BRPI1003542A2 - constructive arrangement introduced in biodegradable coated rapamycin-eluting stent for restenosis inhibition - Google Patents

Abstract

CONSTRUCTIVE ARRANGEMENT INTRODUCED IN BIODEGRADABLE RAPAMICINE ELDER STENT DEVICE FOR RESTENOSIS INHIBITION, represented by an evolutionary solution, is a device that is implantable in order to obtain a wide channel to improve the passage of the lumen flow, said stent (A) being composed of a hollow cylindrical metal platform with several conjugated rings (1) arranged parallel to each other and connected by Iinks (1), the metal platform is made of a cobalt and chromium alloy, called L605 ', the surface of which is polished to prevent platelet and plasma protein aggregation on the stent this platform is composed of an immunosuppressive agent called rapamycin and a biodegradable polymer blend composed of polyamide (lactic acid) and poly (lactic acid-co-glycolic acid), which should also be considered the drug, which is distributed on the surface of the metal platform in concentrations between 0.1 and 10, Opg / mm2, such that the complete degradation of the polymeric blend occurs between 6-9 months and additionally said coating (3) is in the form of a single thin layer and is arranged on the outer (3a) and lateral (3b) faces of the rings (1) and stent (A) links (2) promoting controlled endothelialization and decreasing the likelihood of incidence of thrombosis in the medium and long term.

Description

"CONSTRUCTIVE ARRANGEMENT INTRODUCED IN BIODEGRADABLE RAPAMICINE STENT-ELUCENT STENT DEVICE FOR INHIBITION OF RESTENOSIS"

The present patent application of the title title and object of description and claim in this title is an inventive solution in the field of application dictated by the specialized medicine in vascular diseases, notably for specific pathologies such as aortic aneurysms and dissections, among others. others, where stent devices are used.

A first purpose of the utility model

It lies in providing the stent, notably the balloon component of two radiopaque marks, which indicate the functional length of the balloon and are located within the balloon.

A second goal. of the utility model lies in providing the stent, the constructivity of the optimized metal platform.

A third objective of the utility model is to provide the stent.de with a differentiated elution profile.

A fourth objective of the utility model is to provide the stent, with a differentiated coating, a polymeric blend composed of two biodegradable polymers: poly (lactic acid) and poly (lactic acid-co-glycolic acid).

Thus the new device is composed of a cylindrical metal platform, formed by conjugated rings arranged parallel to each other, covered with biodegradable polymer and an active pharmacological agent, located on a balloon catheter that, after being inflated, expands the stent. and presses it against the artery wall.

The composition of the coating aims to minimize the risks of restenosis and thrombosis after implantation. In other embodiments of the invention, the composition and obtention of the metal platform, as well as the composition and arrangement of the coating, responsible for controlling drug elution in the artery wall are characterized.

Therefore, it is concluded that the new constructive arrangement introduced in a biodegradable coated rapamycin-eluting stent device for restenosis inhibition can be understood as part of an object of practical use, translated by the stent device itself, which is susceptible of industrial application. , translated into functional improvement, meeting the requirements of patentability, in particular as a utility model, as provided for in Article 9 of Law 9,279 (Patent, Trademark and Related Rights Law) of 14 May 1996. .

BACKGROUND OF THE TECHNIQUE: In order to provide truth to the context explained in the introductory table, a brief explanation of the state of the art for stent endoprostheses will be provided, where it will be possible for a technician skilled in the subject to recognize both his positive aspects as limiting, so that at a later time we can discuss the added advantages with the introduction of the improvement object of claim in this cartouche.

The technological basis of stent devices: stents have revolutionized interventional practice for the treatment of ischemic and symptomatic heart disease. In clinical practice, they are increasingly being prescribed to a larger number of patients. In 2007 alone, more than 43,000 stent units were used by the Unified Health System (SUS) in Brazil. However, clinical data demonstrate that

20-25% of patients develop a new stenosis, also called restenosis. In other words, a sequence of complex events causes inflammatory processes in the stent site, causing a new reobstruction. To prevent restenosis, active pharmacological agents were incorporated into the stents, allowing them to be controlled controlled at the implant site, preventing inflammation of the target tissue.

Solutions to identified problems: Researchers have been studying various drugs to incorporate into stents, with the aim of preventing various inflammation, as well as sirolimus, a drug used in this patent and also known as rapamycin. Other widely used immunosuppressive drugs known in the state of the art, such as tacrolimus, everolimus and paclitaxel significantly reduced binary restenosis, repeated revascularization of the target lesion, and late angiographic loss at six months when compared to stents. uncoated.

State of the art: numerous patent applications for this field have been published, among which, patent application may be cited. Title: COMBINATION OF USEFUL RESTENOSIS PREVENTION DRUGS, SN 60 / 204.417, filed May 12 which has among other claims the use of rapamycin and paclitaxel.

In addition, procedures such as using

of drugs, which act as inhibitors and / or antiproliferatives of smooth muscle cells, are widely known in the art. This statement can be evidenced by a critical literature of the patent application Title: USING 4-H-1-BENZOPYRAN-4-ONA DERIVATIVES AS LIKE MUSCLE CELL PROLIFERATION INHIBITORS, US 09 / 243,380; 12/21/1999 US 09 / 468,665, depositor SOUTHERN Research Institute (US).

Also examples of the state of the art are other patent applications filed by the Boston Scientific Laboratory, the scope of which relates to the application of inhibiting agents or anti-proliferation of restenosis, namely: US 5,857,998, Stent and therapeutic delivery system; US 5,954,706, Drug delivery; US 6,358,556, Drug related stent coating; US 6,620,194, Drug coating with topcoat; and US 5,674,192, Drug delivery. In addition, patent applications filed

by the Angiotech laboratory, whose field of application relates to the application of restenosis inhibiting and / or antiproliferation agents, are also listed: US 5,886,026, Anti-angiogenic compositions and methods of use; US 6,333,347, Intrapericardial delivery of anti-microtubule agents; US 6,495,579, Method for treating multiple sclerosis; US 6,506,411, Anti-angiogenic compositions and methods of use; US 6,515,016, Composition and methods of paclitaxel for treating psoriasis; and US 6,544,544, Anti-angiogenic compositions and methods of use. Finally, it is pertinent to cite other patent applications filed by Cordis Laboratory, whose field of application refers to the application of restenosis inhibiting and / or antiproliferation agents, are listed: US 5,882,335, Retrievable drug delivery sytent; US 5,891,108, Drug delivery stent; US 6,146,358, Method and apparatus for delirium of therapeutic agent; US 6,585,764, Stent with therapeutically active dosage of rapamycin coated thereon; and US 6,616,650, Method and apparatus for delivery of therapeutic agent.

Critical analysis of state-of-the-art anticipated solutions: All US applications or patents cited above in this booklet prove that, as a rule, the use of restenosis inhibiting and / or antiproliferation drugs is widely known to the State. Technique, leading to the conclusion that the practice of using rapamycin, among other agents with such characteristics, is of common use and may be the object of application in solutions aiming at the optimization of its elution with the lesion of a coronary artery, for example. example, without harming the Industrial Property Law in the field of Medical application.

In view of this conclusion, from the point of view of the effectiveness of restraining inhibitor and / or anti-proliferation medicinal products, the applicant considered the possibility of gains in relation to the performance of the stent product itself in order to optimize access conditions within the coronary artery.

Within this scope of claim, patent application Pl 0303669-3 A, filed on March 27, 2003, by the Boston Scientific Limited (US or US) laboratory, under the title "STENT PERFECTED", may be cited. No more than 45 embodiments of the stent structural profile are claimed. By way of reference, reference may also be made to patent application Pl 0203650-A, filed on 06/09/2002, by Medinol LTD, under the heading of "SELF-ARTICULATING STRENGER", which generally refers to It refers to extensors implanted in vessels within the body to support and hold vessels open, or to hold other vessels in general.

Despite the good clinical results of drug-eluting stents embedded in its surface, elution kinetics are one of the critical factors regarding device efficiency and safety. In a paper published in 2005 by Eurolntervention (1: 1,58-65) by Serruys P.W. et af, titled "A RANDOMIZED COMPARISON OF A DURABLE POLYMER EVEROLIMUS-ELUTING STENT WITH A BARE METAL CORONARY STENT: THE SPIRIT FIRST TRIAL", shows the effectiveness of an everolimus-eluting stent, also called a stent conv. - optional.

Even though the polymeric matrix represents an advantage in terms of device efficiency, especially related to drug release control, it can also present a safety disadvantage. After drug elution, the polymer remains in contact with the artery and may cause medium and long-term thrombosis. Recent studies show that the use of biodegradable polymers is one of the possible solutions to solve this problem, as well as the reference published in 2008 by Lancet Magazine (27; 372 (9644): 1126-8), by Windecker S. et al. , titled "BIOLIMUS-ELUTING STENT WITH BIODEGRADABLE POLYMER VERSUS SIROLIMUS-ELUTING STENT WITH DURABLE POLYMER FOR CORONARY REVASCULARISATI-ON (LEADERS): A RANDOMISED NON-INFERIORITY TRIAL". In this study, we compared the performance of two stents, one covered with biodegradable polymer and the other with non-degradable polymer.

As a reference, in order to prove the possibility of industrial and commercial application of biodegradable polymeric compounds, the applicant refers to the patent application US 252,645, filed by: Southern Research Institut (US), filed on 27/27 / 89, entitled "PROCESS FOR INSITU FORMATION OF A BODY IMPLANT, PROCESS FOR IN-SITU FORMING A SOLID IMPLANT, BIODEGRADABLE IMPLANT, COMPOSITION FOR THE FORMATION OF A POLYMER THAT IS CURED IN SLTU FORMING A BIODEGRATING IMPLANT IMPLANT FORMING COMPOSITION "wherein a biodegradable polymer solution is injected and has its final healing process within the body. Another document, which is pertinent as regards the elution of pharmacological agents by biodegradable polymers, is patent application Pl 9908893-2 A filed by Merck & CO, Inc. (US), filed with 18/03/1999, entitled "LIQUID POLYMERIC COMPOSITION FOR THE CONTROLLED RELEASE OF HYDROPHONIC BIOACTIVE SUBSTANCES, AND PROCESS FOR THE CONTROLLED RELEASE OF A HYDROPHONIC BIOACTIVE SUBSTANCE IN AN ANIMAL INCLUDING A PHARMACEUTICAL IN AN INCLUDING THE AGENT TO BE hydrophobic were eluted in a controlled manner through a polymeric solution containing, for example, poly (lactic acid-glycolic co-acid)

PROPOSAL: In view of the foregoing, the applicant has devised a new constructive arrangement introduced in a bi-degradable coated stamping device for rapamycin stenting to inhibit restenosis, which must mandatorily have the following predicates:

1. Differentiated efficiency: promoting the support of the injured area inside the lumen and releasing the pharmacological agent in a controlled manner, avoiding restenosis; and

2. Differentiated safety: not allowing medium and long term thrombosis to occur, as well as other complications.

To consolidate the service of the above listed predicates this presents constructive concept based on:

- Implantable pharmacological stent kit consisting of a biodegradable polymer coated metal platform and

an active pharmacological agent. The stent is located on a balloon and is endowed with two radiopaque markings, which indicate the functional length of the balloon and are located inside the balloon. Once inflated, it expands the stent and presses it against the lumen wall, providing a broad channel to improve lumen flow passage and minimize the risk of restenosis and thrombosis after implantation;

- New stent structural profile, consisting of a hollow cylindrical metal platform with several conjugated rings, arranged parallel to each other and linked by links. The metal platform is made of a cobalt and chrome alloy called L605®. Its surface is polished to prevent platelet and plasma protein aggregation on the stent surface, minimizing the chances of stent promoting thrombosis.

- A coating composition consisting of an immunosuppressive agent called rapamycin or sirolimus and a biodegradable polymer blend consisting of poly (lactic acid) and poly (lactic acid-co-glycolic acid). The drug is distributed in the upper

metal platform surface at concentrations between 0.1 and 10.0pg / mm2.

- Arrangement of the coating on the metal platform, which is located on the outer and inner surface of the metal platform. This can promote controlled endothelialization, reducing the likelihood of incidence of thrombosis. In addition, the

The material is composed of a single thin layer applied directly to the surface of the metal platform.

DESCRIPTION OF THE DRAWINGS: In addition to the present description in order to gain a better understanding of the features of the present utility model application, it is attached herewith as a set of drawings, where in an exemplary manner, although not For a limiting embodiment, a preferred embodiment has been shown for the "constructive arrangement introduced in a biodegradable coated rapamycin-eluting stent device for inhibition of restenosis claimed herein, where:

Figure 1 illustrates a segment of the metal platform used in the coating;

Figure 2 illustrates in detail, enlarged detail 1. the constructive concept structure of the ring platform and links to the rings;

Figure 3 shows an enlarged detail 2 of a ring cross-section of the cover arrangement on the metal platform; and

Figure 4 presents an example of the profile of

Rapamycin elution. DETAILED DESCRIPTION: The following detailed description should be read and interpreted with reference to the drawings presented, where they are highly diagrammatic, representing a preferred embodiment, and not intended to limit the scope of the utility model, which is limited only to the set out in the claim framework.

- Kit consisting of a stent coated with a biodegradable polymer blend and a pharmacological agent: the covered stent is positioned over a balloon whose first distinguishing feature is that it has two radiopaque markings indicating the functional length of the balloon and are located inside. the same. Stent expansion and release are promoted by balloon insufflation. The other details of the balloon will not be described in this cartouche as it does not fall within the scope of claims of this patent application.

- The structural profile of the stent (A), which is illustrated in Figures 1 and 2 respectively, whose second distinguishing feature is the constructivity of the metal platform formed by conjugated rings (1) joined by links (2). These rings (1) consist of short cells and thin stems, giving a structure with a high degree of flexibility, especially when in the non-expanded state, facilitating their introduction to the injured area, even in very obstructed lumens.

The metal platform has high structural resistance, both in the conjugated rings (1) and the links (2) that connect them, avoiding rupture before, during and after its implantation. Finally, the arrangement of the conjugate rings (1) allows the stent (A) to have a large radial force, allowing stent contraction not to occur due to vessel compliance.

Taking into consideration the desired properties described above, the metal platform presents a third distinctive feature translated by being made with a cobalt and chrome alloy called L605®.

A fourth distinctive feature of the metal platform is translated into the final finish of the stent surface area (A) 1 in particular, the contour edges, which must be polished. Thus, the incidence of platelet and plasma protein aggregation on the stent surface (A) is minimized, which decreases the chances of stent promoting thrombosis.

From the composition of the profile cover

Tructural: formed by an immunosuppressive agent called rapamycin or sirolimus, and a biodegradable polymer blend consisting of poly (lactic acid) and poly (lactic acid-co-glycolic acid).

Rapamycin is a naturally occurring macrocyclic lactone with potent immunosuppressive and antiproliferative action. This drug was discovered in the 1970s and approved by the US FDA for use in kidney transplant recipients in 1999. It has a low molar mass and is highly lipophilic, which inhibits cell proliferation by blocking cell cycle progression in G1 transmission. -S. Its action is mediated by binding to the intracellular receptor, the FK506 binding protein (FKBP12), whose expression is increased after vascular injury, as occurs with stent implantation. The sirolimus-FKBP12 complex is then linked to a regulatory mammalian target of rapamycin (mTOR), in which it has a number of relevant actions, including inhibiting the translation of a family of proteins essential for cell cycle progression.

The efficiency of immunosuppressants in implantable medical devices has already been mentioned in the "Foundations of the technique", and in addition, by making a more critical analysis of the efficiency of immunosuppressants in stents (A), it can be mentioned that the release profile is an important factor that should be taken into account in the development of this device.JR Costa Jr. et al. (Brazilian Journal of Invasive Cardiology. 2008; 16: 482-488), co- The most efficient commercial products release 50-60% between 7-10 days and about 80% over the remaining 30 days.The constructive arrangement introduced in a biodegradable coated stamping rapamycin-eluting stent device has an elution profile similar to that of Costa Jr., as shown in Figure 4, where this elution profile can be considered as a fifth distinctive feature. related to the elution profile is the drug: polymer ratio, also expressed by the drug distribution on the metal platform surface. The "constructive arrangement introduced in a biodegradable coated rapamycin-eluting stent device for restenosis inhibition" described in this letter has a distribution of rapamycin between 0.1 and 10.0pg / mm2 on the metal platform.

To date, there are no reports in the literature on the long-term effect of non-biodegradable polymeric coating on stents (A) for patients (ten, fifteen or twenty years), as the initiation of clinical studies with drug-eluting stents. started in a shorter period than that. However, the applicant understands that such materials, which will be in contact with the lumen wall and the patient's circulatory system for a lifetime, may cause thrombi. For example, occlusion of a coronary artery by a thrombus can lead to acute myocardial infarction. This possibility was warned in a study published by AV. Finn et al. (Circulation. 2005; 112: 270-278.).

A sixth distinguishing feature of the utility model is that the present stent (A) described in this utility model uses a polymeric blend composed of two biodegradable polymers: poly (lactic acid) and poly ( lactic acid-co-glycolic acid). This polymeric blend has a degradation cycle of 6-9 months, allowing only the metal platform to be in contact with the lumen wall and circulatory system. Thus, the use of a biodegradable polymer proves to be an element of differentiation from everything known in the state of the art and therefore worthy of patent privilege under the Industrial Property Law. effective on the date of this request.

A seventh distinctive feature of the utility model is the new arrangement of the casing on the metal platform, distinguished by the fact that the expanded stent (A) in the lumen, only the outer and lateral faces come into contact with the wall. while the inner face is in contact with the fluid. Depending on the implant site, the biological flow may be very high, allowing complete elution of the drug within hours of implantation. For this reason, the applicant believes that the coating of the internal stent surface does not have a significant influence on the product efficiency, on the contrary, after the complete drug elution, the polymer would still remain in contact with the fluid, increasing the chances of restenosis occurs.

In order to minimize the safety of the stent (A) described herein in this patent, the coating of the "stent (A) 1" ie both the rings (1) and the links (2) is characterized by being located only on the faces external (3a) and lateral (3b) stent (A), as shown in Figure 3. Controlled endothelization can be promoted thereby reducing the likelihood of thrombosis incidence. thin layer applied directly to the surface of the metal platform.

The embodiment described above of the present

This utility model is provided by way of example only. Changes, modifications, and variations may be made for particular embodiments by those skilled in the art without departing from the scope of the invention, which is uniquely defined by the appended claims. Check for what has been described and illustrated

that the "BIODEGRADABLE IMMUNOSUPRESSOR-RAPAMICINE ELDER STENT FOR RESTENOSIS INHIBITION", which falls under industrial property law, fills a gap in the field of application of interventional surgical medicine, offering a technical and operational alternative to procedures deserving for what has been exposed and as a consequence, the respective utility model patent privilege.

Claims (2)

1. "biode- gradable coated rapamycin-eluting stent for restenosis inhibition", where a stent (A) is formed by a component kit, the flexible physical platform to which a balloon is internally installed where this structure is It is coated with a biodegradable polymer and an active pharmacological agent. It is distinguished by the fact that the balloon has two radiopaque markings which indicate the functional length of the balloon and are located within the balloon; the cylindrical and cast metal platform is composed of a plurality of parallel rings (1) disposed parallel to each other and connected by polished surface links (2) made from a cobalt-chrome alloy known as L605®; The metal platform is covered by the immunosuppressive agent being distributed on the surface of the metal platform in concentrations between 0.1 and 10.0pg / mm2, and by a biodegradable polymer blend composed of poly (lactic acid) and poly (acid lactic-glycolic co-acid) whose degradation occurs between six and nine months after implantation; this coating is in the form of a single thin layer arranged especially on the outer (3a) and lateral (3b) faces of the stent platform (A),