WO2006061115A1 - Active substance-releasing stents - Google Patents

Abstract

The invention relates to stents containing angiotensin receptor antagonists, and to methods for producing these stents.

Description

Drug-eluting stents

The present invention relates to angiotensin receptor antagonist-containing stents and to methods of making these stents.

Atherosclerosis has two forms of training. On the one hand, it is characterized by deposits on the inside of the arteries, which narrow the vessel clearing and lead to reduced blood flow. In extreme cases, such deposits can completely occlude the vessel over time. Such constrictions can be diagnosed by angiographic methods. In terminology, this is referred to as arteriosclerotic plaque formation or arteriosclerosis.

On the other hand, there are plaques that do not significantly clog an artery, as it is usually detected with angiography. But in the plaques, an inflammatory process occurs, with the formation of a large lipid core, a thin cap and an increasing content of macrophages, foam cells and other cells. With regard to the pathogenic potential that sudden rupture causes myocardial infarction by immediate lumping, these arteriosclerotic foci are referred to as vulnerable plaques.

Arteriosclerotic coronary diseases are treated with the usual method of balloon dilatation (percutaneous transluminal coronary angioplasty, PTCA). For this purpose, a balloon catheter is introduced into the narrowed or closed artery, which is then widened by expansion of the balloon and the blood flow is thus restored. Here, the acute, immediately after the PTCA occurring (acute restenosis) or the subsequent, subacute (recurrent stenosis, restenosis) resealing of the blood vessel is a problem that occurs in about 30% of cases. The same applies to percutaneous transluminal angioplasty (PTA) for the treatment of peripheral vascular disease, treating peripheral vessels such as the carotid, iliac (ilical), renal (renal), cerebral (cerebral), subclavicular and femopopliteal vessels.

The risk of acute restenosis may be reduced by the use of antiplatelet agents. In addition, mechanical support may be provided to the coronary wall with a generally cylindrical and expandable braid (stent) inserted into the stenotic vessel by means of a balloon catheter and deployed at the site of the stenosis to open the stenotic site. Although this method can easily reduce the risk of restenosis (a few percentage points), there is currently no convincing therapy for recurrent stenosis and late thrombotic events. An important contribution to the problems occurring after stent implantation is provided by the vascular-biological mechanism of enhanced proliferation of vascular smooth muscle cells (VSMC), which re-occludes the artery through muscle tissue and inhibits the endothelialization of the stent support network or only delayed in the vessel wall is integrated.

Therefore, in addition to the combination of stent administration and systemic administration of platelet aggregation inhibitors and antihypertensive agents, those of cell growth inhibitors or indirectly acting as such substances such as blood coagulation factor Xa inhibitors is an established therapy.

A more recent option for the treatment of restenosis is the local administration of drugs by means of a stent, which releases the drug. The combination of drug and stent allows for drug treatment and mechanical stabilization in one application.

For this purpose, stents can be coated with active substance-containing coating materials. The release of active ingredient takes place by diffusion from the lacquer or by degradation of the lacquer when using biodegradable lacquer systems.

Another possibility already described is the generation of small cavities or micropores on the stent surface into which active substances themselves or polymers containing them are introduced (see, for example, EP-A 0 950 386). A drug-free layer can still be applied over it. The release takes place by diffusion or degradation or by a combination of both processes.

In addition, drug-containing stents by melt embedding of the active ingredient in a polymeric carrier z. B. using injection molding. The release of the drug takes place in these stents usually by diffusion.

Thus, the connection of stents with antiproliferative agents allows a high local concentration of active ingredient, without causing the undesirable systemic side effects.

Two stents with the active ingredients paclitaxel and sirolimus are currently on the market, other stents with other drugs are still being tested in clinical trials. (Halkin A, Stone GW, Interv Cardiol 2004; 17 (5): 271-82; McKeage K, Murdoch D, Goa KL, Am J Cardiovasc Drugs 2003; 3 (3): 21 1-30; Dogrgrell SA, Expert Opinion Pharmacother 2004; 5 (11): 2209-20) In the paclitaxel-coated stent, about ten percent of the drug is released within the first ten days, then the release rate steadily decreases. After 30 days there is no ne release more. This prevents the cells from uncontrollably dividing the vessel wall and closing the vessel again. On the other hand, the normal healing process of the vessel is not disturbed. The equipment of a stent with blood coagulation factor Xa inhibitors is described in WO 03/035133 but has not been developed further to the point of application.

Wagenaar investigated the importance of the angiotensin receptor in the cardiovascular system. (Wagenaar LJ, Dissertation, Groningen 2003, ISBN 90-75092-37-7) In an animal model, the angiotensin II type 1 (ATi) receptor is involved in the restenosis after vascular angioplasty. In carotid rats, vascular injury through a balloon catheter causes proliferation of VSMCs, which is ATi-dependent. (Daemen MJ, Lombardi DM, Bosman FT, et al., Circ Res 1991; 68: 450-456) The renin-angiotensin (RAS) system is also involved in other processes responsible for restenosis following balloon angioplasty via the angiotensin receptor.

Rest stenosis following insertion of stents in human coronary arteries differ histologically from restenosis after balloon angioplasty in that in-stent restenotic lesions contain predominantly vascular smooth muscle cells and show greater proliferation of these cells than lesions following balloon angioplasty alone. (Moreno PR, Palacios IF, Leon MN, et al., Am J Cardiol 1999; 84; 462-466). The stimulation of AT ₁ leads in the animal model to the proliferation and migration of VSMCs and thus to the formation of a neointima in the stent. (Hafizi S, Chester AH, Allen SP, et al., Coron Artery Dis 1998; 9; 167-175). In human coronary artery samples obtained by atherectomy, it has been found that smooth muscle cells from in-stent restenotic lesions contain abundant AT _r receptors. (Wagenaar LJ, van Boven AJ, van der Wal AC, et al., Neth Heart J 2001; 9; supplement 3: 3) When applied to humans, the ATi receptor blocker (ARB) valsartan appears to be in-stent. Reduce restenosis rate. (Peters S, Gotting B, Trummel M, et al., J. Invasive Cardiol 2001; 13; 93-97)

At de novo lesions following PTCA and stenting, angiotensin conversion enzyme (ACE) and AT _r receptors are found in macrophages. Less strong ATi-positive smooth muscle cells were observed. In-stent lesions consisted mainly of ATi-expressing VSMCs. (Wagenaar LJ, Van Boven AJ, Van der Wal AC, Cardiovascular Research 2003; 59; 980-987)

Therefore, as drugs for patients undergoing transluminal (coronary angioplasty), those with the mechanism of action may be particularly suitable as angiotensin II type 1 receptor blockers or ATp receptor antagonists, however, in cases where lowering blood pressure is undesirable, the systemic administration of such ARBs should be preventive or treatment of restenosis after PTCA or PTA with or without laying of stents less suitable. Surprisingly, it has now been found that a treatment of restenosis with such ARBs by local application by means of stents which release these active substances slowly is extremely possible, and in particular in the case of the stenotic patient, the risk of hypotension exists.

While sufficient therapeutic success can not be achieved in all cases with the previously available active substances and stents, the new combination of ARBs with a stent enables a more effective treatment and / or prophylaxis of restenosis and / or vulnerable plaques. By local application of these compounds in combination with a stent, it is possible to reduce the dose of the drug required for the prevention of restenosis. Thus, unwanted systemic effects can be minimized. At the same time, the local concentration can be increased and thus the effectiveness can be increased.

The present invention therefore relates to active ingredient-containing stents containing at least one angiotensin II type 1 receptor antagonist.

The invention relates to methods for producing stents, characterized in that the stents are coated with at least one material containing an angiotensin II type 1 receptor antagonist.

The invention relates to methods for producing stents, characterized in that the stents are filled with at least one material containing an angiotensin II type 1 receptor antagonist.

The invention also relates to the use of angiotensin II type 1 receptor antagonists for the preparation of stents containing them.

Preference is given to using angiotensin II type 1 receptor antagonists substances which are referred to as sartans.

Angiotensin II type 1 receptor antagonists are said to be synonymous with angiotensin II type 1 receptor blockers.

The substances referred to as Sartane are structurally more or less related to each other and are z. B. derived from modified at the amino group at least by carboxy or 5-tetrazolyl 2'-substituted 4-aminomethyldiphenyl or para-substituted on the benzene ring 1-benzylimidazole. Particularly preferred are the compounds with the common names Candes artan, eprosartan, irbesartan, losartan, telmisartan and valsartan. Most preferred is telmisartan.

Under the erfϊndungsgemäßen stents both the original pure vessel supporting structures as well as so-called stent-vessel plastics (composite stent-graft devices) understood how this z. B. in WO 01/037892 p.3 Z. 1 to 11 and cited patents are described as generally known.

Conventional stents are used, for example, to manufacture the stents according to the invention, the stent basic body being made of metals or non-degradable plastics such as, for example, polyethylene, polypropylene, polycarbonate, polyurethane and / or polytetrafluoroethylene (PTFE). Furthermore, according to the invention as stent basic stents with different constructions of the metal mesh, which allow different surfaces and folding principles and as, for example, in WO 01/037761 on page 2 Z. 19 to S. 5 line 22 and Figures 1 to 6 and in WO 01/037892 on the Sl Z. 12 to page 2 line 13, p. 6 Z. 1 to 12 and in the detailed description of page 7 line 22 et seq. (to p. 13 end) described.

These stents are coated and / or filled with the active ingredients. Alternatively, for non-metallic stents, the active ingredients may be incorporated directly into the material used to make the stents.

For coating or filling carrier materials are mixed with the active ingredients. The carrier materials used are preferably polymeric carriers, in particular biocompatible, non-biodegradable polymers or polymer blends, such as, by way of example and by way of preference, polyacrylates and copolymers thereof, by way of example and preferably poly (hydroxyethyl) methyl methacrylates; polyvinylpyrrolidones; Cellulose esters and ethers; fluorinated polymers such as by way of example and preferably PTFE; Polyvinyl acetates and their copolymers; crosslinked and uncrosslinked polyurethanes, polyethers or polyesters; polycarbonates; Polydimethylsiloxanes.

Alternatively, biocompatible, biodegradable polymers or polymer blends, such as by way of example and preferably polymers or copolymers of lactide and glycolide, or from prolacton and glycolide; other polyesters; polyorthoesters; polyanhydrides; polyaminoacids; Polysaccharides; polyiminocarbonates; Polyphosphazenes and poly (ether-ester) copolymers used as polymeric carriers. AIs polymeric carrier are also suitable mixtures of biodegradable and / or non-biodegradable polymers. Through these mixtures, the release rate of the drug is optimally adjusted.

The release of the drug may be either by diffusion from the layer or by degradation of the same if a biodegradable system is used.

To produce coated or filled stents, the mixtures of active ingredient (s) and carrier are dissolved, preferably in suitable solvents. These solutions are then replaced by various techniques such. As spraying, dipping or brushing applied to the stent. After subsequent or simultaneous removal of the solvent, the stent, which has been mixed with active substance-containing lacquer, is thus produced. Alternatively, mixtures of active ingredients) and carriers can be melted and applied by the same application methods.

Preferably, the stents are pretreated to effect an enlargement of the outer and / or inner stent surface. Thus, the loading potential is increased and larger paint (drug / polymer) amounts can be applied. For the pretreatment of the stents, for example, different etching techniques but also treatments with ionized radiation are used. Likewise, micropores or cavities can be created in the stents by various techniques.

The active substance contents of the coated or filled stents are as a rule from 0.001% by weight to 50% by weight, preferably from 0.01% by weight to 30% by weight, particularly preferably 0.1% by weight. to 15% by weight in the coating or filling.

In the case of non-metallic stents, the active ingredients can also be incorporated directly into the stent base, for example as a melt embedding.

In this case, active-ingredient-containing polymeric carrier compositions are processed by customary processes, for example by injection molding, to give the final active ingredient-containing form. The release of the active ingredient takes place in the rule, by diffusion.

The active substance contents of stents with embedded active ingredients are as a rule from 0.001% by weight to 70% by weight, preferably from 0.01% by weight to 50% by weight, particularly preferably 0.1% by weight to 30 wt .-% based on the total mass of the material. The active substance-containing stents are optionally additionally coated with a membrane. This membrane serves, by way of example and preferably, for controlling the release of medicaments and / or for protecting the active substance-containing stents from external influences.

The invention further relates to the use of angiotensin II type 1 receptor antagonist-containing stents for the treatment of restenosis and arteriosclerotic deposits such as vulnerable plaques.

The invention further relates to the use of angiotensin II type 1 receptor antagonist-containing stents for the prevention of restenosis and arteriosclerotic deposits such as vulnerable plaques after transluminal (coronary) angioplasty (PTCA or PTA) and placement of a stent.

In addition, in addition to the application according to the invention, systemic and / or local administration of further active substances suitable for the treatment and / or prophylaxis of restenosis and / or vulnerable plaques, such as by way of example and preferably abciximab, eptifibatide, tirofiban, acetylsalicylic acid, ticlopidine or clopidogrel.

The following examples are intended to illustrate the invention without, however, limiting it:

Claims

claims 1. Stents equipped with at least one active ingredient from the class of angiotensin II type 1 receptor antagonists. 2. Stents according to claim 1, wherein the equipment consists of an active substance-containing coating. 3. Stents according to claim 1 to 2, wherein the equipment consists of an active substance-containing filling. 4. Stents according to claim 1 to 3, wherein the equipment consists in that the stent is made of a drug-containing material. 5. Stents according to claim 1 to 4, characterized in that at least one sartan is used as the active ingredient. 6. Stents according to claim 1 to 5, characterized in that at least one active ingredient from the group candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan is used as the active ingredient. 7. Stents according to claim 1 to 6, characterized in that as the active ingredient at least Telmisartan is used. 8. A method for producing stents according to claim 1-7 by coating or filling of the stents. 9. A process for the production of stents according to claim 1-7, by manufacture from drug-containing material.