Hydrogel composition having improved dimensional stability for the treatment of vessel deformations

Abstract

The invention relates to a one-component medical composition in the form of a hydrogel which comprises silicate nanoparticles, water, a hydrogel-forming synthetic polymer and one or more bio-based proteins and / or polymers. Such a composition can be used as a flexible substitute for coil implants in the treatment of aneurysms, tumours or arteriovenous malformations, and due to its extensive biodegradability and improved tolerability, makes long-term anticoagulation therapy unnecessary. The present invention also relates to devices filled with such a composition, and kits which contain such compositions or devices as one component and a medical device, in particular in the form of a stent, as another component.

Description

[0001] Hydrogel composition with improved shape stability for the treatment of vascular malformations

[0002] Description

[0003] The invention relates to a one-component medical composition in the form of a hydrogel comprising silicate nanoparticles, water, a hydrogel-forming synthetic polymer, and one or more bio-based proteins and / or polymers, and is usable, for example, for the treatment of aneurysms, tumors, or arteriovenous malformations. The present invention further relates to devices filled with such a composition and to kits containing such compositions or devices as one component and a medical device in the form of an implant, in particular in the form of a stent, as a further component.

[0004] State of the art

[0005] Liquid embolic agents were introduced 15 years ago and are specially formulated materials designed to self-solidify in situ upon deployment. Once injected, liquid embolic agents undergo a transition to a solid state based on physicochemical mechanisms, including polymerization, precipitation, and cross-linking through ionic, covalent, or thermal processes. However, liquid embolic agents are associated with risks such as catheter entrapment (Qureshi et al., J. Vase. Interv. Neurol., 8:37 (2015)), recanalization rates of up to 36% (Cekirge et al., Neuroradiology, 48:113 (2006)), and leakage during injection, which can cause off-target embolization, angiotoxicity, and / or necrosis.

[0006] US 10,034,958 B2 discloses a pharmaceutical composition in the form of a hemostatic composition that is said to be suitable for wound treatment and the treatment of traumatic injuries. This composition described in US 10,034,958 B2 is a hydrogel composed of gelatin or a gelatin derivative, silicate nanoparticles, and deionized water. The gelatin derivative is, in particular, gelatin reacted with a reagent, whereby the gelatin is functionalized during the reaction, e.g., methacrylated, acrylated, or thiolated.

[0007] Altun, I., et al., Blood-Derived Biomaterial for Catheter-Directed Arterial Embolization. Advanced Materials, 2020. 32(52), pp. 2005-603, describe an embolic material for use with a catheter in the form of a mixture of platelet-rich fibrin from porcine blood, a nanoclay / nanosilicate, and ethiodite oil. The platelet-rich fibrin can be produced from fresh blood within a short time. The embolic material can then be used for the embolization of renal and iliac arteries to achieve rapid hemostasis in acutely injured vessels.

[0008] Hu, J., et al., Bioactive-Tissue-Derived Nanocomposite Hydrogel for Permanent Arterial Embolization and Enhanced Vascular Healing. Advanced Materials, 2020. 32(33): pp. 2002-611 describe a nanocomposite gel composed of decellularized extracellular matrix (ECM) from porcine heart, a nanoclay / nanosilicate, and lohexol for the embolization of renal and iliac arteries. It is suggested that the described ECM-based hydrogel has potential as a next-generation biofunctional embolic agent that can be used to successfully treat a variety of vascular diseases.

[0009] Gahawar, AK, et al., Shear-thinning nanocomposite hydrogels for the treatment of hemorrhage. J American Chemical Society, 2014. 8(10): pp. 9833–9842 describe an embolic gel material based on gelatin, nanosilicate, and water, in which the silicate nanoplatelets can induce blood coagulation by concentrating coagulation factors.

[0010] Baidya, A., et al., A Cohesive Shear-Thinning Biomaterial for Catheter-Based Minimally Invasive Therapeutics ACS Appl. Mater. Interfaces 2022, 14, 38, pp. 42852-42863, describe hydrogels based on gelatin and a platelet-shaped nanosilicate that exhibits shear-thinning properties and has been successfully tested for aneurysm filling in rat and pig models. Baidya was also able to demonstrate that the addition of PDDA (poly(diallyldimethylammonium chloride)) improves the cohesion of the composition without negatively affecting its injectability.

[0011] The approaches and hydrogels described in this prior art still require improvement with regard to the strength properties and dimensional stability that result after injection of the hydrogels into the desired location in the body. In particular, a hydrogel composition should solidify as much as possible after introduction into an aneurysm as a liquid / pasty embolizing agent to prevent dislocation ("washing away") of the introduced material due to blood flowing past the aneurysm. On the other hand, the hydrogel should be sufficiently "flowable" for transport through a narrow channel (catheter) so that the surgeon / user can deliver it to the desired location via the narrow catheter channel with acceptable force. This property is also referred to as shear thinning.

[0012] Other approaches to liquid embolic agents use a two-component mixture, for example, producing a hydrogel from alginate, ion-releasing glass, and glucono-delta-lactone (see, for example, Brady, SA et al., Optimisation of a novel giass-aiginate hydrogel for the treatment of intracranial aneurysms. Carbohydrate Polymers, 2017. 176: pp. 227-235). In this embolic agent, the glucono-delta-lactone hydrolyzes over time to form an acidic aqueous solution, while ions are released from the glass, inducing cross-linking of the alginate. However, a disadvantage of this system is that the components are mixed shortly before use, and the hydrogel must then be processed within a comparatively short time window.

[0013] Deepthi, S. et al., Alginate nanobeads interspersed fibrin network as in situ forming hydrogel for soft tissue engineering. Bioactive Materials, 2018. 3: pp. 194-200 describes a method for forming a liquid, time-hardening embolic agent, in which a first component consists of alginate microbeads with fibrinogen and a second component contains alginate microbeads and thrombin. This agent can be processed using a two-syringe injection system. However, these approaches are associated with the difficulty that two components must be mixed in relatively precise proportions or that there is only a narrow time window for processing.

[0014] Aneurysms are pathological bulges in the arteries that, if left untreated, carry the risk of rupture and subsequent life-threatening internal bleeding. Conventional aneurysm treatment involves stabilizing the artery with a microcatheter, and then filling the bulge with a platinum coil or metal basket that is expanded within the aneurysm. This causes a blood clot to form within the aneurysm, protecting the vessel wall and significantly reducing the risk of bleeding. However, one challenge with this type of treatment is the selection of the correct length prior to stent insertion. Furthermore, the use of platinum coils carries the risk of subsequent dislocation, which jeopardizes the success of the treatment.When inserting the platinum coil, a balloon remodeling catheter is often used to stop the blood flow, which can also be associated with undesirable side effects of the treatment.

[0015] Against this background, there is also a need for aneurysm treatment methods and suitable treatment methods that do not require the insertion of a platinum coil, but allow the aneurysm to be largely closed and eliminated through natural healing processes within the body. Where possible, stress on the vessel wall or restriction of blood flow during treatment should be avoided. The present invention addresses this need.

[0016] Description of the invention

[0017] In the investigations underlying this invention, it was found that an embolic agent formed from nanosilicate and water as well as a hydrogel-forming synthetic polymer and one or more bio-based proteins and / or polymers has suitable properties for use as a liquid embolic agent, and in particular can be injected into an aneurysm using a microcatheter with a very small diameter (e.g., ID 0.017" and smaller). The introduced bio-based protein and / or polymer can be, for example, albumin, but also other proteins such as mucin or silk fibroin, or it is possible to use a polysaccharide biopolymer such as hyaluronic acid, alginic acid salt, and carboxymethylcellulose.The bio-based protein and / or polymer, in combination with the hydrogel-forming synthetic polymer and the silicate nanoparticles, imparts favorable flow properties to the composition, allowing it to be delivered to a desired location, as well as high strength and dimensional stability after delivery, which can even withstand the flow velocity of blood flowing through veins. The embolic agent can be formulated as a storage-stable and directly usable component, which significantly facilitates its processing. Treatment can also be combined with the placement of a temporary stent, in which the stent is placed in front of the aneurysm and the embolic agent is injected into the aneurysm via a jailed microcatheter behind the stent.

[0018] According to a first aspect, the present invention accordingly relates to a one-component medicinal composition in the form of a hydrogel comprising silicate nanoparticles, water, a hydrogel-forming synthetic polymer and one or more bio-based proteins and / or polymers.

[0019] In the context of the application described here, "one-component" refers to the fact that the composition can be processed directly and without prior mixing of various stored components. In contrast to one-component mixtures produced by mixing conventional two-component compositions, the one-component composition is not subject to any relevant changes, e.g., in composition or viscosity, during storage.

[0020] In the context of the invention described here, "medicinal" refers to the fact that all components included in the composition are pharmaceutically safe and / or pharmaceutically effective, or are used in "pharmaceutical" quality. Accordingly, "medicinal" is not to be understood in the sense that components of the composition must interact with a receptor in the body in the sense of a (pharmaceutical) interaction, but rather it is intended that adverse effects on the body are avoided when the composition is introduced into it.

[0021] The silicate nanoparticles contained in the composition according to the invention are clays with silicate layers. Suitable silicate-coated clays include, but are not limited to, laponite, montmorillonite, saponite, hectorite, kaolinite, palygorskite, and sepiolite. Silicate nanoparticles can be produced, for example, by dialysis and similar purification techniques known in the art to remove any impurities. A particularly suitable nanosilicate for the present invention is lithium magnesium sodium silicate, which is commercially available, for example, as Laponite-XLG XR from Altana.

[0022] In a preferred embodiment, the overall charge of the silicate nanoparticles is negative. Furthermore, it is preferred if the silicate nanoparticles have a diameter of about 5 nm to about 60 nm, in particular a diameter of about 10 nm to about 50 nm, more preferably a

[0023] Diameter of about 15 nm to about 40 nm, more preferably a

[0024] Diameter of about 20 nm to about 40 nm and more preferably a

[0025] Diameter of approximately 20 nm to 30 nm. Furthermore, it is preferred for the silicate nanoparticles to have a thickness of approximately 0.5 nm to approximately 2 nm; silicate nanoparticles with a thickness of approximately 1 nm are particularly suitable. Due to such a size, the individual silicate nanoparticles in the stable state exhibit a "house of cards" structure, which aligns parallel under shear conditions (hydrogel liquefies) and from which, in the absence of shear stress, the original structure can instantly regress through the interaction of positively and negatively charged regions. This allows the composition to solidify again into a gel structure.

[0026] For the purposes of the invention specified herein, it is preferred if the silicate nanoparticles comprise or consist of silicate nanoplatelets. As used herein, the term "silicate nanoplatelets" refers to silicate layered clays characterized by a discotic charge distribution on the surface. Silicate nanoplatelets can be produced, for example, by dispersing and sonicating in an aqueous solution. The silicate nanoplatelets preferably have a positively charged edge and a negatively charged surface. The total charge of the silicate nanoplatelets is expediently negative. Silicate nanoplatelets preferred for the purposes of the invention have a diameter of about 5 nm to about 60 nm, for example, a diameter of about 10 nm to about 50 nm, a diameter of about 15 nm to about 40 nm, or a diameter of about 20 to about 30 nm.In some embodiments, the silicate nanoplatelets are about 0.5 nm to about 2 nm, and more preferably about 1 nm thick.

[0027] The proportion of silicate nanoparticles in the composition according to the invention is not subject to any relevant restrictions, provided that the constituents of other components of the composition allow the formation of a hydrogel. A suitable proportion of silicate nanoparticles in the medical composition according to the invention is in the range of about 0.5 to about 30 percent by weight, in particular in the range of about 0.5 to about 20 percent by weight, more preferably about 0.5 to about 10 percent by weight, even more preferably about 1.5 percent to about 7.5 percent by weight, even more preferably about 2.0 to about 6.0 percent by weight, and most preferably about 2.5 to about 5.5 percent by weight. These weight specifications refer to the total weight of the composition according to the invention, in which the weight of radiopaque agents is not taken into account.

[0028] The ratio of silicate nanoparticles to the one or more bio-based proteins and / or polymers in the composition according to the invention is not subject to any relevant restrictions; it is considered advantageous if the amount of bio-based proteins and / or polymers is less than the amount of silicate nanoparticles. The ratio of these components can range from 15:1 to 1.5:1 silicate nanoparticles / protein and / or polymer, with a ratio of 10:1 to 2:1 being particularly preferred.

[0029] The term "biobased" in relation to proteins and polymers in the context of the invention described here refers to proteins and polymers that are produced in biological systems (whereby the specification "biobased" refers to both the proteins and the polymers). In this way, "biobased proteins and / or polymers" contain a content of the carbon isotope "C14" that corresponds to that of living organisms (in contrast, for example, to synthetic polymers conventionally produced from fossil sources, which have a significantly lower C14 content). Biobased polymers are also usually carbohydrates ("polysaccharides"), which are preferred as biobased polymers in the context of the invention described here. Also usable as biobased polymers are "simple" derivatives of polysaccharides, i.e., those that are obtained by reacting a polysaccharide with one or two derivatization reagents (e.g.in the form of alkylating agents); an example of such a derivative is carboxymethylcellulose, which is obtained by reacting cellulose and chloroacetic acid.

[0030] The bio-based protein and / or polymer can generally be of animal origin, human origin, or recombinant origin. The term "recombinant" indicates that the bio-based protein and / or polymer is produced using genetic engineering techniques using non-human cells, but has a structure and composition similar to that of a human protein or polymer (e.g., human hyaluronic acid). A protein to be used as a bio-based protein can be modified to optimize its properties; it is preferred if the modification has no effect on the body's recognition of the protein as "human." In a preferred embodiment, the bio-based protein is a recombinantly produced bio-based protein.

[0031] In the context of the invention described here, the bio-based protein and / or polymer preferably has charged groups (i.e., cationic and / or anionic groups) under physiological conditions (pH approximately 7.4), via which the protein and / or polymer can interact with the silicate nanoparticles. Bio-based polymers preferably have anionic groups under physiological conditions, for example, in the form of carboxyl groups or sulfate groups. In proteins, charged groups are provided by charged side chains and / or polarized amide bonds under physiological conditions.

[0032] In the context of the invention specified here, preferred bio-based proteins and / or polymers in the form of proteins (including glycoproteins) are albumin, mucin, in particular type I, II or III, or silk fibroin. Preferred bio-based polymers in the form of polysaccharides or polysaccharide derivatives are hyaluronic acid (in particular recombinantly produced hyaluronic acid), alginic acid salt (alginate) and carboxymethylcellulose. A very particularly preferred bio-based protein is albumin, e.g. in the form of bovine serum albumin or (preferably recombinantly produced) human serum albumin, with the use of human over bovine serum albumin being preferred. Very particularly preferred in the context of the invention specified here is the use of a combination of albumin with another bio-based protein and / or polymer, for example mucin or alginic acid salt, or the use of alginic acid salt with silk fibroin.

[0033] In the context of the invention described herein, a combination of two bio-based proteins and / or polymers is preferred. For such a combination, it is further preferred if the bio-based proteins and / or polymers are present in a ratio ranging from 5:1 to 1:5, preferably 4:1 to 1:4, and more preferably 3:1 to 1:3. In this way, the effects mediated by the respective components are sufficiently realized.

[0034] The proportion of the bio-based protein(s) and / or polymer(s) in the one-component medicinal composition according to the invention is in most cases in the range of 0.1 to 3 wt.%. At a proportion of less than 0.1 wt.%, the bio-based protein and / or polymer may not impart sufficiently biocompatible and strengthening properties to the composition, while exceeding the upper limit is disadvantageous for cost reasons. A particularly preferred content range is 0.2 to 2 wt.%, and even more preferably 0.5 to 1.5 wt.%.

[0035] By adding the hydrogel-forming synthetic polymer, gel-forming and shear-thinning properties that cannot be sufficiently provided by the bio-based protein and / or polymer are compensated and increased or adjusted to the desired extent. For this purpose, it is necessary that the hydrogel-forming synthetic polymer is capable of forming gels in water alone. Suitable polymers are readily known to those skilled in the art, so that a suitable selection can be accomplished without significant difficulties. Preferred hydrogel-forming synthetic polymers that can be used in the context of the present invention are polyacrylamide, polylysine, polydiallyldimethylammonium chloride, polyvinylpyrrolidone, polyamines, polyimines, polyacrylic acid, and polymethacrylic acid.Polyamines refer in particular to saturated, open-chain, or cyclic organic compounds that contain terminal amino groups and secondary amino groups in the polymer chain. Polyimines refer to polymers of ethyleneimine (or aziridine).

[0036] A particularly preferred hydrogel-forming synthetic polymer in the context of the invention specified here is polyacrylamide, since this polymer is generally well tolerated in biological systems and the gel-forming properties of the polymer can be suitably controlled by the amount of initiator used to prepare the polymer. A particularly suitable polyacrylamide for the purposes of the present invention is a polyacrylamide with a number-average molecular weight Mn in the range from 200,000 g / mol to 100,000 g / mol and in particular in the range from 180,000 g / mol to 120,000 g / mol. The number-average molecular weight Mn is to be determined using a suitable method such as GPC and comparison with suitable standards. The polyacrylamide is used for this purpose in a form that forms a physical gel when mixed with water.

[0037] With regard to the proportion of the hydrogel-forming synthetic polymer, the one-component medicinal composition according to the invention is not subject to any relevant restrictions, provided that the compatibility of the composition with the organism into which the composition is introduced, mediated by the bio-based protein and / or polymer, is not disrupted, and on the other hand, the amount of hydrogel-forming synthetic polymer is sufficiently high that the desired increase in the strength of the hydrogel after application can be achieved. As a rough guide, the content of the hydrogel-forming synthetic polymer should not exceed 5 wt.%, based on the total weight of the composition, which is sufficient in most cases to achieve the desired effects. It is preferred if the hydrogel-forming synthetic polymer, in particular in the form of polyacrylamide, has a proportion in the range of 0.02 to 1 wt.-% in the medicinal composition, with a proportion in the range of 0.05 to 0.6 wt.% being more preferred and a proportion in the range of 0.08 to 0.3 wt.% being even more preferred.

[0038] Alternatively or additionally, the amount of hydrogel-forming synthetic polymer in the one-component medical composition according to the invention is such that the gel at a shear rate of 1 s -1 at 37°C has a viscosity in the range of 5 to 150 Pa s and preferably 8 to 100 Pa s. The corresponding viscosity can be determined in the context of the invention using a suitable measuring device such as a rheometer MCR 92 from Anton Paar with a plate-plate design and a gap of 500 pm by scanning a range for shear rates from 0.01 to 2000 s' 1 be determined, with the measured value being taken at a shear rate of 1 s -1is taken as viscosity. Viscosity here refers to the hydrogels themselves, i.e., without solid / undissolved particles, such as the contrast agents described below.

[0039] The ratio of the bio-based protein and / or polymer to the silicate nanoparticles in the composition according to the invention is not subject to any relevant restrictions and can, for example, be set in the range from about 1.0 to about 0.05. Preferred ratios of bio-based protein and / or polymer to silicate nanoparticles are, for example, in the range from 0.65 to 0.08, in particular 0.45 to 0.1.

[0040] In most cases, water represents the largest component in the compositions according to the invention. Water is preferably present in the composition in a proportion of at least 50 wt.%, based on the total weight of the composition (excluding X-ray visible component), and more preferably about 60 to 97 wt.%, even more preferably about 65 to 96 wt.%, and even more preferably 75 to 96 wt.%. The water is preferably used in the composition according to the invention as deionized water with an electrical conductivity of less than 2 pS / cm, more preferably equal to or less than 1 pS / cm, even more preferably 0.055 to 0.7 pS / cm, and even more preferably in the range of 0.055 to 0.4 pS / cm. The use of deionized water facilitates the stabilization of the silicate nanoparticles in the composition so that they do not aggregate and separate from the composition.In addition to the components described above, the composition according to the invention preferably contains a radiopaque contrast agent. Such a contrast agent allows the area into which the composition according to the invention has been introduced to be visualized by means of imaging techniques, thus allowing assessment of whether a sufficient amount of the composition has been introduced for treatment, for example, into an aneurysm sac.

[0041] Examples of radiopaque components suitable for inclusion in the composition according to the invention include metal particles, such as tantalum particles, gold nanoparticles, tungsten particles, or bismuth, or ethiodized oil, lanthanide-based contrast agents, barium sulfate, iron oxide nanoparticles, bismuth trioxide, zirconium dioxide, or iodine-containing contrast agents. Of these, tantalum particles are preferred as the radiopaque component in the one-component composition according to the invention. However, other radiopaque contrast agents known to the person skilled in the art may also be used, provided they are medically safe.

[0042] If the composition according to the invention contains metal particles, preferably in the form of tantalum particles, as an X-ray visible component, the Meta II particles can have any suitable size from 2 nm to 30 pm. The Meta II particles can have substantially the same size and / or a unimodal particle size distribution or a particle size distribution with multiple maxima. Examples of metal particles that can be present in a composition according to the invention include, without limitation, metal microparticles (e.g., metal particles with an average size of about 2 pm) and metal nanoparticles (e.g., Meta II particles with an average size of <25 nm).For metal particles, it is further preferred if they have an average particle size (determined as number-average particle size by means of microscopic analysis) of less than 0.5 to 10 pm, preferably 0.5 to 8 pm, more preferably 0.5 to 6 pm, even more preferably 0.5 to 4 pm, even more preferably 0.5 to 3 pm and most preferably from 0.5 to 2 pm.

[0043] The medicinal composition according to the invention can, for example,

[0044] Contain tantalum particles with an average size of about 2 pm, or

[0045] Tantalum particles with an average size of about 30 pm. In some cases, the composition of the invention may contain tantalum particles with an average size of about 2 nm.

[0046] The composition according to the invention may contain any amount of radiopaque contrast agent. For example, a composition according to the invention may comprise from about 2% (w / w) to about 30% (w / w) radiopaque contrast agent (e.g., from about 2% (w / w) to about 25% (w / w), from about 2% (w / w) to about 20% (w / w), from about 2% (w / w) to about 15% (w / w), from about 2% (w / w) to about 10% (w / w), from about 2% (w / w) to about 5% (w / w), from about 5% (w / w) to about 30% (w / w), from about 10% (w / w) to about 30% (w / w), from about 15% (w / w) to about 30% (w / w), from about 20% (w / w) to about 30% (w / w), from about 25% (w / w) to about 30% (w / w), from about 5% (w / w) to about 25% (w / w), about 10% (w / w) to about 20% (w / w), about 5% (w / w) to about 10% (w / w), about 10% (w / w) to about 15% (w / w), about 15% (w / w) to about 20% (w / w), or about 20% (w / w) to about 25% (w / w)).These weight specifications refer to the total amount of water, silicate nanoparticles, hydrogel-forming synthetic polymer, and one or more bio-based proteins and / or polymers. The proportion of the radiopaque contrast agent is therefore not included in the reference composition (unlike the weight specifications above). In most cases, the amount of radiopaque contrast agent will be adjusted to achieve the purpose of visualizing the three-dimensional area into which the composition has been introduced, but no excess of the radiopaque agent is included in the composition.

[0047] While not required for the therapeutic success of the composition disclosed herein, it is possible for it to additionally contain one or more additional pharmaceutical agents such as a steroid, an anti-inflammatory compound, or an immunosuppressant. Examples of steroids include corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Examples of anti-inflammatory compounds include aspirin, choline salicylates, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib. Examples of immunosuppressants include azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0048] The viscosity of the one-component medicinal composition is preferably adjusted within a range suitable for liquid embolics. In particular, the one-component medicinal composition according to the invention has a dynamic viscosity in the range of 5 to 150 Pa s (determined at 37°C), and preferably 8 to 100 Pa s. This viscosity is to be determined as indicated above. Due to the viscosity thus adjusted, a force in the range of approximately 40 to 100 N is required for a 1 mL syringe connected to a 2F microcatheter to generate a volume flow of approximately 0.5 ml / min. The dynamic viscosity can conveniently be measured using a plate-plate rheometer (Anton Paar).

[0049] The medicinal composition according to the invention can be prepared by any method known to the person skilled in the art, wherein it is preferred that the composition be prepared by a method comprising the following steps: i) combining silicate nanoparticles and water to form a first mixture; ii) adding hydrogel-forming synthetic polymer and one or more bio-based proteins and / or polymers to the first mixture to form the single-component medicinal composition.

[0050] The aforementioned first mixture, as well as the one-component medicinal composition resulting from the process, is preferably a stable dispersion according to the invention (i.e., storage-stable for a period of at least 6 months without separation of the dispersed components). One advantage of the compositions according to the invention is, as mentioned above, that they can be formulated as a single component and stored stably and sterilely for an extended period of time (as a "ready-to-use formulation"). This makes it possible to apply the composition directly from a storage container to the desired area of ​​application without the need for separate preparation steps. In a further aspect, the present invention accordingly relates to a dispensing device filled with the one-component medicinal composition according to the invention. Such a dispensing device (orThe dispensing device preferably comprises a reservoir region in which the one-component medical composition according to the invention is stored, an outlet, and an actuating unit, the actuation of which dispenses the hydrogel composition from the storage region via the outlet. The actuating device can, for example, be in the form of a piston which is displaceable in the reservoir region and whose position can be changed from the outside by applying pressure to the piston, while the one-component medical composition according to the invention is dispensed from the device via the outlet. A preferred embodiment of such a dispensing device is, for example, a syringe. The outlet is preferably closed, for which purpose the outlet can be equipped, for example, with a screw cap, a Luer screw closure, or another suitable closure system.

[0051] It is further preferred if the delivery device is equipped with or connected to a microcatheter with which the one-component medicinal composition according to the invention can be delivered into a delivery site (such as an aneurysm, an arteriovenous malformation (AVM), a tumor, or another vessel section to be occluded) that is only accessible via a very thin tube (as in a microcatheter). Such a microcatheter preferably has a catheter size of < 3F, in particular < 2.5 F, more preferably < 2 F. Alternatively or additionally, the microcatheter has an inner diameter of < 0.027", preferably < 0.021", preferably < 0.017", and more preferably < 0.013". The designation " stands for a length in inches, ie an inner diameter of 0.017" corresponds to an inner diameter of 0.4318 mm.

[0052] Alternatively or additionally, the device and the composition of the single-component medicinal composition are expediently adapted such that, in combination with the microcatheter, a force of < 80 N, more preferably < 60 N, and even more preferably < 50 N, must be applied to actuate the actuating unit (e.g., in the form of a syringe plunger) to achieve a delivery rate of 0.5 mL / min. For these force specifications, it is preferred if a syringe with a volume of 1 mL and a 2F microcatheter is used as the delivery device.

[0053] While the modification with a microcatheter provides the single-component medical composition of the invention in a form that is particularly suitable for the treatment of aneurysms, the composition of the invention can also be readily used for other purposes, such as the treatment of arteriovenous malformations (AVMs), tumors, or other vascular diseases.

[0054] As mentioned, the one-component medical composition according to the invention can be advantageously used for the treatment of aneurysms, wherein, within the scope of such treatment, a medical device is preferably placed in front of the aneurysm and the composition is introduced into the cavity of the aneurysm, which is covered by the medical device. According to a further aspect, the present invention therefore relates to a kit comprising a one-component medical composition according to the invention or a device filled with such a composition, as each of which was specified above, and a medical device in the form of an implant, in particular for use in a blood vessel.

[0055] In a particularly suitable embodiment, the medical device is designed in the form of an implant as a device for treating aneurysms and can be converted from a radially compressed state to a radially expanded state. The device (10) comprises a lattice structure (11) that is at least partially tubular and has a plurality of cell-forming webs (12) and at least one electrospun membrane (13) that covers the lattice structure (11) at least partially radially outward. Such a medical device is described in detail, for example, in DE 10 2018 105 679 A1.

[0056] The device (10) can additionally be used only temporarily and have a feed wire that can be used to position the device and that is non-detachably connected to the device. For the medical device to be used as a component of the kit, it is advantageous if it has an anti-adhesion layer for atraumatic movement in a blood vessel, wherein the anti-adhesion layer preferably forms at least a first electrospun fabric layer of the membrane (13). Alternatively, it is possible for the anti-adhesion layer to be a coating applied to the membrane (13). The anti-adhesion layer is preferably arranged radially outward and forms a closure of the membrane (13). The anti-adhesion layer can also be applied to the inside of the membrane.

[0057] With regard to the material, the non-stick layer is not subject to any relevant restrictions, provided that the material should impart sufficient non-stick properties. In one embodiment, the non-stick layer comprises fibers made of thermoplastic polyurethane (TPU), in particular based on aromatic polyether polyols, aliphatic polyether polyols, polycarbonate polyols, and / or aromatic polyether silicone, or is formed from such fibers. In a particularly preferred embodiment, the non-stick layer is designed as an electrospun polyurethane nonwoven / membrane. Alternatively, the non-stick layer can comprise fibers or be formed from fibers made of a thermoplastic fluoropolymer material, in particular polyvinylidene fluoride (PVDF), and / or fibers coated with a thermoplastic fluoropolymer material, in particular polyvinylidene fluoride (PVDF).Alternatively, the medical device may be equipped with an electrospun polymer nonwoven / membrane.

[0058] For the medical device in the form of an implant, it is further preferred if the membrane (13) has at least one slit (14) for forming a flap (15) that allows flow radially inwards and blocks flow radially outwards. In other words, the membrane is provided with at least one flap through which an external environment adjacent to the membrane can be fluidically connected to an inner lumen of the lattice structure. Particularly preferably, the membrane has a plurality of such slits, each forming a flap. The slit(s) are preferably introduced by means of laser cutting. The flap is preferably designed as a check valve. When filling in an embolic agent, e.g.The blood present in the aneurysm is displaced into the aneurysm sac via a jailed microcatheter whose tip is located in the aneurysm. In the invention described here, the embolic agent is formed by the inventive single-component medical composition. The blood present there is displaced into the aneurysm sac, causing the at least one valve to open into the inner lumen of the lattice structure and allow the blood to flow out. If the aneurysm sac is not filled, the at least one valve is moved radially outward by the blood flow in the blood vessel or in the inner lumen of the lattice structure, so that the valve blocks a passage and decouples the aneurysm from the blood flow.

[0059] At least one of the mentioned slits expediently has a dimension that is adapted for a connection and / or the insertion of a catheter having a catheter size of < 3F, preferably < 2.5 F, more preferably < 2 F. Alternatively or additionally, it is preferred if the dimension of the slit is adapted such that a catheter with an inner diameter of < 0.027", preferably < 0.021", more preferably < 0.017", and even more preferably < 0.013" can be suitably inserted, ie the dimension is designed such that such a catheter can be inserted into the slit, but the slit is not significantly larger than the outer diameter of this catheter, so that the composition supplied to the catheter cannot escape via a lateral gap.

[0060] To better illustrate the structure of a medical device as it can be used in the context of the invention described here, reference is made to Figures 1 and 2, which are briefly explained below:

[0061] Figure 1 shows a medical device 10 as a stent 10', which has a lattice structure 11 formed from interconnected webs 12. The webs 12 are coupled to one another at web connectors 18, wherein the web connectors 18 each connect four webs 12 to one another. It is possible for the web connectors 18 to connect three webs 12 to one another, or (only) two webs 12 to one another. This can be the case, for example, with short end lines. In Figure 1, the lattice structure 11 is rotationally symmetrical, at least in sections. The lattice structure 11 is radially compressible and independently radially expanding.

[0062] As can be seen in Figure 1, the lattice structure 11 is partially tubular. In other words, the lattice structure 11 has a tubular region 19. The interconnected webs 12 form cells 24 of the lattice structure 11. In particular, in the tubular region 19 of the lattice structure 11, four webs 12 each enclose a cell 24. Figure 1 shows that in the conical region 21, three of the webs 12 each form a cell 24. According to Figure 1, the lattice structure 11 of the stent 10' has a 6-cell design. In a circumferential direction of the lattice structure 11, six cells 24 are arranged in a row, forming a cell ring. In the tubular region 19, the lattice structure 11 comprises several such cell rings arranged axially along the central axis M. In cross-section, the lattice structure 11 therefore has a hexagonal shape, particularly in the tubular region 19.

[0063] Alternatively, the grid structure 11 may have a 3-cell design, a 9-cell design, or a 12-cell design. It is possible for the grid structure 11 to have a cell design with cell rings formed from more than twelve cells.

[0064] The tubular region 19 has a constant diameter along its entire length. However, different diameters of the lattice structure 11 are alternatively possible.

[0065] The lattice structure 11 has a central longitudinal axis M. Additionally, the lattice structure 11 comprises a conical region 21 that adjoins the tubular region 19. The lattice structure 11 has a proximal end 22 and a distal end 16. The distal end 16 is understood to be an end of the lattice structure 11 facing away from a user of the stent 10'. The proximal end 22 is understood to be an end of the lattice structure 11 facing toward the user of the stent 10'.

[0066] The conical region 21 extends from the tubular region 19 toward the proximal end 22. A transport wire can be coupled to the proximal end 22. The conical region 21 is part of the lattice structure 11 and is thus fluid-permeable, so that blood flow is maintained without restriction when the stent 10' is deployed. The distal end 16 is open. Essentially, the distal end 16 of the lattice structure 11 has the same diameter as the tubular region 19. In other words, the distal end 16 is part of the tubular region 19.

[0067] At the distal end 16 of the lattice structure 11, several X-ray-visible elements 17 are arranged. These can also be referred to as X-ray markers 17. The X-ray markers 17 are arranged, as shown in Figure 1, at one end of each pair of converging webs 12. In the present 6-cell design, an X-ray marker 17 is arranged at every other cell 24 of the cell ring. The arrangement of fewer than three or more than three X-ray markers 17 is possible. According to Figure 1, the X-ray markers 17 are sleeves 23 that are attached to the webs 12. Preferably, the sleeves 23 are crimped to the webs 12. Other attachment variants are possible.

[0068] In Figure 1, "DR" denotes the flow direction and 25 denotes the inner lumen of the lattice structure.

[0069] In Figure 1, the membrane 13 of the stent 10' is designed without a passage. In other words, the membrane 13 does not have any additional, separately introduced passage, for example, in the form of a slit, in addition to the pores.

[0070] In the stent 10' according to Figure 2, however, the membrane 13 is provided with a plurality of slits 14 which form flaps 15. As can be seen in Figure 2, the membrane 13 has slits 14 which are distributed over the membrane 13 and are incorporated into a wall, i.e. the wall of the membrane 13 is slitted. As shown in Figure 2, one of the slits 14 is formed within a cell 24 of the lattice structure 11 which spans the membrane 13. The slits 14 are thus distributed such that they are away from the webs 12. None of the slits 14 of the membrane 13 therefore overlaps one of the webs 12 of the lattice structure 11. A microcatheter can be guided through the slits, via which microcatheter the medical composition according to the invention can then be introduced into an area lying outside the membrane. In Figure 2, 26 denotes the outer tissue surface.The stent according to Figure 1 or 2 can be permanently connected to a delivery wire, and in this case, can be used as a temporary device, i.e., a device that remains in the blood vessel only to fill the aneurysm and is subsequently removed. Both configurations can be used as part of the kit according to the invention.

[0071] Also disclosed is a method for treating aneurysms, arteriovenous malformations, or tumors, in which the above-specified single-component medical composition is used to fill cavities by introducing the composition into the cavities. Within the scope of such a treatment, a medical device such as a stent is preferably placed in front of the cavity, and the composition is subsequently introduced into the cavity covered by the medical device, where any existing blood or other fluid is displaced by the introduced composition. In this way, the composition can be applied safely. Within the scope of such a treatment, a stent with a structure and a membrane as described above, particularly in connection with the explanation of the drawings, is expediently used.Within the scope of this method, in a preferred embodiment, a stent covered with electrospun nonwoven fabric can be used, which is positioned over an aneurysm as a temporary neck closure. The composition according to the invention can then be delivered directly via a jailed microcatheter inserted into the aneurysm. After filling and a waiting time of 15-30 minutes, the stent positioned in front of the aneurysm can then be removed again. The advantage of this embodiment of the method is that the distal vessels are supplied with blood while the aneurysm is being filled with the composition according to the invention. Once a soft thrombus has formed from the composition and stagnant blood, the stent can be removed again, thus avoiding the need for long-term subsequent anticoagulant treatment of the patient.

[0072] Furthermore, a use of the above-mentioned one-component medical composition according to the invention for filling cavities and in particular aneurysms in blood vessels is disclosed, wherein the composition is introduced into the cavities and displaces fluid present there, in particular in the form of blood.

[0073] The single-component medical composition according to the invention, when used to fill cavities, particularly in the form of aneurysms, has the particular advantage that the user can freely decide on the degree of filling without pre-selection. During filling, the process can be interrupted and continued at any time. When a syringe is used to introduce the hydrogel, there is no further flow of hydrogel when pressure is released from the syringe plunger, so that the applied amount can be controlled precisely and accurately. Compared to the use of precious metal coils, the medical composition according to the invention additionally promotes thrombus formation, and shorter treatment times and shorter fluoroscopy times are possible for both the user and the patient.

[0074] Since the medical composition according to the invention can be formulated exclusively with biobased materials, such formulations can be degraded in the body over time, thus eliminating the need for long-term anticoagulation therapy, unlike the treatment of aneurysms with coil implants. However, as with such implants, the aneurysm or blood vessel is mechanically closed to the desired degree.

[0075] In the following, the present invention is further illustrated by means of some examples, which, however, should not be construed as limiting the scope of the invention described here in any way: id to a silicate-

[0076] A mixture was prepared from 3.5 g of Laponit-XLG XR, 0.5 g of BSA (bovine serum albumin), and 0.5 g of mucin, which was then made up to 100 g with water. 20 g of tantalum particles were added to this mixture as a contrast agent (reference composition). A composition was prepared analogously to the reference composition, in which 0.25 g of water was replaced by the same amount of polyacrylamide (according to the invention). The respective compositions were filled into a plastic screw-cap jar. After shaking the jar, the reference composition wetted the entire inner surface of the jar (see Fig. 3 B). In contrast, with the inventive composition (Fig. 3 A), a solid, coherent gel of the composition had formed, which adhered "in one piece" to the bottom of the jar.

[0077] Example 2: Various compositions according to the formulations given in Table 1 below were prepared analogously to Example 1: Laponit = Laponit-XLG XR; A = alginate; HAS = human serum albumin; SF = silk fibroin; M = mucin;

[0078] To determine the extrusion force, the hydrogel was filled into a 1 ml syringe and connected to a 2F microcatheter. The syringe was then clamped into a testing machine, and the hydrogel was extruded from the syringe at a defined speed (26 and 52 mm / min, respectively). These speeds correspond to a discharge volume of 0.5 ml and 1 ml / min, respectively. The determined force, including the standard deviation, is shown in Table 1.

[0079] With all compositions E1 to E4, extrusion forces were achieved that were within a range suitable for handling by a human operator. All compositions exhibited a viscosity at a shear rate of 1 s' 1 at 37°C in the range of 10 to 50 Pa s and were dimensionally stable.

[0080] Example 3:

[0081] A hydrogel composition containing 3.5 wt% Laponite-XLG XR, 0.5 wt% human serum albumin, 0.5 wt% mucin, 0.1 wt% polyacrylamide, and 20 wt% tantalum parti-ketone as a contrast agent was filled into a 1 ml syringe and connected to a 2F microcatheter. A plastic model of a branched blood vessel system with a main artery and branching tributary (Y-shaped) and a protrusion in the area of ​​the main artery, simulating an aneurysm, was used as the test construct. Blood flow was simulated with phosphate-buffered saline at a flow rate of 100 ml / min through the main artery and 50 ml / min through the tributary. The pressure in the model was set to 120 / 80 mm Hg.

[0082] A microcatheter was then inserted into the protrusion, followed by a stent (5.5 x 35 mm) positioned in front of the protrusion. The hydrogel composition was then pressed into the protrusion via the microcatheter. The hydrogel composition extruded from the catheter as a solid, coherent strand, filling the protrusion but not leaking into the adjacent vein. After the protrusion was filled, the microcatheter could be withdrawn from the filled cavity.

[0083] Based on the model experiment, it was shown that the described hydrogel composition has suitable properties for use in filling aneurysms in blood vessels.

[0084] List of reference symbols

[0085] 10 Medical Device

[0086] 10' stent

[0087] 11 tubular lattice structure

[0088] 12 bridges

[0089] 13 Membran

[0090] 14 slot

[0091] 15 flap

[0092] 16 distal end

[0093] 17 X-ray marker elements

[0094] 18 web connectors

[0095] 19 tubular area

[0096] 21 conical area

[0097] 22 proximal end

[0098] 23 sleeve

[0099] 24 cells

[0100] 25 inner lumens of the lattice structure

[0101] 26 external fabric area

[0102] M central axis

[0103] DR flow direction

Claims

Claims 1. A single-component medicinal composition in the form of a hydrogel comprising silicate nanoparticles, water, a hydrogel-forming synthetic polymer and one or more bio-based proteins and / or polymers.

2. One-component medical composition according to claim 1, characterized in that the one or more bio-based proteins and / or polymers are selected from the group comprising proteins, preferably in the form of albumin, mucin or silk fibroin, and polysaccharide biopolymers and derivatives thereof, preferably in the form of hyaluronic acid, alginic acid salt and carboxymethylcellulose.

3. A single-component medicinal composition according to claim 1 or 2, characterized in that the bio-based protein and / or polymer comprises a recombinantly produced protein, preferably a recombinantly produced protein and a bio-based polymer, more preferably with a weight ratio in the range of 3:1 to 1:

3.

4. One-component medical composition according to at least one of claims 1 to 3, characterized in that the hydrogel-forming synthetic polymer is selected from the group comprising polyacrylamide, polylysine, polydiallyldimethylammonium chloride, polyvinylpyrrolidone, polyamines, polyimines, polyacrylic acid, and polymethacrylic acid, and is preferably in the form of polyacrylamide.

5. One-component medical composition according to at least one of the preceding claims, characterized in that the hydrogel-forming synthetic polymer, in particular in the form of polyacrylamide, in the medical composition makes up a proportion in the range of 0.02 to 1 wt.%, preferably a proportion in the range of 0.05 to 0.6 % by weight and more preferably in the range of 0.08 to 0.3 % by weight, and / or that the amount of hydrogel-forming synthetic polymer is such that the gel at a shear rate of 1 s -1 at 37°C has a viscosity in the range of 5 to 150 Pa s and preferably 8 to 100 Pa s.

6. A single-component medicinal composition according to at least one of the preceding claims, characterized in that the ratio of bio-based protein and / or polymer to silicate nanoparticles is about 1.0 to about 0.05, preferably 0.65 to 0.08 and more preferably 0.45 to 0.

1.

7. One-component medicinal composition according to at least one of the preceding claims, characterized in that the silicate nanoparticles comprise silicate nanoplatelets, preferably with a diameter in the range of 5 to 60 nm, preferably 10 to 50 nm, more preferably 15 to 40 nm and even more preferably 20 to 30 nm.

8. A single-component medicinal composition according to claim 7, characterized in that the silicate nanoplatelets comprise a positively charged edge and a negatively charged surface and / or are based on lithium magnesium sodium silicate.

9. One-component medical composition according to at least one of the preceding claims, characterized in that the hydrogel further contains an X-ray visible component, which is preferably selected from the group comprising tantalum particles, gold nanoparticles, ethiodized oil, lanthanide-based contrast agents, tungsten particles, iodine-containing contrast agents, iron oxide nanoparticles, bismuth trioxide, zirconium dioxide, barium sulfate and bismuth, wherein tantalum particles are particularly preferably used as the X-ray visible component.

10. A process for the preparation of a one-component medicinal composition, in particular a one-component medicinal A composition according to any one of claims 1 to 9, comprising the steps of: iii) combining silicate nanoparticles and water to form a first mixture; iv) adding hydrogel-forming synthetic polymer and one or more bio-based proteins and / or polymers to the first mixture to form the single-component medicinal composition.

11. A device filled with a single-component medicinal composition for dispensing the same, the device comprising a hydrogel composition according to any one of claims 1 to 9, which is held in a reservoir region of the device, an outlet and an actuating unit, by the actuation of which the hydrogel composition is dispensed from the holding region via the outlet.

12. Device according to claim 11, characterized in that the device is designed as a syringe and / or with a microcatheter for introducing the hydrogel composition into an aneurysm sac, an arteriovenous malformation, a tumor or another vessel section to be closed, wherein the microcatheter preferably has a catheter size of < 3F, in particular < 2.5 F, more preferably < 2 F and / or an inner diameter of < 0.027", preferably < 0.021", preferably < 0.017" and more preferably < 0.013", and / or wherein the device is adapted such that, in combination with the microcatheter, for the realization of a delivery rate of 0.5 mL / min, based on a 1 mL syringe at a 0.017" catheter inner lumen, a force for actuating the actuating unit of < 80 N, preferably < 60 N, and more preferably < 50 N must be spent.

13. A kit comprising a composition according to any one of claims 1 to 9 or a device filled with such a composition according to claim 11 or 12, and a medical device in the form of an implant, in particular for use in a blood vessel.

14. Kit according to claim 13, characterized in that the medical device is designed for the treatment of aneurysms and can be converted from a radially compressed state into a radially expanded state, wherein the device (10) comprises an at least partially tubular lattice structure (11) with a plurality of cell-forming webs (12) and at least one electrospun membrane (13) which covers the lattice structure (11) at least partially radially outwardly.

15. Kit according to claim 14, characterized in that the membrane (13) of the medical device has at least one anti-adhesive layer for atraumatic movement in a blood vessel.

16. Kit according to claim 15, characterized in that the membrane (13) has at least one slit (14) for forming a flap (15) which allows flow radially inwards and blocks flow radially outwards.

17. Kit according to one of claims 13 to 16, characterized in that the medical device is equipped with an electrospun polymer nonwoven / membrane, preferably with a polyurethane nonwoven / membrane.

18. Kit according to one of claims 13 to 17, characterized in that the medical device can be delivered with a catheter size < 3F, preferably < 2.5 F, more preferably < 2 F and / or with a catheter with an inner diameter < 0.027", preferably < 0.021" and more preferably < 0.017".

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