DE202009014776U1 - coating - Google Patents

Abstract

Coating and loading of dilatable catheter balloons and stents comprising the following steps:
1.1) Provision of a dilatable catheter balloon or stent
1.2) Provision of Polyelektrolydmultischichten for coating the catheter balloon or stent as a carrier.
1.3) Provision of paclitaxel in solution for coating / embryo of the present carrier Polyelektrolydmultischichten.

Description

The The present invention relates to a coating for loading of Implants and surfaces, in particular stents and balloon catheters preferably polyelectrolyte / Polyelektrolytmultischichten and with a pharmacologically active ingredient preferably paclitaxel, and the coated medical devices obtained after this coating.

The Implantation of vascular supports such as Stents is now a common surgical procedure for the treatment of stenoses. It is still a very common one Complication the so-called restenosis (recurrent stenosis), d. H. the reclosure of the vessel. An exact Conceptual description of restenosis is in the literature not to be found. The most commonly used morphological definition restenosis is the one that after successful PTA (percutaneous transluminal angioplasty) restenosis as a reduction of the Vessel diameter to less than 50% of normal sets. This is an empirically determined Value, its hemodynamic importance and relationship to clinical symptomatology of a sound scientific basis. In practice, there is often clinical deterioration of a patient as a sign of restenosis of the previously treated Viewed vascular section.

The Restenosis after a stent implantation is one of the main causes for a new hospital stay. The while implantation of the stent caused vascular injuries cause inflammatory reactions that are responsible for the Cure process in the first seven days a crucial one Role-play. Furthermore, in the recent past also revealed that stents containing an active ingredient release Coating are provided to cause late thrombosis can, d. H. besides the problem of restenosis, moreover a long-term problem, namely that of late thrombosis have.

Around to avoid these problems there is also the possibility only by means of a coated catheter balloon and without a stent to perform so-called "biological stenting", d. H. the vessel widening at the narrowed place by dilating a coated catheter balloon, during a short dilatation time of the catheter balloon sufficient pharmacological agent transferred to the vessel wall is that due to the vessel widening and the Drug delivery a renewed narrowing or a renewed Closure of the vessel is omitted.

Such coated catheter balloons are already off WO 2005/089855 A1 known and the international patent application WO 2004/028582 A1 discloses wrinkle balloons which are coated in particular in the folds with a composition of a pharmacological agent and a contrast agent.

A spray coating method for catheter balloons is known in WO 2004/006976 A1 Another application by means of coating of dimethyl sulfoxide and paclitaxel is in the application DE 102007003184A1 described.

Since the drug paclitaxel has been found to be particularly suitable for the prevention of restenosis, in particular the European patent no. EP 0 706 376 B1 It can be seen, however, coated stents have the disadvantages described above with respect to late thrombosis, the object is to apply the active ingredient paclitaxel on an implant / stent / catheter balloon that a coating is formed, which easily and quickly from the implant / stent / Balloon dissolves or is absorbed and can be effectively transferred to the vessel wall.

It it was found that polyelectrolyte multilayers (layer-by-layer Technique) are very well suited for rapid release of the med. Paclitaxel to generate the vessel wall.

These Task is through the technical teaching of independent Claims solved. Further advantageous embodiments The invention results from the dependent claims. the description and the examples.

Surprised It has been found that a coating of the following type is the one asked Task solves very well.

Polyelectrolyte multilayers with the layer-by-layer technique (LbL) - for the development of active ingredient-containing coatings for DES. The LbL technique uses polyelectrolytes of different charge as biomaterials s. In the course of the layered construction, polyelectrolyte multilayers (PEM) are formed, with the attractive electrostatic interaction between the opposite charges of the successive polymer layers playing an important role. The big advantage of this technology is that the assembly of multi-layers is a general and generally applicable method and thus coatings of different composition can be built. In addition, the method enables a control of the layer thickness of coatings in the nanometer range. Due to the modular structure of the multilayers, it is possible to integrate different functionalities into each individual layer. Also a loading and fixation of colloidal particles in the PEM is possible with the LbL technique. The LbL technique is an application of polyelectrolyte complex formation. For this purpose, the substrate is coated layer by layer with polyelectrolyte solutions of alternating charge. At each coating step, polyelectrolytes are deposited on the oppositely charged surface. The coating process is entrophen driven by the liberated counterions and self-limiting due to the electrostatic repulsion. Excess polymer is removed from the multilayer after each polyelectrolyte layer in the layered construction by repeated washing to prevent uncontrolled complex formation in the solution. Provided that a continuous buildup of multilayers takes place under the coating conditions, there is no limitation on the number of polyelectrolyte layers. It is possible to produce PEM with up to 1000 layers. The film thickness of PEM can be set to a few nanometers when dry. For example, the thickness of a single layer, depending on the counterions and coating conditions, of polystyrene sulfonate (PSS) and polydiallyldimethylammonium chloride (PDA) multilayers is in the range of 1-5 nm. For PEM, with weak polyelectrolytes, e.g. B. with polyacrylic acid and thicker layers of about 15 nm can form. In addition to the dipping process, a construction of PEM is also possible by spraying, one-step process and spin coating (coating), which leads to a significant reduction in the preparation time.

Of the charge-controlled construction of polyelectrolyte multilayers a method that allows a variety of different tailor made structures. Come in addition, that depending on the chemical structure of the used Polymers in addition to electrostatic attraction, other intermolecular Interactions, such. B. the hydrogen bonds and hydrophobic interactions, on the formation of multilayers can be involved.

• – Polysaccharide
• – Proteine
• – DNA
• – Lipide
• – Polymer-Wirkstoff-Konjugate
• – Dendrimere
• – anorganische Nanopartikel, wie kolloidales Gold und Quantenpunkte, Fullerene und Kohlenstoffnanoröhren,
• – Viren

In addition to the construction of PEM with synthetically functionalized polyelectrolytes, multilayers with the following materials / structures can be constructed:

• - polysaccharides
• - proteins
• - DNA
• - lipids
• - Polymer-drug conjugates
• - dendrimers
• Inorganic nanoparticles, such as colloidal gold and quantum dots, fullerenes and carbon nanotubes,
• - Viruses

Of the Term polyelectrolyte (PE), according to IUPAC recommendation (International Union of Pure and Applied Chemistry) a polymer of macromolecules, in which an essential part of the building units ionic or ionizable Contains groups or both. Polyelectrolytes combine the Properties of polymers and electrolytes and can the charge can be divided into anionic and cationic. A special case are ampholytic polymers (polyampholytes), the both positively and negatively charged groups or the corresponding ones contain ionizable groups. In nature, PEs are proteins, Nucleic acids or polysaccharides are widely used.

In spite of of a hydrophobic backbone are PEs due to their large size Number of ionic groups in polar solvents such as z. For example, water is readily soluble and dissociates into charged polymer chains and low molecular weight counterions. The respective degree of dissociation and hence the charge density in solution is determined by the acid or base strength of the functional groups.

In addition to the charge, ie anionic or cationic, PE can also be classified according to their strength. Strong PEs are permanently charged and completely dissociated over the entire pH range, whereas weak PE are only ionized in a limited range. Table 1: Overview of possible polyionic compounds for the construction of polyelectrolyte multilayers, protein ₁ , polypeptide ₂ , polysaccharide ₃ , polymer ₄ Polymers as anionic layer Polymers as a cationic layer Albumin ₁ Chitosan ₃ Alginate ₃ Collages ₁ Carboxymethylcellulose ₃ Gelatin A ₁ Chondroitin sulfate ₃ Polyallylamine hydrochloride ₄ Gelatin B ₁ Polyarginine ₂ Heparin ₃ Polydiallyldimethylammonium chloride ₄ Hyaluronic acid ₃ Polydimethylaminoethylmethacrylic acid ₄ Modified Dextrans ₃ Polyethyleneimine ₄ Polyacrylic acid ₄ Polylysine ₂ Polyglutamic acid ₂ Polyornithine ₂ Polymethacrylic acid ₄ and derivatives Protamine ₁ Polystyrenesulfonate ₄ Thaumatin ₁ Polyvinyl sulfonate ₄

The Loading of multilayers with paclitaxel (PTx) were performed on different Polyelectrolyte combinations investigated. Apart from the passive ones Enrichment of the active substance in existing PEM from poly (L-lysine) (PLL) and hyaluronic acid (HA) was also the construction of Multilayers with a hyaluronic acid-paclitaxel conjugate (HA-PTx) and chitosan performed. The two systems show an incomparable release behavior. While no PTx release from PEM with PLL and HA detected within 4 days the coating with the conjugate showed rapid drug release of about 50% of the integrated PTx within 3 hours.

The However, the effectiveness of DES is not just absolute delivered amount of PTx but also from the kinetics of the release dependent. Which PTx dose and release kinetics for Coronary stents is appropriate, is discussed very differently and is additionally dependent on the respective coating system. For the treatment of coronary heart disease (CHD) would be a Dose and release kinetics of PTx optimal, showing a proliferation the smooth vascular musculature as much as possible suppressed and thus prevents restenosis and additionally the desired endothelialization does not affect this becomes with the invention polyelectrolyte multilayers reached.

The The following example represents a possible embodiment of the present invention, but without the scope of protection to limit this concrete example.

Of the Construction of polyelectrolyte multilayers (LbL coatings) took place in immersion at room temperature. For that were the to be coated surfaces in the polyelectrolyte solutions immersed (eg PTCA catheters, stents, etc.) or partially with brought into direct contact with the coating solutions. In front the structure of the multilayers were the surfaces with Water rinsed and, provided the substrate is chemically stable is concentrated with a mixture of concentrated ammonia (25%) Hydrogen peroxide (30% w / w) and water in the ratio 1: 1: 5 (RCA alkaline cleaning, Radio Corporation of America). The RCA cleaning was done on stents, at 70-80 ° C carried out for 20 minutes. Following the RCA cleaning the surfaces were up to neutral pH with water rinsed.

Unless otherwise indicated, all surfaces were labeled with high molecular weight PEI (Mw 750,000, 1 mg / ml, pH 6, 0.2 M NaCl) as "0. Layer "pretreated. This attempted to balance the different charge densities of the different materials. The construction of LbL films was carried out in principle with an excess of polymer (per layer> 10 mg / m ² ). The required amount of polyelectrolyte was calculated based on the total surface area to be coated. Between the individual polyelectrolyte layers was washed at least three times with water to remove unadsorbed polymer.

To prevent stent-induced restenosis requiring a new percutaneous coronary intervention (PCI), since 2003 stents have been used which release antiproliferative drugs. These drug-eluting stents (DES) deliver the drug locally over a longer period of time. According to the invention here is an alternative coating method for DES, which on the one hand should be biodegradable and on the other hand can completely release the drug. Due to the high efficacy and direct release at the site of action, only a very small dose of paclitaxel (PTx) is required to prevent restenosis. However, the previously used Taxus stent, with a loading of about 100 μg / cm ² , emits from the stent coating altogether only 10% of the PTx. In this formulation, the active ingredient is particulate embedded in a polymer matrix and dissolves in the course of release only a small part. The kinetics of the drug delivery is significantly influenced by the degree of loading of the non-degradable polymer (SIBS) with PTx and stagnates after about 14 days. Since paclitaxel is insoluble in SIBS and does not diffuse, no further drug release can occur after all accessible drug crystals are dissolved. This explains the high residual content of PTx of up to 90% as well as the release kinetics dependent on the drug loading.

One Advantage of the polyelectrolyte multilayers used according to the invention by means of LbL technology u. a. in that the construction of multilayers a very universal method is and PLL by another cationic Polymer can be exchanged. For the long-term security DES is a complete stent endothelialization crucial, especially for the prevention of thrombosis. In this It is also known that cell adhesion can also be controlled by PEM. Therefore, the modular opens Build up the possibility of the design of each layer to adapt to the respective requirements. So could structures / polymers be applied as a terminating layer, which z. Legs Support endothelialization. For the drug loading and to control PTx release are polymer-drug conjugates, which after the cleavage of the active ingredient from the polymer chain the active substance release advantageous. Due to the local effect is an additional coupling of transport groups to the high molecular weight polymer according to the model to Ringsdorf not required.

At the The conjugate used according to the invention is the Active substance via an ester bond, in the presence of Water can hydrolyze, bound. By the chemical variation the binding of the drug to the polyelectrolyte can release kinetics be further controlled and also a combination of different stable conjugate to a total coating is with the polyelectrolyte multilayers with LbL technology feasible.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 2005/089855 A1 [0005]
• - WO 2004/028582 A1 [0005]
• WO 2004/006976 A1 [0006]
• DE 102007003184 A1 [0006]
• EP 0706376 B1 [0007]

Claims (8)

Coating and loading of dilatable catheter balloons and stents comprising the following steps: 1.1) Provision a dilatable catheter balloon or stent 1.2) Provision of polyelectrolyte multilayers for coating the catheter balloon or stents as a carrier. 1.3) Provision of paclitaxel in solution for coating / embrittlement of carrier located Polyelektrolydmultischichten. Catheter balloon or stent whose vehicle for paclitaxel consists of polyelectrolyte multilayers. Catheter balloon or stent whose vehicle for paclitaxel from polyelectrolyte multilayers and integrated Growth torches exists. Catheter balloon or stent with a coating consisting of Polyelektrolydmultischichten and a substance for Prevention / reduction of restenosis. Catheter balloon or stent with a carrier layer from polyelectrolyte multilayers and integrated peptides or aptamers, Catheter balloon or stent with a carrier layer polyelectrolyte multilayers and substance consisting of DNA Catheter balloon or stent with a carrier layer polyelectrolyte multilayers and substance consisting of RNA Coating according to Claims 1 to 7, characterized that the original coating also on Coronary and pheripheral stents can apply.