MXPA06004571A - Method for preparing drug eluting medical devices and devices obtained therefrom - Google Patents

Abstract

The present invention relates to a method for preparing a 5 drug eluting medical device comprising the application to a stent of a polymer having functional groups capable of chemically binding biological molecules, characterised in that said application is carried out in a single step by means of cold plasma methods. Moreover, the invention 10 also relates to a medical device obtained therefrom.

Description

METHOD FOR PREPARING MEDICAL DEVICES FOR DRUG LEACHING AND DEVICE OBTAINED WITH IT The present invention relates to a method for preparing medical devices for drug leaching and devices obtained therefrom. In particular, the invention relates to a method for preparing a vascular stent covered with one or more drugs to treat and / or prevent restenosis.

In angioplasty, the use of stents in the treatment of coronary occlusions is currently well known and widely accepted and practiced. Stents are metal mesh prostheses positioned in the stenotic portion of the vessel that remain at the site of the lesion after the leaching system and the balloon have been removed. In this way, the stent compresses the plate and provides the vessel wall with a mechanical support to maintain the diameter of the vessel that is restored by expanding the balloon, and prevents collapse of the vessel.

However, the long-term effectiveness of using intercoronary stents presents the great problem of coronary restenosis after angioplasty, that is, the reocclusion phenomenon of the coronary vessel. In fact, this phenomenon of restenosis occurs between 15-30% of patients undergoing angioplasty with stents, as described for example in Williams DO, Holubkov R, Yeh W et al., "Percutaneous coronary interventions in the current it was compared with 1985-1986: The National Heart, Lung and Blood Institute Registries "(" Percutaneous Interventions in the Current Era Compared with 1985-1986: Registries of the National Heart, Lung, and Blood Institute "), Circulation 2000; 102: 2945-2951.

The stenosis caused by the insertion of the stent is due to the hyperplasia of the newly formed interiors (intima). In particular, the mechanical damage caused by the stent to the wall of the artery and the reaction to the foreign body, caused by the presence of the stent, produce a process of chronic inflammation in the vessel. This phenomenon in turn leads to the leaching of cytokines and developmental factors that promote the activation of the proliferation and migration of smooth muscle cells.

(SMC, acronym in English) -. The growth of these cells together with the production of! an extracellular matrix produces the enlargement of the section of the vessel occupied by the neointima and therefore the process of reduction in the opening of the vessel, - giving rise to the above-mentioned restenosis.

To prevent this problem, several methods have been developed including one that provides the coating of the stent directly with a drug or with a polymer-type cover capable of incorporating the drug and leaching it locally through a control mechanism. A typical example of a covered drug-eluting stent (DES) is described on paper by Takeshi Suzuki and collaborators in Stent-Based Delivery of Sirolimus Reducing Neointimal Formation in a Porcine Coronary Model. "Stent-based delivery of Sirolimus reduces neointimal formation in a porcine coronary model"), Circulation 2001; 1188-1193. The materials used are generally polymers, either degradable or non-degradable, which must have characteristics of adhesion to the metal substrate (stent), the ability to regulate the range of leaching of the drug, an absence of the phenomenon of toxicity and an interaction favorable with the surrounding tissue.

In particular, as far as the latter characteristics are concerned, the interactions of the material with the surrounding tissue are controlled to a large extent by the properties of the material surface. The . The materials used in medical devices in general "do not present optimal surface characteristics, as far as the interaction with the host tissue is concerned." This circumstance manifests itself from a clinical point of view with the activation of the reaction phenomenon to the foreign body and, in particular - for materials in contact with blood, with the formation of thrombi and / or emboli. The extent of the phenomenon is such that the thrombogenicity of synthetic materials is the most serious obstacle to the development of artificial vessels of small sizes.

To try to resolve these disadvantages, procedures have been developed that, through chemical reactions, provide the coverage of the thrombogenic material with natural non-thrombogenic molecules.

The anticoagulant heparin is a typical example. These procedures provide a first step in which Suitable chemical groups for binding heparin, hyaluronic acid or other biomolecules are introduced into the surface of the stent (or the medical device in general), and a second step consisting of the chemical linking of heparin, hyaluronic acid or other biomolecules with certain groups introduced by means of the previous step. Accordingly, the polymers used for the delivery of the drug are not capable as they are of directly agglutinating the biomolecules, but require the above step of introduction of functional groups and subsequently the immobilization of the biomolecules.

There are polymers which themselves contain functional groups such as amine groups or from which amine groups can be generated. These polymers can be applied to the. surface of the stents using conventional technology.

However, it has been found that these polymers suffer from the serious disadvantage of being hydrophilic. and, since the passage of the bound with heparin or other biomolecules generally takes place in a solvent and in particular for heparin in an aqueous environment, there is a large risk of losing at least part of the drug during the preparation of the stent, precisely because of the solubility of the polymer in water; in addition, precisely because of the hydrophilic nature of the polymer, the ability to control the leaching of the drug is limited and is completely inadequate to control the leaching of drugs which in turn are hydrophilic.

In addition, the drug leached in the solution containing heparin and functional groups may interfere with the immobilization reaction, jeopardizing a successful outcome.

The problem addressed by the present invention is therefore that of making available a method for preparing a drug leaching vascular stent, capable of solving the aforementioned disadvantages.

These problems are solved through a method to prepare a medical drug leaching device that simplifies the production process and at the same time prevents the loss of the drug or compound bulls, which could put at risk the preparation of the stent.

Therefore, a first objective of the invention is to make available a method for preparing a medical device as described in the appended claims.

A second objective of the invention is to provide a medical drug leaching device obtainable according to the above-mentioned method.

By the term "medical drug leaching device" is meant a device that will be inserted into the human or animal body, internally or subcutaneously, designed to remain in the human or animal body for a definite period of time or permanently, and that it is capable of leaching a pharmaceutically effective dose of one or more drugs during at least part of the time during which it resides in the human or animal body. This medical device can be a vascular device, a prosthesis, a probe, a catheter, a dental implant or the like. More preferably, this device will be a vascular stent.

Other features and advantages of the present invention will become clear from the following description of a representation that is provided by way of non-limiting example, where: - Figure 1 shows the leaching curve for a hydrophilic drug from a covered stent with polymer according to the state of the art, compared with the leaching curve for a hydrophilic drug from a stent covered with polymer according to the invention; Figure 2 shows the leaching curve for a hydrophobic drug from a stent covered with polymer according to the state of the art, compared, with the leaching curve for a hydrophobic drug from a stent covered with a polymer according to the invention.

Surprisingly, after numerous experiments it was found that if the polymers having functional groups such as the amine groups were applied to the surface of the medical device in a single step, using a cold plasma method, the coverage of the stent was obtained in the form of a hydrophobic film, which adhered well, and with stable and active functional groups capable of rapidly binding heparin, hyaluronic acid or other biomolecule.

The following description will refer to a vascular stent, but could also be applied to any other medical device of the invention.

In particular, it has been observed that polymers with functional amine groups deposited on the metal surface of the stents. Vascular through cold plasma assume hydrophobicity characteristics, excellent adhesion to the stent, a high degree of cross-linking so that it operates as a barrier that slows down the diffusion of a drug, and the ability to bind heparin and other biomolecules through of the amine groups.

The method for preparing a drug leaching vascular stent as described in the invention therefore comprises applying to the stent surface a polymer having stable reactive functional groups, such as, for example, the amine, carboxyl and sulfhydryl groups. , where the application is carried out in a single step by means of cold plasma methods.

According to a first form of - Representation, the polymers are deposited in the form of a film. In particular, the polymers have functional groups capable of forming a covalent bond with the biological molecules, preferably chosen from heparin, hyaluronic acid or antithrombotic substances in general. More particularly, the polymers are selected from the group consisting of polymers containing amine, carboxyl and sulfhydryl groups. Preferably, the polymers with amine groups are derivatives of precursors or monomers chosen from allylamine, heptylane, aliphatic or aromatic amines; polymers with carboxyl groups are derived from precursors or monomers chosen from acrylic acid and methacrylic acid. The polymers with sulfhydryl groups are derived from precursors or monomers chosen from the volatile mercaptans.

The method described by the invention can also provide other polymer layers to be deposited depending on the degree or type of mechanisms for leaching the drug to be obtained. These latter deposits are produced according to methods known in the art, such as immersion in a suitable solution or spraying with a pneumatic spray gun or using the cold plasma method mentioned above. It should be noted that in any case the outermost layer should be deposited according to the cold plasma method using the. above mentioned polymers having functional groups.

The plasma used according to the invention is a cold plasma, that is, the temperature of the total mass of gas in the plasma phase is of the same order as the ambient temperature. The plasma is generated in a conventional reactor of the type - which comprises a treatment chamber in the interior, where there is a support for the material to be treated, with a discharge source located in the vicinity to produce the plasma.

The cold plasma can be produced under vacuum or at atmospheric pressure and can be generated using various electromagnetic sources, that is, sources of various frequencies and various geometries, such as for example radio frequency generators or microwave generators, with electrodes of the inductive or capacitive type .

In general, when the vacuum method is used, the. Cold plasma is produced in a chamber with a pressure that can vary between 0.01 and 10 mbar.

In terms of the treatment conditions, these depend on the electrical power that can vary from 1 to 500 W, the geometry of the source that produces the plasma, which can be inductive or capacitive, and the frequencies of the electromagnetic radiation used to produce the plasma, which may be in the range of the microwave or radio frequency.

In addition, the cold plasma that is generated is characterized by a density of charged species between 108 and 1012 cm3, a condition of substantial charge neutrality (quasi-neutral, ion density, electron density), electron energies from 0.1 to 10 eV or average electrical energy calculated as (ekBT / m) l / 2 (e = 1.9 10-19 C, kB = 1.38 10-23 J / K, m = 9.1 10-31 kg, T = absolute temperature in degrees Kelvin), while ions and neutral particles are at temperatures of the order of room temperature.

The treatment time in a cold plasma is generally not more than 30 minutes, preferably between 0.1 and 20 minutes and even more preferably between 1 and 10 minutes.

- Preferably, the vacuum plasma treatment takes place according to a discontinuous or continuous method. This method will not be 'described' in detail here, since it is widely known in the art.

The cold plasma used can preferably be generated - at a pressure lower than atmospheric pressure. The precursor or monomer to be polymerized in the plasma phase is introduced into the reactor in the form of gas or vapor, with flow ranges ranging from 0.1 to 200 sccm (acronym of cubic centimeters in standard conditions per minute). At this point, the plasma is started and the treatment is performed.

A preferably conventional type of reactor, which is not shown, according to the invention, is represented by a radio frequency plasma reactor, with parallel flat plate electrodes, comprising a treatment chamber, of 'steel, aluminum or glass, connected to a vacuum pump. The precursor or monomer is introduced in the form of gas or vapor into the chamber by means of a suitable feeding system, and a potential difference is applied between the electrodes. In this way, the flow of gas or vapor is ionized, triggering the series of reactions that lead to it being deposited according to the typical methods of plasma polymerization. The precursor or monomer that gave the best results was allylamine since the presence of the double bond substantially increases the rate of deposition and therefore the speed with which optimum thicknesses are reached for use. In particular, the thicknesses that are generally used for a drug leaching polymer are in fact between 0.01 microns and 10 microns. Preferably, as far as allylamine is concerned, the thicknesses vary from 0.1 to 10 microns.

According to a variant representation of the invention, the method for preparing a vascular stent also comprises, before depositing by cold plasma the polymer comprising the functional groups, an application step of at least one layer of the incorporated drug where appropriate in a polymer capable of leaching that drug. This step is performed using conventional methods such as immersion or sprinkling and using conventional polymers.

The nature of the polymers normally used for this step is dictated substantially by the leaching mechanism contemplated for the drug and, in • Any case, within the competence of one. person experienced in the art. For example, in the case of coronary stents for which leaching times of the order of months are required, it will be essential to use polymers that produce a slow leaching mechanism. In the case of hydrophilic drugs, such as the imatinib mesylate (sold under the name of Glivec® by the Novartis company), it will be preferable to use hydrophobic hydrocarbon polymers such as polystyrene, polyethylene, polybutadiene and polyisoprene. Polybutadiene, due to its elastomeric nature, the absence of toxic effects and its availability, is the preferable polymer. In the case of hydrophobic drugs, such as taxol, tacrolimus and the like or dexamethasone, more hydrophilic polymers such as polyamides, polyurethanes, polyacrylates or hydrophilic polymethacrylates can be used. The polyhydroxybutyl methacrylate and the polyhydroxyethyl methacrylate, applied alone or with the hydrophobic component polybutadiene, in order to more finely regulate the leaching mechanism, are the preferred polymers.

As described above, these polymers will preferably be applied in -la. 'form of a solution in organic solvents by immersion or sprinkling. In particular, the technique of sprinkling by means of an air brush or similar systems operated with air, or the technique of sprinkling using ultrasonic nozzles can be used.

The thickness of the deposited layer depends on the nature of the drug, the polymer and the leaching mechanism desired. In any case, the. Indicative values for a person skilled in the art are between 0.5 and 20 microns, preferably between 1 and 10 microns. The adjustments in the bases of what has been established are in any case part of the state of the art.

In regard to the drug to be leached, in general all known drugs for this purpose can be used. In particular, anti-inflammatory drugs, antiproliferative drugs, anti-migrants, or immunosuppressive agents can be used. Preferably, imatinib mesylate, ie, 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3- [[4- (3-pyridinyl) -2-pyrimidinyl] methanesulfonate] can be used. amino] -phenyl] benzamide, marketed under the name of Glivec® by the company Novartis.

The amount of drug that will be combined with the polymer varies according to the class of the drug. For example, when the drug is an anti-inflammatory, it is usually present in amounts between 0.001 mg and 10 mg per device. When the drug is an antiproliferative, it is present in amounts between 0.0001 and 10 mg per device. When the drug has an anti-migratory action, it can be present in amounts from 0.0001 mg to 10 mg per device. When the drug is an immunosuppressant, it is present in amounts from 0.0001 mg to 10 mg per weight per device. When the drug is imatinib mesylate (Glivec®), it is present in amounts from 0.001 mg to 10 mg per device.

The method for preparing a medical device according to the invention also comprises a step of agglutinating / immobilizing the antithrombotic substances on the surface of the polymer carrying the functional groups. In particular, this deposit consists of chemically linking the heparin or the hyaluronic acid, for example, with the amine groups of the polymer which in turn is deposited on the stent using the cold plasma technique.

Preferably, the antithrombotic substance is deposited by immersion of the stent covered with the polymer through the cold plasma method with the functional groups in an aqueous solution, for example of heparin or hyaluronic acid. The aqueous solution generally used comprises from 0.01% to 1% per weight of heparin or hyaluronic acid. This solution is generally prepared by dissolving 0.01 gai "g of heparin, for example, in 100 ce of a regulator, such as phosphate buffer, for example, and adding from 0.001 to 1" g of a substance with an oxidizing action. , such as sodium periodate. After a period of time between 6 and 20 hours of remaining in solution, 20 to 200 cc of a regulator solution such as acetic acid-sodium acetate solution at 0.001-0.1% are added. Then 1 to 10 cc of the solution are taken and placed in a suitable receptacle such as a Petri dish. The stent is then immersed in the tray and 0.001 to 0.01 g of a substance 5 are added with a reductive action, such as cyanoborohydride. After a lapse of time of no more than 30 minutes, preferably between 15 and 30 minutes, the stent is removed and washed with water. Then it is dried in an oven.

. According to a further variant embodiment of the invention, additional biodegradable layers can be applied, with or without a drug, on the layer of heparin, hyaluronic acid or other immobilized molecules that are a result of their normal degradation process. expose heparin, hyaluronic acid or other immobilized biomolecules.

The method according to the invention may also comprise a preliminary step of cleaning and / or washing the surface of the stent, so as to prepare it for the deposition steps mentioned above. Generally, the cleaning / washing step consists of treating it with degreasing solutions, such as organic solvents or water / isopropyl alcohol mixtures, or treating it with cold plasma of air or argon.

This preliminary step can be followed additionally by at least one pretreatment step to promote the adhesion of the drug, where it is properly linked with a leaching polymer, or of subsequent layers. In general, the pretreatment step includes the treatment with cold plasma of air or oxygen, or the plasma deposition of the organic layers that function as promoters of adhesion between the stent and the material to be deposited.

From what has been described up to now, it is clear that the method for preparing a medical device according to the present invention eliminates the treatment step of the leaching polymer of the drug required to insert on its surface the functional groups that are such as to allow the linked with the biomolecules. In fact, this step is eliminated due to the deposition of a particular class of polymers precisely selected by their characteristics of already possessing the groups when they are deposited using cold plasma technology. In addition, combining them with the use of the cold plasma method advantageously allows the polymer to be deposited without damaging the characteristics of its functional groups.

In addition to the above-mentioned examples of the method for preparing the medical device, the polymers selected and deposited by cold plasma promote the binding with biomolecules such as heparin and ensure that these are maintained in situ, preventing dispersion in the aqueous environment during the preparation of the device.

It has also been observed that with the cold plasma deposition of the polymers having functional groups as described above, the relevant drug is leached more slowly, thereby producing a barrier effect. Consequently, this effect allows a more durable antiestenotic action on the part of the drug.

A second objective of the present invention is to make available a medical drug leaching device, obtainable according to the previously described method.

In particular, the medical device can comprise, for example, a structure of the device, at least a first layer covering the surface of the structure and comprising a drug, at least a second layer covering the at least one first layer, comprising A polymer having stable reactive functional groups and a layer of biological molecule applied to the at least one second layer by means of linking with the functional groups, wherein the at least one second layer of polymer with functional groups is deposited on it. less a first layer of drug by means of the cold del-plasma method.

Preferably, the at least one first layer of - drug comprises a - polymer - drug leach as , described earlier. The drug can be chosen from among the drugs listed with reference to the method for preparing the stent.

The at least one second polymer layer having functional groups can be selected from the polymers mentioned above and can be deposited according to the cold plasma method referred to above. Also, with respect to the biomolecule applied to the outer surface of the stent, preferably it can be represented by, but not limited to, any of the substances described above.

The use of polymers having functional groups to cover vascular stents by cold plasma methods is also an object of the present invention. Preferably, the polymers are the polymers that are specified above.

From what has hitherto been established, medical devices prepared according to the aforementioned method are seen as particularly advantageous in comparison with the devices which are criticized in the introductory part of the present description, particularly in regard to the -Lexiviation mechanism of the drug. In fact, it has been observed that the stents described in the invention allow. the most controlled leaching of the drug, due to the particular polymer layer with functional groups that in some way acts as a much more active barrier compared to the polymers of the state of the art.

In addition, the polymers deposited by plasma - They have excellent adhesion to the vascular stent and at the same time proved to be completely free of toxic phenomena.

- Some representations of the invention are described below, by way of non-limiting example only.

EXAMPLE 1. Comparison between the leaching mechanism of a hydrophilic drug of a stent covered with a polymer according to the state of the art, and the mechanism of a stent covered with a polymer according to the invention. mg of the active ingredient imatinib mesylate was extracted from Glivec® drug capsules by dissolving them in water, filtering them to remove the insoluble excipients using Albet '400 filter paper (43-48 microns) and evaporating the water using a Rotavapor (Heidolph) to way to recover the active principle in powder form. Two 11 mm long stainless steel stents, produced by the company INVATEC, were covered using an Artis I airbrush (Efbe, Germany), as follows.

First, 1 cc of a 0.250% polybutadiene solution in cyclohexane, sold by the Aldrich company, having an average molecular weight of 420,000, was applied. After this, 1 cc of a solution obtained by dissolving 10 mg of Imatinib Mesylate (IM) in 1 g of methanol was applied. Then, 1c of a 0.5% polybutadiene solution in cyclohexane was applied, as specified above. Finally, 1 cc of a 0.5% polybutadiene solution in cyclohexane with a molecular weight of between 1,000,000 and 4,000,000 was applied.

At this point, one of the two stents was placed in a EUROPLASMA reactor and went through a cycle of plasma deposition of alilamine (introduced as vapor from an external container that contained it as a liquid) for 8 minutes with the reactor turned on at a power of 200 W at a pressure of 0.2 mbar.

Then, the stents were immersed in test tubes containing 1 cc of physiological solution and the leaching range of the drug was measured by capturing the visible UV spectrum using a Unicam 8700 spectrophotometer and reading the absorbance at 261 nm. The correlation between absorbance and concentration was established by measuring the. Absorbency of solutions of known concentration (calibration curve). The leaching measurements of the drug were made at fixed intervals of time and the physiological solution was changed in each measurement. The leach curves shown in Figure 1 were obtained.

In particular, Figure 1 shows that the deposition of the polymer through the cold plasma significantly delays the leaching of the hydrophilic drug compared to the leaching that results from the application of a polymer according to the state of the art.

EXAMPLE 2. Comparison between the leaching mechanism of a hydrophobic drug of a stent covered with a polymer according to the state of the art, and the mechanism of a stent covered with the polymer according to the invention.

The same procedure described in Example 1, with the difference that a hydrophobic drug, the dexamethasone, was used. mg of. Dexamethasone was dissolved in 1 g of ethanol and applied as described above. The leach curves were again measured as described in Example 1, and the absorbance was read at 264.4 nm. The results shown in Figure 2 were obtained.

It should be noted that also in this case the allylamine polymer deposited through cold plasma provides a remarkable reduction in the leaching mechanism of the drug.

EXAMPLE 3. Comparison of the degree of hydrophilicity between a metal stent treated with heparin and a metal substrate without heparin.

A stent prepared according to example 1, with heparin deposited by cold plasma, passed, by a process of linking with heparin, in the following manner. 0.5 g of heparin (Bioiberica) was dissolved in 100 ce of phosphate buffer and 0.016 g of - sodium periodate (Sigma-Aldrich). After 16 hours of remaining in the solution, 100 cc of 0.05% acetic acid-sodium acetate solution was added. 5ce of this solution was taken and placed in a Petri dish. The stent was then immersed in the tray and 0.01 g of sodium cyanoborohydride (Sigma-Aldrich) was added. After 30 minutes, the stent was removed and washed with water. Then it was dried in an oven. At this point, the. Stent was much more hydrophilic compared to a non-heparinized stent, precisely because of the presence of bound heparin on its surface.

To provide an analytical basis, the same treatment was carried out, as just described, on steel plates ASI 316 L of 1 cm per side, which is the material of which the stent was constituted. A heparinized plate was compared to a non-heparinized plate through a comparison using X-ray photoelectron spectroscopy (XPS) analysis to provide the chemical composition of the surface layer. The XPS analysis was performed using a Perkin Elmer PHI 5500 ESCA instrument. The result of the analysis, expressed in atomic%, is given in table 1 below.

Table 1 In comparison with the untreated specimen, the specimen treated with heparin shows an increase in the 0 / C ratio and in S the expected concentration in the heparinization processes.

EXAMPLE 4 Comparison of the degree of hydrophilicity between a metal stent treated with hyaluronic acid and a metal stent without hyaluronic acid.

A stent prepared according to Example 1 with allylamine deposited by cold plasma went through a process of binding with hyaluronic acid, in the following manner. 0.5 g of hyaluronic acid (Lifecore) was dissolved in 100 cc of deionized water. 5 ce of that solution were taken and placed in a Petri dish. Then the stent was immersed in the tray and 0.03 g of N-hydroxy succinimide and 0.04 g of dimethyl carbodiimide / EDC (both from Sigma-Aldrich) were added. After 30 minutes, the stent was removed and washed with water. Then it was dried in an oven. At this point, the stent was much more hydrophilic compared to a stent not covered with the hyaluronic acid, precisely because of the presence of the hyaluronic acid bound to its surface.

EXAMPLE 5 Production of a stent covered with polymer according to the invention, with immobilization of hyaluronic acid and additional cover with a biodegradable base layer derived from hyaluronan acid.

Of Glivec® drug capsules, - 10 mg of the active ingredient imatinib mesylate was extracted by dissolving in water, filtered to remove the insoluble excipients and water evaporation as described in example 1. Two 11 'stainless steel stents mm in length, produced by the company INVATEC, were coated using an Artis 1 air brush (Efbe, Germany), as follows.

First, 1 cc of a 0.250% solution of polybutadiene was applied in cyclobenzan'o (Aldrich, average molecular weight-420,000). After that, 1 cc of the solution obtained was applied by dissolving 10 mg of Imatinib Mesylate (IM) in 1 g of methanol. Then 1 cc of 0.5% solution of polybutadiene was applied (details, as before) in cyclohexane. Finally, 1 cc of a 0.5% solution of polybutadiene in cyclohexane with a molecular weight between 1,000,000 and 4,000,000 was applied.

At this point, one of the two stents was placed in a EUROPLASMA reactor for plasma treatment and went through a cycle of plasma deposition of allylamine (introduced as steam from an external container that contained it as a liquid) for 8 minutes, with the reactor turned on at a power of 200 W at a pressure of 0.2 .mbar.

Then, 0.5 g of hyaluronic acid (Lifecore) was dissolved in 100 cc of deionized water. 5 ce of that solution were taken and placed in a Petri dish. Then the stent was submerged in the tray and 0.03 g of. N-hydroxy succinimide and 0.04 of dimethyl carbodiimide (EDC) (both from Sigma Aldrich). After 30 minutes, the stent was removed and washed with water and dried. At this point, a layer of water-insoluble and degradable hyaluronic acid derivative, the benzyl ester HYAFF 11) was applied (from Fidia Advanced Biopolymers, Abano Terme, Italy). This material, together with the drug imatinib mesylate, was applied from a solution of 0.2% HYAFF and 1% IM in hexafluoroisopropanol, using an air brush.

In this way, a stent is obtained that leaches the drug from the surface layer of HYAFF and from the underlying layer, where the surface layer will be degraded in situ leaving exposed the surface on which the hyaluronic acid is bound to the barrier layer and functional deposited through plasma.

Claims (41)

1. Method for preparing a medical drug leaching device comprising the application to the device of a polymer having active functional groups capable of chemically agglutinating biological molecules, characterized in that the application takes place in a single step by means of cold plasma methods.

2. Method according to claim 1, wherein the polymers are selected from polymers having amine groups, carboxyl groups and sulfhydryl groups.

3. Method according to claim 2, wherein the precursors of the polymers having amine groups are selected from allylamine, heptylamine, aliphatic amines and aromatic amines.

4. Method according to the. claim 2, wherein the precursors of the polymers having carboxylic groups are selected from acrylic acid and methacrylic acid.

5. Method according to claim 2, wherein the precursors of the polymers having sulfhydryl groups are chosen from volatile mercaptans.

6. Method according to any of claims 1 to 5, wherein cold plasma methods comprise cold plasma produced under vacuum using discontinuous or continuous technology.

7. Method according to claim 6, wherein the vacuum cold plasma is generated at a pressure that can vary between 0.01 and 10 mbar, at a power of between 1 and 500 W and for a period of time of not more than 30 minutes .

8. Method according to any of claims 1 to 5, wherein the cold plasma methods consist of cold plasma produced at atmospheric pressure.

9. Method according to any of claims 1 to 8, wherein the polymer precursor is in the form of a gas.

10. Method according to any of claims 1 to 8, wherein the polymer precursor is in the form of a vapor.

11. Method according to any of claims 1 to 10, wherein the polymer is applied in the form of a film with a thickness between 0.01 and 10 microns.

Method according to any of claims 1 to 11 which also comprises, before the application of the polymer having functional groups, an application step of at least one layer of a drug incorporated where appropriate in a polymer capable of leaching the drug.

13. Method according to claim 12, wherein the drug is chosen from the group consisting of anti-inflammatory, anti-proliferative and anti-migratory drugs, and immunosuppressive agents.

14. Method according to claim 13, wherein the drug is methanesulfonate of 4- [(4-methyl-l-piperazinyl) methyl] -N- [4-methyl-3- [[4- (3-pyridinyl) - 2- pyrimidinyl] amino] -phenyl] benzamide.

15. Method according to any of claims 12 to 14, wherein the leaching polymer of the drug is selected from hydrophobic hydrocarbons, polyamides, polyacrylates, polymethacrylates.

16. Method, according to claim 15, wherein the hydrophobic hydrocarbons are selected from polystyrene, polyethylene, polybutadiene and polyisoprene.

17. Method according to claim 15, wherein the polymer is selected from polyhydroxybutylmethacrylate, polyhydroxymethylmethacrylate, where appropriate in combination with the polybutadiene.

Method according to any of claims 12 to 17, wherein the drug that can be incorporated into a drug leaching polymer is applied "by immersion in a suitable solution or deposited by spraying 19.

Method according to claim 18, wherein the polymer leaching the drug is deposited in the form of a film with a thickness of between 0.5 and 20 microns.

Method according to any of claims 12 to 19 wherein, when the drug is an anti-inflammatory, it is present in amounts between 0.001 mg and 10 mg per device

21. Method according to any of claims 12 to 19 where, when the drug is an antiproliferative, is present in quantities between 0.0001 mg and 10 mg per device.

22. Method according to any of claims 12 to 19 wherein, when the drug has an anti-migratory action, it is present in amounts between 0.0001 mg and.10 mg per device.

23. Method according to any of claims 12 to 19 'wherein, when the drug is an immunosuppressant, it is present in amounts between 0.0001 mg and 10 mg per device.

24. Method according to any of claims 12 to 19 wherein, when the drug is methanesulfonate of 4- [(4-methyl-l-piperazinyl) methyl] -N- [4-methyl-3- [[4- ( 3-pyridinyl) -2-pyrimidinyl] amino] -phenyl] benzamide, is present in amounts between 0.001 mg and 10 mg per device.

25. Method according to any of claims 1 to 24, which also comprises a step of deposition of biological molecules on the surface of the polymer having stable reactive functional groups.

26. Method, according to claim 25, wherein the biological molecules are chosen from antithrombotic substances and hyaluronic acid.

27. Method according to claim 26, wherein the biological molecules are heparin.

28. Method according to claim 26 or 27, wherein the biological molecules are deposited by immersing the medical device in an aqueous solution containing • the biological molecules in a concentration of from 0.01% to 1% by weight. -

29. Method according to any of claims 1 to 28, comprising - also a preliminary cleaning / washing step of the medical device.

30. Method according to claim 29, wherein the preliminary cleaning / washing step is followed by a pretreatment step of the medical device to promote adhesion to this device of the drug incorporated where appropriate in a leaching polymer.

31. Method according to any of claims 1 to 30, which also comprises the application of additional layers of biodegradable polymer on the layer of biological molecule.

32. Method according to any of claims 1 to 31, comprising in succession the application to the surface of the medical device of at least a first layer of methanesulfonate of 4- [(4-methyl-l-piperazinyl) methyl] -N- [4-methyl-3- [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -phenyl] benzamide included where appropriate in a polymer, the cold plasma application of at least one second layer of allylamine polymer , the binding of heparin to the at least one second layer and the application of at least one third layer of biodegradable polymer on the heparin.

33. Medical drug leaching device obtained by the method according to any of the preceding claims.

34. Medical device according to claim 33, comprising a structure of the device, at least a first layer covering the surface of the structure comprising a drug, at least a second layer covering the at least one first layer, comprising a polymer having stable reactive functional groups and a layer of biological molecule linked to the at least one second layer by means of chemical bonding with the functional groups, wherein the at least one second layer of polymer is deposited thereon. at least one first layer by means of a cold plasma method.

35. Medical device according to claim 34, wherein the drug is a drug as described in any of claims 13 to 32.

36. Medical device according to any of claims 34 or 35, wherein the drug leaching polymer. is a polymer as described in any of claims 16 to 18.

37. Medical device according to any of claims 34 to 36, wherein the polymer having stable reactive functional groups is one of the polymers described in any of the claims. 2 to 5.

38. Medical device according to any of claims 34 to 37, wherein the biological molecule is any of the molecules in claim 26.

39. Medical device according to any of claims 34 to 37, wherein the device chosen from among vascular devices, prostheses, probes, catheters, dental implants or the like.

40. Medical device according to claim 39, the device being a vascular stent.

41. Use of polymers having reactive functional groups chosen from the polymers described in any of claims 2 to 5, to cover medical devices, preferably vascular stents, by means of the cold plasma deposition methods.