US-12616781-B2 - Tubular nonwoven structure as active agent carrier for the atraumatic treatment of hollow organs, and a process for producing the same

US12616781B2US 12616781 B2US12616781 B2US 12616781B2US-12616781-B2

Abstract

A tubular nonwoven structure as an active agent carrier (“sleeve”) for the atraumatic treatment of hollow organs, in particular applicable via a balloon catheter, as well as a method for the production thereof, wherein the sleeve is folded about a longitudinal sleeve axis in an initial state and is unfoldable in a final state for attachment to an inner wall of a hollow organ, the tubular sleeve is formed of first biodegradable polymer nanofibers and the folding of the sleeve is directed as pleating about a longitudinal sleeve axis, a medicinal active agent is incorporated into the first polymer nanofibers and/or is arranged in interspaces between the polymer nanofibers, and the first polymer fibers are formed such that the polymer fibers degrade over a period of 2 weeks to 3 months so that the active agent can be delivered to a hollow organ wall in this period of time.

Inventors

Andrea Brohm-Schmitz-Rode
Thomas Schmitz-Rode

Assignees

BVS—Best Vascular Solutions GmbH

Dates

Publication Date: 20260505
Application Date: 20210602
Priority Date: 20200605

Claims (18)

1 . Tubular nonwoven structure as a carrier of an active agent, hereinafter referred to as a tubular sleeve, for atraumatic treatment of hollow organs, for application via a balloon catheter, wherein the tubular sleeve is folded about a longitudinal sleeve axis in an initial state and can be unfolded in a final state for attachment to an inner wall of a hollow organ, and the folding of the tubular sleeve is directed as pleating around the longitudinal sleeve axis, wherein the tubular sleeve is formed of areal zones comprising a plurality of first biodegradable polymer nanofibers and areal zones comprising a plurality of second biodegradable polymer nanofibers, wherein a medicinal active agent is incorporated into the plurality of first biodegradable polymer nanofibers and/or is arranged in interspaces between the plurality of first biodegradable polymer nanofibers, and wherein the areal zones comprising the plurality of first biodegradable polymer nanofibers are formed in such a way that the plurality of first biodegradable polymer nanofibers degrades over an adjustable period of time of 2 weeks to 3 months so that the active agent can be delivered to a hollow organ wall in this period of time, and the plurality of first biodegradable polymer nanofibers degrades more slowly than the plurality of second biodegradable polymer nanofibers, and the areal zones comprising the plurality of first biodegradable polymer nanofibers form microflakes which are in coherence with the areal zones comprising the plurality of second biodegradable polymer nanofibers.
2 . Tubular sleeve according to claim 1 , wherein the plurality of second biodegradable polymer nanofibers or further polymer nanofibers are formed such that the polymer nanofibers degrade over an adjustable period of time of 1 second to 2 weeks.
3 . Tubular sleeve according to claim 1 , wherein a biocompatible polymer of the first polymer nanofibers consists of polymers based on at least one of the group consisting of: lactic acid (polylactide, PLA), glycolic acid (polyglycolide, PGA) and their copolymers (poly (lactide-co-glycolide), PLGA), poly (ϵ-caprolactone), polyethylene glycol, polyethylene oxide, polysebacic acid, poly (trimethylene carbonate), poly (ethylene-co-vinyl acetate), poly (1,5-dioxepan-2-one), polyvinylpyrrolidone (PVP), poly-p-dioxanone (PPDX) and their compounds and copolymers or mixtures thereof, the polymer nanofibers having a fiber diameter in a range from 300 to 2000 nm.
4 . Tubular sleeve according to claim 1 , wherein the tubular sleeve is provided with a medical agent comprising at least one of the group consisting of an antiproliferative agent, a long-term stable depot gestagen, an antiprogesterone, a spermicide, and cytostatic agents.
5 . Tubular sleeve according to claim 4 , wherein the antiproliferative agent is sirolimus or other limus derivatives or paclitaxel (PTX); the long-term stable depot gestagen is etonogestrel or levonorgestrel; the antiprogesterone is mifepristone; the spermicide is nonoxinol 9; and the cytostatic agents are mitomycin, capecitabine or methotrexate (MTX).
6 . Tubular sleeve according to claim 1 , wherein the tubular sleeve comprises a radial support layer formed by polymer nano-fibers with higher strength and/or by an additional polymer layer.
7 . Tubular sleeve according to claim 6 , wherein the additional polymer layer is a laser-cut tubular degradable polymer semi-finished product, or a layer formed by Melt Electrospinning Writing.
8 . Tubular sleeve according to claim1 , wherein at least an outer circumferential wall of the tubular sleeve has adhesive properties and/or is provided with a coating such that the circumferential wall adheres to an inner wall of a hollow organ during unfolding.
9 . Method of producing the tubular sleeve according to claim 1 , comprising the following steps: providing a mixture of at least one polymer dissolved in a solvent and a medicinal agent, i.) applying the mixture layer by layer to a cylindrical support to form a tubular nonwoven sleeve of polymer nanofibers, pleating, folding and coiling the tubular sleeve in the same direction about the longitudinal axis after removal of the support, and mounting the tubular sleeve onto a balloon of a balloon catheter, or ii.) applying the mixture layer by layer directly to a support in the form of an inflated balloon of a balloon catheter to which a separation layer has previously been applied to form a tubular nonwoven sleeve of polymer nanofibers, and pleating, folding and winding the tubular sleeve together with the balloon membrane of the balloon catheter after deflation of the balloon.
10 . Method according to claim 9 , wherein the application of the solution to the cylindrical support or directly to the balloon is carried out by at least one of the group consisting of: spraying with an air jet (air spraying), spinning in an electric field (electrospinning), a combination of spraying with an air jet and spinning in an electric field (electrostatic air spraying), dipping in a solution (dip coating), applying a continuous melt strand (melt electrospinning writing), and applying discontinuously using 3D printing.
11 . Method according to claim 9 , wherein substances with a sufficiently high vapor pressure are provided as solvents for the mixture by spraying or electrospinning.
12 . Method according to claim 9 , wherein a first slowly degradable polymer is dissolved in a first solvent, or a solvent mixture of two or more solvents, and a second rapidly degradable polymer is dissolved in the first solvent or in a second solvent, or in a second solvent mixture of two or more solvents.
13 . Method according to claim 9 , comprising adding a protective colloid to the mixture, which improves the mixing and prevents the water-insoluble medicinal agent from separating, wherein the protective colloid is a rapidly soluble polymer.
14 . Method according to claim 9 , comprising applying a separation layer to the support prior to the application of the mixture.
15 . Method according to claim 9 , comprising introducing intermittent longitudinal cuts into the tubular sleeve prior to pleating and folding, wherein the pleating and folding of the tubular nonwoven sleeve can be guided and facilitated by the intermittent longitudinal slits.
16 . The method according to claim 9 , wherein the carrier support is a cylindrical support body or an inflated balloon.
17 . The method according to claim 9 , wherein the tubular nonwoven sleeve is pleated and folded together with the balloon membrane of the balloon catheter and wrapped around a catheter shaft.
18 . The method according to claim 9 , comprising applying the separation layer to an outer surface of the inflated balloon of the balloon catheter, and then applying the tubular sleeve onto the separation layer.

Description

FIELD OF THE INVENTION The present invention relates to a tubular sleeve and a system for atraumatic treatment of hollow organs and a method of fabrication. The present invention relates to a tubular nonwoven structure (hereinafter also referred to as “sleeve”) and a system for atraumatic treatment of hollow organs, as well as a method of producing the same. BACKGROUND OF THE INVENTION Stents are known for the scaffolding of constrictions (stenoses) in human hollow organs, such as blood vessels. A stent (vascular support) is a medical implant that can be inserted into a hollow organ. It is usually a tubular mesh structure made of metal or plastic. The stent is intended to support the affected section of a hollow organ and in this way keep it permanently open. Usually, stents are delivered to the implantation site by means of a catheter or a balloon catheter. For this purpose, the stent can be arranged in a compressed state on a balloon catheter. The stent should have the smallest possible outer diameter in order to cause as little damage as possible to the corresponding hollow organ when it is introduced into the human and/or animal body. For this purpose, radial forces are usually applied to the stent, resulting in a concentric diameter reduction. Once the stent is positioned at the implantation site, the balloon catheter is inflated so that the stent expands concentrically. However, the stent material may in some cases cause clot formation (thrombosis). Furthermore, mechanical stress during inflation of the balloon catheter may cause injury to the hollow organ wall of the hollow organ. The stent often leads to chronic irritation in the long term. The hollow organ wall reacts to this irritation with an overproduction of wall cells and so-called extracellular matrix (hyperplasia). Such vessel wall proliferation can be so severe that it leads to re-narrowing of the blood vessel (restenosis). Because of the thrombogenicity of the tears in the hollow organ wall and also of the stent material, drug anticoagulation treatment is often given to prevent clot formation. However, this therapy may have side effects. Therefore, a reduction of such medication would be desirable. Furthermore, attempts are often made to reduce vessel wall proliferation by so-called “drug eluting stents”. Such stents are usually coated with a polymer in which antiproliferative agents are incorporated or these stents are doped with such agents. The release of the antiproliferative agents at the site of implantation reduces the overproduction of wall cells. However, in some patients, these agents prevent the stent from growing into the wall of the vessel. After discontinuation of anticoagulation medication, so-called late thrombosis may occur, because the stent has not grown into the vessel wall, not at all or not completely. To avoid the above problems, new stent concepts are being pursued, including so-called bioresorbable stents. These can be made of biodegradable metal alloys, e.g. with a high magnesium content, or of biodegradable polymers, e.g. polylactide. It is envisaged that such stents support the vessel wall for several months and are then be biodegraded by the body's own substances. In this way, the mechanical irritation of the vessel wall is also reduced and there should be less restenosis. According to initial studies, however, even with biodegradable stents, loading with antiproliferative agents cannot be dispensed with, because the excessive vascular wall reaction must be suppressed in the first few months after implantation. Such devices and processes are described in DE 10 2012 007 640, WO 02 076 700 A1, U.S. Pat. No. 5,443,495 A1, DE 10 2006 020 687 A1, US 2005/0 090 888 A1, DE 2005 056 529, US 2002/0 045 930 A1, US 2005/0 125 053 A1, US 2008/0 262 594, U.S. Pat. Nos. 5,507,770 A, 6,059,823 A and US 2010/249946 A1. The dilatation of constrictions (stenoses) of hollow organs using balloon catheters is an integral part of minimally invasive therapy. This applies in particular to the blood vessels. Within the framework of so-called endovascular therapy atherosclerosis-related constrictions and occlusions of blood vessels are treated by balloon dilatation. Typically, a balloon catheter is inserted into the vascular system under imaging control. After placing the balloon in the area of the lesion to be treated, the balloon is expanded under high pressure. However, this standard treatment may be associated with serious complications. The balloon expansion injures the vessel wall. Typically, longitudinal tears occur in the vessel wall. This injury may result in clot (thrombus) adhesion in the first few days after treatment. In the following days up to a period of about three months, the blood vessel wall responds to the dilatation trauma with an exuberant wall reaction. Smooth muscle cells in the vessel wall are stimulated by the trauma and produce extracellular matrix (“intimal hyperplasia”). The associated increase in volume in