Sustained Controlled Release Device for Therapeutic Active Substances and Use Thereof

Abstract

A device (7) for the sustained controlled release of a therapeutic active substance, either alone or after being implanted in combination with further implantable elements (1, 3), said device (7) comprising one layer (8) of a material containing at least one therapeutic active substance, said layer (8) being in the form of a biodegradable matrix consisting of a mixture of a first component (A) in the form of a copolymer (PLGA) of DL-lactide and glycolide having a molar ratio of DL-lactide to glycolide in the range of 40:60 to 60:40 and a weight average molecular weight (MW w ) in the range of 100,000 to 150,000 g / mol, at 60 to 95 dry weight %, and a second component (B) in the form of polyethylene glycol (PEG) at 5 to 40 dry weight %, the dry weights of components (A) and (B) complementing 100% of the matrix, and at least one of said therapeutic active substances being dissolved and / or suspended in said matrix.

Description

Technical Field

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

Background Art

[0002] Non-degradable implantable devices that are implanted to remain in a fixed position need to be configured to avoid a negative foreign body reaction in the patient. This applies not only to fully implanted implants such as breast implants or pacemakers, but also to implants that require long-term transdermal delivery. Certain types of implantable medical devices require long-term transdermal delivery between the inside and outside of the device. Examples of such devices include left ventricular assist devices, tissue expanders, arteriovenous shunts, and gastric lap bands. The transdermal portion of the device may be in the form of a catheter, a gas insufflation tube, or one or several electrical wires. These types of transdermal medical devices are susceptible to infection.

[0003] To improve the compatibility between the surrounding tissue and the actual implantable medical device, by providing a pouch for the implantable medical device before insertion into the body, an optimal interface can be provided between the surrounding tissue and the implant, complications can be avoided, and the healing of the device can be assisted.

[0004] The problem with implantable medical devices, especially those that perform long-term transdermal delivery, is the high infection rate after implantation. Typically, this infection is treated by administering antibiotics, either alone or in combination with local flushing with an antibiotic solution, orally or intravenously. However, this may not be sufficient, especially in the case of implants placed in physiologically sensitive locations in the body where orally administered antibiotics cannot reach quickly enough simultaneously.

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

[0006] Wound dressings are designed to actively promote wound healing by supporting the wound area, protecting the wound area from infection, and in certain cases, creating a favorable environment for cell growth.

[0007] The response to a wound, defined as an injury to body tissue, includes an inflammatory phase, a migratory phase, and a remodeling phase. The inflammatory phase is an acute response to the wound, the purpose of which is to quickly seal the wound and produce chemotactic factors that cause cells to migrate into the wound to initiate the wound healing process. During the migratory phase, cells rapidly migrate into the wound and begin to construct a temporary extracellular matrix that serves as the basis for the healing tissue. In the remodeling stage, the newly formed tissue gradually matures into its permanent form.

[0008] Standard wound dressings promote wound healing by: 1. approximating wound edges and mechanically holding them to allow for easier cell migration; 2. mechanically occluding the wound to prevent contamination by pathogens; and 3. in some advanced dressings, providing an environment that actively promotes more rapid wound healing, usually by exposing the wound tissue to a hydrated gel. Improved materials for these applications are desirable.

[0009] In reconstructive surgery, not only commercially available silicone implants (e.g., breast, calf, buttock, chest, biceps), but also the above-described implanted medical devices often fail due to foreign body reactions and encapsulation by scar tissue. Improved materials / coatings are desirable for such applications.

[0010] In cosmetics, disposable flat and amorphous cellulose masks are available as masks (e.g., face, hands, and feet) that enhance skin hydration, as well as absorption of metabolic waste products and release of nutrients or other compounds to the skin.

[0011] WO2015040106A1 proposes a method for the self - organized production of cellulose elements with a three - dimensional surface structure that can be used as a material for such pouches. In a first step, it includes a mold having a three - dimensionally surface - structured first surface that is oxygen - permeable on one side in a complementary manner, a liquid growth medium containing cellulose - producing bacteria, the mold being arranged to form a liquid / air interface of the liquid growth medium such that the side having the first surface is in direct contact with the liquid growth medium, and the opposite side facing an ambient gas containing air or specially provided oxygen. The bacteria are made to produce and deposit cellulose on the first surface until a continuous cellulose layer having an element with a thickness of at least 0.3 mm is formed, and a surface with a three - dimensional surface structure complementary to it is developed at the interface with the first surface; in a second step, the element is removed from the mold. Further, this invention relates to an element created using such a method and the use of such an element for various applications. The corresponding pouch provides optimal compatibility with the surrounding tissue not only immediately after implantation but also over a longer period when the implant is retained in the body.

[0012] US - A - 2019009063 discloses an inflatable balloon surrounded by an expandable cover that gradually becomes more porous / permeable during expansion. The balloon is coated or surrounded by a matrix containing a pharmaceutically active agent. During the expansion of the balloon, the pharmaceutically active agent is released or extruded into a body cavity such as an artery or vein through the expandable cover.

[0013] US - A - 2007141106 provides a medical system for the administration of pharmaceuticals to a patient in vivo. This medical system includes a medical implant that can be placed inside the patient's body. The pharmaceutical is placed on the medical implant and is at least partially coated with a reactive coating. The reactive coating acts to control the release of the pharmaceutical. An energy unit is provided to transmit an energy signal to the reactive coating, and the reactive coating reacts to the energy signal to increase the release rate of the pharmaceutical.

[0014] WO-A-2008136856 describes a biodegradable and absorbable polymer pouch for use with a cardiac rhythm management device (CRM) and other implantable medical devices (IMDs), i.e., a pouch, cover, or other container that can wrap, surround, and / or hold a CRM or other IMD in place, inhibit or reduce bacterial growth, provide analgesia, and / or inhibit scarring or fibrosis on or around a CRM or other IMD. Optionally, the biodegradable and absorbable pouch of this invention contains one or more drugs in a polymer matrix to provide a prophylactic effect and reduce side effects or complications associated with the surgery or implantation of a CRM or other IMD.

[0015] US-A-2020197712 describes an absorbent nonwoven pouch that at least partially surrounds an implantable medical device and an improved method for manufacturing an implantable medical device pouch. The nonwoven pouch may contain one or more drugs. An implantable medical device placed within the pouch prior to implantation is prevented from moving from the implantation site by ingrowth of tissue into the pouch. Antibiotics may be incorporated into the pouch to prevent postoperative infection. The pouch can be formed without a polymer coating in fewer steps than conventional pouches. The nonwoven pouch can be formed in one step by dry spinning instead of using multiple processing steps. In embodiments, the nonwoven pouch is smoother on the inside than the outside and snugly fits the implantable medical device inside while promoting ingrowth of external tissue. In embodiments, the nonwoven pouch eliminates the use of knitted or woven multifilament fibers that can trap bacteria and lead to postoperative infection.

[0016] Steele et al. (Acta Biomater. 2011 May;7(5):1973 - 1983, doi:10.1016 / j.actbio.2011.02.002) typically report 1 μg day -1 cm -2A thin film of poly(lactic acid-co-glycolic acid) (PLGA) incorporating paclitaxel with a slow release rate of paclitaxel of the order has been reported. For implementation as a medical device, a zero-order release rate (i.e., 1 - 15 μg day -1 cm -2 ) is desirable for various tissues and pathologies. Polyethylene glycol (PEG) with molecular weights of 8 and 35 kDa was incorporated into PLGA containing 10 wt% paclitaxel at weight ratios of 15%, 25%, and 50%. The mechanical properties were evaluated for potential use as a medical implant, the release rate of paclitaxel was quantified as a percentage of release, and a more clinically useful release rate was quantified in μg day -1 cm -2 . The quantification of paclitaxel was correlated with the release of PEG from PLGA to further understand its role in paclitaxel / PLGA release modulation. PEG release was found to correlate 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 and partitioning compounds to increase the release rate of hydrophobic drugs such as paclitaxel from PLGA films, where paclitaxel is normally uniformly dispersed / dissolved. Two formulations are promising as medical device thin films when optimized for tensile strength, elongation, and drug release. For the slow release rate of paclitaxel, an average of 3.8 μg day -1 cm -2 was achieved for over 30 days using 15% 35k PEG, while a high drug release rate of 12 μg day -1 cm -2 was maintained for up to 12 days using 25% 8 kDa PEG.

[0017] KR-B-100376083 relates to a biocompatible and biodegradable polymer matrix for a sustained-release implant containing a hydrophilic drug or a salt thereof, whereby the polymer matrix has an improved drug release rate and an initial burst effect. The biocompatible and biodegradable polymer matrix for a sustained-release implant containing a hydrophilic drug or a salt thereof is produced by the following steps: a) dissolving a first polymer selected from poly(d,l-lactide-co-glycolide) (PLGA), polyglycolide (PGA), and polylactic acid (PLA), a second polymer, polyethylene glycol (PEG), and a surfactant in an organic solvent; b) dissolving a hydrophilic drug or a salt thereof in water; adding the solution produced in step b) to the solution produced in step a), and stirring the resulting mixture 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 can include a body structure formed of a compliant material including one or more compliant biocompatible polymers and one or more bioactive agents. The body structure can define a central opening through which a subcutaneous element of the implantable medical device passes. Other embodiments are also included in this specification.

Summary of the Invention

[0019] The object of the present invention is to provide an improved and optimized device for releasing, preferably in a sustained and controlled manner, at least one therapeutic active substance, either alone or in combination with other implantable elements, after implantation. These implantable elements may be one or a combination of the following devices, namely hip prostheses, joint prostheses, knee prostheses, bone fusion hardware, breast implants, cochlear implants, intrauterine devices (IUDs), dental implants, ear tubes, implantable insulin pumps, implantable pulse generators, implantable sensors, joint fusion hardware, metal screws, muscle fusion hardware, pins, plates and rods, surgical meshes, orthopedic spacers, drive lines, catheters, and may include pacemakers, nerve stimulators, ventricular assist devices (VADs), etc.

[0020] More specifically, the present invention according to the first aspect relates to the device according to claim 1.

[0021] Similarly, the present invention proposes a device for releasing, preferably in a sustained and controlled manner, a therapeutic active substance, either alone or in combination with a further implantable element, after implantation. According to the present invention, the device comprises at least one therapeutic active substance and comprises or consists of at least one layer of a material that provides sustained and controlled release of said substance under physiological conditions.

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

[0023] The dry weights of components (A) and (B) complement 100% of the matrix.

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

[0025] As shown below, this very special matrix having these two defined components provides an optimal release and biodegradability profile for the layer and is used for other purposes, but is particularly used in the corresponding layer to avoid inflammation after implantation, especially when implanting a non-degradable implant. Also, the proposed matrix dissolves various types of therapeutic active substances and, in particular, simultaneously dissolves and makes available controlled-release therapeutic active substances that are water-soluble (hydrophilic) and water-insoluble (hydrophobic). Similarly, the proposed matrix is particularly suitable and compatible for the combined administration of at least two different therapeutic active substances, such as minocycline and rifampicin. Furthermore, the proposed matrix provides an ambient environment that enables a longer effective period and stabilizes the corresponding therapeutic active substances, preventing the conversion / decomposition of the API.

[0026] Here, the hydrophilicity and hydrophobicity of molecules, particularly therapeutic active substances, are defined in terms of their solubility in water. Solubility is a chemical property of a molecule in a particular solvent and depends on both their chemical nature and the environmental conditions of temperature and pH. Thus, for the purposes of this specification, we define hydrophobicity as the low solubility of a molecule in water, specifically less than 5 mg / ml, preferably less than 3 mg / ml, particularly 2.5 mg / ml or less (however, more preferably more than 0.1 mg / ml, or even more than 0.5 mg / ml), and hydrophilicity as the high solubility of a molecule in water, specifically more than 20 mg / ml, preferably more than 40 mg / ml, particularly more than 45 mg / ml. This is at pH 7 at room temperature (20 degrees) or body temperature (37 degrees). Solubility is measured in distilled and deionized water and is expressed in mg / mL.

[0027] Accordingly, according to a preferred embodiment, there are at least two therapeutically active substances in the matrix, one of which is hydrophobic and one is hydrophilic. Preferably, rifampin is selected as the hydrophobic active substance and minocycline is selected as the hydrophilic active substance.

[0028] Preferably, in this case, the difference in solubility in water is more than 10-fold (milligrams / milliliter), more preferably more than 20-fold, most preferably more than 35-fold, or in the range of 30 to 40-fold.

[0029] Preferably, when there is one hydrophobic therapeutically active substance and one hydrophilic therapeutically active substance, the weight ratio of each therapeutically active substance to PLGA is in the range of 15 to 40%, preferably in the range of 20 to 35% in each case. More preferably, the weight ratio of the hydrophilic therapeutically 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 therapeutically active substance, preferably rifampin, to PLGA is in the range of 25 to 40%, preferably in the range of 30 to 35%.

[0030] In fact, the proposed matrix has been found to be surprisingly suitable and compatible for simultaneously incorporating hydrophobic and hydrophilic therapeutically active substances and controllably releasing both substances in a manner as similar as possible.

[0031] Accordingly, minocycline is hydrophilic because it can dissolve in water up to 50 mg / mL at room temperature at neutral pH, i.e., pH 7.

[0032] Rifampin is hydrophobic because it can only dissolve in water up to 2.5 mg / mL at room temperature at neutral pH, i.e., pH 7.

[0033] Accordingly, under these conditions, there is a 35-fold difference in the water solubility of the two molecules.

[0034] What is important in the matrix is that it is necessary to utilize the different solubilities of the two types of molecules in the PEG-PLGA structure in order to load both types of molecules in a sufficient amount.

[0035] Generally, the proposed devices in the form of films or the like do not have a barrier function, and in particular, they cannot restore or substitute for, for example, the skin barrier function.

[0036] Furthermore, the proposed devices are essentially inelastic and cannot be stretched for placement, and attempting to stretch them will break the devices.

[0037] According to a first preferred embodiment, the molar ratio of DL-lactide to glycolide in 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] More preferably, the first component (A) has a weight average molecular weight (MW w ) 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 in addition, the first component (A) preferably has a number average molecular weight (MW n ) in the range of 50,000 to 100,000 g / mol, preferably in the range of 60,000 to 80,000 g / mol, and most preferably in the range of 65,000 to 75,000 g / mol.

[0040] Alternatively, or in addition, preferably, the first component (A) has an intrinsic viscosity midpoint in the range of 0.8 to 1.2 dl / g, preferably in the range of 0.9 to 1.1 dl / g (measured in chloroform at 25 °C, c = 0.1 g / dl in both cases).

[0041] According to yet another preferred embodiment of the proposed device, the second component (B) has a weight average molecular weight (MW w ) 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 second component (B) has a freezing point in the range of 45 to 68 °C, preferably in the range of 50 to 65 °C, most preferably in the range of 55 to 60 °C.

[0043] As a ratio, preferably, the layer comprises a matrix consisting of a mixture of 75 to 92 dry weight %, preferably 80 to 90 dry weight %, most preferably 84 to 88 dry weight % of component (A) and 8 to 25 dry weight %, preferably 10 to 20 dry weight %, most preferably 12 to 16 dry weight % of component (B), and the dry weights of components (A) and (B) complement 100% of the matrix.

[0044] Typically, at least one therapeutic active substance comprises at least one antibiotic, preservative, hemostatic agent, anti-inflammatory agent, chemotherapeutic agent, hormone, chemokine, growth factor, peptide, or bactericide, or a combination thereof, and preferably, at least one therapeutic active substance is selected from at least one antibiotic selected from the group consisting of tetracyclines, penicillins, macrolides, ansamycins, and preferably is selected from the group consisting of tetracycline, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, doxycycline, tigecycline, eravacycline, sarecycline, omadacycline, rifampicin, or a combination thereof, particularly a combination of minomycin HCl and rifampicin.

[0045] The concentration of the therapeutically active agent in the layer, or in the case of several therapeutically active agents, the total concentration of the therapeutically active agents, is preferably in the range of 5-50%, preferably in the range of 10-45%, or in the range of 25-40%, in each case expressed as dry % w / w of the total layer.

[0046] It is particularly preferred that the at least one therapeutically active substance layer comprises minocycline, in particular in the form of minocycline HCl, in combination with rifampicin in a total concentration ranging from 20 to 40% by weight, preferably 25 to 35% by weight, in each case expressed as dry % w / w relative to the total of the layer.

[0047] In this case, preferably the concentration of minocycline, in particular in the form of minocycline HCl, is in the range 10-20% by weight, more preferably in the range 14-18% and / or the concentration of rifampicin is in the range 15-25% by weight, preferably in the range 17-22% by weight, in each case expressed as dry % w / w of the total layer.

[0048] According to a particularly preferred embodiment, the layer (8) comprises 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; 12-16% by dry weight, weight average molecular weight MW in the range of 3700-4400 g / mol w and a second component (B) having the following structure: the dry weights of components (A) and (B) make up 100% of said layer; The at least one therapeutically active layer comprises a combination of minocycline, particularly in the form of minocycline HCl, and rifampicin in a total concentration of 25-35% by weight, the concentration of minocycline, particularly in the form of minocycline HCl, being in the range of 14-18% and the concentration of rifampicin being in the range of 17-22% by weight, in each case expressed as dry % w / w of the total layer.

[0049] Preferably, for the intended use, the device is preferably in the form of at least one or only one self - supporting film, mesh, non - woven structure or combination thereof 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.

[0050] More preferably, the device is in the form of a film or patch having a maximum elongation in the lateral direction of 30 cm, preferably in the range of 0.5 to 15 cm, more preferably in the range of 1 to 10 cm.

[0051] Such a film or patch is preferably of circular, oval or polygonal shape, preferably rectangular or square shape, and optionally has rounded edges.

[0052] The device may consist of two or more of the above - mentioned layers in combination with a single or at least one additional support layer (which may preferably be biodegradable or non - biodegradable).

[0053] The device may be in the form of a lattice, non - woven or woven fabric, or preferably a continuous layer. The device may also be in the form of at least one strip that is wrapped around a non - degradable implant during use. Further, the device may be in the form of a pouch of the corresponding material or an elastic film such as a wrap film for completely enclosing a non - degradable implant during use.

[0054] The layer is preferably provided as at least two sheets which are placed on the opposing main surfaces of the non - degradable implantable device prior to insertion into the wet or high - humidity cellulose pouch according to the use as further described below.

[0055] Most preferably, the device consists of a single layer as defined above.

[0056] According to a further aspect of the present invention, the present invention relates to a method for manufacturing the device defined above. According to this method, preferably in a first step, the first component (A) is preferably dissolved completely in an organic solvent selected from the group consisting of acetonitrile, acetone, anisole, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, dioxane, tetrahydrofuran, toluene, or combinations thereof, preferably at a temperature in the range of 15 to 30 °C, preferably at room temperature (20 to 25 °C) with stirring, to form a solution of the first component (A).

[0057] More preferably, in a second step, the second component (B) and at least one therapeutic active substance are added to the solution of the first component (A). Also in this case, this step is preferably carried out at a temperature in the range of 15 to 30 °C, preferably at room temperature with stirring, preferably in the same mixing device as in the first step. Subsequently, preferably in a solution casting or solution coating process, preferably on a release material, at least one solvent is evaporated to form a device.

[0058] According to a first preferred embodiment of the proposed method, after the first step and before performing 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), preferably, the further organic solvent is 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-trichloroethene, 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, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid, or a combination thereof.

[0059] Preferably, the further 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.

[0060] According to a further preferred embodiment of the method, in the first step, the first component (A) is dissolved at a concentration in the range of 10 to 35% w / v, preferably in the range of 20 to 30% w / v, per volume of the organic solvent in each case.

[0061] According to yet another aspect of the present invention, the present invention relates to the use of the device defined above for creating an implantable device.

[0062] According to a preferred embodiment of this 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 such device, and preferably in a second step, this is inserted through its opening into at least one wet or high-humidity pouch of self-supporting hydrogel, cellulose, or collagen.

[0063] In fact, at least one high-humidity pouch of self-supporting hydrogel, cellulose, or collagen is inelastic, which is preferably such that, even at low stress (where the stress value of σ is a low value of 0.005, 0.01, or 0.5 MPa, or in the range of 0.01 - 0.1 MPa), after applying and releasing stress in the stress-strain curve of load unloading, the material of the pouch cannot return to its initial non-distorted state, which is preferably quantifiable.

[0064] The cellulose layer of the pouch can be provided as a non-degradable pouch and thus is associated with the non-degradable implantable device over its entire lifetime. Alternatively, the cellulose layer can also be provided as a degradable element that is reabsorbed by the body over a certain period.

[0065] Important elements of this use can be as follows.

[0066] In particular, a therapeutic active substance in the form of an antibiotic should be provided in an effective way to avoid post-implantation infections and the like. A cellulose pouch that remains in a fixed position after implantation and is suitable for remaining around a non-degradable implant device and is thus adapted is usually produced by a biochemical process involving organisms, so it is particularly impossible to incorporate the corresponding therapeutic active substance into the cellulose pouch material. Furthermore, the cellulose pouch material cannot be prepared and provided as a dry layer for many practical reasons regarding storage and packaging, preparation and use. Also, it is impossible to impregnate or coat the pouch material after the manufacturing process using the therapeutic active substance. This is because wet or high-humidity cellulose is adversely affected by the presence of an antibiotic or other therapeutic active substance during storage, and the direct presence of such a material on a wet or high-humidity cellulose pouch material changes its properties and the coating on the wet cellulose does not adhere. Furthermore, many therapeutic active substances deteriorate when stored under wet or high-humidity conditions, so the storage time is significantly reduced. Moreover, dipping a cellulose pouch into a solution containing an API does not result in a sustained release of the API, so it is not a suitable alternative to the proposed solution.

[0067] Therefore, the proposed approach provides a very simple and versatile solution to post-implantation infections and the like. The proposed method is independent of non-degradable implant devices, i.e., it can be combined with any type of non-degradable implant device.

[0068] The cellulose pouch is porous and is open to allow the therapeutic active substance to diffuse through the pouch material. The cellulose pouch not only enables the penetration of the therapeutic active substance but also disperses the therapeutic active substance throughout its surface, thereby essentially equalizing the release of the therapeutic active substance over the entire surface even if the entire inner surface of the pouch is not covered by a separate layer.

[0069] Typically, the bacteria that cause problems in the implantation process are usually present on the surface of the implantable device. By accurately placing the layer on its surface, the antibiotic is precisely positioned where its action is required, and its dosage is highly controlled, for example, in contrast to an immersion coating process.

[0070] According to a first preferred embodiment, the wet or highly humid cellulose pouch has a water content in the range of 50 - 98%, preferably in the range of 90 - 98%.

[0071] According to a further preferred embodiment, the wet or highly humid cellulose pouch has a diffusion rate, or diffusion constant or mass diffusivity, of a therapeutic active substance in water that is typically in the range of 10 -11 ~10 -10 m 2 / s, preferably in the range of 10 -10 ~9×10 -10 m 2 / s, and preferably these values are given for the cellulose pouch. In practice, these values are determined for the effective diffusivity of the therapeutic active substance (e.g., minocycline, especially minocycline in the form of minocycline HCl, and rifampicin) throughout the cellulose layer and are measured in water at 37°C in comparison to the free diffusion of the same molecule in water. This deviation is caused by the porosity and tortuosity of the porous material.

[0072] The wet or highly humid cellulose pouch typically has a thickness of at least 0.3 mm, preferably in the range of 0.5 - 10 mm or 0.5 - 5 mm.

[0073] The wet or highly humid cellulose pouch may have a three-dimensional surface structure with a height in the range of 0.5 to 2 μm, at least on its outer surface. In the case of a groove / ridge three-dimensional structure, it may have a structure periodicity in the range of 0.5 to 100 μm. In the case of a columnar three-dimensional structure, it may have a structure periodicity in the range of 5 to 50 μm, preferably in the range of 7 to 15 μm, in at least one dimension, preferably in three different directions. Preferably, the three-dimensional structure is as described in WO2015040106A1, and its content regarding the manufacture of the three-dimensional structure and the cellulose pouch material is explicitly included in this disclosure.

[0074] Thus, according to a preferred embodiment, the wet or highly humid cellulose pouch is manufactured prior to the first step using self-assembled manufacture of cellulose elements with a three-dimensional surface structure, and a mold is provided that has a first surface that is three-dimensionally surface-structured in a complementary manner and is oxygen-permeable on one side. A liquid growth medium containing cellulose-producing bacteria is provided. The mold is arranged to form a liquid / air interface of the liquid growth medium such that the side having the first surface is in direct contact with the liquid growth medium, and the opposite side faces air or the surrounding gas containing specially provided oxygen. The bacteria are caused to produce and deposit cellulose on the first surface until a continuous cellulose layer having an element with a thickness of at least 0.3 mm is formed, and a surface having a three-dimensional surface structure complementary to it is developed on the interface with the first surface; in the next step, the element is removed from the mold and the pouch is manufactured from the element.

[0075] Preferably, between this manufacture, which may involve the actual formation of a pouch having an opening by sealing the edges after folding the sheet, and the first step, the element or pouch can be stored in a wet environment, preferably in a corresponding suitable and adapted container.

[0076] The non-degradable implantable device can be selected from the group consisting of, for example, cardiovascular implants and / or devices, particularly pacemakers or defibrillators; nerve stimulation devices, nerve regulation devices, implantable pulse generators, preferably cosmetic implants in the form of breast implants, cuff implants, pectoralis implants, biceps implants, gluteal implants, hip implants; orthopedic prostheses; sensors and / or electrical stimulation devices; drainage systems, preferably catheters; pump or tubing systems; ophthalmic devices; auditory devices; and bionic devices.

[0077] Subsequent to the second step, in the third step, the opening is typically closed, preferably by suturing, crimping, or adhesion, or a combination thereof, and in particular, when there are elements such as tubes and / or wiring attached to and connected to the non-degradable implantable device, the opening remains through.

[0078] Furthermore, the present invention relates to a kit of parts for use in the above method, comprising at least one, preferably wet or high-humidity pouch, in the form of a pouch of at least one of preferably self-supporting hydrogel, cellulose, or collagen, having an opening in a first wet package, and the above at least one device in a separate wet or dry package, preferably a dry package.

[0079] Preferably, at least two devices are provided in such a separate package, and preferably, the devices are in the form of a rectangle or two-dimensional sheet having a length and / or width in the range of 50 to 110 mm, preferably in the range of 60 to 90 mm.

[0080] Preferably, the devices are in the form of a rectangle having 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.

[0081] Preferably, the first package contains elements for maintaining a controlled humidity, preferably in the form of an aluminum or aluminum plastic laminate pouch, and / or the separate package contains elements for maintaining a dry state, preferably a desiccant element.

[0082] Further embodiments of the invention are described in the dependent claims.

[0083] Preferred embodiments of the invention are described below with reference to the drawings, which are for illustrative purposes of the presently preferred embodiments of the invention and are not intended to limit the invention.

Brief Description of the Drawings

[0084]

Figure 1

Figure 2a

Figure 2b

Modes for Carrying Out the Invention

[0085] In Figures 1(a) to (c), devices 7 of different shapes are schematically shown. In these figures, the device consists of a single layer 8 of a matrix having the API defined above.

[0086] As shown in the side view of FIG. 1(d), the device 7 may include two or more layers 8, for example, it may have a central support layer 9, which is also preferably biodegradable. The two layers 8 of the matrix having the API are provided on both sides of the support layer 9. The support layer 9 may be in the form of a lattice or a mesh, while the layer 8 is typically a continuous layer.

[0087] FIGS. 1(e) and (f) schematically show a possible use of such a device using an example of a pacemaker. The cellulose pouch 1 is provided as a separate element in a wet or high-humidity form. The cellulose pouch 1 is typically taken out from a package that provides wet storage by the corresponding personnel. Tools for handling these cellulose pouches may be used to simplify the procedure. The pouch is typically based on a patch having one edge folded back, a sealed edge 5 and only one opening 2, thereby forming an actual pouch for inserting a non-degradable implantable device.

[0088] Separately, a non-degradable implantable device 3 is provided. In this case, the implantable device 3 is a pacemaker having an actual core element with a front and a back, and thus is a substantially rectangular flat device. The implantable device 3 further has a wiring 4 that can be attached to an external device 6. However, the proposed method can also be implemented by an implantable device without external wiring or tubing, such as a breast implant.

[0089] Before insertion, the front and back surfaces of the non-degradable implantable device 3 are covered by the controlled release device or pad 7. These controlled release pads 7 are provided as separate elements and are typically unpacked from the corresponding dry storage package. As described above, typically, the pouch and these controlled release pads are provided as a kit of parts, in separate packages, or in separate compartments of one larger package, to facilitate use. The fabrication of these release pads 7 is described in more detail below. The release pads 7 may be manually placed in contact with and facing the front and back surfaces of the non-degradable implantable device, and in particular, in the case of very thin dry controlled release pads 7, there may be assistance by the electrostatic attraction between the device 3 and each sheet of the release pad 7.

[0090] This assembly of the non-degradable implantable device 3 and the two controlled release pads 7 is now removed and inserted through the opening into the pouch 1, and the result of that process is illustrated in Figure 1(e). Subsequently, typically, the opening is closed in this case by the suture 10.

[0091] This prepared implantable device is then implanted into the human body following this preparation method. Under the conditions in the human body (temperature, physiological fluids), the therapeutic active substance begins to diffuse / move into the surrounding body tissue through the porous cellulose patch material. If the therapeutic active substance is an antibiotic, the antibiotic is then released (in a sustained release manner) to the parts of the tissue where the risk of infection is highest for a defined period of time. Thus, it is a very targeted release of the active agent to the exact location and for the required time. In this case, the dosage of the antibiotic can be made as low as possible. In this process shown in Figure 1(f), the sheet 7 either only releases the active ingredient or, if the sheet 7 is degradable or soluble, the whole of it begins to disintegrate simultaneously with the release of the active ingredient (the partially disintegrated element shown at 11) and completely disappears after a certain time. By then, the release 12 of the active ingredient has occurred.

[0092] To demonstrate the inventive step, it is explained how the finally claimed subject matter, in particular the selection of the specific polymer mixture for the matrix, was developed and in which context.

[0093] First stage: In the first selection stage, several different polymers were evaluated. The design boundaries were as follows. · A combination of water-soluble and water-insoluble therapeutic active substances, in particular, as an exemplary system, minocycline which is API-water-soluble and rifampicin which is water-insoluble must be released in a controlled manner. - Rifampicin (7.6 mg) and minocycline (11.9 mg) per film homogeneous enclosure. - Dissolution profile. · Usefulness - Flexible but not brittle - Without sharp edges (any shape possible) - Thin (any thickness possible) - Slightly adhesive (easily adheres to the target implant but can also be removed if necessary) · Shelf life - over 1 year · Sterilization - possible using radiation and / or ethylene oxide

[0094] The following polymers were tested and the results annotated. · Polyvinyl alcohol (PVA) - Tested extensively but had to be discarded because it dissolved rapidly in water. Therefore, this excipient is not suitable for sustained release applications. · Hydroxypropylmethylcellulose (HPMC) - The test ended immediately because HPMC absorbed a large amount of water and a hydrogel was formed. This is in contrast to the low water solubility of rifampicin. · Silicone - Preliminary tests were carried out and a homogeneous film was obtained. However, a suitable embedding grade of silicone was not obtained. · Ethylene - vinyl acetate (EVA) - Tested extensively and optimized. However, it was found that EVA is non-biodegradable and this option was discarded. · Developed a formulation that results in a good film with polylactic acid (PLA) - poly(lactic - co - glycolic acid) (PLGA). By adding PEG, a film with good elasticity could be formed. In the initial formulation, the dissolution profiles of the two APIs were much slower than the intended design. Therefore, this solution needed to be optimized. · Polyurethane (PU) is a good candidate for obtaining homogeneous films with both APIs. However, since PU is non - biodegradable, this option was discarded.

[0095] Conclusion of the first selection stage: By adding PEG as a plasticizer, a method for producing biodegradable PLA / PLGA - based polymers could be developed. However, second - stage optimization was needed to solve the following problems. 1. The dissolution of the API was incomplete and reached a plateau before the full amount was released. The API seems to be trapped in the polymer. 2. The film was too brittle and difficult to peel from the backing foil without tearing.

[0096] Second stage: Summarize the main objectives as follows. 1. Prepare placebo films containing multiple grades of PLGA polymers (Table 1) using the solvent - casting method. Evaluate both single - layer and double - layer film designs. 2. Evaluate the solubility of rifampicin and minocycline in several solvents and determine the ideal solvent for film formulation. 3. Introduce rifampicin and minocycline into the placebo formulation and evaluate the film properties after API addition. 4. Based on the information provided, create HPLC assays and drug elution methods. Optimize the methods for use in formulation development.

[0097]

Table 1

[0098] Using these test materials, the following results were obtained.

[0099] An ideal viscosity was obtained with a PDLG1 material with a solids content of 15% (number average molecular weight 60,000 + / - 6,000 g / mol, weight average molecular weight 125,000 + / - 10,000 g / mol, glass transition temperature 48.5 °C) to which 3.0 g of polymer was added, and a gel was formed over time, providing the possibility of reprocessing. The film thickness was 0.42 mm, and the film properties were malleable with low tensile elongation, but still a significant number of bubbles were formed during coating due to skinning.

[0100] With a PDLG2 material with a solids content of 21% (number average molecular weight 50,000 + / - 2,000 g / mol, weight average molecular weight 90,000 + / - 3,000 g / mol, glass transition temperature 49.5 °C) to which 4.0 g of polymer was added, the viscosity became extremely low, but a uniform coating was obtained, and the film thickness was approximately 0.34 mm. The layer was malleable, soft to the touch, and easy to compress. The tensile strength was insufficient.

[0101] With a Resomer505 material with the same polymer added and the same solids content (number average molecular weight 50,000 + / - 1,000 g / mol, weight average molecular weight 80,000 + / - 2,000 g / mol, glass transition temperature 48.2 °C), the viscosity became extremely low, and there was significant flow during coating. The tensile strength was extremely low.

[0102] With a Resomer750 material with 15% polymer added and a solids content of 3.0 g, a layer with extremely low viscosity and low tensile strength was obtained.

[0103] Results of the second stage Feasibility of an active coating. The following procedures were tested. · "Dip coating" with API followed by polymer · "Immersion Coating" with Polymer and API · "Solvent Casting" in Drug Suspension

[0104] Conclusion: · Minocycline HCl is not soluble in most PLGA solvents (THF, acetone, ethyl acetate), but is highly soluble in methanol. The use of dichloromethane (DCM) could be an alternative approach. · Films with appropriate physical properties can be made from PLGA by both the solvent casting method and the immersion coating method. · An increase in drug elution is observed in formulations with a higher drug-to-polymer ratio (50:50 vs 80:20). · Suspended drug (minocycline) appears to elute from the film matrix faster than dissolved drug (rifampicin).

[0105] Based on these results, two formulations were tested. · Formulation 1 - A single thin film of PLGA containing both APIs. · Formulation 2 - Two separate film layers, each containing one API. The results for appearance and elution profiles compared to the reference medical device are reported in the following figures.

[0106] Conclusion: · Significant degradation of minocycline HCl occurred during the elution tests for all prototypes. Investigation / optimization was required to obtain accurate elution test results for minocycline HCl. · Formulation 1 does not meet the desired in vitro release characteristics. The amount of suspended drug needs to be reduced. · The rifampicin elution results for Formulation 2 (two separate thin films combined to make the final product) were lower than those of the reference medical device (TYRX) at all time points. However, the elution profile curve closely matches that of the reference medical device. Further optimization of this formulation is required to match the in vitro release characteristics of TYRX.

[0107] Stage 3: Film optimization. Multiple aspects requiring optimization: · Avoid decomposition from minocycline to epiminocycline. · Use of the plasticizer PEG-4000 and obtain an effect against API decomposition. · Film appearance, mechanics, coating weight, and drug stability.

[0108] Results: · For any API, the influence of film thickness on drug elution is fairly low. · Formulations containing PEG-4000 have different elution profiles (lower initial drug release). · The elution profiles are promising and are evaluated within cellulose bags and when the film is exposed to sterilization. · To evaluate the influence of the substrate on release at early time points, it is necessary to coat the drug layer on a PGA substrate. · PEG-4000 promotes API decomposition when used outside of the optimal ratio.

[0109] Based on these results, the final formulation identified below was derived. Considerations for the film composition: · Two antibiotics - minocycline HCl (7.6 mg per dose), rifampicin (11.9 mg per dose) · A copolymer having PLGA-DL-lactide and glycolide in a molar ratio of 50 / 50 and a median intrinsic viscosity of 1.0 dl / g · A single layer achievable with a higher coating weight containing a plasticizer (PEG4000) · A double layer (extrusion of PGA material) capable of reducing coating variation / curvature

[0110] Physical properties: · Film size - approximately 15 cm 2 (approx. 3 x 5 cm) · Film thickness - providing the required physical properties · Adhesion to Implanted Devices · Does not tear or stretch when removed from the liner · Can be applied to the pacemaker using forceps · Shape is retained when inserted into a cellulose bag.

[0111] Elution Profile: · In the drug elution test, an extension of the linear release of both APIs was observed. Rifampicin eluted at a slower, more linear rate than minocycline HCl. · Introduction of the cellulose coating to the in vitro test resulted in slower drug elution. · The results are not changed by sterilization (Figure 2).

[0112] Fabrication of Optimized Pads: Table 2 summarizes the materials used for formulation and mixing. One roll of release liner was used. A paper core was used instead of a plastic core.

[0113]

Table 2

[0114] The mixture was mixed and stirred using a mixer. To avoid evaporation of the solvent during mixing, the bottle was capped.

[0115] Coating was performed using a pilot coater. The mixture was coated onto the release liner using a knife over roll coating technique. To minimize losses, the mixture was manually added to the coating head using a sample sampler.

[0116] 1.3 Summary Results of the Process Mixing and coating were performed in a clean room environment with controlled temperature and humidity. The mixing process followed the following order. 1. Acetonitrile 2. PLGA 3. Methanol 4. Minocycline HCl, rifampicin, and PEG 5. The mixing container was degassed. All mixing steps (1 - 5) were carried out at room temperature. After mixing, the mixture was kept under vacuum. Then, the container was sealed and kept under atmospheric pressure after sampling.

[0117] The coating process is as follows. 1. A web was provided on the pilot coater. 2. The drying section of the pilot coater was started. 3. 3. The coating gap was set to the desired coating thickness. 4. After the drying section reached the target temperature, the coating line was started. 5. A part of the mixture was manually fed to the coating equipment. 6. The mixture was coated. The resulting laminate was wound around a paper core in the form of a roll coming out of the drying section.

[0118] The preliminary process parameters for the coating and drying process were initially defined during the formulation development / prototype stage of the project and were successfully tried during the manufacture of the informal placebo batch. These preliminary CPPs are summarized in Table 4.

[0119]

Table 3

Explanation of Symbols

[0120] 1 Cellulose pouch 2 Opening of 1 3 Non - degradable embedded device 4 Wiring / tube to 3 5 Sealed edge of 1 6 External device of 3 7 Device, controlled - release pad 8 External layer 9 Intermediate layer 10 Suture 11 Partial decomposability / solubility 7 12 Release of active agents and antibiotics

Claims

1. A device (7) for the release, preferably sustained controlled release, of a therapeutically active substance after implantation, either alone or in combination with further implantable elements (1, 3), The material comprises at least one layer (8) of a material that contains at least one therapeutically active substance and provides sustained controlled release of the substance under physiological conditions, The aforementioned layer (8) The first component (A) of the DL-lactide-glycolide copolymer (PLGA) is in the form of 60-95% dry weight, with a molar ratio of DL-lactide to glycolide in the range of 40:60 to 60:40 and a weight-average molecular weight (MWw) in the range of 100,000 to 150,000 g / mol. The second component (B) in the form of polyethylene glycol (PEG) is 5 to 40% by dry weight. It contains a biodegradable matrix consisting of a mixture of the following: The dry weights of components (A) and (B) complement 100% of the matrix. Device (7), wherein at least one of the therapeutic active substances is dissolved and / or suspended in the matrix.

2. The device (7) according to claim 1, wherein the first component (A) has a molar ratio of DL-lactide to glycolide 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 claim 1 or 2, The first component (A) has a weight-average molecular weight (MWw) 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, the first component (A) has a number average molecular weight (MWn) in the range of 50,000 to 100,000 g / mol, preferably in the range of 60,000 to 80,000 g / mol, and most preferably in the range of 65,000 to 75,000 g / mol. and / or the first component (A) has an intrinsic viscosity midpoint in the range of 0.8 to 1.2 dl / g, preferably in the range of 0.9 to 1.1 dl / g (in either case measured in chloroform at 25°C, c = 0.1 g / dl), device (7).

4. The device (7) according to claim 1 or 2, The second component (B) has a weight-average molecular weight (MWw) in the range of 3000 to 5500 g / mol, preferably in the range of 3200 to 4800 g / mol, and most preferably in the range of 3700 to 4400 g / mol. and / or, the second component (B) has a solidification point in the range of 45 to 68°C, preferably in the range of 50 to 65°C, most preferably in the range of 55 to 60°C, in the device (7).

5. The device (7) according to claim 1 or 2, The aforementioned layer (8) is Component (A) in an amount of 75-92% by dry weight, preferably 80-90% by dry weight, most preferably 84-88% by dry weight, It comprises a matrix consisting of a mixture of component (B) in an amount of 8 to 25% by dry weight, preferably 10 to 20% by dry weight, and most preferably 12 to 16% by dry weight. Device (7), wherein the dry weights of components (A) and (B) complement 100% of the matrix.

6. Device (7) according to claim 1 or 2, wherein at least one therapeutic active substance comprises at least one antibiotic, antiseptic, hemostatic agent, anti-inflammatory agent, chemotherapeutic agent, hormone, chemokine, growth factor, peptide or bactericide, or a combination thereof, preferably at least one therapeutic active substance is selected from at least one antibiotic selected from the group consisting of tetracycline, penicillin, macrolide or ansamycin, preferably tetracycline, chlortetracycline, oxytetracycline, demeclocycline, rimecycline, meclocycline, metacycline, minocycline in particular in the form of minocycline HCl, lolitetracycline, doxycycline, tigecycline, ellabacycline, thalecycline, omadacycline, rifampicin, or a combination thereof, in particular, selected from the group consisting of a combination of minocycline in the form of minocycline HCl and rifampicin.

7. Device (7) according to claim 6, wherein the concentration of the therapeutic active substance in the layer (8), or in the case of several therapeutic active substances, the total concentration of the therapeutic active substances, 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 any case expressed as dry % w / w relative to the entire layer (8).

8. The device (7) according to claim 1 or 2, wherein the layer (8) as at least one therapeutic active substance contains a combination of minocycline, particularly minocycline in the form of minocycline HCl, and rifampicin, in a total concentration ranging from 20 to 40% by weight, preferably 25 to 35% by weight, in either case expressed as dry % w / w relative to the whole of the layer. Preferably, the concentration of minocycline, particularly minocycline HCl, 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 either case expressed as dry % w / w relative to the entire layer, in device (7).

9. The device (7) according to claim 1 or 2, wherein the layer (8) is A first component (A) having a weight-average molecular weight in the range of 120,000 to 130,000 g / mol is used in an amount of 84 to 88% by dry weight, A second component (B) having a weight-average molecular weight MWw in the range of 3700 to 4400 g / mol is added in an amount of 12 to 16% by dry weight. It contains a matrix consisting of a mixture of the following: The dry weights of components (A) and (B) complement 100% of the layer (8), The layer (8) as at least one therapeutically active substance contains a combination of minocycline, particularly minocycline HCl, and rifampicin at a total concentration of 25-35% by weight. The concentration of minocycline, particularly minocycline HCl, is in the range of 14–18% by weight, and the concentration of rifampicin is in the range of 17–22% by weight. In either case, the device (7) is expressed as a dry % w / w relative to the entire layer.

10. The device (7) according to claim 1 or 2, wherein the device (7) is preferably in the form of at least one self-supporting film, mesh, nonwoven fabric structure, or a combination thereof, having a thickness in the range of 2.5 to 100 μm, preferably in the range of 10 to 30 μm. More preferably, the form is a film or patch having a maximum elongation of 30 cm in the lateral direction, preferably in the range of 0.5 to 15 cm, more preferably in the range of 1 to 10 cm. More preferably, the film or patch is circular, elliptical, or polygonal in shape, preferably rectangular or square, and optionally has rounded edges. and / or, the device (7) may consist of two or more layers (8) in combination with a single or at least one additional support layer (9), or most preferably, the device (7) consists of a single layer (8).

11. A method for manufacturing the device (7) according to claim 1 or 2, In the first step, the first component (A) is preferably dissolved in an organic solvent selected from the group consisting of acetonitrile, toluene, anisole, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, dioxane, tetrahydrofuran, toluene, or a combination thereof. Preferably, completely dissolve it under stirring at a temperature in the range of 15 to 30°C, preferably at room temperature (20 to 25°C). The solution of the first component (A) is solidified, In the second step, the second component (B) and at least one of the therapeutic active substances are used. Preferably, the first component (A) is added to the solution under stirring at a temperature in the range of 15 to 30°C, preferably at room temperature. Next, a manufacturing method comprising forming the device by preferably evaporating at least one of the solvents onto a release material in a solution casting or solution coating process.

12. The method according to claim 11, wherein, after the first step and before 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), Preferably, the further organic solvent is 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, methylcyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, xylene, acetic acid, heptane, acetone, isobutyl acetate, anisole, Selected from the group consisting of 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 combinations thereof, Preferably, the further 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, in the first step, the first component (A) is dissolved in each case at a concentration in the range of 10 to 35% w / v, preferably 20 to 30% w / v, per volume of the organic solvent.

13. A use of the device (7) according to claim 1 or 2 for creating an implantable device, In the first step, an implantable device (3), preferably a non-disassemblable implantable device (3), is at least partially covered or surrounded by at least one such device (7), Preferably, in the second step, it is inserted through its opening (2) into a moist or high-humidity pouch (1) of at least one of a self-supporting hydrogel, cellulose, or collagen.

14. A kit of parts, The first wet package contains at least one wet or high-humidity pouch (1) having an opening (2), preferably in the form of at least one pouch made of a self-supporting hydrogel, cellulose, or collagen, At least one device (7) according to claim 1 or 2, in a separate wet or dry package, preferably in a dry package, and A kit of parts, including...

15. A kit of components according to claim 14, wherein at least two devices (7) are provided in the separate package, preferably the devices are in the form of a rectangle or a two-dimensional sheet having a length and / or width in the range of 50 to 110 mm, preferably 60 to 90 mm, and preferably the devices are in the form of a rectangle having a length in the range of 70 to 110 mm, preferably 80 to 90 mm, and a width in the range of 50 to 90 mm, preferably 60 to 80 mm. and / or, preferably, the first package includes an element for maintaining controlled humidity, preferably in the form of an aluminum or aluminum-plastic laminate pouch. and / or, the separate package comprises a kit of parts, including an element for maintaining a dry state, preferably a desiccant element.

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