Resorbable sheet material comprising porous collagen sponge and nanoparticles or microparticles which release active ingredients in a controlled manner, use thereof, and method for the production thereof

Abstract

The invention relates to a profiled sheet material which has a resorbable porous collagen sponge in which resorbable nanoparticles or microparticles or combinations thereof are dispersed, wherein the nanoparticles or microparticles have at least two different release profiles for the controlled and / or delayed release of pharmaceutical active ingredients. The invention further relates to a method for producing the sheet material and to the use thereof in a method for treating wounds or in a method for local pharmacotherapy.

Description

[0001] 4232-3-PCT MD2B LifeScience GmbH

[0002] Resorbable flat material with porous collagen sponge and controlled active ingredient-releasing nano- or micro-parts, no description of its use and method for its manufacture.

[0003] The invention relates to a flat material comprising a resorbable porous collagen sponge in which resorbable nano- or microparticles, or combinations thereof, are dispersed, wherein the nano- or microparticles exhibit at least two different release profiles for the controlled and / or delayed release of pharmaceutical agents. The invention further relates to a method for producing the flat material and its use in a wound treatment method or in a local pharmacotherapy method.

[0004] Background of the invention

[0005] The background and objective of the invention are explained below using the example of treating wounds with drug-releasing wound dressings. However, it is clear to those skilled in the art that these statements apply analogously to any drug-releasing delivery system, for example, to transdermal delivery systems such as plasters for the topical treatment of skin diseases.

[0006] Modern wound care has made significant progress in recent decades, with collagen-containing wound dressings with drug delivery considered a major breakthrough. These innovative products combine the natural healing properties of collagen with the targeted delivery of therapeutic agents to accelerate the healing process and minimize complications.

[0007] Collagen is a natural protein found in skin and connective tissue. It plays a key role in wound healing by serving as a scaffold for tissue regeneration. Collagen promotes cell migration and proliferation, supports the formation of new tissue, and improves wound strength. Because of these properties, collagen is an ideal ingredient for wound dressings. 4232-3-PCT MD2B LifeScience GmbH

[0008] Collagen-containing wound dressings are able to maintain a moist wound environment, which is essential for optimal healing. They reduce pain and minimize scarring by protecting the wound from external influences and holding the wound edges together. These dressings are particularly effective for chronic wounds, such as diabetic foot ulcers, pressure ulcers, and venous ulcers, which are difficult to treat due to impaired healing.

[0009] The combination of collagen with the controlled release of therapeutic agents significantly increases the efficacy of wound dressings. These agents can include, for example, antibiotics, antiseptics, anti-inflammatories, or growth factors. By delivering these substances directly to the wound site, local therapy is optimized, reducing systemic side effects and shortening the healing time. The release of the agents can be controlled by various mechanisms, such as hydrolytic degradation or pH-sensitive polymers.

[0010] However, problems can also arise when using drug-eluting wound dressings. For example, some patients may be allergic to the collagen backing material or the added active ingredients, which can lead to inflammation or other allergic reactions. In some cases, the released active ingredients can cause hypersensitivity reactions or impair healing if they are not precisely tailored to the specific needs of the wound. It is therefore important that the choice of wound dressing is individually tailored to the patient and the specific needs of the wound. Furthermore, conventional drug-eluting wound dressings have the disadvantage that they release a large proportion of the active ingredient in an early phase of application (the so-called burst effect) and only a small amount in later phases. Therefore, their use for covering wounds inside the body, e.g.,After tumor resection, the use of drug-eluting dressings is limited if a second surgical procedure is required to replace the dressing with fresh drug. Another limitation of conventional drug-eluting dressings is that the use of two or more drugs is often not possible, as the drug release profiles cannot be coordinated as required or desired. For example, in the case of tumor resection, it would be advantageous to use a dressing designed for 4232-3-PCT MD2B LifeScience GmbH.

[0011] to have available, for example, an antibiotic and / or analgesic that is rapidly released in an early phase of application to prevent infection of the wound and to relieve pain, and an antitumor agent that is released over a longer period to kill any tumor cells that may remain in the wound bed.

[0012] The present invention was made in light of the prior art described above.

[0013] Summary of the invention

[0014] According to the invention, a flat material is provided according to the main claim, which has a resorbable porous collagen sponge in which resorbable nano- or microparticles or combinations thereof are dispersed, wherein the nano- or microparticles have at least two different release profiles for the controlled and / or delayed release of one or more optional pharmaceutical active ingredient(s).

[0015] Advantageously, the flat material can be profiled, i.e., specially processed to obtain a specific structure or shape, so that it may, for example, have patterns, grooves, bumps, ridges or other textures on its surface.

[0016] Further aspects of the invention relate to the use of the flat material according to the invention in a method for wound treatment or in a method for local pharmacotherapy according to independent claim 27, as well as a method for producing the flat material according to the invention according to independent claim 31.

[0017] The advantages of the flat material according to the invention include, in particular, the possibility of selecting two or more active ingredients tailored to the specific needs of an individual patient and of individually adjusting or coordinating their release profiles to achieve the desired effect. Three-dimensional (human) tissue-based disease models (e.g., of tumors) can be used for disease-specific adjustment or coordinating, enabling the optimization of active ingredients or their release profiles by taking into account the specific cell biology (e.g., 4232-3-PCT MD2B LifeScience GmbH).

[0018] Tumor biology), cell kinetics, local concentration, possible resistance (e.g., of tumor cells), toxicity (e.g., systemic toxicity), metabolism, distribution in the relevant system compartment (e.g., patient body), and excretion from it.

[0019] Advantageous and / or preferred embodiments of the invention are the subject of the dependent claims.

[0020] Detailed description of embodiments of the invention

[0021] The invention is described in detail below, whereby the disclosed specific embodiments of the invention, examples or results are intended only for illustration and are in no way to be interpreted as a limitation of the scope of protection of the invention as defined in the attached claims.

[0022] Definitions

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by a person skilled in the art in the technical field of the invention. The person skilled in the art may also refer in full to the following introductory explanations.

[0024] The use of definite or indefinite articles (“der”, “die”, “das”, “ein”, “eine”) is to be understood (especially in connection with the claims) as including at least one element or component, unless otherwise stated here or the context clearly indicates otherwise.

[0025] The conjunction "or" is to be understood as an inclusive and not an exclusive "or", i.e., as "and / or", unless otherwise stated here or the context clearly indicates otherwise. 4232-3-PCT MD2B LifeScience GmbH

[0026] The terms “comprise”, “contain”, “exhibit” or variations thereof are to be understood as meaning that further elements or components may be present, but do not have to be; i.e., the case “consisting of” should also be included.

[0027] The use of terms such as "for example", "e.g", "like" or variations thereof is intended solely to better illustrate the invention and must in no way be interpreted as a limitation of the scope of protection of the invention as defined in the attached claims.

[0028] All numerical values, whether explicitly stated or not, are to be understood as approximate values ​​(at least within the usual margin of error). Furthermore, the specification of value ranges serves only as an abbreviation and, unless otherwise stated, refers to every single value that falls within the range, even if that value is not individually specified.

[0029] The following is a (non-exhaustive) definition and explanation of terms used in this description.

[0030] Analgesics

[0031] Analgesics are medications used to relieve or eliminate pain. They work by inhibiting the sensation of pain or by influencing pain perception in the brain. There are several classes of analgesics, including non-opioid analgesics (such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen), opioid analgesics (such as morphine and oxycodone), and adjuvant analgesics, which were originally developed for other uses but also have pain-relieving properties (such as antidepressants and anticonvulsants).

[0032] antibiotics

[0033] Antibiotics are medications used to fight bacterial infections. They work either by inhibiting bacterial growth (bacteriostatic) or by killing them (bactericidal). Antibiotics are specifically directed against bacteria and have no effect on viruses, fungi, or other microorganisms. There are different classes of antibiotics, distinguished by their mechanism of action and their spectrum of antibacterial activity.

[0034] Differentiate activity.

[0035] antibody

[0036] Antibodies are specialized proteins produced by B cells of the immune system. They recognize and bind specifically to antigens (foreign substances such as viruses, bacteria, or toxins) to neutralize them or enable their destruction by other components of the immune system. Each antibody is unique and specifically adapted to a particular antigen, making it a crucial component of the immune response. Monoclonal antibodies are identical antibodies produced by a single clone of B cells (a single cell line). They are directed against a specific antigen and are widely used in medicine to diagnose and treat various diseases, including cancer, autoimmune disorders, and infectious diseases. Their high specificity allows monoclonal antibodies to target specific cells or molecules in the body.

[0037] Antibody-drug conjugates

[0038] Antibody-drug conjugates (ADCs) are targeted cancer therapies that combine a monoclonal antibody with a potent drug. The antibody binds specifically to an antigen on the surface of cancer cells, thereby delivering the drug directly to the tumor cells. This allows for precise drug delivery, minimizes damage to healthy cells, and reduces side effects. ADCs combine the specificity of antibodies with the efficacy of chemotherapeutic agents.

[0039] Anti-metastasis drugs

[0040] Anti-metastatic agents are drugs or substances that aim to prevent the spread of cancer cells from a primary tumor to other parts of the body (metastasis). They work through various mechanisms, such as inhibiting cell migration and invasion, blocking the formation of new blood vessels (angiogenesis) necessary for tumor growth, or strengthening the immune system against metastasizing cells. These agents are an important part of cancer therapy because metastases are often the leading cause of cancer-related deaths. 4232-3-PCT MD2B LifeScience GmbH

[0041] Antineoplastics

[0042] Antineoplastic drugs are medications used to treat cancer. They work by inhibiting the growth and multiplication of cancer cells or by killing them. These drugs can work in different ways, for example, by damaging the DNA of cancer cells, blocking growth factors, or inhibiting specific enzymes necessary for cell division. Antineoplastic drugs are often used in combination with other therapies, such as surgery or radiation therapy, to increase the effectiveness of cancer treatment.

[0043] Anti-inflammatory drugs

[0044] Anti-inflammatory drugs are medications used to relieve inflammation. They work by inhibiting or reducing the inflammatory response in the body, leading to a reduction in pain, swelling, redness, and other inflammatory symptoms. These medications are commonly used to treat conditions such as arthritis, rheumatic diseases, injuries, and other conditions accompanied by inflammation. There are several types of anti-inflammatory drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, and other anti-inflammatory medications.

[0045] Antiseptics

[0046] Antiseptics are chemical substances that inhibit the growth of microorganisms such as bacteria, viruses, and fungi, or that kill them. They are primarily used to disinfect skin, mucous membranes, and wounds to prevent infections. Antiseptics are essential components in medicine and nursing for maintaining hygiene and reducing the risk of infection.

[0047] Anti-tumor antibodies

[0048] Anti-tumor antibodies are special proteins that target specific molecules or structures on cancer cells. They can inhibit tumor growth by acting directly on the tumor cells, stimulating the immune system to recognize and destroy tumor cells, or blocking the tumor's blood supply. This 4232-3-PCT MD2B LifeScience GmbH

[0049] Antibodies are used in cancer therapy and can be used alone or in combination with other treatments such as chemotherapy or immunotherapy.

[0050] Biologics

[0051] Biologics are drugs that contain biologically manufactured substances or are derived from biological sources. They can be proteins, antibodies, or other biologically active molecules that act specifically within biological systems. Biologics are frequently used to treat autoimmune diseases, cancer, and other serious illnesses. They differ from traditional chemical drugs in their complex structure and their production from living organisms such as cells or microorganisms.

[0052] Burst effect

[0053] The "burst effect" in drug release refers to an abrupt increase in drug concentration (e.g., in the bloodstream) after administration of a dosage form, followed by a rapid decrease. This effect frequently occurs with drugs in a rapid-release formulation, such as some tablets or capsules. The burst effect can cause the drug concentration (e.g., in the blood) to temporarily rise above the therapeutic range, followed by a rapid decrease below the effective range, potentially leading to undesirable side effects or insufficient efficacy. Minimizing the burst effect is a key objective in the development of controlled-release drug formulations to maintain a consistent and predictable drug concentration (e.g., in the bloodstream).

[0054] Cytostatics

[0055] Cytostatics, also known as chemotherapeutic agents, are drugs that inhibit or stop the growth and division of cells, including rapidly growing cancer cells. They are used in cancer therapy to kill tumor cells or slow their growth. Cytostatics can work in various ways, for example, by disrupting DNA synthesis or blocking cell division. Cytostatics are a subcategory of anti-neoplastic agents. 4232-3-PCT MD2B LifeScience GmbH

[0056] Exosomes

[0057] Exosomes are small extracellular vesicles released by most cells that play important roles in cell-to-cell communication and the transport of proteins, nucleic acids, and other molecules between cells. Exosomes are being intensively researched as drug delivery vehicles. Their natural ability to transport biological molecules such as proteins, RNA, and lipids makes them promising candidates for drug delivery.

[0058] Extracellular matrix

[0059] The extracellular matrix (ECM) is a complex structure located outside of cells that supports, shapes, and connects tissues throughout the body. It consists of a variety of proteins, glycoproteins, and other molecules embedded in a gel-like or fibrous substance. The ECM plays a crucial role in cell adhesion, cell communication, cell migration, and the regulation of cell functions. It is present in almost all tissues of the body and serves as a structural framework that supports the form and function of tissues and organs.

[0060] flat material

[0061] Flat material refers to materials that are in a flat form and typically have a small thickness compared to their length and width. Depending on the application, these materials can be, for example, various types of bandages, gauze, plasters, or coverings, as defined in the invention. The English term "patch" or "patches" is also used in this application.

[0062] Release profile

[0063] The release profile of a drug describes how quickly and to what extent a drug is released from a dosage form (e.g., tablet, capsule) into the body. It encompasses the course of drug release, typically as a function of time or other parameters such as gastrointestinal transit. The release profile is important for determining the efficacy, safety, and dosage of drugs. Different release profiles may be required for different therapeutic applications. 4232-3-PCT MD2B LifeScience GmbH

[0064] Needs are used, e.g. immediate release, delayed release or controlled release.

[0065] gelatin

[0066] Gelatin is a natural protein derived from animal collagen. It is produced by heating collagen from the skin, bones, and connective tissue of animals such as cattle or pigs. Gelatin forms gels, thickens liquids, and is often used as a stabilizer, thickener, or gelling agent.

[0067] Hypoallergen

[0068] "Hypoallergenic" refers to products or substances that are less likely to trigger allergic reactions. It means the product contains fewer allergens or has been processed to reduce or remove potential allergens. Hypoallergenic products are often developed for people with allergies or sensitive skin to minimize the risk of allergic reactions.

[0069] Collagen

[0070] Collagen is the most abundant protein in the human body and forms an essential structural component of connective tissue, skin, bones, tendons, and other tissues. It gives skin firmness and elasticity, strengthens bones, and supports the structure of organs and blood vessels. Collagen is derived from animal tissue or produced synthetically (through genetic engineering) and is an important ingredient in cosmetics and medical products for supporting skin health, joint health, and other applications.

[0071] Collagen sponge

[0072] A collagen sponge is a medical product made from collagen fibers and is frequently used in wound healing and tissue regeneration. These sponges can be made from animal or synthetic collagen and serve as a matrix that supports cell migration, cell adhesion, and tissue regeneration. They are commonly used in surgery, particularly in the treatment of burns, ulcers, or other wounds, to promote wound healing and support the growth of new tissue. 4232-3-PCT MD2B LifeScience GmbH

[0073] Controlled drug release

[0074] Controlled release refers to a technique in which the release of a drug from a dosage form is precisely controlled to achieve a specific therapeutic effect. This technique makes it possible to control the drug concentration in the body over a specific period by releasing the drug slowly and steadily. This can be achieved through the use of special formulations, such as delayed-release or sustained-release preparations, or through innovative drug delivery systems, such as implants or transdermal patches. Controlled release helps improve the efficacy, safety, and patient acceptance of drugs by reducing dosing frequency and minimizing unwanted side effects.

[0075] Liposomes

[0076] Liposomes are small, closed, spherical vesicles composed of one or more lipid bilayers. These bilayers can enclose an aqueous solution, with the hydrophilic part of the lipids facing outwards and the hydrophobic part facing inwards. They are often used as delivery systems for drugs or active pharmaceutical ingredients (APIs) because they can encapsulate both hydrophobic (fat-soluble) and hydrophilic (water-soluble) substances. This allows liposomes to improve the stability, bioavailability, and targeted delivery of APIs. Liposomes are used in various fields, such as drug delivery and cosmetics, to enhance the effectiveness and safety of products.

[0077] Local therapy

[0078] "Local therapy" refers to the application of medications or treatments directly at the site of the disease or symptom. This form of therapy aims to deliver active ingredients precisely and locally where they are needed and can take various forms, including ointments, creams, gels, patches, sprays, or local injections. Local therapy is often used to treat skin conditions, pain, inflammation, infections, or other conditions where local application is effective and targeted without burdening the entire body. 4232-3-PCT MD2B LifeScience GmbH

[0079] microparticles

[0080] Microparticles are tiny particles with dimensions in the micrometer range, typically between 0.1 and 100 micrometers. They can be made from various materials such as plastics, metals, ceramics, or biodegradable polymers. Microparticles are used in various applications, for example, as carriers for active ingredients to enable controlled release.

[0081] Micelles

[0082] Micelles are tiny, spherical structures that spontaneously form from amphiphilic molecules in an aqueous solution. These molecules have a hydrophilic (water-loving) and a hydrophobic (water-repelling) part. In a solution, the hydrophobic parts of the molecules align themselves in the interior of the sphere, while the hydrophilic parts face outwards and interact with the surrounding water. Micelles are frequently used in drug delivery and cosmetics to transport or dissolve hydrophobic active ingredients, as they can encapsulate them within their hydrophilic shell, thus improving their stability and bioavailability.

[0083] Nanoparticles

[0084] Nanoparticles are extremely small particles with dimensions in the nanometer range, typically less than 100 nanometers in at least one dimension. They can be made of various materials such as metals, polymers, or biological molecules. Nanoparticles have a wide range of applications in fields such as medicine and cosmetics. Due to their minuscule size, nanoparticles possess unique physical, chemical, and biological properties that are used for innovative applications, for example, in medicine for targeted drug delivery, imaging, and diagnostics.

[0085] Particle diameter

[0086] The particle diameter is the characteristic size of a particle, usually considered as the average over its maximum dimensions in a given space. Depending on the type of material, the particle diameter can be measured or defined in various ways, e.g., as the aerodynamic diameter, optical diameter, or hydrodynamic diameter. Several methods exist for measuring the particle diameter, depending on the particle properties and the specific requirements of the analysis. Examples include light scattering, laser diffraction, optical and electron microscopic imaging, sieve analysis, and sedimentation analysis.

[0087] Pharmaceutical excipients

[0088] Pharmaceutical excipients, also known as inactive ingredients or additives, are non-active components in medicinal products used in their manufacture, formulation, and processing. They serve to improve the stability, tolerability, shelf life, efficacy, and / or dosage form of a medicinal product. Examples of pharmaceutical excipients include fillers, binders, release agents, coatings, solvents and diluents, preservatives, and flavorings.

[0089] Pleural mesothelioma

[0090] Malignant pleural mesothelioma is a malignant tumor of the pleura. It is a rare form of cancer that originates in the mesothelium, the membrane that covers and protects most of the body's internal organs. The incidence in Germany is 1.1 per 100,000 inhabitants. Occupational asbestos exposure is found in 70 to 80 percent of all mesothelioma cases, with men being affected four times more often than women (80 percent). Mesotheliomas develop in the lining of the lungs (pleural mesothelioma), the lining of the abdominal cavity (peritoneal mesothelioma), and the lining of the heart (pericardial mesothelioma). The most common form of mesothelioma develops in the lining of the lungs. In the chest, the mesothelium consists of two layers: one surrounding the lungs themselves and the other forming the inner lining of the chest wall.A small amount of fluid is normally produced between these two layers, which facilitates organ mobility. Mesotheliomas develop when the normal cells of the mesothelium are allowed to divide unchecked.

[0091] pore size

[0092] Pore ​​size refers to the dimensions of the openings or cavities in a porous material. It is often measured in micrometers or nanometers and can vary depending on the material and manufacturing process. Pore size is an important parameter for the function of porous materials, as it determines what types of molecules or particles can pass through the material. Depending on the application, materials with different pore sizes can be used to enable specific functions such as filtration, adsorption, separation, or drug delivery. Pore size can be measured in various ways, depending on the material properties and the application requirements. Examples of measurement methods include mercury intrusion porosimetry, gas adsorption measurement, and optical and electron microscopic imaging.

[0093] Porous

[0094] "Porous" describes the property of a material to have small cavities or pores within it. These pores can vary in size and shape and allow liquids, gases, or other substances to pass through the material. Porous materials are used in a wide variety of applications, including biomaterials and membranes, where their porous structure helps to enable specific functions, such as filtration, adsorption, or drug delivery.

[0095] Recombinant human collagen

[0096] Recombinant human collagen is a form of collagen protein produced through genetic engineering, typically in bacteria, yeast, or mammalian cells. It is manufactured from human genes and exhibits similar structural and functional properties to naturally occurring collagen. Recombinant human collagen is used in medicine and the cosmetics industry, particularly in wound healing, tissue regeneration, bone reconstruction, and cosmetic skin treatments. It offers an alternative source to collagen material of animal origin and may reduce the risk of allergic reactions or disease transmission.

[0097] Absorbable

[0098] "Resorbable" refers to a material's ability to be broken down and completely absorbed by the body. In medical applications, this means that after use, the material is slowly broken down by natural metabolic processes without the need for surgical removal. Resorbable materials are commonly used in surgery, particularly in implants and sutures, to provide temporary support or repair without remaining permanently in the body. siRNA stands for "small interfering RNA" and refers to short RNA molecules capable of regulating gene expression by selectively degrading specific mRNA molecules.They can help reduce or switch off the activity of certain genes, potentially enabling therapeutic applications in the treatment of diseases caused by abnormal gene expression, such as cancer, viral infections, or genetic disorders. siRNA is used in RNA interference (RNAi), a natural cellular mechanism for regulating gene expression.

[0099] Viral vectors

[0100] Viral vectors are genetic tools based on modified viruses used in genetic engineering to deliver specific genes into target cells. They are frequently used in gene therapy and vaccine development. Viral vectors may contain the genetic material of a virus required to infect cells, but with the other viral genes inactivated or removed and a desired gene, such as a therapeutic one, inserted instead. The vector infects the target cells, which then express the foreign gene, thus carrying out the desired function.

[0101] Virus-like particles

[0102] Virus-like particles (VLPs) are self-assembled structures that mimic the morphology of viruses but do not contain viral DNA or RNA and are therefore non-infectious. They consist of the structural proteins of a virus and can be produced using recombinant DNA technology. VLPs are useful for vaccine development and the study of viral infections because they can stimulate the immune system without causing actual infection. 4232-3-PCT MD2B LifeScience GmbH

[0103] Growth factors

[0104] Growth factors are proteins or signaling molecules that regulate cell growth, cell division, differentiation, and other cellular processes. They interact with specific receptors on the cell surface and activate signaling pathways within the cell, influencing cell behavior. Growth factors play a crucial role in the development, regeneration, and maintenance of tissues in the body. They are used in medicine and biotechnology to control cell proliferation and achieve therapeutic effects, such as promoting wound healing, treating diseases, or creating cell cultures for research.

[0105] Drug release control agents

[0106] Drug release agents are excipients used to control or regulate the release of an active ingredient from a drug formulation. They can help control the rate of drug release in the body to maintain a targeted and consistent drug concentration, for example, in the bloodstream. These agents can be in various forms, such as matrix systems, coatings, or specialized carrier materials. They are used in the development of controlled-release drugs, which can provide longer duration of action and a reduced number of doses.

[0107] Agents that promote drug absorption

[0108] Substances that promote the absorption of an active ingredient are excipients that serve to improve the uptake or absorption of an active ingredient in the body. They can, for example, increase the permeability of cell membranes or utilize other mechanisms to increase the bioavailability of an active ingredient, e.g., in the bloodstream, and thus enhance its therapeutic effect.

[0109] Active ingredient stabilizers

[0110] Drug stabilizers are pharmaceutical excipients used to improve the stability of an active ingredient in a drug. They protect the active ingredient from chemical degradation, oxidation, moisture, or other influences that could impair its efficacy. These stabilizers can take various forms, such as 4232-3-PCT MD2B LifeScience GmbH.

[0111] Cryoprotectors, storage stabilizers, pH stabilizers (buffer systems), pH regulators, thermal stabilizers, humidity stabilizers and antioxidants, and are crucial for maintaining the quality and efficacy of a drug during its storage and use.

[0112] Cytoreductive tumor therapy

[0113] Cytoreductive tumor therapy refers to treatments aimed at reducing the size of a tumor or decreasing the number of cancer cells in the body. This can be achieved through various approaches, including surgery (e.g., tumor resection), radiation therapy, chemotherapy, targeted therapies, or immunotherapies. The primary goal is to inhibit tumor growth or shrink the tumor to alleviate symptoms, improve prognosis, and potentially increase the likelihood of complete remission.

[0114] Embodiments of the invention

[0115] Design 1

[0116] A flat material comprising a resorbable porous collagen sponge in which resorbable nano- or microparticles, or combinations thereof, are dispersed, wherein the nano- or microparticles have at least two different release profiles for the controlled and / or delayed release of one or more optional pharmaceutical active ingredient(s). The flat material according to the invention can be provided without optional pharmaceutical active ingredient(s). The flat material can be designed, for example, in the form of a bandage, gauze, or plaster. The optional profiling of the flat material can, for example, be a local thickening in the form of a bump or an elongated ridge, the number and dimensions of which can be designed and arranged so that the areas to be treated come into contact with them. Advantageously, for example,During tissue resections (such as tumor removal), the profiling should be designed to fill the resulting cavity, allowing the surrounding tissue to come into contact with it and absorb the released active ingredient 4232-3-PCT MD2B LifeScience GmbH. The collagen material used is not subject to any special restrictions. For example, commercially available collagen can be used.

[0117] Design 2

[0118] A flat material according to embodiment 1, wherein the nano- or microparticles contain one or more pharmaceutical active ingredient(s) for controlled and / or delayed release. The choice of active ingredient(s) is based on the desired or required therapeutic effect and is not subject to any particular restrictions. The release profile is optimized in vitro in tissue models depending on the intended use.

[0119] embodiment 3

[0120] A flat material according to embodiment 2, wherein the nano- or microparticles contain one or more pharmaceutical active substance(s) selected from the group consisting of antiseptics, antibiotics, analgesics, anti-inflammatory drugs, antineoplastic agents, anti-metastatic agents, antibodies (e.g., anti-tumor antibodies), antibody-drug conjugates, peptides, biologics, siRNA, mRNA and combinations thereof.

[0121] Design 4

[0122] A flat material according to embodiment 3, wherein the antineoplastics are cytostatics.

[0123] Design 5

[0124] A flat material according to embodiment 3, wherein the antiseptic is selected from octenidine dihydrochloride (octenidine), povidone-iodine and polyhexanide.

[0125] Design 6

[0126] A flat material according to embodiment 3, wherein the antibiotics consist of aminocoumarins, aminoglycosides (e.g., streptomycin), beta-lactams (penicillins, cephalosporins, monobactams, carbapenems), quinolones (e.g., fluoroquinolones), diaminopyrimidines, glyco-peptide antibiotics, lincosamides, lipopeptide antibiotics, macrolides, ketolides, nitroimidazoles, polypeptide antibiotics, polyether antibiotics, oxazolidinones, sulfonamides, 4232-3-PCT MD2B LifeScience GmbH

[0127] Streptogramins, tetracyclines, rifampicin, chloramphenicol, tigecycline, mupirocin, fosfomycin and combinations thereof are selected.

[0128] Design 7

[0129] A flat material according to embodiment 3, wherein the analgesics are selected from bupivacaine, lidocaine and combinations thereof.

[0130] Design 8

[0131] A flat material according to embodiment 3, wherein the antineoplastic agents are selected from the group consisting of carmustine (BCNU), pemetrexed, temozolomide, cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, raltitrexed, doxorubicin, cyclophosphamide, anthracycline, etoposide, vincristine, capecitabine, ifosfamide, sunitinib, imatinib, everolism, lomustine (CCNU), procarbazine (PCV), nimustine (ACNU), fotemustine, asunercept (APG101), siRNA, kinase inhibitors and combinations thereof.

[0132] Design 9

[0133] A flat material according to embodiment 3, wherein the anti-tumor antibodies are selected from the group consisting of bevacizumab, nivolumab, ipilimumab, pembrolizumab, durvalumab, atezolizumab, ramucirumab, tremelimumab, avelumab and combinations thereof.

[0134] Design 10

[0135] A flat material according to one of the preceding embodiments, wherein the collagen sponge comprises collagen selected from cross-linked human, animal, genetically engineered collagens (e.g., recombinant human collagen) and combinations thereof.

[0136] Design 11

[0137] A flat material according to embodiment 10, wherein the collagen is hypoallergenic.

[0138] Design 12 4232-3-PCT MD2B LifeScience GmbH

[0139] A flat material according to embodiments 10 or 11, wherein the collagen is partially denatured and / or hydrolyzed.

[0140] embodiment 13

[0141] A flat material according to embodiment 12, wherein the partially denatured and / or hydrolyzed collagen is gelatin.

[0142] embodiment 14

[0143] A flat material according to one of the preceding embodiments, wherein the collagen sponge further comprises an extracellular matrix component selected from the group consisting of elastin, glycosaminoglycans, proteoglycans, glucans, hydrolysates and chemically modified derivatives thereof, as well as combinations thereof.

[0144] Design 15

[0145] A flat material according to one of the preceding embodiments, wherein the collagen sponge has pores with a diameter in the range of 20 pm to 600 pm, for example in the range of 50 pm to 100 pm. Specific examples are pore diameters of 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550 and 600 pm, as well as ranges bounded by these pore diameters as upper and lower limits.

[0146] Design 16

[0147] A flat material according to one of the preceding embodiments, wherein the resorbable nano- or microparticles are selected from the group consisting of liposomes, polymer particles, micelles, exosomes, virus particles, viral vectors, virus-like particles and combinations thereof.

[0148] embodiment 17

[0149] A flat material according to embodiment 16, wherein the polymer particles comprise polymeric material consisting of polypeptides, polysaccharides and derivatives thereof, polyvinyl alcohols (PVA), polyvinylpyrrolidones (PVP), poly(meth)acrylates, polyalkylcyanoacrylates 4232-3-PCT MD2B LifeScience GmbH

[0150] (PACA), acrylic copolymers, polyethylene vinyl acetate copolymers, polyhydroxyalkanoates, hydrocolloids, polyanhydrides, polyorthoesters, poly-e-caprolactone (PCL), copolymers or block copolymers of poly-e-caprolactone and polylactides, polyamino acids, polyurethanes, polyethylene glycols, polylactic acid or polylactides (PLA), polyglycolic acid or polyglycolides (PGA), polycarbonates, copolymers or block copolymers of polylactides and polyglycolides (PLGA), copolyesters of lactic acid and glycolic acid (PLG), poly-L-lysine and their homologs and cocondensates. Suitable examples include the biodegradable PLA, PGA and PLGA (co)polymers of the RESOMER® product line manufactured by Evonik Operations GmbH, Germany.

[0151] Design 18

[0152] A flat material according to one of the preceding embodiments, wherein the resorbable nano- or microparticles have a mean particle diameter of 0.01 pm to 1500 pm, for example from 20 pm to 150 pm. Specific examples are particle diameters of 0.01, 0.03, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 3, 5, 8, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400 and 1500 pm, as well as ranges defined by these particle diameters as upper and lower limits.

[0153] Design 19

[0154] A flat material according to one of the preceding embodiments, wherein the volume fraction of the resorbable nano- or microparticles is up to 30 vol% based on the total volume of the collagen sponge. Examples of specific volume fractions are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 18, 20, 22, 25, 28 and 30 vol%, as well as ranges defined as upper and lower limits by these volume fractions.

[0155] Design 20

[0156] A flat material according to one of the preceding embodiments, wherein the pharmaceutical active ingredient(s) contained in the resorbable nano- or microparticles is / are present in an amount of up to 80% by weight based on the total mass of the nano- or microparticles. Examples of specific amounts of active ingredient are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 4232-3-PCT MD2B LifeScience GmbH

[0157] 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 and 80 wt.% as well as ranges defined as upper and lower limits of these amounts of active ingredient.

[0158] Design 21

[0159] A flat material according to one of the preceding embodiments, wherein the resorbable nano- or microparticles contain pharmaceutical excipients. Examples of pharmaceutical excipients include drug stabilizers, drug release control agents, and drug absorption enhancers. Combinations thereof may also be used. Examples of drug stabilizers include cryoprotectants, storage stabilizers, pH stabilizers, thermal stabilizers, humidity stabilizers, and antioxidants. Combinations thereof may also be used.

[0160] Design 22

[0161] A flat material according to one of the preceding embodiments, wherein the release of a therapeutically effective amount of the pharmaceutical active ingredient(s) from the nanoparticles or microparticles occurs over a period of 2 hours to 50 days, e.g., 2 hours to 48 hours. Examples of specific release periods are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 45, and 48 hours; 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 45, and 50 days; and ranges delimited by these release periods as upper and lower limits.

[0162] embodiment 23

[0163] A flat material according to one of the preceding embodiments with a thickness of 0.1 to 40 mm. Examples of specific thicknesses are 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35 and 40 mm, as well as ranges bounded by these thicknesses as upper and lower limits.

[0164] embodiment 24

[0165] A flat material according to one of the preceding embodiments, wherein the flat material is implantable. 4232-3-PCT MD2B LifeScience GmbH

[0166] Design 25

[0167] A flat material according to one of the preceding embodiments, wherein the flat material is profiled.

[0168] According to a further aspect of the invention, the flat material according to the invention can be used in a method for wound treatment or in a method for local pharmacotherapy, e.g., after cytoreductive surgical tumor therapy. An example is the local pharmacotherapy of pleural mesothelioma, e.g., after cytoreductive surgical tumor therapy of pleural mesothelioma.

[0169] The following examples further explain the invention. These examples are intended only to illustrate the invention and must not be interpreted as limiting the scope of protection of the invention as defined in the accompanying claims.

[0170] Character description

[0171] Figure 1 shows the time course of the fluorescence intensity of the model substance ATTO 590 from two polymer particles with different release profiles.

[0172] Figure 2 shows the release profile of the fluorescently labeled substance (ATTO565) from Gelatine X-Pure 10P Patches with various crosslinkers over a period of 28 to 45 days.

[0173] Figure 3 shows the cell viability of stromal cells (fibroblasts) after 2 weeks of incubation with antibiotic-loaded patches in the AlamarBlue assay. It is clearly evident that the antibiotic encapsulated in the flat material retained its biological efficacy. The AlamarBlue assay procedure, which can be applied to the testing of nanomaterials, is generally described in Langhin EM et al.: “The alamar blue assay in the context of safety testing of nanomaterials” Front Toxicol. 2022 Sep 28;4:981701. doi: 10.3389 / ftox.2022.981701. PMID: 36245792; PMCID: PMC9554156. 4232-3-PCT MD2B LifeScience GmbH

[0174] Figure 4 shows the cell viability of a tumor cell line after three days of incubation with 5-fluorouracil (5-FU) particles in the MTT assay. It is clearly evident that the tumor cells are killed by the cytotoxic agents. As is known to those skilled in the art, an MTT assay (also MTT test) is a colorimetric method in which the metabolic activity of living cells is measured by detecting the reduction of (yellow, water-soluble) MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to (violet, water-insoluble) formazan by mitochondrial dehydrogenases, as described, for example, in Kumar A et al.: "Anti-cancer drug-mediated increase in mitochondrial mass limits the application of metabolic viability-based MTT assay in cytotoxicity screening", Cytotechnology. 2024 Jun;76(3):301-311. doi: 10.1007 / sl0616-024-00618-l. Epub 2024 Mar 21. PMID: 38736730; PMCID: PMC11082113.

[0175] Figure 5 shows an / nv / tro release curve. (1) shows the UV absorption curve of the formulation RG504H, streptomycin, 1000 rpm (solid line with support points as filled triangles). / nv / tro release curve (2) shows the UV absorption curve of the formulation RG504H, carbenicilin, 1000 rpm (dashed line with support points as filled squares).

[0176] Figure 6 shows a / nv / tro release curve. (1) shows the fluorescence profile of the formulation RG752H, IgG antibody (APC), 800 rpm (solid line with support points as filled squares).

[0177] Figure 7 shows a / nv / tro release curve. (1) shows the fluorescence profile of the formulation RG752H, IgG antibody (FITC), 800 rpm (solid line with support points as filled squares).

[0178] Figure 8 shows an in vitro release assay. (1) is the distance between the center of the streptomycin hole and the first bacterial colony. In vitro release assay (2) is the distance between the center of the carbenicilin hole and the first bacterial colony. In vitro release assay (3) is the distance between the center of the negative control and the first bacterial colony.

[0179] Examples of implementation 4232-3-PCT MD2B LifeScience GmbH

[0180] Production of the flat material according to the invention.

[0181] The following process steps for producing the flat material according to the invention are to be understood as alternative or combined process steps.

[0182] The process for producing a flat material according to the invention comprises the following steps: a) producing resorbable nano- or micro(polymer)particles with at least two different release profiles for the controlled and / or delayed release of at least one optionally included pharmaceutical active ingredient, b) producing an aqueous suspension of collagen (or, for example, gelatin) and the particles produced in step a), c) optionally adding crosslinking agents and excipients, d) mixing the suspension to achieve homogeneous distribution, e) gelling the suspension to obtain a hydrogel, f) freezing and freeze-drying the hydrogel obtained, g) optionally rehydrating the freeze-dried hydrogel.

[0183] The production of the nano / microparticles used in the flat material according to the invention can be carried out using the known emulsion-evaporation method. The emulsion-evaporation process is based on the emulsion of a polymer solution in a suitable continuous phase and the subsequent evaporation of the polymer solvent. Various processes are known that are based on a simple (o / w), (w / o), (o / o) emulsion or a complex ((w / o) / w) or ((o / o) / w) emulsion, cf. e.g. DE 103 50654 Al. According to the invention, any of these processes can be used. For example, ethyl acetate or dichloromethane can be used as the organic solvent phase, and polyvinyl alcohol (PVA) can be used as the aqueous phase.The materials used and the resulting chemical phases are mixed at defined stirrer speeds, with the stirring speed and duration determined by the desired particle size and the desired amount of encapsulated active ingredient. The particle size and number of particles per unit volume are determined photometrically. 4232-3-PCT MD2B LifeScience GmbH.

[0184] The resulting particle emulsion is then mixed with the selected collagen / gelatin material, double distilled water (ddH2O) and a chemical crosslinker such as elastin, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (alone or in combination with N-hydroxysuccinimide (NHS)), poly(ethylene glycol) (PEG) with crosslinking reactive end groups (for example, a 4-arm PEG with NHS ester group(s)) or 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) while gently swirling.

[0185] The resulting hydrogel is stored in a tray or in a freezer container for controlled cooling rates (using coolants such as isopropyl alcohol) at room temperature or up to 4°C for up to 40 hours, thereby initiating the gelation phase.

[0186] The distribution of particles in the flat material according to the invention takes place during the gelling phase. Optional surface structuring or additional shaping is achieved using the selected freezing containers. Depending on the composition of the flat material and the associated gelling time, a time-defined gelling-sedimentation process follows (static) or dynamically, e.g., via a rotary system, vibrating plate, or laboratory rocker.

[0187] Freezing cycles follow the gelling phase. These can be carried out using deep-freeze storage units, cold storage chambers with different temperatures (e.g., 5, -20, -80°C), or liquid nitrogen. The freezing cycle (especially as described by temperature and duration) influences crystallization and thus the pore structure.

[0188] The freeze-drying process (lyophilization) is carried out using commercially available laboratory or industrial freeze-drying equipment. The pressure is adjusted according to the sublimation pressure curve, for example, from -55°C, 0.021 mbar to -20°C, 1.03 mbar.

[0189] Following freeze-drying, a rehydration phase optionally takes place under controlled conditions (e.g., temperature, humidity, and time). 4232-3-PCT MD2B LifeScience GmbH

[0190] Determination of the pore size of the collagen sponges used in the flat material according to the invention

[0191] A sample (e.g., 5 x 2 x 2 mm) is taken from the center of the flat material. Images of a cross-section of the sample are acquired using scanning electron microscopy (SEM). Magnification: 50–100x. The analysis is performed using image processing software (e.g., ImageJ, developed by the National Institutes of Health, USA, and The Laboratory for Optical and Computational Instrumentation, University of Wisconsin, USA). At least 15 pores, evenly distributed within the field of view, are measured. The smallest and largest pores in the field of view are included. Two measurement points are selected for each pore, reflecting the smallest and largest diameters for non-circular pores. The statistical report presents the smallest and largest pore sizes, the median value calculated from the at least 15 pores, and the standard deviation.

[0192] Determination of the particle size of the nano- or microparticles used in the flat material according to the invention

[0193] The particle size and distribution are determined by laser diffraction particle size analysis (e.g., Malvern Mastersizer®). D0, D50 (median, mean particle size), and D90 are determined. A spherical particle shape is desirable but not strictly necessary for the purposes of the invention.

[0194] Optimization of the composition of the flat material according to the invention

[0195] The composition of the flat material according to the invention can be determined and optimally adjusted in advance in an in vitro produced human 3D tissue model, depending on the intended use or therapy. This approach is advantageous due to the local effects of the active ingredient(s) to be released in a physiological multi-compartment system such as a wound, e.g., when the flat material according to the invention is to be used to treat a wound resulting from tumor resection with antibiotics and antitumor agents. 4232-3-PCT MD2B LifeScience GmbH

[0196] Healthy human stromal cells, such as fibroblasts, can be co-cultured with cell lines representing, for example, a tumor entity, on a collagenous scaffold or in a hydrogel. After a defined maturation period of 10 to 28 days, depending on the tissue model, these human 3D tissue models are introduced into a perfusing bioreactor system, as described, for example, in Schuerlein S, et al., A versatile modular bioreactor platform for Tissue Engineering, Biotechnol 2017 Feb;12(2):1600326. doi: 10.1002 / biot.201600326. PMID (PubMedID): 27492568. The perfusion of the 3D tissue model reflects the physiological supply of the tissue to be treated. The selected cell types of the co-culture are arranged in the tissue model in the same way as in the tissue to be treated.By using a bioreactor, the tissue model can be kept viable for up to 8 weeks and functionally characterized, for example, by optical methods (such as microscopy) or by measuring typical metabolic activity using an Alamar Blue assay or the concentration of unbound NADH using FLIM analysis (FLIM = Fluorescence Lifetime Imaging Microscopy). The inventive flat material, optimized for a desired therapeutic application, can then be applied to this tissue model. For example, if the release of antibiotics from the inventive flat material is to be determined, a bacterial biofilm is first applied to the tissue model.

[0197] The release of the active ingredient(s) from the flat material according to the invention can now be measured in the perfusate, for example, by taking samples of the perfusate from the reactor circuit at defined intervals and analyzing them, for example, by HPLC. Using a 3D tissue model, it is determined whether, for example, the tumor cells or the biofilm are killed, but the stromal cells remain alive. This can be done, for example, using optical methods (e.g., by determining the cell viability of the stromal cells through a window in the bioreactor using microscopy at defined intervals) and / or by determining the metabolic activity. Furthermore, the absorption of the flat material according to the invention by the stromal cells can be monitored and adjusted accordingly over a long culture period. 4232-3-PCT MD2B LifeScience GmbH

[0198] To adjust the effective release, it is checked, for example, whether the tumor cells introduced into the tissue model are killed, while the stromal cells can resume tissue regeneration. During the experiment, key parameters such as the percentage of viable tumor cells, the percentage of remaining metabolic activity, and the procollagen synthesis rate of the stromal cells are measured, thus determining the ideal absorption times based on the specific tumor biology, cell kinetics, and pharmacology of the active substance(s). By using identical tissue models in parallel-operated bioreactors, the composition of the flat material according to the invention can be optimized depending on the therapeutic application.Through the perfusion unit of the bioreactors, the physiological compartments of the tissues in the human body are reflected, and both the metabolism and the excretion and toxicity of active substances can be determined in vitro and used for adjusting the composition of the flat material according to the invention.

[0199] By combining human 3D tissue models and differently composed flat materials according to the invention, the complex optimization requirements of the flat material according to the invention for the respective therapeutic application can be met. Furthermore, this approach enables the optimization of the drug-specific local concentrations released from the flat material according to the invention and an estimation of the drug distribution in the body and the associated systemic toxicity.

[0200] Example 1:

[0201] Production of Polv(DL-lactide-co-glvcolide) 50:50 particles containing the model substance ATTO 590

[0202] ATTO 590 serves as a model substance because its molecular weight is similar to that of, for example, cytostatic drugs (such as paclitaxel or doxorubicin) or antibiotics (such as streptomycin). Its fluorescent properties are used to determine an exact release profile using dyes. 4232-3-PCT MD2B LifeScience GmbH

[0203] The production of poly(D,L-lactide) particles containing the model substance is based on the emulsion-evaporation method. The resorbable polymers poly(D,L-lactide-co-glycolide) 50:50 RESOMER® RG 504 H and poly(D,L-lactide-co-glycolide) 50:50 RESOMER® RG 752 H from Evonik Operations GmbH, Germany, were used. The model substance ATTO 590 was obtained from ATTO-TEC GmbH, Germany.

[0204] ATTO 590 in dimethyl sulfoxide (DMSO) is added to a solution of RG 504 H or RG 752 H in ethyl acetate (Ultraturrax) or dichloromethane (DCM) (magnetic stirrer). The organic phase is emulsified in an aqueous polyvinyl alcohol solution by stirring (Ultraturrax or magnetic stirrer). After two minutes, the volatile ethyl acetate / DCM is completely removed by evaporation under constant stirring in a fume hood. The resulting aqueous particle suspension is centrifuged, and the particle sediment is washed three times with 90 mL of double-distilled water (ddH2O).

[0205] Production example (model substance ATTO 590 and RESOMER RG 504 H)

[0206] The solution of the polymer RESOMER RG 504 H in ethyl acetate is placed in a 50 ml Falcon® tube at room temperature. Stirring is carried out using a magnetic stirrer at 350 rpm for 10 minutes while the o-phase (ATTO 590, DMSO) is added. The organic solution is then added to the 1% PVA solution (w-phase), which has been stored on ice, while stirring with an Ultraturrax (IKA, 13,000 rpm). After two minutes, the solution is stirred for 24 hours using a magnetic stirrer (350 rpm) until the ethyl acetate has completely evaporated. A 2 ml sample of the remaining particle solution is taken, centrifuged, the supernatant is decanted, and the mixture is then washed three times with ddH₂O. 4232-3-PCT MD2B LifeScience GmbH

[0207] Example 2:

[0208] Release study with fluorescence model substance containing poly(D,L-lactide-co-glvcolide)

[0209] 50:50 particles

[0210] The particle solution is centrifuged, the supernatant is decanted, and washed with PBS buffer. A Transwell® (pore size < particle diameter) is inserted into a 12-well plate. 750 pl of particle solution is added to the Transwell®, while the space between the wells is filled with PBS. The mixture is incubated at 37°C for 45 days. Within defined time intervals, samples (200 pl) are taken from the space between the wells, and the fluorescence intensity of the released model substance is determined using a microplate reader (TECAN Spark, Tecan Trading AG) (Figure 1).

[0211] Example 3:

[0212] Introducing the particles and producing the flat material

[0213] 150 mg of gelatin (EMPROVE® ESSENTIAL, Merck KGaA) is dissolved in 1.5 ml of ddH₂O with continuous stirring (magnetic stirrer, 700 rpm) for 7 min. The solution, previously heated to 50°C, is cooled to room temperature and mixed with ddH₂O and 2 ml of the particle solution described above by vortexing. After adding a 10% solution of purified water and elastin (ELMA®, matrihealth GmbH), the suspension is mixed in a rotary laboratory mixer for 30 h. 6.4 ml of the suspension is poured into a shallow container and, after a 24 h gelation period, frozen at -20°C for a further 24 h and then freeze-dried.

[0214] Example 4:

[0215] Production of gelatin / collagen flat material

[0216] A hydrogel measuring 4 cm x 4 cm x 0.6 cm was produced using recombinant human collagen I sequences (Vecollan®) or collagen or gelatin from various sources, including animal sources. For example, bovine and porcine gelatin were used, processed using various known chemical crosslinking methods. Crosslinkers used included 4232-3-PCT MD2B LifeScience GmbH, four-arm polyethylene glycol with succinimidyl groups (4-arm PEG-SG), a combination of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM).

[0217] For preparation, the collagen / gelatin was dissolved in a suitable solvent, for example, double-distilled water (ddHzO) or phosphate-buffered saline (PBS). The application of heat aided dissolution by increasing both solubility and the rate of the dissolution process.

[0218] Example 5:

[0219] Introducing the particles and producing the flat material with the PEG crosslinker

[0220] 200 mg of gelatin (EMPROVE® ESSENTIAL, Merck KGaA) were dissolved in 2 ml of double-distilled water (ddH₂O) with continuous stirring (magnetic stirrer, 700 rpm) for 7 min. The solution, previously heated to 50°C, was cooled to room temperature. To prepare a 9.8 ml hydrogel, 1.96 ml of the previously dissolved gelatin was mixed with 4.9 ml of double-distilled water and 10% HEPES buffer (4-(2-hydroxyethyl)-1-piperazinethanesulfonic acid) at pH 8. Pre-washed and prepared microparticles were added to the solution before the crosslinking agent was added. Subsequently, a four-arm polyethylene glycol crosslinker (4-arm PEG-SG) was added. The mixture was then stirred continuously and gently for 45 seconds, i.e., at approximately 200 rpm, to ensure homogeneous particle distribution.

[0221] The solution was poured into a 3D-printed mold whose surface had been previously coated with Teflon adhesive (polytetrafluoroethylene, PTFE) to prevent sticking. The filled mold was stored at room temperature in a humid environment until the gel had completely gelled. The hydrogel was then placed in a holding device and slowly deep-frozen at -20 °C for 24 hours. Finally, freeze-drying (lyophilization) was performed in a freeze-drying system (e.g., Alpha 1-2 LDplus, manufactured by Martin Christ, Germany) to produce the patch. 4232-3-PCT MD2B LifeScience GmbH

[0222] Freeze-drying program:

[0223] Example 6:

[0224] Introducing the particles and producing the flat material with the EDC crosslinker and

[0225] NHS

[0226] 380 mg of gelatin (X-Pure® 10P HBHV, Rousselot Biomedical) are mixed with 9.5 ml of 1x PBS. After adding 1x PBS to the gelatin, it should be allowed to swell for 10 minutes at room temperature before the centrifuge tube is placed in a water bath preheated to 60 °C for 30 minutes. After 15 minutes, the solution can be stirred gently by hand. To prepare a 9.8 ml hydrogel, 9.31 ml of previously dissolved gelatin were mixed with 196 lp EDC and 196 lp NHS solutions. To prepare the EDC and NHS solutions, 38 mg of EDC powder are dissolved in 200 lp ddH z O and 9.2 mg NHS in 200 pl ddH z O completely dissolved. Pre-washed and prepared microparticles were added to the solution before the addition of the crosslinking agent.

[0227] The solution was poured into a 3D-printed mold whose surface had been previously coated with Teflon adhesive (polytetrafluoroethylene, PTFE) to prevent sticking. The filled mold was incubated at 37 °C for 30 minutes until the gel had completely gelled. The hydrogel was then placed in a holding fixture and frozen at -20 °C for 24 hours. Finally, freeze-drying (lyophilization) was performed in a suitable freeze-drying system (e.g., Alpha 1-2 LDplus) to produce the flat material. 4232-3-PCT MD2B LifeScience GmbH

[0228] Freeze-drying program:

[0229] Flat materials (patches) containing microparticles with fluorescent materials such as ATTO 565, as well as antibacterial agents such as streptomycin and carbenicillin, fluorescence-labeled antibodies (IgG), and a cytostatic agent 5-fluorouracil (5-FU), were produced according to the above process.

[0230] Example 7:

[0231] Release profiles of Gelatin X-Pure 10P

[0232] Figure 2 shows the release profile of X-Pure 10P patches with different crosslinkers over a period of 35 days. The patches with DMTMM showed the highest release (1). Fluorescence increased continuously until day 21, reaching values ​​above 420 RFU (Relative Fluorescence Units). Afterward, the fluorescence decreased significantly until day 35. The EDC&NHS-crosslinked patches (2) also showed a continuous increase until day 21, with maximum values ​​around 280 RFU. Afterward, the fluorescence decreased slightly. The patches with PEG (3) reached a fluorescence of approximately 240 RFU by day 21 and subsequently showed stable values ​​until day 35. The release curve (4) represents the release of PBS, which serves as a control to ensure that no PBS signal distorts the results.

[0233] Example 8:

[0234] Release of antibacterial agents onto hydrogels with cells

[0235] A gelatin-based hydrogel was loaded with a fibroblast cell line and poured into Trans-well® inserts (wells with a permeable membrane that allows drugs of a defined size to diffuse through; manufacturer Corning), which were placed in a 6-well plate. 4232-3-PCT MD2B LifeScience GmbH

[0236] The plate was then transferred to an incubator to allow cell adhesion and proliferation.

[0237] After incubation, a patch containing microparticles of streptomycin was applied to one of the cell-loaded hydrogels. Another patch containing microparticles of carbenicillin was applied to a separate, also cell-loaded, hydrogel. A third hydrogel with the same incubation time, but without a patch, served as a reference.

[0238] Cell activity was quantified after two weeks of incubation using an AlamarBlue assay.

[0239] Figure 3 shows the effect of streptomycin and carbenicillin on the cell activity of the fibroblast cell line 3T3. Compared to the hydrogel containing only cells, without any active ingredient added to the patch, a significant decrease in activity can be observed.

[0240] Table 1: Percentage loss of cell activity

[0241] Example 9:

[0242] Release of particles loaded with the cytostatic drug 5-fluorouracil (5-FU)

[0243] 5-Fluorouracil (5-FU) is cytotoxic to human cells because it specifically inhibits DNA and RNA synthesis.

[0244] To investigate the cytotoxic effect, a tumor cell line (FADU) was seeded into 12-well plates and incubated for two days. This was followed by a three-day treatment with 5-fluorouracil microparticles, administered at both 20 mg and 60 mg concentrations. Cell viability was determined using an MTT assay after the incubation period. Two wells containing untreated tumor cells served as controls. 4232-3-PCT MD2B LifeScience GmbH

[0245] Figure 4 shows that the cell activity of cells treated with 5-FU-filled microparticles decreases compared to cells not treated with microparticles. The higher the concentration of particles, the greater the decrease in cell activity.

[0246] Table 2: Percentage loss of cell activity

[0247] Example 10:

[0248] Production of poly(D,L-lactide-co-glvcolide) 50:50 or 75:25 particles containing antibiotics or IgG antibodies

[0249] The production of poly(D,L-lactide) particles containing antibiotics (streptomicyn, carbenicilin) ​​or IgG antibodies is based, for example, on the emulsion-evaporation method. The resorbable polymers poly(D,L-lactide-co-glycolide) 50:50 RESOMER* RG 504 H and poly(D,L-lactide-co-glycolide) 75:50 RESOMER* RG 752 H from Evonik Operations GmbH, Germany, were used.

[0250] Antibiotics or antibodies dissolved in double-distilled water (ddH₂O) are added to a solution of RG 504 H or RG 752 H in ethyl acetate or dichloromethane (DCM) and emulsified for several minutes at high stirring speed, for example, approximately 8,000 RPM. The organic phase is emulsified in an aqueous polyvinyl alcohol solution by stirring (magnetic stirrer). After two minutes, the volatile ethyl acetate / DCM is completely removed by evaporation under constant stirring in a fume hood. The resulting aqueous particle suspension is centrifuged, and the particle sediment is washed three times with 90 mL of double-distilled water (ddH₂O).

[0251] Example 11:

[0252] Manufacturing example (antibiotics or antibodies and RESOMER RG 504 H) 4232-3-PCT MD2B LifeScience GmbH

[0253] The solution of the polymer RESOMER RG 504 H in dichloromethane is placed in a 50 ml Falcon® tube at room temperature. A magnetic stirrer is used to stir the mixture at a speed of, for example, 350 rpm for 10 minutes while the organic phase is added. The organic solution is then added to the 1% PVA solution (water phase), which is stored on ice, while stirring with an Ultraturrax (IKA, 9500 rpm). After two minutes, the solution is stirred for more than 3 hours using a magnetic stirrer (500–1000 rpm) until the dichloromethane has completely evaporated. Two ml of the remaining particle solution are taken, centrifuged, the supernatant is decanted, and the mixture is then washed three times with ddH2O.

[0254] Example 12:

[0255] Release study with fluorescence model substance or UV-absorbing substance containing poly(D,L-lactide-co-glycolide) 50:50 particles

[0256] The particle solution is centrifuged, the supernatant is decanted, and washed with PBS buffer. A Transwell® (pore size < particle diameter) is placed in a 12-well plate. 750 pl of particle solution are added to the Transwell®, while the space between the wells is filled with PBS. Incubation takes place at 37°C for 45 days. Within defined time intervals, samples (200 pl) are taken from the space between the wells, and the absorption of the released antibiotics or the fluorescence intensity of the released antibodies (4232-3-PCT MD2B LifeScience GmbH) is determined using a microplate reader (TECAN Spark, Tecan Trading AG) (Figures 5, 6, 7).

[0257] Figure 5: The / nv / tro release curve (1) shows the UV absorption profile of formulation RG504H, streptomycin, 1000 rpm (solid line with support points as filled triangles). The / nv / tro release curve (2) shows the UV absorption profile of formulation RG504H, carbenicilin, 1000 rpm (dashed line with support points as filled squares).

[0258] Figure 6: The / nv / tro release curve (1) shows the fluorescence profile of the formulation RG752H, IgG antibody (APC), 800 rpm (solid line with support points as filled squares). / nv / tro release curve.

[0259] Figure 7: The / nv / tro release curve (1) shows the fluorescence profile of the formulation RG752H, IgG antibody (FITC), 800 rpm (solid line with support points as filled squares). / nv / tro release curve.

[0260] Hemmhoff test with antibiotic-containing poly(DL-lactide-co-glycolide) 50:50 particles

[0261] To verify whether the process parameters for particle production influence biological activity, a modified zone of inhibition assay was performed. The particle solution was centrifuged, the supernatant decanted, and washed with PBS buffer. The particles were then placed in a 9 cm diameter Petri dish filled with agar and containing three 1.5 cm diameter sampling wells. 600 µl of washed streptomycin particles were placed in the first well, the same amount of washed carbenicillin particles in the second well, and the third well was filled with PBS as a negative control. The Petri dish was incubated at 37 °C for 24 hours to ensure the release of the antibiotics into the agar. After one day of release in the agar plate, antibiotic-sensitive bacterial strains were streaked onto the plate, which was then incubated at 32 °C for two further days.

[0262] Figure 8: / nv / tro release test. (1) is the distance between the center of the streptomycin hole and the first bacterial colony. / nv / tro release test (2) is the distance between the center of the carbenicilin hole and the first bacterial colony. In vitro 4232-3-PCT MD2B LifeScience GmbH

[0263] Release test (3) is the distance between the center of the negative control and the first bacterial colony.

[0264] It is clear to those skilled in the technical field of the invention that the representative embodiments and details of the invention described above are intended only to illustrate the present invention, and that various modifications and alterations can be made without thereby departing from the scope of protection of the invention as defined in the attached claims.

Claims

4232-3-PCT MD2B LifeScience GmbH Patent claims 1. Flat material comprising a resorbable porous collagen sponge in which resorbable nano- or microparticles or combinations thereof are dispersed, wherein the nano- or microparticles exhibit at least two different release profiles for the controlled and / or delayed release of one or more optional pharmaceutical active ingredient(s).

2. Flat material according to claim 1, wherein the nano- or microparticles contain one or more pharmaceutical active ingredient(s) for controlled and / or delayed release.

3. Flat material according to claim 2, wherein the nano- or microparticles contain one or more pharmaceutical active ingredient(s) selected from the group consisting of antiseptics, antibiotics, analgesics, anti-inflammatory drugs, antineoplastic agents, anti-metastatic agents, antibodies (e.g., anti-tumor antibodies), antibody-drug conjugates, peptides, biologics, siRNA, mRNA and combinations thereof.

4. Flat material according to claim 3, wherein the antineoplastics are cytostatics.

5. Flat material according to claim 3, wherein the antiseptic is selected from octenidine dihydrochloride (octenidine), povidone-iodine and polyhexanide.

6. Flat material according to claim 3, wherein the antibiotics are selected from the group consisting of aminocoumarins, aminoglycosides, beta-lactams, quinolones, diaminopyrimidines, glycopeptide antibiotics, lincosamides, lipopeptide antibiotics, macrolides, ketolides, nitroimidazoles, polypeptide antibiotics, polyether antibiotics, oxazolidinones, sulfonamides, streptogramins, tetracyclines, rifampicin, chloramphenicol, tigecycline, mupirocin, fosfomycin and combinations thereof.

7. Flat material according to claim 3, wherein the analgesics are selected from bupivacaine, lidocaine and combinations thereof. 4232-3-PCT MD2B LifeScience GmbH 8. Flat material according to claim 3, wherein the antineoplastic agents are selected from the group consisting of carmustine (BCNU), pemetrexed, temozolomide, cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, raltitrexed, doxorubicin, cyclophosphamide, anthracycline, etoposide, vincristine, capecitabine, ifosfamide, sunitinib, imatinib, everolism, lomustine (CCNU), procarbazine (PCV), nimustine (ACNU), fotemustine, asunercept (APG101), siRNA, kinase inhibitors and combinations thereof.

9. Flat material according to claim 3, wherein the anti-tumor antibodies are selected from the group consisting of bevacizumab, nivolumab, ipilimumab, pembrolizumab, durvalumab, atezolizumab, ramucirumab, tremelimumab, avelumab and combinations thereof.

10. Flat material according to any of the preceding claims, wherein the collagen sponge comprises collagen selected from the group consisting of cross-linked human, animal, genetically engineered collagens and combinations thereof.

11. Flat material according to claim 10, wherein the collagen is hypoallergenic.

12. Flat material according to claims 10 or 11, wherein the collagen is partially denatured and / or hydrolyzed.

13. Flat material according to claim 12, wherein the partially denatured and / or hydrolyzed collagen is gelatin.

14. Flat material according to any of the preceding claims, wherein the collagen sponge further comprises an extracellular matrix component selected from the group consisting of elastin, glycosaminoglycans, proteoglycans, glucans, hydrolysates and chemically modified derivatives thereof and combinations thereof.

15. Flat material according to one of the preceding claims, wherein the collagen sponge has pores with a diameter in the range of 20 pm to 600 pm.

16. Flat material according to one of the preceding claims, wherein the resorbable Nano- or microparticles are selected from the group consisting of liposomes, polymer particles, micelles, exosomes, virus particles, viral vectors, virus-like particles and combinations thereof. 4232-3-PCT MD2B LifeScience GmbH 17. Flat material according to claim 16, wherein the polymer particles comprise polymeric material consisting of polypeptides, polysaccharides and derivatives thereof, polyvinyl alcohols (PVA), polyvinylpyrrolidones (PVP), poly(meth)acrylates, polyalkylcyanoacrylates (PACA), acrylic copolymers, polyethylene vinyl acetate copolymers, polyhydroxyalkanoates, hydrocolloids, polyanhydrides, polyorthoesters, poly-e-caprolactone (PCL), copolymers or block copolymers of poly-e-caprolactone and polylactides, polyamino acids, polyurethanes, polyethylene glycols, polylactic acid or polylactides (PLA), polyglycolic acid or polyglycolides (PGA), polycarbonates, copolymers or block copolymers of polylactides and polyglycolides (PLGA), copolyesters of lactic acid and glycolic acid (PLG), poly-L-lysine and their homologs and Co-condensates are selected from the existing group.

18. Flat material according to any of the preceding claims, wherein the resorbable nano- or microparticles have a mean particle diameter of 0.01 pm to 1500 pm.

19. Flat material according to claim 18, wherein the resorbable nano- or microparticles have a mean particle diameter of 20 pm to 150 pm.

20. Flat material according to one of the preceding claims, wherein the volume fraction of the resorbable nano- or microparticles is up to 30 vol% based on the total volume of the collagen sponge.

21. Flat material according to one of the preceding claims, wherein the pharmaceutical active ingredient(s) contained in the resorbable nano- or microparticles is / are contained in an amount of up to 80% by weight based on the total mass of the nano- or microparticles.

22. Flat material according to one of the preceding claims, wherein the resorbable nano- or microparticles contain pharmaceutical excipients.

23. Flat material according to one of the preceding claims, wherein the release of a therapeutically effective amount of the pharmaceutical active ingredient(s) from the nano- or Microparticles are released over a period of 2 hours to 50 days. 4232-3-PCT MD2B LifeScience GmbH 24. Flat material according to one of the preceding claims with a thickness of 0.1 to 40 mm.

25. Flat material according to any of the preceding claims, wherein the flat material is implantable.

26. Flat material according to one of the preceding claims, wherein the flat material is profiled.

27. Flat material according to one of the preceding claims, for use in a method for the local pharmacotherapy of malignant pleural mesotheliomas.

28. Use of a flat material according to any one of claims 1 to 27 in a method for wound treatment or in a method for local pharmacotherapy.

29. Use according to claim 28 in a method for wound treatment or for local pharmacotherapy following cytoreductive surgical tumor therapy.

30. Use according to claim 28 in a method for local pharmacotherapy of pleural mesothelioma.

31. Use according to claim 29 in a method for local pharmacotherapy following cytoreductive surgical tumor therapy of pleural mesothelioma.

32. A method for producing a flat material according to any one of claims 1 to 27, comprising the steps of: a) producing resorbable nano- or microparticles with at least two different release profiles for the controlled and / or delayed release of at least one optionally included pharmaceutical active ingredient, b) producing an aqueous suspension of collagen and the particles produced in step a), c) optionally adding crosslinking agents and excipients, d) mixing the suspension to achieve homogeneous distribution, e) gelling the suspension to obtain a hydrogel, f) freezing and freeze-drying the resulting hydrogel. 4232-3-PCT MD2B LifeScience GmbH g) if necessary, rehydration of the freeze-dried hydrogel.

33. Flat material comprising a resorbable porous collagen sponge in which resorbable nano- or microparticles or combinations thereof are dispersed, wherein the nano- or microparticles have at least two different release profiles for the controlled and / or delayed release of one or more optional pharmaceutical^) active substance(s), for use in a method for the local pharmacotherapy of malignant pleural mesothelioma.

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