BR102016012105A2 - CYLINDRICAL TUBULAR PROTECTIVE DEVICE; AND PROTETIC DEVICE WITH BIOLOGICAL SUPPORT MATRIX FOR DRUG RELEASE; WITH OR WITHOUT POLYMERS - Google Patents

Abstract

cylindrical tubular prosthetic device; and prosthetic device with biological support matrix for drug release; with or without polymers a prosthetic device 31, expandable, metallic or biocompatible resin, whose spatial structure is arranged in hexagonal cells, co-located with each other, arranged longitudinally of the prosthesis, together with its internal release matrix 32 is described. This is represented by an artificial biological membrane, whose spatial arrangement is in hexagonal cells 34, which come from the cells that make up the stretcher itself, open, on the inner surface of the same. microcapsules or liposomes 33 contained within the hexagonal cells forming the supporting biological membrane 32 are aggregated and sustained in an intracellular matrix. In this sense, the microcapsules / liposomes will be gradually and selectively released by a pharmacological combining action by dissolving the matrix 35 of a specific layer.

Description

CYLINDRIC TUBULAR PROTETIC DEVICE; And Prosthetic Device with Biological Support Matrix for Drug Release; WITH OR WITHOUT POLYMERS.

FIELD OF INVENTION

[001] The present invention relates to HUMAN BODY IMPLANT MEDICAL DEVICES, and more specifically to expandable, prosthetically shaped, commonly formed metallic devices having favorable anatomical, physiological and mechanical properties used for the correction of stenoses or narrowing of the vascular wall or body duets, aiming to maintain their support for a longer period of time, besides promoting an ideal remodeling process due to the balanced healing activity of the affected vascular wall.

BACKGROUND OF THE INVENTION

Over the last twenty years, a number of coronary prosthetic devices have been produced and applied on a large scale with the aim of promoting a reasonable expansion or dilation of a localized narrowing in the vascular system, or maintaining careful patency in a vascular duet, also representing a possible alternative to conventional revascularization surgery. In certain pathological circumstances such as coronary atherosclerosis, where there is the growth of a tumor of smooth muscle cells, associated with the impregnation of fats, collagen, fibrin and cells of the hematopoietic system, affecting several layers of the arterial wall and producing a restriction on flow. The use of percutaneous interventional therapeutic techniques, represented by coronary angioplasty, combined with other methods, has been receptive and favorably assimilated in the most diverse medical-scientific institutions around the world.

In these situations, the use of expandable coronary metal prostheses is of great importance in complementing the initial therapeutic technique to obtain a better post-procedural outcome, in controlling atherosclerotic plaque growth and definitive restoration of vascular blood flow; as well as preventing reobstruction of the treated vessel or ruling out the danger of acute or late occlusion phenomena caused by arterial wall dissections during the procedure or complications inherent to the fat plate itself.

[004] Of the various currently applicable prostheses, some undergo differentiation as far as the spatial geometric pattern is concerned, as they may be spiral, lattice, interconnected cell scales, joint-joined circumferential ring clusters, among others; regarding the constitution of drugs and polymers on their surface, such as pharmacological stents; as well as in relation to the various forms of medical applicability, namely: maintaining openings in the urinary, respiratory and biliary tract, sustaining digestive tract organ tone, use of inferior vena cava filters to prevent episodes of pulmonary embolism, etc.

The prodromes of the implant technique of these prosthetic devices report from 1969, when Dr. Charles Dotter and colleagues investigated the benefit of experimental use of a stainless steel spiral vascular prosthetic device applied to canine animal experimental popliteal arteries. ; which presented temporally compatible structural patency, but with inevitable narrowing of the vascular lumen. Staying on this same research front, it was able to further develop a spiral bioprosthesis, molded in nitinol, a metal alloy that has thermal memory properties. Such a device required a cooling technique prior to its insertion, and the subsequent administration of local heat (electric heating) until its full expansion, with recovery of its initial configuration, unlike current balloon catheters that are widely used for its expansion. insufflation; this process was reflected in great disadvantage, causing serious injury to the surrounding vascular tissues and increasing the blood thrombogenic potential.

State-of-the-art acquisition began with the release of Cesare Gianturco's precursor endoprosthesis, referenced in US Patent No. 4,580,568, 1,986, which was refined three years later, detailed in US Patent No. 4,800. .882, where the initial zigzag configuration, made of stainless steel and monofilament, was replaced by another spiral coil configuration, also monofilament, consisting of low profile stainless steel with low radiopacity. The former was deliberate with a retraction sheath and had compatible dimensions for use in large dog pots, to the extent that the latter required deformation of plastic material for its expansion (balloon catheter), and allowed extensions available in twelve and twenty millimeters, with variable diameters from 2.5 (two and a half) to 4 (four) millimeters.

[007] In this new generation, there was a mandatory need for the use of 8F large internal light guide catheters (greater than 0.86 inches) and the use of 0.018 inch or 0.014 metal guide rope with reinforced inner support, whereas In 1995, the currently available stent graft was further increased in its configuration, with the addition of a stainless steel longitudinal bar along its entire length to prevent deformation of the prosthesis, spacing or waking of the stems and occurrence of elastic retraction after its release. Still in this more modern standard, the balloon catheters are smaller in profile, which allows the use of smaller guide catheters, being able to reach higher pressures, in addition to the conventional coronary angioplasty guide ropes. , with 0.014 inches. Radiopaque gold marks have been added to the ends of this latest generation of Gianturco prostheses for safer and more accurate positioning.

Among a wide variety of widely used prosthetic devices is the primarily used Palmaz-Schatz stent graft. Expandable through plastic mechanical deformation, Palmaz US Patent Nos. 4,776,337 and US Patent No. 4,733,665, dated 1,988, demonstrate a tubular intraluminal prosthesis consisting of stainless steel monofilaments, or woven, on its surface, forming a plurality elongated constituents, intersecting each other, until they reach the beginning and end edges of the tubular stent graft. They are observed in two distinct forms as to the geometric distribution pattern of the mesh, both pre and post expansion. It has an initial non-expandable shape, which allows its passage through support and position radiopaque tubes, called guide catheters, and an expanded final shape, which is acquired by applying centrifugal and radially directed pressure. whose intensity will directly determine the expandability potential of the stent graft, located through the body duet. Another noteworthy reference is US Patent No. 5,102,417, by Palmaz and Schatz, supplemented by US Patent No. 5,195,984, which provides for a differentiation in earlier models, as the expandable tubular junctions are connected by a bridge (linkage). 1 mm, flexible, usually helical. The joints have a slight stiffness, but with the flexible joint, the prosthesis may present folding, especially when coupled to curved blood vessels. Such a joint is somewhat limited in range of motion, but the prosthesis had great radial force, exhibited high resistance to elastic retraction, and provided good vascular structure support. Its overall flexibility and radiopacity were somewhat reduced, characterizing a disadvantage, as well as its similarity to other stainless steel prostheses, because only through fluoroscopic techniques, visualization was allowed, the certainty of an accurate deliberation of the prosthesis through the duet. or vessel, which is vital for a successful therapeutic outcome.

Similarly, we observe U.S. Patent

No. 4,886,062 by Wiktor demonstrating a balloon expandable prosthetic device consisting of stainless steel, copper alloy, titanium or gold. In this remote era, several other examples of patents for intravascular prosthetic devices may be referenced as follows: U.S. Patent No. 5,019,090, to Pinchuk; U.S. Patent No. 5,161,547 to Tower; U.S. Patent No. 4,969,458 to Wiktor; U.S. Patent No. 4,655,771 to Wallsten; U.S. Patent No. 5,195,984 to Schatz; PI Patent 9508353-7 A, Israel; among others.

[010] Until the beginning of the current century, despite the superb effort for the industrial creation and development of all of these aforementioned types of coronary prostheses, restenosis ("de novo" atheromatous plate narrowing) of the treated vessel with this type of advent, was still shown to be reasonable, and, why not say, unacceptable, ranging from 14% to 60% in the first six months after prosthesis implantation, depending on the population studied, material configuration and constitution, number implanted prostheses, treated vessel, lesion location, lesion length, minimum lumen diameter of the vessel after the procedure and its minimum luminal gain, etc. This fact is relevantly supported by the occurrence of hyperplasia or intimate hyperproliferation of the treated vessel wall, since trivially there is an endothelial proliferation that incorporates the prosthesis to the vascular wall until one week after the procedure and three months after the procedure; fact that many claim to reduce the thrombogenicity of the prosthesis.

[011] In fact, with the primary development of coronary endoprostheses from 1986 onwards, the relevant objectives were to improve short- and long-term outcomes of coronary balloon angioplasty, reduce the incidence of acute occlusion and delayed restenosis. Several randomized studies, including STRESS and BENESTENT, comparing the use of this type of stent with conventional angioplasty have demonstrated the efficacy of the first alternative, in the case of PALMAZ-SCHATZ prosthesis, in reducing restenosis rates after coronary angioplasty. From these works, among others, a field was opened for the investigation of various types of coronary prostheses, or "stents".

[012] Immediate success after the procedure was satisfactory (98%), and subacute intra-prosthetic thrombosis, occurring in the first three weeks, was found in 3% of cases. Despite the acknowledgment of this fact, there are no formal reports on the type of injury that responds to the various therapeutic alternatives. Until this time, balloon angioplasty had been considered the therapy of choice for the treatment of vascular restenosis in this situation, with a high primary success rate, but also vessel reobstruction, although worldwide literature had already advocated technological innovations such as radiation brachytherapy, laser and viral replication techniques (adjuvant gene therapy), see multicenter study ITALICS; still needing further scientific evidence.

[013] As previously stated, restenosis after stent placement was still present at considerable levels from 1999 to 2000, as these were metal devices with mechanical properties that could provide TIMI III flow (complete revascularization), with complete immediate angiographic success after the procedure, but in the long term, there was a decrease in clinical success due to vascular restenosis, at rates of 15% -20% in that period.

[014] Such devices had only a static feature, as they did not interact, modifying the properties of the affected vascular wall, which would only be possible with local action of drugs, so far tested in the control of the atherosclerotic evolutionary process. Since their use in 1987, coronary stents have been increasingly employed in the treatment of increasingly complex pathological conditions, but frustrating expectations that they would be able to curb neointimal proliferation of the vascular wall. From their applicability, stents alone can prevent the phenomenon of post-intervention elastic vascular recoil and also seem to act on adverse remodeling, but in restraining intra-stent restenosis, the additional use of a release strategy of antiproliferative agents of the stent itself, acting in the synergistic reduction of the restenotic lesion was necessary.

From 1990 onwards, the approval of two of the most important stents employed to date, Gianturco-Roubin (Cook) and Palmaz-Schatz, has made the use of this type of stent graft universally viable, as only the Palmaz-Schatz model, up to 1996, reached 1,000,000 treated patients worldwide.

[016] Regarding the clinical context, endoprostheses have current applicability in both acute ischemic syndromes (unstable angina and myocardial infarction) and stable chronic coronary artery disease. With regard to acute myocardial infarction, its use has ranged from the primary interventional condition, such as rescue circumstances after failure of fibrinolytic treatment, and elective indication when severe residual stenosis is found.

[017] Therefore, the first stents were developed with the aim of increasing short and long term outcomes in coronary angioplasty procedures, but with the introduction of the first pharmacological stents, immediate results demonstrated a significant reduction in restenosis rates, but these concurrently caused a chemical scan of the subendothelial and neointimal layers of the vascular wall, rather than preventing balanced tissue neoformation. Later effects related to polymeric biodegradation, involving the late thrombosis phenomenon, inevitably emerged.

[018] At the academic-scientific level, it is recommended as the ideal stent one that offers a biocompatible platform of polymeric material or, when absent, provides effective and safe drug release rates and concentrations at the affected site, as well as electrochemical properties. and biomolecular, and high absorption capacity of the vascular wall. As a reference for records on drug-eluting stents, PI 0317150-7 A (Publication Date: 11/01/2005); PI 0213279-6 A (Date Posted: 26/10/2004); PI 0503201-6 A (Published Date: 13/03/2007); US 20100191323 Al (Published Date: Jul 29, 2010); US 20090182404 Al (Published Date: 16/07/2009).

[019] It is therefore the primary object of the invention to develop a biocompatible, nonpolymeric intracoronary device for the gradual and controlled release of multiple drugs through extrinsic factors such as self-administered drugs. or released via organic implants, with the analysis of their scientific viability and industrial production, and which has the following peculiarities: [020] Mechanical and physiological properties: - expandability; - flexibility; - radial force; - radiopacity; - complacency; - high profile; - adaptability to vascular anatomy; - low percentage of metal coverage.

[021] Electrochemical and biomolecular properties: - antithrombogenicity; anti-chemotaxis; - high absorption by the vascular wall (good diffusion coefficient of the wrapping system); - antiproliferative and antimitogenous activity; - high biocompatibility.

[022] In fact, by controlling the proliferative vascular response or intimal hyperplasia, the aim is to significantly reduce late restenosis rates and emerging post-stent complications, whether late acute intra- or peri-acute thrombosis. stents. As a pioneering project, this privilege has a nonpolymeric biological matrix constituting a release coating on its interior, which has the function of eluting chemical biomolecules, with anti-atherogenic, antiproliferative and vascular wall restructuring properties, providing the storage and multiliberation function of drugs, stored and grouped in microcapsules or microspheres (liposomes), wrapped in a network (matrix) of macromolecular protein composition, or a biological film that has chemical reaction compatibility with the various types of medication to be administered extrinsically (orally). Such a mechanism would be responsible for minimizing the late effects of polymer degradation, as the first stents were introduced in 2001 with single-drug release platforms, leading to the dreaded long-term complications related to the necessary and massive oral antithrombotic prophylaxis (anticoagulation) as well as late stent thrombosis.

SUMMARY OF THE INVENTION

[023] The skeleton of the non-polymer matrix prosthetic drug delivery system, namely cylindrical tubular prosthetic device or stent type prosthetic device itself, is comprised of a fenestrated tubular diagram of regular cylindrical shape, multifilament, without, however, middle joint; characterized by having an initial diameter, which allows its release intravascularly or in any organic lumen-containing duet, and an expanded final diameter by applying radial force and centrifugation via balloon catheter, or simply being self-expanding. This force is achieved by insufflation of said catheter, the dilated portion of the catheter that surrounds the guide, and its intensity will determine the support of the final diameter of the prosthesis, and then expanded, will determine the permanent dilatation of the vascular lumen or organic duet. It can be cast in stainless steel, nitinol alloys, whether or not coated with inorganic chemicals (polishing), as well as biocompatible organic resins such as artificial cartilage or saponaceous. Nitinol is composed of a nickel-titanium alloy with thermal memory properties, often used in medical prosthetics and orthotics; Good biocompatibility: minimal inflammatory response in adjacent tissues, without material corrosion. The first intravascular stents described by Dotter and subsequent authors were nitinol.

However, despite all these advantages, the possibility of using inorganic material as a covering that increases the biocompatibility of the prosthesis, as well as its antithrombogenicity, will be discussed later.

[025] Its spatial structure is arranged in hexagonal cells, co-adapted to each other, in the shape of beehive, honeycomb, arranged longitudinally of the prosthesis. Globally, visually observing, we obtain a structure with spatial distribution of a honeycomb wall, with cells growing axially from the prosthesis.

[026] Initially, at the experimental production level, the objective is the elaboration of prostheses in diameters of 4.0 mm and 5.0 mm, with lengths ranging from 12 mm, 18 mm and 24 mm, not discarding posteriorly the molding in smaller diameter and longer length. The thickness of their cell stems may range from 0.08 to 0.12 mm, so that their metal-coated area reaches indices of less than 20%; important to reduce the tendency to thrombosis and trauma of the vascular wall, which is also a consequence of the process of finishing the prosthesis, which includes the chemical polishing of the nails and the laser cutting for the material configuration and its spatial structure. .

[027] The internal release matrix, internal coating, is represented by a biocompatible artificial biological membrane, which may consist of phospholipids, or similar substrate, and may or may not be microporous, provided that it permits good diffusion and release capacity. drugs. The spatial geometric design is arranged in also hexagonal cells that come from the extension of the support prosthesis, that is, the cells that make up the spatial conformation of the stent itself, open, on the entire inner surface of the stent, ie, towards the vascular light.

Microcapsules or liposomes, contained within the hexagonal cells that form the biological supporting membrane, are arranged in aggregate and sustained form, immersed in a matrix that forms chains or networks of protein macromolecules, or these conjugated to other organic molecules such as phospholipids, in the form of a biological film or gel, so as to provide sufficient sustainability and an optimal fixation rate.

In this sense, the microcapsules / liposomes will be gradually and selectively released through a pharmacological combination and reaction action, by the rupture of the connecting bridges and stabilization of macromolecular protein chains, a process that occurs via enzymatic degradation. A process also known as protein fixation to biologically compatible resin contained in porous or non-porous surfaces, such as the use of albumin, with the aim of increasing the matrix porosity coefficient.

[030] The significant efficiency shown by biocompatible macromolecules in the selection of reagents and high specificity interaction mechanisms at chemical reaction sites has been promoting a growing interest in the field of research involving thinner macromolecule films in association with optimized materials and as well as biological protein macromolecules.

[031] In liquid or crystal form, drugs released from the encapsulated or liposomal structure will be gradually and protocolally subjected to experimental model research, computational analysis, preclinical and clinical studies in order to effectively and reliably evaluate optimal concentration to be achieved in vessel lumen, best diffusion coefficient, velocity and release intervals, vascular locus half-life, metabolism and toxicity, among other aspects; It is emphasized that during all stages of the process of elaboration, evaluation, production, in vitro and in vivo scientific feasibility tests, any type of product may be modified, deleted, added or merged. drugs, according to the necessary formalities, as well as obliterating or reconstructing pertinent elements, provided that there are no profound changes in the previously envisioned global set.

[032] The present invention is objectively established to attenuate or eliminate the occurrence of later restenosis (recurrent atheromatous plaque growth), and further prevent late acute thrombosis, even after balloon angioplasty and / or placement of Stretch-type prosthesis of the vascular wall, arising from a variety of factors, namely: 1. Myointimal hyperplasia, or proliferation of neointimal tissue, is one of the main mechanisms responsible for intrastent restenosis. (*) 2. Certain chronic diseases such as diabetes, unstable angina, among others. 3. Regarding aspects of the vascular anatomy itself: restenotic chronic lesions, smaller reference diameters of the treated vessel, ie, the vascular basal caliber from which a post-procedure result is optimized, plaque extension approached (plaques larger than 15 mm in length have a higher risk of post-stent restenosis and late acute thrombosis). 4. Measurement of the minimum light diameter at the end of the intervention and the calculation of the immediate gain of the treated site diameter (minimum post-procedural light diameter minus pre-procedural minimum light diameter). (*) It is believed that the presence of the pharmacological prosthesis inside the vessel under tension triggers an inflammatory reaction due to the confinement of platelet thrombus. The inflammation inherent in the process stimulates the migration of smooth muscle cells towards the subintimal region, proliferating with varying intensity alongside secretion of extracellular matrix cells, which may result in the formation of a new obstructive intima. This "in situ" prosthesis, therefore, stimulates hyperplasia and the formation of a new intima through the injury of the vessel, since it affects the internal elastic lamina.

BRIEF DESCRIPTION OF DRAWINGS

According to the respective figures presented in this report, this privilege of invention will be the object of appreciation and understanding, generally in this topic, and in more detail with the information described below.

[034] FIGURE 1 is a perspective illustration of a standardized stent type cylindrical tubular prosthetic device, intraluminally expandable, on a metal support or biocompatible resin, with its spatial structure arranged in hexagonal cells, co-fitted with each other, in the shape of a house. bees, honeycomb, arranged longitudinally of the prosthesis. Globally, visually observing, we obtain a structure with spatial distribution of a honeycomb wall, with cells that grow in the axial direction of the prosthesis, presenting an initial predilatation diameter, which allows its positioning in intravascular lumen or duet. organic.

[035] FIGURE 2 and FIGURE 3 are a perspective illustration of the same prosthetic device of FIGURE 1, together with its described internal internal release coating, which is represented by a biocompatible artificial biological membrane and may be constituted by phospholipids and proteins, or similar substrate, may be microporous or not, as long as it permits good diffusion and drug release. The spatial geometric design is arranged in also hexagonal cells that come from the extension of the support prosthesis, that is, the cells that make up the spatial conformation of the stent itself, open, on the entire inner surface of the stent, ie, towards the vascular light.

FIGURE 4 shows, from a close focus, the microcapsules or liposomes contained within the hexagonal cells that form the supporting biological membrane, and which are arranged in aggregate and sustained form, immersed in a matrix that forms chains or networks. protein macromolecules, or these conjugated to other organic molecules such as phospholipids, in the form of a biological film or gel, so as to provide sufficient sustainability and an optimal fixation rate.

[037] FIGURES 5 and 6 are perspective illustrations of said intraluminally expandable cylindrical tubular prosthetic device, intraluminally expandable, with its internal drug delivery matrix, in an approximate section showing how this matrix is disposed, namely in also hexagonal cells, which come from the prolongation of the supporting prosthesis, that is, from the cells themselves that make up the spatial conformation of the prosthesis, properly opened, on the entire inner surface of the stent, that is, towards the vascular light. The microcapsules or liposomes contained within the hexagonal cells forming the biological supporting membrane are arranged to be aggregated and sustained in homogeneous layers on top of one another (in the figures, represented by different colors, ie each layer). shown in a certain color, representing a liposome / microcapsule modality, containing a different type of drug), immersed in a matrix that forms chains or networks of protein macromolecules, or other types of biomolecules, so as to provide sufficient sustainability and optimality. fixation rate. Each layer will be formed by a support matrix of different chemical composition, aiming to provide the specificity and selectivity of the release of a given drug, contained in the liposomes / microcapsules, according to the type of medication administered by the patient. falling into the bloodstream, reaching the stent surface, will be responsible for interacting with the particular support matrix of a given layer, for which it is programmed, dissolving it and releasing, selectively and specifically, a certain type of drug, aiming not to only the control of vascular restenosis, but also modulating the inflammatory and proliferative response of the myointimal wall, an adversity that often occurred in the implantation of polymeric drug-eluting stents in general.

FIGURES 7 and 8 are perspective illustrations of said intraluminally expandable, standardized stent type cylindrical tubular prosthetic device with its internal drug delivery matrix and the schematic representation of the substance administered orally via the intradermal venous implant. , among others, gradually reaching the stent surface, where it will be responsible for interacting in the specific sites for which it is programmed, dissolving the support matrix of the drug to be released, a process that occurs from the upper (outer) layers to the lowest (deepest).

FIGURES 9 and 10 are a perspective illustration of the same prosthetic device of FIGURE 1, depicting the arrival of the administered substances / medications so that, reaching the light of the vessel in which the prosthetic device is located, interact with the matrix. supporting the layers that form and fill the inner cavity of each hexagonal cell of the release platform. Obviously, these substances will interact with the first layers of the supporting matrix located towards the vessel light, ie only and specifically with those layers whose chemical constituents are reactive to the action of these substances, thus providing the release of microcapsules / liposomes. stored and supported by this matrix. Thus, it is patent the possibility of effecting a selectivity and diversity in the mechanism of drug delivery applied intra-stent or intra-prosthetic device. In color schematic presentations, the various representations of each type of medication administered are differentiated by each color, and it is also applied to microcapsules / liposomes programmed to be released from the specific layer (hexagonal cell support matrix).

FIGURES 11 to 16 sequentially depict the perspective illustration of the substance / medication interaction mechanism that reaches the stent with its inner surface on which the liposome / microcapsule support layers are conjugated and progressively released for action. in the vascular wall. Microcapsules / liposomes in which antimoproliferative, antiatherogenic and antithrombogenic drugs will be soaked alone or conjugated to controlled slow release biological substrate, and temporally controlled release vehicle dispersed between the same microcapsules in any presentation, whether solid, liquid, gel, etc.

FIGURES 17 to 24 represent in perspective view a new process of arrival of a different substance administered to the inner surface of the stent, culminating, as described in the last paragraph, with the release of other types of intrauterine drugs. stent, compatible and scheduled for release according to the action of the substance administered by the patient.

FIGURES 25 to 29 demonstrate in perspective view the same intraluminal drug delivery system as the previous figures, in which, in a subsequent step of re-administration of another type of substance, already reaches, interacts with and releases another type of intra-medication. -stent, contained in microcapsules / liposomes aggregated and supported in different layer, consisting of compatible support matrix.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

More specifically, certain references are set forth below with reference to FIGURES 1, 2, 3 and 4 which illustrate a first embodiment of an expandable intraluminal cylindrical tubular prosthetic device, or simply an esthetic prosthetic device, or simply prosthesis, or stent, constructed in accordance with the standards of the present invention. It is to be understood that the terms "expandable intraluminal cylindrical tubular prosthetic device", "stent type prosthetic device", stent or simply "prosthesis" are applied simultaneously to denote the present invention, as the latter may be ascribed to its use. vascular segments in general, as well as organic duets, in order to correct stenoses or narrowing and sustain their tone.

FIGURE 1 shows the stent type prosthetic device 31, in metal support or in biocompatible resin, with its spatial structure arranged in hexagonal cells, co-mutually arranged, in the shape of a beehive, honeycomb, arranged in a direction. length of the prosthesis, detailed in FIGURES 2, 3 and 4, associated or in conjunction with its internal release matrix, described internal coating, which is represented by biocompatible artificial biological membrane and may consist of phospholipids and proteins, or the like. substrate and may be microporous or not, provided that it permits good diffusion and drug release capacity 32.

[045] With reference to FIGURES 1, 2, 3 and 4 the estentor type prosthetic device 31 is constituted on its surface by fenestrated tubular diagram, without presenting a median joint of regular cylindrical, multifilament shape, associated with internal release coating. 32, which may be a self-expanding or balloon-expanding device.

See now in greater detail with reference to FIGURE 4 illustrating the stent type prosthetic device 31 showing, from a close focus, the microcapsules or liposomes 33 contained within the hexagonal cells 34 forming the membrane. and are arranged in a matrix that forms chains or networks of protein macromolecules 35, or conjugated to other organic molecules such as phospholipids, in the form of a biological film or gel, so that they provide sufficient sustainability and an optimal fixation rate.

[047] FIGURES 5 and 6 are perspective illustrations of said intraluminally expandable, standardized stent type cylindrical tubular prosthetic device 31, with its internal drug delivery matrix 32, in an approximate section showing how this matrix is disposed, either. , also in hexagonal cells 34, which result from the prolongation of the supporting prosthesis, that is, from the cells that make up the spatial conformation of the prosthesis itself, open, on the entire inner surface of the stent 31, that is, towards the light. vascular. Microcapsules or liposomes 33 contained within the hexagonal cells 34 forming the biological supporting membrane are shown to be arranged and sustained in homogeneous layers on top of one another (in the figures, represented by different colors, or that is, each layer shown in a given color, representing a liposome / microcapsule modality, containing a different type of drug), immersed in a matrix that forms chains or networks of protein 35 macromolecules, or other types of biomolecules, so as to provide sufficient sustainability and an optimal fixation rate. Each layer will be formed by a support matrix of different chemical composition, aiming to provide the specificity and selectivity of the release of a given drug, contained in the liposomes / microcapsules, according to the type of medication administered by the patient. falling into the bloodstream, reaching the stent surface, will be responsible for interacting with the particular support matrix of a given layer, for which it is programmed, dissolving it and releasing, selectively and specifically, a certain type of drug, aiming not to only the control of vascular restenosis, but also modulating the inflammatory and proliferative response of the myointimal wall, an adversity that often occurred in the implantation of polymeric drug-eluting stents in general.

FIGURES 7 and 8 are perspective illustrations of said intraluminally expandable, standardized stent type cylindrical tubular prosthetic device 31 with its internal drug delivery matrix 32, and the schematic representation of the substance administered orally 36 via the implant. intradermal, venous, among others, gradually reaching the stent surface, where it will be responsible for interacting in the specific sites to which it is programmed, dissolving the support matrix of the drug to be released 35, a process that occurs from the highest layers. (external) to the lowest (deep).

FIGURES 9, 10, 11, 12, 13, 14, 15 and 16 are a perspective illustration of the same prosthetic device of FIGURE 1, with its internal drug delivery matrix 32, in an approximate section showing how it is. The matrix is also available in hexagonal cells 34, which result from the prolongation of the support prosthesis, that is, the cells themselves that make up the spatial conformation of the prosthesis, properly open, on the entire inner surface of the stent, ie. towards the vascular light, with the microcapsules or liposomes 33 contained within the hexagonal cells forming the biological supporting membrane, and arranged in a homogeneous layer on top of one another; such FIGURES depict the arrival of the administered substances / medications so that, reaching the light of the vessel in which the prosthetic device is located, interact with the support matrix of the layers 35 forming and filling the inner cavity of each hexagonal cell of the release platform. . Obviously, these substances will interact with the first layers of the supporting matrix located towards the vessel light, ie only and specifically with those layers whose chemical constituents are reactive to the action of these substances, thus providing the release of microcapsules / liposomes. stored and supported by this matrix. Thus, it is patent the possibility of effecting a selectivity and diversity in the mechanism of drug delivery applied intra-stent or intra-prosthetic device. In schematic color presentations, the various representations of each kind of medication administered are differentiated by each color, and it is also applied to microcapsules / liposomes programmed to be released from the specific layer (hexagonal cell support matrix) 35.

[050] FIGS. 17 to 24 represent in perspective view a new process of arrival of a different substance administered 36 to the inner surface of the stent, culminating, as described in the last paragraph, with the release of other types of intrauterine drugs. -stent 33, compatible and scheduled for release according to the action of the substance administered 36 by the patient.

FIGURES 25 to 29, similarly, demonstrate in perspective view the same intraluminal drug delivery system 33 as in the previous figures, where in a subsequent step of further administration of another substance 36, it already reaches, interact and release another type of intra-stent medication, contained in aggregated microcapsules / liposomes 33 and supported in a different layer, consisting of a compatible support matrix 35.

Finally, FIG. 30 summarizes in perspective illustration of the same prosthetic device of FIGS. 1, 2 and 3, together with its internal release matrix, described internal coating 32, which is represented by an artificial biological membrane. biocompatible, arranged in hexagonal cells that result from the prolongation of the support prosthesis, that is, the cells that make up the spatial conformation of the stent itself, containing the microcapsules or liposomes 33, and these aggregates and sustained, immersed in a matrix that forms protein macromolecule chains or networks 35 so as to provide sufficient sustainability and an optimal attachment rate.

[053] Tens of millions of patients worldwide undergo coronary interventional procedures annually, and vascular stents represent, in this case, the largest advance in the area, and are routinely used in over 90% of cases. A reasonable number of advantages and applicability can be found as: - Treatment of multivascular atherosclerotic disease; - Dilatation of organic duets, as in the urogenital system, respiratory and biliary tract, as well as congenital stenoses of vascular origin; - Biological coating has its acceptable application as coating of artificial and natural heart valves, intravascular filters, and intraorganic devices such as the IUD. - Pioneering, it is the only device to offer an ideal support platform for stem cell deposit and release, aiming at promoting the balanced remodeling process and physiological resolution of the affected vascular wall.

Claims (10)

1. CYLINDRIC TUBULAR PROTETIC DEVICE, fenestrated, metallic, or constituting flexible or cartilage biological resin, of high biocompatibility, type "stent", characterized by being released in intravascular pathways and organic duets. Cylindrical tubular prosthetic device according to claim 1, characterized in that it has a spatial structure arranged in hexagonal cells, co-adapted to each other, in a beehive, honeycomb conformation, arranged longitudinally of the prosthesis. Cylindrical tubular prosthetic device according to claim 2, characterized by a structure containing a drug release platform, that is, an internal release matrix, an internal coating, which is represented by an artificial, biocompatible biological membrane, which may consist of phospholipids, or similar substrate, which may be microporous or not, provided that it permits good diffusion and drug release capacity. Cylindrical tubular prosthetic device according to claim 3, characterized in that the internal drug delivery matrix has a spatial geometric design that is also arranged in hexagonal cells, which result from the prolongation of the support prosthesis, that is, the cells themselves. make up the spatial conformation of the stent itself, open, all over the inner surface of the stent, that is, towards the vascular light. Cylindrical tubular prosthetic device according to claims 3 and 4, characterized in that the microcapsules or liposomes contained within the hexagonal cells that form the biological support membrane are arranged and sustained, immersed in a matrix that forms chains or macromolecule networks of proteins, or these conjugated to other organic molecules such as phospholipids, in the form of biological film or gel, so as to provide sufficient sustainability and an optimal fixation rate. Cylindrical tubular prosthetic device according to claim 5, characterized in that the drugs located inside the microcapsules have a controlled release coefficient and can be prepared in liquid, solid or gel form, allowing good diffusion and release capacity in vascular light. . Cylindrical tubular prosthetic device according to claims 3 and 4, characterized in that the internal drug release matrix, besides having multiple layers, may contain interconnection holes or gaps between its cells, aiming to allow greater diffusion and accessibility of the drugs released also in relation to the vascular wall "protected" by the prosthesis. Cylindrical tubular prosthetic device according to claims 1 and 2, characterized in that it is self-expanding or by balloon catheter. Cylindrical tubular prosthetic device according to claim 5, characterized in that it has an internal drug release matrix arranged in hexagonal cells containing microcapsules or liposomes which, in this sense, would be gradually and selectively released through a combination and pharmacological reaction, in each supporting layer of the microcapsules or liposomes, by the substance administered by the patient, via exogenous or endogenous (biological implants). Cylindrical tubular prosthetic device according to claim 9, characterized in that each support layer of the microcapsules or liposomes will be formed by a support matrix of different chemical composition, aiming to provide the specificity and selectivity of the release of a given drug. contained in the liposomes / microcapsules according to the type of medication administered by the patient.