Method, apparatus, and kit for producing pharmaceutically active coatings

Abstract

The present invention provides a simple and time-efficient method, kit, and apparatus for coating articles with a pharmaceutically active polymer layer containing a pharmaceutical active ingredient. [Solution] A method for producing a pharmaceutically active polymer coating, comprising the following steps: a) A step of dissolving a specific non-hydrolyzable polymer or copolymer in a specific solvent or solvent mixture at 20°C and standard pressure to form a polymer solution 1, b) A step of dissolving or suspending the active pharmaceutical ingredient in polymer solution 1 to form polymer solution 2, c) The step of applying polymer solution 2 to the surface of the article to be coated, d) A step of evaporating the solvent or solvent mixture to leave a polymer layer on the surface of the article to be coated, wherein the active pharmaceutical ingredient is dispersed in the polymer layer. A method comprising the above, characterized in that the polymer layer does not contain any pore-forming agent soluble in aqueous solution.

Description

Technical Field

[0001] The present invention relates to a method for coating an implant using a polymer layer containing at least one pharmaceutical active ingredient. The present invention also relates to a kit of parts suitable for carrying out the method according to the present invention, and to a corresponding device obtainable from the kit of parts.

Background Art

[0002] The present invention relates to a method for coating an implant using a polymer layer containing at least one pharmaceutical active ingredient. This method is particularly suitable for intraoperative coating, i.e., coating implants commonly used in trauma surgery and orthopedics, such as intramedullary nails and bone plates, with a polymer in which a pharmaceutical active ingredient, preferably an anti-infective agent, is dispersed, at a time close to the surgery. The coated implant is intended to be used particularly for the correction of sepsis in trauma surgery and orthopedics. The coated implant acts as a local drug delivery system after being implanted in the human body. Aqueous body fluids such as blood and wound secretions can elute the pharmaceutical active ingredient from the polymer layer and release them around the implant. The surface of the implant can be temporarily protected from microbial colonization, for example, by the released pharmaceutical active ingredient.

[0003] Intramedullary nails and osteosynthesis plates are conventional technologies and have been successfully used worldwide for fracture treatment in trauma surgery. Unfortunately, after fracture treatment, infection of the surrounding bone and soft tissue by microorganisms, particularly bacteria, and commonly skin pathogens such as Staphylococcus aureus and Staphylococcus epidermidis, can sometimes occur. When such infection occurs, surgical treatment of the infected tissue area is essential, in which case the treated area of ​​infected tissue is removed. Furthermore, systemic antibiotics are generally used after necrotic tissue resection to reduce bacteria. For example, it is desirable that intramedullary nails or osteosynthesis plates allow for mechanical stabilization of fractured bone tissue after surgical treatment, and that they simultaneously release local antiinfective agents for the purpose of locally suppressing microorganisms remaining in the resected tissue.

[0004] Intramedullary nails with antibiotic-containing polymethyl methacrylate bone adhesive coatings have long been known and have shown clinical efficacy (N. Walter, M. Rupp, J. Krueckel, Volker Alt: Individual and commercially available antimicrobial coatings for intramedullary nails for the treatment of infected long bone non-unions: a systematic review. Injury 53S3 (2022), pp. 75-80). After implantation of the coated intramedullary nail, the antibiotic particles contained in the polymethyl methacrylate bone adhesive layer are leached from the adhesive layer by aqueous bodily fluids such as wound secretions and blood, resulting in a locally high antibiotic concentration on the surface of the coated intramedullary nail. These locally high antibiotic concentrations, in combination with systemic antibiotics, reduce residual microorganisms after necrotic tissue resection.

[0005] Of particular interest are intramedullary nails that are coated during surgery. Intraoperative coating allows for the incorporation of anti-infective agents precisely matched to the bacteria present, such as polymethyl methacrylate bone adhesive. Until now, intraoperative coating has been performed by mixing anti-infective agents into adhesive powder, mixing the thus modified adhesive powder with a monomer solution, and manually shaping the resulting adhesive paste around the nail to be coated. Achieving a uniform layer thickness along the entire length of the intramedullary nail is difficult. As a result, at least a portion of the coated nail's cross-section may be too large, making it impossible to implant it into bone that has already been resected of necrotic tissue.

[0006] Our own practical experience has shown that a relatively small amount of anti-infective agent can be added to polymethyl methacrylate bone adhesive because a high content of the anti-infective agent makes the adhesive paste too viscous to be used for coating intramedullary nails. Furthermore, the adhesion of the adhesive to the metal surface is impaired as the concentration of the anti-infective agent increases.

[0007] A thin coating with a high proportion of anti-infective agents is desirable. This eliminates problems related to the radial expansion of the intramedullary nail while simultaneously enabling high local release of anti-infective agents.

[0008] In addition to coating with polymethyl methacrylate bone adhesive containing anti-infective agents, direct coating of implants with antibiotics and antibiotics suspended or dissolved in polymers is also possible.

[0009] U.S. Patent Application Publication 2007 / 0134287(A) describes an antibiotic coating solution comprising a readily evaporating solvent and an antibiotic dissolved therein.

[0010] U.S. Patent No. 11,517,650(B) describes a similar coating solution in which an antibiotic is dissolved in a rapidly evaporating solvent, and energy is supplied by ultrasonic irradiation to accelerate the dissolution process. This solution is then used for antibiotic coating.

[0011] European Patent No. 1243259(B) discloses a coating comprising polymethyl methacrylate and a hydrophilic polymer such as a polyether on which an antibiotic is suspended. A drawback of the disclosed copolymer is that the polymer coating obtained according to European Patent No. 1243259(B) is relatively thick. Furthermore, to achieve sufficient release of the antibiotic, it is necessary to add a hydrophilic polyether to the coating. The hydrophilic polyether is water-soluble and acts as a pore-forming agent.

[0012] A similar concept is described in European Patent No. 1112095(B). This document presents a layer of D,L-polylactide with suspended antibiotics. The coating is performed by first dissolving the polylactide in a rapidly evaporating solvent, and then suspending antibiotic particles in this solution. When this suspension is applied to the implant surface, the solvent evaporates, leaving a D,L-polylactide film. The antibiotic particles are immobilized within the D,L-polylactide film and can be eluted from this film by the action of aqueous bodily fluids such as wound secretions and blood. The D,L-polylactide film can be hydrolyzed and decomposed by the action of water or aqueous solution to produce water-soluble secondary products.

[0013] The coating methods described in the prior art are generally complex and time-consuming to implement. Furthermore, the prior art methods have limited possibilities for changing the active pharmaceutical ingredient, making it impossible to select a suitable active pharmaceutical ingredient immediately before or during surgery. Moreover, the prior art methods are disadvantageous in that they typically result in a relatively thick coating and require the use of unsuitable ingredients to allow release from the polymer matrix.

[0014] Object of the invention The object of the present invention is to develop a simple and time-efficient method for coating articles with a pharmaceutically active polymer layer containing at least one active pharmaceutical ingredient. The coating method should be designed so that surgical staff can easily incorporate any active pharmaceutical ingredient into the coating. The polymer layer shall be made from a biocompatible polymer that is not hydrolyzed or enzymatically degraded in the human body. Furthermore, the polymer layer should be able to be applied to surfaces such as implants and osteosynthesis plates using the simplest means under surgical conditions. The polymer layer shall not peel off the surface within 7 days in the presence of water at 37°C. Any health risks to surgical staff from toxic solvents during the coating process must be avoided. Furthermore, this method makes it possible to produce a polymer layer having a minimum proportion of 10% by weight of the active ingredient. Furthermore, the polymer layer shall not soften under the influence of aqueous bodily fluids and shall have a thin but consistent thickness. Finally, the polymer coating produced according to the present invention shall have good water and heat resistance.

[0015] A kit of parts is provided having components suitable for the manufacture and application of a coating solution containing an active ingredient for coating a polymer layer.

[0016] Another objective is to provide a device that can be obtained from a kit of parts.

[0017] The object of the present invention is achieved by the means described in claims 1 to 15. [Overview of the Initiative]

[0018] The primary objective of the present invention is to achieve a method for producing a pharmaceutically active polymer coating.

[0019] Next, the method according to the present invention comprises at least the following method steps, namely a) Dissolving a non-hydrolyzable polymer or copolymer characterized by a number average molar mass of more than 200,000 g / mol, more preferably more than 400,000 g / mol, and even more preferably more than 600,000 g / mol, determined by gel permeation chromatography, in a solvent or solvent mixture characterized by a vapor pressure of at least 95 hPa at 20 °C and standard pressure to form Polymer Solution 1; b) Dissolving or suspending at least one pharmaceutical active ingredient in Polymer Solution 1 to form Polymer Solution 2; c) Applying Polymer Solution 2 to the surface of the article to be coated; d) Evaporating the solvent or solvent mixture to leave a polymer layer on the surface of the article to be coated, wherein at least one pharmaceutical active ingredient is dispersed in the polymer layer. Characterized in that the polymer layer does not contain any pore-forming agent soluble in an aqueous solution.

[0020] Furthermore, the present invention relates to the following components for carrying out the method according to the present invention, namely i) A solvent-resistant container having an opening; ii) A solvent-resistant closure element suitable for closing the container; iii) An application aid; iv) Polymer Solution 1 as defined in the method according to the present invention; v) Optionally, one or more mixtures; vi) Optionally, one or more pharmaceutical active ingredients in separate packages. The present invention also relates to a kit of parts comprising these.

[0021] The protection scope of the present invention also includes an apparatus for carrying out the method according to the present invention, and this apparatus can be obtained by a medical kit of parts or provided independently thereof.

[0022] Furthermore, the scope of the present invention also encompasses medical implants provided with a polymer coating obtained by the method according to the present invention. The use of medical implants for the prevention of infection after surgical procedures is also claimed herein.

[0023] Hereinafter, the present invention will be described in detail.

Mode for Carrying Out the Invention

[0024] I. Definitions In the context of the present invention, the term "polymer solution 1" refers to a solution or solvent mixture in which at least one polymer or copolymer having a number average molar mass of more than 200,000 g / mol, more preferably more than 400,000 g / mol, and even more preferably more than 600,000 g / mol as determined by gel permeation chromatography, and having a vapor pressure of at least 95 hPa at २० °C and standard pressure, i.e., १,०१३.२५ hPa, is present.

[0025] In the context of the present invention, the term "polymer solution 2" refers to a solution and / or suspension in which a pharmaceutical active ingredient is dissolved or suspended in polymer solution 1.

[0026] In the context of the present invention, the term "coating aid" refers to any element suitable for distributing, preferably uniformly, a solution or suspension on a surface. Specifically, coating aids include painting elements, spraying elements, or even dipping dishes.

[0027] In the context of the present invention, the term "mixer" refers to an element suitable for completely, particularly mechanically, mixing a solution or suspension. The term "mixer" specifically includes not only mixing rods such as stirring rods but also mixing elements such as balls or magnetic stirrers.

[0028] It should be noted that in the translation of the temperature value "२० °C" and pressure value "१,०१३.२५ hPa", the original text seems to use some non-standard symbols. If these are specific notations in the original language that need to be accurately understood in the context, it may be necessary to further clarify their meaning. The above translation is based on a literal conversion as much as possible.In the sense of the present invention, when referring to an explicitly specified numerical value within a range such as X to Y, or at least X to at least Y, or greater than X to greater than Y, this also specifically includes all values ​​implicitly existing between them, as suggested by the decimal designation. Thus, if the value is 1 to 10, it also includes 2, 3, 4, 5, 6, 7, 8, and 9. If the value is 1.0 to 2.0, it also includes 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. If the value is 1.00 to 1.10, it also includes 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, and 1.09.

[0029] II. Method The present invention relates, firstly, to a method for coating the surface of an article, such as an implant, with a polymer layer in which at least one active pharmaceutical ingredient is dispersed. The method according to the present invention can be carried out by, for example, a medical professional with minimal effort, and an article having a polymer layer in which the active pharmaceutical ingredient is dispersed can be obtained. The article can then release the dispersed active pharmaceutical ingredient over a specific period of time at a suitable location, for example, in vivo. The method according to the present invention is as follows: a) A step of forming a polymer solution 1 by dissolving a non-hydrolyzable polymer or copolymer, characterized by a number average molar mass greater than 200,000 g / mol, more preferably greater than 400,000 g / mol, and more preferably greater than 600,000 g / mol, determined by gel permeation chromatography, in a solvent or solvent mixture characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure. b) The step of dissolving or suspending at least one pharmaceutical active ingredient in polymer solution 1 to form polymer solution 2, c) The step of applying polymer solution 2 to the surface of the article to be coated, d) A step of evaporating a solvent or solvent mixture to leave a polymer layer on an article to be coated, wherein at least one active pharmaceutical ingredient is dispersed in the polymer layer. It is characterized by containing the above, and the polymer layer does not contain any pore-forming agent.

[0030] In the sense of the present invention, a non-hydrolyzable polymer or copolymer is selected that is characterized by a number-average molar mass greater than 200,000 g / mol, more preferably greater than 400,000 g / mol, and more preferably greater than 600,000 g / mol, as determined by gel permeation chromatography, and is suitable for contact with living organisms and does not cause harm to those organisms.

[0031] Furthermore, according to the present invention, the non-hydrolyzable polymer or copolymer is defined as being dissolved or suspended in a solvent or solvent mixture characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure. In the sense of the present invention, the solvent or solvent mixture preferably has the property of evaporating relatively rapidly under normal ambient conditions, for example at 20°C and standard pressure. This is advantageous because the polymer dissolved in the solvent or solvent mixture remains relatively quickly on the surface of an article as a polymer coating by applying the polymer solution without additional effort such as drying in an oven. In the sense of the present invention, a further preferred property of the solvent or solvent mixture is that it can come into contact with living organisms without having any damaging effect on them, such as toxic effects.

[0032] Therefore, in particular, according to the present invention, firstly, the polymer solution 1 is formed from a polymer or copolymer having a number average molar mass greater than 200,000 g / mol, more preferably greater than 400,000 g / mol, and more preferably greater than 600,000 g / mol, as determined by gel permeation chromatography, in a suitable solvent or solvent mixture characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure, and none of these substances in the polymer solution 1 have any damaging effect on living organisms, such as toxic effects.

[0033] Suitable non-hydrolyzable polymers or copolymers for use in the method according to the present invention are those with a specific preferred number average molar mass (M n ) has. Therefore, in the sense of the present invention, preferred polymers or copolymers have a number average molar mass (M) greater than 200,000 g / mol. n For example, 200,000 g / mol, 210,000 g / mol, 220,000 g / mol, 230,000 g / mol, 240,000 g / mol, 250,000 g / mol, 260,000 g / mol, 270,000 g / mol, 280,000 g / mol, 290,000 g / mol or greater than 300,000 g / mol, 310,000 g / mol, 320,000 g / mol, 330,000 g / mol, 340,000 g / mol, 350,000 g / mol, 360,000 g / mol, 370,000 g / mol, 380,000 g / mol, 390,000 g / mol or greater than 400,000 g / m³ It has a number-average molar mass of ol, 410,000 g / mol, 420,000 g / mol, 430,000 g / mol, 440,000 g / mol, 450,000 g / mol, 460,000 g / mol, 470,000 g / mol, 480,000 g / mol, greater than 490,000 g / mol, or greater than 500,000 g / mol, 510,000 g / mol, 520,000 g / mol, 530,000 g / mol, 540,000 g / mol, 550,000 g / mol, 560,000 g / mol, 570,000 g / mol, 580,000 g / mol, greater than 590,000 g / mol, or greater than 600,000 g / mol.

[0034] The number-average molar mass of the non-hydrolyzable polymers and copolymers used in accordance with the present invention is particularly preferably greater than 550,000 g / mol.

[0035] In the sense of the present invention, the number average molar mass (M) of the polymer or copolymer. n ) is determined by gel permeation chromatography (GPC).

[0036] According to the present invention, non-hydrolyzable polymers and copolymers having a number-average molar mass exceeding 200,000 g / mol have been found to yield polymer layers that are not excessively sticky and can be easily applied to surfaces. The present invention has also been found to be particularly suitable for producing polymer layers that adhere to surfaces, are neither brittle nor crackable, and can absorb and release pharmaceutical active ingredients.

[0037] According to the present invention, for polymer solution 1 having a glass transition temperature (Tg) above 47°C, it is preferable to use a non-hydrolyzable polymer or copolymer. Preferably, the polymer or copolymer for polymer solution 1 has a glass transition temperature above 60°C, more preferably above 80°C, and even more preferably above 100°C. Therefore, preferred glass transition temperatures (Tg) for polymers or copolymers used in polymer solution 1 according to the present invention are 47°C, 48°C, above 49°C, or 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, above 59°C, or 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 6 The temperature is 8°C, greater than 69°C, or greater than 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, or greater than 79°C, or greater than 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, or greater than 89°C, or greater than 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, or greater than 100°C.

[0038] Surprisingly, according to the present invention, non-hydrolyzable polymers or copolymers having a glass transition temperature (Tg) of over 47°C, preferably over 60°C, more preferably over 80°C, and particularly over 100°C are found to be suitable in the sense of the present invention. This is because these polymers or copolymers remained stable without dissolving in an aqueous medium at a temperature of 37°C for at least 7 days. Such water and heat resistance is desirable when articles coated by the method and means of the present invention are positioned in vivo at a suitable site of action, together with at least one pharmaceutical active ingredient dispersed in the polymer layer.

[0039] In the sense of the present invention, the glass transition temperature (Tg) is determined by differential scanning calorimetry (DSC) at a heating rate of 10 K / min, in accordance with ISO 11357 or DIN 53765.

[0040] According to the present invention, it is even more preferable that the non-hydrolyzable polymer or copolymer that is a component of the polymer solution 1 according to the present invention does not contain reactive double bonds. Reactive double bonds refer to sites in the polymer backbone that have CC double bonds and which, due to external influences that often occur, can cause undesirable and uncontrolled reactions. Such double bonds can be readily oxidized, for example, when exposed to gamma rays in the presence of oxygen, and the double bonds can lead to crosslinking between polymer chains. This damage can cause the polymer solution to gel, meaning that the polymer solution is no longer fluid and therefore can no longer be uniformly applied. Conversely, if the polymer solution of the present invention does not contain double bonds in the dissolved polymer, it can be readily sterilized by gamma irradiation, which constitutes an advantage of the present invention for medical applications.

[0041] A further preferred property of the non-hydrolyzable polymer or copolymer that is a component of polymer solution 1 in the method according to the present invention is that the polymer layer produced therefrom is neither too hard nor too brittle. That is, even when the coated article is deformed, the polymer layer maintains its flexibility and does not collapse.

[0042] In the sense of the present invention, hydrophobic polymers and copolymers having the properties of the present invention have been found to be particularly suitable for carrying out the methods of the present invention. Surprisingly, according to the present invention, non-hydrolyzable polymers and copolymers of polymethyl methacrylate have been found to be particularly suitable for forming polymer layers in the sense of the present invention. In particular, non-hydrolyzable polymers and copolymers of polymethyl methacrylate characterized by a preferred range of glass transition temperatures and optionally by a number-average molar mass according to the present invention are suitable for carrying out the methods of the present invention. Furthermore, it is preferable to use non-hydrolyzable polymers and copolymers of polymethyl methacrylate that do not have crystalline components, i.e., are preferably completely amorphous. Strong intermolecular interactions that normally play a role in crystalline compounds will adversely affect the properties of the polymer layer by potentially leading to increased brittleness and crack formation. In contrast, preferably amorphous, more preferably non-hydrolyzable polymers and copolymers in the sense of the present invention form weaker, more dispersive interactions, such as dipole interactions and van der Waals interactions, which, at a macroscopic level, result in a material that is more moldable without brittleness and cracking. As a result, polymers and copolymers having the properties of the present invention are particularly suitable for the method of forming a polymer layer according to the present invention.

[0043] Non-hydrolyzable polymers and copolymers derived from polymethyl methacrylate and characterized by the desirable properties according to the present invention are preferred in the sense of the methods according to the present invention because they have excellent biocompatibility. Therefore, they can be used in vivo, which is preferred because polymer layers formed using the methods according to the present invention are preferably used for in vivo applications. Polymers and copolymers derived from polymethyl methacrylate are non-cytotoxic and resistant to hydrolysis.

[0044] In the context of this invention, when referring to a copolymer of polymethyl methacrylate, it specifically means a copolymer that can be produced by polymerization of methyl methacrylate and comonomers methyl acrylate, ethyl acrylate, ethyl methacrylate, and styrene.

[0045] In the sense of the present invention, it has been found that the use of non-hydrolyzable polymers and copolymers having preferred properties according to the present invention results in polymer coatings that have desired brittleness, can absorb high-content pharmaceutical active ingredients, and can reliably release the pharmaceutical active ingredients at the target site.

[0046] A special feature of the present invention is that the non-hydrolyzable polymers and copolymers do not require additives that are typically added in the prior art, such as pore-forming agents.

[0047] In the sense of the present invention, a pore-forming agent is, in particular, a component of a polymer layer that can form pores in a water-insoluble polymer layer under the action of water. A pore-forming agent is, in particular, a water-soluble and / or hydrolyzable substance. Examples of pore-forming agents include poly-α-hydroxy acids or oligomers for producing poly-α-hydroxy acids, in particular polyglycols, polylactic acids such as D,L-polylactic acid, polytyrosine carbonates and oligomeric ethylene glycol compounds, in particular oligomeric ethylene glycol compounds having a number-average molar mass in the range of 120 g / mol to 35,000 g / mol, starch, gelatin, cellulose, lactic acid, in particular α-hydroxy acids such as D,L-lactic acid, ethylene glycol and diethylene glycol, sugar alcohols such as mannitol, xylene, and sorbitol, amino acids such as alanine, glycine, tyrosine, and serine, and surfactants such as fatty alcohols.

[0048] The pore-forming agent includes, in particular, a substance that, at a concentration of 1 g / liter in phosphate-buffered saline at 25°C (i.e., 137 mM sodium chloride, 2.7 mM potassium chloride, and 12 mM total phosphate, pH 7.4), is substantially completely dissolved and / or decomposed within 24 hours.

[0049] Conventional methods known for producing polymer coatings in which pharmaceutical active ingredients are dispersed require the addition of further additives, such as pore-forming agents, to the polymer coating. This modifies the polymer coating so that it can absorb a sufficient amount of pharmaceutical active ingredients and release them again at the target site. The method according to the present invention provides a polymer coating that does not require such additives.

[0050] Overall, the number-average molar mass (M) is greater than 200,000 g / mol, more preferably greater than 400,000 g / mol, and more preferably greater than 600,000 g / mol. n In the context of the present invention, amorphous hydrophobic polymers or copolymers of polymethyl methacrylate having a glass transition temperature (Tg) of over 47°C, more preferably over 60°C, more preferably over 80°C, and more preferably over 100°C are particularly preferred.

[0051] Furthermore, according to the present invention, it is preferable to use a solvent or solvent mixture containing less than 8% by weight of water to produce the polymer solution 1 according to the present invention. The solvent or solvent mixture more preferably contains less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, or less than 2% by weight of water. Contamination of the solvent or solvent mixture with water may cause aggregation of active ingredient particles in the polymer solution 2 in the case of hygroscopic pharmaceutical active ingredients. Therefore, a water content as low as possible, less than 2% by weight, is particularly preferable.

[0052] According to the present invention, it is advantageous if the solvent or solvent mixture is compatible with the polymer or copolymer for the polymer solution 1. In other words, the solvent or solvent mixture is preferably used to increase the solubility of a particular monomer or comonomer for the polymer or copolymer.

[0053] In the sense of the method according to the present invention, the solvent or solvent mixture preferably includes acetate esters, acetoacetate esters, acetone, diacetone alcohol, ethyl methyl ketone, butyl methyl ketone, and / or mixtures thereof. In the sense of the present invention, it is also preferable to use a mixture of acetate ester with another solvent, such as acetoacetate ester, preferably acetate acetate, acetone, diacetone alcohol, ethyl methyl ketone, and / or butyl methyl ketone. Particularly preferred solvents in the sense of the present invention are acetate esters, especially ethyl acetate.

[0054] Ethyl acetate is non-toxic, has a vapor pressure of 98.4 hPa at 20°C and standard pressure, and a boiling point of 77°C at standard pressure. Therefore, ethyl acetate evaporates relatively quickly at room temperature. Another advantageous property of ethyl acetate is that its odor is perceived as pleasant to most people. Therefore, when manufacturing polymer coated articles in the sense of the method according to the present invention, and the articles may need to be suitable for in vivo medical applications, ethyl acetate is preferred not only for its excellent physical and toxicological qualities but also for its olfactory perception by professionals and, where applicable, patients. Ethyl acetate is also easy to handle and, unlike other solvents with similar properties, does not damage the most typical plastic articles used in the kits of parts according to the present invention, which are further described below.

[0055] According to the present invention, it has been found that, surprisingly, ethyl acetate solutions of polymers and copolymers presented herein, when applied to the surface of an article, preferably a metal surface of the article, adhere very well and form a stable polymer layer upon evaporation of the solvent. The evaporation process essentially occurs within 1 to 2 minutes at room temperature of 23°C. Therefore, ethyl acetate is particularly well suited in the sense of the present invention for producing coatings relatively quickly and without considerable effort.

[0056] A polymer solution 1 comprising a preferred polymer or copolymer according to the present invention and a solvent or solvent mixture presented by the present invention preferably has a polymer content of 2% to 18% by weight, i.e., for example, at least 2% by weight, at least 3% by weight, at least 4% by weight, at least 5% by weight, at least 6% by weight, at least 7% by weight, at least 8% by weight, at least 9% by weight, preferably at least 10% by weight. According to the present invention, polymer content of 18% by weight or less, 17% by weight or less, 16% by weight or less, 15% by weight or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, and 11% by weight or less is also preferred.

[0057] A polymer content of 9% to 11% by weight is particularly preferred. At this polymer concentration, the polymer solution can be easily mixed with the active pharmaceutical ingredient and then easily applied to a surface.

[0058] Higher polymer concentrations than 18% by weight are possible, but as the polymer concentration increases, properties such as the applicability or sprayability of the polymer solution may decrease, because the polymer solution may consequently aggregate or become viscous.

[0059] In contrast, if the polymer concentration is too low, this can have a negative effect on the polymer layer-forming properties of polymer solution 2. This means, for example, that if polymer solution 2 with too low a polymer concentration is applied, a complete polymer layer will not be formed, but rather a porous polymer layer will be formed.

[0060] In the sense of the present invention, at least one pharmaceutical active ingredient is dissolved or dispersed in the obtained polymer solution 1. According to the present invention, in principle, any pharmaceutical active ingredient that can be brought into contact with the polymer solution 1 without decomposition is preferred. According to the present invention, the pharmaceutical active ingredient can be dissolved in the polymer solution 1 or suspended in the polymer solution 1.

[0061] Preferably, the active pharmaceutical ingredient is suspended in the polymer solution 1. Many active pharmaceutical ingredients currently available have low solubility in common solvents. This often results in low concentrations of the active pharmaceutical ingredient in the polymer solution, and further, in the coating obtained from the solution. This means low bioavailability at use, and it becomes problematic to transport a sufficient amount of the active pharmaceutical ingredient to the desired site of action. Therefore, a suspension of the active pharmaceutical ingredient in a solvent or solvent mixture is preferred because it allows for the achievement of higher concentrations.

[0062] In the sense of the present invention, a solution or suspension obtained when a pharmaceutical active ingredient is dissolved or suspended in polymer solution 1 according to the present invention is referred to as polymer solution 2, even if it is a suspension.

[0063] In the sense of the present invention, a polymer solution 2 comprising a solvent or solvent mixture, a dissolved polymer or copolymer, and at least one dissolved or suspended active pharmaceutical ingredient is then applied to the surface of an article to obtain a polymer layer thereon, the polymer layer having the active pharmaceutical ingredient dispersed therein.

[0064] After application, the selected solvent evaporates relatively quickly, preferably under standard ambient conditions, preferably without requiring any additional effort such as drying in a suitable oven or hot air dryer. This leaves an article having a polymer layer in which the pharmaceutical active ingredient is dispersed.

[0065] In the sense of the method according to the present invention, at least one pharmaceutical active ingredient is dissolved or suspended in polymer solution 1 for the purpose of obtaining polymer solution 2. Possible pharmaceutical active ingredients include, for example, active ingredients from the classes of anti-infective agents, bacteriophages, cell proliferation inhibitors, analgesics, hormones, and growth factors. Articles coated with polymer solution 2 can then continuously release the active ingredient, particularly from the listed classes, locally at the site of action and in vivo, over a specific period of time.

[0066] The term "anti-infective drug" refers to antimicrobial active ingredients that may be of microbial, semi-synthetic, or even synthetic origin.

[0067] In the context of this invention, the term "bacteriophage" refers to an active ingredient used antimicrobially in a targeted manner for therapeutic purposes.

[0068] The term "cell proliferation inhibitor" refers to an active ingredient that has toxic effects on cells and is typically used to treat cancer.

[0069] The term "analgesic" refers to an active ingredient that has analgesic or pain-relieving effects.

[0070] Hormones and growth factors are substances produced by the body, or active ingredients derived from substances produced by the body, and can influence bodily processes such as metabolism.

[0071] In the sense of the method according to the present invention, pharmaceutical active ingredients such as gentamicin, tobramycin, amikacin, clindamycin, colistin, moxifloxacin, levofloxacin, ciprofloxacin, vancomycin, teicoplanin, daptomycin, doxycycline, ampicillin, amoxicillin, meropenem, fluconazole, amphotericin B, caspofungin, micafungin, and mixtures of the aforementioned active ingredients are particularly preferably dissolved or suspended in polymer solution 2.

[0072] In the sense of the present invention, it is very particularly preferred that the active pharmaceutical ingredient is in particulate form before being dissolved or suspended. In other words, the active ingredient exists as a solid characterized by a specific particle size range. The active pharmaceutical ingredient exists with a particle size of preferably less than 250 μm, and preferably less than 100 μm, before dissolution or suspension. The particle sizes are particularly less than 240 μm, less than 230 μm, less than 220 μm, less than 210 μm, less than 200 μm, less than 190 μm, less than 180 μm, less than 170 μm, less than 160 μm, less than 150 μm, less than 140 μm, less than 130 μm, less than 120 μm, and less than 110 μm. In the sense of the present invention, the particle size is determined by a sieving process.

[0073] According to the present invention, it has been found that finely sieved particulate pharmaceutical active ingredients are particularly preferred because, in the form of a suspension, they promote the formation of a uniform polymer coating. Larger particles tend to aggregate or form an uneven coating, which is undesirable according to the present invention. Smaller particles are also preferred when the objective is to dissolve the pharmaceutical active ingredients because smaller particles generally dissolve faster than larger particles due to their unfavorable surface-to-volume ratio.

[0074] When carrying out the method according to the present invention, it is preferable to use a mixture to assist the dissolution or suspension process in order to promote the formation of a uniform suspension or complete dissolution of the active pharmaceutical ingredient. For example, the polymer solution 2 can be stirred with a standard laboratory glass or a stirring rod to stir the active pharmaceutical ingredient in the polymer solution 1 until it is dissolved or uniformly suspended. It is also conceivable to use a mixing element such as a ball made of glass, ceramic, metal, or other material, or a magnetic stirring element called a magnetic stirrer or stirring rod. In the case of various balls, preferably a sealed container containing the ball, the polymer solution 1, and the active pharmaceutical ingredient can be used, and this container is then shaken by hand or using a shaking device. A magnetic stirring element allows the mixture of the polymer solution 1 and the active pharmaceutical ingredient to be stirred on a magnetic stirring plate.

[0075] The concentration of the active pharmaceutical ingredient to be achieved in the polymer coating obtained by the method according to the present invention is substantially physically dependent on the polymer content in the polymer solution 2. Preferably, the polymer or copolymer to the active pharmaceutical ingredient is present in the polymer solution 2 in the same ratio as that obtained in the final polymer coating. In the method of the present invention, a weight ratio of polymer or copolymer to active pharmaceutical ingredient of 1.00:0.05 to 1.00:1.50 is preferably used. This means that the weight ratio of polymer and copolymer to active pharmaceutical ingredient is, for example, 1.00:0.05 to 1.00:1.50, 1.00:0.30 to 1.00:1.30, 1.00:0.60 to 1.00:1.15, or 1.00:0.95 to 1.00:1.05. It is remarkable that the method according to the present invention enables the production of coatings having an active ingredient content higher than the polymer content. This makes it possible to achieve a high packing density on the coated surface.

[0076] An advantage of the present invention is that the polymer coating according to the present invention can have a very high packing density of pharmaceutical active ingredients, yet the layer remains stable at the target site, and there is no need to add additives such as pore-forming agents to the polymer coating for the purpose of continuously releasing the pharmaceutical active ingredients. Therefore, it is possible to achieve a remarkably high packing density of pharmaceutical active ingredients in the polymer layer without using components commonly used in the prior art. Accordingly, the method of the present invention makes it possible to obtain a polymer layer that has excellent adhesive properties, is not brittle, and contains a large amount of pharmaceutical active ingredients, without adversely affecting the properties of the polymer coating. Therefore, the ratio of polymer and copolymer to pharmaceutical active ingredients according to the present invention is preferably 1.00 to 1.00 or higher.

[0077] When the polymer solution 2 according to the present invention is prepared according to the steps described above, it can, in principle, be applied to all types of articles in the sense of the method according to the present invention for the purpose of creating a polymer layer on which the active pharmaceutical ingredient is dispersed. In the sense of the method according to the present invention, it is particularly preferable that the application is carried out using a simple method that does not require much effort, for example, by applying the polymer solution 2 to the surface, by immersing the article to be coated in a container containing the polymer solution 2, or by spraying the polymer solution 2 onto the surface.

[0078] In the sense of this method, when the polymer solution 2 is applied, it is even more preferable that the surface of the article to be coated has a temperature in the range of 10°C to 30°C, i.e., for example, 10°C to 30°C, 10°C to 28°C, 10°C to 26°C, 10°C to 24°C, 10°C to 22°C, or 10°C to 20°C.

[0079] The surface temperature of the article to be coated is preferably 10°C to 30°C. Below 10°C, the solvent or solvent mixture may take several minutes to evaporate, which is undesirable in the sense of the present invention. Above 30°C, according to the present invention, it has been found that the solvent or solvent mixture evaporates too quickly, making it difficult to apply a uniform layer to the surface by coating the polymer solution 2.

[0080] The method according to the present invention makes it possible to produce a uniform coating. In the sense of the present invention, a uniform coating means that the surface of an article is completely covered with a coating obtained from polymer solution 2. This also means that the polymer coating preferably does not have any visual signs of cracking or brittleness, adheres sufficiently firmly to the surface of the article, and prevents them from being removed without the application of force or the action of chemical or physical means.

[0081] The polymer coating in which the pharmaceutical active ingredient is dispersed, obtained by the present invention, has a layer thickness of more than 50 μm. In particular, the layer thickness is more than 60 μm, more than 70 μm, more than 80 μm, more than 90 μm, more than 100 μm, more than 110 μm, more than 120 μm, more than 130 μm, more than 140 μm, or more than 150 μm. However, the layer thickness may be up to 500 μm, up to 450 μm, up to 400 μm, up to 350 μm, or up to 300 μm. In particular, the coating obtained on a surface by the method according to the present invention does not show signs of cracking or brittleness and has a uniform thickness.

[0082] According to the present invention, it has been found that relatively thin coatings obtained by the method according to the present invention promote the release of pharmaceutical active ingredients dispersed in the coating at the site of action. In contrast to conventional coatings from the prior art, there is no need to add hydrophilic components such as polyethers to the polymer or copolymer.

[0083] In principle, in the sense of the method according to the present invention, all articles, especially articles for use in medical applications, and more specifically medical implants, can be coated with a polymer coating containing one or more active pharmaceutical ingredients.

[0084] Therefore, using the method according to the present invention, it is possible to coat, for example, medical implants, such as intramedullary nails or osteosynthesis plates, with a pharmaceutically active polymer coating. Due to the easily handled components of polymer solutions 1 and 2, this method can be carried out with little effort and provides coated implants within minutes. These implants can be inserted and continuously release the active ingredients directly at the target site.

[0085] The method according to the present invention, in particular, within the framework of the parameters defined in Table 1, is as follows: a) Number average molar mass (M n A non-hydrolyzable polymer or copolymer having A and a glass transition temperature (Tg) B is dissolved in solvent C or a solvent mixture consisting of one or more solvents C to form a polymer solution 1. b) Dissolving or suspending at least one pharmaceutical active ingredient in polymer solution 1 to form polymer solution 2, c) Applying polymer solution 2 to the surface of the article, d) The solvent or solvent mixture is evaporated to leave a polymer layer on the article to be coated, and at least one active pharmaceutical ingredient is dispersed in the polymer layer. This can be implemented, and the polymer layer is characterized by not containing any pore-forming agent.

[0086] [Table 1-1]

[0087] [Table 1-2]

[0088] Particularly preferred embodiments of the method according to the present invention are described below. In this particularly preferred embodiment, the method according to the present invention comprises the following method steps, namely a) A step of forming a polymer solution 1 by dissolving a polymer or copolymer characterized by a number-average molar mass of more than 200,000 g / mol in an acetate ester, or a mixture of an acetate ester and at least one further solvent characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure, b) The step of dissolving or suspending at least one particulate antiinfectant in polymer solution 1 to form polymer solution 2, c) The step of applying polymer solution 2 to the surface of the medical implant, d) A step of evaporating a solvent or solvent mixture to leave a polymer layer on the implant surface, wherein at least one particulate antiinfective agent is dispersed in the polymer layer. It is characterized in that the polymer layer does not contain any pore-forming agents.

[0089] Further particularly preferred embodiments of the method according to the present invention include, in particular, the following method steps, namely a) A step of forming a polymer solution 1 by dissolving a polymethyl methacrylate or polymethyl-co-methyl acrylate characterized by a number-average molar mass of more than 200,000 g / mol in an acetate ester, or a mixture of an acetate ester and at least one further solvent characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure, b) The step of dissolving or suspending at least one particulate antiinfectant in polymer solution 1 to form polymer solution 2, c) The step of applying polymer solution 2 to the surface of the medical implant, d) A step of evaporating a solvent or solvent mixture to leave a polymer layer on the implant surface, wherein at least one particulate antiinfective agent is dispersed in the polymer layer. It is characterized by containing the above, and the polymer layer does not contain any pore-forming agent.

[0090] Further particularly preferred embodiments of the method according to the present invention include, in particular, the following method steps, namely a) A step of forming a polymer solution 1 by dissolving a polymethyl methacrylate or polymethyl-co-methyl acrylate characterized by a number-average molar mass of more than 200,000 g / mol in ethyl acetate, or a mixture of ethyl acetate and at least one further solvent characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure, b) Dissolving or suspending at least one particulate antiinfective agent selected from the group consisting of gentamicin sulfate, vancomycin hydrochloride, clindamycin hydrochloride, daptomycin, and mixtures thereof in polymer solution 1 to form polymer solution 2; c) The step of applying polymer solution 2 to the surface of the medical implant, d) A step of evaporating a solvent or solvent mixture to leave a polymer layer on the implant surface, wherein at least one particulate antiinfective agent is dispersed in the polymer layer. It is characterized by containing the above, and the polymer layer does not contain any pore-forming agent.

[0091] Further particularly preferred embodiments of the method according to the present invention include, in particular, the following method steps, namely a) Dissolving 9% to 11% by weight of polymethyl methacrylate or polymethyl-co-methyl acrylate, characterized by a number-average molar mass of over 200,000 g / mol and a glass transition temperature of over 47°C, in ethyl acetate, or a mixture of ethyl acetate and at least one further solvent characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure, to form polymer solution 1; b) A step of suspending at least one particulate antiinfective agent selected from the group consisting of gentamicin sulfate, vancomycin hydrochloride, clindamycin hydrochloride, daptomycin, and mixtures thereof in polymer solution 1 to form polymer solution 2, c) The step of applying polymer solution 2 to the surface of the medical implant, d) A step of evaporating a solvent or solvent mixture to leave a polymer layer on the implant surface, wherein at least one particulate antiinfective agent is dispersed in the polymer layer. It is characterized by containing and the polymer layer not containing any pore-forming agent. .

[0092] The method according to the present invention provides a coated article having a polymer layer in which a pharmaceutical active ingredient is dispersed. This article can then be introduced into a living organism, for example, in the form of an implant, in which the active ingredient is continuously released.

[0093] The present invention also includes a kit of parts and an apparatus obtained from the kit of parts for carrying out the method according to the present invention. The kit of parts and apparatus according to the present invention are described in more detail below.

[0094] III. Kits of Parts and Equipment The present invention also claims a kit of parts (hereinafter referred to as the Kit) for carrying out the method according to the present invention. The Kit, in the sense of the present invention, provides all the components required by a professional to carry out the method according to the present invention.

[0095] However, in addition, an apparatus that is useful for carrying out the method according to the present invention and obtained from the kit according to the present invention is also claimed.

[0096] The kit according to the present invention comprises the following components, namely i) A solvent-resistant container having an opening, ii) A solvent-resistant closure element suitable for closing a container, iii) Application aid and, iv) The polymer solution 1 described above, v) Optionally, a mixture and, vi) Optionally, one or more active pharmaceutical ingredients in separate packaging, Includes.

[0097] Therefore, in the sense of the present invention, at least one solvent-resistant container suitable for holding such solvents or solvent mixtures without damage is provided for the kit. Furthermore, at least one closure element, such as a screw or plug closure, is provided on the container, and this closure element is also solvent-resistant. This makes it possible to provide optionally pre-prepared polymer solutions in a container suitable for professional personnel as needed.

[0098] In the sense of the present invention, the kit also includes a dispensing aid, for which any conceivable elements are suitable for uniformly distributing the solution or suspension prepared according to the present invention onto a surface.

[0099] In the context of the present invention, it is advantageous if the completed polymer solution 1 described above is already in a solvent-resistant container from the outset. For example, if the implant is coated immediately before insertion in vivo, it is easier for the professional staff if there is no need to first weigh out the required amount of polymer or copolymer and dissolve it in a suitable solvent.

[0100] Therefore, in a preferred embodiment, the kit according to the present invention already contains the above-described polymer solution 1 in a solvent-resistant container.

[0101] In the sense of the present invention, it is also conceivable to add the above-mentioned mixture to a kit for carrying out the method according to the present invention. In principle, the active pharmaceutical ingredient can be sufficiently dissolved or dispersed by shaking a sealed container having the polymer solution 1. However, to facilitate the process, a mixture such as a mixing rod can be included in the kit, or a mixture such as a mixing element can be provided directly in the container for the polymer solution 1.

[0102] Furthermore, in order to obtain the polymer solution 2 of the target concentration as easily as possible, it is conceivable to configure the kit according to the present invention from the outset so that the pharmaceutical active ingredients are provided in separate packaging. However, this is not essential, as flexibility in the selection of the pharmaceutical active ingredients or their concentration may also be desirable.

[0103] The kit according to the present invention enables, for example, medical personnel in an operating room to mix any pharmaceutical active ingredient into polymer solution 1 in a very short time, and immediately after mixing, to apply the resulting polymer solution 2 to the surface of an implant, for example, using an application aid.

[0104] In the sense of the kit according to the present invention, it is preferable that the container has an opening with a diameter of at least 1 cm, preferably at least 2 cm, and particularly preferably at least 3 cm. When mixing the polymer solution 1 with a suitable pharmaceutical active ingredient, it is advantageous that the opening has one of the preferred minimum sizes. This makes it possible to access the polymer solution 1 through the opening of the container using a mixing tool such as a stirring rod or spatula and mix it with the pharmaceutical active ingredient.

[0105] The opening of the container is preferably located at the top of the container.

[0106] The application aids according to the present invention may include any type of article that enables the application of a solution or suspension to the surface of an article. In the sense of the present invention, it is preferable to use application aids that can be readily provided in a kit, such as a brush or a spray cap. According to the present invention, these application aids can be combined with, for example, a solvent-resistant closure element.

[0107] The mixture in the sense of the apparatus according to the present invention particularly includes the aforementioned mixtures suitable for the method according to the present invention. This includes, for example, a stirring rod or a mixing rod such as a spatula. Alternatively, at least one freely movable mixture can be placed in the container, and plastic balls, glass balls, and ceramic balls are preferred as the mixture. In this modified embodiment, the active pharmaceutical ingredient is added to the polymer solution 1, and the mixture is shaken after closing the container. Due to the action of the mixture, the active pharmaceutical ingredient is suspended or dissolved in the polymer solution 1.

[0108] The diameter of the mixture, particularly the mixing elements, is preferably at most half the inner diameter of the container. This means that there is still sufficient space around the mixture so that the polymer solution can flow around it as it moves within the container during mixing.

[0109] In a preferred modified embodiment of the kit according to the present invention, at least some of the components of the kit are physically connected to one another. This preferably relates to a container and a closure element and / or a closure element and an application aid. For example, a closure element can be attached to the container so that it is not accidentally left behind when the pharmaceutical active ingredient is added to the polymer solution 1. It is also preferable that an application aid, such as a brush, is connected to the inside of the closure element, or that the closure element itself is, for example, a spray bottle cap.

[0110] Therefore, a particularly preferred modification of the kit according to the present invention is, in particular, the following components, namely i) A solvent-resistant container having an opening, ii) A solvent-resistant closure element suitable for closing a container, which can be optionally attached to the container, iii) A brush optionally attached within the closing element such that the closing element protrudes into the interior of the container when the closing element is used to close the container, iv) The polymer solution 1 described above, v) At least one mixture in the container or a separate mixing rod, vi) Optionally, one or more active pharmaceutical ingredients in separate packaging, Includes.

[0111] Starting from this kit according to the present invention, a corresponding apparatus can be prepared before carrying out the method according to the present invention. The above corresponding description relating to the kit according to the present invention also applies to the claimed apparatus.

[0112] IV. Medical Implants and Prevention of Infection In the sense of the present invention, it is possible to provide articles such as medical implants having a pharmaceutically active polymer coating using the method according to the present invention, and then use these medical implants to prevent infection in place of uncoated implants.

[0113] Therefore, the present invention also relates to medical implants having the above-mentioned coating.

[0114] The medical implant according to the present invention is coated with a polymer coating obtained using the method according to the present invention, and the active pharmaceutical ingredient is dispersed in this polymer coating. Therefore, the polymer coating is characterized by a ratio of polymer or copolymer to active pharmaceutical ingredient of 1.00:0.05 to 1.00:1.50, as described above.

[0115] The polymer coating of medical implants has, as mentioned above, a glass transition temperature (Tg) of over 47°C, preferably over 60°C, more preferably over 80°C, and particularly over 100°C, and a number-average molar mass (M) of over 200,000 g / mol, more preferably over 400,000 g / mol, and more preferably over 600,000 g / mol. n It contains a polymer having ).

[0116] The polymer coating for medical implants preferably does not exhibit any visual signs of cracking or brittleness and, as described above, is characterized by a layer thickness of 50 μm to 200 μm.

[0117] When pharmaceutical active ingredients are dispersed in a polymer coating, the coated medical implant can have pharmaceutical effects. According to the present invention, it has been found that the dispersed active ingredients are released from the polymer coating matrix in a warm aqueous environment.

[0118] After surgery, bone or tissue material is exposed to the external environment, for example through an incision, so the risk of infection is usually increased. Furthermore, patients undergoing surgery are often weakened, reducing their body's ability to fight infection.

[0119] In the sense of the present invention, medical implants coated with a pharmaceutically active polymer using the method according to the present invention may, in particular, be intramedullary nails or osteosynthesis plates, which then act to prevent infection at the in vivo implantation site. Intramedullary nails are used for intramedullary nail fixation to correct fractures of long bones. Osteosynthesis plates are used in osteosynthesis, a surgical procedure to treat fractures, in which bone fragments are joined together with the help of this plate.

[0120] In the sense of the present invention, medical implants coated with a pharmaceutically active polymer using the method according to the present invention can therefore prevent infection, particularly after surgery in cases of fractures such as intramedullary nailing. [Examples]

[0121] a) Investigation of the properties of polymer coatings Polymethyl methacrylate and polymethyl methacrylate-co-methyl acrylate having number-average molar masses of approximately 100,000 g / mol, 200,000 g / mol, 550,000 g / mol, 700,000 g / mol, and 1,250,000 g / mol were dissolved in ethyl acetate at 5.0% and 10% by weight, respectively. These solutions were applied to stainless steel surfaces, and the properties of the remaining polymer layer were examined after the ethyl acetate evaporated. It was found that using polymethyl methacrylate with a number-average molar mass of less than 200,000 g / mol resulted in a more brittle and less adhesive coating than using polymethyl methacrylate and polymethyl methacrylate-co-methyl acrylate with number-average molar masses of 200,000 g / mol or more.

[0122] b) Investigation of the concentration of active ingredients in polymer coatings For the following tests, a polymethyl methacrylate-methyl acrylate copolymer with a number-average molar mass of approximately 550,000 g / mol, and a stainless steel cylinder (CoCr28Mo6, ASTM F75 alloy) with a diameter of 10.0 mm and a length of 60.0 mm were used. Gentamicin sulfate, vancomycin hydrochloride, clindamycin hydrochloride, and daptomycin were mixed with a 10 wt% solution of polymethyl methacrylate-methyl acrylate copolymer in ethyl acetate (Tables 2 and 3). The antiinfective agents were present as powders with an average particle size of less than 100 μm. The resulting dispersion was milky white and turbid.

[0123] Mixtures 1-10 were applied to a stainless steel cylinder using a brush. The area covered was 10.20 cm², which is half the size of the steel cylinder. 2 Only the following was coated. Five stainless steel cylinders were coated for each mixture. After the ethyl acetate evaporated, the mass of the coating was determined by gravimetric analysis. The coated stainless steel cylinders were then stored in distilled water at 37°C for 24 hours. The stainless steel cylinders were then dried, and the mass loss due to the release of the anti-infective agent was determined by gravimetric analysis.

[0124] [Table 2]

[0125] [Table 3]

[0126] Tables 2 and 3 show the composition of the mixture referred to as polymer solution 2 for mixtures 1 to 10. The effect of increasing the concentration of the active ingredient was investigated using mixtures 1 to 7. The effect of substance identity on the same mass ratio was investigated using mixtures 8 to 10.

[0127] [Table 4]

[0128] The theoretical mass loss during the complete dissolution of gentamicin sulfate is 20% by weight. An average mass loss of 33% by weight was found.

[0129] [Table 5]

[0130] The theoretical mass loss during the complete dissolution of gentamicin sulfate is 33% by weight. An average mass loss of 42% by weight was found.

[0131] [Table 6]

[0132] The theoretical mass loss during the complete dissolution of gentamicin sulfate is 43% by weight. An average mass loss of 40% by weight was found.

[0133] [Table 7]

[0134] The theoretical mass loss during the complete dissolution of gentamicin sulfate is 50% by weight. An average mass loss of 50% by weight was found.

[0135] [Table 8]

[0136] The theoretical mass loss during the complete dissolution of gentamicin sulfate is 55% by weight. An average mass loss of 56% by weight was found.

[0137] [Table 9]

[0138] The theoretical mass loss during the complete dissolution of gentamicin sulfate is 60% by weight. An average mass loss of 63% by weight was found.

[0139] [Table 10]

[0140] The theoretical mass loss during the complete dissolution of gentamicin sulfate is 71% by weight. An average mass loss of 71% by weight was found.

[0141] [Table 11]

[0142] The theoretical mass loss for complete dissolution of vancomycin hydrochloride is 50% by weight. An average mass loss of 49% by weight was observed. Vancomycin hydrochloride eluted almost completely from the coating.

[0143] [Table 12]

[0144] The theoretical mass loss during the complete dissolution of clindamycin hydrochloride is 50% by weight. An average mass loss of 45% by weight was observed. Clindamycin hydrochloride eluted almost completely from the coating.

[0145] [Table 13]

[0146] The theoretical mass loss during the complete dissolution of daptomycin is 50% by weight. An average mass loss of 40% by weight was observed. Residual daptomycin remained in the coating.

[0147] The reasons why the average mass loss was higher than theoretically calculated were investigated for the results shown in Tables 4, 5, 8, and 9. For this purpose, each type of coating was examined using a scanning electron microscope before and after storage in hot water (Figure 1).

[0148] Encapsulations or inclusions were found to be formed throughout the polymer coating, and then opened when stored in water at 37°C. Separation of small particles from the polymer layer or weighing errors are assumed to explain the mass loss.

[0149] The results indicate that, within the limits of weighing error, the antibiotic was substantially quantitatively released from the coating by the action of water.

[0150] c) Antimicrobial activity of coatings 4, 6, 8, and 10 The eluates from tests 4, 6, 8, and 10 were tested for their antimicrobial activity. For this purpose, inhibition zone tests were performed using the test bacterium Bacillus subtilis ATCC 6633 and nutrient agar 1. Heated nutrient agar 1 was mixed with a suspension of Bacillus subtilis spores, and the inoculated nutrient agar 1 was poured into a Petri dish. After cooling to room temperature, the solidified agar was perforated. 50 μL of undiluted eluate or 50 μL of 1:50 diluted eluate was added to the perforations in the nutrient agar. Aqueous solutions of gentamicin sulfate, vancomycin hydrochloride, and clindamycin hydrochloride were also included as controls. The agar plates were then incubated at 37°C for 24 hours. Figures 2 and 3 show the schematic distribution of different samples (labeled HE-3 and HE-4) on the plates, respectively, and also show actual images of the plates at the end of the experiment.

[0151] [Table 14]

[0152] [Table 15] [Brief explanation of the drawing]

[0153] [Figure 1] The images show a) a scanning electron microscope image of a coating manufactured according to the present invention before incubation of the support at 37°C for 24 hours, and b) an image of the same coating after the incubation process. a) shows the coating in which inclusions in the form of closed bubbles of the active ingredient and optionally unpolymerized material are visible. b) shows the same coating, but with open inclusions that can be seen as dark openings. [Figure 2]The images show an agar plate inoculated with bacterial HE-3, a schematic sample distribution (a), and the carrier after incubation at 37°C for 24 hours (b). The sample descriptions in Table 14 correspond to the scheme shown in (a). In each case, one of the sample solutions shown in Table 14 was spread onto one of the perforations, which appear as black circles in (b), and then diffused in a circular pattern into the bacterial culture. The inhibition zone, where the bacterial concentration is reduced, appears as a circular region around the cavity. [Figure 3] The images show an agar plate inoculated with bacterial HE-4, a schematic sample distribution (a), and the carrier after incubation at 37°C for 24 hours (b). The sample descriptions in Table 15 correspond to the scheme shown in a). In each case, one of the sample solutions shown in Table 15 was spread onto one of the perforations, which appear as black circles in b), and then diffused in a circular pattern into the bacterial culture. The inhibition zone, where the bacterial concentration is reduced, appears as a circular region around the cavity.

Claims

1. A method for producing a pharmaceutically active polymer coating, comprising the following method steps, namely a) A step of forming a polymer solution 1 by dissolving a non-hydrolyzable polymer or copolymer, characterized by a number average molar mass greater than 200,000 g / mol, more preferably greater than 400,000 g / mol, and more preferably greater than 600,000 g / mol, determined by gel permeation chromatography, in a solvent or solvent mixture characterized by a vapor pressure of at least 95 hPa at 20°C and standard pressure, b) A step of dissolving or suspending at least one pharmaceutical active ingredient in the polymer solution 1 to form a polymer solution 2, c) The step of applying the polymer solution 2 to the surface of the article to be coated, d) A step of evaporating the solvent or solvent mixture to leave a polymer layer on the surface of the article to be coated, wherein the polymer layer contains at least one active pharmaceutical ingredient. A method comprising the above, wherein the polymer layer does not contain any pore-forming agent soluble in aqueous solution.

2. The method according to claim 1, characterized in that the polymer or copolymer has a glass transition temperature of more than 47°C, more preferably more than 60°C, more preferably more than 80°C, and more preferably more than 100°C.

3. The method according to claim 1, characterized in that the polymer or copolymer is based on polymethyl methacrylate, and in the case of a copolymer, the comonomer is selected from the group consisting of methyl acrylate, ethyl acrylate, ethyl methacrylate, styrene, and mixtures thereof.

4. The method according to claim 1, characterized in that the solvent or solvent mixture has a water content of less than 8% by weight, more preferably less than 5% by weight, and more preferably less than 2% by weight.

5. The method according to claim 1, characterized in that the solvent or solvent mixture is selected from the group consisting of acetate esters, acetoacetate esters, acetone, diacetone alcohol, ethyl methyl ketone, butyl methyl ketone, and mixtures thereof.

6. The method according to claim 1, characterized in that the content of the polymer or copolymer in the polymer solution 1 is 2% to 18% by weight, preferably 9% to 11% by weight.

7. The method according to claim 1, characterized in that the pharmaceutical active ingredient is selected from the group consisting of anti-infective agents, bacteriophages, cell proliferation inhibitors, analgesics, hormones, growth factors, and mixtures thereof.

8. The method according to claim 1, characterized in that the active pharmaceutical ingredient in step b) is added as particulate solid having a particle size of less than 250 μm, more preferably less than 100 μm, determined by sieving, for dissolving or suspending in the polymer solution 1 to obtain the polymer solution 2.

9. The method according to claim 1, characterized in that the weight ratio of the polymer or copolymer to the active pharmaceutical ingredient is 1.00:0.05 to 1.00:1.

50.

10. The method according to claim 1, characterized in that the polymer layer has a layer thickness of 50 to 500 μm.

11. In particular, a medical kit for carrying out the method described in claim 1, The following components, Call i) A solvent-resistant container having an opening, ii) A solvent-resistant closure element suitable for closing the container, iii) Application aid and, iv) A polymer solution 1 obtained according to the method described in claim 1, v) Optionally, one or more mixtures, vi) Optionally, one or more active pharmaceutical ingredients in separate packaging, A medical kit including [item name].

12. The opening of the container has a diameter of at least 1 cm, preferably at least 2 cm, more preferably at least 3 cm, and / or The application aid is selected from a brush or a sprayer cap, and / or The mixture is selected from at least one mixing rod and / or at least one mixing element provided in the container in the polymer solution 1, and / or One or more of the elements listed in i) to iii) of the medical kit components are attached to each other. A medical kit according to claim 11, characterized by the above.

13. An apparatus for carrying out the method according to claim 1, comprising the components of the medical kit described in claim 11.

14. A medical implant coated with a polymer coating having dispersed pharmaceutical active ingredients obtained by the method described in claim 1.

15. A medical implant according to claim 14 for preventing infection after surgical procedures.

Images