FR2927813A1 - Implantable medical device e.g. intravascular stent, for e.g. vascular stenosis treatment of human, has retention/protection layer comprising film forming agent and hydrophobic agent that controls disintegration speed of protection layer - Google Patents

Abstract

The device has a ceramic coating layer, and a hemispherical microreservoir (30) e.g. microcavity, for supporting or receiving a water-soluble therapeutically active agent/medicine (36) that is in the form of solid state. A solid external biodegradable and biocompatible retention/protection layer (38) comprises a biodegradable and biocompatible film forming agent and a biocompatible hydrophobic agent that controls the disintegration speed of the retention/protection layer. The hydrophobic agent comprises dexamethasone or its derivatives such as dexamethasone acetate or dexamethasone phosphate. The biodegradable and biocompatible film forming agent comprises polyalkyleneglycol constituted of polyethyleneglycol, polyvinylpyrrolidone and mixtures of polyalkyleneglycol and polyvinylpyrrolidone.

Description

Hexacath case? FRO 21/02/2008

The invention relates to a medical device implantable on a protective layer / retention of an active agent or drug, especially water-soluble. More specifically, this implantable medical device comprises an active agent or drug especially water-soluble, and is characterized in that it comprises at least one protective layer and / or retention to achieve the protection / retention of the active agent or drug up to at its implantation site, said layer comprising a biocompatible and biodegradable film-forming agent; and at least one hydrophobic agent, preferably biocompatible, for controlling the degradability rate of the protective or retention layer. Within the scope of the present invention, the meaning of the following terms is understood in the description and the claims: - active or therapeutically active agent is any agent or product or substance or composition, taken alone or in combination with another agent, product or substance which has a therapeutic activity which can prevent or slow down or treat a disease of living beings, in particular humans and animals. - a drug is used here indifferently to have the same meaning and is either an agent or a product or a substance, which alone or in combination with another agent, product or substance, has a therapeutic activity to prevent or slow down or treat a disease or a composition comprising at least one of the therapeutically active agents, usually with a pharmaceutically acceptable excipient. - Stent: tubular prosthesis, placed inside an anatomical cavity in order to preserve its internal lumen, it can be in the form of an expandable metal tube provided with openings, in the tubular wall, of different types of shapes and sizes. - fihnogE'in agent: an agent capable of forming a film; Hexacath case? FRO 2 21/02/2008

biocompatible and biodegradable film-forming agent: a film-forming agent capable of forming a film which, on the one hand, does not generate tissue reactions and, on the other hand, can be resorbed and gradually eliminated by the body; hydrophobic agent: a weakly soluble agent in an aqueous medium, this hydrophobic agent thus makes it possible to regulate the degree of solubility of a biocompatible and biodegradable film or layer in an aqueous medium and in particular in blood or plasma. In the context of the present invention, the hydrophobic agent makes it possible to control the rate of disintegration of the protective or retention layer. biocompatible hydrophobic agent means that the hydrophobic agent does not generate tissue reactions. In the context of the present invention, the term "biodegradable" means that the protective / retention layer disappears at the implantation site whatever the mechanism of action. Without limitation, this protective / retention layer is disintegrated by being physically dissolved by the surrounding environment and in particular by the speed of blood circulation in the blood vessels and also because of a dissolution resulting from the aqueous medium or environment.

The invention provides a better protection of the active ingredient or drug to its intended destination.

STATE OF THE ART US Pat. No. 5,874,419 discloses compositions comprising a cyclodextrin polyionic derivative combined with a growth factor, preferably a heparin-binding growth factor. This composition can be used in a method for inhibiting restenosis according to various routes of administration, one of which comprises diffusion of an aqueous suspension or dispersion of the saccharide derivative directly into the arterial wall. FRO 21/02/2008

has the major disadvantage of diffusion of aqueous suspension of dispersion of the saccharide derivative by the modified infusion balloon catheter, which necessarily implies diffusion limited in time and with almost instantaneous administration of the active principle. Active ingredient or water-soluble drug: is meant an active ingredient or a drug that is soluble in an aqueous medium and in an assimilated aqueous medium such as blood or plasma medium.

OBJECTS OF THE INVENTION The main object of the present invention is to solve the new technical problem of providing a technical solution which makes it possible to administer a therapeutically active agent or a particularly water-soluble drug, in solid form or phase, while by being protected on its path to the site of administration by a protective layer / retention which according to a particular embodiment, the disintegration can be advantageously controlled over a given period of time. It is another object of the present invention to solve this new technical problem according to a technical solution which allows the administration of this therapeutically active agent or of this medicament according to a usual route of administration, with, if possible, a solution making it possible to determine the quantity and / or the period of time of release of the active agent or drug, and in particular compatible with the use of an implantable medical device, in particular a stent. The main purpose of the present invention is also to solve the above-mentioned new technical problems, according to a technical solution that makes it possible to perform a treatment of restenosis, and in particular of vascular restenosis, and in particular at the cardiac level.

Hexacath case? FR0 421/02/2008 All of these technical problems is solved for the first time by the present invention, in a safe and reliable manner, usable on an industrial and medical scale.

DETAILED DESCRIPTION OF THE INVENTION According to a first aspect, the invention relates to an implantable medical device comprising a therapeutically active agent or drug, especially a water-soluble one, characterized in that it comprises means for receiving said therapeutically active agent or drug, in solid form. ; and at least one biocompatible and biodegradable protection / retention layer for effecting the protection of the therapeutically active agent or drug to its implanted site, said protective layer comprising at least one biocompatible and biodegradable film-forming agent, and at least one hydrophobic agent, preferably biocompatible, to control the rate of disintegration of the protective layer / retention. According to another optional feature, the biocompatible and biodegradable film-forming agent is chosen from a polyalkylene glycol, a polyvinylpyrrolidone, or mixtures thereof in all proportions.

According to yet another optional feature, the polyalkylene glycol comprises or consists of polyethylene glycol. According to an optional feature, the biocompatible hydrophobic agent comprises dexamethasone or a derivative of dexamethasone. According to yet another particular characteristic, the dexamethasone derivative comprises dexamethasone, dexamethasone phosphate, dexamethasone acetate. According to another optional feature, the relative ratio of the biocompatible and biodegradable film-forming agent to the hydrophobic agent ranges from 99% to 1% film-forming agent for 1% to 99% by weight hydrophobic agent Hexacath case. FRO 5 21/02/2008

According to yet another optional feature, the protective / retention layer deposited on the active principle or drug itself previously deposited or loaded onto the above-mentioned receiving means comprises from 01 to 100 μg of dexamethasone component per mm 2 of protection / retention. According to yet another optional feature, the implantable medical device comprises an outer surface and said means for receiving said agent or drug is at least partly located on at least a portion of the outer surface and in particular may comprise a surface sculpture of the medical device. The surface sculpture may comprise in a particular embodiment reservoir formations defining a predetermined reservoir volume for said active agent or drug alone or in total individual reservoir formation volumes. According to a particular feature, said reservoir formations may be selected from the group consisting of incisions, channels, grooves, wells or cavities. According to another particular characteristic, said reservoir formations may be of micrometric size, in particular in the range between about 1 μm and about 600 μm, in average size. According to a particular embodiment, the medical device comprises a stent having an outer surface and an inner surface, said means for receiving said active agent or drug are at least partly located on at least a portion of said outer surface and comprise a surface sculpture of the stent. An example of an implantable medical device, which may be a stent, which includes a surface sculpture, is disclosed in the referenced ER 1 180 903 BI and to which the 30 rad man can take any useful information.

Hexacath case? FRO 6 21/02/2008

This document shows the realization of the formation of reservoirs on the surface of the implantable medical device such as a stent, which may be in the form of incisions, in the form of channels or grooves, and which may have a closed perimeter on the sidewalls and an open top to provide reservoirs for the active agent or drug selectively applied to the formations. All the formations described as well as the formation method can be used in the context of the present invention. On the other hand, according to a particular embodiment, it may be used in the context of the invention any implantable medical device including any stent of the prior art, and in particular those described in EP 1 180 903 or in EP 1 277 449, documents also included by reference. This last document shows the prediction of recesses made on the internal surface of the stent.

Another example of a method for producing stent for angioplasty with a surface sculpture is described in EP 0 850 604 BI which is also incorporated by reference. According to another particular embodiment of the invention, it is possible to use an implantable medical device such as a stent, as described in the applicant's previous document Hexacath EP 1 884 864. According to another particular characteristic, the implantable medical device, such as a stent, may be provided with a more specific surface sculpture, including the formation on the outer surface of the implantable medical device at least in part of microreservoirs, such as microwells or microcavities, having in a particular embodiment a hemispherical or ovoid shape, or an ellipsoidal contour, in which the bottom of the microreservoirs may be of any shape and in particular of non-concave shape. It should be noted that the size, shape and number of the 30 cubic meters, such as microwells or microcavities, determine on the one hand Hexacath case? FR0 7 21/02/2008

the amount of active agent or drug embedded and the period of time of release thereof. The method of manufacturing microreservoirs, such as microwells or microcavities, is well known to those skilled in the art and may result from previous prior art documents revealing a surface sculpture of a stent. Any new surface sculpture is of course included within the scope of the invention. According to yet another optional feature, the stent comprises a substrate and at least one ceramic coating layer 10 with optionally at least one intermediate non-porous metal adhesion layer. According to yet another optional feature, the stent comprises on its surface a multitude of microreservoirs, said active agent or drug being deposited inside said microreservoirs. According to yet another optional feature, a biocompatible and biodegradable protection and / or retention layer is deposited on the outer surface, in solid form or phase, in said microreservoirs, above said drug or active agent to ensure its protection to its implantation site, as well as the release of said active agent or drug in the vicinity of the implanted site.

Other technical characteristics of the Protection layer and / or Retention are given below:

The protective and / or retention layer constitutes a film system controlling the protection / retention of active agent (s) or water-soluble drug (s) in the context of implantable medical devices, of which include implants such as coronary implants including stents, which may be microsculpted.

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Furthermore, during the implantation process of these implantable medical devices, for example a stent, an implant or a prosthesis, and in particular during the phase of ascending to the implantation site, this protection / retention layer makes it possible to protect and to avoid the loss of active agent embedded with said implantable device. Thus, the retention of the active agent is effective to the site of implantation and thus ensures and control the delivery of the amount of active agent or drug. According to a particular characteristic, an implantable microsculpture device may be used, in particular a microsculpture stent. By microsculptures is meant the manufacture of microsculptures such as cavities, wells or grooves on the surface, in particular outer surface, of the implantable medical device, making it possible to carry a volume or a controlled mass of active agent or drug. Such an implantable medical device may be made of various so-called biocompatible materials well known to those skilled in the art, for example stainless steel 316L, nitinol, which may be covered with one or more layers improving the mechanical properties as described in Applicant's previous document WO 2006/067031.

The constituent elements of the retention layer:

The retention layer consists of one or more biocompatible and bioabsorbable biogenic agents and a hydrophobic agent, preferably biocompatible, for delaying the disintegration of the retention layer.

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Film-forming agents:

The biocompatible and biodegradable film-forming agent may be chosen from a polyalkylene glycol, a polyvinylpyrrolidone, and mixtures thereof in all proportions. The polyalkylene glycol may be polyethylene glycol, in particular polyethylene glycol 8000. The biocompatible and bioabsorbable film-forming agent has a concentration in the film forming the protective / retention layer greater than 1% by weight if it is the only film-forming agent. constituent of the retention layer. The use of any other biocompatible and bioabsorbable polymer of the family of glycols is possible as well as any combination of these glycol polymers that can give a final result a copolymer.

A biocompatible and bioabsorbable polymer such as Polyvinyl Pyrrolidone PVP (CAS number: 9003-39-8) can also be used as a film-forming agent for the protective / retention layer. In addition, a combination of film-forming agent based on glycolic polymer and PVP can also be used.

Agents to delay the disintegration of the protective / retention layer:

To delay the disintegration, in particular the disintegration and / or dissolution, of the protective / retention layer of the active agent or drug, use will be made of a hydrophobic agent, preferably a biocompatible agent, or a mixture of agents, at least one of which is hydrophobic. As a hydrophobic agent, dexamethasone or shear drift, which is very slightly soluble in Hexacath case, will be used in particular. FRO 10 21/02/2008

aqueous medium. Dexamethasone is an agent for effectively delaying the disintegration of the retention layer. The dexamethasone agent is biocompatible. In addition, all derivatives of dexamethasone having a relative hydrophobicity, such as for example the disodium salt of dexamethasone phosphate (CAS No. 2392-39-4) or dexamethasone acetate (CAS No. 1177-87-3) can be used as an agent for delaying the disintegration of the protective / retention layer. It will be understood by those skilled in the art that candidates eligible as an agent for delaying the disintegration of the protective / retention layer must give a hydrophobic character relative to the protective / retention layer and preferably have a recognized safety in this type. of application and a biocompatible character of proven long standing.

Deposition mode:

The deposition of the protective / retention layer on the surface of the implantable medical device may take place by any technique known to those skilled in the art, such as for example by spraying, nebulizing or spraying such as the so-called air spray technique. vaporization, nebulization or ultrasonic spray or any other system that can deposit films by nebulization, spraying solutions. Deposition of the protective / retention layer may also be carried out by the so-called jetting technique. This so-called jetting technique, well known to those skilled in the art, is directly derived from the techniques of deposition or inkjet printing or Ink-jet Hexacath case? FRO 21/02/2008

The protective / retention layer can still be made by a so-called dipping or dipping technique. It is unnecessary to describe in more detail all these techniques because all these techniques are well known to those skilled in the art.

Composition of the Protection layer / Retention:

The physicochemical characteristics of this layer or film control its disintegration over time when the film is subjected to aqueous, plasma and / or blood conditions.

Lists of constitutive elements, roles and compositions of the retention-elution layer: For this purpose, the best current embodiment of the protective / retention layer is given below. It is apparent to those skilled in the art that other film-forming agents or other agents for retarding the rate of disintegration of the retention layer can be used in an equivalent manner.

Hexacath case? FR0 12 21/02/2008 component 1 Main role Role Composition in the secondary film PEG 8000 Agent agent> 1% weight% film-forming bioavailability Dexamethasone 'Agent No activity at 99% weight allowing due to m. to 100 retard the of a quantity microg / mm2 speed of too weak of surface of disintegration the layer of the layer of protection / retention retention Water Solvents Modification 0-15% volumic of the surface tension of the deposited film Methanol 40-100 % volumic Ethano 0-20% by volume anol 0-40% by volume Butanol and / or 0-40% by volume isobutanol Performance, retention time of the retention film: from 1 to 45 minutes. Thickness of the protective / retention film: 0.1 to 20 gm. According to one particular embodiment, it is possible to provide from 40 to 70 by weight of hydrophobic agent and from 60 to 30% by weight of film-forming agent in the protective / retention layer. Thickness of the Protection / Retention Layer and its possible number of underlays:

It is generally desirable that the total thickness of the protection / retention layer is not too great. Indeed, too great a thickness could change the profile and decrease the navigability of the implantable medical device, such as a stent. It is generally desirable that the total thickness of the protective / retention layer does not exceed 20 microns (microns). 10 Hexacath cas7 FRO 13 21/02/2008

The simplest case is that the protective layer / retention is composed of a single layer of thickness and composition data. However, depending on the needs, one can consider the case where the protective layer / retention is composed of several layers of protection / retention of thicknesses and variable compositions. The total thickness of the protective / retention layer is then the sum of the thicknesses of the different sub-layers that constitute it.

Distribution and concentration of agent for delaying the disintegration of the protective / retention layer:

The total concentration of agent for delaying the disintegration of the protective / retention layer is set by the total mass of this agent relative to the total mass of the protection / retention layer. The agent for delaying the disintegration of the protective / retention layer can be uniformly or evenly distributed over the entire thickness of the protective / retention layer. In this case, the retention force or the rate of disintegration or disappearance (decrease in thickness) of the protective / retention layer is constant over the entire thickness of the protective / retention layer. For some purposes, it is possible to obtain a variable protection / retention force depending on the thickness of the retention layer. We are talking about obtaining a gradient of the protection / retention force. To achieve this gradient of the protection / retention force, the concentration of the agent to retard the disintegration of the protective / retention layer varies depending on the thickness of the protective / retention layer. Thus, in a so-called monolayer protection / retention layer, a gradient of the ragent concentration to delay the disintegration of the Hexacath layer case? FRO 14 21/02/2008

protection / retention over the entire thickness will provide a gradient of the retention force in said layer. A similar result can be obtained by combining several retention sub-layers of different compositions and thicknesses. The gradient of the retention force will be the resultant of the retention forces of the different individual sub-layers. In addition, it is preferable that the protection / retention force decreases with the retention layer usage time with a zero protection / retention force objective at the time of placement and deployment of the stent at the locus of the stent. intervention.

Roles of solvents:

The solvents used do not enter into the composition of the protective / retention layer since they are totally evaporated to obtain the so-called dry layer in the solid state or state of protection / retention. However, the use of a mixture of solvents makes it possible to modify practically at will the deposition parameters of the protective / retention layer such as homogeneity, distribution, thickness, drying time, etc.

METHOD OF TREATMENT

According to a second aspect, the present invention is also directed to a method of treating a subject, human or animal, in need thereof comprising providing an implantable medical device as defined in the present specification and claims, and implanting this implantable medical device at the appropriate place of said subject, in order to redlise the appropriate treatment Hexacath case? FRO 15 21/02/2008

This appropriate treatment may be a medical treatment with an active agent or a drug which is desired a local action at the implantation site. This active agent or this drug can be used to prevent or repair damage to tissue or bone, to regulate the healing of an injury, to prevent or minimize the risk of restenosis, to inhibit or otherwise promote angiogenesis. Those skilled in the art will readily understand that the invention can be used to perform various treatments in a subject. Other objects, features and advantages of the invention will become apparent in light of the following explanatory description referring to several examples or embodiments of the invention given merely by way of illustration and which can not in in no way limit the scope of the invention. In the examples, all percentages are given by weight, the temperature is in degrees Celsius, the pressure is atmospheric pressure unless otherwise indicated.

DESCRIPTION OF THE FIGURES FIG. 1 represents a first embodiment of an implantable medical device, and in particular a stent, having an external surface comprising a surface sculpture; FIG. 2 represents an enlarged view along the zone of the arrow II of FIG. 1, of a curved portion of the implantable medical device, in particular a stent, from above the outer surface, to better see the sculpture of area ; FIG. 3 represents a still enlarged view of a cross-section along section line III-III of FIG. 2 of a microsculpture, hereinafter a microscope or a microcavity, to show the solid deposit of me (i) ment (s) and the outer solid layer of Hexacath case? FRO 16 21/02/2008

protection / retention, within said microsculpture, here a microreservoir.

Examples of the invention Example 1 Preparation of an implantable medical device, in particular a stent, having an external surface comprising a surface sculpture With reference to FIG. 1, an implantable medical device 10, for example here a stent, was taken. 20, made here of 316L stainless steel or a 316L stainless steel coated with at least one transition layer, in particular of titanium oxynitride, as described in the previous patent of HEXACATH EP 1 684 654. The device 10, such as a stent 20, comprising an outer surface 31, intended to come into contact with the internal tissues of a subject, in particular a blood vessel, and an inner surface 33, has been subjected to the formation of a surface sculpture so that it comprises reservoir formations 30 defining a predefined reservoir volume for depositing an active agent or drug in one phase or in the solid state, as described hereinafter in Example 2. Formation of the In this example, said surface sculpture has been provided in particular in the form of multiple micro-size reservoirs having a microwell or micro-cavity shape with one or more side walls 32 and a bottom wall 34, here of substantially hemispherical shape, as well as an upper opening 37. The method of obtaining this type of surface microscopy by techniques known as Micro Patterning, Electrochemical Machining or PhotoElectrochemical Machining is well known to those skilled in the art.

Hexacath case? FRO 17 1/02/2008

The various steps which made it possible to obtain this type of these stent microsculptures of this example 1 are as follows: Step 1: The starting platform is a stent, preferably a stent of the brand Helistent 316L stainless steel 5 company Hexacath, France. Step 2: Preparation for microsculpture A cataphoretic type protective lacquer is deposited in a controlled manner on the stent. By a laser ablation technique, well known to those skilled in the art, a hemispherical imprinting pattern is created on the outer surface of the stent on the surface of the deposited lacquer. Step 3: Creation of the microsculpture network in the form of microreservoirs such as microcavities or microwells. By an electrochemical machining technique in an acidic medium, the microsculpture network in the form of microreservoirs such as microcavities or microwells is created. The size of these microreservoirs is directly related to the electrochemical machining time. For example, a stent with a length of 16 mm and more, especially a stent of the Helistent brand of Hexacath company can count a number of 2900 1% hemispherical microreservoirs of a determined diameter corresponding to a desired controlled volume. In this exemplary embodiment, the average diameter of the hemispherical microreservoirs 30 is about 65 μm, the depth is about 32 μm on average; and the total volume of all hemispherical microcavities is about 0.2 microliters (pl). It is understood that the formation of these reservoirs makes it possible to deposit the interior of these at least one layer in form or in the solid state Hexacath case? FR0 18 21/02/2008

one or more active agent (s) or drug (s), as given for example in Example 2 below by way of illustration.

Example 2 Deposition of an active agent or drug in solid form or state such as L-arginine on a microsculpture stent

Deposition of an active agent or drug, in solid form or form (36), comprising L-arginine, of a 10 microsculpture stent, as described in Example 1 ci above, for example by the implementation of the following different technical steps: Step 1: Cleaning of the stent microsculptures, described in Example 1 embodiment, ultrasonic assisted washing medium with hot air finish or organic solvent vapor phase . Step 2: Low pressure plasma surface activation with an oxidizing reactive atmosphere. For example, this activation of the surface was carried out using a machine, model Femto 3 of the brand Diener Electronics available commercially. An example of low pressure plasma activation conditions is a 10 minute plasma treatment with oxygen gas at a pressure of 0.50 mbar and a power of 75 watts. Step 3, filling the microreservoirs with active agent. Various techniques such as dipping (dipping or dipping) or spraying (air spray, ultrasonic spray or other spraying technique or solution nebulization) or ink-jetting can be used to specifically fill the microreservoirs of the stent. Technical conditions satisfying the filling of the microreservoirs 30, here micro-cavities, are the spray-air spray Hexacath case FRO 19 21/02/2008

an aqueous solution with 15% by volume of isopropyl alcohol containing 20% by weight of L-arginine. Thus, the aqueous solution of L-arginine was vaporized on the device 10 such as a stent 20, as obtained in Example 1 with the micro-size reservoirs 30, to form a solid deposition layer 36 of the active agent or drug comprising L-arginine on the inner surfaces 32-34 of the reservoirs which are in the form of microwells or hemispherical microcavities. The quantity of L-arginine deposited in the microreservoirs 30, such as microwells or microcavities, was well controlled by the total volume thereof, as well as by the proportion of L-arginine in the solution for the solid deposition of this one.

Example 3 Prediction and deposition of an outer solid layer of protection / retention preferably biocompatible and biodegradable

On the implantable medical device 10, as obtained in Example 2, provided with medicament here comprising L-arginine, it was further deposited a biocompatible and biodegradable outer layer 38 in the following manner: An outer solid layer Protection / Retention 38 has been formed by first preparing a 50% by weight solution of film forming agents comprising commercially available polyethylene glycol 8000; 50% by weight of dexamethasone, as hydrophobic agent; solubilized in a solvent mixture comprising, for example, 40-100% by volume of methanol and 0 to 40% by volume of butanol. According to a first specific embodiment, this solution has been vaporized to air on the implantable medical device 10, here an intravascular stent 20, comprising the drug comprising L-arginine, Hexacath case. FR0 20 21/02/2008

as obtained in Example 2 to obtain a solid outer layer of protection / retention with a thickness of between 0.1 and 20 μm. it has been deposited a protective layer / retention composition and thickness given (s), for example by the aforementioned technique of nebulization / spraying. In addition, this retention layer was obtained by a standard commercial air nebulization / spray system. Preferably, the model used is a BADGER model 150Tm airbrush (WE-150-4 PK serial number) with dimensions of 10 M and L nozzles. This Badger 15OTM was coupled to a WE type air compressor. -Atlantis model TF 368, 220 volts and 135 Watts. Due to the essentially instantaneous vaporization of the solution and the very low solubility of the active agent or drug, in this case L-arginine, there was no substantial disintegration of the active ingredient or drug during the formation of the protective layer / solid external retention. According to a second specific embodiment, this solution could be selectively deposited on microcavities comprising the drug comprising L-arginine, as obtained in Example 2, of the implantable medical device 10, here an intravascular stent. to obtain a solid outer layer of protection / retention 38 with a thickness of between 0.1 and 20 μm. a protective / retention layer of given composition and thickness has been deposited, for example by the aforementioned technique of Ink-Jetting or inkjet. In addition, this retention layer was obtained using a microdrop generation module based on the principle of drop on Demand technologies known to those skilled in the art. Preferentially, a given number of 60 micrometers microdroplets of diameter having a volume of 0.1 nL (nanoliter) have been selectively deposited on the inicrocavity including the Hexacath case. FRO 21 21/02/2008

a medicament comprising L-arginine, as obtained in Example 2, of the implantable medical device 10, here an intravascular stent 20, to obtain a solid outer layer of protection / retention 38 having a thickness of between 0.1 and 20 dam. Due to the essentially instantaneous evaporation of the solution and the very low solubility of the active agent or drug, in this case L-arginine, there was no substantial disintegration of the active agent or drug when of the formation of the protective layer / solid external retention. Example 4 Additional tests

Various examples of diapers 38 of protection / retention have been made. These various examples illustrate some variations in behavior and therefore variations in the retention force under given in-vitro conditions.

In-vitro conditions common to these different examples:

Work Setting # 1: PBS Phosphate Buffer at pH 7.4 Work Setting # 2: Pigment plasma at pH 7.4 Working Volume: 50 mL Workplace Temperature: 37 ° C 0.5 ° C RPM non-laminar forced convection. Deposition of the protective / retention layer on an implantable medical device

On a given surface, for example, a medical device 30 such as a stent 20 made of stainless steel, vylable type 316L Hexacath case FRO 22 21/02/2008

or stainless steel coated with a layer of biocompatible ceramic Titanium OxyNitride, according to the prior patent Hexacath applicant W02006 / 067 031, it was deposited a Retention protection layer 38 of composition and thickness given (s), for example by the aforementioned technique of nebulization / spraying. In addition, the different retention layer thicknesses, of the embodiments given below, were obtained by a standard commercial air nebulization / spray system. Preferably, the model used is a 0 BADGER airbrush, model 15OTM (WE-150-4 PK serial no.) With nozzle sizes M and L. This Badger 15OTM was coupled to a WE type air compressor membrane -Atlantis model TF 368, 220 volts and 135 Watts.

Protective / retention layer disintegration test This protective / retention layer was then immersed in a working environment and subjected to forced convection. These environments, in-vitro, subjected to forced convection allow to simulate, in part, the conditions encountered in vivo during the implantation of implantable medical devices such as stents. One of the parameters for measuring the strength and therefore the retention force is the measurement of the disintegration rate of this layer. The rate of disintegration of the retention layer is directly related to the rate of occurrence of dexamethasone in the workplace. The concentration of Dexamethasone is therefore monitored in the workplace as a function of time. The technique used to monitor the dexamethasone concentration over time is High Pressure Liquid Chromatography or HPLC. 35 40 Hexacath case? FR0 23 21/02/2008 No. 1 and No. 2 316L stainless steel and 316L stainless steel coated with monolayer titanium OxyNitride of thickness 0.1 to 20 microns, preferably about 12 microns Composition of the protective / retention layer: PEG 8000 80% Dexamethasone 20% from 1 to 45 minutes but preferably about 6 minutes (all configurations)

No. 1 and No. 2 316L stainless steel and 316L stainless steel coated with monolayer titanium OxyNitride 0.1 to 20 microns thick but preferably 10 microns PEG 8000 67%

from 1 to 45 minutes but preferably about 17 minutes (all configurations) Example 4-3:

Workplace: # 1 and # 2 Implant Surface Material (Stent): 316L Stainless Steel and 316L Stainless Steel Coated with Titanium OxyNitride Protective / Retention Layer: Monolayer Thickness (0.1 to 20 microns but preferably 10 microns Example 4- 1:

Workplace: Implant surface material (stent):

Protection / Retention Layer: Holding Time of Retention Layer: 1.5

Example 4-2:

Work Setting: Implant Surface Material (Stent): 25 Protective / Retention Layer:

Retention Layer Composition: 33% Dexamethasone Retention Layer Holding Time: Hexacath Case? FR0 24 21/02/2008 Composition of the retention layer: PEG 8000 34% - PVP K30-33% -Dexamethasone 33% Hold time of the Retention layer: from 1 to 45 minutes but preferably about 12 minutes (All configurations) Example 4 -4:

Workplace: # 1 and # 2 10 Implant Surface Material (Stent): 316L Stainless Steel and 316L Stainless Steel Coated with Titanium OxyNitride Protective / Retention Layer: Monolayer Thickness 15 to 15 20 microns but preferably 10 microns Composition of the retention layer: PEG 8000 50% Dexamethasone 50% Hold time of the Retention Layer: 1 to 45 minutes but preferably about 40 minutes (All configurations) It is understood that thanks to the invention, it is possible to obtain a protective / retention layer whose rate of disintegration is adjustable at will in order to allow a controlled release of the active agent or the drug which will be deposited in a solid layer 36 on the implantable medical device 10 (or 20) before the deposition of the protective / retention layer 38 itself.

It will thus be understood that the invention makes it possible to solve all the technical problems previously stated in a simple, safe and reliable manner, usable on an industrial and medical scale, as well as to implement a treatment method providing an effect Unexpectedly improved technique compared with the state of the prior art.

Claims (15)

1. Implantable medical device (10) to be implanted at an implantation site, comprising a therapeutically active agent or drug (36), in particular water-soluble, characterized in that it comprises means (30) for receiving said active agent or drug in solid form; and at least one biocompatible and biodegradable protection / retention layer (38) for providing protection for the active agent or drug (36) to its location, said biocompatible and biodegradable protective layer (38) comprising at least one biocompatible and biodegradable film-forming agent, and at least one hydrophobic agent, preferably biocompatible, for controlling the rate of disintegration of the protective / retention layer. 2. Device according to claim 1, characterized in that the biocompatible and biodegradable film-forming agent is chosen from a polyalkylene glycol, a polyvinylpyrrolidone, or mixtures thereof in all proportions. 3. Device according to claim 2, characterized in that the polyalkylene glycol comprises or consists of polyethylene glycol. 4. Device according to one of claims 1 to 3, characterized in that the hydrophobic agent comprises dexamethasone or a derivative of dexamethasone. 5. Device according to claim 4, characterized in that the dexamethasone derivative comprises dexamethasone, dexamethasone phosphate and dexamethasone acetate. 30Hexacath case? FR0 26 21/02/2008 6. Device according to one of claims 1 to 5, characterized in that the relative ratio by weight between the biocompatible and biodegradable film-forming agent and the hydrophobic agent ranges from 99% to 1% of film-forming agent for 1% to 99% by weight of hydrophobic agent. 7. Device according to one of claims 1 to 6, characterized in that the protective layer / retention comprises from 0.1 to 100 μg of dexamethasone per mm 2 of protective / retention layer surface. 10 8. Device according to one of claims 1 to 7, characterized in that the implantable medical device (10) comprises an inner surface (33) and an outer surface (31), and said means (30) for receiving the agent The drug or drug is at least partially located on at least a portion of the outer surface (31) which comprises a surface sculpture. 9. Device according to claim 8, characterized in that the surface sculpture comprises the formation of reservoirs defining a predetermined reservoir volume for the active agent or drug, alone or in total of the individual reservoir formation volume. 10. Device according to claim 9, characterized in that the reservoir formations may be chosen from the group comprising incisions, channels, wells or cavities. 11. Device according to claim 9 or 10, characterized in that the reservoir formations may be of micrometric size, in particular between about 1 pm and about 600 pm, in particular between 10 and 150 pm, in average size. 30Hexacath case? FRO 27 21/02/2008 12. Device according to one of claims 1 to 10, characterized in that the implantable medical device (10) comprises or consists of a stent (20); a prosthesis such as orthopedic prosthesis; an implant, such as a dental implant; or a surgical cord or cord. 13. Device according to one of claims 1 to 11, characterized in that the implantable medical device (10) comprises a substrate and at least one ceramic coating layer with optionally at least one intermediate nonporous metal adhesion layer. 10 14. Device according to one of claims 1 to 13, characterized in that the implantable medical device (10), such as a stent (20), comprises on its outer surface (31) a multitude of microreservoirs (30) such microcavities or microwells, said active agent or drug being deposited inside said microreservoirs. 15. Device according to one of claims 9 to 14, characterized in that said protective layer / retention (38) is deposited on the outer surface, said tanks (30), such as microcavities or microwells, 20 above the solid deposition of said drug or active agent (36) to ensure its protection to its implantation site.