Multi-component composition for particle removal

Description

[0001] The present invention relates to a gel-forming multi-component composition comprising a component containing at least one crosslinkable polymer and a component containing at least one crosslinking agent, wherein both components contain at least one dye, and a crosslinked gel, as well as such a composition or such a gel for use in a method for removing unwanted particles from a patient.

[0002] Further aspects of the present invention or related to it, as well as preferred embodiments, are described below and in the attached patent claims.

[0003] The accumulation of unwanted waste products or deposits of various kinds is a common problem in the human body. Well-known examples include gallstones and kidney stones. Gallstones occur in approximately 10 to 15% of the adult population, with Western industrialized countries being particularly affected. About half of the German population over the age of 60 has gallstones. While gallstones often remain asymptomatic, in some cases they cause colic with severe pain, elevated liver enzymes, and general symptoms of illness, even leading to jaundice (icterus).

[0004] From an epidemiological perspective, kidney stones are one of the most common diseases in the world. In Germany, the incidence rate in 2000 was 1.45%, which corresponds to approximately 1,200,000 new cases per year. In Germany alone, there are an estimated 750,000 treatment cases annually. The number of stone removal procedures in Germany is estimated at around 400,000 per year, roughly half of which are for recurrent stones. These figures can be extrapolated to millions of such procedures worldwide. With costs exceeding €1.5 billion, kidney stones represent a significant expense for the German healthcare system. Kidney stones can also cause severe pain, trigger nephritis, damage the kidneys, or even lead to acute kidney failure (usually affecting one side of the body).

[0005] Salivary stones can form in any gland in the mouth. Often, these are flushed out of the glandular ducts on their own. However, such stones can also become lodged in the ducts and, for example, lead to acute, painful inflammation of the salivary glands.

[0006] The causes of both problems are diverse and range from unhealthy, high-fat diets or lack of fluids or exercise to diseases such as diabetes mellitus or gout, and even genetic predisposition.

[0007] Salivary, gallstones, pancreatic, or kidney stones are often only discovered at an advanced stage, usually when the first (more serious) symptoms appear. The stones can be located within the organs themselves or in the ducts draining from them. In most cases, the stones are already too large to be removed whole using minimally invasive procedures. In this case, the stones are broken up and the individual fragments removed, for example, with the help of an endoscope. In some cases, multiple stones form, which must also be completely removed.

[0008] For example, a method for treating kidney stones by selectively dissolving the deposits using quaternary ammonium salts is described in US 5,244,913.

[0009] It is not only in the case of salivary, gallstones, or kidney stones that multiple unwanted particles need to be removed from a patient. In other cases as well, for example with comminuted fractures (where splinters of the body's own bone) or abrasions (where foreign bodies such as stones, metal, plastic, or wood splinters or fragments thereof) a large number of particles must be removed from the patient as completely as possible.

[0010] All these cases have in common that a large number of particles must be removed from the patient as easily as possible, but also as completely as possible.

[0011] If, for example, salivary, gallstones, pancreatic, or kidney stones do not pass naturally, or if there are medical indications for immediate treatment, endoscopy (minimally invasive endoscopic techniques) represents the therapeutic "gold standard" alongside extracorporeal shock wave lithotripsy (ESWL). Given the increasing evidence of poorer outcomes with ESWL, endoscopic procedures are preferred. It is estimated that currently 60-70% of all stone patients are treated endoscopically. This trend is increasing. Using endoscopic techniques, kidney stones are fragmented and removed on-site. A problem that remains unresolved is the presence of small residual fragments (<2 mm) that cannot be effectively removed during treatment. Remaining kidney stone fragments act as "crystallization nuclei," from which new stones develop in 70% of cases.This, in turn, leads to further medical problems and the need for treatment. Such fragments were previously referred to as clinically irrelevant residual fragments (CIRFs), but in recent years it has become clear that they are indeed clinically relevant.

[0012] In lithotripsy, kidney stones are broken up using extracorporeal shock waves or endoscopically inserted laser or compressed air probes. This produces fragments of varying sizes, which can either be removed with grasping instruments or flushed out. One problem with lithotripsy is that the fragments can disperse during fragmentation or enter hard-to-reach areas.

[0013] WO 2005 / 037062 concerns a method by which kidney stones are contained (not enclosed) within a specific area using a polymer plug, thereby largely preventing tissue damage from the resulting fragments during lithotripsy. According to WO 2005 / 037062, a gel-forming fluid, such as a thermosensitive polymer that forms a gel plug at body temperature, is injected into the lumen on at least one side of the kidney stone. The polymer does not typically come into contact with the kidney stone itself, but serves to increase the efficiency of lithotripsy by preventing displacement of the kidney stone and protecting the surrounding tissue from damage caused by fragmentation. The use of this system is explicitly recommended and permitted only outside the kidney.

[0014] One approach to removing objects, such as blood clots, from the body using an adhesive is described in US 2008 / 0065012. The adhesive is spread on a surface and introduced into the body using a catheter. Once the object has adhered to the surface, the catheter is withdrawn, taking the object with it.

[0015] Biological macromolecule-based adhesives, and in particular gel-forming polymer systems, are increasingly finding applications in medical technology. Their high biocompatibility is one of the most important selection criteria.

[0016] US Patent 6,663,594 B2 describes a method for immobilizing an object, such as a kidney stone, within the body by injecting a gel-forming fluid. Upon contact with the object, a gel forms, which at least partially captures and immobilizes it. This immobilization allows the object to be subsequently fragmented without risking the fragments being dispersed, or enables its removal from the body using an endoscopic instrument. The gel prevents the object or fragments from shifting and becoming entangled with the instrument. After removal of the object or fragments, the gel is dissolved or extracted using an endoscopic instrument.A disadvantage of this method is that when kidney stones are broken up, the already hardened gel can be damaged, potentially releasing fragments or causing individual fragments to escape from the polymer. Grasping the fragments within the gel is not possible with conventional grasping tools. Furthermore, the described procedure is very time-consuming, as the stones or stone fragments must be grasped and removed individually. As a result, there is a relatively high probability that some stone fragments will remain.

[0017] A particular problem with lithotripsy is the occurrence of small to medium-sized stone fragments (especially < 2 mm), also known as "gravel," as these fragments cannot be efficiently grasped or flushed out. Residual fragments of this size slip through the mesh of the grasping instruments (forceps or baskets), making gravel extraction very time-consuming and practically impossible in the case of larger stone masses. However, the retention of such kidney stone fragments leads to the formation of new kidney stones in a very high percentage of cases, as the fragments act as "crystallization nuclei."

[0018] WO 2014 / 173467 describes a gel-forming system comprising a component containing one or more crosslinkable polymers, a component containing one or more crosslinking agents, and optionally a component containing magnetizable particles. The gel-forming system can be used for the removal of urinary stones. The urinary stone(s) are fragmented. Subsequently, the component containing one or more crosslinking agents and the component containing magnetizable particles are mixed and injected via catheter through an endoscope into the area of ​​the urinary tract containing the fragments of the fragmented urinary stone(s). The component containing one or more crosslinkable polymers is then added, forming a gel. The solidified gel partially or completely encapsulates the urinary stone(s).the fragments thereof and can be removed using a grasping instrument via the operating endoscope along with the kidney stones or the fragments thereof.

[0019] However, experience has shown that a colorless gel presents some difficulties in removing kidney stones or their fragments. The exact quantity and location of the injected component(s) cannot be precisely controlled. Furthermore, it is impossible to determine whether gel formation is complete, and the resulting colorless gel is difficult to locate endoscopically. Additionally, it cannot be determined whether the individual components are disturbed by the use of a rinsing solution or an excessive dosage, potentially diluting them to such an extent that proper function cannot be guaranteed.

[0020] To address these problems, Cloutier J, Cordeiro ER, Kamphuis GM, Villa L, Letendre J, de la Rosette JJ, Traxer O (2014) "The glueclot technique: a new technique description for small calyceal stone fragments removal" Urolithiasis 42 (5):441-444, describe the use of autologous blood. However, the blood must first be drawn, which adds another step to the procedure. Furthermore, the formation of a blood clot from clotted blood takes significantly longer than the formation of a solidified gel from the components of WO 2014 / 173467. The low color contrast between the blood and the patient's tissue also complicates the application. Additionally, the treating physician wishes to see the embedded stone fragments as a means of verifying the success of the procedure. However, this is not possible within the blood clot due to the strong inherent color of the blood. However, thinning the blood would prevent the formation of a solid blood clot or greatly reduce its firmness.Additionally, the patient's own blood cannot be applied to the area of ​​the stone fragments, e.g., in a distal renal calyx, using a fine catheter (blood has too high a viscosity for this).

[0021] The gel-forming system of WO 2014 / 173467 may additionally contain one or more dyes that make it easier to visualize the solidified gel or one, both, several or all of the components used (before setting) endoscopically.

[0022] Similarly, WO 2014 / 173468 describes a kit for producing a cross-linked gel that may contain iron oxide particles.

[0023] However, it has become apparent that the use of many such dyes also has significant disadvantages, for example, when the gel becomes opaque, similar to a blood clot as described in Cloutier J, Cordeiro ER, Kamphuis GM, Villa L, Letendre J, de la Rosette JJ, Traxer O (2014) "The glueclot technique: a new technique description for small calyceal stone fragments removal" Urolithiasis 42 (5):441-444). A colorless or transparent gel allows for monitoring the encapsulation of the kidney stones or their fragments during gel formation. If the kidney stones or their fragments are not, or only minimally, encapsulated, removing the gel will not result in the (complete) removal of the kidney stones or their fragments.During the procedure, it is therefore not possible to check the success of a colored gel, which may require a re-injection of the components and gel formation, significantly prolonging the procedure.

[0024] The use of dyes has proven particularly problematic because the dyes stain not only the gel but also the surrounding tissue. While the dye allows the gel to be visualized endoscopically, this drastically complicates the complete removal of the gel without damaging the surrounding tissue.

[0025] It was also found that the consistency of the gel that forms is negatively affected by many dyes. This creates the risk that the resulting gel will not be firm enough for removal and can only be removed endoscopically with considerable effort, along with the kidney stones or their fragments. Conversely, certain coloring substances can cause the gel to become too firm or rubbery. This results in the gel not dissolving, or dissolving poorly, or being unable to be broken down into smaller pieces using graspers.

[0026] The use of dyes therefore brings advantages, but so far these can only be realized by accepting the disadvantages described.

[0027] Similar problems, as well as the advantages and disadvantages of using dye(s), also arise in the removal of salivary, pancreatic or gallstones, as well as other body stones as described herein, and can easily be applied to other cases in which particles need to be removed from a patient, for example, the other cases described above.

[0028] The primary objective of the present invention was therefore to provide a method by which particles can be removed from a patient, and by which the above-mentioned advantages, or as many of these advantages as possible, can be achieved without the listed disadvantages, or with as few of the disadvantages as possible.

[0029] In particular, the object of the present invention was to provide an improved means suitable for reliably extracting particles from the body.

[0030] The primary object of the present invention is achieved by a gel-forming multi-component composition, preferably a two-component composition, for forming a gel, the composition consisting of or comprising a component (A) containing one or more crosslinkable, preferably cationically crosslinkable polymers, and a component (B) containing one or more crosslinking agents for crosslinking the crosslinkable polymer(s), wherein component (A) and component (B) comprise at least one dye, wherein the dye(s) in component (A) is / are different from the dye(s) in component (B), wherein the at least one dye imparts a transparent color to the gel and optionally to component (A) and / or component (B), wherein the at least one dye facilitates the crosslinking of the polymer(s).the crosslinkable polymers are not impaired when components (A) and (B) are brought into contact, wherein the at least one dye does not leach out of the gel formed, and wherein the at least one dye is a colored molecule selected from the group consisting of dextrans, polyethylene glycol, starch, gellan, polyelectrolytes such as poly(I-Iysine) and other polyamino acids, such as poly(ornithine), poly(arginine), poly(histidine); polypeptides and proteins such as e.g.Gelatin, as well as polysaccharides such as chitosan, alginates such as sodium alginate, polyglycolic acid (PGA), polylactic acid (PLA), poly-2-hydroxybutyrate (PHB), polycaprolactone (PCL), poly(lactic-co-glycolic) acid (PLGA), protamine sulfate, spermidine, albumin, carrageenan, furcellaran, pectin, xanthan gum, hyaluronic acid, sodium carboxymethylcellulose, heparin, heparan sulfate, cellulose derivatives or sodium carboxymethylcellulose, chondroitin sulfate, dermatan sulfate and dextran sulfate, for use in a procedure for removing unwanted particles from a patient.

[0031] The term "gel-forming composition", as used herein, is preferably to be understood as meaning that the composition is not only suitable for forming a gel, but that a gel is actually formed by mixing the components of the composition.

[0032] The gel produced by mixing the components of the composition is preferably a hydrogel.

[0033] Furthermore, it is preferred that the dye, or at least one of the dyes, has a high contrast to the patient's tissue in which the multi-component composition is used. It is also preferred that the dye, or at least one of the dyes, does not cause a red or yellow-orange coloration.

[0034] Furthermore, it is particularly preferred that the dye is physiologically harmless and can therefore be used without problems in application on / in a patient.

[0035] It was surprisingly discovered that some dyes allow for transparent coloring without exhibiting the aforementioned negative characteristics. On the one hand, the solidified gel can be colored by the dye; on the other hand, the unsolidified mixture of components (A) and (B), as well as any other components, can also be colored.

[0036] Preferably, the dye colors the solidified gel and / or the mixture of components (A) and (B), as well as any further components, and / or component(s) (A) and / or (B), and / or any further components present, with a transparent color. Preferably, the solidified gel contains the dye(s). Preferably, three or all components contain at least one dye. Preferably, the dye(s) can also be added to the respective component (as described above) shortly before use.

[0037] The term "transparent," as used herein, describes the property of an object or material (here, a solidified gel and, optionally, component(s) (A), (B), and / or optionally, further components) to transmit light. The term, as used herein, encompasses not only complete light transmission but also the property of being only partially translucent. The opposite of "transparent" is "opaque," i.e., not permeable to light. Preferably, the term "transparent" describes all materials that are not "opaque." The calculation of transmission (permeability of light) and its reciprocal, opacity O, as well as the methods used for measuring luminous flux, are known to those skilled in the art. Preferably, the transmission or luminous flux is measured by UV-Vis spectroscopy.The transmission T is generally calculated as the ratio of the luminous flux incident on a material (I 0 ) to the luminous flux I transmitted by that material: . T = I / I 0 O = I 0 / I

[0038] A value of T = 100% or O = 1 signifies complete transparency, whereas a value of T = 0% or O = ∞ describes complete opacity. Preferably, the term "transparent" describes a transmission T of more than 15%, more preferably of at least 16%, particularly preferably of at least 17%, and most preferably of at least 18%.

[0039] The transmission T is preferably measured with a UV-Vis spectrometer, preferably by measurement in the visible spectrum, particularly preferably in a range of 400 to 800 nm.

[0040] Preferably, the transmission T is measured using a method that includes the following steps: (i) Providing a gel according to the invention, (ii) Providing a reference, preferably water, (iii) Measuring the transmission T with a spectrometer, preferably with a UV-vis spectrometer, preferably by measuring in the visible spectrum, particularly preferably in a range of 400 to 800 nm.

[0041] Preferably in the procedure, the gel from step (i) and the reference from step (ii) are introduced into containers suitable for measurement, preferably cuvettes.

[0042] Further preferred features are described in Example 5, wherein a method for measuring the transmission T may include or consist of one, several or all of the features from Example 5.

[0043] A transparent colorant, as defined herein, allows the user to utilize the advantages of a dye. For example, the transparent colorant is helpful when filling the application device or aid (e.g., a catheter). It also aids in dosing at the application site within the patient's body: the transparent colorant indicates where the colored component is being applied, how much is being applied, and where the colored component has already been applied. A transparent colorant is also helpful during gel formation, as it makes it possible to see if any turbulence occurs during application. After removing the solidified gel, along with the particles it contains, from the patient's body, the transparent colorant can also be used to determine whether any gel components remain.At the same time, a transparent coloring can also be used to check the success of the treatment: The transparent coloring makes it visible whether the particles to be removed are already enclosed by the gel, or which particles are already enclosed and where more gel is needed to remove the particles.

[0044] It has been shown that dyes that allow for white or black coloring often do not allow for transparency (cf. Fig. 1 Therefore, it is preferred that the or at least one of the at least one dye does not cause a black or white coloration.

[0045] Besides the concentration of a dye used, the type of dye has a major influence on the formation of a transparent color. The chemical structure, including electron distribution, charges, and molecular mass or composition, primarily determines a dye's suitability for producing a transparent color.

[0046] The term "not impairing the crosslinking of the crosslinkable polymer(s) when the components are brought into contact," as used herein, means that crosslinking of the crosslinkable polymer(s) remains possible when the components are brought into contact, and a solidified gel can form. The addition of substances such as dyes may slow down the crosslinking process, but in this case, it is not considered impaired, as crosslinking still occurs. Preferably, the dye(s) used do not change, or substantially do not change, the time required for crosslinking. The same applies to the possibility of re-dissolving the gel.

[0047] It is particularly advantageous if the dye does not leach out of the solidified gel and / or from the component containing the dye. In this case, no surrounding patient tissue is stained, and the dye can serve as an indicator for the gel or the component containing the dye. This allows for verification that the solidified gel has been completely removed from the patient. Furthermore, the risk of confusing the gel with the patient's tissue is minimized, and during subsequent gel removal, only the gel itself, including the particles it encapsulates, is removed, not the patient's own tissue, which should not be removed. Accidental damage to surrounding patient tissue is thus minimized.

[0048] Preferably, a dye according to the present invention is a chemical structure that partially absorbs and reflects light in the visible light spectrum and, in turn, remits light of a specific wavelength or a specific wavelength pattern in the visible wavelength range. A dye contains a chromophore.

[0049] Dyes containing or consisting of self-colored large molecules have proven particularly advantageous. Such molecules can be selected from the group consisting of dextrans, preferably with a molecular mass of at least 10 kDa, particularly preferably at least 20 kDa; polyethylene glycol, starch, gellan, poly-Iy electrolytes such as poly-I-Iysine and other polyamino acids, such as polyornithine, polyarginine, polyhistidine; Polypeptides and proteins such as gelatin, as well as polysaccharides such as chitosan, alginates such as sodium alginate, polyglycolic acid (PGA), polylactic acid (PLA), poly-2-hydroxybutyrate (PHB), polycaprolactone (PCL), poly(lactic-co-glycolic)ic acid (PLGA), protamine sulfate, spermidine, albumin, carrageenan, furcellaran, pectin, xanthan gum, hyaluronic acid, sodium carboxymethylcellulose, heparin, heparan sulfate, various cellulose derivatives or sodium carboxymethylcellulose, chondroitin sulfate, dermatan sulfate and dextran sulfate.

[0050] Such molecules are then preferably color-coded so that they can serve as dyes according to the invention. Such labeling can be carried out in particular by means of reactive dyes.

[0051] Reactive dyes are preferably understood as chemical compounds with a chromophore that have one or more functions enabling the formation of a covalent bond. This bond is formed via a "reactive anchor" which consists of, for example, halogen-substituted aromatic heterocycles such as "monochlorotriazines", "monofluorotriazines", "difluoropyrimidines", "difluorochloropyrimidines", and "dichloroquinoxaline carbonamides".

[0052] Vinyl sulfone dyes, which form a covalent bond via a vinyl sulfone group, such as "CI Reactive Black 5, CI Reactive Blue 19, CI Reactive Orange 107, CI Reactive Red 239", are also preferably considered reactive dyes.

[0053] For such color-coding of molecules as described above, those sold under the brands Cibacron (Ciba Ltd.) and Procion (ICI) are particularly suitable, e.g., Cibacron Blue (F3G-A), CI Reactive Blue 235, CI Reactive Blue 204, CI Reactive Blue 7, CI Reactive Red 1, Cibacron Orange GE, Cibacron Brilliant Blue FBR-P, Cibacron Blue F3G-A, Cibacron Brilliant Red 3B-A, Cibacron Brown 3GR-A, Cibacron Scarlet Red 2G, Cibacron Scarlet Red 4G-P, Cibacron Brilliant Red BA, Procion Brilliant Orange HGRS, Procion Blue HBS, Procion Brilliant Red H7BS, Procion Orange-Brown HGS, Procion Scarlet Red H3GS, Procion Red H3B. Procion Red HE2B, Procion Red P3BN, Procion Red MX2B, Procion Blue MX3G, Procion Yellow MXR, Procion Yellow H5G, Procion Red H8BN, Procion Green H-4G, Procion Brown H-GR, Procion Blue MX-G, Procion Blue HE-RD, Procion Blue HB, Procion Blue MXR, Procion Yellow HA, Procion Green HE-4BD, Procion Red HE7B, Procion Red MX5B, Procion Red MY.8 B, Procion Ruby MXB, Procion Scarlet MXG, Procion Orange MXG, Procion Yellow MX6G, Procion Brown H2G, Procion Yellow MX8G, Procion Turquoise HA, Procion Turquoise H7G, Procion Brown MX5BR, Procion Blue MX7RX, Procion Blue MX4G.

[0054] Preferably, such color marking is achieved by covalent bonding of such a substance to the large molecules as described above. Dextran blue has proven to be a particularly preferred dye according to the invention. Preferably, the dyes are formed from a combination of a large molecule, as described herein, and at least one marker, as described herein.

[0055] Large molecules are particularly advantageous because their size prevents them from dissolving from the solidified gel. Preferably, the dye is large enough that its movement through the solidified gel is essentially prevented. Preferably, movement of the dye through the unsolidified gel is possible.

[0056] Preferably, a dye, as described herein, can be covalently, ionically, via hydrophobic interactions, via hydrogen bonds and / or via van der Waals interactions bound to, or interacting with, the one or more polymer(s) of component (A) and / or component (B) according to the present invention.

[0057] Preferably, a dye, as described herein, can be covalently or ionically bonded to one or more further components of component (A) and / or component (B) according to the present invention.

[0058] Particularly (but not only) for the coloring of component (B), not only dyes based on large molecules, as described herein, are suitable, but also smaller dyes, provided that these adhere to the solidified gel via physical interactions such as charge, which preferably also substantially prevents movement of the dye through the solidified gel.

[0059] Advantageously, the dyes used according to the invention can color component(s) (A) and (B) to facilitate or control their localization and dosage. Furthermore, confusion between composition (A) and / or (B) and / or the prepared gel and the patient's tissue is advantageously avoided.

[0060] Component (A) and component (B) each comprise at least one dye, and the dye(s) in component (A) is / are different from the dye(s) in component (B). This has proven particularly advantageous because it allows for a color distinction between components (A) and (B). It also preferably and advantageously makes it possible to determine whether components (A) and (B) have already mixed or have been mixed, since a mixture of the two components preferably produces a color that differs from the color of the dyed components (A) and / or (B).

[0061] Preferably, component (A) and component (B) each comprise at least one dye comprising a large molecule, as described herein. Preferably, only component (A) or only component (B) comprises at least one dye comprising a large molecule, as described herein. Preferably, only component (A) or only component (B) comprises at least one dye comprising a large molecule, as described herein, and the other component, component (B) or component (A), comprises a smaller dye, as described herein.

[0062] The polymers or polymer units of component (A) are preferably cross-linked via ionic interactions (see component (B)). Therefore, a variety of macromolecules that act as ligands of mono- or polyvalent cations and can form chelate complexes are suitable for the application according to the invention. These include, in particular, hydrogels, biocompatible sugar-based (e.g., modified celluloses) or proteinogenic adhesives, or fibrin- or collagen-based systems (particularly preferred polymers are described below).

[0063] Preferably, the(s) of one, several or all of the crosslinkable polymers of component (A) are selected from the group consisting of polysaccharides, in particular polysaccharides with deprotonated or deprotonatable functional groups, preferably carboxy groups, preferably polysaccharides from the group of polyuronides, particularly preferably polysaccharides from the group of alginates and pectins, and their respective chemical derivatives.

[0064] Polysaccharides such as dextrans, carrageenans, alginates, gellans, and pectins are particularly suitable for use in the body because they do not cause inflammatory reactions or immune rejection and pose a low risk of tissue trauma. Furthermore, they are biodegradable and possess numerous carboxylic acid groups that can form chelate complexes with polyvalent cations or be chemically cross-linked. Advantageously, they are able to cross-link underwater and at physiological temperatures and can be easily handled in solution. Cross-linking occurs rapidly but without clogging the patient's delicate tissue structures or the endoscopic instruments. The resulting gels exhibit sufficient stability and flexibility to be extracted along with the particles.

[0065] Suitable cations preferably serve as crosslinking agents for component (B). Advantageously, these are generally cations that occur naturally in physiological systems. Advantageously, no additional (aggressive) reagents need to be added to initiate crosslinking under physiological conditions. Furthermore, no undesirable byproducts are advantageously formed.

[0066] According to the invention, preferred compositions are those that can set under physiological conditions. To form stable cross-links via cation bridges, it is advantageous if the polymers of component (A) possess functional groups (in sufficient number) that are present as negatively charged units even at (slightly) acidic pH. In some compositions, for example, the degree or rate of cross-linking can be controlled by adjustable parameters such as the concentrations or pH values ​​of the individual components.

[0067] Additionally or alternatively, the crosslinking agent(s) of component (B) is / are preferably selected from the group consisting of divalent and trivalent cations, preferably lead, copper, barium, strontium, cadmium, calcium, cobalt, nickel, zinc, manganese and magnesium ions, particularly preferably iron and calcium ions.

[0068] Iron and calcium ions are naturally occurring cations in physiological systems that can be easily administered in the form of biocompatible solutions. They possess suitable coordination chemistry and can form stable chelate complexes for cross-linking.

[0069] According to the invention, the dye can comprise a polymer, wherein the polymer of the dye and one or more of the crosslinkable polymer(s) of component (A) can correspond. In this case, the one or more of the crosslinkable polymer(s) of component (A) and the polymer of the dye are based on the same polymers, whereby the type of monomers from which these polymers are built, and preferably not the number of monomers, is of primary importance.

[0070] A composition according to the invention may additionally contain further components. For example, substances that promote gel formation and / or the incorporation of particles may be added to components (A) and / or (B) and / or one or more further components of a composition according to the invention. Such substances may, for example, be crosslinking agents to increase the stability of the gel.

[0071] According to the invention, it is therefore preferred that the component (A), the component (B), and / or (a) further component(s) optionally contained in the composition contains one or more substances for improving the crosslinking of the crosslinkable polymer(s), in particular crosslinking agents, preferably amino acids.

[0072] Preferably, the concentration of the crosslinking agent(s) contained in component (B), based on the total volume of component (B), is at least 0.01 mol / L and is preferably in the range of 0.01 to 3.0 mol / L, particularly preferably in the range of 0.1 to 1.0 mol / L. If one of the crosslinking agents also constitutes a dye as described herein, this crosslinking agent is taken into account as such for the calculation of the concentration of the crosslinking agent(s) contained in component (B).

[0073] Component (B) may contain other components besides the aforementioned crosslinking agents. To calculate the total quantity of the crosslinking agent(s) in component (B), the entire component (B), including all other components present alongside the crosslinking agent(s), serves as the basis for the calculation.

[0074] The amount of crosslinking agent present influences both the rate of the crosslinking reaction and the stability and flexibility of the crosslinked gel. The amounts specified in the preferred embodiment of the present invention described above ensure that a stable and flexible gel is formed as quickly as possible, which can optionally be removed from the body in one piece.

[0075] According to a further preferred embodiment of the present invention, component (A) and / or component (B) has an acidic pH value, preferably a pH value in the range of 3.5 to 4.5. According to a further preferred embodiment of the present invention, component (A) and / or component (B) has a neutral pH value, preferably a pH value in the range of 6.5 to 8.0, and particularly preferably a pH value in the range of 7.0 to 7.5.

[0076] At a pH in the range of 3.5 to 4.5, the cations of component (B) are freely available in solution and thus available for complexation. Advantageously, in this pH range, the acid groups on the polysaccharide are largely deprotonated, resulting in an effective crosslinking reaction. If a buffered solution (at a pH of approximately 4) is introduced in the area of ​​the particles to be removed, the solubility decreases as a result of the introduction of the preferably polysaccharide-containing component (A). This process takes a certain amount of time, during which the particles to be removed become embedded. Advantageously, the rate of the crosslinking reaction can thus be controlled via the pH of the components used.

[0077] A neutral pH value has proven to be particularly harmless to body tissue.

[0078] According to the invention, the composition preferably also contains magnetizable particles, wherein the magnetizable particles are part of component (A) and / or part of component (B) and / or the composition also includes component (C) containing magnetizable particles, so that the cross-linked gel also contains magnetizable particles.

[0079] The addition of magnetizable particles opens up a new and advantageous method for removing the solidified gel from the body by utilizing its magnetic properties. For example, a magnetic fishing rod or, in particular, a magnetic retrieval basket can be used, which combines the advantages of an anchor and a conventional retrieval basket.

[0080] According to a preferred embodiment of the present invention, the magnetizable particles are selected from particles containing or consisting of ferromagnetic elements such as iron, nickel and cobalt, as well as alloys such as AlNiCo, SmCo, Nd 2 Fe 14 B, Ni 80 Fe 20 , NiFeCo and / or their oxides such as iron oxide particles, in particular iron oxide nanoparticles of Fe 3 O 4 and / or γ-Fe 2 O 3 .

[0081] According to a further preferred embodiment of the present invention, the cross-linked gel contains no magnetizable particles.

[0082] In the event that the cross-linked gel also contains magnetizable particles, it is preferably the case that the magnetizable particles do not, or do not significantly, negatively affect the color and / or coloring of the gel in the sense of the invention.

[0083] Iron oxide particles have proven suitable in medical and pharmaceutical applications, for example as an intravenously administered contrast agent for magnetic resonance imaging or for tumor therapy. To increase biocompatibility and colloidal stability, such particles are usually coated with substances such as dextrans, polyvinyl alcohols, dimercaptosuccinic acid, etc.

[0084] Preferably, the total amount of magnetizable particles, based on the total weight of the component (A), (B), or (C) containing the magnetizable particles, is at least 0.1 wt.% and is preferably in the range of 0.1 to 70 wt.%, particularly preferably in the range of 1 to 11 wt.%. To ensure that the gel containing the particles can be efficiently removed from the body by utilizing magnetic interactions, it is necessary to incorporate a suitable amount of magnetizable particles into the cross-linked gel. If one of the magnetizable particles also represents a dye as described herein, this magnetizable particle is taken into account as such for the calculation of the total amount of magnetizable particles. Preferably, the magnetizable particle(s) is / are not a dye as described herein.

[0085] Components (A) and / or (B) and / or (C) (if present) may contain additional components besides those already mentioned. To calculate the total number of magnetizable particles in the component containing these particles, as described above, the entire component (A), (B), or (C), including any additional components present, is used. If several components (A), (B), or (C) contain magnetizable particles, the total number of magnetizable particles in each component is preferably calculated separately.

[0086] If, in addition to components (A) and (B), the composition according to the invention contains several further components, and one of these further components comprises magnetizable particles as described above, then this component is considered component (C). If several of the further components comprise magnetizable particles as described above, and these several components exist as separate components, then preferably the component with the highest concentration of magnetizable particles as described above is considered component (C).

[0087] The invention preferably relates to a gel-forming multi-component composition, preferably a two-component composition, for forming a gel, The composition consists of or comprises a component (A) containing one or more crosslinkable, preferably cationically crosslinkable, polymers, and a component (B) containing one or more crosslinking agents for crosslinking the crosslinkable polymer(s), wherein component (A) and component (B) comprise at least one dye, the at least one dye being a dye as described herein. Preferably, the dye is selected from a combination of a large molecule as described herein and at least one label as described herein, or a small dye as described herein, for use in a method for removing unwanted particles from a patient.

[0088] What was said above regarding the preferred embodiments of the multi-component composition also applies here accordingly.

[0089] Also described herein is a cross-linked gel consisting of or comprising one or more polymer(s), magnetizable particles and at least one dye, each as described or defined herein, wherein the cross-linked gel can be produced or manufactured by (i) Providing a component (A) containing one or more crosslinkable polymers, preferably cationically crosslinkable polymers, and providing a component (B) containing one or more crosslinking agents for crosslinking the crosslinkable polymer(s), and, optionally, providing a component (C) or further component(s) (if any), wherein the component (A) and / or the component (B) and / or, if any, the component (C) contains magnetizable particles, (ii) bringing the components (A) and (B) and, optionally, (C) and further components (if any) into contact under conditions that promote crosslinking of the polymer(s).The crosslinkable polymers enable the formation of a crosslinked gel, wherein component (A) and / or component (B) comprise at least one dye, wherein the at least one dye imparts a transparent color to the gel and optionally to component (A) and / or component (B), wherein the at least one dye does not impair the crosslinking of the crosslinkable polymer(s) upon contact of components (A) and (B), and wherein the at least one dye does not leach out of the gel formed.

[0090] What has been said herein regarding the gel-forming multi-component composition, in particular its advantages and preferred configurations, applies accordingly to the cross-linked gel described herein. Likewise, what has been said with regard to component (A), (B), or (C) (if any), or further components (if any), and their respective constituents, applies accordingly.

[0091] Component (A) and component (B) each comprise at least one dye and the dye(s) in component (A) is / are different from the dye(s) in component (B).

[0092] Preferably, the process for producing the gel, as described above, additionally comprises the following step: staining component (A) and / or (B) and / or (C) (if any) and / or further components (if any) with a dye as described herein, in particular as preferably described herein.

[0093] The staining step is preferably carried out before the contacting step (ii) of the previously described procedure.

[0094] Preferably, the(s) of one, several or all of the crosslinkable polymers of component (A) are selected from the group consisting of polysaccharides, in particular dextrans and polysaccharides with deprotonated or deprotonatable functional groups, preferably carboxy groups, preferably dextrans and polysaccharides from the group of polyuronides, particularly preferably dextrans and polysaccharides from the group of alginates and pectins.

[0095] Additionally or alternatively, the crosslinking agent(s) of component (B) is / are preferably selected from the group consisting of divalent and trivalent cations, preferably iron and calcium ions.

[0096] Additionally or alternatively, the magnetizable particles are preferably selected from particles containing or consisting of ferromagnetic element(s) such as iron, nickel and cobalt, as well as alloys such as AlNiCo, SmCo, Nd 2 Fe 14 B, Ni 80 Fe 20 , NiFeCo and / or their oxides such as iron oxide particles, in particular iron oxide nanoparticles made of Fe 3 O 4 and / or γ-Fe 2 O 3 .

[0097] The magnetizable particles can enter the gel-forming system in any way. They can be part of one or both of the compositions (A) and / or (B), or they can be added as part of another composition (C).

[0098] Preferably, the total amount of magnetizable particles, based on the total weight of the component (A), (B), or (C) containing the magnetizable particles, is at least 0.1 wt.% and is preferably in the range of 0.1 to 70 wt.%, particularly preferably in the range of 1 to 11 wt.%. If one of the magnetizable particles also represents a dye as described herein, this magnetizable particle is taken into account as such for the calculation of the total amount of magnetizable particles. Preferably, the magnetizable particle(s) is / are not a dye as described herein.

[0099] Components (A) and / or (B) and / or (C) (if any) and / or further components (if any) may contain additional components besides those already mentioned. To calculate the total number of magnetizable particles in the component containing these particles, as described above, the entire component (A), (B), or (C), or further component(s) (if any), including any components present in addition to those already mentioned, is used. If several components (A), (B), or (C) contain magnetizable particles, the total number of magnetizable particles in each component is preferably calculated separately for each component.

[0100] Additionally or alternatively, the concentration of the crosslinking agent(s) contained in component (B), based on the total volume of component (B), is preferably at least 0.1 mol / L and is preferably in the range of 0.1 to 3.0 mol / L, particularly preferably in the range of 0.1 to 1.0 mol / L. If one of the crosslinking agents also constitutes a dye as described herein, this crosslinking agent is taken into account as such for the calculation of the concentration of the crosslinking agent(s) contained in component (B).

[0101] Component (B) may contain other components besides the aforementioned crosslinking agents. To calculate the total quantity of the crosslinking agent(s) in component (B), the entire component (B) is used, including all other components present alongside the crosslinking agent(s).

[0102] Also described herein is a cross-linked gel consisting of or comprising one or more polymer(s), magnetizable particles and at least one dye, each as described or defined herein, wherein the cross-linked gel can be produced or manufactured by (i) Providing a component (A) comprising one or more crosslinkable polymers, preferably cationically crosslinkable polymers, and providing a component (B) comprising one or more crosslinking agents for crosslinking the crosslinkable polymer(s), and, optionally, providing a component (C) or further component(s) (if any), wherein the component (A) and / or the component (B) and / or, if any, the component (C) contains magnetizable particles, (ii) bringing the components (A) and (B) and optionally (C) and further components (if any) into contact under conditions that enable crosslinking of the crosslinkable polymer(s) to form a crosslinked gel, wherein component (A) and component (B) comprise at least one dye, the at least one dye being a dye as described herein.Preferably, the dye is selected from a combination of a large molecule, as described herein, and at least one label, as described herein, or a small dye, as described herein.

[0103] What was said above regarding the preferred embodiments of the cross-linked gel or the multi-component composition also applies here accordingly.

[0104] The present invention relates to a gel-forming composition as described herein for use in a method for removing unwanted particles from a patient.

[0105] The aforementioned removal of unwanted particles constitutes an invasive, surgical procedure. Purely cosmetic applications are not affected by this. The removal of unwanted particles is carried out in a targeted manner; the unwanted particles are deliberately removed from the body.

[0106] The particles to be removed (undesired particles) within the meaning of the present invention can be particles of any kind that must or can be removed from the patient's body from a medical perspective. Preferably, the term "particles to be removed" describes all particles to be removed (undesired particles) in a human or animal, whether self-generated, formed with external assistance, or immobilized by external introduction. Such particles can preferably be removed together.

[0107] Preferably, the particles are deposits, precipitation products, foreign bodies and / or fragments thereof, and / or splinters of endogenous structures. Deposits can be, in particular, urinary stones, salivary stones, gallstones, pancreatic stones, or kidney stones. Precipitation products are particles such as gallstones, which are a byproduct of bile. Foreign bodies can be, for example, mineral fragments, metal, plastic, or wood splinters that enter the body through injuries such as abrasions. The term "fragments thereof" refers to the aforementioned particle types and clarifies that these can be broken down into smaller parts or fragments before or during removal. It is also possible that only parts (fragments) are removed by the application, while the remaining fragments are removed in a subsequent step or process.Fragments of the body's own structures can arise during surgical procedures, such as the insertion or removal of implants, and can therefore include bone fragments or milling remnants. However, this also particularly includes fragments of other structures, such as cartilage tissue or tumor fragments, which may have arisen during a previous or concurrent surgical procedure. The term "fragment" encompasses structures of any shape and size.

[0108] Preferably, the removal of the unwanted particles is carried out as a process comprising the following steps: (i) Providing component (A) and (B) and, where applicable, (C) and any further component(s) (if any), (ii) Introducing component (A) and (B) and, where applicable, (C) and any further component(s) (if any) into the patient's body into an area containing particles to be removed, under conditions which, upon contact of component (A) with component (B), enable crosslinking of the crosslinkable polymer(s) to form a crosslinked gel that partially or completely encapsulates the particles to be removed, (iii) Removing the crosslinked gel together with the particles encapsulated therein from the area of ​​the patient's body.

[0109] Components (A), (B), and (C), if applicable, or further components (if any), can be introduced simultaneously or sequentially in step (ii). Components can also be mixed before being introduced into the body. Individual components can also be mixed before being introduced into the body, while other components are only brought into contact with one or more other components within the body. Components (A), (B), and (C), if applicable, or further components (if any), can also be introduced into the body simultaneously but separately, i.e., in distinct forms.

[0110] Preferably the method comprises the following further step, which takes place before step (ii): (i.2) Fragmenting one or more particles in the area of ​​the patient's body, so that two or more, preferably a plurality of fragments of the particle(s) are formed.

[0111] If this step is performed, the particles may already exist as fragments, which are then further broken down into fragments of their own by this step.

[0112] Preferably, the term "multiple fragments" includes at least 5, preferably at least 10, particularly preferably at least 15, and most preferably at least 20 fragments. If a particle that is fragmented in this step already exists as a fragment, the term "multiple fragments of the particle(s)" refers to the already fragmented particle and the fragments that result from it.

[0113] The process may additionally or alternatively include the following further step, which is preferably carried out before step (ii) and preferably after step (i.2) (if any): (i.3) joining two or more particles or two or more fragments, each as described above, or particles and fragments.

[0114] Preferably, the combined particles and / or fragments will continue to be referred to as particles and / or fragments.

[0115] Figure 1 (left) shows a pig kidney in which a gel according to the invention with dextran blue (white arrow) and a comparison gel with black dye (black arrow) were produced. Figure 1 (right) shows the removed gels, top: transparent, according to the invention; bottom: non-transparent, not according to the invention.

[0116] Figure 2 shows the pig kidneys used for the experiments (left) and a cut-open pig kidney (right).

[0117] Figure 3 Figure 1 shows a disposable syringe with a component (A) according to the invention described herein (left) and a disposable syringe with a non-inventive component (A) (right); in this state no difference can be seen.

[0118] Figure 4Figure 1 shows a pig kidney (left) in which a gel according to the invention was produced (center, white arrow) and removed (right). No staining of the kidney tissue is visible.

[0119] Figure 5 Figure 1 shows a pig kidney (left) containing kidney stones, in which a gel according to the invention was produced that surrounds the kidney stones (center, white arrow) and has been removed (right). The removed gel contains the kidney stones.

[0120] Figure 6 Figure 1 shows a pig kidney in which a non-inventive gel containing Brilliant Blue FCF was prepared (top left, white arrow: not yet solidified; top right, white arrow: solidified) and removed (bottom). The kidney tissue was stained (bottom; white arrows). The stain could not be removed by washing (bottom left) (bottom right; white arrow).

[0121] Figure 7Figure 1 shows a pig kidney (left) with kidney stones in which a non-inventive gel containing brilliant green BS (also called Green S) was prepared (left: not yet solidified). The kidney tissue was stained (right; white arrow, bracket).

[0122] Figure 8 Figure 1 shows a comparison of experiments with compositions according to the invention (bottom) and compositions not according to the invention (top). With the compositions not according to the invention, the kidney tissue stained (white arrow in each case); left: overview; right: magnification.

[0123] The present invention will now be explained in more detail using selected examples. Examples Example 1: Production of components (A), (B) and (C)

[0124] To prepare an exemplary component (A), 5 g of dextran blue and 4 g of sodium alginate are dissolved in 1 L of water.

[0125] To prepare an exemplary component (B), 10 g of calcium chloride dihydrate are dissolved in 1 L of water.

[0126] To prepare an exemplary component (C), a particle suspension containing 4 to 40 mM iron (0.35 to 3.5 g per liter) is prepared in water or physiological buffer (M. Geppert et al., Nanotechnology 22 (2011) 145101). This solution is added to A or B at a concentration of 1% to 50%. Example 2: Selection of different dyes

[0127] 2 g of alginate are dissolved in 200 mL of water and stained with various dyes. Component (B) is prepared according to Example 1 and mixed with component (A) to form a solidified gel.

[0128] The following colorants were used: yellow (riboflavin, E101ii, 29 mg / mL; quinoline yellow E104; curcumin E100; lutein E161b; tartrazine E102; carotenes E160; sunset yellow FCF E110), red (carmine, E120, 29 mg / mL), blue (brilliant blue, FCF E133, 2 mM), green (chlorophyllin, E141, 1 mM = 3 mg / mL), white (titanium dioxide, E171, 7 mg / mL), and colorless (no colorant).

[0129] It was found that colored gels could be produced using various dyes. Gels colored green or blue proved particularly advantageous, as they provided excellent contrast to organic tissue (renal mucosa) and were easily visible to the naked eye under laboratory lighting.

[0130] Next, the following dyes were also tested as described above: Brilliant Blue FCF, Dextran Blue, Methylene Blue, Sodium Copper Chlorophyllin, Titanium Dioxide, Trypan Blue, and Indigo Carmine. Of these dyes, only Dextran Blue falls within the list of stained molecules described in claim 1.

[0131] The experiments show that the biocompatibility of the colors varies depending on the concentrations used, that the colors can diffuse out of a hydrogel at different rates, that the colors used can have a negative impact on gel formation, and that they can also affect the dynamics of gel dissolution.

[0132] In particular, dextran blue and sodium copper chlorophyllin fully met the requirements. Example 3: Comparison of Brilliant Blue FCF, Patent Blue V, Indiqocarmine, anthocyanins and Dextran Blue

[0133] One component (A) was prepared according to Example 1 using dextran blue. Further components (A) were prepared according to Example 2, using Brilliant Blue FCF (Dr. Oetker baking and food coloring "blue"), Patent Blue V (E131), Indigo Carmine E(132) or Anthocyanins E(163) as colorants.

[0134] Component (B) was prepared according to Example 1 and stained with 0.023 g of riboflavin.

[0135] Both components were injected using disposable syringes ( Fig. 2 ) in pig kidneys ( Fig. 3 The gel was introduced, forming a solidified gel. The gels were removed and the pig kidneys were checked for staining.

[0136] It was shown that dextran blue met all requirements, enabled a transparently colored gel, and did not stain the surrounding kidney tissue ( Figs. 4 and 5), whereas the dyes Brilliant Blue FCF, Patent Blue V, Indigo Carmine and Anthocyanins were unsuitable because they stained the surrounding kidney tissue ( Figs. 6 and 7 Even after repeated washing, the dye could not be removed from the kidney tissue ( Fig. 6 ). Comparison shows that Dextran Blue was suitable, but Brilliant Blue FCF was not ( Fig. 8 ).

[0137] Of these dyes, only dextran blue falls under the list of colored molecules described in claim 1. Example 4: Application of a gel-forming system according to the invention for the removal of urinary stones

[0138] Access to the urinary tract lumen (e.g., the renal pelvis and calyces) is established either ureterorenoscopically (through the urethra, bladder, and ureter) or percutaneously (through a skin puncture in the flank). A special sheath (possibly a polymer tube with metal components) with an inner diameter of 3 to 9 mm is inserted. An endoscope is then advanced through the access sheath into the urinary tract lumen (e.g., the renal pelvis and calyces), the surgical area is inspected, and the urinary stone(s) are visualized. The urinary stone(s) are then fragmented, for example, using a holmium laser. The large and medium-sized fragments are removed with a stone retrieval instrument. Subsequently, a catheter is inserted via the endoscope (through the access point) and up to 3 mL, in particular 300 to 500 µL of a component (A) according to Example 1 is applied to the area of ​​the urinary tract (e.g. into the renal pelvis and calyces) in such a way that A removes the stones or the fragments of the stone or the kidney.The fragmented kidney stone(s) is surrounded or embedded. Then, up to 9 mL of component (B) according to Example 1 is applied near B, also via the catheter located in the endoscope. Active mixing of A and B is not necessary. Gel formation occurs within a few seconds to one minute. The catheter can be flushed with 0.9% NaCl solution between the application of A and B. A grasping instrument is then inserted through the access sheath of the surgical endoscope. The solidified gel is grasped with the instrument, either in one piece or in several pieces, and removed from the body by extraction. Example 5: Measuring the transmission T to determine transparency

[0139] Component (A) was prepared according to Example 1. Component (B) was prepared according to Example 1 and stained with 0.023 g of riboflavin. Components (A) and (B) were mixed together, resulting in the formation of a gel.

[0140] To measure the transmission T, the spectrum in the visible spectrum from 400-800 nm was recorded with a step size of 1 nm.

[0141] The substance to be measured is placed in standard cuvettes so that a layer thickness of 10 mm is achieved: The gel is cut to size, placed in the cuvette, and, if necessary, topped up with additional component (B) to remove any air bubbles. A layer thickness of 10 mm is achieved. Water, poured into the cuvette to achieve a layer thickness of 10 mm, was used as a reference.

[0142] The intensity of each measurement point of the gel is compared to the reference (water) and represented as a percentage of the reference (water = 100%).

[0143] The transmission T is determined as the arithmetic mean of all partial intensities between 400 and 800 nm in percent.

[0144] To determine the minimum transmission T values ​​necessary for transparency, a text with black letters was positioned behind each cuvette. Gels where the letters were still visible through the filled cuvette (= transparent gel) or no longer visible (= opaque gel) were measured for their transmission T.

[0145] In the gel according to the invention, consisting of components (A) and (B) as described above, the black letters were visible through the filled cuvette (transparent gel). Transmission T of the gel was measured at values ​​between 19 and 25% in several tests.

[0146] Further gels, not according to the invention, were prepared and placed in cuvettes as described above. However, the black letters were not visible through the filled cuvette (opaque gels). A transmission T between 12% and 15% was measured for these gels. It follows that gels with a transmission T of up to 15% are still opaque.

Claims

1. Gel-forming multi-component composition, preferably two-component composition, for forming a gel, the composition comprising or consisting of a component (A), comprising one or more cross-linkable, preferably cationically cross-linkable polymer(s), and a component (B), comprising one or more cross-linking agent(s) for cross-linking the cross-linkable polymers, wherein component (A) and component (B) comprise at least one dye, wherein the dye(s) in component (A) is / are different from the dye(s) in component (B), wherein the at least one dye provides a transparent staining of the gel and optionally of component (A) and / or component (B), wherein the at least one dye does not impair the cross-linking of the cross-linkable polymer(s) when contacting components (A) and (B), wherein the at least one dye does not leak from the formed gel, and wherein the at least one dye comprises or consists of a stained molecule selected from the group consisting of dextrans, polyehtlyene glycol, starch, gellans, polyelectrolytes such as poly-I-lysine and other poly-amino acids such as poly(orni-thine), poly(arginine), poly(histidine); polypeptides and proteins such as gelatin, as well as polysaccharides such as chitosan, alginates such as sodium alginate, poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly-2-hydroxy butyrate (PHB), polycaprolactone (PCL), poly(lactic-co-glycolic) acid (PLGA), protamine sulfate, spermidine, albumin, carrageenan, furcellarane, pectin, xanthan, hyaluronic acid, sodium carboxymethyl cellulose, heparin, heparane sulfate, cellulose derivatives or sodium carboxymethyl cellulose, chondroitine sulfate, dermatan sulfate and dextran sulfate, for use in a method for removing undesired particles from a patient.

2. Gel-forming composition for use according to claim 1, wherein the, one, more or all cross-linkable polymer(s) of component (A) is / are selected from the group consisting of polysaccharides, particularly dextrans and polysaccharides with deprotonized or deprotonizable functional groups, preferably carboxy groups, preferably dextrans and polysaccharides from the group of polyuronides, particularly preferably dextrans and polysaccharides from the group of alginates and pectins, and / or wherein the, one, more or all cross-linking agent(s) of component (B) is / are selected from the group consisting of bi- or tri-valent cations, preferably iron and calcium ions.

3. Gel-forming composition for use according to any of the preceding claims, wherein the concentration of the cross-linking agent(s) present in component (B), related to the total volume of component (B), is at least 0.1 mol / L and is preferably in the range of from 0.1 to 3.0 mol / L, particularly preferably in the range of from 0.1 to 1.0 mol / L.

4. Gel-forming composition for use according to any of the preceding claims, wherein component (B) has a neutral pH value, preferably a pH value in the range of from 6.5 to 8.0, particularly preferably a pH in the range of from 7.0 to 7.5.

5. Gel-forming composition for use according to any of the preceding claims, wherein the composition further comprises magnetisable particles, wherein the magnetisable particles are a component of component (A) and / or component of component (B), and / or wherein the composition further comprises component (C), which contains magnetisable particles, preferably wherein the magnetisable particles are selected from particles comprising or consisting of ferromagnetic element(s) such as iron, nickel, and cobalt, as well as alloys such as AlNiCo, SmCo, Nd2Fe14B, Ni80Fe20, NiFeCo, and / or their oxides such as iron oxide particles, particularly iron oxide particles from Fe3O4 and / or γ-Fe2O3.

6. Gel-forming composition for use according to claim 5, wherein the total amount of the magnetisable particles, related to the total weight of the components (A), (B), or respectively, (C) containing the magnetisable particles, is at least 0.1 wt.-% and is preferably in the range of from 0.1 to 70 wt.-%, particularly preferably in the range of from 1 to 11 wt.-%.

7. Gel-forming composition for use according to any of the preceding claims, wherein component (A), component (B), optionally component (C), and / or a further component (D) optionally present in the composition comprises one or more substances for improving the cross-linking of the cross-linkable polymer(s), particularly cross-linkers, preferably amino acids.

8. Gel-forming composition for use according to any of claims 1 to 7, wherein the particles are deposits, precipitation products, foreign particles and / or fragments thereof and / or splinters of endogenous structures.

9. Gel-forming composition for use according to claim 8, wherein the method comprises the following step(s): (i) providing component (A) and (B) as well as optionally (C), (ii) introducing components (A) and (B) as well as optionally (c) into the body of the patient in a area comprising particles to be removed, under conditions allowing a cross-linking of the cross-linkable polymer(s) under contact of component (A) with component (B), such that a cross-linked gel is formed, which partially or fully encloses the particle(s) to be removed, (iii) removing the cross-linked gel including the particles enclosed therein from the area of the body of the patient.

10. Gel-forming composition for use according to any of claims 8 or 9, wherein the method further comprises the step, which is performed temporally before step (ii): fragmenting one or more particle(s) in the area of the body of the patient, such that two or more, preferably a plurality of fragments of the particle(s) is / are obtained.