DE4336209C2 - Method for producing a vascular prosthesis coated with antithrombotic agents - Google Patents

Description

The invention relates to a method for producing an antithrombotic Agent-coated stent made of thread-resorbable material that can be absorbed by the body.

Balloon dilatation of peripheral, renal and coronary arterial stenoses can lead to a tear in the inner skin of the vessel, d. H. come to a dissection of the intima, what eventually lead to vascular occlusion. Are available as therapeutic measures then an emergency bypass operation or the implantation of a vascular prosthesis or Vascular support, a so-called stent, is available in the vessel. Such stents are tubular and lattice-shaped implants which, with a reduced diameter, fit into the damaged vessel introduced and only at the location of the vessel that is to be supported be expanded to their final diameter. This expansion of the stents occurs either due to its (inherent) elasticity (so-called self-expanding Stents), or it is inflated by a pump located inside the stent Balloon causes (so-called balloon expandable stents). The known stents exist usually made of metal, for example surgical stainless steel, tantalum or nitinol; in Polymer stents have also recently been proposed.

EP 04 66 105 A2 describes a vascular prosthesis, which, however, is based on its Structure is not intended as a stent, but rather as a vascular replacement. These Vascular prosthesis cannot be dilated and therefore cannot be used like a stent by means of a Catheter advanced through a blood vessel to a damaged location and there positioned and dilated. Furthermore, the essence of this application is to create a biocompatible inner surface of a vascular prosthesis. To this end will the use of biological material, especially collagen and Elastin fibers, proposed for the production of the inner layer. For stabilization this inner "biological" layer is a second on the outside of this layer, synthetic layer applied.

In US-PS 50 61 275 a stent made of metal threads is claimed. This includes plastics and biocompatible materials as stent material mentioned. However, only the manufacture of a stent is used as an exemplary embodiment  Described metal threads of a certain alloy. This stent will become one Subjected to temperature treatment of 520 ° C, which means the metal threads in the new Shape should be fixed.

A major disadvantage of the known stents, in particular the stents made of metal, consists of either being a permanent foreign body in the treated vessel remain or have to be removed as part of another operation.

To overcome this problem, stents have been proposed which are made of material that can be absorbed by the body. In EP 04 28 479 A1 described, for example, a stent made of polycaprolactone; also stents made of poly-L Lactic acid, a material that is also resorbable by the body, is known (cf. Agrawal, C.M. et al "Evaluation of Poly (L-lactic acid) as a material for intravascular stents "; Biomaterials, 13 (3), 176-182; 1992).

All of the aforementioned stents have a common thrombogenicity, which despite intensive drug anticoagulation for subacute stent thrombosis with Formation of an infarction (with stents in coronary arteries). Under drug-based anticoagulation is given here as anticoagulant Understand substances that spread throughout the blood vessel system and thus in anticoagulant in the entire blood vessel system. A disadvantage of drug anticoagulation is that also at the insertion point of the Stent, usually in the thigh or groin area, problems with wound healing occur because blood clotting is suppressed at this point as well.

EP 05 28 039 A1 describes a stent made of thread-like resorbable material described, which is produced by braiding and with antithrombotic Agents can be coated. A disadvantage of the manufacturing process of this stent is that the thread mesh before the temperature treatment from the shaping cylinder is withdrawn, with the result that the stent during the subsequent Temperature treatment shrinks.

DE-PS 28 31 360 describes the heparinization of a surface with blood in Touching medical object, which, however, is not sufficient resorbable material. The resorbability of the material results in There are special problems with a heparin coating, however in particular, a too rapid detachment of the heparin layer in the course of absorption. This is also the reason why when using absorbable materials mostly  it is proposed to incorporate the heparin into the resorbable material (cf. EP 05 28 039 A1) instead of applying it in one layer on the outside.

The object of the present invention is to produce a resorbable material to make available stent available, which avoids the disadvantages mentioned, that is is broken down in the body and its use the necessity of the previously usual drug anticoagulation reduced or makes it unnecessary.

This object is achieved in that either first the thread-like material wrapped around a pressure and heat stable forme cylinder and then when pressed is sintered between 100 and 2000 bar and elevated temperature (claim 1), or that first the thread-like material around a pressure and heat stable form cylinder is braided and then cured at elevated temperature (claim 2), wherein then in both cases the stent withdrawn from the forme cylinder with heparin as antithrombotic agent is coated.

In principle, the coating of surfaces with heparin is already known. So is with Kido, D.K. et al ("Thrombogenicity of Heparin and Non-Heparin Coated Catheters"; MNR 3; 535-539; 1982) described that heparin-coated cardiac catheters have a have significantly lower thrombogenicity than non-heparin-coated catheters. However, these catheters described here were only for about one or two each Hours of use and they were not made of resorbable material.

So on the one hand, the use of resorbable material for stents per se is known and on the other hand the basic possibility of heparin coating of surfaces is already known, despite the serious disadvantages, has so far not been Stent made of heparin-coated absorbable material proposed or known.

The coating of the stent with heparin leads to local anticoagulation, which is effective only in the area of the stent and is therefore limited to the area in to which it is required. The other areas where at the same time one Blood coagulation is therefore not affected.

A stent according to the invention is produced - generally described - in such a way that the absorbable material is wrapped or knotted like a lattice or net (braided) and is first brought into a cylindrical shape; then this cylinder thermally treated (hardened or sintered) and finally heparinized.  

Special refinements and developments of the present invention are Subject of subclaims 2 to 9.

A stent manufactured, ie braided, according to the second embodiment is harder than a stent manufactured according to the first embodiment. After the sintering process - as shown in FIG. 2 - radial slots are made in the stent, which make it easier to stretch the stent in the longitudinal direction and thus also to reduce its diameter. The stent is then withdrawn from the cylinder serving as the shape and coated with heparin.

This stent made of resorbable material coated with heparin can with very small inner diameters, for example 2 mm, can be realized and is therefore especially suitable for smaller vessels, especially coronary arteries. Straight With such small stents, effective local anticoagulation is special important because the risk of thrombus formation is disproportionately high.

The stent according to the invention is preferably designed to be balloon-expandable and can be attached to known way as the other previously known balloon expandable stents in the vessel to be supported. The stents made by sintering are stiffer than the hardened stents and can alternatively be used in a self-expanding Form be formed.

In the following exemplary embodiments, the production of Stents according to the invention explained in more detail.

example 1

The starting material for the production of a stent according to the invention is synthetic, resorbable suture material made from polyglycolic acid-trimethylene carbonate copolymer with a thread size of 6-0, which corresponds to a thread diameter of 0.07 to 0.099 mm. Such a material is already known as surgical suture material (cf. Katz, AR et al; "A new synthetic monofilament absorbable suture made from polytrimethylene carbonate"; Surgery, Gynecology & Obstetrics 161, 213-222; 1985). Six or even eight threads - as shown in FIG. 1 for four threads - were wound with double wraps around a temperature-resistant metal cylinder with an outside diameter of 4 mm. The braid was cured with the metal cylinder for 30 minutes in a nitrogen atmosphere at a temperature of 180 ° C. This was then rapidly cooled in a stream of the inert gas. The hardened braid was then pulled off the metal cylinder and heparinized as follows, ie coated with heparin:
The following solutions are required in connection with heparinization:
Solution I:
A: Adjust 9 mg heparin / 22 ml ultrapure water to pH 3.0 (at 60 ° C) with HCl.

B: 24 mg hexadecylamine hydrochloride / 3 ml ultrapure water adjust to pH 3.0 (at 50 ° C) with HCl.

Solution A is mixed with solution B at 60 ° C; the resulting colloidal Solution is diluted to 125 ml with ultrapure water.

Solution H:
Adjust 0.07 mg / ml heparin solution to pH 3.0 (at 50 ° C) with HCl.

The treatment (exposure) of the braid then proceeded as follows:

1 min in solution I at 60 ° C, then Rinse 5 × with distilled water, then 5 min in solution H at 60 ° C, then Rinse 5 × with distilled water, and then repeat the entire process ten times.

Finally, the braid was exposed to 0.25% glutaraldehyde solution for 20 min at 60 ° C treated and then rinsed five times with distilled water.

The excess of amine (hexadecylamine hydrochloride) Heparin molecules surrounded by a double layer of this cationic surfactant and thus form stable colloidal particles with a positive net charge. By Adsorption of these positively charged particles on the stent mesh and reversal of the positively charged surface through exposure to a heparin solution becomes heparin thus ionically bound to the braid in several layers. By the subsequent Treatment with glutaraldehyde crosslinks the heparin molecules.  

Example 2

As in Example 1, synthetic, resorbable suture material made from polyglycolic acid / trimethylene carbonate copolymer with a thread size of 6-0 (thread diameter 0.07 to 0.099 mm) serves as the starting material for the production of a stent according to the invention. The threads were wrapped as tightly as possible in several (two to ten) layers around a temperature and pressure-resistant metal cylinder with an outside diameter of 4 mm. This cylinder, wrapped with the suture material, was brought into a cylindrical bore of a temperature and pressure-resistant, in particular two-part, metal block. The cylindrical bore of the metal block has a thickness corresponding to the thickness of the wound thread layers, in particular a slightly smaller diameter, and is, for. B. realized by appropriate abutting two each provided on one side with trough-shaped recesses with a semicircular cross-section metal blocks. At a temperature of 180 ° C and a pressure of 700 bar, the suture was thermally treated for 10 minutes, ie sintered. In order to ensure its deformability, the suture material sintered to form a tube was provided with radial slots, each of which extends over approximately 1/4 of the tube circumference (cf. FIG. 2). The sintered casing was then removed from the shaping metal cylinder and - just as specified in Example 1 - the coating was carried out with heparin.

Example 3

Serves as the starting material for the production of a stent according to the invention synthetic, absorbable suture made of polydioxanone with a Thread diameter of 30 µm. The threads were turned as tightly as possible in 25 layers a temperature and pressure resistant metal cylinder with 4 mm outer diameter wrapped. This cylinder, wrapped with the suture material, was turned into a cylindrical one Drilling a temperature and pressure resistant metal block, as in example 2 is described. At a temperature of 100 ° C and a pressure of 700 bar the suture was thermally treated for 10 min. H. sintered. The attachment of radial slots to ensure deformability and the subsequent Coating with heparin was carried out as described in Example 2.

Stents of the type described above were tested in vitro. It was demonstrated that the heparinized stents compared to non-heparin coated Stents actually have a greatly reduced thrombogenicity.

Claims (9)

1. A process for producing a stent coated with antithrombotic agents from thread-resorbable material resorbable by the body, characterized in that the thread-like material is first wound around a pressure- and heat-stable form cylinder and then sintered at pressures between 100 and 2000 bar and elevated temperature, and that the stent withdrawn from the forme cylinder is coated with heparin as an antithrombotic agent. 2. Method for producing a coated with antithrombotic agents Stent made of thread-resorbable material, characterized, that first the thread-like material around a pressure and heat stable Form cylinder is braided and then hardened at elevated temperature, and that the stent withdrawn from the forme cylinder with heparin as antithrombotic agent is coated. 3. A method for producing a stent according to claim 2, characterized, that the thread-like material in double wraps on the forme cylinder is braided. 4. A method for producing a stent according to claim 1, 2 or 3, characterized, that as a material that is resorbable by the body, a polyglycolic acid Trimethylene carbonate copolymer and / or a polydioxanone is used. 5. A method for producing a stent according to claim 3, characterized, that several, especially 6 or 8, threads in double wraps on the pressure and heat stable form cylinder to a lattice or net-like cylinder to be braided.   6. A method for producing a stent according to claim 1, characterized, that the cylindrical shape of the stent by 2 to 50, in particular 3 to 25, superimposed tight windings of thread-like material around one pressure and heat stable form cylinder is achieved. 7. A method for producing a stent according to claim 2, characterized, that the filamentary material brought into cylindrical form under atmospheric pressure a temperature treatment between 150 ° C and 250 ° C, especially between 170 ° C and 190 ° C, optionally in an inert atmosphere. 8. A method of making a stent according to claim 6, wherein the filamentary Material consists of polyglycolic acid-trimethylene carbonate copolymer, characterized, that the thread material made into a cylinder is under a pressure between 100 and 2000 bar, in particular 700 bar, a temperature treatment between 150 ° C. and 250 ° C, in particular between 170 ° C and 190 ° C, is subjected. 9. A method of making a stent according to claim 6, wherein the filamentary Material consists of polydioxanone, characterized, that the thread material made into a cylinder is under a pressure between 100 and 2000 bar, in particular 700 bar, a temperature treatment between 50 ° C and 150 ° C, in particular between 80 ° C and 120 ° C, is subjected.