WO2003008004A1

WO2003008004A1 - Changes of properties of a stent to prevent restenosis

Info

Publication number: WO2003008004A1
Application number: PCT/SE2002/001388
Authority: WO
Inventors: Oÿvind REITAN
Original assignee: Individual
Current assignee: Individual
Priority date: 2001-07-20
Filing date: 2002-07-16
Publication date: 2003-01-30
Anticipated expiration: 2004-01-20
Also published as: SE0102578D0; SE0102578L

Abstract

The present invention relates to a stent intended for implantation in a blood-vessel. The stent or the surface of the stent has the ability to modify one or several in for instance the blood naturally existing substances or added substances that come in contact with the stent or its surface and that they after this modification exhibit a biological activity with a growth inhibiting effect on the adjacent tissue for instance through a catalytic reaction, without changing the active part of the stent or the surface of the stent or at most reducing the active part only to a minor extent.

Description

Changes of properties of a stent to prevent restenosis

Modern treatment of narrowing (stenosis) in human blood vessels includes increasing use of metal grafts, socalled stents.

The initial result is often very good, but a problem is the occurrence of restenosis in the stented area in about 20 to 30% and therefore represents a clinical problem.

Present research focuses on the problem, but till now it has been difficult to prevent restenosis, which is probably related to a stent' s property. The present invention is aiming at solving this problem.

Background

Disorders following narrowings in blood vessels are common. Especially in the western countries diseases in heart and vessels cause a great part of the morbidity.

Some causes are genetically determined as for instance patients with high levels of cholesterol and also some patients with diabetes. However, a part of the morbidity is caused by the mode of living, as smoking habits, consumption of high caloric diet and reduced physical activity.

All cells in the body need blood to perform their different tasks. The blood is transported to the different organs in the body through the blood vessels. Whereas the arteries transport the blood f om the heart to the different organs, the veins lead the blood back to the heart. The arteries are mostly affected with narrowings, winch diminish the blood flow to the different organs. Because vessels exist in all parts of the body, all organ systems can be influenced by reduced blood flow, although some organs are more likely to be affected than others. The consequences for the patient depend on the affected area or organ. Some people suffer from reduced blood flow to the legs, to the kidneys to the brain or in the hearts' own vessels, the coronary arteries. The symptoms from the heart depend on the degree of the stenosis. Small stenoses may not give any symptoms, whereas pronounced stenoses give rise to discomfort by physical exercise. By increasing physical activity the heart needs to increase the pump work in order to meet the increasing oxygen demand of the body. The increased pump work also increases the oxygen demand of the heart. Above a certain level the blood flow in the coronary arteries will be limited due to the stenosis and the heart will experience a relative lack of blood supply which causes the typical chest pain known as "angina". There are all grades of angina: some patients experience angina only during high physical activity whereas others experience angina even at rest.

When a coronary artery acutely occludes, the area of the heart muscle supplied by the vessels is suddenly deprived of blood and oxygen. If the flow in the vessel is not restored quickly, for instance a couple of hours, the area will die and a heart infarction will develop. The result is that the contracting muscle in the area will be replaced by an non contracting scar tissue. The magnitude of the damage decides the influence on the pump function of the heart. A small infarction may not be of clinical relevance, whereas a big infarction can reduce the pump function and lead to an overt heart failure.

Treatment of stenoses in blood vessels The treatment of stenoses in blood vessels is aimed at restoring the normal blood flow. Apart from pharmacological treatment surgical treatment is an option, most often by making a bypass across the narrowed part of the vessel. Modern treatment also includes the use of catheter-born techniques by the use of the PTCA procedure (percutaneous transluminal catheter angioplasty) when a small balloon at the tip of a catheter dilates the stenotic part of a vessel.

Sometimes this procedure is enough for a good result, but more often small meshed metal tubes, stents, have been deployed in the narrowed area of the vessel to reinforce the wall of the vessel and to prevent a recoil of the treated area. The stent is mounted on the dilating balloon and when the balloon is inflated, the stent expands and attaches to the wall of the vessel. After the stent has been fixed, it can not be removed. The use of stents in the vessels has been increasing over the years, and depending on the hospital performing the treatment, 40 to 80% of all stenoses will be treated with a stent implantation. The reason is that the primary result is very good and recoil of the vessel is effectively prevented. However, the vessels in the heart have small diameters and the stents are normally limited to vessels greater than 2- 3mm.

Specific stent problems

A stent is made of metal, either stainless steel or nitinol, an alloy consisting of titan and nickel. Metal in a vessel is a foreign material to the blood and may cause different problems. Two different problems are clearly defined.

1. Activation of the coagulation system

A stent placed inside a blood vessel represents a foreign material to the body. This will almost always activate the coagulation system and represented a few years ago a clinical problem because of a sudden formation of blood clots inside the stent and a sudden occlusion of the vessel. In addition to the foreign material a stent implantation also led to a minor damage of the wall of the vessel, which also activated the coagulation system. A sudden occlusion is often due to an increased activity of the thrombocytes. However, new pharmaceuticals (thrombocyte aggregation inhibitors) like clopidogrel can effectively prevent activation of the thrombocytes and prevent clots to develop and avoid a sudden occlusion of the vessel. During the time on thrombocyte aggregation inhibitors the metal is covered by the endothelium, the natural barrier of the vessel against the blood.

2. A greater problem today is the development of in-stent re-stenosis, which means a narrowing of the vessel inside the actual stent-segment. Various studies show that this occurs in about 20 - 30% of all patients receiving a stent resulting in a re-angina in about 10 - 15% of the cases thus representing a clinical problem. Examination of the vessels shows that although the endothelium has covered the metal stent, the tissue continues to grow through the mesh of the stent and fill the lumen of the vessel. The tissue consists to a great part of smooth muscle cells and connective tissue and reduces the diameter of the vessel.

The reason for the growth is not known in detailed, but several factors play together when new tissue develops. For instance may "platelet derived growth factor" play a role but even otlier factors originating from the blood or the surrounding tissue. Principles for modern treatment

Growth of new tissue is characterised by increased cell division. It is not known in details which mechanisms start the process, but a stent can in different ways influence the surrounding tissue. Because a stent nonnally is made of a metal alloy different metal ions can be released and irritate the surrounding cells or galvanic electric current can occur, which also might be of importance.

To restrain growth of unwanted tissue in general, different methods have been applied: use of irradiation, cell division inhibitors (cytostatica), which are used in the treatment of cancers, or specific substances that inflicts with certain steps in the cell division process. Many of these principles may also be applied to inhibit growth of new tissue in a stent.

1. Coating of a stent with an active substance

Experiments have been performed with coating of stents with cytostatica or other growth inhibiting substances. The active substance is normally attached to a matrix substance, which bonds to the stent surface and releases the growth inhibiting substance in a controlled slow release manner. Studies with taxol and rapamycin have shown positive effect in inhibiting growth of tissue, but new growth may start again when the active substance is totally released. 2. Local treatment with radioactive irradiation

One of the most convincing treatments to reduce new growth in stents has been the application of radioactive irradiation inside the stent area after deployment of the stent. A special catheter containing a radioactive substance at the tip is placed in the stented area for a calculated amount of time to deliver the appropriate radiation. The procedure is relatively complicated because of the safety measurements connected to the use of radioactive material to avoid contamination of the patient and personnel. However, studies have shown reduced re-stenosis after long term follow-up.

Treatment with radioactive stent

Radioactive stents have also been constructed, either by making the whole stent radioactive or by making the stent radioactive before the implantation. Irradiation by these stents has reduced in-stent restenosis inside the stent area, but stenosis has been encountered at the in and outlet of the stent where the radiation has been too weak. Even if treatment with radioactivity may prevent growth of new tissue, the problem is the costly and cumbersome handling of the radioactive material, often with long half times. The present invention

The present invention aims at solving the problem with the late in-stent restenosis.

Cell growth is a complex matter involving many different growth factors and substances. If one or more of these key substances could be blocked, cell growth could theoretically be inhibited. Some studies have shown that the "platelet derived growth factor" from thrombocytes, which stimulates the cell growth of fibroblasts can be inhibited with nitric oxide (NO), the active substance of nitro- glycerine, commonly used to cure angina. Research will probably find many substances to inhibit cell growth, but one of the problems by coating the stent with these substances are that they will be released and disappear after a certain amount of time. To avoid this problem, the surface of the present stent is coated with a matrix (for instance a polyurethane polymer), which contains a substance that acts as a catalyst.

A catalyst is a substance that has the ability to change the property of other substances. One example of a catalyst is an enzyme that cleaves a protein into one active part and one non-active part. An example from the physiology is the production of insulin, which is a product of pro-insulin. Through an enzymatic process the pro-insulin is cleaved into the active insulin and an inactive C-peptide before it is released into the blood circulation. In the chemical industry it is known that different surfaces covered with platinum can be used as a catalyst and speed up certain chemical processes.

A catalyst is a substance that facilitates a certain biochemical or chemical reaction without being consumed by the reaction itself.

The aim of the present invention is to give the stent or the surface of the stent the property of increasing the concentration of substances that inhibit unwanted cell growth in the stent area and prevent in-stent restenosis.

The actual growth inhibiting substances can be radioactive, become radioactive or be non-radioactive from different sources. The examples below rare given to illustrate the pharmacological principles through known and are not necessarily related to the coating of the stent.

1. A substance enters the body and because of the activity of the stent or the coating is cleaved into an active and a non-active substance.

Substances from the nitro-glycerine family are used to treat angina. These pharmaceuticals contain all NO3- groups either as mono-, di or trinitrates. Enzymatically with help of a reductase (mitochondrial aldehyde dehydrogenase) these groups are cleaved off and form NO-groups, which dilate the vessels, but also exert an inhibitory effect on cell growth after implantation of a stent in a vessel. 2. A chemical substance enters the body as an inactive pro-drug and is changed into an active drug because of the property of the stent.

One example is proguanil against malaria, which enters the body in an inactive form and is chemically changed to the active substance, cycloguanil via enzymatic influence.

3. Free or bound substances located near the stent that are changed in biological activity due to the stent and exhibit inhibition on cell growth on the adjacent tissue. One example is the synthesis of NO in the body of L-arginin and oxygen (O2) by the enzyme NO-synthase. If the stent were covered with this enzyme, the amount of NO is expected to increase in the area around the stent.

4. A substance that enters the body in active or inactive form and is concentrated around the stent because of the properties of the stent.

An example is the stent is magnetic and the substance is attached to a carrier which is attracted by the magnetism thereby concentrating the substance around the stent area.

5. A substance that enters the body in an active or inactive form and concentrates on the stent or in the stent area because of the properties of the stent or the stent surface.

Example is an attachment of the substance to a protein or peptide that binds to a receptor on the surface of the stent and concentrates the substance on the stent and in the area around the stent. 6. Blockage of the enzymatic process to remove one or more cell growth inhibiting substance that enters the body increases the concentration of the substances in the area around the stent.

7. Blockage of the enzymatic process to remove one or more naturally existing cell growth inhibiting substances increases the concentration of the substances in the area around the stent.

The stent is coated with a substance that blocks a catalytic enzyme system. As an example is mentioned the angiotensin II converting enzyme inhibitors that blocks the formation of angiotensin II from angiotensin I, a principle that is used to treat hypertension.

8. The coating of the stent induces formation of a substance that leads to formation of a cell growth inhibiting substance.

Studies with two different calcium antagonists, nicardipin and benidipine have shown that these substances induce formation of the enzyme NO-synthase, so called inducible NO-synthase (iNOS). This enzyme produces NO from L-arginine and oxygen and NO inhibits cell growth. Nicardipin has also been shown to block the removal of the NO.

While calcium antagonists have different chemical structure, it is expected that the property to induce NO-synthase is connected to the calcium antagonist property and therefore valid for the whole class of calcium antagonists.

Claims

1. Stent intended for implantation in a blood vessel characterized in that the stent or the surface of the stent has the ability to modify one or several in^ for instance the bloody naturally existing substances that come in contact with the stent or its surface and that they after this modification exhibit a biological activity with a growth inhibiting effect on the adjacent tissue for instance through a catalytic reaction, without changing the active part of the stent or the surface of the stent or at most reducing the active parj/to a minor extent.

2. Stent according to claim 1, characterized in that the said modification implies liberation of nitric oxide (NO).

3. Stent according to claim 1 or 2, characterized in that it can activate one, in for instance blood, normally existing substance to achieve the desired effect.

4. Stent according to claim 1 or 2, characterized in that it can activate one in for instance blood added substance to achieve the desired effect.

5. Stent according to any of the former claims, characterized in that it is coated with a substance to which an active substance can fasten.

6. Stent according to claim 4, characterized in that it can cleave one to the body fluid added substance in an active and an inactive part.

7. Stent according to claim 3 or 4, characterized in that it can liberate a growth inhibiting substance for instance nitric oxide (NO) from the combination of L-arginine and oxygen with help of the enzyme NO- synthase.

8. Stent according to any of the preceding claims, characterized in that it is magnetic and that the active substance is connected to a magnetic carrier in order to be attracted and concentrate on the stent.

9. Stent according to any of the claims 1-7, characterized in that it is covered with a receptor for a protein- or a part of a protein (peptide) and that the active substance is connected to such a protein or a part of a protein.

10. Stent according to any of the preceding claims, characterized in that it is coated with a substance that prevents neutralization of naturally existing or added substances that normally are metabolized in the body.

1. Stent according to any of the preceding claims, characterized in that it is coated with a matrix, for instance a polyurethane polymer, which contains a substance that acts as a catalyst.

12. Stent according to any of the preceding claims, characterized in that it is coated with a substance from the nitro-glycerine family containing NO3- groups, either as mono-, di- or trinitrates which with help of a reductase, for instance mitochondrial aldehyde dehydrogenase, cleave off and form NO-groups, which dilate the wessel and also exert an inhibitory effect on cell growth after implantation of the stent.

13. Stent according to any of the preceding claims, characterized in that it is coated with a calicium antagonist, for instance nicardipin or benidipine, inducing formation of the enzym NO-synthase, so called inducible NO-synthase (iNOS), producing NO from L-arginine and oxygen inhibiting cell growth and also blocking removal of NO.