Hydrogels for treating inflammatory bowel diseases

Abstract

The present invention relates to therapeutic compositions containing a hydrogel, in particular hydrogel particles, and optionally at least one pharmaceutically acceptable carrier for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient.

Description

[0001] DESCRIPTION

[0002] Hydrogels for the treatment of inflammatory bowel diseases

[0003] The present invention relates to therapeutic compositions containing a hydrogel, in particular hydrogel particles, and at least one pharmaceutically acceptable carrier for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient.

[0004] Inflammatory diseases pose a serious threat to the health of both human and animal patients. The spectrum of such diseases ranges from acute to chronic inflammation of various tissue and organ systems. Unlike, for example, superficial skin inflammations or intra-articular inflammations, inflammations of the gastrointestinal tract present a particular challenge for the development of promising therapeutics due to the comparatively more difficult accessibility and the fluctuating aqueous environment, in which the intestinal flora and the respective nutrient intake are significant influencing factors.

[0005] Inflammatory bowel diseases (IBD) are chronic inflammations of the gastrointestinal tract, particularly the intestines. The most common forms of IBD include Crohn's disease and ulcerative colitis. A rarer form is indeterminate colitis. Worldwide, an increasing number of people are affected by these diseases, with roughly equal rates of women and men. The causes of IBD are not yet fully understood. Current understanding suggests they are multifactorial diseases in which various factors may play a role, such as genetic predisposition, smoking, diet, hygiene, and the composition of the gut flora (microbiome). IBD is not curable. Currently, only the symptoms can be treated, with varying degrees of success from person to person.

[0006] The use of currently available medications, such as aminosalicylates and their precursors, steroids, or immunosuppressants, is often hampered by significant side effects and sometimes insufficient efficacy. Therefore, therapies with fewer side effects and more effective than those currently available are needed.

[0007] The use of heparin for the parenteral treatment of IBD is also known. Pharmaceutical compositions for the treatment of inflammatory bowel diseases, which use heparin or heparin derivatives and are suitable for oral administration, are known from WO2023097925A1 and W02003049721A1.

[0008] The proposed or implemented treatment approaches still have room for improvement with regard to their effectiveness, patient compliance, and side effect profile.

[0009] The technical problem underlying the present invention is to overcome the disadvantages of known methods for the treatment of inflammatory bowel diseases and of the therapeutic compositions used in these methods. In particular, the technical problem of the present invention is to provide a therapeutic composition that leads to improved treatment of inflammatory bowel diseases, especially one that is capable of treating both symptomatic and causal inflammatory bowel diseases, wherein the composition should ideally have no or few side effects while maintaining high efficacy and patient compliance.

[0010] The present invention solves the underlying technical problem in particular through the subject matter of the independent claims as well as the teachings of the dependent claims and the present description.

[0011] The invention relates to a therapeutic composition for the treatment of inflammatory bowel diseases comprising at least one hydrogel, wherein the hydrogel has at least one polyionic polymer component which is covalently linked to at least one uncharged polymer component and / or, in particular, a non-polymeric crosslinking component to form a network, and wherein the at least one polyionic polymer component has sulfate or sulfonate groups.

[0012] The invention relates in particular to a therapeutic composition comprising a hydrogel for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient, wherein the hydrogel has at least one polyionic polymer component which is covalently linked to at least one uncharged polymer component and / or a non-polymeric crosslinking component to form a network, wherein the at least one polyionic polymer component has sulfate or sulfonate groups and wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

[0013] The invention relates in particular to a therapeutic composition comprising a hydrogel for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient, wherein the hydrogel has at least one polyionic polymer component which is covalently linked to at least one uncharged polymer component and / or a non-polymeric crosslinking component to form a network, wherein the at least one polyionic polymer component has sulfate or sulfonate groups and wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component.

[0014] In a preferred embodiment, the hydrogel is in the form of dried hydrogel, for example as dried hydrogel particles. In this form, the hydrogel can be applied without the addition of pharmaceutically acceptable carriers, for example as granules of dried hydrogel particles.

[0015] In a preferred embodiment, the composition comprises at least one pharmaceutically acceptable carrier.

[0016] The invention therefore preferably relates to a therapeutic composition for the treatment of inflammatory bowel diseases comprising at least one hydrogel and at least one pharmaceutically acceptable carrier, wherein the hydrogel has at least one polyionic polymer component which is covalently linked to at least one uncharged polymer component and / or, in particular, a non-polymeric crosslinking component to form a network, and wherein the at least one polyionic polymer component has sulfate or sulfonate groups.

[0017] The invention relates to a therapeutic composition for the treatment of inflammatory bowel diseases, comprising at least one hydrogel and optionally at least one pharmaceutically acceptable carrier, wherein the hydrogel has at least one polyionic polymer component covalently linked to at least one uncharged polymer component or a non-polymeric crosslinking component or to both components, forming a network, and wherein the at least one polyionic polymer component has sulfate or sulfonate groups. These sulfate or sulfonate groups are present in the hydrogel as free, i.e., unbound and ionizable, and in particular negatively charged under physiological conditions, groups.These sulfate or sulfonate groups also exist in the composition according to the invention, and in particular also in the presence of the pharmaceutically acceptable carrier, as free, i.e. unbound and ionizable, and in particular negatively charged groups under physiological conditions.

[0018] In a preferred embodiment, the invention therefore relates to a therapeutic, in particular anti-inflammatory and anti-inflammatory, composition comprising at least two elements. These two elements are, on the one hand, the at least one hydrogel and, on the other hand, the at least one pharmaceutically acceptable carrier.

[0019] In a preferred embodiment, the therapeutic composition comprises exactly one hydrogel, i.e., a single hydrogel, wherein the hydrogel has at least one polyionic polymer component which is covalently linked to at least one uncharged polymer component and / or, in particular, a non-polymeric crosslinking component to form a network, and wherein the at least one polyionic polymer component has sulfate or sulfonate groups.

[0020] The hydrogel used according to the invention comprises at least two components, namely at least one, in particular exactly one, polyionic polymer component, in particular a polyanionic polymer component, in particular a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-comaleic acid) component, or a glycosaminoglycan (GAG) component and at least one, in particular exactly one, non-polymeric crosslinking component or, optionally, at least one, in particular exactly one, uncharged polymer component, in particular a polyethylene glycol (PEG) component.

[0021] In one embodiment, a second or further polyionic polymer component may be present in the composition or, in particular, in the polymer network of the hydrogel, wherein this second or further polyionic polymer component may or may not have sulfate or sulfonate groups. The hydrogel thus comprises at least one polyionic polymer component.At least one polymer component, preferably exactly one polymer component, of which at least one polyionic polymer component is covalently linked to at least one uncharged polymer component and / or a non-polymeric crosslinking component to form a network, wherein the at least one polyionic polymer component linked to form a network has sulfate or sulfonate groups and is preferably a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

[0022] In a preferred embodiment of the composition according to the invention, the at least two elements preferably provided are present in a mixed form without forming a chemical bond with each other; in particular, the hydrogel is not covalently or non-covalently connected with the pharmaceutically acceptable carrier, but the hydrogel is merely in physical mixture with the at least one pharmaceutically acceptable carrier.

[0023] In a preferred embodiment of the composition according to the invention, the at least two elements preferably provided are present in a chemically covalently bonded form, i.e., they enter into a chemical covalent bond with each other, in particular the hydrogel is chemically covalently bonded with the pharmaceutically acceptable carrier, wherein the sulfate or sulfonate groups do not participate in the chemically covalent bond, but are present as free and ionizable groups, in particular negatively charged under physiological conditions.

[0024] In a preferred embodiment of the composition according to the invention, the at least two elements preferably provided are present in a chemically non-covalently bonded form, i.e., they form a non-covalent bond with each other; in particular, the hydrogel is non-covalently bonded with the pharmaceutically acceptable carrier.

[0025] In a particularly preferred embodiment, the at least one pharmaceutically acceptable carrier is a solid, semi-liquid, or liquid carrier. In a particularly preferred embodiment, the hydrogel is in the form of hydrogel particles or in the form of a non-particulate hydrogel.

[0026] In a particularly preferred embodiment, the hydrogel is in the form of hydrogel particles.

[0027] In a particularly preferred embodiment, the hydrogel is present in a mixture with the pharmaceutically acceptable carrier, or in a covalently or non-covalently carrier-bound form. Thus, in one embodiment, the hydrogel can be covalently or non-covalently bonded to the at least one pharmaceutically acceptable carrier, in particular to a semi-liquid or solid carrier.

[0028] In a particularly preferred embodiment, the hydrogel, which is covalently or non-covalently bonded to the at least one pharmaceutically acceptable carrier, can be converted into particulate form after its manufacture, i.e., exist in particulate form. Such a therapeutic composition is also referred to here as a composition containing a "particulate carrier-bound hydrogel".

[0029] In a particularly preferred embodiment, the hydrogel, which is covalently or non-covalently linked to the at least one pharmaceutically acceptable carrier and is present in particulate form, can be mixed with another pharmaceutically acceptable carrier, in particular with a liquid carrier.

[0030] In a particularly preferred embodiment, the hydrogel, which is in covalently or non-covalently carrier-bound form, particularly in particulate or non-particulate form, is in the form of a coating of a solid pharmaceutically acceptable carrier.

[0031] In a particularly preferred embodiment, the coating can be a coating of the solid pharmaceutically acceptable carrier with hydrogel particles.

[0032] In a particularly preferred embodiment, the coating can be a coating of the solid, pharmaceutically acceptable carrier with a non-particulate hydrogel. In a particularly preferred embodiment, the therapeutic composition is in the form of a suspension.

[0033] In a particularly preferred embodiment, the therapeutic composition comprises the hydrogel, in particular hydrogel particles, together with at least one liquid pharmaceutically acceptable carrier in the form of a suspension.

[0034] In a particularly preferred embodiment, the therapeutic composition comprises at least two pharmaceutically acceptable carriers, wherein the hydrogel is present in a mixture with at least one solid or semi-solid carrier and this mixture is present in a liquid carrier, in particular in the form of a suspension.

[0035] In a particularly preferred embodiment, the therapeutic composition comprises at least two pharmaceutically acceptable carriers, wherein the hydrogel is covalently or non-covalently bound to a solid or semi-solid carrier and the carrier-bound hydrogel is present in a liquid carrier, in particular as a particulate carrier-bound hydrogel, especially in the form of a suspension.

[0036] In a particularly preferred embodiment, the suspension is a suspension of hydrogel particles in a liquid pharmaceutically acceptable carrier or a suspension of particulate carrier-bound hydrogel in a liquid pharmaceutically acceptable carrier.

[0037] In a particularly preferred embodiment, the therapeutic composition is in the form of an encapsulated or non-encapsulated suspension.

[0038] In a particularly preferred embodiment, the therapeutic composition is in the form of encapsulated or non-encapsulated, rarely dried, hydrogel particles.

[0039] In a particularly preferred embodiment, the therapeutic composition is in the form of encapsulated or non-encapsulated, rarely swollen hydrogel particles.

[0040] According to the invention, in one embodiment, the at least one uncharged polymer component is covalently bonded to the at least one polyionic polymer component, in particular directly or by means of a crosslinking component. The uncharged polymer component and the polyionic polymer component covalently bonded to it thus together, optionally with the additional presence of the non-polymeric crosslinking component, form the hydrogel by creating a network.

[0041] According to a further embodiment of the invention, the at least one non-polymeric crosslinking component is covalently bonded to the at least one polyionic polymer component, in particular directly. The at least one non-polymeric crosslinking component and the polyionic polymer component covalently bonded to it thus together form the hydrogel by creating a network.

[0042] The invention therefore provides in particular that the at least one polyionic polymer component is directly covalently connected or via at least one crosslinking component to the at least one uncharged polymer component to form a network, or, in a further embodiment, that the at least one polyionic polymer component is connected to the at least one crosslinking component to form a network.

[0043] The invention therefore provides in particular that the at least one polyionic polymer component is directly covalently connected to the at least one uncharged polymer component to form a network.

[0044] The at least one polyionic polymer component (here also referred to as the charged polymer component or building block) has, according to the invention, sulfate or sulfonate groups, in particular sulfate groups. According to the invention, these sulfate or sulfonate groups are not covalently bonded to the uncharged polymer component, in particular not to the polyethylene glycol component, or to the pharmaceutically acceptable support. According to the invention, these sulfate or sulfonate groups are not covalently bonded to the non-polymeric crosslinking component.

[0045] Accordingly, the sulfate and sulfonate groups are preferably present in the polymer network in the form of anionic groups and are thus able to interact with cationic groups due to their electrical charge, thereby binding and releasing positively charged molecules, particularly chemokines. The PSS-MA or glycosaminoglycan preferably used to produce the polymer network also contains carboxylate or carboxyl groups, which primarily serve to establish covalent bonds with other components of the polymer network, especially with the uncharged polymer component and / or the non-polymeric crosslinking component. Thus, at least some carboxylate or carboxyl groups of the glycosaminoglycan or PSS-MA component are not free groups but participate in the covalent bonding of components of the polymer network to one another.

[0046] Without being bound to theory, the sulfate or sulfonate groups in the hydrogel are preferably present in a substantially deprotonated form. These deprotonated sulfate or sulfonate groups can undergo charge compensation or form charge interactions with counterions and / or proteins. Sulfate or sulfonate groups can therefore form reversible bonds with soluble molecules via non-covalent interactions, particularly charge interactions, especially when they come into contact with biofluids or tissues, which preferably contain soluble molecules. In some embodiments, the sulfate or sulfonate groups can be present in a protonated form.

[0047] The polyionic polymer used for the production of the hydrogel preferably has, in addition to the sulfate or sulfonate groups, at least two further functional groups, in particular selected from the group consisting of amino groups, thiol groups, maleimide groups, vinyl sulfone groups, acrylate groups, carboxyl groups, and combinations thereof, especially carboxyl or maleimide groups, with which the polyionic polymer is covalently linked to the uncharged polymer used for the production of the hydrogel and / or the non-polymeric crosslinking component, so that a hydrogel is formed which has at least one polyionic polymer component that is crosslinked via at least one uncharged polymer component or at least one non-polymeric crosslinking component, thus forming a network. The at least two functional groups of the polyionic polymer can be the same or different, in particular they are the same.

[0048] In a preferred embodiment of the present invention, the uncharged polymer used to produce the hydrogel has a functional group, in particular an end group, selected from the group consisting of amino groups, thiol groups, maleimide groups, vinyl sulfone groups, acrylate groups, carboxyl groups, and combinations thereof, at each free end of the polymer. The uncharged polymer is thus functionalized, in particular end-group functionalized. Via these reactive functional groups, in particular end groups, the at least one uncharged polymer is preferably linked to the at least one polyionic polymer, thus forming the network of the hydrogel. The at least two functional groups of the uncharged polymer can be the same or different; in particular, they are the same.

[0049] The uncharged polymer can be linear or branched, in particular multi-armed, meaning that in a preferred embodiment of the present invention it consists of several branched chains. In particular, the uncharged polymer is star-shaped, i.e., multi-armed with a center from which several, in particular four or eight, in particular four, in particular of equal length, chains branch off from corresponding repeating units.

[0050] In preferred embodiments of the present invention, the non-polymeric crosslinking molecule used to produce the hydrogel has at least two functional groups, in particular end groups, selected from the group consisting of amino groups, thiol groups, maleimide groups, vinyl sulfone groups, acrylate groups, carboxyl groups, hydroxylated aromatic groups, and combinations thereof. The non-polymeric crosslinking molecule is thus functionalized, in particular end-group functionalized. Via these reactive functional groups, in particular end groups, the at least one non-polymeric crosslinking molecule is preferably linked to the at least one polyionic polymer, thereby forming the network of the hydrogel. The at least two functional groups of the non-polymeric crosslinking molecule can be the same or different; in particular, they are the same.

[0051] The therapeutic composition of the present invention is characterized in particular by its particularly advantageous suitability for the treatment of inflammatory bowel diseases.

[0052] The composition according to the invention showed high efficacy after application in experimental animals without any side effects. The therapeutic composition according to the invention can advantageously bind pro-inflammatory cytokines, particularly chemokines such as interleukin-8 (IL-8), in the gastrointestinal tract and thus prevent chemokine-induced immune cell migration. The hydrogel used according to the invention exhibits a sequestering effect in the form of binding pro-inflammatory cytokines, which leads to a reduction and prevention of inflammatory processes in the tissue of the gastrointestinal tract. The ability provided by the invention to bind, i.e., sequester, pro-inflammatory chemokines and thus exert an anti-inflammatory effect therefore allows for the highly advantageous treatment of IBD in situ.This is particularly surprising given the unique aqueous environment of the gastrointestinal tract with its wet epithelium, which is characterized by the presence of large quantities of nutrients and microbes of the intestinal flora. The hydrogel used according to the invention, and in particular the hydrogel particles used according to the invention, can be administered precisely to the site of inflammation and—unlike therapeutics based on chemical substances—do not spread undesirably throughout the body, which can lead to side effects and reduced efficacy. Advantageously, the hydrogel, due to its negative charge, can adhere specifically to inflamed, positively charged tissue in the gastrointestinal tract.The hydrogel used according to the invention and the composition containing this hydrogel can particularly preferably be formulated without active ingredients, i.e., free of pharmaceutically active agents, since the agent exerting the therapeutic effect according to the invention, namely the hydrogel, is not a pharmaceutically active component, but rather exerts its therapeutic effect solely through its sequestrating action. The resulting high patient compliance of the composition according to the invention is therefore also advantageous. Furthermore, the present compositions are particularly easy to apply, especially orally or rectally.

[0053] The hydrogel used according to the invention has a sequestrating effect on the one hand in the form of sequestration of cytokines present in biofluids, but also in the form of direct sequestration of cytokines directly from tissues, for example the mucosa, in particular directly from the glycocalyx of the cells or the ECM (extracellular matrix).

[0054] The therapeutic composition according to the invention, containing the hydrogel, is produced in a preferred embodiment according to the invention by covalently linking at least one uncharged polymer with at least one polyionic polymer directly or via at least one crosslinking component, thereby forming a hydrogel, wherein this hydrogel accordingly has at least one uncharged polymer component that is covalently linked with at least one polyionic polymer component to form a network.

[0055] The therapeutic composition according to the invention, comprising the hydrogel and at least one pharmaceutically acceptable carrier, is produced in a preferred embodiment by covalently linking at least one uncharged polymer with at least one polyionic polymer directly or via at least one crosslinking component, thereby forming a hydrogel. This hydrogel accordingly comprises at least one uncharged polymer component covalently linked with at least one polyionic polymer component to form a network. This hydrogel, particularly in the form of hydrogel particles, is associated with at least one pharmaceutically acceptable carrier. The association can be effected by purely physical mixing, by chemical covalent bonding, or by non-covalent bonding.

[0056] In a preferred embodiment, the at least one, preferably exactly one, polyionic polymer can be covalently linked to two different uncharged polymer components directly or via at least one crosslinking component to form the hydrogel. In this way, the charge properties can advantageously be further varied. In one embodiment, a second or further polyionic polymer component can be present in the composition or, in particular, in the polymer network of the hydrogel, wherein this second or further polyionic polymer component may or may not have sulfate or sulfonate groups.

[0057] The therapeutic composition according to the invention, comprising the hydrogel and optionally at least one pharmaceutically acceptable carrier, is produced in a preferred embodiment according to the invention by directly covalently linking at least one non-polymeric crosslinking molecule with at least one polyionic polymer to form a hydrogel, wherein this hydrogel accordingly has at least one non-polymeric crosslinking component which is covalently linked with at least one polyionic polymer component to form a network, and wherein this hydrogel, in particular in the form of hydrogel particles, is associated with at least one pharmaceutically acceptable carrier.

[0058] In a preferred embodiment, the at least one uncharged polymer has an average molecular weight of 5,000 to 25,000, in particular 10,000 to 19,000 Da. In a preferred embodiment, the repeating unit of the at least one uncharged polymer component has an average molecular weight of 30 to 55, in particular 40 to 50 Da.

[0059] In a particularly preferred embodiment, the at least one uncharged polymer component is a linear uncharged polymer component.

[0060] In a particularly preferred embodiment, the at least one uncharged polymer component is a branched, in particular multi-armed, uncharged polymer component.

[0061] In a particularly preferred embodiment, the at least one multi-armed uncharged polymer component is a four-armed or eight-armed uncharged polymer component.

[0062] In a particularly preferred embodiment, the at least one uncharged polymer component is selected from the group consisting of polyethylene glycol (PEG) component, poly(2-oxazoline) (POx) component, polyvinylpyrrolidone (PVP) component, polyvinyl alcohol (PVA) component, polyacrylamide (PAM) component and combinations thereof.

[0063] In a particularly preferred embodiment, the at least one multi-armed uncharged polymer component is a PEG component.

[0064] In a particularly preferred embodiment, the at least one uncharged polymer component is a polyethylene glycol component, in particular a linear or multi-arm polyethylene glycol component.

[0065] In a particularly preferred embodiment, the at least one multi-armed uncharged polymer component is a four-armed polyethylene glycol component.

[0066] In another preferred embodiment, the at least one multi-armed uncharged polymer component is an eight-armed polyethylene glycol component.

[0067] In a particularly preferred embodiment, the at least one multi-armed uncharged polymer component is star-PEG, also known as starPEG.

[0068] In a preferred embodiment, the uncharged polymer used for the production of the hydrogel according to the invention has a functional group, in particular an end group, selected from the group consisting of an amino group, a thiol group, a maleimide group, a vinyl sulfone group, and an acrylate group at each free end of the polymer chain.

[0069] Carboxyl groups and combinations thereof. The uncharged polymer is thus, in particular, end-group functionalized. The at least two functional groups of the uncharged polymer can be the same or different; in particular, they are identical.

[0070] In a particularly preferred embodiment, the uncharged polymer used for the production of the hydrogel according to the invention has at least two amino groups, in particular terminal amino groups.

[0071] In a particularly preferred embodiment, the uncharged polymer used for the production of the hydrogel according to the invention has at least two carboxyl groups, in particular terminal carboxyl groups.

[0072] In a preferred embodiment, the at least one polyionic polymer component used for the production of the hydrogel according to the invention is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) or a glycosaminoglycan component, in particular heparin or selectively desulfated heparin, in particular selectively N-desulfated or selectively 6ON-desulfated heparin.

[0073] In a preferred embodiment, the polyionic polymer component used for the production of the hydrogel according to the invention is a poly(4-styrenesulfonic acid)-based polymer component, in particular poly(4-styrenesulfonic acid-co-maleic acid) (here also referred to as PSS-MA) or poly(4-styrenesulfonic acid) (here also referred to as PSSA). PSS-MA preferably comprises anionic sulfonate groups and carboxylate groups. The use of PSS-MA has proven to be particularly effective and therefore advantageous. In a preferred embodiment, the PSS-MA has maleimide groups for network formation.

[0074] In a preferred embodiment, the polyionic polymer component used for the production of the hydrogel used according to the invention is poly(4-styrenesulfonic acid-co-maleic acid), particularly in a molar ratio of sulfonic acid to maleic acid of 1:1. In a preferred embodiment, the polyionic polymer component used for the production of the hydrogel used according to the invention, poly(4-styrenesulfonic acid-co-maleic acid), particularly in a molar ratio of sulfonic acid to maleic acid of 1:1, is combined with an uncharged polymer implemented as a linear or multi-arm polyethylene glycol component, particularly PEG, to form the network.

[0075] In a preferred embodiment, the polyionic polymer component is a glycosaminoglycan component.

[0076] In a particularly preferred embodiment, the glycosaminoglycan used for the production of the hydrogel according to the invention is selected from the group consisting of chondroitin sulfate, dextran sulfate, dermatan sulfate, glucosamine sulfate, heparin, selectively desulfated heparin, heparan sulfate, and hyaluronan sulfate. In particular, the glycosaminoglycan is heparin, heparan sulfate, or dextran sulfate, especially heparin or selectively desulfated heparin, and in particular selectively N (nitrogen)-desulfated heparin or selectively 6ON-desulfated heparin.

[0077] In a preferred embodiment, the polyionic polymer component is a sulfated GAG, a selectively desulfated GAG, in particular heparin, selectively desulfated heparin derivatives, in particular selectively N-desulfated heparin or selectively 6ON-desulfated heparin, chondroitin sulfate, dermatan sulfate or keratan sulfate.

[0078] Sulfated and selectively desulfated GAGs preferably comprise anionic sulfate groups and carboxylate groups.

[0079] In a particularly preferred embodiment, the glycosaminoglycan used for the production of the hydrogel used according to the invention is a desulfated glycosaminoglycan, in particular a selectively N-desulfated or 6ON-desulfated glycosaminoglycan, in particular a selectively N-desulfated or 6ON-desulfated heparin.

[0080] In a particularly preferred embodiment, the glycosaminoglycan used for the production of the hydrogel according to the invention is a selectively N-desulfated heparin obtainable according to the synthesis procedure from Atallah et al. (Biomaterials. 2018 Oct; 181:227-239. doi: 10.1016 / j.biomaterials.2018.07.056. Epub 2018 Jul 30). In a preferred embodiment, the average molecular weight of the polyionic polymer is 3 to 30, in particular 4 to 14 kDa, in particular 10 to 14 kDa, in particular 13 to 14 kDa.

[0081] In a preferred embodiment, the average molecular weight of the polyionic polymer is 3 to 40, in particular 8 to 25 kDa, in particular 10 to 24 kDa, in particular 19 to 21 kDa.

[0082] In a preferred embodiment, 20 to 90, in particular 40 to 80, in particular 40 to 77, in particular 40 to 70, in particular 65 to 80, in particular 65 to 75 sulfate or sulfonate groups are present per polyionic polymer molecule.

[0083] In a preferred embodiment, 40 to 55, in particular 40 to 50, in particular 45 to 50 sulfate or sulfonate groups are present per desulfated glycosaminoglycan, in particular per selectively N-desulfated glycosaminoglycan, in particular per selectively N-desulfated heparin.

[0084] In a preferred embodiment, the repeating unit of the at least one polyionic polymer component has an average molecular weight of 200 to 600, in particular 400 to 550, in particular 420 to 470 Da.

[0085] In a preferred embodiment, the repeating unit of the at least one polyionic polymer component has an average molecular weight of 200 to 350, in particular 250 to 350, especially 250 to 300 Da.

[0086] In a preferred embodiment, each repeating unit of the at least one polyionic polymer component contains 0.9 to 4.5, in particular 1.0 to 4.5, in particular 1.5 to 4.5, in particular 2.0 to 3.0 sulfate or sulfonate groups.

[0087] In a preferred embodiment, 1.0 to 4.5, in particular 1.5 to 2.0 sulfate or sulfonate groups are present per repeating unit of the at least one polyionic polymer component, in particular per desulfated glycosaminoglycan, in particular per selectively N-desulfated glycosaminoglycan, in particular per selectively N-desulfated heparin.

[0088] In a preferred embodiment, the non-polymeric crosslinking molecule used for the production of the hydrogel according to the invention has at least two functional groups suitable for forming a covalent bond to the polyionic polymer component, in particular selected from the group consisting of amino group, thiol group, maleimide group, vinyl sulfone group, acrylate group, carboxyl group, hydroxylated aromatic group and combinations thereof.

[0089] The non-polymeric crosslinking molecule, which constitutes the non-polymeric crosslinking component in the hydrogel, is thus functionalized, in particular end-group functionalized. Via these reactive functional groups, the at least one non-polymeric crosslinking molecule is preferentially linked to the at least one polyionic polymer, thereby forming the network of the hydrogel. The at least two functional groups of the non-polymeric crosslinking molecule can be the same or different; in particular, they can be the same.

[0090] In a preferred embodiment, the crosslinker molecule is a non-polymeric bifunctional crosslinker molecule.

[0091] In a preferred embodiment, the crosslinking molecule has at least two amino groups. In a particularly preferred embodiment, the crosslinking molecule with at least two amino groups is selected from the group consisting of ethylenediamine, propylenediamine (1,3-diaminopropane), butane-1,4-diamine, pentane-1,5-diamine (cadaverine), hexamethylene-1,6-diamine, and combinations thereof.

[0092] In a preferred embodiment, the crosslinking molecule has at least two carboxyl groups. In a particularly preferred embodiment, the crosslinking molecule with at least two carboxyl groups is selected from the group consisting of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, and combinations thereof.

[0093] In a particularly preferred embodiment, the crosslinking molecule is a molecule with at least two different functional groups, in particular at least two functional groups which are able to crosslink the polyionic polymer component and the uncharged polymer component, in particular N-(2-Aminoethyl) maleimide.

[0094] In a preferred embodiment, the at least one non-polymeric crosslinking component is selected from the group consisting of ethylenediamine, propylenediamine (1,3-diaminopropane), butane-1,4-diamine, pentane-1,5-diamine (cadaverine), hexamethylene-1,6-diamine, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, N-(2-aminoethyl)maleimide and combinations thereof.

[0095] In a particularly preferred embodiment, the crosslinking molecule is in particular an enzymatically cleavable sequence, in particular a matrix metalloprotease (MMP)-responsive element, cathepsin-responsive element, elastase-responsive element, blood coagulation enzyme-responsive element, for example a thrombin-responsive element, a kallikrein-responsive element, in particular a bacterial protease-responsive element or an elastase-responsive element.

[0096] In a preferred embodiment, the enzymatically cleavable sequences are flanked at both the C- and N-terminal ends by a cysteine. The polyionic polymer and the uncharged polymer, or at least two polyionic polymers, are crosslinked via the respective cysteine.

[0097] In a preferred embodiment, the polyionic polymer component used for the production of the hydrogel according to the invention is covalently linked with a non-polymeric crosslinking component, in particular a peptide.

[0098] In a preferred embodiment, the uncharged polymer component and the polyionic polymer component preferably used for the production of the hydrogel according to the invention are covalently linked together by means of a non-polymeric crosslinking component, in particular peptides.

[0099] In a preferred embodiment, the non-polymeric crosslinking component and the polyionic polymer component are covalently linked to each other via at least one amide bond.

[0100] In a preferred embodiment, the uncharged polymer component and the polyionic polymer component are covalently linked to each other via at least one amide bond by means of a non-polymeric crosslinking component.

[0101] In a further preferred embodiment, the uncharged polymer component and the polyionic polymer component used for the production of the hydrogel according to the invention are directly covalently linked to each other, in particular by means of an amide bond, thiol-amine bond, disulfide bond or bioorthogonal thioether bond obtainable by thiol-maleimide, thiol-vinyl sulfone or thiol-acrylate reaction.

[0102] In a preferred embodiment, the uncharged polymer component used for the production of the hydrogel according to the invention, in particular an uncharged polymer component containing amino groups, and the polyionic polymer component, in particular a polyionic polymer component containing carboxyl groups, are directly covalently linked to one another by means of an amide bond. In a preferred embodiment, the amide bond is enabled by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysulfosuccinimide (EDC / sNHS) activation at the carboxyl groups of the polyionic polymer component.

[0103] In a further preferred embodiment, the non-polymeric crosslinking component used for the production of the hydrogel according to the invention and the polyionic polymer component are directly covalently linked to each other, in particular by means of an amide bond, thiol-amine bond, disulfide bond or bioorthogonal thioether bond obtainable by thiol-maleimide, thiol-vinylsulfone or thiol-acrylate reaction.

[0104] In a preferred embodiment, the non-polymeric crosslinking component used for the production of the hydrogel according to the invention, in particular a non-polymeric crosslinking component having amino groups, and the polyionic polymer component, in particular a polyionic polymer component having carboxyl groups, are directly covalently linked to one another by means of an amide bond. In a preferred embodiment, the amide bond is enabled by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysulfosuccinimide (EDC / sNHS) activation at the carboxyl groups of the polyionic polymer component.

[0105] In a preferred embodiment, the hydrogel comprises at least two, in particular two, different non-polymeric crosslinking components. In a particularly preferred embodiment, the hydrogel comprises a non-polymeric crosslinking component having at least two carboxyl groups, in particular one end-functionalized with a carboxyl group, and a non-polymeric crosslinking component having at least two amino groups, in particular one end-functionalized with an amino group.Preferably, the non-polymeric crosslinking component having at least two carboxyl groups can be linked via at least one amide bond to the non-polymeric crosslinking component having preferably amino groups, and the non-polymeric crosslinking component having at least two amino groups can be linked via at least one amide bond to the polyionic polymer component having preferably carboxyl groups, in particular heparin, wherein in a preferred embodiment the amide bond is enabled by means of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysulfosuccinimide (EDC / sNHS) activation at the carboxyl groups of the non-polymeric crosslinking molecule and the polyionic polymer component.

[0106] In a preferred embodiment, the hydrogel comprises at least two, in particular two, different uncharged polymer components. In a particularly preferred embodiment, the hydrogel comprises an uncharged polymer component having at least two carboxyl groups, in particular one end-group functionalized with each carboxyl group, and an uncharged polymer component having at least two amino groups, in particular one end-group functionalized with each amino group.Preferably, the uncharged polymer component having at least two carboxyl groups can be linked via at least one amide bond to the preferably amino group-having uncharged polymer component, and the uncharged polymer component having at least two amino groups can be linked via at least one amide bond to the preferably carboxyl group-having polyionic polymer component, in particular heparin, wherein in a preferred embodiment the amide bond is enabled by means of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysulfosuccinimide (EDC / sNHS) activation at the carboxyl groups of the uncharged polymer component and the polyionic polymer component.

[0107] In a preferred embodiment, the hydrogel comprises an uncharged polymer component. In a particularly preferred embodiment, the hydrogel comprises an uncharged polymer component having at least two amino groups, in particular one end-group functionalized with an amino group. Preferably, the uncharged polymer component having at least two amino groups can be linked to the polyionic polymer component, preferably heparin, which preferably has carboxyl groups, via at least one amide bond. In a preferred embodiment, the amide bond is enabled by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide / N-hydroxysulfosuccinimide (EDC / sNHS) activation at the carboxyl groups of the polyionic polymer component.

[0108] In a preferred embodiment, the components of the hydrogel can also be UV-crosslinked.

[0109] In a particularly preferred embodiment, the uncharged polymer, which is end-group functionalized in particular with a carboxyl group, is a multi-armed, in particular eight-armed, PEG.

[0110] In a particularly preferred embodiment, the uncharged polymer, which is end-group functionalized in particular with one amino group at each end, is a multi-armed, in particular four-armed, PEG.

[0111] In a particularly preferred embodiment, the hydrogel, and in particular the hydrogel particles, is present in the therapeutic composition in a dried state, especially without any pharmaceutically acceptable carrier. In this embodiment, the therapeutic composition consists of the hydrogel, and in particular the dried hydrogel particles.

[0112] In a particularly preferred embodiment, the hydrogel, in particular the hydrogel particles, in the therapeutic composition is in a dried state with at least one pharmaceutically acceptable, in particular dry, carrier.

[0113] In a particularly preferred embodiment, the hydrogel, in particular the hydrogel particles, in the therapeutic composition is present in a swollen state in a liquid, pharmaceutically acceptable carrier.

[0114] In a particularly preferred embodiment, the hydrogel, and in particular the hydrogel particles, is present in the therapeutic composition in a swollen state, particularly in an aqueous solution, especially water, or in a buffered aqueous solution, particularly PBS, in a swollen form. In a preferred embodiment, the hydrogel, and in particular the hydrogel particles, can swell to 0.75 to 2.5 times the size of the hydrogel, and in particular the hydrogel particles, directly after hydrogel formation.

[0115] In a preferred embodiment, the hydrogel content, in particular the hydrogel particles in swollen state, in the composition according to the invention is 0.1 to 65 vol.%, in particular 1 to 60 vol.%, in particular 9 to 55 vol.%, in particular 10 to 50 vol.% (in each case based on the total volume of the composition).

[0116] In a preferred embodiment, the hydrogel content, in particular the hydrogel particles in a swollen state, in the composition according to the invention is 0.1 to 65 vol.% (based on the total volume of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.00002 to 1.6 mmol / g (based on the total mass of the composition).

[0117] In a preferred embodiment, the hydrogel content, in particular the hydrogel particles in a swollen state, in the composition according to the invention is 1 to 60 vol.% (based on the total volume of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.0002 to 1.4 mmol / g (based on the total mass of the composition).

[0118] In a preferred embodiment, the hydrogel content, in particular the hydrogel particles in the swollen state, in the composition according to the invention is 9 to 55 vol.% (based on the total volume of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.0018 to 1.3 mmol / g (based on the total mass of the composition).

[0119] In a preferred embodiment, the hydrogel content, in particular the hydrogel particles in a swollen state, in the composition according to the invention is 10 to 50 vol.% (based on the total volume of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.002 to 1.2 mmol / g (based on the total mass of the composition).

[0120] In a preferred embodiment, the hydrogel content, in particular the

[0121] Hydrogel particles in a swollen state, in the composition according to the invention, 10 to 50 vol% (based on the total volume of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.002 to 1.2 mmol / g (based on the total mass of the composition), and wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or a selectively desulfated heparin.

[0122] In a preferred embodiment, the hydrogel content, in particular the hydrogel particles in the swollen state, in the composition according to the invention is 10 to 50 vol% and the pharmaceutical carrier content is 90 to 50 vol% (each based on the total volume of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.002 to 1.2 mmol / g, in particular 0.01 to 0.1 mmol / g (each based on the total mass of the composition), and wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or a selectively desulfated heparin.

[0123] In a preferred embodiment, the hydrogel content is 1 to 99 vol% and the pharmaceutical carrier content is 99 to 1 vol% (each based on the total volume of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.0002 to 2.3 mmol / g (each based on the total mass of the composition), and wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-comaleic acid) component, or heparin or selectively desulfated heparin.

[0124] In a preferred embodiment, the hydrogel, in particular the hydrogel particles, especially in the swollen state, has a storage modulus of at most 40.0 kPa, in particular of at most 22.0 kPa, in particular of at most 20.0 kPa, in particular of at most 15.0 kPa, in particular of at most 10.0 kPa.

[0125] In a preferred embodiment, the hydrogel, and in particular the hydrogel particles, especially in the swollen state, has a storage modulus of 0.1 to 40.0 kPa, in particular 0.1 to 22.0 kPa, in particular 0.1 to 20.0 kPa, in particular less than 0.1 to 15.0 kPa, in particular less than 0.1 to 10.0 kPa. In a preferred embodiment, the hydrogel particles, especially in the swollen state, have a mean diameter (also referred to as mean particle diameter or mean size) of at most 5000 pm, in particular at most 3000 pm, in particular at most 300 pm, in particular at most 200 pm, in particular at most 80 pm.

[0126] In a preferred embodiment, the hydrogel particles, particularly in the swollen state, have a mean diameter (size) of 1 to 5000 pm, particularly of 1 to 3000 pm, particularly of 1 to 300 pm, particularly of 10 to 300 pm, particularly of 1 to 200 pm, particularly of 10 to 200 pm, particularly of 5 to 150 pm, particularly of 10 to 80 pm. In a preferred embodiment, the hydrogel particles, particularly in the swollen state, have a mean diameter (size) of 10 to 150 pm, wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or a selectively desulfated heparin, in particular wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component.

[0127] Preferably, the mean diameter of the hydrogel particles is determined by means of fluorescence microscopy, preferably with a dye which has a reactive group, in particular an amine group.

[0128] In a preferred embodiment, the hydrogel particles, particularly in the swollen state, are spherical particles, especially with a narrow size distribution. In a preferred embodiment, the hydrogel particles are spherical particles with deviations of < 10% from the mean particle diameter, especially with a mean diameter in the range of 10–300 pm.

[0129] In a preferred embodiment, the hydrogel particles, particularly in the swollen state, have a spherical shape.

[0130] In a preferred embodiment, the hydrogel particles, particularly in the swollen state, have a size distribution with a deviation of less than 15%, particularly less than 10%, of the mean size.

[0131] In a preferred embodiment, the hydrogel, in particular the hydrogel particles, especially in the swollen state, has a sulfate or sulfonate group concentration of at least 0.1 mmol / l, in particular at least 10 mmol / l, in particular at least 100 mmol / l, in particular 0.1 to 800 mmol / l, in particular 10 to 800 mmol / l, in particular 20 to 500 mmol / l, in particular 20 to 200 mmol / l, in particular 50 to 200 mmol / l, in the volume of the hydrogel.

[0132] In a particularly preferred embodiment, the hydrogel, and in particular the hydrogel particles, comprises sulfate groups. In a particularly preferred embodiment, the hydrogel, and in particular the hydrogel particles, especially in the swollen state, comprises sulfate groups in a concentration of at least 0.1 mmol / L, in particular at least 10 mmol / L, in particular at least 100 mmol / L, in particular 0.1 to 800 mmol / L, in particular 10 to 800 mmol / L, in particular 20 to 500 mmol / L, in particular 20 to 200 mmol / L, and in particular 50 to 200 mmol / L, in the volume of the hydrogel in the swollen state.

[0133] In a particularly preferred embodiment, the hydrogel, and in particular the hydrogel particles, comprises sulfonate groups. In a particularly preferred embodiment, the hydrogel, and in particular the hydrogel particles, especially in the swollen state, comprises sulfonate groups in a concentration of at least 0.1 mmol / L, in particular at least 10 mmol / L, in particular at least 100 mmol / L, in particular 0.1 to 800 mmol / L, in particular 10 to 800 mmol / L, in particular 20 to 500 mmol / L, in particular 20 to 200 mmol / L, and in particular 50 to 200 mmol / L, in the volume of the hydrogel in the swollen state.

[0134] In a particularly preferred embodiment, the hydrogel, in particular the hydrogel particles, has a number of sulfate or sulfonate groups per dry mass (polymer network in dried, non-hydrated state) of at least 0.01 mmol / g, in particular at least 0.1 mmol / g, in particular at least 1 mmol / g, in particular 0.01 to 8 mmol / g, in particular 0.1 to 8 mmol / g, in particular 0.2 to 5 mmol / g, in particular 0.2 to 2 mmol / g, in particular 0.5 to 2 mmol / g.

[0135] In a particularly preferred embodiment, the hydrogel, in particular the hydrogel particles, has a number of sulfate or sulfonate groups per dry mass (polymer network in dried, non-hydrated state) of at least 0.01 mmol / g, in particular at least 0.1 mmol / g, in particular at least 1 mmol / g, in particular 0.01 to 8 mmol / g, in particular 0.1 to 8 mmol / g, in particular 0.2 to 5 mmol / g, in particular 0.2 to 2 mmol / g, in particular 0.5 to 2 mmol / g, wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or a selectively desulfated heparin.

[0136] In a particularly preferred embodiment, the hydrogel, in particular the hydrogel particles, has a number of sulfate or sulfonate groups per dry mass (polymer network in dried, non-hydrated state) of 0.02 to 5 mmol / g, in particular wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-comaleic acid) component, or heparin or selectively desulfated heparin.

[0137] In a particularly preferred embodiment, the hydrogel, in particular the hydrogel particles, has a number of sulfate or sulfonate groups per dry mass (polymer network in dried, non-hydrated state) of 0.2 to 5 mmol / g, wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

[0138] In a preferred embodiment, the hydrogel, and in particular the hydrogel particles, especially in the swollen state, has a mean mesh size of at least 5 nm, and in particular at least 5.7 nm. The minimum mean mesh size ensures that all relevant signaling molecules with a diameter of 3 to 5 nm can penetrate the hydrogel particles quickly and without steric obstruction, and that the ability of the signaling molecules to diffuse through the particles depends essentially on the charge properties of the particles and the resulting interaction with the signaling molecules.

[0139] In a preferred embodiment, the hydrogel, in particular the hydrogel particles, especially in the swollen state, has a mean mesh size of 5 to 30 nm, in particular 5.7 to 30 nm.

[0140] In a preferred embodiment, the composition according to the invention has a content of 30 to 99 vol.%, in particular 30 to 85 vol.%, in particular 40 to 80 vol.% of pharmaceutically acceptable carrier (in each case based on the total volume of the composition). In a preferred embodiment, the composition according to the invention has a content of 30 to 99 vol.% of pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0002 to 1.7 mmol / g (based on the total mass of the composition).

[0141] In a preferred embodiment, the composition according to the invention has a content of 30 to 85 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.003 to 1.7 mmol / g (based on the total mass of the composition).

[0142] In a preferred embodiment, the composition according to the invention has a content of 40 to 80 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0039 to 1.4 mmol / g (based on the total mass of the composition).

[0143] In a preferred embodiment, the composition according to the invention has a content of 40 to 80 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0039 to 1.4 mmol / g (based on the total mass of the composition), wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

[0144] In a preferred embodiment, the composition according to the invention has a content of 40 to 80 vol% pharmaceutically acceptable carrier and a content of hydrogel, in particular of the hydrogel particles in the swollen state, of 60 to 20 vol% (each based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0039 to 1.4 mmol / g, in particular 0.01 to 0.1 mmol / g (each based on the total mass of the composition), wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or a selectively desulfated heparin.

[0145] In a preferred embodiment, the composition according to the invention has a content of at least 75 vol.%, in particular 75 to 99 vol.%, of pharmaceutically acceptable carrier (in each case based on the total volume of the composition).

[0146] In a preferred embodiment, the composition according to the invention has a content of at least 75 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of at least 0.005 mmol / g (based on the total mass of the composition).

[0147] In a preferred embodiment, the composition according to the invention has a content of at least 75 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of at least 0.005 mmol / g (based on the total mass of the composition), wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

[0148] In a preferred embodiment, the composition according to the invention has a content of 75 to 99 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0002 to 0.6 mmol / g (based on the total mass of the composition).

[0149] In a preferred embodiment, the composition according to the invention has a content of 75 to 99 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0002 to 0.6 mmol / g (based on the total mass of the composition), wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

[0150] In a preferred embodiment, the composition according to the invention has a content of 1 to 75 vol.%, in particular 1 to 30 vol.%, in particular 5 to 30 vol.% of pharmaceutically acceptable carrier (in each case based on the total volume of the composition).

[0151] In a preferred embodiment, the composition according to the invention has a content of 1 to 75 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0049 to 2.3 mmol / g (based on the total mass of the composition).

[0152] In a preferred embodiment, the composition according to the invention has a content of 1 to 75 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0049 to 2.3 mmol / g (based on the total mass of the composition), wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

[0153] In a preferred embodiment, the composition according to the invention has a content of 1 to 30 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.014 to 2.3 mmol / g (based on the total mass of the composition).

[0154] In a preferred embodiment, the composition according to the invention has a content of 5 to 30 vol% pharmaceutically acceptable carrier (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.014 to 2.2 mmol / g (based on the total mass of the composition).

[0155] In a preferred embodiment, the composition according to the invention has a content of at least 1 vol.%, in particular 4 to 25 vol.%, of hydrogel, in particular hydrogel particles, especially in the swollen state, (in each case based on the total volume of the composition). In a preferred embodiment, the composition according to the invention has a content of at least 1 vol.% hydrogel, in particular hydrogel particles, especially in the swollen state, (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of at least 0.0002 mmol / g (based on the composition).

[0156] In a preferred embodiment, the composition according to the invention has a content of 4 to 25 vol% hydrogel, in particular hydrogel particles, especially in the swollen state, (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0008 to 0.6 mmol / g (based on the total mass of the composition).

[0157] In a preferred embodiment, the composition according to the invention has a content of 4 to 25 vol% hydrogel, in particular hydrogel particles, especially in the swollen state, (based on the total volume of the composition) and a number of sulfate / sulfonate groups in the composition of 0.0008 to 0.6 mmol / g (based on the total mass of the composition), wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or a selectively desulfated heparin.

[0158] In a preferred embodiment, the mass fraction of the polymer network (i.e., with the polyionic component) of the composition according to the invention is 0.04 to 99 wt.%, in particular 0.04 to 5 wt.%, in particular 15 to 99 wt.%, in particular 60 to 99 wt.% (in each case based on the total mass of the composition).

[0159] In a preferred embodiment, the mass fraction of the polymer network (i.e., with the polyionic component) of the composition according to the invention is 0.04 to 99 wt.% (based on the total mass of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.0003 to 6.0 mmol / g (based on the total mass of the composition).

[0160] In a preferred embodiment, the mass fraction of the polymer network (i.e., with the polyionic component) of the composition according to the invention is 0.04 to 5 wt.% (based on the total mass of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.0003 to 0.3 mmol / g (based on the total mass of the composition).

[0161] In a preferred embodiment, the mass fraction of the polymer network (i.e., with the polyionic component) of the composition according to the invention is 0.04 to 5 wt.% (based on the total mass of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.0003 to 0.3 mmol / g, in particular 0.01 to 0.1 mmol / g (each based on the total mass of the composition), and wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or a selectively desulfated heparin.

[0162] In a preferred embodiment, the mass fraction of the polymer network (i.e., with the polyionic component) of the composition according to the invention is 15 to 99 wt.% (based on the total mass of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.095 to 6.0 mmol / g (based on the total mass of the composition).

[0163] In a preferred embodiment, the mass fraction of the polymer network (i.e., with the polyionic component) of the composition according to the invention is 60 to 99 wt.% (based on the total mass of the composition), wherein the composition has a number of sulfate / sulfonate groups of 0.38 to 6.0 mmol / g (based on the total mass of the composition).

[0164] In a particularly preferred embodiment, the at least one pharmaceutically acceptable carrier is an aqueous liquid, in particular water or an aqueous buffered solution, in particular phosphate-buffered saline (PBS) or RPMI (Roswell Park Memorial Institute) medium, optionally RPMI and BSA (bovine serum albumin).

[0165] In a particularly preferred embodiment, the at least one pharmaceutically acceptable carrier, in particular the aqueous liquid, has a pH value of 2 to 9, in particular of 6.5 to 8.0, in particular 6.8 to 7.6, in particular 7.0 to 7.5, in particular 7.4.

[0166] In a preferred embodiment, the composition according to the invention is in the form of a suspension of hydrogel particles or of particulate carrier-bound hydrogel in a pharmaceutically acceptable carrier formulated as an aqueous liquid. The aqueous carrier can be designed for rectal administration, in particular for an enema, or for oral administration.

[0167] In a particularly preferred embodiment, the at least one pharmaceutically acceptable carrier is a solid or semi-liquid carrier, in particular a matrix, in particular a polymer carrier.

[0168] In a preferred embodiment, the polymer carrier is a polymer mesh, a polymer foam, a gel, a textile or a woven fabric, in particular a knitted fabric, a nonwoven fabric, a microparticle, a woven fabric, a knitted fabric, a perforated film, a fiber or a fiber mesh.

[0169] In a preferred embodiment, the polymer support is made of a synthetic polymer, in particular polyester, POx (poly(2-oxazoline)), polyalkylene oxide polymer, PEG, polyamide, cellulose, polyurethane, silicone polymer, polystyrene or polyethylene.

[0170] If, according to the invention, the hydrogel, in particular in particulate or non-particulate form, is chemically covalently linked to the pharmaceutically acceptable carrier, this can be achieved, for example, via protease-cleavable peptide linkers.

[0171] In a preferred embodiment, the polymer support is a polyurethane foam.

[0172] In a preferred embodiment, the polymer support is a polyester fiber network.

[0173] In a preferred embodiment, the polymer support comprises a swellable polymer, in particular CMC (carboxymethylcellulose), pectin or gelatin.

[0174] In a preferred embodiment, the polymer support is hydratable.

[0175] In a particularly preferred embodiment, the at least one pharmaceutically acceptable carrier is a fat, in particular a hard fat.

[0176] In a particularly preferred embodiment, the matrix comprises at least one gelling or gelled substance. In a preferred embodiment, the composition according to the invention is in the form of hydrogel particles integrated in a gel.

[0177] In a preferred embodiment, the composition according to the invention is in the form of suppositories (here also referred to as suppositories), rectal foam, rectal suspension, tablet, prolonged-release tablet, gastro-resistant tablet, gastro-resistant prolonged-release tablet, gastro-resistant granules, gastro-resistant prolonged-release granules or oral suspension.

[0178] In a preferred embodiment, the composition according to the invention is contained in a capsule or tablet, in particular a capsule, especially for oral administration.

[0179] In a preferred embodiment, the composition according to the invention is in the form of an encapsulated or non-encapsulated composition.

[0180] In a preferred embodiment, the composition according to the invention is in a suppository, particularly suitable for rectal administration.

[0181] In a preferred embodiment, the composition according to the invention is in the form of a sustained-release composition, i.e., a composition that allows a sustained release of the hydrogel in the gastrointestinal tract.

[0182] In a preferred embodiment, the pharmaceutically acceptable carrier is a carrier that allows for delayed release.

[0183] In a preferred embodiment, the pharmaceutically acceptable carrier is biocompatible but not bioabsorbable or degradable.

[0184] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a tablet, is selected from the group consisting of magnesium stearate, methacrylic acid-methyl methacrylate copolymer (particularly 1:2), triethyl citrate, yellow iron oxide (El 72), red iron oxide (El 72), macrogol, microcrystalline cellulose, glycerol monostearate (particularly 40-55), hypromellose, maize starch, polysorbate 80, potassium dihydrogen phosphate, colloidal silicon dioxide and sodium carboxymethyl starch (type A).

[0185] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a suppository, is selected from the group consisting of hard fat, povidone K30, macrogol 6000, magnesium stearate (Ph. Eur.) and talc, in particular hard fat, docusate sodium and cetyl alcohol (Ph. Eur.).

[0186] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly used in an enteric-coated tablet, is selected from the group consisting of lactose monohydrate, sodium carboxymethyl starch (especially type A), (Ph.Eur.) talc, povidone (especially 25 000), magnesium stearate (Ph.Eur.) [especially vegetable], triethyl citrate, methacrylic acid-methyl methacrylate copolymer (especially 1 :2) (Ph.Eur.), macrogol 6000 and iron(III) hydroxide oxide x H2O.

[0187] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in an enteric-coated tablet, is selected from the group consisting of sodium carbonate; microcrystalline cellulose; silicon dioxide, in particular highly dispersed silicon dioxide; glycine; povidone; croscarmellose sodium; calcium stearate; methacrylic acid-methyl methacrylate copolymer (in particular 1:1); methacrylic acid-methyl methacrylate copolymer (in particular 1:2); methacrylic acid-ethyl acrylate copolymer dispersion (in particular 1:1), in particular 30%; talc; triethyl citrate; titanium dioxide (E 171); iron(III) oxide (E 172); iron(III) hydroxide oxide (E 172) and macrogol 6000.

[0188] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly used in an enteric-coated tablet, is selected from the group consisting of microcrystalline cellulose, povidone K25, croscarmellose sodium, methacrylic acid-methyl methacrylate copolymer (particularly 1:1) (Ph. Eur.), methacrylic acid-methyl methacrylate copolymer (particularly 1:2) (Ph. Eur.), calcium stearate (Ph. Eur.) [particularly vegetable], talc, macrogol 6000, hypromellose, highly dispersed silicon dioxide, iron(III) hydroxide oxide x H2O and titanium dioxide (E 171).

[0189] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in an enteric-coated prolonged-release tablet, is selected from the group consisting of carmellose sodium; carnauba wax; stearic acid (Ph. Eur.); hydrated silicon dioxide; sodium carboxymethyl starch (particularly type A) (Ph. Eur.); talc; magnesium stearate (Ph. Eur.); methacrylic acid-methyl methacrylate copolymer (particularly (1:1) and (1:2)) (Ph. Eur.); triethyl citrate; titanium dioxide (E171); iron(III) oxide (E172); and macrogol 6000. In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a prolonged-release tablet, is selected from the group consisting of povidone K30, ethylcellulose, magnesium stearate (Ph. Eur.), talc, and microcrystalline cellulose.

[0190] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in an enteric-coated granule, is selected from the group consisting of microcrystalline cellulose, dispersible cellulose powder, lactose monohydrate, citric acid, ascorbic acid, butylhydroxyanisole, hypromellose, methacrylic acid-ethyl acrylate copolymer (particularly 1:1), especially with a molecular weight of approximately 250,000 (Eudragit L 100-55), methacrylic acid-methyl methacrylate copolymer (particularly 1:2) with a molecular weight of approximately 135,000 (Eudragit S 100), triethyl citrate, talc, titanium dioxide, mannitol, orange flavor 84257 Givaudan, and sorbitol.

[0191] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a sustained-release granule, is selected from the group consisting of aspartame (E 951), carmellose sodium (Ph. Eur.), citric acid, highly dispersed silicon dioxide, hypromellose, magnesium stearate (Ph. Eur.) [particularly vegetable], methacrylic acid-methyl methacrylate copolymer (particularly 1:1) (Ph. Eur.) (particularly MW: approx. 135,000) (Eudragit L 100), methylcellulose, microcrystalline cellulose, polyacrylate dispersion, particularly 40% (particularly Eudragit NE 40 D; contains 2% nonoxynol 100), povidone K 25, simethicone, sorbic acid (Ph. Eur.), talc, titanium dioxide (E171), triethyl citrate, and Vanilla custard flavoring (contains sucrose).

[0192] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a rectal foam, is selected from the group consisting of petrolatum, sorbitan oleate; polysorbate 20; macrogol 1000 fatty acid esters, (C14C18) fatty alcohols (C14C18) mixture; highly dispersed silicon dioxide; sodium metabisulfite (Ph. Eur.); sodium edetate (Ph. Eur.); methyl 4-hydroxybenzoate (Ph. Eur.); propyl 4-hydroxybenzoate (Ph. Eur.).

[0193] Sodium monohydrogen phosphate dodecahydrate (Ph.Eur.), sodium dihydrogen phosphate dihydrate; glycerol, macrogol 300 and purified water.

[0194] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a rectal foam, is selected from the group consisting of sodium metabisulfite (Ph. Eur.) (E 223), cetylstearyl alcohol (Ph. Eur.), polysorbate 60, sodium edetate (Ph. Eur.), and propylene glycol. In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a rectal suspension, is selected from the group consisting of sodium benzoate; potassium metabisulfite (Ph. Eur.); carbomer 934; sodium edetate (Ph. Eur.); potassium acetate; xanthan gum; and purified water.

[0195] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a rectal suspension, is selected from the group consisting of sodium metabisulfite (Ph. Eur.), sodium edetate (Ph. Eur.), sodium acetate 3H2O, hydrochloric acid and purified water.

[0196] In a preferred embodiment, the pharmaceutically acceptable carrier, particularly when used in a rectal suspension, is selected from the group consisting of carbomer 35000, potassium acetate, potassium metabisulfite (Ph. Eur.) (E 224), sodium benzoate (E 211), sodium edetate (Ph. Eur.), purified water and xanthan gum.

[0197] In a preferred embodiment, the therapeutic composition used according to the invention contains no pharmaceutically active substance.

[0198] In a preferred embodiment, the therapeutic composition used according to the invention contains at least one pharmaceutically active substance.

[0199] In a preferred embodiment, the therapeutic composition used according to the invention contains at least one pharmaceutically active substance selected from the group consisting of mesalazine, budesonide, budesonide MMX, and combinations thereof. The combination of the hydrogel used according to the invention with the at least one pharmaceutically active substance can exert a synergistic effect.

[0200] The combination of the hydrogel used according to the invention with the at least one pharmaceutically active substance can also be advantageous insofar as the hydrogel, in particular the hydrogel particles, can be used for the targeted release of the pharmaceutically active substance.

[0201] The preferred combination with budesonide can be used in particular for the treatment of Crohn's disease. The preferred combination with budesonide MMX (multi-matrix) can be used in particular for the treatment of ulcerative colitis.

[0202] In a preferred embodiment, the therapeutic composition used according to the invention contains no gelatin or collagen or both, in particular no free, unbound collagen or gelatin or both.

[0203] In a preferred embodiment, the therapeutic composition used according to the invention contains no heparin or heparin derivative, in particular no free, unbound heparin or heparin derivative.

[0204] In a preferred embodiment, the therapeutic composition used according to the invention contains no nitrates or nitrites or their sources.

[0205] In a preferred embodiment, the therapeutic composition used according to the invention contains no other components or substances except for the hydrogel, in particular a single hydrogel, and a single or of two, in particular a single, pharmaceutically acceptable carrier.

[0206] In a preferred embodiment, the therapeutic composition used according to the invention contains no other polymers except for the polymers forming the hydrogel, in particular a single hydrogel.

[0207] In a preferred embodiment, the composition according to the invention is an injectable therapeutic composition.

[0208] In a preferred embodiment, the composition according to the invention is an orally applicable therapeutic composition.

[0209] In a preferred embodiment, the composition according to the invention is a rectally applicable therapeutic composition.

[0210] In a preferred embodiment, the composition according to the invention is capable of lowering the concentration of at least one free cytokine, in particular a chemokine, especially IL-8, in an ambient solution. In a preferred embodiment, the composition according to the invention has the ability to reduce the concentration of at least one free cytokine, in particular a chemokine, especially IL-8, in a cytokine-containing model solution.

[0211] The liquid reduces the concentration of at least one free cytokine by 70 to 80%.

[0212] In a particularly preferred embodiment of the present invention, the free cytokine, in particular chemokine, is a pro-inflammatory cytokine, in particular chemokine.

[0213] In a particularly preferred embodiment, the free cytokine is selected from the group consisting of IL-8, IP-10, MCP-1, MIP-1alpha, MIP-1beta, MCP1, CXCL1, RANTES and combinations thereof, in particular IL-8.

[0214] The present invention also relates to the use of the hydrogel used in the present therapeutic composition, in particular the hydrogel particles, in a therapeutic method for the treatment of inflammatory bowel diseases together with at least one pharmaceutically acceptable carrier.

[0215] The invention relates in particular to therapeutic methods for the treatment of inflammatory bowel diseases using a therapeutic composition of the present invention.

[0216] The present invention also relates to a method for the treatment of inflammatory bowel diseases, wherein a therapeutic composition of the present invention is applied to a human or animal patient in an effective amount, in particular administered orally or rectally.

[0217] The invention relates in particular to methods for the treatment of inflammatory bowel diseases using a therapeutic composition, in particular comprising a hydrogel, in particular hydrogel particles, and at least one pharmaceutically acceptable carrier, wherein the hydrogel, in particular the hydrogel particles, comprises at least one polyethylene glycol component which is covalently linked to at least one polyionic polymer component, and wherein the at least one polyionic polymer component comprises sulfate or sulfonate groups, and wherein an effective amount of the composition according to the invention is applied to a human or animal patient, in particular administered orally or rectally.

[0218] The invention relates in particular to a therapeutic composition comprising a hydrogel for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient, wherein the hydrogel has at least one polyionic polymer component which is covalently linked to at least one uncharged polymer component and / or a non-polymeric crosslinking component to form a network, and wherein the at least one polyionic polymer component has sulfate or sulfonate groups.

[0219] In a particularly preferred embodiment of the present invention, the therapeutic composition and the therapeutic method for treating inflammatory bowel diseases are characterized in that the therapy of inflammatory bowel diseases is achieved through the cytokine-reducing effect provided according to the invention, in particular an inflammation-resolving or anti-inflammatory effect.

[0220] In the context of the present invention, the term "hydrogel" refers to a polymer network composed of polymer components that can bind water, i.e., is characterized by its ability to bind water. The molecules that constitute the polymer network are chemically linked to this polymer network by covalent bonds. Accordingly, the term "hydrogel" denotes, according to the invention, a polymer network capable of swelling in water. Due to the hydrophilic polymer components present in the network, the hydrogel swells in water with a considerable increase in volume, without losing its material cohesion and integrity. The hydrogel can exist in particulate form as hydrogel particles or in non-particulate form, also referred to here as non-particulate bulk material.The hydrogel, in particular the hydrogel particles or non-particulate bulk material, can be in dried form or in a liquid in a swollen (here also referred to as "hydrated") form.

[0221] In the context of the present invention, the terms "hydrogel, hydrogel particles or polymer network in a swollen state", "hydrogel, hydrogel particles or polymer network after equilibrium swelling", or "hydrogel, hydrogel particles or polymer network in a swollen state" are understood to mean hydrogel, hydrogel particles or the polymer network present in preferably physiological saline solution (PBS) and which have absorbed the maximum absorbable amount of liquid in this solution, i.e., are swollen. The hydrogel, hydrogel particles or polymer network have therefore reached their maximum volume expansion in the swollen state, at which point they have absorbed the maximum absorbable amount of liquid.Accordingly, this refers to a state of the particles or polymer network in which the particles or polymer network, in a pharmaceutically acceptable carrier, particularly PBS, have increased their volume relative to the volume present immediately after preparation. The volume swelling is preferably calculated from the change in volume of the hydrogel present immediately after network formation compared to the volume of the swollen hydrogel obtained after incorporation into PBS and the subsequent swelling process. The swollen state is characterized by reaching the equilibrium degree of swelling of the hydrogel, particularly the hydrogel particles, in the solution, i.e., preferably PBS.Thermodynamically, in this state, the expansive forces (osmotic / electrostatic forces and forces due to the excluded volume of the polymer chains) and the elastic restoring forces (due to the covalently bonded network chains) are balanced (see also Freudenberg et al., DOI: 10.1002 / adfm.201101868). Consequently, the hydrogel particles or the polymer network no longer change their state with respect to the degree of swelling in the same solution once they have reached the swollen state. The swollen state can preferably be achieved by incubating the hydrogel particles or the polymer network in a solution, particularly PBS, until their degree of swelling no longer changes, preferably for 1 h, particularly 4 h, particularly 12 h, and particularly 24 h.

[0222] The "swelling" is preferably calculated from the volume change of the polymer network test specimen after network formation and the subsequent swelling in PBS, particularly according to the example in Section AL. According to the invention, the swelling is preferably measured by polymerizing 67 µl of unpolymerized hydrogel mixture with the same chemical composition as the hydrogels to be produced, in particular hydrogel particles, between two 9 mm glass substrates (Menzel-Gläser, Germany) treated with Sigmacote (Sigma-Aldrich, Germany) for 16 h at room temperature, and then removing the resulting hydrogel discs from the glass substrates. The diameter of the hydrogel discs after polymerization was optically determined using an FLA-3100 scanner (Fujitsu, Japan) (diameter of the hydrogel directly after crosslinking / hydrogel formation).Subsequently, the hydrogel discs were swollen for 24 h in phosphate-buffered saline (PBS), 0.9% NaCl buffered to pH 7.4 (Sigma-Aldrich, Germany) under physiological conditions, and their diameters were again determined using the FLA-3100 scanner (Fujitsu, Japan). The degree of swelling of the hydrogels was calculated from the measured diameters using the following equation: Degree of swelling = (diameter of the swollen hydrogel). 3 / (Diameter of the hydrogel directly after cross-linking / hydrogel formation) 3 .

[0223] In connection with the present invention, the term “hydrogel particle” is understood to mean a physical manifestation of the material “hydrogel”, in particular a hydrogel in particle form.

[0224] In the context of the present invention, the term "network" refers to a polymer network, in particular three-dimensionally linked polymer chains. The polymer chains are linked to one another via crosslinking points and are preferably configured as a permanent network, wherein the polymer chains are connected to one another via chemical crosslinking points in the form of covalent bonds. The polymer network according to the present invention has the ability to swell in water, i.e., to absorb water, and is therefore also referred to as a "hydrogel" in connection with the present invention.

[0225] In connection with the present invention, the "concentration of sulfate or sulfonate groups of the hydrogel" is understood to mean the number of free sulfate or sulfonate groups, expressed in moles per volume, present in the entire volume formed by the hydrogel. This concentration is preferably expressed in mmol / L. In a preferred embodiment, the concentration of sulfate or sulfonate groups is calculated by multiplying the concentration of the polyionic polymer component in the swollen hydrogel by the number of repeating units and the number of sulfate or sulfonate groups per repeating unit.

[0226] In connection with the present invention, a “selectively N-desulfated glycosaminoglycan” or “selectively N-desulfated heparin” is understood to mean that the sulfate groups bound to nitrogen atoms of the glycosaminoglycan have been completely or predominantly removed and thus have a lower proportion of sulfate groups compared to the non-desulfated glycosaminoglycan, the lower proportion of sulfate groups being based on the elimination or reduction of the sulfate group content on nitrogen atoms of the glycosaminoglycan.Where the term “PI” is used in connection with the present application, it preferably refers to the concentration of sulfate or sulfonate groups, in particular the charge properties, which preferably result from the concentration of the sulfate or sulfonate groups after equilibrium swelling in physiological saline (PBS), or in particular the global charge density, which preferably results from the concentration of the sulfate or sulfonate groups, especially in the unit mmol / L. In connection with the present invention, the charge density PI is determined by the method described in the example in Section AL.

[0227] The concentration of the polyionic polymer component in the hydrogel, especially hydrogel particles, in the swollen state is calculated by dividing the concentration of the polyionic polymer used in crosslinking by the degree of swelling.

[0228] In connection with the present invention, “star-PEG” or “starPEG” is understood to be a polyethylene glycol molecule comprising a center with several, for example four or eight, in particular four, in particular of equal length, chains covalently bonded to it.

[0229] In the context of the present invention, a "biofluid" is understood to be a liquid that is present in or originates from a living biological system. A biofluid can, for example, be a bodily fluid of a human or animal, in particular a fluid present in a tissue of the human or animal.

[0230] In connection with the present invention, a “lipopolysaccharide” is understood to be a compound of fat-like (lipo) and sugar components (polysaccharides) that can be obtained from the outer membrane of gram-negative bacteria and that can act as an allergen, endotoxin and / or, in particular, a strong inflammatory agent.

[0231] In connection with the present invention, a "non-polymeric crosslinking component" is understood to be an enzymatically cleavable peptide or short molecule having at least two crosslinking-capable groups, wherein the short molecule is a molecule that is itself not suitable for polymerization or a monomer or oligomer with 2 to 10 repeating units, in particular 3 to 4 repeating units. In connection with the present invention, the "volume fraction" of the hydrogel, in particular the hydrogel particles, and of the pharmaceutically compatible carrier are determined by the method described in Example, Section B.

[0232] In connection with the present invention, the "storage module" of the hydrogel, in particular of the hydrogel particles, is understood to be the elastic component of the complex shear modulus. The elastic component is proportional to the proportion of deformation energy that is stored in the material and can be recovered from the material after unloading. This energy is preferably determined in chemically / physically identical hydrogel discs by means of oscillatory rheometry in a plate / plate arrangement by frequency-dependent measurement of the shear modulus. The storage modules specified according to the invention are the storage modules of hydrogel, in particular swollen hydrogel particles, in physiological saline (PBS) solution. In a preferred embodiment, the storage module is determined according to the procedure and measurement method according to the example in Section A1.

[0233] In connection with the present invention, the term “diameter” means the mean diameter of the hydrogel particles, wherein the “diameter” of the hydrogel particles is determined by the method described in the example, Section A2.

[0234] In the context of the present invention, the term "cytokines" refers to proteins that regulate cell growth and / or differentiation. Some cytokines are growth factors, while others play an important role in immunological responses and inflammatory processes and are also referred to as mediators. According to the invention, cytokines preferably include interferons, interleukins, colony-stimulating factors, tumor necrosis factors, and "chemokines," i.e., small signaling molecules.

[0235] In the context of the present invention, the "reduction of the concentration of cytokines, in particular chemokines," is understood to mean that the concentration of free cytokines, in particular chemokines, is reduced in a model liquid, in particular a PB S / B SA solution or an RPMI / B SA solution. This is achieved essentially, without being bound to the theory, by binding the cytokine, in particular chemokine, to the hydrogel particles of the compositions according to the invention, in particular by sequestration. The reduction is preferably measured by adding a predetermined amount of cytokine, in particular chemokine, to a model liquid of a specific volume, wherein a material to be tested, in particular the present therapeutic composition, in particular the hydrogel particles, is present in this model liquid.In connection with the present invention, the “reduction of the concentration of cytokines, in particular chemokines” is determined by means of the method described in the example, section B2.

[0236] In connection with the present invention, the term "crosslinking" is understood to mean the formation of covalent bonds between a polyionic polymer component with at least one uncharged polymer component or with a non-polymeric crosslinking component or with both, preferably by mixing the components together.

[0237] In the context of the present invention, the term “inflammatory bowel disease” is understood to mean an “acute inflammatory” or “chronic inflammatory bowel disease (IBD)”.

[0238] In a preferred embodiment, the “inflammatory bowel disease” is a chronic inflammatory bowel disease, in particular “Crohn’s disease”, “ulcerative colitis” or “indeterminate colitis”.

[0239] In a preferred embodiment, the inflammatory bowel disease is “ulcerative colitis”.

[0240] In a preferred embodiment, the treatment is intended for acute flare-ups or for long-term treatment to prevent or avoid relapses (relapse prophylaxis) of ulcerative colitis.

[0241] In a preferred embodiment, the treatment is a treatment for mild and moderately severe cases of ulcerative colitis.

[0242] In a preferred embodiment, the treatment is a treatment in the area of ​​the large intestine (sigmoid colon) and the rectum, in particular only the rectum.

[0243] In a preferred embodiment, the treatment is for distal or left-sided ulcerative colitis, in particular distal ulcerative colitis. Ulcerative colitis is a disease of the colon (large intestine) and rectum (large intestine) characterized by reddened and swollen (inflamed) intestinal mucosa, frequent and bloody bowel movements accompanied by abdominal cramps.

[0244] In a preferred embodiment, the inflammatory bowel disease is “Crohn's disease”.

[0245] In a preferred embodiment, the treatment is intended for acute flare-ups, in particular active Crohn's disease, or for long-term treatment to prevent or avoid relapses or recurrences (relapse prophylaxis) of Crohn's disease.

[0246] In a particularly preferred embodiment, a therapy for inflammatory bowel disease, in particular chronic inflammatory bowel diseases, according to the present invention leads to symptomatic improvement.

[0247] In a particularly preferred embodiment, a therapy for inflammatory bowel disease, in particular chronic inflammatory bowel disease, according to the present invention leads to a reduction or elimination of at least some of the clinical symptoms of an inflammatory, in particular chronic, inflammatory bowel disease, in particular a reduction or prevention of, in particular a reduction of, inflammatory processes, in particular a reduction of the concentration of inflammatory cytokines, and / or pathological immune reactions.

[0248] In a preferred embodiment, an advantageous effect of the present invention is achieved when an inflammatory response is reduced in a mouse model, in particular when a measure of the extent of an inflammatory response is reduced. Preferably, in connection with the present invention, a measure of the severity of the inflammatory response is selected from the group consisting of body weight loss, intestinal shortening, the disease activity index (DAI, determined according to the method published in Digestive Diseases and Sciences, 1993, 38(9), 1722-1734), the concentration of pro-inflammatory chemokines (e.g., MCP1 or CXCL1, the latter being a murine homolog of IL-8), and the number of immune cells, especially granulocytes, in the tissue, preferably a combination thereof.

[0249] In the context of the present invention, the term "polyionic component" or "polyionic polymer component" or "polyionic polymer" refers to the polyionic unit (also referred to as a charged building block), and the term "uncharged polymer component" or "non-polymeric crosslinking component" refers to the uncharged polymer unit or crosslinking unit that are integrally present in the molecular network of the polymer network. The components of the polymer network are building blocks of the polymer network and are provided in the process for producing the polymer network in the form of a polyionic component, non-polymeric crosslinkers, and uncharged polymers. The term "at least one component" refers to the number of building blocks of which the polymer network consists and can range from 1 to 100,000, preferably 10 to 10,000, or more preferably 100 to 1,000 building blocks.

[0250] The structural formula of the PSS-MA component, which has the sulfonate (sulfonic acid) group and the carboxylate (carboxylic acid) group, is (where x and y are each an integer >1 of the recurring unit):

[0251] Within the scope of the present invention, the term "sulfonate group" refers to the anionic, deprotonated or protonated form of a sulfonic acid group, in particular the anionic form.

[0252] Within the scope of the present invention, the term "sulfate group" refers to the anionic, deprotonated or protonated form of a sulfuric acid group, in particular the anionic form.

[0253] In the context of the present invention, the term "oral administration" preferably means any form of oral administration of a composition in an effective quantity to a patient that effects the targeted delivery and localization of the composition in the patient's gastrointestinal tract. Accordingly, oral administration includes the patient swallowing the composition, for example, a tablet, capsule, granules, or suspension, or enteral nutrition via a nasogastric tube.

[0254] In the context of the present invention, the term "rectal administration" preferably means any form of rectal administration of a composition in an effective quantity to a patient that effects the targeted delivery and localization of the composition in the patient's gastrointestinal tract. Accordingly, rectal administration includes a rectal enema of the composition by the patient, the administration of suppositories, rectal foam, rectal granules, rectal suspensions, or capsules via a rectal tube.

[0255] In the context of the present invention, the term "effective amount" preferably means an amount of a composition that provides the composition of the present invention in a sufficient quantity to achieve a desired treatment outcome in a patient. An effective amount can be administered to the patient in one or more doses to achieve the desired treatment outcome.

[0256] Within the scope of the present invention, the term "use" in connection with a therapeutic method of the present composition means offering, in particular advertising, marketing, teaching or prescribing or selling or administering, in particular ingestion, the present composition and / or a method in which this composition is used, to a patient, such as by medical prescription, packaging, package leaflet, medical information, advice from an expert or physician or pharmacist, technical information in text or oral form, including on the Internet, all of which also include off-label or cross-label use.

[0257] In connection with the present invention, the term "at least one" is understood to mean a quantity expressing a number of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and so on. In a particularly preferred embodiment, the term "at least one" can represent exactly the number 1. In another preferred embodiment, the term "at least one" can also mean 2, 3, 4, 5, 6, or 7. Where quantitative information, in particular percentages, of components of a product or composition is given in connection with the present invention, these, unless explicitly stated otherwise or it is apparent to a person skilled in the art, add up to 100% of the composition and / or product together with the other explicitly stated or apparent components of the composition or product.In connection with the present invention, volumes of pharmaceutically acceptable carriers, expressed in vol.%, add up to 100 vol.% when combined with corresponding volumes of hydrogel, particularly hydrogel particles, expressed in vol.%.

[0258] Insofar as the “presence”, “containing”, “exhibiting” or “content” of a component is expressly mentioned or implied in connection with the present invention, this means that the respective component is present, in particular in a measurable quantity.

[0259] Insofar as the presence, containment or "existence" of a component in an amount of 0 [unit], in particular mg / kg, pg / kg or wt.%, is expressly mentioned or implied in connection with the present invention, this means that the respective components are not present in a measurable amount, in particular are not present.

[0260] In the context of the present invention, the term "and / or" means that all members of a group connected by the term "and / or" are disclosed both alternatively to one another and cumulatively to one another in any combination. For the expression "A, B and / or C", this means that the following disclosure content is to be understood: a) A or B or C, or b) (A and B), or c) (A and C), or d) (B and C), or e) (A and B and C).

[0261] In the context of the present invention, the terms "comprising" and "comprising" are understood to mean that, in addition to the elements explicitly covered by these terms, further, unmentioned elements may be present. In the context of the present invention, these terms are also understood to mean that only the explicitly mentioned elements are covered and no further elements are present. In this particular embodiment, the meaning of the terms "comprising" and "comprising" is synonymous with the term "consisting of." Furthermore, the terms "comprising" and "comprising" also encompass compositions that, in addition to the explicitly mentioned elements, contain further unmentioned elements that are, however, of a functionally and qualitatively subordinate nature. In this embodiment, the terms "comprising" and "comprising" are synonymous with the term "essentially consisting of."The term "consisting of" means that only the explicitly mentioned elements are present and the presence of further elements is excluded.

[0262] Further embodiments of the present invention are the subject matter of the dependent claims and further independent claims.

[0263] The invention is explained in more detail using the following example and the accompanying figures.

[0264] The figures show:

[0265] Figure 1A shows hydrogel particles obtained from polymer mesh plants by mechanical comminution.

[0266] Figure 1B shows macroporous particles produced using method A2.2.3).

[0267] Figure IC shows hydrogel particles obtained using a microfluidic device,

[0268] Figure ID shows further hydrogel particles obtained using a microfluidic device,

[0269] Figure 2 shows results from sequestration experiments,

[0270] Figure 3 shows results on the reduction of immune cell migration from human whole blood,

[0271] Figure 4 shows results regarding the treatment of colitis in a mouse model, Figure 5A shows the hematoxylin and eosin staining of histological sections with particles of type HP9 from formulation F10 adhering to inflamed intestinal tissue (position marked with a dashed line), Figure 5B shows the hematoxylin and eosin staining of histological sections with particles of type HP6 from formulation F8 adhering to inflamed intestinal tissue (position marked with a dashed line) and

[0272] Figure 5C: shows the hematoxylin and eosin staining of histological sections with particles of type HP8 from formulation F9 attached to inflamed intestinal tissue (position marked with a dashed line).

[0273] EXAMPLE

[0274] A) Manufacturing instructions for the hydrogel

[0275] Al: Description of polymer network properties

[0276] Section A1 describes the polymer network properties in general. In Section A2, the polymer networks are transformed into the particle format of hydrogel particles through various processes. The polymer network properties (swelling, stiffness, charge density) depend only on the chemical composition and are independent of the processing into the particle formats.

[0277] The polymer network according to the invention consists of charged building blocks, i.e., the polyionic polymer component, such as glycosaminoglycan, in particular heparin with carboxyl groups (building block GP1) or with maleimide groups, or poly(4-styrenesulfonic acid-co-maleic acid) (PSS-MA) with carboxyl groups (building block GP5) or with maleimide groups (building block GP6), and / or uncharged building blocks, i.e., non-polymeric crosslinking components and / or the uncharged polymer components, for example, uncharged polymers in the form of multi-arm polyethylene glycols (PEG) in amine-terminated (building block UGP1) and / or carboxyl-terminated form (building block UGP3) or in thiol-terminated (building block UGP2) and / or maleimide-terminated form (building block UGP4, see Table 1). The building blocks are covalently cross-linked to form a polymer network, which can be achieved via two processes (carbodiimide chemistry, process AL I) and thiol-maleimide Michael addition, process A1.2)).

[0278] Definition of the molar ratio of the reactive components:

[0279] The polymer network formation can be achieved via carbodiimide chemistry between reactive components with carboxyl groups (GP1, GP5, UGP3) and amino groups (UGP1) (Process ALI, see below) or between reactive components with maleimide groups (GP2, GP3, GP4, GP6, UGP4) and thiol groups (UGP2) (Process A1.2, see below). The structures of the polymer networks preferred according to the invention are defined by the molar concentrations of the polymer network-forming reactive components in the polymer network mixture during crosslinking (see Table 2). These concentrations describe the concentration of the polymer network-forming building blocks immediately after mixing in the reaction state. From these concentrations, the molar ratios of the polymer network building blocks (reactive components) during network formation can be determined, i.e.,the molar ratio of components with amino groups to components with carboxyl groups or of components with thiol groups to components with maleimide groups can be calculated (see Table 2).

[0280] Definition of elastic polymer network and “storage module”:

[0281] The polymer network materials are characterized by the mixing ratios according to Table 2, with the formation of an elastic polymer network serving as a significant criterion. This means that after swelling in PBS, an elastic polymer network results which does not dissolve and is preferably characterized by a storage modulus (determined by rheometry) directly correlated with the elasticity / stiffness of the network, ranging from 0.1 to 22 kPa (Table 2, column L). The storage modulus of the polymer networks is determined by oscillatory rheometry (in kilopascals) using an Ares shear rheometer from TA Instruments, United Kingdom.For this purpose, fully swollen polymer network discs (swollen for 24 h in PBS) are punched out to a diameter of 8 mm in a 9 mm plate-plate measuring setup. Measurements are taken at increasing frequencies from 1 to 100 rad / s at room temperature with minimal deformation (2%), and the mean value is determined over the entire frequency range (one measurement per sample). The reported values ​​are the mean values ​​of four independently produced polymer network discs and are given with or without the standard deviation (SD).

[0282] Definition of "charge density (PI)":

[0283] Besides the storage module, the second important parameter is the charge density in the polymer network, expressed as the concentration of anionically charged sulfate / sulfonate groups in the polymer network after equilibrium swelling in physiological saline (PBS) in mmol / L (see parameter PI in Table 2, column K). For the following calculations, it is assumed that all network building blocks are quantitatively incorporated into the polymer network and remain in the polymer network during the subsequent equilibrium swelling step in PBS. Therefore, the charge properties of the polymer networks (the sulfate / sulfonate concentration PI, Table 2, column K) can be calculated from the reaction mixtures using the molar concentration of the charged building blocks in the reaction mixture (see Table 2, column D) and the degree of volume swelling (see Table 2, column H).First, the concentration of the polyionic polymer component in the swollen polymer network (Table 2, column J) is calculated by dividing the concentration of the polyionic polymer used for polymer network formation (Table 2, column D) by the degree of swelling (Table 2, column H). The concentration of the sulfate or sulfonate groups in the swollen polymer network (parameter PI, Table 2, column K) is then calculated by multiplying the concentration of the polyionic polymer component (the charged building block) in the swollen polymer network (Table 2, column J) by the number of sulfate / sulfonate groups per polymer molecule (Table 1). A parameter range of PI from 0.01 mmol / L to 800 mmol / L is provided for this calculation; particularly advantageous ranges are 20 to 500 mmol / L, and especially 50 to 200 mmol / L.

[0284] Definition of "swelling":

[0285] The swelling is calculated from the volume change of the polymer network test specimens after network formation and the subsequent swelling in PBS. The swelling is measured by polymerizing 67 pl of unpolymerized polymer network mixture with the same chemical composition as the hydrogel particles to be produced between two 9 mm glass substrates (Menzel-Gläser, Germany) treated with Sigmacote (Sigma-Aldrich, Germany) for 16 h at room temperature, and then removing the resulting polymer network discs from the glass substrates. The diameter of the polymer network discs after polymerization is optically determined using an FLA-3100 scanner (Fujitsu, Japan) (diameter of the polymer network disc immediately after crosslinking).Subsequently, the polymer network discs are swollen for 24 h in phosphate-buffered saline (PBS), 0.9% NaCl buffered to pH 7.4 (Sigma-Aldrich, Germany) under physiological conditions, and their diameters are again determined using the FLA-3100 scanner (Fujitsu, Japan). The swelling of the polymer networks is calculated from the determined diameters using the following equation: Swelling = (diameter of the swollen polymer network disc). A 3 / (Diameter of the polymer network disk directly after network formation) A 3. Only the polymer networks swollen in PBS are used for further characterization (rheometry to determine the storage modulus, sequestration of IL-8) and the preparation of compositions. Al.l) Crosslinking of the polymer networks using carbodiimide chemistry

[0286] The polymer network is preferably obtained according to method Al. l) by activating the carboxyl groups of the charged building block (GP1, GP5) with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) / N-hydroxysulfosuccinimide (sNHS) and either by direct crosslinking with the uncharged building block containing amino groups (UGP1) or via crosslinker molecules with at least two amino groups, each with amide formation. To vary the charge properties (especially the parameter PI, the global charge density), a second uncharged building block with carboxyl groups (for example, building block UGP3, 8-ArmPEG, carboxytermini ert)) can also be used as a third building block of the polymer network, which, like the charged building block, is activated at the carboxyl groups via EDC / sNHS.The network is then formed via crosslinking between a charged building block (GP1 or GP5) and / or an uncharged building block UGP3 on the one hand, and an uncharged building block UGP1 (amine-terminated) on the other. The structures of the polymer networks preferred according to the invention are defined by the molar concentrations of the reactive components in the polymer network mixture during crosslinking (see Table 2). These concentrations describe the concentration of the network-forming building blocks immediately after mixing in the reaction state. From these concentrations, the molar ratios of the polymer network building blocks during network formation can be calculated (see Table 2). Network formation takes place over a period of 12 hours, whereby the polymer network formed after this period corresponds to the polymer network state after crosslinking, in particular after process step A).To produce the polymer meshes of types 1-9, 16, and 20, all components (GP1, GP5, UGP1, UGP3) are dissolved for 5 minutes by ultrasonic treatment. The initial concentrations are chosen so that, after mixing the 1 to 3 volume parts (for components GP1, GP5, UGP1, UGP3), the concentration of the building blocks GP1, GP5, UGP1, and UGP3 in the final reaction mixture corresponds to the values ​​in Table 2. The activation reagents EDC / sNHS are dissolved stoichiometrically in ultrapure water in the ratio of the amino groups present in the reaction mixture (4 times the molar concentration of building block UGP1 due to its molecular architecture with the 4-arm PEG) as follows: 2 mol EDC per mol amino group and 1 mol sNHS per 1 mol amino group result in the final reaction mixture.The activation reagents are then combined with the carboxyl group-bearing components (GP1, GP5, UGP3) and activated for 10 minutes at room temperature. Subsequently, component UGP1 is added to the mixture of the components with carboxyl groups and the activation reagents to initiate the covalent network formation of the material.

[0287]

[0288] Table 2: Formation procedure and physicochemical description of the polymer networks, types 1 to 21. The number of sulfate / sulfonate groups per dry mass (column O) is calculated using the number of sulfate / sulfonate groups per molecule (Table 1) and the weight fraction of GP in the dry mass of the polymer network in the dried / unhydrated state. The latter is determined from the molecular weights (Table 1) and the proportions of GPs and UGPs in the polymer network mixture during network formation, unswelled.

[0289]

[0290] A 1.2) Crosslinking of polymer networks using thiol-maleimide Michael Addition

[0291] The polymer network is preferably obtained by method Al.2) by crosslinking the charged building block with maleimide groups (GP2, GP3, GP4, GP6, maleimide functionalization according to the synthesis procedure published in Journal of Controlled Release, 2013, 167, 248-255, desulfation according to the synthesis procedure published in Biomaterials, 2018, 181, 227-239) with the thiol-terminated uncharged building block (UGP2) and / or via crosslinker molecules with at least two thiol groups, each with thioether formation. To vary the charge properties (especially the parameter PI, the global charge density), a second uncharged building block with maleimide functionalization (for example, building block UGP4, 4-arm PEG, maleimide-terminated) can also be used as a third building block of the polymer network.The network is then formed by crosslinking between a charged building block (GP2, GP3, GP4, or GP6) and / or an uncharged building block UGP4 on the one hand, and an uncharged building block UGP2 (thiol-terminated) on the other. The structures of the polymer networks preferred according to the invention are defined by the molar concentrations of the reactive components in the polymer network mixture during crosslinking (see Table 2). These concentrations describe the concentration of the network-forming building blocks immediately after mixing in the reaction state. From these concentrations, the molar ratios of the polymer network building blocks during network formation can be calculated (see Table 2). Network formation takes place over a period of 10 minutes, whereby the polymer network formed after this period corresponds to the polymer network state after crosslinking, in particular after process step A).To produce the polymer networks of types 10-15, 17-19, and 21, the components (GP2, GP3, GP4, GP6, UGP2, UGP4) are dissolved for 5 minutes by ultrasonic treatment (the initial concentrations are selected such that, after mixing the 1 to 3 volume parts (for the components GP2, GP3, GP4, GP6, UGP2, UGP4), the concentration of the building blocks GP2, GP3, GP4, GP6, UGP2, UGP4 in the final reaction mixture corresponds to the values ​​in Table 2). The maleimide-functionalized component (GP2, GP3, GP4, GP6, UGP4) is then mixed with the thiol-terminated component (UGP2) to initiate the covalent polymer network formation of the material. If a maleimide-functionalized charged component (GP2, GP3, GP4, GP6) and a maleimide-terminated uncharged component (UGP4) are used, These are combined before mixing with the thiol-terminated component. A2: Manufacturing procedure for the hydrogel particles.

[0292] The polymer networks, according to the formation procedure in Al), can preferably be processed into hydrogel particles of the preferred size range by four different methods. The hydrogel particles are present in a swollen (hydrated) state (e.g., in physiological saline (PBS)). The hydrogel particles can also be present in a dried (dehydrated) state and subsequently rehydrated. The composition and physical properties of the different particles are summarized in Table 3.

[0293] Definition of the “mean diameter” (size) of the hydrogel particles:

[0294] The target parameter is the predominant mean particle size (mean diameter) in the final particle suspension. The size of the resulting particles (diameter for spherical particles according to methods A2.2–A2.4), diameter of a circle with the same projection area for non-spherical particles according to method A2.1) is characterized by bright-field microscopy (e.g., 1X73, Olympus, Hamburg, Germany) and Fiji / ImageJ after equilibrium swelling in physiological saline (PBS).

[0295] A2.1 Production of the particles by processing the volume gels

[0296] The particles can be produced by process A2.1) from bulk gel materials produced according to process A1) by suitable mechanical comminution, for example, milling, cryogenic milling, shredding, high-pressure or ultrasonic treatment of the polymer networks. Ultrasonic comminution is advantageously used for this purpose, in which polymer networks completely swollen in PBS according to process A1) are treated as gel bodies in five times their volume of PBS for 10 minutes at full power in a Bandelin Sonoplus ultrasonic homogenizer (Germany). The particle mixture can then be filtered through a filter with a mean pore size of 200 pm to remove any remaining larger fragments. Other filter pore sizes (e.g.,pluriStrainer 1-1000 pm, pluriSelect, Leipzig, Germany) are possible, as are combinations of filters with larger (separation of larger fragments) and smaller pore sizes (separation of smaller fragments). Figure 1A shows such hydrogel particles obtained by mechanical comminution from polymer mesh plants.

[0297] A2.2 Production of Particles by Emulsification The particles can alternatively be produced by method A2.2) via crosslinking according to method A2.1). For this purpose, a water-in-oil emulsion is used as follows. The solutions of components (GP1, GP5, UGP3) + EDC / sNHS and component UGP1 (concentrations and mixture according to the Al formation procedure) are premixed, and 200 pl of the polymer network reaction mixture (aqueous phase) is added to 4 mL of toluene (the non-solubular medium (organic phase) containing Synperonic PEP 105 as a stabilizer). The two-phase system is stirred at room temperature (600 rpm) for 13 minutes to form droplets. After 12 minutes, an additional 1 mL of a higher concentration Synperonic solution (20 mg / mL) is added to prevent droplet agglomeration.The droplets formed in the dispersion react during the subsequent residence time in a collection container for 1-12 hours. They are then purified and completely swollen by removing the toluene (after centrifugation with 400 g for 2 minutes) and washing several times in PBS. The resulting particle mixture can then be filtered through a filter or a combination of filters with different pore sizes (e.g., pluriStrainer 1-1000 pm, pluri Select, Leipzig, Germany) to remove any remaining larger and / or smaller fragments.

[0298] A2.2.3 Production of Macroporous Particles

[0299] To produce macroporous particles of the polymer network, the dispersion formed according to process A.2.2) (after 13 min of stirring) is cooled to -20 °C in an ethanol bath cooled by an immersion chiller (TC 100E-F-NR, Huber, Germany). The frozen droplets are stirred for 2 hours at -20 °C before settling and remaining overnight at -20 °C. The particles are freeze-dried overnight to remove the organic phase and ice crystals. Subsequently, the particle mixture can be filtered through a filter or a combination of filters with different pore sizes (e.g., pluriStrainer 1-1000 pm, pluriSelect, Leipzig, Germany) to remove any remaining larger and / or smaller fragments. The particles are washed three times with ethanol and twice with PBS. Figure 1B shows macroporous particles produced by process A2.2.3).

[0300] A2.3 Production of particles by emulsification using a microfluidic approach and carbodiimide chemistry

[0301] The particles can alternatively be produced by process A2.3 via crosslinking according to process Al. l) using suitable microfluidic methods, in particular flow focusing, as follows: For this purpose, the solutions of components (GP1, GP5, UGP3) + EDC / sNHS and component UGP1 (concentrations and mixture according to the formation procedure of Al) are premixed at 4 °C and then fed through a microfluidic chip with a crossover arrangement (one aqueous phase inlet for the cooled gel mixture and one inlet for the organic phase) at a flow rate of 10-20 pl / min (of the aqueous phase of the polymer network) into an organic phase consisting of 3M™ Novec™ 7500 Engineered Fluid (3-Ethoxy-l, 1, 1,2, 3, 4, 4, 5, 5, 6, 6,6-dodecafluoro-2-(trifluoromethyl)hexane) and 1% PFPE-PEG-PFPE surfactant (Krytox™ 157 FSH (DuPont) - Jeffamine™ ED 600 Amines (Huntsman) - Krytox™ 157 FSH (DuPont), available from the synthesis procedure published in Lab Chip, 2008, 8, 1632-1639) are dispersed into droplets at a flow rate of 10-20 pl / min. The geometry of the microfluidic chip and the ratios of the flow rates of the two phases determine the final particle size. The droplets formed in the dispersion react within the flow path and during a subsequent residence time in a collection container for a period of 1-12 hours. They are then treated by adding a 1:1 volume fraction of 1H, 1H, 2H,The 2H-perfluoro-l-octanol and Novec™ 7500 phases were separated and subsequently purified and fully swollen by repeated washing in PBS. This process yields spherical particles with a narrow size distribution, exhibiting deviations of less than 10% of the mean particle diameter. This diameter can be adjusted via the channel size of the microfluidic device within a range of 10–300 pm. Figure IC shows such hydrogel particles obtained using a microfluidic device.

[0302] Alternatively, macroporous hydrogel articles can be produced using procedure A2.2.3). For this purpose, the formed droplets are collected at 4°C and then further processed according to procedure A2.2.3).

[0303] A2.4 Production of particles by emulsification with microfluidic approach and thiol-maleimide Michael Addition

[0304] The particles can alternatively be produced by method A2.4 (via crosslinking according to method A1.2) using suitable microfluidic methods, in particular flow focusing, as follows: The hydrogel particles are synthesized from PDMS (SYLGARD™ 184 Silicon Elastomer Kit, Dow, Midland, USA) by microfluidic-assisted formation of water-in-oil emulsions using flow-focusing devices (according to the method published in bioRxiv 2024.01.05.574387). Prior to synthesis, the components are treated with 0.5% (v / v) trichloro-(1H,1H,2H,2H-perfluorooctyl)silane (aber, Karlsruhe, Germany) in fluorinated oil (hydrofluoroether; HFE, Novec™ 7500) to increase the hydrophobicity of the channel walls. During particle synthesis, the organic phase and the building block solutions are transferred through polyethylene tubing (e.g., by syringe pumps such as LA-30, Landgraf Laborsysteme HLL GmbH, Langenhagen, Germany or 11 Pico Plus Elite, Harvard Apparatus, Holliston, USA) using syringe pumps (e.g.,A. Hartenstein GmbH, Würzburg, Germany) are injected together into the device. The aqueous phase (dispersed phase) thus consists of three parts: the two solutions of the building blocks and phosphate-buffered saline (PBS) (Sigma-Aldrich Merck KGaA, Darmstadt, Germany). The solution of the thiol-terminated building block (UGP2) is injected into one channel, the solution of the maleimide-functionalized building blocks (GP2, GP3, GP4, GP6, UGP4) into a second channel, and PBS into a third channel, each at a rate of 50–130 pl / h. In the microfluidic device, which defines the size criteria (diameter), the three channels converge and meet the organic (continuous) phase (injection at 300–1300 pl / h) at an orthogonal angle, leading to droplet formation. Crosslinking of the components occurs after droplet formation and mixing of the different precursor solutions in the outlet channel of the microfluidic device.The concentrations of the building blocks correspond to the formation formula of Al). The fluorinated oil used for the organic phase of the emulsion (continuous phase) is stabilized with 1% w / v of an internally synthesized triblock copolymer surfactant (Krytox™ 157 FSH (DuPont) - Jeffamine™ ED 600 Amines (Huntsman) - Krytox™ 157 FSH (DuPont), available from the synthesis formula published in Lab Chip, 2008, 8, 1632-1639). The particle (water)-in-oil emulsions are collected in a reaction tube and then stored at 4 °C for further processing. A microscope (e.g. Primovert, Zeiss, Oberkochen, Germany) and a high-speed camera (e.g. Phantom Miro eX4, Vision Research, Wayne, USA) are used to monitor the operation of the device.To break the emulsion and transfer the particles into an aqueous buffer (PBS), the particles are washed several times with pure HFE and then incubated with continuous stirring in reaction vessels containing HFE with 20% (v / v) perfluorooctanol (Alfa Aesar, Haverhill, USA) and PBS. The remaining organic phase is filtered from the reaction tube after a centrifugation step at 500 x g. This process yields spherical particles with a narrow size distribution, with deviations of < 10% of the mean particle diameter. This diameter can be adjusted via the channel size of the microfluidic device in the range of 10–300 pm. Figure ID shows such hydrogel particles obtained using a microfluidic device. Table 3: Composition and physicochemical description of the hydrogel particles.

[0305] B) Manufacturing instructions for therapeutic formulations for administration in

[0306] Gastrointestinal tract and evidence of efficacy

[0307] Bl: Description of the therapeutic formulations

[0308] The therapeutic composition for use in inflammatory bowel diseases comprises, in particular, a mixture of hydrogel particles and a pharmaceutically acceptable carrier. The composition (designated F1-F10, see Table 4) is prepared by mixing variable volume fractions of the two components: 1) hydrogel particles and 2) PBS or RPMI + 0.1% BSA, forming a suspension. Component 1 (hydrogel particles) is specified according to the polymer network formation instructions according to A1) (polymer network types 1-21, see Table 2) and a manufacturing process according to A2) (HP1-HP9, see Table 3). Mixing is carried out according to the volume fractions listed in Table 4. Components 1 and 2 are mixed by suitable homogenization (for example, by stirring for 5 minutes at a speed of 200 rpm).

[0309] Definition of the "volume fraction" of the hydrogel particles:

[0310] The target parameter of the composition is the volume fraction of the hydrogel particles. To calculate the volume fraction, the mean volume of the particles is first calculated based on their mean diameter (calculation for a sphere using the diameter for spherical particles according to methods A2.2-A2.4) and using the diameter of a circle with the same projection area for non-spherical particles according to method A2.1)), and then multiplied by the concentration of the particles in the mixture. To determine the particle concentration in the suspension, the particles in a defined volume are counted under a microscope (e.g., 1X73, Olympus, Hamburg, Germany). The volume fraction of the hydrogel particles in the composition can be adjusted by adding or removing the carrier (component 2) and corresponds to the specifications in Table 4.

[0311] Table 4: Formation procedure for therapeutic compositions, Fl to F10. The number of sulfate-sulfonate groups in the final composition is calculated from the weight fraction of dry hydrogel particles in the final composition (Table 4) and the number of sulfate / sulfonate groups per dry mass (Table 2, column O). B2: Sequestration of inflammatory factors in vitro. The composition also exhibits the significant property of potentially sequestering pro-inflammatory chemokines. The composition is characterized by its ability to bind a certain percentage of factors from the group of pro-inflammatory chemokines from an application-relevant solution.

[0312] Interleukin-8 (IL-8, CXCL8) is an important soluble signaling molecule that, as a chemokine, regulates the migration of immune cells and acts, for example, as a highly potent chemoattractant for neutrophils. To characterize IL-8 binding, a 0.1% albumin solution (BSA) in PBS is prepared, containing approximately 20, 200, and 2000 ng / ml of IL-8 (8.9 kDa, Peprotec). The composition (see Table 4, 250 pl each) is then contacted with a volume of 250 pl of the IL-8 solution for 24 hours at room temperature in a centrifuge filter with a pore size of 0.2 pm (Corning Costar SpinX, Sigma-Aldrich Merck KGaA, Darmstadt, Germany). The IL-8 solution is then collected by centrifugation to determine the depletion of IL-8 in the supernatant compared to an untreated control solution (without hydrogel particles) using ELISA (DuoSet kit, R&D Systems, Minneapolis, USA).

[0313] The results are shown in Figure 2 and demonstrate a depletion that depends on the polymer network type, but not on the particle type (n=3, mean + SD). The polymer network in composition F4 (polymer network type 21, see Table 2, particle type HP9, see Table 3) contains only uncharged building blocks (UGP2 and UGP4) and binds IL-8 least weakly. All compositions with charged building blocks (F1-F3) bind at least 80% IL-8. Compositions F2 and F3, which contain the building block GP6 in the polymer network (polymer network type 17, see Table 2, particle types HP1 and HP8, see Table 3), both bind more than 95% IL-8 and thus surprisingly deplete the solution more than composition Fl, which contains the building block GP2 in the polymer network (polymer network type 11, see Table 2, particle type HP6).

[0314] B3: Reduction of immune cell migration from human whole blood

[0315] The composition also exhibits the significant property of reducing immune cell migration by sequestering pro-inflammatory chemokines. This composition is characterized by its ability to reduce the migration of immune cells from a tissue relevant to the application by a certain percentage. To analyze the potential of the compositions to sequester IL-8 and reduce granulocyte migration, 450 gl of compositions F5-F7, as well as pure RPMI + 0.1% BSA (without hydrogel particles as a control), are brought into contact with 450 gl of IL-8 solution (10 ng / ml) in RPMI with 0.1% BSA in centrifuge filters (0.2 gm pore size) for 24 hours on a shaker (60 rpm). The supernatant is then collected by centrifugation, and 850 gl are transferred to a 24-well plate (TPP, Trasadingen, Switzerland).Cell migration is determined as follows: Fresh human whole blood is drawn from healthy human volunteers who have not taken any medication in the preceding 10 days, and the blood is anticoagulated with hirudin (Refludan 1 gM; Celgene, Munich, Germany). Subsequently, 200 g of blood is transferred into hanging Transwell inserts (8 gM; PET, Merck Millipore), and the inserts are placed into 24-well plates containing the supernatants. The samples are incubated at 37 °C and 5% CO2 for two hours. The migrated blood cells are collected from the bottom of the wells and washed with RPMI before being analyzed by flow cytometry. For flow cytometry, the cells are treated with an FcR blocking reagent (Miltenyi Biotec, Bergisch Gladbach, Germany) and stained with a PE-labeled anti-human CD15 antibody (BioLegend, USA) for 30 minutes in the dark at room temperature.The erythrocytes are then lysed by adding lysis solution (Becton Dickinson, Franklin Lakes, USA) and additional washing in lysis solution. CD15+ granulocytes are counted using an LSRFortessa flow cytometer (Becton Dickinson, Heidelberg, Germany).

[0316] The results are shown in Figure 3 and demonstrate a reduction in granulocytes that depends on the polymer network type (n=4, mean + SD, Student's t-test, * (** (p < 0.01), **** p < 0.0001), ns stands for not statistically significant). The polymer network in composition F7 (polymer network type 21, see Table 2, particle type HP9, see Table 3) contains only uncharged building blocks (UGP2 and UGP4) and does not lead to a reduction in granulocyte migration compared to the control (without hydrogel particles). All compositions with charged building blocks (F5 and F6) significantly reduce cell migration compared to the control, with surprisingly, composition F6, which contains the building block GP6 in the polymer network (polymer network type 17, see Table 2, particle type HP8, see Table 3), reducing cell migration more than composition F5, which contains the building block GP2 in the polymer network (polymer network type 11, see Table 2, particle type HP6).

[0317] B4: Treatment of colitis in a mouse model. A particularly advantageous property of the composition is the reduction of inflammation in the damaged intestine. To determine the reduction of inflammation in the intestine, a mouse model (C57BL / 6J mice) is used in which colitis is induced by administering dextran sulfate sodium salt (DSS, MP Biomedicals, 2% in H2O, according to the method published in Science Immunology, 2021, Vol. 6, No. 65, p. eabf7473) in the drinking water every 5 days. A measure of the severity of inflammation is the loss of body weight, a shortening of the intestine, the disease activity index (DAI, determined according to the method published in Digestive Diseases and Sciences, 1993, 38(9), 1722-1734), the concentration of pro-inflammatory chemokines (e.g. MCP1 or CXCL1, the latter being a murine homolog of IL-8), and the number of immune cells, especially granulocytes, in the tissue.

[0318] To determine the inflammatory status of the tissue, samples from the distal part of the mouse colon are frozen in liquid nitrogen and stored at -80 °C until further analysis. The samples are homogenized using a bead mill with 4.7 mm stainless steel beads (SpeedMill PLUS and innuSpeed ​​Lysis Tubes J, Analytic Jena GmbH, Jena, Germany). Homogenization buffer (500 pl / 100 mg sample; Thermo Fisher, Dreieich, Germany) is added, and the samples are milled in six 30-second intervals. Tissue debris is pelletized by centrifugation at 10,000 x g for 10 minutes, and protein concentrations are determined by multiplex immunoassay (Luminex).

[0319] Immunohistochemistry for the determination of immune cells in tissue was performed on paraffin-embedded tissues. After deparaffinization, antigen recovery was carried out in citrate buffer (1.8% 0.1 M citric acid, 8.2% 0.1 M sodium citrate) for 25 min at 95 °C; the sections were washed in PBS, incubated in H₂O₂ for 10 min, blocked in 1% BSA in PBS-Tween 20, incubated for 1 h at room temperature with the primary antibody (anti-mouse Ly6G, E6Z1T, 1:100, Cell Signaling Technology), and washed in PBS. The sections were incubated with EnVision secondary antibodies (Dako, Hamburg, Germany) for 30 min at room temperature, washed, incubated with the EnVision DAB Kit (Dako), counterstained with Hemalaun, and embedded with Entellan (Merck Millipore).

[0320] Two days (Figure 4A, B, DF) or five days (Figure 4C) after the start of DSS administration, daily rectal administration of the composition (200 pl / day) is initiated. The data in Figures A, B, C, and DF are each from separate trials. The results are shown in Figure 4 (mean + SD, Student's t-test, * (p < 0.05), ** (p < 0.01), *** (p < 0.001) or **** (p < 0.0001), ns stands for not statistically significant) and demonstrate a reduction in inflammation that is dependent on the polymer network type and, surprisingly, is strongest for composition F9, which contains the charged building block GP6 in the polymer network (polymer network type 17, see Table 2; particle type HP8, see Table 3). The body weight loss of the mice is lowest with treatment with composition F9 (Figure 4A, n=4) and thus significantly lower than with the control treatment with PBS (without hydrogel particles).Intestinal shortening is also least pronounced with the treatment using composition F9 compared to the control treatment with composition F10 (hydrogel particles containing only uncharged building blocks in the polymer network, Figure 4B, n=9 for F8, n=7 for F9, n=10 for F10). Intestinal shortening is also reduced by composition F8 (polymer network type 11, see Table 2, particle type HP6, see Table 3), which contains the charged building block GP2 in the polymer network (Figure 4B), albeit to a lesser extent than by composition F9. The DAI (Figure 4C, n=6 for PBS, n=10 for F10, n=9 for F9) is significantly lower with the treatment using composition F9 than with the control treatment using PBS. A control treatment with composition F10 (hydrogel particles containing only uncharged building blocks in the polymer network) does not lead to a reduction in the DAI.After nine days of treatment with composition F9, significantly lower concentrations of the pro-inflammatory chemokines MCP1 (Figure 4D, n=5) and CXCL1 (Figure 4E, n=5) and a lower number of Ly6G+ granulocytes were detectable in intestinal tissue compared to the control treatment (Figure 4F, n=8 for F8, n=6 for F9, n=8 for F10, Mann-Whitney U test). Figure 5A shows the hematoxylin and eosin staining of histological sections with particles attached to inflamed intestinal tissue (position marked with a dashed line) of type HP9 from formulation Fl 0, Figure 5B of type HP6 from formulation F8, and Figure 5C of type HP8 from formulation F9. A very weak adhesion of a few particles of the uncharged type HP9 to the inflamed intestinal tissue is evident (F10, PEG-PEG).A significantly increased adhesion of the charged particles of type HP6 (F8, PEG-Heparin) and type HP8 (F9, PEG-PSS-MA) to the inflamed areas in the intestine is evident in Figures 5B and 5C (particles are located directly adjacent to the inflamed intestinal tissue infiltrated with immune cells), with the number of adherent particles (as a measure of adhesion) increasing in the following order: type HP9 (F10, PEG-PEG) ≤ HP6 (F8, PEG-Heparin) ≤ type HP8 (F9, PEG-PSS-MA). In particular, Figure 5C shows a very large number of adherent hydrogel particles of type HP8 in the area of ​​the inflamed intestinal tissue. To further determine the reduction of inflammation in the intestine, a mouse model (C57BL / 6J mice) is used in which T-cell-mediated colitis is induced by treatment with trinitrobenzenesulfonic acid (TNBS, Sigma-Aldrich, 2.5% in ethanol, according to method published in Current Protocols in Pharmacology, 2009, 46.1, 5-55).One indicator of the severity of the inflammation is weight loss. One day after starting the DSS.

[0321] Administration begins with daily rectal administration of the composition (200 pl / day).

[0322] The results show that the mice treated with composition F9 have a significantly higher body weight after five days than the corresponding control groups (PBS and composition F10) (Figure 4 G, n=6 for PBS, n=6 for F10, n=5 for F9).

Claims

REQUIREMENTS 1. Therapeutic composition comprising a hydrogel for use in a procedure for the treatment of inflammatory diseases in the gastrointestinal tract of a human or animal patient, wherein the hydrogel has at least one polyionic polymer component which is covalently linked to at least one uncharged polymer component and / or a non-polymeric crosslinking component to form a network, wherein the at least one polyionic polymer component has sulfate or sulfonate groups and wherein the at least one polyionic polymer component is a poly(4-styrenesulfonic acid)-based polymer component, in particular a poly(4-styrenesulfonic acid-co-maleic acid) component, or heparin or selectively desulfated heparin.

2. Therapeutic composition for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient according to claim 1, wherein the therapeutic composition comprises at least one pharmaceutically acceptable carrier.

3. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to claim 2, wherein the at least one pharmaceutically acceptable carrier is a solid, semi-liquid or liquid carrier.

4. Therapeutic composition for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the hydrogel is in the form of hydrogel particles or in the form of a non-particulate hydrogel.

5. Therapeutic composition for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient according to any one of the preceding claims 2 to 4, wherein the hydrogel is in mixture with the pharmaceutically acceptable carrier or in covalently or non-covalently carrier-bound form.

6. Therapeutic composition for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient according to claim 5, wherein the hydrogel, which is in covalently or non-covalently carrier-bound form, is in the form of a coating of the pharmaceutically acceptable carrier.

7. Therapeutic composition for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the therapeutic composition is in the form of a suspension.

8. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the suspension is a suspension of hydrogel particles in a liquid pharmaceutically acceptable carrier or a suspension of particulate carrier-bound hydrogel in a liquid pharmaceutically acceptable carrier.

9. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any one of the preceding claims 2 to 8, wherein the hydrogel content is 1 to 99 vol% and the pharmaceutical carrier content is 99 to 1 vol% (each based on the total volume of the composition) and wherein the composition has a number of sulfate / sulfonate groups of 0.0002 to 2.3 mmol / g (each based on the total mass of the composition).

10. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the at least one uncharged polymer component is selected from the group consisting of polyethylene glycol (PEG) component, poly(2-oxazoline) (POx) component, polyvinylpyrrolidone (PVP) component, polyvinyl alcohol (PVA) component, polyacrylamide (PAM) component and combinations thereof.

11. Therapeutic composition for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the at least one uncharged polymer component is a polyethylene glycol component, in particular a linear or multi-armed, in particular four- or eight-armed, polyethylene glycol component.

12. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the at least one non-polymeric crosslinking component is selected from the group consisting of ethylenediamine, propylenediamine (1,3-diaminopropane), butane-1,4-diamine, pentane-1,5-diamine (cadaverine), hexamethylene-1,6-diamine, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, N-(2-aminoethyl) maleimide and combinations thereof.

13. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the uncharged polymer component and the polyionic polymer component are covalently linked to each other by means of at least one crosslinking component, in particular peptides, or directly, in particular by means of an amide bond, thiol-amine bond, disulfide bond or bioorthogonal thioether bond obtainable by thiol-maleimide, thiol-vinylsulfone or thiol-acrylate reaction.

14. Therapeutic composition according to any of the preceding claims, wherein the hydrogel has a number of sulfate or sulfonate groups per dry mass (polymer network in dried, non-hydrated state) of 0.02 to 5 mmol / g.

15. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the hydrogel particles have a mean diameter of at most 5000 pm, in particular at most 300 pm, in particular at most 80 pm (in each case measured on hydrogel particles swollen in physiological saline (PBS) solution).

16. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the hydrogel, in particular the hydrogel particles, has a sulfate or sulfonate group concentration of at least 0.01 mmol / l, in particular at least 10 mmol / l, in particular at least 100 mmol / l, in particular 0.01 to 800 mmol / l, in particular 10 to 800 mmol / l, in particular 20 to 500 mmol / l, in particular 20 to 200 mmol / l, in particular 50 to 200 mmol / l (in each case measured in the volume of hydrogel, in particular swollen hydrogel particles, in physiological saline (PBS) solution).

17. Therapeutic composition for use in a method for treating inflammatory diseases in the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the composition comprises a mass fraction of the polymer mesh of 0.04 to 99 wt.%, in particular 0.04 to 5 wt.%, in particular 60 to 99 wt.% (in each case based on the total mass of the composition).

18. Therapeutic composition for use in a method for treating inflammatory diseases of the gastrointestinal tract of a human or animal patient according to any of the preceding claims, wherein the composition comprises at least one pharmaceutically active substance, in particular selected from the group consisting of an aminosalicylate, in particular mesalazine (5-aminosalicylic acid), budesonide, budesonide MMX and a combination thereof.

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