured amount of CRC-015 drug released over time from a drug-coated device placed in a suitable liquid medium.

[0016] definition As used herein, the term "coated" or "coating" in reference to a stent refers to a covering, compound or substance applied to the surface of the stent, which may include drugs or therapeutic compounds present in or on the covering, as well as any other substances applied to the surface of the stent for the purpose of facilitating delivery of a drug from the stent surface to a target.

[0017] As used herein, the term "elution" refers to the migration of a drug or therapeutic agent from a coating, where the amount is determined as the total amount of drug or therapeutic agent expelled from a porous surface covering that is an integral part of the coating. As used herein, the term "polymer" refers to a material made up entirely of repeating structural units or monomers joined together by covalent chemical bonds. As used herein, the term "subject" refers to any animal, including humans, to which administration of an adjuvant composition is desired. "Subject" includes mammals and non-mammals, examples of which include primates, livestock, companion animals, laboratory animals, captive wild animals, reptiles, and fish. As used herein, the term "encapsulated" refers to the complete surrounding of an element of material with another material.

[0018] Stents The stents of the present invention may be made from any suitable biocompatible metal and may be inserted into the vascular system of an individual. The stents include a metal base that includes materials such as stainless steel, titanium, or similarly biocompatible alloys thereof. The stents of the present invention are substantially tubular or cylindrical in design and are radially expandable when positioned at a desired target, such as within the vascular system or adjacent a vessel wall. The stents can be configured to be self-expanding or balloon-expandable.

[0019] coating The present invention provides a coating comprising a porous surface covering specially adapted to carry a drug with a very high payload. The porous surface covering encapsulates the stent. In this application, the coating in the form of a porous surface covering is formed of a porous sheet disposed on the inner and / or outer surface of the stent, and extends over the gaps between the stent struts. The encapsulation is accomplished by applying high temperature and pressure to at least one sheet of porous material placed on the stent. The porous material is in one embodiment a nonwoven fabric. The nonwoven fabric is composed of polymeric fibers. The temperature and pressure are selected to transition the polymer to a semi-molten state and to cause the fibers to adhere to each other when compressed. The compression results in a porous stent covering in the form of a thin web or mesh that maintains flexibility and structural integrity, and is capable of loading and retaining a higher amount of the therapeutic agent described herein. In addition, the application of high temperature and pressure causes the porous surface cover to have a sponge-like shape capable of absorbing a large amount of the drug-containing formulation. The average diameter of the nonwoven fibers is preferably 0.25 to 2.00 micrometers. Various fiber diameters can be used, particularly to adopt the desired porosity. The smaller the fiber diameter, the lower the porosity that can be achieved. In such an embodiment, the fiber diameter may range from 0.25 to 0.85 micrometers.

[0020] The inner and outer surfaces of the porous covering may have the same characteristics, such as porosity, and may belong to the same material surface covering. It is also possible to provide a porous covering with different characteristics between the inner and outer surfaces. The variations in characteristics may belong to different porosities, materials, hydrophilicity or lipophilicity, density, and the like, as well as combinations of the aforementioned characteristics. The luminal (inner) surface is desirably smooth to reduce the incorporation of biliary sludge and food. In such an embodiment, the inner surface of the porous covering exhibits low porosity, preferably less than 5%, or no porosity at all. No porosity may be achieved by providing a smooth polymer layer, for example in the form of a polymer film. The abluminal surface should be porous enough to retain high therapeutic levels of the drug and to efficiently elute the drug from the stent system. It is therefore recommended that the porous surface covering of the drug-eluting stent system exhibits an increasing porosity gradient from the luminal surface to the abluminal surface of the stent system. In one embodiment of the drug-eluting stent system of the present invention, the porous covering portion has a porosity gradient ranging from 0%-5% on the inner (luminal) surface to 20%-40% on the outer (abluminal) surface.

[0021] In one embodiment of the drug-eluting stent system of the present invention, the porous covering has a density gradient from a high density on the inner (luminal) surface to a lower density on the outer (abluminal) surface. The maximum density of the porous covering is the density in a smooth polymeric material used for the fiber that does not exhibit any porosity. In the present invention described herein, when one side surface (inner or outer) exhibits zero porosity, the opposite side must simultaneously exhibit the porosity of the porous surface covering. Thus, at least one surface, preferably the outer (abluminal) surface, exhibits porosity. It should be understood that the "surface on the XX side of the surface" refers to which side of the surface of a stent having an inner, i.e., luminal, surface and an outer, i.e., abluminal, surface. Having a surface covering from one side of the surface to the other side of the surface means that both sides of the surface of the stent are covered, and the stent is necessarily encapsulated. The total thickness of the porous surface covering is preferably within the range of 20 to 100 micrometers. In this way, the porous surface covering integrated with the stent is flexible yet strong enough to withstand the external pressure caused by tissue ingrowth.

[0022] In one aspect, the amount of the at least one therapeutic agent applied to the drug-eluting stent system is about 1 mm 2 Between 0.5 μg and 5.0 μg per stent, depending on stent size, preferably with a surface area of ​​1 mm 2 In another preferred embodiment, the drug loading of the at least one therapeutic agent per unit area on the stent is from about 1.0 μg to 3.0 μg per mm of surface area. 2 Approximately 4.0 μg to 5.0 μg per mm2 of surface area. Note that this is the flat area, not taking into account the area of ​​the pores. Thus, at least one therapeutic agent as defined herein is preferably present in an amount of about 1.0 μg per mm2 of surface area. 2 In particular embodiments, the IgG is present in the porous surface covering at a concentration of at least 0.05 μg, preferably at least 0.5 μg, more preferably at least 1.0 μg, and most preferably at least 3.0 μg per mm of surface area.2 At least one therapeutic agent is applied only to the abluminal surface of the drug-eluting stent system in an amount of 0.5 μg-5.0 μg / mm, preferably 4.0 μg-5.0 μg / mm. That is, it is only the abluminal surface of the porous covering that exhibits these drug loadings, whereas the luminal surface of the porous stent covering contains either no, or less than 0.05 μg / mm of the at least one therapeutic agent. 2 ~1.0μg / mm 2 Only the drug load is presented.

[0023] In another aspect, the therapeutic agent is applied to the porous surface covering by using a formulation that preferably contains at least one therapeutic agent dissolved in a suitable solvent at a concentration of at least 2.0% by weight. A solvent that is non-toxic, capable of dissolving the therapeutic agent, and has a low enough vapor pressure to facilitate easy drying is preferred for preparing the formulation. Examples of solvents that meet at least one of these requirements are acetone, acetonitrile, tetrahydrofuran, chloroform, dichloromethane, and ethanol.

[0024] In a preferred embodiment, the porous surface covering portion is a nonwoven fabric. The nonwoven fabric is preferably produced by electrospinning. In electrospinning, a polymer solution, preferably a solution containing a nonwoven polymer as mentioned above, is delivered through a metal nozzle. A high voltage is applied between the metal nozzle and the base structure. The base structure has a different electric potential than the metal nozzle. By supplying the polymer solution and the voltage difference between the nozzle and the base structure, the filaments are applied as a nonwoven fabric on the surface of the base structure. The nonwoven fabric fibers are composed of a biocompatible polymer, preferably a biocompatible polymer having biostable properties. In one embodiment of the present invention, the electrospun fibers are composed of a polymer selected from the group including or consisting of polytetrafluoroethylene, fluorinated ethylene propylene, Dacron, polyethylene terephthalate, polyurethane, polycarbonate, polypropylene, Pebax, polyethylene, and biopolymers such as collagen, fibrin, and elastin. In a further preferred embodiment, the electrospun fibers are composed of polytetrafluoroethylene or polyurethane.

[0025] Furthermore, to encapsulate the stent in the porous covering, two different nonwoven sheets can be applied to the luminal surface of the stent and the abluminal surface of the stent, respectively. In a preferred embodiment, the inner surface of the porous covering is made of polytetrafluoroethylene with low porosity, preferably less than 5% or zero porosity. Such inner surface of the porous covering can be made of polytetrafluoroethylene sheet, preferably with a relatively small fiber diameter, such as 1 μm, to add additional strength to the covering, thereby preventing hyperplasia and tumor parenchyma penetration. In addition to encapsulating and applying a therapeutic agent, at least one of the porous sheets, preferably the nonwoven sheets, used to encapsulate the stent can be provided with a sealant, thereby reducing or eliminating the porosity on one surface of the porous covering, preferably the luminal surface. Suitable sealants include, but are not limited to, silicones, silanes, polyurethanes, polysulfones, thermoplastic elastomers, PVC and other vinyl materials, fatty alcohols such as docosanol, polysorbate 80 and other surfactants, and flexible, biocompatible organic polymers such as polycaprolactone.

[0026] The porous surface cover part encapsulating the stent is preferably formed to have a mesh pore size in the range of 1 micron to 5 microns. The mesh pore size may be determined under scanning electron microscopy. In one aspect of the invention, the porous surface cover part has a porosity in the range of 20% to 40% of the surface area, preferably 30%. As mentioned above, the porous surface cover part encapsulating the stent may have a porosity gradient, preferably an increasing porosity gradient from the luminal surface to the abluminal surface of the porous surface cover part.

[0027] Therapeutic Agents At least one therapeutic agent is a macrocyclic triene immunosuppressant compound having the following structure: [ka] [Wherein, R is C(O)-(CH2) n In the most preferred embodiment, C(O)-(CH2) is -X, n is 0, 1 or 2, and X is a cyclic hydrocarbon having 3 to 9 carbons, optionally containing one or more unsaturated bonds. n -X has one of the following structures: [ka]

[0028] In particular, the macrocyclic triene immunosuppressant compounds of the present invention have more than one embodiment and can be described as including at least one of the following species as set forth in Table 1: [Table 1]

[0029] CRC-015 is an overall genus term and is used to refer to each of the following species listed in Table 3: CRC-015a, CRC-015b, CRC-015c, CRC-015d, CRC-015e, CRC-015f, CRC-015g, and CRC-015h.

[0030] A combination of several drugs may be applied to the surface of the stent system or to multiple surfaces of the stent system. Among the macrocyclic triene family of compounds other than the CRC-15 compounds, the drugs are everolimus, zotarolimus, biolimus, sirolimus, and novolimus. Other drugs used in the systemic treatment of pancreatic adenocarcinoma may be applied locally through the use of an implantable stent graft. These drugs include gemcitibane, paclitaxel, nab-paclitaxel, docetaxel, 5-fluorouracil (FU), flurouracil, irinotecan, oxaliplatin, cic-platinen, and leucovorin.

[0031] Furthermore, it is recognized that combination of drugs can enhance the therapeutic effect. The CRC-015 compound disclosed herein can be combined with the following anti-cancer drugs along with the covered stent of the present invention. These anti-cancer drugs can be selected from the group including or consisting of capecitabine, erlotinib, fluorouracil (5-FU), gemcitabine, irinotecan, leucovorin, paclitaxel, Nab-paclitaxel, irinotecan and oxaliplatin.

[0032] In one embodiment of the drug-eluting stent system of the present invention, the luminal and abluminal surfaces of the surface covering are loaded with different therapeutic agents. Both surfaces can be loaded with different combinations of drugs. In one embodiment for the abluminal surface, at least one or the only therapeutic agent is a macrocyclic triene immunosuppressant compound having the following structure: [ka] [Wherein, R is C(O)-(CH2) n In the most preferred embodiment, C(O)-(CH2) is -X, n is 0, 1 or 2, and X is a cyclic hydrocarbon having 3 to 9 carbons, optionally containing one or more unsaturated bonds. n -X has one of the following structures: [ka]

[0033] In a further embodiment, the drug-eluting stent system is loaded with at least one of the CRC-15 compounds defined herein on the abluminal surface and a suitable anticoagulant, such as heparin, on the luminal surface. Antibiotics and other drugs that inhibit bacterial membrane formation or antimicrobial materials may be applied to the luminal surface.

[0034] The at least one therapeutic agent in the coating of the drug-eluting stent system proposed herein may be accompanied by at least one suitable excipient material that may have the effect of prolonging the presence of the agent in the tissue and is selected from the group including or consisting of polyester-based polymers, such as polylactic acid (PLA) and / or polyglycolic acid (PGA), fatty alcohols, fatty acids, lipids, steroids, polymers, waxes and oils, etc.

[0035] Elution The drug-eluting stent of the present invention further provides a measured elution rate based on the formulation and nature of the therapeutic agent applied to the porous surface covering and the porosity of the covering. The coating provides a stable elution rate, calculated based on the degree of dissociation of the drug from the covering, once the stent system is deployed. An advantage of the present invention is that the porous surface covering allows for the retention of a higher dose of drug, which is a prerequisite for cancer therapy. Thus, in one aspect, the present invention is directed to a method of treating (i) bile duct obstruction, or (ii) pancreatic duct obstruction, or (iii) pancreatic cancer, by placing the drug-eluting stent system described herein in the bile duct or pancreatic duct.

[0036] method One aspect of the invention is a method for preparing a drug eluting stent system, comprising the steps of: (a) providing at least one sheet having a surface of a porous material; (b) placing the at least one sheet on at least one of a luminal or abluminal surface of a stent; (c) applying high temperature and pressure to encapsulate the stent in the porous material, thereby providing the stent with a porous surface covering; (d) applying a therapeutic solution to the porous surface covering; and (e) drying the porous surface covering portion to which the therapeutic solution has been applied. The present invention is directed to a method, comprising:

[0037] In one embodiment, step (c) is carried out in such a manner that the temperature is in the range of 55°C to 90°C and the pressure is in the range of 0.13MPa to 1.25MPa. Furthermore, step (b) may be carried out in such a manner that the sheet is placed on the luminal and abluminal surfaces of the stent. The method proposed herein can also be carried out such that steps (a) and (b) are carried out simultaneously by applying a sheet of porous material directly onto the surface of the stent. Step (a) is preferably carried out by electrospraying or other means, in particular electrospinning, on a flat surface. Each sheet is then cut to size before being applied to a bare stent, preferably made of metal. Preferably, step (a) is carried out in such a manner that two sheets of porous material, preferably electrospun, are provided. Furthermore, step (a) is carried out in such a manner that two different sheets of porous material, preferably electrospun, are provided. Step (b) is then correspondingly performed in such a manner that one of two sheets of the same or different material is placed on the luminal surface of the stent, while a second sheet of porous material is placed on the abluminal surface of the stent. Also, when providing a porosity gradient in the drug-eluting stent system proposed herein, two or more sheets of different porosity can be used on each surface of the stent to provide a more diverse gradient.

[0038] In particular, the porosity preferably increases from the luminal surface to the abluminal surface of the stent system. In particular, to obtain a smooth inner surface of the porous covering with low or no porosity, step (a) can be carried out in such a manner that at least one sheet of porous material is used and a second sheet with less or no porosity is used. In this embodiment, the sheet of porous material is placed on the abluminal surface of the stent, whereas the sheet with less or no porosity is placed on the luminal surface of the stent. The stent encapsulation obtained by carrying out step (c) will then be carried out between one porous material on the abluminal surface and one non-porous material on the luminal surface. Furthermore, when a porous material on the abluminal surface is combined with a less porous material on the luminal surface, step (c) can be carried out in such a manner that the few and / or narrow pores on the luminal surface are closed by using high temperatures, in particular by slightly melting the material on the luminal surface. Additionally, a step (f) comprising applying at least one sealant to the luminal surface of the porous surface covering may be incorporated into the methods proposed herein.

[0039] example 1. Preparation of the Stent Example A:In one design form, the invention encompasses an expandable prosthesis (stent) in which a metallic structural base comprising nickel-titanium alloy is further encapsulated with a biocompatible porous mesh. The prosthesis self-expands to its full diameter at human or animal body temperature without the aid of a deployment balloon. The mesh pore size is between 1 micron and 5 microns as measured under scanning electron microscopy. The tubular prosthesis is sandwiched between two sheets of porous PFTE or polyurethane material that have been pre-cast onto a flat surface by electrospray or other means and cut to size prior to application to a bare metallic stent. A coating containing the anti-proliferative drug CRC-015 is dissolved in acetone and applied to the stent using a precision syringe applicator that determines the amount of drug to be applied. The porous mesh covering allows for the retention of higher doses of the drug, a prerequisite for cancer therapy. The coated device is then allowed to dry at room temperature for 24 hours. When placed in an appropriate liquid elution medium, the drug separates from the mesh surface into the surrounding medium. An example encapsulated device measuring 40 mm in length and 7 mm in diameter was coated with 4.5 mg of CRC-015 drug dissolved in acetone solvent. The coated device was dried and then placed in a glass container containing 10 mL of 18% (w / w) acetonitrile in phosphate buffer. The container was then placed on a Heidoph model Promax 1020 shaking table, temperature controlled at 37° C., and shaken at a frequency of 200 strokes per minute. Samples of the liquid medium were assayed for drug content. Composite curves of drug elution from the stent over time indicate that consistent values ​​of drug are released from the stent over a period of at least 60 days.

[0040] Example B In another design, a stent containing a cobalt chromium metal mesh was covered with a polyurethane mesh by direct application using an electrospray technique. After drying, the covered stent was ready for drug application. A 120 kHz Micromist nozzle from Sonotek Inc. was used to deposit a 10-35 micron thick coating with a drug formulation containing CRC-015 onto the outer mesh surface. The drug-coated prosthesis was allowed to dry at room temperature for 24 hours and then placed onto a balloon catheter using a crimping device. In human use, the balloon was positioned at the site of the stenosis or stenosis and inflated, expanding the device until it reached its final diameter, allowing the drug contained in the mesh covering to elute into the surrounding tissue.

[0041] Example C A polymer-free CRC-015 solution was prepared by dissolving CRC-015 in acetone to prepare a 30 mg / mL CRC-015 solution. Paclitaxel was then added and dissolved in this solution to a final paclitaxel concentration of 10 mg / mL. This drug-loaded solution is used to coat a covered stent using the disclosed method to prepare a therapeutic combination device capable of inhibiting two different metabolic processes in cancer. It has been found that the two drugs can be applied to the covered stent separately or together, and applying them separately allows for different drugs to be delivered in different areas.

[0042] Example D A polymer-containing CRC-015 solution was prepared by dissolving CRC-015 in acetone to prepare a 20 mg / mL CRC-015 solution. PLA was added to this solution and dissolved to a final PLA concentration of 10 mg / mL. This drug and polymer combined solution was used to coat a covered stent using the method disclosed above. The addition of a polymer can be used to further modify the drug elution rate from the covered stent of the present invention.

[0043] Numerous modifications and variations of the described examples and embodiments will be apparent to those skilled in the art in light of the above teachings. The disclosed examples and embodiments may incorporate some or all of the features disclosed herein. It is therefore intended to include all such modifications and alternative embodiments as may fall within the true scope of the invention.

[0044] Non-clinical trial A To evaluate the antistenotic properties of CRC-015 loaded on the self-expanding covered stent proposed herein, a study was conducted by implanting the stent in the superficial femoral artery (SFA) and deep artery (Profundus Artery) of farm swine for 28 days. Two farm swine (sus scrofa, approximately 3 months old) were sedated, intubated, and placed under general anesthesia with isoflurane. All animals were pretreated with aspirin (80 mg) and Plavix™ 2 days prior to the scheduled surgical procedure and continued daily until the follow up procedure. A dose of CRC-015 of 2.0 μg / mm 2Two covered stents, 6.0 mm and 7.0 mm in diameter and 40 mm in length, were deployed in the peripheral SFA and deep vessels of one hind limb. The contralateral femoral artery was used for catheter and guide access. The stent graft material was 2x2 Bioweb Electrospun PTFE, excipient free. The electronspun graft material was pressurized at elevated temperature to encapsulate the stent proposed herein. The delivery system was an over-the-wire balloon type, requiring a 0.035" wire passing through a dual lumen shaft with a hydrophilic surface coating. The total length of the delivery system catheter was 150 cm. For necropsy, animals were euthanized using sodium pentobarbital after heparinization. The vascular system was accessed and a sheath was inserted into the arterial system. Saline was infused into the arterial system. When the venous effluent flowing from the pretreated vessels began to become clear, the infusion was stopped and the treated arteries were excised. These vessels were appropriately labeled, fixed in 10% neutral formalin, and sent to a pathologist for tissue processing. In one animal, the SFA appeared occluded, but the deep vessels were widely patent. In the second animal, both the SFA and deep vessels were widely patent.

[0045] Non-clinical trial B The primary objective of this study was to evaluate the feasibility of deploying a CRC-015 DCB (drug coated balloon) and a CRC-015 coated biliary stent graft in the bile duct of domestic pigs. Two farmed pigs (sus scrofa, aged 3 months or older) were selected because their size was similar to that of humans and therefore the instrumentation used in human trials could be used. The animals were euthanized 27 days after successful implantation. Evaluations included ductal patency and inflammatory response at 28 days. The CRC-015 DCB and CRC 015 stent graft delivery systems proposed herein were inserted by direct needle puncture into the common bile duct near the duodenum. The puncture site was sutured after stent deployment and delivery system retrieval. The DCB was deployed in the proximal part of the bile duct (close to the gallbladder), and the stent graft was deployed in the distal part of the bile duct (far from the gallbladder). The test article (TA) used in this study was a 6 mm × 40 mm CRC-015DCB, a 0.035 guidewire (4 μg / mm 2 ) and 6 mm × 30 mm CRC-015 biliary stent graft system (4 μg / mm 2 ) and the 7 mm × 30 mm CRC-015 biliary stent graft system (4 μg / mm 2 ) was.

[0046] After terminating the animals, the facility veterinarian concluded that all animals were in good clinical condition and gained weight normally throughout the study period (from treatment to terminal procedure). Clinical pathology showed some iatrogenic excursions from normal ranges (e.g., reticulocytosis, elevated AST or CK) due to blood loss, anesthesia, injections, surgery, and other procedures, as would be expected in a surgical animal model. No abnormal elevations in bilirubin (total, direct, or indirect bilirubin) were reported at the time of sacrifice, suggesting that TA does not interfere with normal bile duct flow. Two animals showed some deviations indicative of an inflammatory state. One animal also showed deviations in platelet count and globulins, but mainly increased fibrinogen at the time of sacrifice compared to normal levels before implantation. The role of TA as a possible etiological or contributing factor in causing these changes remains to be elucidated. The study pathologist concluded that the necropsy findings revealed liver adhesions that were interpreted as secondary to the implantation procedure. Histopathologically, the tissue reaction to the CRC-015 stent-graft was characterized by minimal or mild subacute inflammation in the mucosa, muscularis and / or serosa, minimal or mild mucosal necrosis, and minimal or mild angiogenesis. These changes were determined to be related to the implantation of the stent-graft into the bile duct. Multifocal hemorrhage, most likely related to the removal of the bile duct, was seen in the muscularis and / or serosa in both animals. No epithelialization of the luminal aspect of the CRC-015 stent-graft was observed. Fibrin infiltration, fibrosis, and mineralization were not seen in sections of either the stented or proximal non-stented bile duct. In conclusion, autopsy findings revealed liver adhesions that were interpreted as secondary to the implantation procedure. Histopathological evaluation revealed minimal or mild inflammation, angiogenesis, and mucosal necrosis.

Claims

1. 1. A drug eluting stent system used to deliver at least one therapeutic agent to a target, said target preferably being a bile duct or a pancreatic duct, comprising: (a) a radially expandable stent; and (b) a coating comprising a porous surface covering and at least one therapeutic agent that is an antiproliferative agent; Including, the porous surface covering portion has a porosity of 20% to 40% of its surface area on the abluminal surface and a porosity of less than 5% of its surface area on the luminal surface; the at least one therapeutic agent is an antiproliferative agent; The stent is encapsulated by the coating, provided that The at least one therapeutic agent is applied to the porous surface covering at a concentration of 3.0 to 5.0 μg / mm ２ and is applied only to the abluminal side of the drug-eluting stent system, except that the porous surface covering extends over the interstices between the struts of the stent; and The porous surface cover portion is a nonwoven fabric, the nonwoven fabric being composed of electrospun fibers, the electrospun fibers being It is composed of a polymer selected from the group including or consisting of polytetrafluoroethylene, fluorinated ethylene propylene, Dacron, polyethylene terephthalate, polyurethane, polycarbonate, polypropylene, Pebax, polyethylene, and the biopolymers collagen, fibrin, and elastin.

2. The drug eluting stent system of claim 1, wherein the at least one therapeutic agent is a macrocyclic triene immunosuppressant compound.

3. 2. The drug eluting stent system of claim 1, wherein the at least one therapeutic agent has the following structure: 【Chemistry 1】 [In the formula, R is C(O)-(CH ２ ) ｎ -X, n is 0, 1 or 2, and X is a cyclic hydrocarbon having 3 to 9 carbons, optionally containing one or more unsaturated bonds.

4. C(O)-(CH ２ ) ｎ The drug eluting stent system of claim 3 , wherein -X further has one of the following structures: 【Chemistry 2】

5. The drug eluting stent system of claim 1, wherein the porous surface covering has a porosity in the range of 20% to 40% of its surface area.

6. The drug loading per unit area of ​​the stent of at least one therapeutic agent is about 4.0 μg / mm2 of surface area. ２ ~5.0 μg / mm ２ The drug-eluting stent system according to claim 1 ,

7. 1. A method for preparing a drug eluting stent system, comprising: (a) providing two distinct sheets of porous material; (b) depositing one of the two sheets on the luminal side of the stent and a second sheet of porous material on at least one of the abluminal surfaces of the stent, the sheet on the luminal surface being less porous or non-porous than the sheet on the abluminal surface such that porosity increases from the luminal surface to the abluminal surface of the stent system; (c) applying elevated temperature and pressure to encapsulate the stent within the porous material, thereby providing the stent with a porous surface covering; (d) applying a therapeutic solution to the porous surface covering, the application being only on the abluminal side of the drug-eluting stent system; and (e) drying the porous surface covering portion to which the therapeutic solution has been applied. Including, The above process, wherein in step (c), the temperature is in the range of 55° C. to 90° C. and the pressure is in the range of 0.13 MPa to 1.25 MPa.

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