Device for sustained controlled release of therapeutically active substances and use thereof

Abstract

A device (7) for sustained controlled release of a therapeutically active substance after implantation of the device alone or in combination with a further implantable element (1, 3), the device (7) comprising a material layer (8) containing at least one therapeutically active substance, wherein the layer (8) comprises a biodegradable matrix consisting of a mixture of: 60% to 95% by dry weight of a first component (A) in the form of a copolymer of DL-lactide and glycolide (PLGA), with the molar ratio of DL-lactide to glycolide being in the range of 40: 60 to 60: 40, and the weight average molecular weight (MWw) of the first component (A) being in the range of 100,000 to 150,000 g / mol; and 5% to 40%, by dry weight, of a second component (B) in the form of polyethylene glycol (PEG), the dry weight of component (A) and component (B) being supplemented to 100% of the matrix in which the at least one therapeutically active substance is dissolved and / or suspended.

Description

Technical Field

[0001] The present invention relates to devices, in particular films or layers, for the sustained controlled release of therapeutically active substances, as well as to methods for the manufacture of such devices and the use of such devices. Background Art

[0002] Non-degradable implantable devices that are implanted to remain in place need to be constructed to avoid negative foreign body responses in patients. This applies to fully embedded implants, such as breast implants or pacemakers, but also to implants that require long-term transdermal communication. Certain types of implantable medical devices require long-term transdermal communication between the internal and external parts of the device. Some examples of such devices include left ventricular assist devices, tissue expanders, arteriovenous shunts, and gastric lap bands. The transdermal portion of the device can be in the form of a catheter, a gas insufflation tube, or one or more wires. These types of transdermal medical devices are susceptible to infection.

[0003] To improve compatibility between the surrounding tissue and the actual implantable medical device, a pocket may be provided into which the implantable medical device is placed prior to insertion into the body to provide an optimal interface between the surrounding tissue and the implant, avoid complications and aid healing of the device.

[0004] A problem with implantable medical devices, particularly those with long-term transdermal communication, is the high rate of infection following implantation. Typically, this is treated with oral or intravenous antibiotics alone, or in combination with local irrigation with antibiotic solutions, however, this may be insufficient, particularly where the implant is located in a physiologically vulnerable location in the body that cannot be quickly reached by orally administered antibiotics.

[0005] There remains a need to reduce the incidence of infections associated with implantable devices.

[0006] Wound dressings are designed to support the injured area, protect it from infection, and, in some cases, actively promote wound healing by creating an environment that is conducive to cell growth.

[0007] The response to trauma, defined as the breakdown of body tissue, involves an inflammatory phase, a migration phase, and a remodeling phase. The inflammatory phase is an acute response to the wound, and its purpose is to quickly seal the wound and produce chemical factors that utilize cells to migrate into the wound and begin the wound healing process. During the migration phase, cells migrate rapidly into the wound and begin to lay down a temporary extracellular matrix that will be the basis of the healing tissue. During the remodeling phase, the newly generated tissue slowly matures into its permanent form.

[0008] Standard wound dressings promote wound healing by: 1. Mechanically holding the wound edges together to allow easier cell migration; 2. Mechanically sealing the wound to prevent pathogen contamination; 3. In some advanced dressings, providing an environment that actively promotes faster wound healing, often by exposing the injured tissue to a hydrated gel. Improved materials for these applications would be desirable.

[0009] In plastic surgery, not only commercial silicone implants (e.g., breast, calf, buttocks, chest, biceps) but also the above-mentioned implantable medical devices often fail due to foreign body reaction and scar tissue encapsulation. For such applications, improved materials / coatings would also be desirable.

[0010] In cosmetics, disposable flat and unstructured cellulose masks (eg, face, hands, and feet) can be used as masks to enhance skin hydration as well as absorption of metabolic waste products and delivery of nutrients or other compounds to the skin.

[0011] WO2015040106A1 proposes a method for self-assembly producing a topographical surface structured cellulose element that can be used as a material for such a bag, wherein in a first step, a mold having a first surface on one side is provided, the first surface is topographically surface structured in a complementary manner and the first surface is oxygen-permeable, wherein a liquid growth medium containing cellulose-producing bacteria is provided, and wherein the mold is placed to form a liquid / air interface of the liquid growth medium, so that one side of the mold having the first surface is in direct contact with the liquid growth medium, and the opposite side faces the air or a specially provided oxygen-containing gas environment, allowing the bacteria to produce and deposit cellulose on the first surface, and forming a topographically surface structured surface complementary to it on its interface, until a continuous cellulose layer with an element thickness of at least 0.3 mm is formed; and wherein in a second step, the element is removed from the mold. In addition, the present invention relates to an element manufactured using such a method and the use of such an element for a variety of applications. The corresponding bag not only provides optimal compatibility with surrounding tissues directly after implantation, but also provides optimal compatibility over a longer time span when the implant remains in the body.

[0012] US-A-2019009063 discloses an expandable balloon surrounded by an expandable cover that becomes increasingly porous / permeable during expansion. The balloon is coated or wrapped with a matrix containing a pharmaceutically active agent. During balloon expansion, the pharmaceutically active agent is released or extruded into a body cavity (e.g., an artery or vein) through the expandable cover.

[0013] US-A-2007141106 provides a medical system for administering a medicament to a patient in vivo. The medical system includes a medical implant positionable in the patient's body. The medicament is disposed on the medical implant and is at least partially coated with a reactive coating. The reactive coating functions to control the release of the medicament. An energy unit is provided for transmitting an energy signal to the reactive coating, wherein the reactive coating reacts with the energy signal to increase the release rate of the medicament.

[0014] WO-A-2008136856 describes a biodegradable and absorbable polymer bag for use with cardiac rhythm management (CRM) devices and other implantable medical devices (IMDs), i.e., a bag, cover or other container capable of encapsulating, surrounding and / or retaining a CRM or other IMD for the purpose of securing the CRM or other IMD in place, inhibiting or reducing bacterial growth, providing pain relief and / or inhibiting scarring or fibrosis on or around the CRM or other IMD. Optionally, the biodegradable and absorbable bag of the present invention contains one or more drugs in a polymer matrix to provide a preventive effect and mitigate side effects or complications associated with surgery or implantation of a CRM or other IMD.

[0015] US-A-2020197712 describes a nonwoven absorbable bag that at least partially wraps an implantable medical device and an improved method for producing an implantable medical device bag. The nonwoven bag may contain one or more drugs. The implantable medical device placed in the bag before implantation grows into the bag through tissue, preventing migration from the implantation site. Antibiotics can be incorporated into the bag to prevent postoperative infection. Compared with conventional bags, the bag can be formed with fewer steps and there is no polymer coating. The nonwoven bag can be formed in one step by dry spinning (dry spinning) instead of using multiple processing steps. In some embodiments, the inside of the nonwoven bag is smoother than the outside, so as to fit the implantable medical device tightly inside while promoting external tissue ingrowth. In some embodiments, the nonwoven bag eliminates the use of knitted or woven multifilament fibers that can capture bacteria and cause postoperative infection.

[0016] Steele et al (Acta Biomater. 2011 May; 7(5): 1973-1983, doi: 10.1016 / j.actbio.2011.02.002) reported poly(lactic acid-co-glycolic acid) (PLGA) films incorporating paclitaxel, which generally had a slow release rate of paclitaxel on the order of 1 μg day(-1) cm(-2). For implementation as a medical device, a range of zero-order release rates (i.e., 1 to 15 μg day(-1) cm(-2)) can be expected for different tissues and pathologies. Polyethylene glycol (PEG) with molecular weights of 8 kDa and 35 kDa was incorporated into PLGA containing 10 wt% paclitaxel at 15%, 25%, and 50% by weight. Mechanical properties were evaluated for potential use as medical implants and the release rate of paclitaxel was quantified as a percentage of release and a more clinically useful release rate in μg day(-1) cm(-2). Paclitaxel quantification was correlated with PEG release from PLGA to further understand its role in regulating paclitaxel / PLGA release. PEG release was found to be correlated with paclitaxel release and the level of crystallinity of PEG in the PLGA film, as measured by Raman spectroscopy. This supports the concept of using phase separation, partitioning compounds to increase the release rate of hydrophobic drugs (such as paclitaxel) from PLGA films, in which paclitaxel is normally uniformly distributed / dissolved. Both formulations have promise for use in medical device films when optimized for tensile strength, elongation, and drug release. Using 15% 35k PEG, a slow paclitaxel release rate of an average of 3.8 μg day(-1) cm(-2) was achieved for >30 days, while using 25% 8kDa PEG, a high drug release rate of 12 μg day(-1) cm(-2) was maintained for up to 12 days.

[0017] KR-B-100376083 relates to providing a biocompatible and biodegradable polymer matrix for sustained release implants containing a hydrophilic drug or its salt, so that the macromolecular matrix has an improved drug release rate and an initial burst effect. The biocompatible and biodegradable polymer matrix for sustained release implants containing a hydrophilic drug or its salt is produced by the following steps: a) dissolving a first polymer selected from poly (d, 1-lactide-co-glycolide) (PLGA), polyglycolide (PGA) and polylactide (PLA), a second polymer of polyethylene glycol (PEG) and a surfactant in an organic solvent; b) dissolving the hydrophilic drug or its salt in water, adding the solution produced in step (b) to the solution produced in step a) and stirring them to produce a water-in-oil (W / O) emulsion; and c) removing water and the organic solvent from the W / O emulsion.

[0018] US-A-2015196497 describes a biocompatible polymer controlled release matrix barrier structure for delivering one or more bioactive agents from an implantable medical device. In one embodiment, a biocompatible polymer controlled release matrix barrier structure is included. The biocompatible polymer controlled release matrix may include a main structure formed of a compliant material, the compliant material comprising one or more compliant biocompatible polymers and one or more bioactive agents. The main structure may define a central hole through which a subcutaneous element of an implantable medical device passes. Other embodiments are included herein. Summary of the invention

[0019] The object of the present invention is to provide an improved and optimized device for releasing (preferably sustained controlled release) at least one therapeutically active substance after implantation of the device alone or in combination with other implantable elements. These implantable elements may be one or a combination of the following devices: artificial hip, artificial joint, artificial knee, bone fusion hardware, breast implant, cochlear implant, intrauterine device (IUD), dental implant, ear tube, implantable insulin pump, implantable pulse generator, implantable sensor, joint fusion hardware, metal screw, muscle fusion hardware, pins, plates and rods, surgical mesh, orthopedic spacer, transmission system, catheter, thus including pacemaker, neurostimulator, ventricular assist device (VAD), etc.

[0020] More specifically, the invention relates according to a first aspect to a device as defined in claim 1 .

[0021] Accordingly, the present invention proposes such a device, which is used to release (preferably sustained controlled release) a therapeutically active substance after implantation of the device alone or in combination with other implantable elements. According to the present invention, the device comprises or consists of at least one material layer, which contains at least one therapeutically active substance and provides sustained controlled release of the substance under physiological conditions.

[0022] According to the present invention, the layer comprises a biodegradable matrix consisting of a mixture of 60% to 95% by dry weight of a first component (A) in the form of a copolymer of DL-lactide and glycolide (poly(lactic-co-glycolic acid), PLGA), wherein the molar ratio of DL-lactide to glycolide is in the range of 40:60 to 60:40, and wherein the weight average molecular weight MW of the first component (A) is w In the range of 100,000 to 150,000 g / mol, and 5% to 40% by dry weight of a second component (B) in the form of polyethylene glycol (PEG).

[0023] The dry weight of component (A) and component (B) makes up to 100% of the matrix.

[0024] According to the invention, at least one therapeutically active substance is dissolved and / or suspended in the matrix.

[0025] As will be shown below, this very specific matrix with these two components defined provides optimal release and biodegradability characteristics for the layer, particularly for the corresponding layer to avoid post-implantation inflammation when implanting non-degradable implants, but also for other purposes. In addition, the proposed matrix allows dissolving different types of therapeutic active substances, particularly it allows dissolving water-soluble (hydrophilic) and water-insoluble (hydrophobic) therapeutic active substances simultaneously and makes water-soluble (hydrophilic) and water-insoluble (hydrophobic) therapeutic active substances can be used for controlled release. Accordingly, the proposed matrix is ​​particularly suitable for and is suitable for combined application with at least two different therapeutic active substances (such as minocycline and rifampicin). In addition, the proposed matrix provides an environment for stabilizing the corresponding therapeutic active substance, allowing a longer shelf life and preventing the conversion / degradation of API.

[0026] In this article, the inventors define the hydrophilicity and hydrophobicity of a molecule with reference to its solubility in water (particularly a therapeutic active substance). Solubility is the chemical property of a molecule in a particular solvent, which depends on the chemical and environmental conditions of both temperature and pH. Therefore, for the purpose of this document, the inventors define hydrophobicity as the low solubility of a molecule in water, particularly less than 5 mg / ml, preferably less than 3 mg / ml, and particularly up to 2.5 mg / ml (but further preferably still greater than 0.1 mg / ml, or even greater than 0.5 mg / ml) solubility, and define hydrophilicity as the high solubility of a molecule in water, particularly greater than 20 mg / ml, preferably greater than 40 mg / ml, and particularly greater than 45 mg / ml solubility. This is at room temperature (20 degrees) or body temperature (37 degrees) and pH 7. Solubility is measured in distilled and deionized water and is given in mg / mL.

[0027] Therefore, according to a preferred embodiment, at least two therapeutically active substances are present in the matrix, one of which is hydrophobic and one of which is hydrophilic. Preferably, the hydrophobic active substance is chosen to be rifampicin and the hydrophilic active substance is chosen to be minocycline.

[0028] Preferably, in this case, the difference in solubility in water is greater than 10 times (in mg / ml), more preferably greater than 20 times, and most preferably greater than 35 times or in the range of 30 to 40 times.

[0029] Preferably, in the presence of one hydrophobic therapeutic active substance and one hydrophilic therapeutic active substance, the weight ratio of the respective therapeutic active substance to PLGA is in each case in the range of 15% to 40%, preferably in the range of 20% to 35%. More preferably, the weight ratio of the hydrophilic therapeutic active substance (preferably minocycline) to PLGA is in the range of 15% to 30%, preferably in the range of 20% to 25%, and the weight ratio of the hydrophobic therapeutic active substance (preferably rifampicin) to PLGA is in the range of 25% to 40%, preferably in the range of 30% to 35%.

[0030] In fact, it was found that the proposed matrix unexpectedly proves to be suitable and appropriate for absorbing both hydrophobic and hydrophilic therapeutic active substances simultaneously and for controllably releasing both substances in a manner that is as similar as possible.

[0031] Thus, minocycline is hydrophilic as it is soluble in water at neutral pH (ie, pH 7) at room temperature at up to 50 mg / mL.

[0032] Rifampicin is hydrophobic in that it is soluble in water only up to 2.5 mg / mL at room temperature at neutral pH (ie, pH 7).

[0033] Thus, under these conditions, the water solubility of the two molecules differed by a factor of 35.

[0034] The key to the matrix is ​​that in order to load sufficient amounts of the two types of molecules, the inventors need to take advantage of the different solubility of the two molecules in the PEG-PLGA structure.

[0035] Generally speaking, the proposed device in the form of a membrane or the like does not have a barrier function, in particular it cannot restore or replace the barrier function of, for example, the skin.

[0036] Furthermore, the proposed device is substantially inelastic and cannot be stretched for placement without tearing the device.

[0037] According to a first preferred embodiment, the molar ratio of DL-lactide to glycolide of the first component (A) is in the range of 45:55 to 55:45, preferably in the range of 48:52 to 52:48, or in the range of about 50:50.

[0038] It is also preferred that the weight average molecular weight (MW w ) is in the range of 110,000 to 140,000 g / mol, preferably in the range of 120,000 to 130,000 g / mol.

[0039] Alternatively or additionally, if the number average molecular weight (MWn ) is in the range of 50,000 to 100,000 g / mol, preferably in the range of 60,000 to 80,000 g / mol, most preferably in the range of 65,000 to 75,000 g / mol.

[0040] Alternatively or additionally, the first component (A) preferably has an inherent viscosity midpoint in the range from 0.8 to 1.2 dl / g, preferably in the range from 0.9 to 1.1 dl / g (measured in each case in chloroform, 25° C., c=0.1 g / dl).

[0041] According to a further preferred embodiment of the proposed device, the weight average molecular weight (MW w ) is in the range of 3000 to 5500 g / mol, preferably in the range of 3200 to 4800 g / mol, most preferably in the range of 3700 to 4400 g / mol.

[0042] Typically and preferably, the solidification point of the second component (B) is in the range of 45°C to 68°C, preferably in the range of 50°C to 65°C, most preferably in the range of 55°C to 60°C.

[0043] As regards the proportions, preferably, the layer comprises a matrix consisting of a mixture of:

[0044] 75 to 92% by dry weight, preferably 80 to 90% by dry weight, most preferably 84 to 88% by dry weight of component (A), and 8 to 25% by dry weight, preferably 10 to 20% by dry weight, most preferably 12 to 16% by dry weight of component (B),

[0045] The dry weight of component (A) and component (B) makes up to 100% of the matrix.

[0046] Generally speaking, the at least one therapeutically active substance comprises at least one antibiotic, antiseptic, hemostatic agent, anti-inflammatory agent, chemotherapeutic agent, hormone, chemokine, growth factor, peptide or disinfectant, or a combination thereof, wherein preferably, the at least one therapeutically active substance is selected from at least one antibiotic selected from the group of tetracyclines, penicillins, macrolides, ansamycins, wherein the antibiotic is preferably selected from tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, hydropyracycline, doxycycline, tigecycline, eracycline, sarecycline, omadacycline, rifampicin, or a combination thereof, in particular a combination of minocycline hydrochloride and rifampicin.

[0047] The concentration of the therapeutically active substance in the layer, or in the case of several therapeutically active substances the total therapeutically active substance concentration in the layer, is preferably in the range of 5% to 50%, preferably in the range of 10% to 45% or in the range of 25% to 40%, in each case given as % w / w dry weight relative to the total dry weight of the layer.

[0048] It is particularly preferred if the layer comprises as at least one therapeutically active substance a combination of rifampicin and minocycline, in particular in the form of minocycline hydrochloride, a total concentration of 20 to 40% by weight, preferably in the range of 25 to 35% by weight, in each case given as % w / w dry weight relative to the total dry weight of the layer.

[0049] In this case, it is preferred that the concentration of minocycline (especially in the form of minocycline hydrochloride) is in the range of 10 to 20% by weight, more preferably in the range of 14 to 18% by weight, and / or the concentration of rifampicin is in the range of 15 to 25% by weight, preferably in the range of 17 to 22% by weight, in each case given as % w / w dry weight relative to the total dry weight of the layer.

[0050] According to a particularly preferred embodiment, the layer (8) comprises a matrix consisting of a mixture of:

[0051] 84% to 88% by dry weight of a first component (A) having a weight average molecular weight in the range of 120,000 to 130,000 g / mol,

[0052] and 12 to 16% by dry weight of a second component (B) having a weight average molecular weight MWw in the range of 3700 to 4400 g / mol,

[0053] The dry weight of component (A) and component (B) is made up to 100% of the layer,

[0054] and wherein the layer comprises as at least one therapeutically active substance a combination of rifampicin and minocycline (particularly in the form of minocycline hydrochloride) in a total concentration of 25 to 35% by weight, wherein the concentration of minocycline (particularly in the form of minocycline hydrochloride) is in the range of 14 to 18% and the concentration of rifampicin is in the range of 17 to 22% by weight, in each case given as % w / w dry weight relative to the total dry weight of the layer.

[0055] Preferably for the envisaged applications the device takes the form of at least one or only one self-supporting film, web, nonwoven structure or a combination thereof, preferably having a thickness in the range of 2.5 to 100 μm or 2.5 to 50 μm, preferably in the range of 10 to 30 μm.

[0056] Also preferably, the device is in the form of a film or patch having a maximum extension in the lateral direction of 30 cm, preferably an extension in the range of 0.5 to 15 cm, more preferably an extension in the range of 1 to 10 cm.

[0057] Such a film or patch preferably takes a circular, oval or polygonal shape, preferably a rectangular or square shape, optionally with rounded edges.

[0058] The device may consist of a single said layer or more than one said layer in combination with at least one further support layer (which support layer may preferably be biodegradable or non-degradable).

[0059] The device can adopt the form of grid, nonwoven or weaving, or preferably adopt the form of continuous layer. The device can also adopt the form of at least one strip, which is wound around the non-degradable implant in use. In addition, the device can adopt the form of the bag of corresponding material or the form of stretchable film (such as plastic wrap) to wrap around the non-degradable implant fully in use.

[0060] Said layers are preferably provided as at least two sheets which are placed on opposite main faces of the non-degradable implantable device before insertion into said wet or moist cellulose bag according to the use as further specified below.

[0061] Most preferably, the device consists of a single layer as defined above.

[0062] According to another aspect of the invention, the invention relates to a method for manufacturing a device as defined above. According to the method, preferably in a first step, the first component (A) is completely dissolved in an organic solvent, preferably selected from the group consisting of acetonitrile, acetone, anisole, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, dioxane, tetrahydrofuran, toluene, or a combination thereof, preferably under stirring at a temperature in the range of 15°C to 30°C, preferably at room temperature (20°C to 25°C), to solidify the solution of the first component (A).

[0063] Also preferably, in a second step, the second component (B) and at least one therapeutically active substance are added to the solution of the first component (A). Again, this preferably takes place under stirring at a temperature in the range of 15° C. to 30° C., preferably at room temperature, preferably in the same mixing device as used for the first step. Then, the device is subsequently formed by evaporating at least one solvent, which is preferably carried out in a solution casting or solution coating process, preferably on a release material.

[0064] According to a first preferred embodiment of the proposed method, after the first step and before carrying out the second step, an additional organic solvent different from the organic solvent used in the first step is added to the solution of the first component (A), wherein preferably, the additional organic solvent is selected from the group consisting of acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, Pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethylene, xylene, acetic acid, heptane, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethanol, 1-pentanol, ethyl acetate, 1-propanol, ethyl ether, 2-propanol, ethyl formate, propyl acetate, formic acid, triethylamine, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, or a combination thereof.

[0065] The additional solvent is preferably added to the solution of the first component (A) in a proportion in the range of 20% to 40% v / v, preferably in the range of 25% to 35% v / v.

[0066] According to another preferred embodiment of the process, in the first step, the first component (A) is dissolved in a concentration in the range of 10 to 35% w / v, preferably in the range of 20 to 30% w / v, in each case based on the volume of the organic solvent.

[0067] According to yet another aspect of the invention, it relates to the use of a device as defined above for the preparation of an implantable device.

[0068] According to a preferred aspect of the use, in a first step, an implantable device, preferably a non-degradable implantable device (e.g. a pacemaker) is at least partially covered or surrounded by at least one layer of such a device, and preferably, in a second step, it is inserted into a wet bag or a moist bag through an opening of the wet bag or a moist bag, wherein the wet bag or the moist bag is at least one of a self-supporting hydrogel, cellulose or collagen.

[0069] In fact, the wet bag of at least one of the self-supporting hydrogel, cellulose or collagen is inelastic, which can be preferably quantified as the inability of the material of the bag to recover to its initial unstrained state after applying and releasing tension on the loading and unloading stress-strain curves, even using low stresses (stress values ​​σ as low as 0.005, 0.01 or 0.5 MPa or in the range of 0.01 to 0.1 MPa).

[0070] The cellulose layer of the bag can be provided as a non-degradable bag, thus accompanying the entire life of the non-degradable implantable device. In the alternative, the cellulose layer can be provided as a degradable element, which is absorbed by the body in a certain amount of time.

[0071] The key elements of this use can be as follows:

[0072] The therapeutically active substance (particularly in the form of an antibiotic) should be provided in an effective manner to avoid post-implantation infection, etc. Cellulose bags that are suitable and adapted to remain in place after implantation and remain around non-degradable implantable devices are usually produced in biochemical processes involving living organisms, so it is impossible to incorporate the corresponding therapeutically active substance into the cellulose bag material, especially for antibiotics. In addition, due to many practical reasons related to storage and packaging, preparation and use, the cellulose bag material cannot be prepared and then provided as a dry layer. Similarly, it is impossible to impregnate or coat the bag material with the therapeutically active substance after the preparation process, because the wet or moist cellulose will be affected by the presence of the antibiotic or another therapeutically active substance during storage, and because such a material is directly present on the wet or moist cellulose bag material will change its properties, and the coating on the wet cellulose will not adhere. In addition, due to degradation reasons, most therapeutically active substances cannot be stored under wet or moist conditions without significantly shortening the storage time. In addition, soaking the cellulose bag in a solution containing the API does not result in a sustained release of the API, so it is not a suitable alternative to the proposed solution.

[0073] Hence, the proposed method provides a very simple and universal solution for post-implantation infections etc. The proposed method is independent of non-degradable implantable devices, ie it can be combined with any type of non-degradable implantable device.

[0074] The cellulose bag is porous and open for diffusion of the therapeutically active substance through the material of the bag. The cellulose bag not only allows penetration of the therapeutically active substance, but also distributes the therapeutically active substance over its surface, thereby releasing the therapeutically active substance substantially uniformly over the entire surface, even if the entire inner surface of the bag is not covered by a separate layer.

[0075] Typically, bacteria that cause problems during implantation are usually located on the surface of the implantable device. By positioning the layer exactly on this surface, the antibiotic is positioned exactly where it needs to act and, in contrast to, for example, a dip coating process, its dosage is highly controlled.

[0076] According to a first preferred embodiment, the water content of the wet or moist cellulose bag is in the range of 50% to 98%, preferably in the range of 90% to 98%.

[0077] According to another preferred embodiment, the wet or moist cellulose bag has a diffusion rate or more precisely a diffusion constant or mass diffusion rate for the therapeutically active substance in water of 10 -11 Up to 10 -10 m 2 / s, preferably within the range of 10 -10 Up to 9*10 -10 m 2 / s, wherein preferably these values ​​are given for cellulose bags. In practice, the values ​​of the effective diffusion rates of therapeutic active substances (e.g. minocycline (particularly in the form of minocycline hydrochloride) and rifampicin) through the cellulose layer are determined and measured in water at 37 degrees and compared with the deviations of the free diffusion of the same molecules in water. This deviation is introduced by the porosity and tortuosity of the porous material.

[0078] The thickness of the wet or moist cellulose bag is typically at least 0.3 mm, preferably in the range of 0.5 to 10 mm or in the range of 0.5 to 5 mm.

[0079] The wet or moist cellulose bag may have, at least on its outer surface, a topographic surface structure with a height in the range of 0.5 to 2 μm, and in the case of a groove / ridge topography, a periodicity in the range of 0.5 to 100 μm, and in the case of a columnar topography, a periodicity in at least one dimension (preferably in three different directions) in the range of 5 to 50 μm, preferably in the range of 7 to 15 μm. Preferably, the topography is a topography as described in WO2015040106A1, the use of which for the topography and for the manufacture of cellulose bag material is expressly included in the present disclosure.

[0080] Thus, according to a preferred embodiment, the first step is preceded by the production of a wet or moist cellulose bag using a self-assembly production of a topographically surface structured cellulose element, wherein a mould having a first surface on one side, which first surface is topographically surface structured in a complementary manner and which first surface is oxygen permeable, wherein a liquid growth medium containing cellulose producing bacteria is provided, and wherein the mould is positioned to form a liquid / air interface of the liquid growth medium, such that the side of the mould having the first surface is in direct contact with the liquid growth medium and the opposite side faces an ambient environment of air or a specially provided oxygen-containing gas, allowing the bacteria to produce and deposit cellulose on the first surface and to form a topographically surface structured surface complementary thereto at the interface thereof, until a continuous cellulose layer having an element thickness of at least 0.3 mm is formed;

[0081] And wherein in a subsequent step the element is removed from the mould and the bag is produced from the element.

[0082] Preferably, between this production (which may require actually forming the bag with the opening by sealing the edges after folding the sheet) and the first step, the element or bag can be stored in a moist environment, preferably in a correspondingly suitable and adapted container.

[0083] The non-degradable implantable device can, for example, be selected from the following group: cardiovascular implants and / or devices, in particular pacemakers or cardioverter-defibrillators; neurostimulators, neuroregulators, implantable pulse generators, cosmetic implants, preferably in the form of breast implants, cuff implants, pectoral implants, biceps implants, buttock implants, gluteal muscle implants; orthopedic prostheses; sensors and / or electrical stimulation devices; drainage systems, preferably catheters; pumps or tubing systems; ophthalmic devices; hearing devices; bionic devices.

[0084] After the second step, in a third step, the opening is typically closed, preferably by suturing, crimping or gluing, or a combination thereof, wherein elements, in particular tubes and / or wiring (if present) attached to and connected to the non-degradable implantable device, still penetrate the opening.

[0085] In addition, the present invention relates to a kit for use in the method as described above, comprising:

[0086] Preferably at least one wet or moist bag, preferably in the form of a bag of at least one of a self-supporting hydrogel, cellulose or collagen, having an opening in the first wet package;

[0087] and at least one device as given above, in a separate wet pack or dry pack, preferably in a dry pack.

[0088] Preferably, at least two layers of means are provided in such an individual package, and preferably the means are in the form of rectangular or square sheets having a length and / or width in the range of 50 to 110 mm, preferably in the range of 60 to 90 mm.

[0089] Preferably, they take the form of a rectangle with a length in the range 70 to 110 mm, preferably in the range 80 to 90 mm, and a width in the range 50 to 90 mm, preferably in the range 60 to 80 mm.

[0090] Preferably, the first package comprises an element for maintaining controlled humidity, preferably in the form of an aluminium or aluminium-plastic laminate bag, and / or the separate package comprises an element for maintaining dryness, preferably a desiccant element.

[0091] Further embodiments of the invention are specified in the dependent claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Some preferred embodiments of the present invention are described below with reference to the accompanying drawings, which are for the purpose of illustrating the current preferred embodiments of the present invention rather than for the purpose of limiting the same. In the drawings:

[0093] Figure 1 In a) to c) are shown top views of devices of different shapes as proposed, and in d) a side view of such a device in a multilayer design, in e) a non-degradable implantable device is shown, in which two separate devices are inserted into a pocket; in f) a schematic diagram of the release of a therapeutically active substance from an implantable device is shown;

[0094] Figure 2 shows the elution profiles of rifampicin before and after sterilization by irradiation at 25 or 40 Kgy in a) (mean values ​​of API released in mg / dose), and the elution profiles of minocycline before and after sterilization by irradiation at 25 or 40 Kgy in b) (mean values ​​of API released in mg / dose). DETAILED DESCRIPTION

[0095] exist Figure 1 In the figure, the device 7 is schematically shown and its different shapes are shown in the figures a) to c). In the case of these figures, the device consists of a single layer 8 with a matrix with API as defined above.

[0096] like Figure 1d), the device 7 may comprise more than one layer 8, for example it may have a central support layer 9, which is then also preferably biodegradable, and two layers 8 of the matrix with the API are arranged on either side of this support layer 9. The support layer 9 may also be in the form of a grid or a mesh, whereas the layer 8 is typically a continuous layer.

[0097] Figure 1 e) and f) The example of using a pacemaker schematically illustrates the possible use of such a device. The cellulose bag 1 is provided as a separate element in wet or moist form. It is usually taken out by the corresponding personnel from the packaging that provides wet storage. Tools can be used to handle these cellulose bags to simplify the steps. The bag is based on a patch, which is usually folded on one edge and has a sealed edge 5 and only one opening 2, forming the actual bag for inserting the non-degradable implantable device.

[0098] A non-degradable implantable device 3 is provided separately. In this case, it is a pacemaker with the actual core element having a front surface and a back surface, so it is a flat, almost rectangular device. It also contains wiring 4 that can be attached to an external device 6. However, the proposed method can also be implemented with implantable devices that do not have wiring or tubes leading to the outside, such as breast implants, etc.

[0099] Before insertion, the front and rear surfaces of the non-degradable implantable device 3 are covered by controlled release devices or pads 7. These controlled release pads 7 are provided as separate elements and are usually taken out from corresponding dry storage packaging. As mentioned above, usually bags and these controlled release pads are provided in separate packaging or in a separate compartment of a larger package, as a test kit, so that they can be used. The manufacture of these release pads 7 will be further described below. They can be manually arranged to contact with the front and rear surfaces of the non-degradable implantable device and face the front and rear surfaces of the non-degradable implantable device, and this can be assisted by the electrostatic attraction between the corresponding sheets of the device 3 and the release pad 7, particularly in the case of very thin dry controlled release pads 7.

[0100] This assembly of the non-degradable implantable device 3 and the two controlled release pads 7 is now taken and inserted into the bag 1 through the opening and the result of this process is Figure 1 After this, the opening is usually closed by means of sutures 10 in this case.

[0101] Then, after this preparation method, the prepared implantable device is implanted in the human body. Under the conditions (temperature, physiological fluid) in the human body, the therapeutic active substance begins to diffuse / migrate to the surrounding body tissues through the porous cellulose patch material. If the therapeutic active substance is an antibiotic, then accordingly, it is released (sustained release) to the part of the tissue with the highest risk of infection within a limited time period. Therefore, it is a very targeted selective release of the active agent, accurately releasing the active agent to the position and releasing it over time as needed. Accordingly, the lowest possible dose of antibiotics can be used.

[0102] In this process, Figure 1 f) shows that the tablets 7 either release only the active ingredient or, if they are degradable or soluble, there is a whole which starts to disintegrate while releasing the active ingredient (partially degraded elements are shown as 11) and disappears completely after a certain time. Prior to this, the release of the active ingredient 12 occurs.

[0103] In order to demonstrate the inventive step of the invention, it will be described how and in what context the ultimately claimed subject matter was developed, in particular the specific polymer blend selection of the matrix.

[0104] Phase 1

[0105] In the first selection phase, several different polymers were evaluated. The design boundaries were as follows:

[0106] • Combinations of water-soluble and water-insoluble therapeutic active substances should be released in a controlled manner, in particular taking the API - minocycline (which is water-soluble) - rifampicin (which is water-insoluble) as an example system.

[0107] o Each film contains Rifampicin (7.6 mg) and Minocycline (11.9 mg) evenly.

[0108] oElution profile.

[0109] Availability

[0110] oFlexible but not brittle

[0111] o No sharp edges (in any possible shape)

[0112] oThin (any possible thickness)

[0113] o Mildly adherent (easy to adhere to target implant – but also removable if needed)

[0114] Shelf life: more than 1 year

[0115] Sterilization – can be done by irradiation and / or Et-oxide

[0116] The following polymers were tested and the results are described:

[0117] Polyvinyl alcohol (PVA) - Extensively tested, however had to be abandoned due to its rapid dissolution in water. Therefore, the excipient is not suitable for sustained release applications.

[0118] Hydroxypropyl methylcellulose (HPMC) - The test was terminated quickly because HPMC absorbed large amounts of water and formed a hydrogel. This is in contrast to the low water solubility of rifampicin.

[0119] Silicone - Initial testing was performed and produced a uniform film. However, no suitable implant grade silicone was available.

[0120] Ethylene-vinyl acetate (EVA) - Extensive testing and optimization were performed. However, EVA was shown to be non-biodegradable and this option was abandoned. Polylactic acid (PLA) - polylactic-co-glycolic acid (PLGA) - A formulation was developed that produced a good film. The addition of PEG enabled the formation of a film with good elasticity. In the initial formulation, the dissolution profile of both APIs was much slower than the intended design. Therefore, there was a need to optimize this solution.

[0121] • Polyurethane (PU) - a good candidate to obtain a homogenous film with both APIs. However, polyurethane is not biodegradable and this option was abandoned.

[0122] Conclusion of the first selection phase: A process for producing biodegradable PLA / PLGA based polymers can be developed by adding PEG as a plasticizer.

[0123] However, the second stage of optimization is necessary to address the following challenges:

[0124] 1. The API does not dissolve completely and reaches a plateau before releasing the entire amount. The API appears to be trapped in the polymer.

[0125] 2. The resulting film is too brittle and difficult to peel from the backing foil without tearing.

[0126] Phase 2:

[0127] The main objectives are outlined below:

[0128] 1. Placebo films with various grades of PLGA polymer (Table 1) were prepared using a solvent casting method. Both single-layer and bi-layer film designs were evaluated.

[0129] 2. To evaluate the solubility of rifampicin and minocycline in several solvents and determine the ideal solvent for film formulation.

[0130] 3. Rifampicin and minocycline were introduced into the placebo formulation and the membrane properties after the addition of API were evaluated.

[0131] 4. Create HPLC assay and drug elution methods based on the information provided. Optimize methods for formulation development.

[0132] Table 1: Identified PLGA polymer samples

[0133]

[0134] Using these test materials, the following results were obtained:

[0135] The solids content of the PDLG 1 material (molecular weight (number average) 60'000 + / - 6'000 g / mol, molecular weight (weight average) 125'000 + / - 10'000 g / mol, glass transition temperature 48.5°C) was 15% and the addition of 3.0 g of polymer resulted in an ideal viscosity, gel formation over time, and the possibility of reprocessing. The film thickness was 0.42 mm and the film properties were: ductile, low tensile elasticity, but there was still significant bubble formation during coating due to skinning.

[0136] The solid content of the PDLG 2 material (molecular weight (number average) 50'000 + / - 2'000 g / mol, molecular weight (weight average) 90'000 + / - 3'000 g / mol, glass transition temperature 49.5°C) was 21% and the addition of 4.0 g of polymer resulted in a viscosity that was too low, but the coating was uniform with a film thickness of about 0.34 mm. The layer was ductile, soft to the touch and easily compressible. The tensile strength was insufficient.

[0137] Resomer 505 material (MW (number average) 50'000 + / - 1'000 g / mol, MW (weight average) 80'000 + / - 2'000 g / mol, glass transition temperature 48.2°C) has the same solid content and the addition of polymer results in a viscosity that is too low and considerable flow during coating. The tensile strength is too low. The solid content of Resomer 750 material is 3.0 g and the addition of 15% polymer results in a layer with too low viscosity and low tensile strength.

[0138] Results Phase 2

[0139] Active coating feasibility. The following operations were tested,

[0140] API followed by polymer “dip coating”

[0141] Polymer and API "dip coating"

[0142] Drug “Solvent Casting” in Suspension

[0143] in conclusion:

[0144] • Minocycline HCl is insoluble in most PLGA solvents (THF, acetone, ethyl acetate), but is highly soluble in methanol. Using dichloromethane (DCM) may be an alternative. • Membranes with suitable physical properties can be prepared from PLGA by both solvent casting and dip coating methods.

[0145] • Enhanced drug elution was observed in formulations with higher drug to polymer ratio (50:50 vs 80:20).

[0146] • The suspended drug (minocycline) showed faster elution from the membrane matrix than the dissolved drug (rifampicin).

[0147] Based on these results, two formulations were tested:

[0148] Formulation 1 - one layer of PLGA film with two APIs.

[0149] • Formulation 2 - two separate film layers each containing an API.

[0150] Results of the visual appearance and elution profiles compared to the predicted devices are reported in the figure below.

[0151] in conclusion:

[0152] Minocycline HCl degraded significantly during elution testing of all prototypes. Research / optimization is required to obtain accurate elution test results for minocycline HCl.

[0153] Formulation 1 does not meet the desired in vitro release characteristics. The amount of suspended drug needs to be reduced.

[0154] Formulation 2 (two separate films combined to make the final product) Rifampicin elution results were lower than the predicted device (TYRX) at all time points. However, the elution profile matched the predicted device very well. Further optimization of this formulation is required to match the in vitro release characteristics of TYRX.

[0155] Phase 3:

[0156] Membrane optimization. Multiple aspects need to be optimized:

[0157] Prevent degradation of minocycline to epiminocycline.

[0158] · Use of PEG-4000 plasticizer and its effect on API degradation.

[0159] Film appearance, mechanics, coating weight and drug stability.

[0160] result:

[0161] • The effect of film thickness on drug elution of either API was quite low.

[0162] • Formulations with PEG-4000 had a different elution profile (lower initial drug release).

[0163] • The elution profile is promising and has been evaluated in cellulose bags and when the membranes are exposed to sterilization. • The drug layer needs to be coated on a PGA substrate to evaluate the effect of the substrate on release at early time points.

[0164] PEG-400o enhances API degradation if used outside of good proportions

[0165] These results resulted in a final formulation that was characterized by:

[0166] Membrane composition considerations:

[0167] Two antibiotics: minocycline hydrochloride (7.6 mg / dose) and rifampicin (11.9 mg / dose)

[0168] PLGA - a copolymer of DL-lactide and glycolide in a 50 / 50 molar ratio with an intrinsic viscosity midpoint of 1.0 dl / g

[0169] Single layer feasible at higher coating weights of plasticizer (PEG 4000)

[0170] Double layer can reduce coating variability / curling (extrusion of PGA materials)

[0171] Physical Features:

[0172] Film size: 15cm 2 (about 3×5cm)

[0173] Film thickness – provides the desired physical characteristics

[0174] Adhesion to implantable devices

[0175] No tearing or stretching when removed from liner

[0176] Can be applied to pacemakers using tweezers

[0177] ·Maintains shape when inserted into cellulose bag.

[0178] Elution profile:

[0179] Prolonged linear release of both APIs was observed in drug elution testing. Rifampicin eluted at a slower, more linear rate than minocycline HCl.

[0180] • The introduction of a cellulose coating into the in vitro test slowed down drug elution.

[0181] Sterilization did not change the results (Figure 2).

[0182] Optimizing pad manufacturing:

[0183] Table 2 summarizes the formulations and materials used for mixing. A roll of release liner was used. Paper cores were used as an alternative to plastic cores.

[0184] Table 2: Mixing of materials and formulations

[0185]

[0186] The blend was mixed and a mixer was used to provide agitation. To avoid evaporation of the solvent during mixing, the bottle was capped.

[0187] The coating was done on a Pilot Coater. The blend was coated onto a release liner using a knife over roll coating technique. To minimize losses, the blend was added manually to the coating head through a sampling thief.

[0188] 1.3 Process summary results

[0189] Mixing and coating are performed in a cleanroom environment with controlled temperature and humidity.

[0190] The mixing process follows the following sequence:

[0191] 1. Acetonitrile.

[0192] 2.PLGA.

[0193] 3. Methanol.

[0194] 4. Minocycline hydrochloride, rifampicin and PEG.

[0195] 5. Degas the mixing vessel.

[0196] All mixing steps (1 to 5) were performed at room temperature.

[0197] After mixing, the blend was kept under vacuum. Then after sampling, the container was sealed and kept at atmospheric pressure.

[0198] The coating process is as follows:

[0199] 1. Net the Pilot Coater.

[0200] 2. Start the dry section of the Pilot Coater. 3.

[0201] 3. Set the coating gap to the desired coating thickness.

[0202] 4. Once the dryer section reaches the target temperature, start the coating line.

[0203] 5. Manually deliver a portion of the blend to the coating equipment.

[0204] 6. The blend was coated. The resulting laminate coming out of the dryer section was wound in roll form on a paper core.

[0205] Preliminary process parameters for the coating and drying processes were initially defined during the formulation development / prototype phase of the project and successfully tested during informal placebo batch manufacturing. These preliminary CPPs are summarized in Table 4.

[0206] Table 4: Coating process parameters

[0207]

[0208]

[0209] Reference Symbols List

[0210] 1 cellulose bag 8 outer layers

[0211] 2 1 opening 9 middle layer

[0212] 3 Non-degradable implantable devices 10 Sutures

[0213] 4 Wiring / tube leading to 3 11 Partially degraded / dissolved 7

[0214] 5 1 Sealed edge 12 Release of active agent (antibiotic)

[0215] 6 3 External Devices

[0216] 7 Device, controlled release pad

Claims

1. A device (7) for releasing, preferably sustained controlled release, of a therapeutically active substance after implantation of the device alone or in combination with another implantable element (1, 3), the device (7) comprising at least one material layer (8) comprising at least one therapeutically active substance and providing sustained controlled release of the substance under physiological conditions, wherein the layer (8) comprises a biodegradable matrix consisting of a mixture of: 60% to 95% by dry weight of the first component (A) in the form of a copolymer of DL-lactide and glycolide (PLGA), wherein the molar ratio of DL-lactide to glycolide is in the range of 40:60 to 60:40, and the weight average molecular weight (MW w ) is in the range of 100,000 to 150,000 g / mol; and 5% to 40% by dry weight of a second component (B) in the form of polyethylene glycol (PEG), The dry weight of component (A) and component (B) is supplemented to 100% of the matrix, The at least one therapeutically active substance is dissolved and / or suspended in the matrix.

2. The device (7) according to claim 1, wherein the molar ratio of DL-lactide to glycolide of the first component (A) is in the range of 45:55 to 55:45, preferably in the range of 48:52 to 52:48, or in the range of about 50:

50.

3. The device (7) according to any one of the preceding claims, wherein the weight average molecular weight (MW w ) is in the range of 110,000 to 140,000 g / mol, preferably in the range of 120,000 to 130,000 g / mol, and / or wherein the number average molecular weight (MW n ) is in the range of 50,000 to 100,000 g / mol, preferably in the range of 60,000 to 80,000 g / mol, most preferably in the range of 65,000 to 75,000 g / mol, and / or wherein the intrinsic viscosity midpoint of the first component (A) is in the range from 0.8 to 1.2 dl / g, preferably in the range from 0.9 to 1.1 dl / g (measured in each case in chloroform, 25° C., c=0.1 g / dl).

4. The device (7) according to any one of the preceding claims, wherein the weight average molecular weight (MW w ) is in the range of 3000 to 5500 g / mol, preferably in the range of 3200 to 4800 g / mol, most preferably in the range of 3700 to 4400 g / mol, And / or wherein the second component (B) has a solidification point in the range of 45°C to 68°C, preferably in the range of 50°C to 65°C, most preferably in the range of 55°C to 60°C.

5. The device (7) according to any one of the preceding claims, wherein the layer (8) comprises a matrix consisting of a mixture of: 75 to 92% by dry weight, preferably 80 to 90% by dry weight, most preferably 84 to 88% by dry weight of component (A), and 8 to 25% by dry weight, preferably 10 to 20% by dry weight, most preferably 12 to 16% by dry weight of component (B), The dry weight of component (A) and component (B) makes up to 100% of the matrix.

6. The device (7) according to any of the preceding claims, wherein the at least one therapeutically active substance comprises at least one antibiotic, antiseptic, hemostatic, anti-inflammatory, chemotherapeutic, hormone, chemokine, growth factor, peptide or disinfectant, or a combination thereof, wherein preferably, the at least one therapeutically active substance is selected from at least one antibiotic selected from the group of tetracyclines, penicillins, macrolides, ansamycins, wherein the antibiotic is preferably selected from tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, metacycline, minocycline, in particular in the form of minocycline hydrochloride, hydropyracycline, doxycycline, tigecycline, eracycline, sarecycline, omadacycline, rifampicin, or a combination thereof, in particular a combination of rifampicin and minocycline, in particular in the form of minocycline hydrochloride.

7. Device (7) according to claim 6, wherein the concentration of the therapeutically active substance in the layer (8), or in the case of several therapeutically active substances the total concentration of the therapeutically active substances in the layer (8), is in the range of 5% to 50%, preferably in the range of 10% to 45% or in the range of 25% to 40%, in each case given as % w / w dry weight relative to the total dry weight of the layer (8).

8. Device (7) according to any of the preceding claims, wherein the layer (8) comprises as at least one therapeutically active substance a combination of rifampicin and minocycline, in particular in the form of minocycline hydrochloride, in a total concentration of 20% to 40% by weight, preferably in the range of 25% to 35% by weight, in each case given as % w / w dry weight relative to the total dry weight of the layer, Preferably, the concentration of minocycline, especially in the form of minocycline hydrochloride, is in the range of 10% to 20% by weight, more preferably in the range of 14% to 18%, and / or wherein the concentration of rifampicin is in the range of 15 to 25% by weight, preferably in the range of 17 to 22% by weight, in each case given as % w / w dry weight relative to the total dry weight of the layer.

9. The device (7) according to any one of the preceding claims, wherein the layer (8) comprises a matrix consisting of a mixture of: 84% to 88% by dry weight of a first component (A) having a weight average molecular weight in the range of 120,000 to 130,000 g / mol, and 12 to 16% by dry weight of a second component (B) having a weight average molecular weight MWw in the range of 3700 to 4400 g / mol, The dry weight of components (A) and (B) is sufficient to make up 100% of the layer (8), and wherein the layer (8) comprises as at least one therapeutically active substance a combination of rifampicin and minocycline, in particular in the form of minocycline hydrochloride, in a total concentration of 25 to 35% by weight, wherein the concentration of minocycline, particularly in the form of minocycline hydrochloride, is in the range of 14% to 18% by weight, and the concentration of rifampicin is in the range of 17% to 22% by weight, In each case it is given as % w / w dry weight relative to the total dry weight of the layer in question.

10. The device (7) according to any one of the preceding claims, wherein the device (7) is in the form of at least one or only one self-supporting film (8), a web, a nonwoven structure or a combination thereof, preferably having a thickness in the range of 2.5 to 100 μm, preferably in the range of 10 to 30 μm, The device (7) is preferably in the form of a film or patch, the maximum extension of the film or patch in the transverse direction is 30 cm, preferably the extension range is 0.5 to 15 cm, more preferably the extension range is 1 to 10 cm, It is also preferred that the film or patch is circular, oval or polygonal in shape, preferably rectangular or square, optionally with rounded edges, and And / or wherein the device may consist of a single said layer (8) or more than one said layer (8) in combination with at least one additional supporting layer (9), or most preferably, the device (7) consists of a single layer (8).

11. Method for producing a device (7) according to any one of the preceding claims, wherein: In the first step, the first component (A) is completely dissolved in an organic solvent, which is preferably selected from the group consisting of acetonitrile, toluene, anisole, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, dioxane, tetrahydrofuran, toluene, or a combination thereof. Preferably, the reaction is carried out at a temperature in the range of 15°C to 30°C, preferably at room temperature (20°C to 25°C), with stirring. to solidify the solution of the first component (A), And among them: In a second step, said second component (B) and said at least one therapeutically active substance are added to said solution of said first component (A), Preferably, the reaction is carried out under stirring at a temperature in the range of 15°C to 30°C, preferably at room temperature, The device is subsequently formed by evaporating at least one solvent, preferably in a solution casting or solution coating process, preferably on a release material.

12. The method according to the preceding claim, wherein after the first step and before carrying out the second step, a further organic solvent different from the organic solvent used in the first step is added to the solution of the first component (A), wherein preferably the further organic solvent is selected from the group consisting of acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane , pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethylene, xylene, acetic acid, heptane, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methyl ethyl ketone, tert-butyl methyl ether, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethanol, 1-pentanol, ethyl acetate, 1-propanol, ethyl ether, 2-propanol, ethyl formate, propyl acetate, formic acid, triethylamine, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyltetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, or a combination thereof, Wherein preferably, the additional solvent is added to the solution of the first component (A) in a proportion in the range of 20% to 40% v / v, preferably in the range of 25% to 35% v / v, and / or wherein in the first step, the first component (A) is dissolved in a concentration in the range of 10% to 35% w / v, preferably in the range of 20% to 30% w / v, in each case based on the volume of the organic solvent.

13. Use of the device (7) according to any one of the preceding claims 1 to 10 for the preparation of an implantable device, wherein in a first step, an implantable device (3), preferably a non-degradable implantable device (3), is at least partially covered or surrounded by at least one such device (7), And preferably, in the second step, it is inserted into a wet bag or moist bag (1) through an opening (2) of the wet bag or moist bag (1), wherein the wet bag or moist bag (1) is at least one of a self-supporting hydrogel, cellulose or collagen (1).

14. Kit for use according to the preceding claims, comprising: at least one wet bag or moist bag (1), preferably in the form of a bag of at least one of a self-supporting hydrogel, cellulose or collagen (1), having an opening (2) in a first wet package; and at least one device (7) according to any of the preceding claims 1 to 10, in a separate wet or dry package, preferably in a dry package.

15. Kit according to claim 14, wherein at least two devices (7) are provided in the individual packaging, and wherein preferably the devices are in the form of rectangular or square pieces with a length and / or width in the range of 50 to 110 mm, preferably in the range of 60 to 90 mm, wherein the devices are preferably in the form of rectangles with a length in the range of 70 to 110 mm, preferably in the range of 80 to 90 mm, and a width in the range of 50 to 90 mm, preferably in the range of 60 to 80 mm, and / or wherein preferably, the first packaging comprises an element for maintaining controlled humidity, the element preferably being in the form of an aluminium or aluminium-plastic laminate bag, And / or wherein the individual packaging comprises an element for maintaining dryness, preferably a desiccant element.

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