MEDICAL DEVICE WITH A BIOCOMPATIBLE COATING

Abstract

An implantable medical device comprising (a) a metallic substrate and (b) a bisphosphonate wherein both phosphorus atoms contained in the bisphosphonate are covalently attached to a same carbon atom. The bisphosphonate continuously coats the external surface of the metallic substrate as monolayer and as outermost layer. At least one phosphonate moiety of the bisphosphonate is covalently and directly bonded to the external surface of the metallic substrate and/or covalently bonded to another molecule of the bisphosphonate in the coating.

Claims

1. A vascular endoprosthesis comprising: (a) a metallic substrate; and (b) a bisphosphonate having the general formula (I), ##STR00004## wherein R.sup.1 represents (i) —C.sub.1-5 unsubstituted alkyl, or (ii) Cl; R.sup.2 represents —H, —OH or —Cl; M.sup.1, M.sup.2, M.sup.3, M.sup.4 are each a hydrogen atom or a metallic atom, the bisphosphonate is continuously coated on an external surface of the metallic substrate as a monolayer and as an outermost layer, and at least one phosphonate moiety of the bisphosphonate is covalently and directly bonded to the external surface of the metallic substrate in the coating.

2. The vascular endoprosthesis according to claim 1 wherein R.sup.1 represents —CH.sub.3 and R.sup.2 represents —OH.

3. The vascular endoprosthesis according to claim 1, wherein the surface phosphorus-atom concentration of the coating of the bisphosphonate is at least 70% P.

4. The vascular endoprosthesis according to claim 1, wherein the surface phosphorus-atom concentration of the coating of the bisphosphonate is at least 80% P.

5. The vascular endoprosthesis according to claim 1, selected from the group consisting of stents, stentgraft, filter, heart valve, coronary stents and peripheral stents.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0056] FIG. 1 is comparative graph showing platelet rich plasma (PRP) adhesion on a bare-metal surface as comparative example (CEX) and on a bisphosphonate coating according to the invention (INV).

[0057] FIG. 2 is comparative graph showing platelet poor plasma (PPP) adhesion on a bare-metal surface as comparative example (CEX) and on a bisphosphonate coating according to the invention (INV).

[0058] FIG. 3 is comparative graph showing relative endothelialisation on a bare-metal surface as comparative example (CEX) and on a bisphosphonate coating according to the invention (INV).

[0059] FIG. 4 is comparative graph showing relative inflammation with a bare-metal surface as comparative example (CEX) and with a bisphosphonate coating according to the invention (INV).

DETAILED DESCRIPTION OF THE INVENTION

[0060] The terms “implantable medical device” and “implant” are used synonymously here and are understood to include medical or therapeutic implants, such as vascular endoprosthesis, intraluminal endoprosthesis, stents, coronary stents, peripheral stents, surgical and/or orthopedic implant for temporary use, such as surgical screws, plates, nails and other fastening means, permanent surgical or orthopedic implants, such as bone prosthesis or joint prosthesis.

[0061] The term of “vascular endoprosthesis” are used synonymously here and are understood to include stents, stentgraft, filter, heart valve, coronary stents and peripheral stents.

[0062] The implantable medical device according to the present invention comprises, or essentially consists of, a metallic substrate which is selected from the group consisting of iron, magnesium, nickel, tungsten, titanium, zirconium, niobium, tantalum, zinc or silicon and, if necessary, a second component of one or several metals from the group consisting of lithium, sodium, potassium, calcium, manganese, iron or tungsten, preferably of a zinc-calcium alloy. In a further practical example, the metallic substrate consists of a memory effect material of one or several materials from the group consisting of nickel titanium alloys and copper zinc aluminium alloys, but preferably of nitinol. In a further practical example, the metallic substrate of the medical device consists of stainless steel, preferably of a Cr—Ni—Fe steel, in this case, preferably the alloy 316L, or a Co—Cr steel such as Phynox. In preferred embodiments of the present invention, the implantable medical devices are stents, in particular metal stents, preferably self-expanding stents.

[0063] This invention is related to a coating for a metallic substrate comprising a bisphosphonate layer derived from a bisphosphonic acid, the two phosphorus atoms of the bisphosphonic acid are covalently attached to same carbon atom.

[0064] U.S. Pat. No. 5,431,920 discloses a composition in dosage form comprising a bisphosphonic acid as active ingredient for treating metabolic bone diseases such as osteoporosis.

[0065] European Pat No. 1,508,343 discloses a multilayer coating for an implant device for use of bone fixation. The coating comprises two types of bisphosphate layers; one is designed to release from the multilayer coating immediately after the implant device has been inserted and the other designed slowly released over time for the long-time use of the implant device. The latter type of bisphosphate layer is strongly bonded to a plurality of protein layers which are immobilized on a surface of the implant device. The former type of bisphosphate is loosely bonded to the latter type of layers as outermost layer of the coating.

[0066] According to the present invention, a bisphosphonate coats a metallic surface of an implantable medical device as monolayer and as outermost layer. At least one phosphonate moiety of the bisphosphonate is covalently and directly bonded to the metallic surface. Some molecules of the bisphosphonate may covalently bond to another molecule of the bisphosphonate in the coating. Therefore, after implantation, the bisphosphonate or bisphosphonic acid is not released by the coating as an active ingredient but permanently stays on the surface as a part of the coating. Surprisingly the mere presence of the bisphosphonate layer provides biocompatibility to the coating and reduces the inflammatory response and/or promotes the formation of an endothelial cell layer on the coating while significantly decreasing the activation and adhesion of platelet. As a result, the risks of restenosis and thrombosis are strongly reduced.

[0067] “Phosphate group” means a functional group comprising phosphorus attached to four oxygens and with net negative charge, thus presented as PO.sub.4.sub.−. “Phosphonic acid” is an organic compound containing C—PO(OH).sub.2 group. “Phosphonate” is a salt or ester of an phosphonic acid and has a general formula R.sup.1—PO(OR.sup.2).sub.2 group (where R.sup.1 represents alkyl or aryl and R.sup.2 represents alkyl, aryl or a counter cation of the salts). For purposes of the present invention, “bisphosphonate” refers to compounds having two phosphonate (PO.sub.3) groups in the molecule. Bisphosphonates according to the present invention have a common P—C—P “backbone”, namely, the two phosphonate (PO.sub.3) groups covalently linked to one carbon atom.

[0068] In preferred embodiments of the present invention, a bisphosphonic acid used for providing the bisphosphonate monolayer on the metallic surface of the implantable medical device has the general formula (I) or a salt thereof.

##STR00003##

[0069] In the formula (I) R.sup.1 represents —C.sub.1-5 alkyl (which is unsubstituted or substituted with —NH.sub.2, pyridyl, pyrrolidyl or —NR.sup.3R.sup.4), —NHR.sup.5, —SR.sup.6 or —Cl; R.sup.2 represents —H, —OH, or —Cl; R.sup.3 represents —H or —C.sub.1-5 alkyl; R.sup.4 represents —C.sub.1-5 alkyl; R.sup.5 represents —C.sub.1-10 alkyl or —C.sub.3-10 cycloalkyl; R.sup.6 represents phenyl.

[0070] As used herein, “alkyl” is intended to include both branched- and straight-chain saturated aliphatic hydro carbon groups having the specified number of carbon atoms; “cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0071] In preferred embodiments of the present invention, the bisphosphonic acid can be selected from the group consisting of 1-hydroxyethylidene-1,1-diphosphonic acid (etidronic acid), alendronic acid, clodronic acid, pamidronic acid, tiludronic acid and risedronic acid, preferably 1-hydroxyethylidene-1,1-diphosphonic acid (etidronic acid).

[0072] The bisphosphonate in the coating according to the present invention continuously coats the external surface of the metallic substrate as monolayer and as outermost layer, and at least one phosphonate moiety of each molecule of the bisphosphonate is covalently and directly bonded to the external surface of the metallic substrate and/or covalently bonded to another molecule of the bisphosphonate in the coating.

[0073] Induction heating is a widely used method to heat metallic substrates directly and contactless by electromagnetic induction, where eddy currents are generated within the metal and resistance leads to Joule heating of the metal. An induction heater (for any process) consists of an electromagnet such as coil, through which a high-frequency alternating current (AC) is passed.

[0074] In a preferred embodiment, a container made of non-conductive material comprising a metallic substrate to be coated and a liquid carrier containing the bisphosphonic acid compound is located inside of a conductive coil. The metallic substrate is subject to the eddy current produced by passing through the coil a AC with a power output of between 50 and 500 kW and a frequency between 150 and 250 kHz, so as to obtain a bisphosphate layer on a surface of the metallic substrate with a desirable thickness. The concentration of the bisphosphonic acid compound is between 10.sup.−2 and 10.sup.−4 mol/l, preferably 10.sup.−3 mol/l. The bisphosphonic acid compound is preferably dissolved in the liquid carrier. The liquid carrier may be alcohol such as methanol and ethanol and isopropanol, THF, DMF, water or a mixture thereof.

[0075] In a further preferred embodiment, a metallic substrate to be coated is immersed in a liquid carrier containing the bisphosphonic acid at a concentration between 10.sup.−2 and 10.sup.−4 M and the liquid carrier is heated by conventional means for at least 24 h at a temperature of at least 70° C.

[0076] The metallic substrate may be subject to a thermal treatment (TT) so as to promote the formation of a thick oxidized layer on the metallic substrate.

[0077] Surface compositions (total atomic concentration %) of bisphosphate monolayers on a metallic substrate has been measured with X-ray photoelectron spectroscopy (XPS). The surface phosphorus-atom concentration of the coating of the bisphosphate substrate is at least 70% P, preferably at least 90% P.

EXAMPLES

Example 1: (Formation of a Coating)

[0078] 5 mm Phynox stents in 2 cm long were provided as medical device to be coated. The Phynox surface was modified by a thermal treatment (TT) in an oven for 15 min at 550° C., and then a chemical treatment (CT, immersing the stent into a solution of 0.1% HF and 20% HNO.sub.3 for 15 min and then immersing the stent in solution of 2.5% HNO.sub.3 for 30 min) was performed. The stents were subjected to an ethylene oxide sterilization process before surface treatment. Etidronic acid (EA) aqueous solution was obtained by dilution 1000× of the mother solution (60% v/v). The stent was immersed into the solution and heated at 80° C. for 48 hours.

Example 2: (Induction Heating)

[0079] 5 mm Phynox stents in 2 cm long stent were provided as medical device to be coated. The Phynox surface was modified by a thermal treatment (TT) in an oven for 15 min at 550° C., and then a chemical treatment (CT, immersing the stent into a solution of 0.1% HF and 20% HNO.sub.3 for 15 min and then immersing the stent in solution of 2.5% HNO.sub.3 for 30 min) was performed. Etidronic acid aqueous solution was prepared at a concentration of 10.sup.−3 M. The stents were immersed into the solution and subjected to the induction heating with Ambrell EasyHeat induction heating system with a power output of 110 kW and a frequency of 198 kHz. The used solenoid was composed of 7 spires with an internal diameter of 9 cm.

Example 3: (Platelet Adhesion)

[0080] Blood was collected in 3.6 ml sodium citrate 3.5% vials to prevent coagulation. Full blood was being centrifuged at two different rotation speeds in order to obtain two different types of plasma. The first type (a plasma rich in platelets (PRP)) was obtained by centrifugation at 900 rpm, and the second type (a plasma poor in platelets (PPP)) was obtained by centrifugation at 1500 rpm. In order to have sufficient volume for the test, plasma was diluted in HBSS (Hank's buffered salt solution). Platelets adhesion was assessed by spectrophotometry. The amount of total protein was evaluated by measurement of the absorbance at 280 nm. The bare-metal stents and the ones with the EA coating were prepared as described in example 1 and immersed in one of the two plasma solutions for 24 hours, at 37° C. and under constant agitation (STAT-FAX 2200 Thermostated agitator). When completed the stents are rinsed with HBSS buffer and then treated with 125 μl lysis solution. Total absorbance at 280 nm is than being measured. Raw data were normalized by dividing every sample value by the average of the control for every experiment (PRP and PPP).

[0081] FIGS. 1 and 2 show respectively PRP and PPP adhesions to the bare-metal surface (CEX) and to the EA coating according to the invention (INV). The difference between the PRP and the PPP value reflects the amount of platelets adsorbed on the surface.

[0082] Conclusion: An important (40% !) decrease of platelet aggregation was observed on the EA coating according to the invention compared to the bare-metal surface.

Example 4: (Endothelial Cells Growth: Endothelialisation)

[0083] The bare-metal stents and the ones with the EA coating were prepared as described in example 1 and incubated with 70.000 cells (EA.hY926) per well for 7 days (37° C., CO.sub.2 5%). This large amount of cells was meant to enhance the probability for cells to be trapped into the meshing of the stents. 80% (4 ml out of 5 ml) of the culture medium was replaced twice during the incubation period (after 1 and 4 days). When completed the stents are rinsed with HBSS buffer and then treated with 125 μl lysis solution. Total absorbance at 280 nm is than being measured.

[0084] FIG. 3 shows relative endothelialisation on the bare-metal surface (CEX) and on the EA coating according to the invention (INV).

[0085] Conclusion: a same level of endothelial cells growth was observed on the EA coating as compared to the bare-metal surface. Thus, desirable ability of wall cell regeneration is not reduced while decreasing platelet aggregation.

Example 5: (Inflammation Induction)

[0086] The IL-8 values obtained with the bare-metal stents and with the EA coating stents prepared as described in example 1 were measured in the medium using a regular ELISA set in accordance with the instructions provided.

[0087] FIG. 4 shows relative inflammation with the bare-metal surface (CEX) and with the EA coating according to the invention (INV).

[0088] Conclusion: The inflammatory response induced with the EA coating was significantly improved, i.e., 23% lower, compared to the bare-metal surface.

[0089] Accordingly, the bisphosphonate coating according to the present invention exhibited a significant decease of platelet adhesion and cell inflammatory response compared to the bare-metal surface while keeping rapid promotion of endothelial cell growth thereon.