WO2010102796A2

WO2010102796A2 - Device for applying active ingredients to the wall of a body vessel

Info

Publication number: WO2010102796A2
Application number: PCT/EP2010/001482
Authority: WO
Inventors: Ralf Hannes; Ulrich Speck
Original assignee: Phenox Gmbh; Innora Gmbh
Priority date: 2009-03-10
Filing date: 2010-03-10
Publication date: 2010-09-16
Also published as: WO2010102796A3; DE102009011931A1

Abstract

The invention relates to a device for applying active ingredients to the wall of a body vessel for treating the vessel wall, comprising a catheter, a guide element and a distal element arranged on the guide element. The distal element is equipped with a soft, atraumatic surface that can be adapted to the vessel wall and carries the active ingredient and strives for a greater diameter after exiting the catheter than the maximum diameter of the vessel in the segment of the body vessel to be treated, wherein the greater diameter is effected by elastic forces in the distal element.

Description

Device for applying active ingredients to the wall of a body of the body

The invention relates to a device for applying active substances to the wall of a body vessel with a catheter, a guide element and a distal element arranged on the guide element, which is suitable and intended to come into contact with the wall of the body vessel after emerging from the catheter.

Many, sometimes very serious illnesses do not affect the whole body or much of it but are limited to a narrow tissue, part of an organ or a section of a blood vessel. For the treatment of such diseases, a variety of instruments have been developed that have an exclusively or preferably local mechanical, thermal, chemical, electrical or pharmacological effect.

For the treatment of arterial narrowing or. _, Closures due to arteriosclerotic wall thickening or thrombus deposition or sudden embolic events use catheters which are inserted through a small opening in an artery and at the distal end contain a tool for treatment of the diseased or dysfunctional vessel. Such tools can be pleated balloons that expand and, optionally, stent-stabilize vascular constrictions, self-expanding stents, or cutting instruments for reaming the vessels, lasers, claws for removing thrombi or foreign bodies, or as recently introduced soft brushes that hold a blood clot and, if handled properly, can help remove it from the body.

In some cases, the above instruments have been combined with drugs to acutely support the effect of the medical device on the pharmacological effects of these substances. Medical devices, especially those that come in contact with blood, have been provided with anticoagulants. This also applies to the structures described in WO 2006/021407 and WO 2008/034615, which provide effective coatings for fixing thrombi located in the vessel lumen to the medical device for the purpose of thrombus removal or coatings or impregnations with thrombolytically active substances. The goal here is the direct and direct influence of the thrombus, but not the application of drugs to the vessel wall. Of great importance has been the coating of implantable stents with agents for inhibiting cell proliferation, wherein the drugs are released from a polymer matrix over days, weeks or months directly into the vessel wall. The benefit is an inhibition of excessive tissue growth caused by vascular wall injury, which in many patients results in a re-narrowing of the artery. Rapid release of drugs from stents has not been proven in clinical trials.

A somewhat different principle has been pursued with the coating of balloons: Here it is possible to achieve the same or even a stronger effect by rapid release of a slightly higher dose of active ingredient during the balloon expansion lasting only about 1 minute than in the long-lasting release of implanted stents , It is essential that the drug is pressed into the vessel wall at high pressure in the expansion of the lumen of the artery.

Another method of local drug treatment of arterial walls is based on the targeted administration of a concentrated solution of a lipophilic active substance into the vessel segment to be treated, either in free flow or in small balloons separated proximally and distally, for the short time of treatment vessels not perfused by blood. In both cases, however, only a weaker effect is achieved and a fairly large proportion of the drug enters the general cycle. Many medical devices have been coated with drugs in the past, but in many cases are not designed to treat the surrounding delicate tissue such as a blood vessel wall but to inhibit blood clotting or to prevent infection of long-term implanted catheters or permanent implants that cause blood clotting or to dissolve blood clots. Furthermore, drug-coated medical devices have been described which serve to inhibit local tumor growth in bone, also using high pressures.

The above-described methods of drug administration are mostly for the purpose of treating defined vasoconstrictions or closures. However, vascular diseases are often not restricted to the severely narrowed or closed areas but extend over a long distance, whereby the vessel diameter can vary greatly. Single inflammatory plaques represent a great risk for sudden vascular occlusion by thrombus formation without the prior narrowing of the lumen. Various procedures (atherectomy, laser, thrombectomy) of vessel recanalization leave more or less severely injured and irregular vessel walls, mechanically by the usual Balloon dilatation and stent placement should not be further damaged. For all these cases, there is no acute and location-selective treatment method.

The described methods for local drug application in vessels such. B. arteries have disadvantages that limit their use or make practical use impossible. As far as liquid preparations are concerned, only a very small proportion of the drug is actually taken up in the vessel wall, although sometimes elaborate and / or vessel wall damaging applicators such as double balloon catheters, perforated balloons, injection catheters etc. are used. Balloons are limited to the irregularities of the vessel walls without high pressure, even if they are formed from very soft membranes (US 7,179,251) or have a spongy surface (US 6,364,856).

It is an object of this invention to provide new medical devices as excipients and suitable pharmaceutical preparations that bring a drug in high concentration and as selectively as possible to the site of action without or without additional vascular wall injury.

This object is achieved with a device of the type mentioned above, wherein the distal element is equipped with a soft, adaptable to the vessel wall and atraumatic surface that carries the drug and after exiting the catheter seeks a larger diameter than the maximum vessel diameter in to be treated segment of the body vessel, wherein the larger diameter is caused by elastic forces in the distal element.

Unlike the known impregnation of the vessel wall with an active ingredient via a high pressure inflated dilatation balloon, the invention allows to achieve a much better and more targeted delivery of the drug to the vessel wall in vessels with very irregular diameter and curved course. The transfer of the active substance to the

Surface of the vessel wall takes place in a gentle, completely atraumatic manner, wherein the dosage can be selectively adjusted within a range and in particular exclusively elastic forces of the distal element to

Use come.

The distal element must be suitable for coming into contact with the wall of the corresponding body vessel, for the most part a vascular vessel, after exiting the catheter, that is, fitting against the vessel surface over a large area. The large-area contact is important for the transfer of the drug from the surface of the distal element to the vessel wall. For this purpose, the distal element is equipped with a soft, adaptable, atraumatic and flexible surface that carries the active ingredient. The active ingredient means that the surface is coated with the active ingredient, the active ingredient is incorporated into the surface, such as by soaking or Impregnate or that the active ingredient is connected in another way with the surface, such that it can be transferred to the vessel wall.

The surface of the distal element is soft and atraumatic, d. H. it should under no circumstances bring about an injury to the vessel wall. Soft, flexible and adaptable means that the distal element can cling to the vessel wall and make a large-area contact.

Preferably, the guide member is a guide wire to which the distal member may be connected or which becomes a part of the distal member in the distal region.

The distal element may be formed with a brush, sponge or pile structure. A brush structure consists, for example, of brush-shaped individual filaments or filament bundles which are fastened to a central structure extending in the longitudinal axis, for example a wire or plastic body in the distal region or in an element adjoining the distal region of the guide wire. This may be, for example, a braided element of a plurality of individual wires, in which the individual filaments or filament bundles are woven. In the brush or pile structure, the individual bristles or fibers may have any orientation, such as at right angles to the course of the central element, retrogard, distally inclined or in the form of outwardly flared bundles.

Suitable materials for the brush, sponge or pile structure are in particular plastics approved for medical use, for example polyethylene, polypropylene, polyamide and polyester. Sponge and pile structures are designed so that they are superficially wettable by the active ingredients and / or can take up the active ingredient in its structure, so that it is transferred to it upon contact with a vessel wall and optionally pressed against it at low pressure. In a brush structure, the active ingredient is located in particular at the outer end of the bristles and fibers. According to a particular embodiment, the distal element peripherally has a structured and conformable skin extending, for example, over an underlying brush structure. The structured skin can be made of one of the aforementioned materials and have pores or pits on the surface into which the active substance is introduced. The skin may also have a fleece, pile or sponge structure. The enveloping structures in a preferred embodiment are open to the intravascular space or, if they completely enclose a lumen, there is access to a central channel which extends to a port leading outside the patient's body. The structures differ from the known balloons (eg US Pat. No. 7,179,251) in that the connection to the blood or via a channel in the catheter shaft to a container outside the body serves exclusively to equalize the pressure during expansion without the pressure in the interior of the structure exceeding the blood pressure increase.

The active ingredient can also be incorporated in the material of the skin, in the fleece, pile or sponge structure, such that it is released over the duration of application to the vessel wall.

Furthermore, in the device according to the invention, the skin and the distal element can be present separately, so that the skin with the active substance can be applied first and is pressed by the distal element of the device in the second step against the vessel wall. Skin and distal element of the device thus form a unit according to the invention at the place of use, as well as in the one-piece device. The skin may consist of a conventional material, as used in medicine for similar purposes, for example as a film of polyethylene, polypropylene, polyamide, PTFE or polyester. It is understood that instead of a simple skin, a fleece, pile or sponge structure can be used.

This variant is particularly suitable when the distal element, as described below, has a basket structure. The same applies to a stent structure in which the skin or film is first applied and then the stent is placed. According to another embodiment, the distal element may have a basket structure covered with the above-mentioned structured and conformable skin. The basket structure may for example consist of a self-expanding wire mesh and be made for example of Nitinol. Such basket structures are known per se.

The active ingredient is preferably present in a lipophilic matrix, the lipophilic character of which may be determined on the one hand by the active ingredient itself, on the other hand by suitable additives. Lipophilic in this context means that the distribution coefficient between cells and a physiological NaCl solution is preferably> = 1 or the solubility in an organic solvent is> 10 mg / ml or the solubility in ethanol is> 10 mg / ml. In particular, the partition coefficient between butanol and water is> 1.

In order to improve the detachment or dissolution of sparingly water-soluble active ingredients, it is possible to add hydrophilic auxiliaries or active substances or else solubilizers which are common in pharmacy.

To increase the application security, it is expedient, the device in its distal region, d. H. especially at the distal element, to be provided with radiopaque markers. Such labeling techniques are known per se. According to a particular embodiment, in particular the distal end of the guide wire or the support structure of the distal element is radiopaque or equipped with radiopaque materials.

Finally, the invention also relates to the use of the device described above as a carrier of active substances which are to be applied to the wall of a body vessel, in particular a blood vessel.

In the following, the invention will be described in detail with respect to the individual elements. Suitable carriers are catheters or other medical devices which are not intended for prolonged (ie> 15 min) or permanent retention in the body, with a distal component which can be introduced into the body, which on the one hand can be expanded without great force and, on the other hand, the changing diameter of For example, it adjusts blood vessels in such a way that it always comes to a wall contact over the entire diameter of the vessel, without the vessel wall is thereby significantly damaged or an existing damage is further aggravated. However, these products may or may have a mechanical smoothing effect, but without leaving marked vessel wall injuries such as cracks, etc., such as high pressure angioplasty without or with stent placement. Examples of such medical devices are sponges, optionally coated with a thin, permeable and / or structured skin, other soft hollow body with a membrane whose outer surface may be structured or brush or brush-like structures as described for example in WO 2006/021407 and WO 2008 No. 034615 are without or with this enclosing smooth or structured membrane. Instead of hairs or bristles that are round in cross-section, flat bands or circular sectors are likewise suitable, and these can be roughened or structured as desired in the area. The outer contour of such example consisting of soft nylon filament brush may be cylindrical, trapezoidal or wedge-shaped, round or otherwise shaped.

Complete wall contact with only gentle pressure with a nonuniform cross-section is achieved by a soft self-expanding balloon with no longitudinal length axis constant in length. At constant volume, the balloon diameter is shifted by a small tensile force in the direction of the longitudinal axis in a wide range. A sufficient dose of active ingredient can in turn be achieved by appropriate structuring of the membrane. Many other configurations are conceivable that serve the same purpose - to cause wall contact in an irregularly shaped vessel without substantially damaging the vessel wall.

The drug carriers (eg brushes, sponges, membranes) mounted on a wire or shaft up to 3 m long become of small cross-section compressed and advanced in this form to the site of treatment or to a somewhat distal location. Only there they are brought into contact either by release from a hose limiting their cross-section or by insufflation with the tissue to be treated. The actual treatment is carried out by withdrawal or advancement of the expanded drug carrier through the area to be treated and / or by rotation of the carrier about the longitudinal axis. If necessary, for the short time of drug transfer from the carrier to the vessel wall, blood flow may be interrupted by means of a balloon located proximally or distally of the drug carrier.

For local application, very different drugs are suitable depending on the nature of the disease. For the prophylaxis and therapy of vascular constrictions and other predominantly space-occupying processes cytostatic active substances are used as they are used for example in tumor therapy systemically or for restenosis prophylaxis on stents or balloon catheters.

For the treatment of low or non-stenosing, for example inflammatory, lipid-rich or infectious vascular wall alterations, cytostatics may be used for their anti-inflammatory properties, immunosuppressants, steroidal and non-steroidal anti-inflammatory drugs, statins, antioxidants, anticoagulants or mixtures of individual drugs; a variety of such substances are described in textbooks of pharmacology and numerous patents, z. B. US 2008/0118544 or DE 10 2007 036 685.1. Preferred active ingredients are paclitaxel, docetaxel, protaxel and other taxanes, methotrexate, 2-deoxyglucose, thalidomide, triamcinolone (acetonide), betamethasone (17-monopropionate), dexamethasone and its derivatives, genistein, sirolimus, everolimus and other mTOR inhibitors, atorvastatin, cerivastatin , Fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, doxycycline, minocycline, probucol, tocopherols, ascorbic acid, arsenic trioxide and other arsenic salts and compounds, bismuth salts and compounds. As far as applicable, the active substances in question are also bound as salts or complex compounds or covalently, for example in the form of prodrugs or in turn effective derivatives can be used. If necessary, mixtures of certain active ingredients can be used, wherein each active ingredient is to be dosed according to its potency.

According to the invention, in particular active ingredients are used whose main point of attack is the vessel wall, in contrast to drugs which primarily inhibit or promote blood coagulation or dissolve blood clots or otherwise act on blood components. However, anticoagulants may additionally be applied to the surfaces of the invention

Medical devices are applied to coagulate on the necessarily large surfaces of the coated or impregnated

Prevent medical products.

The main effect is not thrombolysis or promoting blood clotting; Rather, the active ingredient groups and active ingredients, insofar as they are disclosed in WO 2006/021407 and WO 2008/034615, may not be included.

For effective transfer of the medical devices described above into the vessel wall, lipophilic substances or substances having a partition coefficient between physiological NaCl solution and cells, for example, isolated vascular smooth muscle cells of <1 or good solubility in organic solvents are preferred. The medicaments can be applied to the medical devices in any solid, suspended, emulsified, soluble or otherwise customary pharmaceutical preparation. Preferred is the use on the medical devices in dry form, if necessary after drying, particularly preferred is the use in the form of particles of defined size. These may contain the active compound in pure form, amorphous or crystalline or bound in any manner to particulate carriers or included in particulate structures. Such structures can be solid particles of a substance or mixtures of substances, capsules, liposomes, micelles or drops of liquid as they are part of emulsions. The preferred particle size is between 10 nm and 5 μm. Larger particles are suitable if they do not cause embolisms due to their solubility or other properties. The dosage of the drugs depends on their potency, the indication and the size of the vascular or tissue area to be treated. The preferred dose on the excipient is in the range from 1000 μg to 50 mg, the dose delivered per mm ² vascular wall being usually 0.1-10 μg, in exceptional cases also up to or even more than 20 μg. When administering a combination of active substances, the information for each active substance applies individually.

High demands are to be made on the preparations of the active ingredients, since they should be sterilizable and chemically stable for a long time if possible, adhere well enough to the carrier, must not be washed off quickly in the blood stream, and without high pressure on contact with the vessel wall These must pass over and be absorbed into the tissue. The conditions of drug transfer to the vessel wall are not at all comparable to the conditions in the known drug-eluting stents which are permanently implanted and whose struts remain in intimate contact with the vessel wall. Even with the drug-coated balloons, the conditions for drug transfer into the vessel wall are much cheaper. The drugs are pressed against the vessel wall by the high pressure balloons (5-20 atü), and it is this pressure which causes vascular wall injury, which ultimately triggers vascular lumen constricting hyperplasia.

The drugs are present on the carrier either in solid form or dissolved, emulsified, suspended in the form of a viscous, water or blood non-fast and readily miscible liquid, cream or paste, optionally embedded in a suitable matrix. To avoid premature detachment of the active ingredient-containing preparation from the carrier, it can be protected by an insertion tube to the place of treatment, for example, a peripheral or cerebral artery, advanced and only released there. If the drugs are in solid form, they may be crystals, amorphous particles, specially preformed structures such as microcapsules or thin, non-structured layers on the surface of the supports, or poorly defined layers, such as formed during evaporation of solvents or solvent mixtures , For the coating of various medical devices with a wide spectrum of drugs, a variety of excipients have been described which improve the chemical stability of the drug, enhance or reduce adhesion to the surface of the carrier, or promote the dissolution of poorly water soluble drugs, or the inclusion of any drugs in the drug Improve tissue and also have utility for the coating of novel supports as described herein; polyvinyl chloride, acrylates, complex polysaccharides (WO 94/23787); Hyaluronic acid, lipids, fibrin glue (USP 6,146,358); Sugars, proteins, numerous phospholipids, cholesterol, amphiphilic substances (US 2003/064965); Oils, triglycerides (esters of 9-15 carbon carboxylic acids), fatty acids, antioxidants (US 5,571,523); Contrast agents, in particular X-ray contrast agents (WO 2004/028582); Phospholipids (DE 102004046 244); Phosphatidylglycerol, dioleoylphosphatidylglycerol, isopropyl myristate (WO 98/24427); Ascorbic acid (WO 99/62510) and many other substances (US 2008/0118544). Preferred auxiliaries for the purposes of the present invention are natural substances and compounds and salts derived therefrom and such as phospholipids and other lipids, bile acids and their salts, ascorbic acid and its esters such as ascorbic acid-6-palmitate, sodium lauryl sulfate, urea, salicylic acid, glycerol but also polyethylene glycols of different Molecular weights (DE 10 2007 036 685.1)

The auxiliaries can be added to the coating medium or applied previously or subsequently to the surface of the support to be coated. Preference is given to mass ratios of active ingredient to excipient of from 100: 1 to 1:10, particular preference to ratios of from 10: 1 to 1: 1.

The suitable coating methods correspond to the state of the art. A coating is possible by dipping in a suitable liquid (solution, emulsion, suspension, etc.) or semi-liquid (gel, paste, cream, etc.) preparation, spraying, brushing, pipetting and the use of various volume measuring devices for the exact dosage of the applied active ingredient. Dry ingredients can be precisely dosed by electrostatic process are applied and held by an adhesive or roughened or textured surface. Particularly preferred are threads, brushes, tufts, sponges, etc., which carry a coating in the outer, ie peripheral, region of the usually circular cross-section of the distal element, ie, distally of the central longitudinal axis. A coating of the outer area is achieved, for example, by tangential spraying or by rolling the distal element via an adhesive active substance-containing paste.

An important field of application is the acute treatment of diseases of the vascular walls, which does not provide a direct and substantial extension of the

Lumens need. These are, above all, not narrowed vessels or vessels with non-flow-limiting stenoses, with inflammatory wall changes, microbial arteriosclerosis; Other relevant applications are

Vascular wall injuries after surgical or minimally invasive procedures, which are at risk of hyperproliferation of the vessel wall

Use of dilatation balloons or stents is undesirable or impossible.

In addition, the described excipients may be used wherever local administration of drugs is desired and the site of administration is not readily accessible from the outside. Examples are all gait systems such as bronchi, bile ducts, ureters etc, smaller body cavities but also the local tumor therapy, possibly in addition to other locally effective methods.

1 shows a device 1 according to the invention for the application of active substances to a vessel wall with a guide wire 2, a distal element 3, which is equipped with a brush structure which consists of a platinum metal core 5 with radially protruding bristles or filaments 4. The core 5 may be formed as a micro spiral, in which the filaments 4 are clamped or glued. The device 1 is advanced by a catheter 6 to the site. The active substance 7 is located at the outer end of the filaments 4, shown in the form of small aggregates or lumps.

The invention is further illustrated by the following examples. The examples relate to coatings of the brush-shaped components as described in WO 2006/021407 and WO 2008/034615. The surfaces of other geometric shapes and functional structures can be coated in a similar or analogous manner with drugs, as is apparent from the general description.

example 1

Coating of the distal element with orthogonal structure according to WO 2006/021407 (Phenox clot retriever, diameter proximal 2 mm, distal 4 mm, length 20 mm)

Coating solution: 0.5 ml of water + 35.0 mg of urea + 4.5 ml of tetrahydrofuran + 250 mg of paclitaxel

Coating by a single immersion in the coating solution, rapid removal, horizontal positioning of the longitudinal axis and slow, uniform rotational movement about the longitudinal axis;

Dry for 3 h at room temperature

Determination of paclitaxel content by HPLC: 777 μg

Column: Waters Symmetry C18, 5.0 μm, 4.6 x 250 mm

Melting agent: acetonitrile (55%) / buffer (0.005 M Kpi buffer, pH 3.5) (45%)

Flow rate: 1 ml / min

Detection: 230 nm

Sample volume: 20 μl

Retention time: 9 min Example 2

Coating solution: 30 mg paclitaxel in 1 ml ethanol

Coating: Horizontal positioning of the long axis of the Phenox Clot Retriewer and slow, even rotation about the longitudinal axis; Apply 17 μl of the coating solution using a 25 μl Hamilton microsyringe (Bonaduz / switzenand), moving the tip of the syringe needle evenly from distal to proximal and back in the area of the brush.

Dry for 1 h at room temperature

Determination of paclitaxel content by HPLC: 467 μg

Example 3

Coating solution: 0.45 ml ethanol + 100 μl aqueous solution of the iodinated X-ray contrast agent lopamidol (755 mg / ml) + 4.45 ml acetone + 250 mg paclitaxel

Coating: Horizontal positioning of the long axis of the Phenox Clot Retriewer and slow, even rotation about the longitudinal axis; Spray with the solution. Dry for 3 h at room temperature

Determination of paclitaxel content by HPLC: 730 μg

Example 4

Procedure according to Example (1), but repeated dipping at a distance of> 3 h 2 times

Determination of paclitaxel content by HPLC: 1560 μg

Example 5

Coating solution: 50 mg rapamycin in 1 ml ethanol

Coating by three dips into the coating solution, rapid removal, horizontal positioning of the longitudinal axis and slow, uniform rotational movement about the longitudinal axis; Dry for> 3 h at room temperature after each dipping. Determination of Paclitaxel Content by HPLC: Column: Waters Symmetry C18, 5.0 μm _; 4.6 x 250 mm

Plasticizer: methanol / acetonitrile / water, 30% / 52% / 18% (v / v / v). Flow rate: 1 ml / min

Detection: 276nm

Sample volume: 20 μl Retention time: 14 min / 11.5 min Content: 2 448 μg rapamycin - Claims -

Claims

claims

1. A device for applying active substances to the wall of a body vessel for the treatment of the vessel wall, comprising a catheter, a guide element and a guide element arranged on the distal element, characterized in that the distal element is equipped with a soft, adaptable to the vessel wall and atraumatic surface , which carries at least one active substance and after exiting the catheter strives for a larger diameter than corresponds to the maximum vessel diameter in the segment of the body vessel to be treated, wherein the larger diameter is caused by elastic forces in the distal element.

2. Device according to claim 1, characterized in that the guide element is a guide wire.

3. A device according to claim 2, characterized in that the distal element has a brush, sponge or pile structure.

4. Apparatus according to claim 2 or 3, characterized in that the distal element consists of brush-shaped arranged individual filaments or filament bundles, which are fixed to the guide wire.

5. Device according to one of claims 3 or 4, characterized in that the distal element is coated with a structured and adaptable to the vessel wall skin.

6. The device according to claim 5, characterized in that the skin has a fleece, pile or sponge structure.

7. The device according to claim 1 or 2, characterized in that the distal element has a basket structure, which is coated with a structured and adaptable to the vessel wall skin.

8. The device according to claim 7, characterized in that the basket structure is self-expanding.

9. Apparatus according to claim 8, characterized in that the basket structure consists of Nitinol.

10. Device according to one of claims 7 to 9, characterized in that the skin has a fleece, pile or sponge structure.

11. The device according to claim 1, characterized in that the distal element is a self-expanding balloon, which is coated with a structured and adaptable to the vessel wall further skin.

12. The device according to claim 11, characterized in that the further skin has a fleece, pile or sponge structure.

13. Device according to one of the preceding claims, characterized in that the active ingredient is present in a lipophilic matrix.

14. Device according to one of the preceding claims, characterized in that the at least one active substance is preferably located distally of the central longitudinal axis in the peripheral region of the distal element.

15. The device according to claim 13, characterized in that the lipophilic matrix has a distribution coefficient between physiological saline and cells of <1.

16. Device according to one of the preceding claims, characterized in that the distal element has radiopaque marker.