MULTI-LAYER ORAL THIN FILM

Description

[0001] The present invention relates to a multilayer oral thin film, a method for its production, and the multilayer oral thin film for use as a pharmaceutical.

[0002] Oral thin films are thin films containing at least one pharmaceutically active ingredient that are placed directly into the oral cavity or applied to the oral mucosa, where they dissolve or swell, releasing the active ingredient. These are primarily thin, single- or multi-layered, polymer-based films containing the active ingredient, which, when applied to the mucosa, especially the oral mucosa, can deliver the active ingredient directly into it. The excellent blood supply of the oral mucosa ensures rapid absorption of the active ingredient into the bloodstream. This delivery system has the advantage that the active ingredient is largely absorbed through the mucosa, thus avoiding the "first-pass metabolism" that occurs with conventional tablet-based drug administration. The active ingredient can be dissolved, emulsified, or dispersed within the film.

[0003] Mašek Josef, et al. Multi-layered nanofibrous mucoadhesive films for buccal and sublingual administration of drug-delivery and vaccination nanoparticles - important step towards effective mucosal vaccines. J Control Release. March 10, 2017; pages 183-195, describes nanofiber-based mucoadhesive films developed for the oromucosal administration of nanocarriers for drug and vaccine delivery.

[0004] Prajapati Vipul et al. Pullulan-based oral thin film formulation of zolmitriptan: Development and optimization using factorial design. Int J Biol Macromol., February 1, 2018; pages 2075-2085, describes a study on the formulation and characterization of pullulan-based oral thin films (OTF) of zolmitriptan using solvent casting techniques.

[0005] Yogyata S Pathare et al. "Polymers used for Fast Disintegrating Oral Films: A Review", International J. of Pharmaceutical Sciences Review and Research, July 1, 2013, pages 169-178, describes the current developments in the field of oral thin films as a new delivery system for the oral administration of drugs.

[0006] Current oral thin films have the disadvantage that, if they are intended to remain on a patient's mucosa for an extended period, they are subject to permanent erosion. This results in a large portion of the material being swallowed, preventing it from remaining at the application site for the desired duration. However, the retention time can be crucial for the transmucosal transport of the pharmaceutically active ingredient. Furthermore, many active ingredients have an unpleasant taste and are perceived as disagreeable, especially upon contact with the tongue.

[0007] A protective layer on the back prevents liquid from penetrating the formulation and dissolving it too quickly, allowing the active ingredient to remain at the application site for maximum time to achieve optimal permeation through the mucosa or delayed release. Another effect of the backing layer is that it prevents the applied film from detaching from the application site and adhering to other areas, such as teeth. Furthermore, the backing layer can mask any unpleasant taste caused by the active ingredient.

[0008] Insoluble or slowly soluble polymers or polymer films are frequently used as materials for such backing layers. However, these have the disadvantage that they must be removed or swallowed after the application is complete.

[0009] Backing layers made of slowly soluble polymers also have the disadvantage of being based on long-chain, high-molecular-weight polymers. Due to their high viscosity, these are difficult to process (long drying times, irregular films). Furthermore, they tend to increase the viscosity of saliva in the oral cavity, resulting in a slimy feeling.

[0010] Another problem is the often inadequate bond between the active ingredient layer and the backing layer. There is a risk that the two parts will separate during storage if, for example, they react differently to humidity.

[0011] The object of the present invention is to overcome the aforementioned disadvantages of the prior art. In particular, the object of the present invention is to provide a multilayered oral thin film comprising at least one backing layer, wherein the backing layer should, in particular, have a low melting point, negligible toxicity, and a smooth surface. Furthermore, the backing layer should dissolve as slowly as possible, thus protecting the applied film from being swallowed and the tongue from direct contact with the active ingredient, which prevents or reduces an unpleasant taste from the active ingredient. The active ingredient should also be protected from additional saliva, which is particularly advantageous if the active ingredient or its permeation is pH-sensitive and the pH value would change due to excessive saliva.

[0012] Furthermore, a manufacturing process for such a film should be provided that ensures a firm bond between the active ingredient-containing layer and the backing layer in the oral thin film.

[0013] The above problem is solved by a multilayer oral thin film according to claim 1, in particular by a multilayer oral thin film comprising a matrix layer containing at least one polymer and at least one pharmaceutically active ingredient and at least one back layer, wherein the at least one back layer comprises at least one polyethylene glycol in an amount of 60 to 100 wt.%, based on the total weight of the at least one back layer.

[0014] Such a multilayered oral thin film has the advantage that the polyethylene glycol layer, due to its smooth surface, low melting point, and low toxicity, is well-suited as a backing layer for oral thin films. The polyethylene glycol layer dissolves slowly in the mouth (slower than the drug layer), thus protecting the applied oral thin film from being swallowed and also preventing the tongue from direct contact with the drug, which prevents or reduces an unpleasant taste. Furthermore, the drug is protected from additional saliva, which is advantageous, for example, if the drug or its permeation is pH-sensitive and the pH value would otherwise change due to excessive saliva.The different roughness of the two layers (the layer containing polyethylene glycol is rather smooth, and the drug-containing layer is rather rough) can be used by the patient to determine which side of the oral thin film is being applied to the mucosa. Due to the different roughness, the patient can also tell by feel whether the oral thin film is correctly positioned in the mouth.

[0015] Additionally, the back layer can be colored with dye to improve visibility.

[0016] Furthermore, it is possible to incorporate flavorings to improve the mouthfeel during application, which is a major advantage over known films.

[0017] In this document, "comprehensive" can also mean "consisting of".

[0018] The term back layer refers to a layer of the multilayered oral thin film, which represents one of the outermost layers of the multilayered oral thin film.

[0019] Polyethylene glycols (PEG) are compounds of the general formula:

[0020] Higher molecular weight solid polyethylene glycols (melting point approximately 65 °C) are also frequently referred to as polyethylene oxides or polyoxyethylenes (abbreviated PEO or, less commonly, PEOX) or polywaxes. In this document, the terms "polyethylene glycol" and "polyethylene oxide" are used interchangeably.

[0021] The multilayer oral thin film according to the invention is preferably characterized in that the matrix layer comprises at least one water-soluble polymer.

[0022] Water-soluble polymers encompass chemically very diverse natural or synthetic polymers, whose common characteristic is their solubility in water or aqueous media. A prerequisite is that these polymers possess a sufficient number of hydrophilic groups to ensure water solubility and are not cross-linked. The hydrophilic groups can be non-ionic, anionic, cationic, and / or zwitterionic.

[0023] Water-soluble is preferably understood to mean a solubility of greater than 100 g / L in water at 25°C.

[0024] The at least one water-soluble polymer is preferably selected from the group consisting of starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propylcellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinylpyrrolidone / vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums, with polyvinyl alcohols being particularly preferred.

[0025] The multilayer oral thin film according to the invention is preferably characterized in that the at least one polymer, preferably the water-soluble polymer, is present in the drug-containing matrix layer of the multilayer oral thin film in an amount of 10 to 90 wt.%, preferably 20 to 60 wt.%, particularly preferably 30 to 50 wt.%, based on the total weight of the drug-containing matrix layer.

[0026] The at least one pharmaceutically active ingredient is not subject to any restrictions in principle, but is preferably selected from all pharmaceutically active ingredients suitable for oral and / or transmucosal administration.

[0027] According to the present invention, the pharmaceutically active substance also includes all pharmaceutically acceptable salts and solvates of the respective pharmaceutically active substance.

[0028] Preferred active ingredients are selected from the group comprising the drug classes of analgesics, hormones, hypnotics, sedatives, antiepileptics, stimulants, psychoneurotropics, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutic agents and narcotics, although this group is not exhaustive.

[0029] Particularly preferably, the at least one pharmaceutically active ingredient is ketamine and / or a pharmaceutically acceptable salt or solvate thereof, preferably ketamine HCl.

[0030] Ketamine is understood to mean (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, (R)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, as well as the racemate (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

[0031] Particularly preferred is (S)-ketamine or a pharmaceutically acceptable salt thereof, especially (S)-ketamine·HCl, as the only stereoisomer of ketamine, since the analgesic and anesthetic potency of (S)-ketamine is about three times higher than that of the (R)-form.

[0032] The active ingredient content in the matrix layer can vary within relatively wide limits. A range of 10 to 60 wt.%, based on the dry weight of the matrix layer, can be considered suitable. In one embodiment, the proportion of active ingredient in the matrix layer is closer to the lower end of this range, for example, if the active ingredient has a strongly unpleasant taste that must be masked with a larger quantity of taste-masking agents. In this case, a range of 10 to 40 wt.% can be considered suitable. In another embodiment, the proportion of active ingredient in the dosage form according to the invention is closer to the upper end, with a content of 40 to 60 wt.% and, in particular, a content of 45 to 55 wt.% being considered especially preferred.

[0033] Particularly preferably, (S)-ketamine or a pharmaceutically acceptable salt thereof is present in the matrix layer in an amount of 45 to 55 wt.%, based on the dry weight of the drug-containing matrix layer.

[0034] The multilayer oral thin film according to the invention is further preferably characterized in that the matrix layer comprises at least one excipient selected from the group consisting of colorants, flavorings, sweeteners, plasticizers, flavor-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0035] Each of these auxiliary materials is preferably contained in the matrix layer in an amount of 0.1 to 40 wt.%, preferably 0.1 to 30 wt.%, particularly preferably 0.1 to 15 wt.%, most preferably 0.1 to 10 wt.% or 0.1 to 5 wt.%, based on the total weight of the matrix layer.

[0036] The at least one polyethylene glycol preferably has an average molecular weight of at least 20,000 g / mol to 7,000,000 g / mol, preferably of 40,000 g / mol to 500,000 g / mol, particularly preferably of 95,000 g / mol to 105,000 g / mol, and especially of about 100,000 g / mol.

[0037] The molecular weight is derived from the rheological measurements described below.

[0038] The multilayer oral thin film according to the invention is further preferably characterized in that the at least one polyethylene glycol has a viscosity of 30 mPa s to 50 mPa s, measured at 25°C.

[0039] The stated viscosities refer to a 5 wt% solution of polyethylene glycol in water and are measured on a Brookfield viscometer, Model RVF, with spindle No. 1 at 50 rpm and at a temperature of 25°C.

[0040] A polyethylene glycol known under the trade name POLYOX WSR N-10 (Dow Chemical) is particularly preferred.

[0041] The multilayer oral thin film according to the invention is further preferably characterized in that the at least one polyethylene glycol is contained in the at least one back layer in an amount of 80 to 100 wt.%, based on the total weight of the at least one back layer.

[0042] The multilayer oral thin film according to the invention is further preferably characterized in that the at least one polyethylene glycol is contained in an amount of 65 to 100 wt.% or 70 to 100 wt.% or 85 to 100 wt.% or 90 to 100 wt.% or 95 to 100 wt.%, based on the total weight of the at least one back layer.

[0043] The multilayer oral thin film according to the invention is further preferably characterized in that the at least one polyethylene glycol is contained in an amount of 60 to 97.5 wt.% or 65 to 97.5 wt.% or 70 to 97.5 wt.% or 80 to 97.5 wt.% or 85 to 97.5 wt.% or 90 to 97.5 wt.% or 95 to 97.5 wt.%, based on the total weight of the at least one back layer.

[0044] The multilayer oral thin film according to the invention is further preferably characterized in that the at least one polyethylene glycol is present in an amount of 60 to 97.5 wt.% or 65 to 97.5 wt.% or 70 to 97.5 wt.% or 80 to 97.5 wt.% or 85 to 97.5 wt.% or 90 to 97.5 wt.% or 95 to 97.5 wt.%, and additionally 2 to 2.5 wt.% of at least one plasticizer, preferably glycerol, based on the total weight of the at least one back layer in which at least one back layer is contained.

[0045] The multilayer oral thin film according to the invention is preferably characterized in that the at least one back layer comprises at least one excipient selected from the group consisting of colorants, flavorings, sweeteners, flavor-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0046] Each of these auxiliary materials is preferably contained in this layer in an amount of 0.1 to 10 wt.%, preferably 0.1 to 5 wt.%, particularly preferably 0.1 to 2.5 wt.%, based on the total weight of the backing layer.

[0047] The multilayer oral thin film according to the invention is preferably characterized in that the at least one back layer contains at least one plasticizer, preferably glycerol, preferably in an amount of 0.5 to 5 wt.%, particularly preferably in an amount of 2 to 2.5 wt.%, based on the total weight of the at least one back layer.

[0048] The multilayer oral thin film according to the invention is in principle not limited in the number of layers it contains.

[0049] Thus, embodiments are conceivable in which the multilayered oral thin film has several active ingredient-containing matrix layers.

[0050] It is also conceivable to implement embodiments in which the multilayer oral thin film has two back layers on opposite sides of the multilayer oral thin film.

[0051] In particular, at least one adhesive layer can be present between the at least one matrix layer and the at least one back layer in order to bond the at least one matrix layer and the at least one back layer together as firmly as possible.

[0052] An adhesive layer is understood to be a layer that can act as an adhesive, as defined in DIN EN 923:2016-03. A non-adhesive layer, therefore, cannot act as an adhesive as defined above.

[0053] Water-soluble adhesive layers, such as those described in DE 10 2014 127 452 A1, are particularly suitable as adhesive layers, the content of which is hereby fully incorporated.

[0054] Suitable adhesive layers comprise at least one water-soluble polymer and at least one plasticizer, wherein the at least one water-soluble polymer in the at least one water-soluble adhesive layer comprises shellac, a vinylpyrrolidone / vinyl acetate copolymer, a polyvinylcaprolactam / polyvinyl acetate / polyethylene glycol copolymer, hydroxypropyl cellulose or hydroxypropyl methylcellulose, and / or polyvinylpyrrolidone, and wherein the at least one plasticizer in the at least one water-soluble adhesive layer comprises glycerin, polyethylene glycol, in particular polyethylene glycol 200, and / or tributyl citrate. The weight ratio of the at least one water-soluble polymer to the at least one plasticizer in the at least one adhesive layer is preferably about 85 to 50 to about 15 to 50.

[0055] Such an adhesive layer, containing at least one water-soluble polymer and at least one plasticizer, can act as an intermediate water-soluble adhesive layer, firmly bonding two further layers that are not adhesive in themselves, thus enabling the construction of multilayer oral films without multiple overcoatings.

[0056] The multilayer oral thin film according to the invention is preferably characterized in that the multilayer oral thin film consists of exactly two layers, namely the matrix layer containing at least one polymer and at least one pharmaceutically active ingredient and a back layer containing at least one polyethylene glycol.

[0057] In one embodiment, the active ingredient-containing matrix layer can represent a smooth film.

[0058] Preferably, the multilayer oral thin film according to the invention is characterized in that the matrix layer is in the form of a solidified foam having cavities.

[0059] The cavities and the associated larger surface area of ​​the films facilitate the entry of water, saliva or other bodily fluids into the interior of the dosage form, thus accelerating the dissolution of the dosage form and the release of the active ingredient.

[0060] Furthermore, with a rapidly absorbed drug, the transmucosal absorption can be improved by the rapid dissolution of the matrix layer.

[0061] Secondly, the wall thickness of the aforementioned cavities is preferably small, since these, for example, represent solidified bubbles, so that rapid dissolution or destruction of these cavities takes place.

[0062] Another advantage of this embodiment is that, despite the comparatively high basis weight, faster drying can be achieved by manufacturing it as a foam than with a comparable non-foamed composition.

[0063] Preferably, the multilayer oral thin film according to the invention is characterized in that the cavities are isolated from each other and preferably have the form of bubbles, wherein the cavities are filled with air or a gas, preferably with an inert gas, particularly preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

[0064] According to another embodiment, the cavities are provided to be interconnected, preferably by forming a continuous channel system penetrating the matrix.

[0065] Preferably, the aforementioned cavities have a volume fraction of 5 to 98%, more preferably 50 to 80%, based on the total volume of the matrix layer. This favorably influences the desired effect of accelerating the dissolution of the matrix layer.

[0066] Furthermore, surfactants or surface-active substances can be added to the matrix polymer or the polymer matrix for foam formation or to the resulting foam before or after drying in order to improve the stability of the foam before or after drying.

[0067] Another parameter influencing the properties of the dosage form according to the invention is the diameter of the cavities or bubbles. The bubbles or cavities are preferably generated using a foaming machine, with which the diameter of the bubbles can be adjusted within a wide range, almost arbitrarily. Thus, the mean diameter, determined, for example, by microtomography or microscopy of the bubbles or cavities, can be in the range of 1 to 350 µm. A diameter in the range of 40 to 200 µm is particularly preferred.

[0068] The multilayer oral thin film according to the invention preferably has a rough side with a mean roughness Ra greater than 2.0 µm and a smooth side with a mean roughness Ra less than 1.0 µm.

[0069] In another embodiment, the multilayer oral thin film according to the invention is characterized in that the multilayer oral thin film has a rough side and a smooth side, wherein the rough side has a mean roughness Ra of 1.0 µm more than the smooth side.

[0070] Roughness measurement can be performed, for example, on a KLA Tencor P15 profilometer with a 2 µm radius probe tip. For this purpose, a surface scan is performed on both sides of an oral thin film over an area of ​​2 mm x 2 mm. Within this 2 mm x 2 mm scan area, three line scans are randomly selected, and the roughness parameters Ra, Rq, Rp, and Rv are determined.

[0071] The following roughness parameters can be determined to evaluate the sample: Ra: Mean roughness, indicates the average distance of a measurement point from the center line. Rq: Quadratic roughness (also RMS roughness), is calculated from the mean of the squared deviations and corresponds to the root mean square. Rp: Peak height, distance between the center line and the highest measurement. Rv: Valley depth, distance between the center line and the lowest measurement.

[0072] The multilayer oral thin film according to the invention is further preferably characterized in that the multilayer oral thin film has a release of the at least one pharmaceutically active ingredient that is at least 30% slower than the matrix layer alone without a backing layer.

[0073] This means that the presence of the backing layer on the matrix layer can delay the release of the at least one pharmaceutically active ingredient by at least 30%.

[0074] The oral thin film according to the invention preferably has an area of ​​0.5 cm² to 10 cm², particularly preferably of 1 cm² to 8 cm².

[0075] The oral thin film according to the invention is preferably characterized in that the basis weight of the multilayer oral thin film is 10 to 500 g / m², preferably 70 to 400 g / m².

[0076] The basis weight of the matrix layer is preferably at least 10 g / m², more preferably at least 20 g / m² or at least 30 g / m², or most preferably at least 50 g / m² or is less than or equal to 400 g / m², more preferably less than or equal to 350 g / m² or less than or equal to 300 g / m², or most preferably less than or equal to 150 g / m². Preferably, the basis weight is 10 to 400 g / m², more preferably 20 to 350 g / m² or 30 to 300 g / m², and most preferably 50 to 150 g / m².

[0077] The basis weight of the backing layer is important for controlling the dissolution behavior and the backing layer's function in protecting the active ingredient from dissolving in saliva. A specific thickness is advisable to ensure adequate protection of the active ingredient and sufficient dissolution time, which should normally be at least as long as the active permeation requirement and thus the dissolution time of the matrix layer.

[0078] It is therefore preferred that the backing layer has an areal weight of at least 10 g / m², more preferably at least 20 g / m² or at least 30 g / m², most preferably at least 50 g / m², or an areal weight of less than or equal to 400 g / m², more preferably less than or equal to 350 g / m² or less than or equal to 300 g / m², or most preferably less than or equal to 150 g / m², or an areal weight of 10 to 400 g / m², more preferably of 20 to 350 g / m² or of 30 to 300 g / m², most preferably of 50 to 150 g / m².

[0079] Preferably, the matrix layer and the at least one back layer each have a layer thickness of about 10 µm to about 500 µm, particularly preferably from about 20 µm to about 300 µm.

[0080] The backing layer can be the same size as, or larger than, the matrix layer. In certain embodiments, the size of the backing layer and the size of the drug-containing matrix layer are the same, while in other embodiments, the backing layer is larger than the surface area of ​​the matrix layer. While a layer structure with backing and matrix layers of the same size is easier to manufacture, as a two-layer sheet can be die-cut to provide the layer structure, a layer structure with a backing layer larger than the matrix layer is more difficult to manufacture but offers the advantage of a lower risk of active drug leakage, since the edge of the matrix layer is also covered by the backing layer.

[0081] The present invention further relates to a method for producing the multilayer oral thin film according to the invention, comprising the steps of: a) Preparing and spreading a solution or suspension comprising the at least one polyethylene glycol and subsequently drying the spread solution or suspension to obtain a film comprising the at least one polyethylene glycol; b) Preparing a solution, dispersion, or melt comprising at least the at least one polymer and the at least one pharmaceutical active ingredient; b1) Optionally, foaming the solution, dispersion, or melt from step b) by introducing a gas or gas mixture, by chemical gas generation, or by releasing a dissolved gas; c) Spreading the solution, dispersion, or melt from step b) or the optionally foamed solution, dispersion, or melt from step b1) onto the film obtained in step a) comprising the at least one polyethylene glycol to obtain a composite; d) Drying the composite obtained in step c) to obtain a multilayer oral thin film.

[0082] Steps a) and b) can be performed in any order.

[0083] It is clear to the expert that step b1) is only necessary if the active ingredient-containing matrix layer is to be in the form of a solidified foam with cavities.

[0084] In step c), additional layers, such as an adhesive layer, may also be present on the matrix layer.

[0085] The joining of the two films from steps a) and b) can, in principle, be carried out using methods familiar to those skilled in the art. For example, a further film can be applied to a first film by means of a coating, whereby it is essentially irrelevant which film is coated onto which film, as long as the backing layer forms one of the outermost layers. Furthermore, the two layers can be bonded together by an adhesive layer, as described above.

[0086] Preferably, the layers are bonded together by applying heat. For this purpose, the drying process in step d) is carried out at a temperature higher than the melting point of the matrix layer and / or the backing layer. This causes the matrix layer and / or the backing layer to partially melt, thus ensuring a strong bond between the two layers upon subsequent cooling.

[0087] Suitable temperatures are 40 to 100 °C, preferably 55 to 80 °C. Drying preferably takes place for a duration of 10 to 60 minutes.

[0088] In a further embodiment, the method according to the invention is characterized in that the aforementioned steps c) and d) are replaced by the steps c2) Spreading out the solution, dispersion or melt from step b) or the optionally foamed solution, dispersion or melt from step b1) to obtain a film comprising the at least one polymer and the at least one pharmaceutical active ingredient, and d2) joining the films obtained in step a) and c2), preferably by laminating by applying heat above the melting point of one of the polymers contained in the films to obtain a multilayer oral thin film.

[0089] The modified process also makes it easy to produce embodiments of the multilayer oral thin film in which both sides of the drug-containing matrix layer are covered by a layer comprising at least one polyethylene glycol. Such multilayer oral thin films dissolve very slowly.

[0090] The present invention further relates to a multilayer oral thin film obtainable by the method described above.

[0091] Furthermore, the present invention relates to a multilayer oral thin film, as described above, or obtainable by the method described above, as a pharmaceutical.

[0092] The present invention further relates to a multilayer oral thin film, as described above or obtainable by the method described above, wherein ketamine, preferably S-ketamine, is used as a pharmaceutically active agent for use in the treatment of pain and / or depression, in particular for reducing the risk of suicide, and / or for use as a general anesthetic, preferably for induction and maintenance of general anesthesia or as an adjunct to regional anesthesia and / or as an analgesic.

[0093] The preferred embodiments listed above for the multilayer oral thin film according to the invention also apply to the method according to the invention, the multilayer oral thin film obtained by this method and its use as a medicinal product.

[0094] The invention is explained in more detail below using non-limiting examples. Example 1:

[0095] Example formulation consisting of a polyethylene glycol (Polyox) backing layer and an S-ketamine-containing matrix layer in the form of a foam. Table 1: material Quantity [wt.%] Drug-containing matrix layer S-Ketamine HCl 50,00 PVA 4-88 41,70 Saccharin Na 1,00 Sucralose 2,00 Glycerol 2,30 Flavoring 1 1,00 Flavoring 2 2,00 Process solvents Water Back shift Polyox WSR N10 97,50 Glycerol 2,30 dye 0,20 Process solvents Water Basis weight (dry) Drug-containing matrix layer: 118.7 g / m² Back layer: 100 g / m²< Coating weight (including residual water) Drug-containing matrix layer: 121.9 g / m² Back layer: 101.5 g / m²< S-ketamine base in mg / oral thin film 14.9 mg / 2.9 cm² Equivalent to 17.2 mg S-ketamine HCl PVA 4-88: Polyvinyl alcohol Polyox WSR N10: Polyethylene glycol with a molecular weight of 100,000 g / mol from Dow Chemical

[0096] The multilayer oral thin film according to the above composition was prepared as follows.

[0097] The raw materials for the backing layer are processed into a homogeneous mass using established weighing and stirring techniques, as well as suitable mixing tools and motors. This mass is then applied to a web-shaped substrate (with a specific basis weight) using coating tools (e.g., film drawing machines). The wet film is then dried in a drying oven at 70°C for 15 minutes.

[0098] The raw materials for the active ingredient-containing matrix layer are processed into a homogeneous mass using established weighing and stirring techniques, as well as suitable stirring tools and motors. This mass is then foamed using stirring techniques, and the resulting foam is applied to the dry backing layer. This is again done using coating tools (e.g., film forming machines). The resulting film, consisting of the backing layer and the matrix layer, is then dried again at 70°C for 15 minutes in a drying oven.

[0099] This multilayered film can be packaged into smaller oral thin films after drying. Example 2:

[0100] Example formulation consisting of a polyethylene glycol (Polyox) backing layer and an S-ketamine-containing matrix layer in the form of a foam, wherein the layers are produced individually and finally joined together by lamination. Table 2: Drug-containing matrix layer Quantity [wt.%] (S)-Ketamine HCl 50,00 % PVA 4-88 41,70 % Saccharin Na 1,00 % Sucralose 2,00 % Glycerol 2,30 % Flavoring 1 1,00 % Flavoring 2 2,00 % Process solvents Purified water basis weight (dry) 117.3 g / m² Basis weight (incl. residual solvent) 121.9 g / m² Back shift Quantity [wt.%] Polyox WSR N10 97,50 % Glycerol 2,3 % dye 0,20 % Process solvents Purified water Basis weight (dry) 98.2 g / m² Basis weight (incl. residual solvent) 101.5 g / m²<

[0101] The raw materials for the backing layer are processed into a homogeneous mass using established weighing and stirring techniques, as well as suitable mixing tools and motors. This mass is then applied to a web-shaped substrate (with a specific basis weight) using coating tools (e.g., film drawing machines). The wet film is then dried in a drying oven at 70°C for 15 minutes.

[0102] The raw materials for the active ingredient-containing matrix layer are processed into a homogeneous mass using established weighing and stirring techniques, as well as suitable stirring tools and motors. This mass is then foamed using stirring techniques, and the resulting foam is coated onto a web-shaped substrate. This is again done using coating tools (e.g., film forming machines). The moist film is then dried in a drying oven at 70°C for 15 minutes.

[0103] The two layers were joined together by lamination. For this purpose, the back layer was briefly heated to 70 °C and then bonded to the active ingredient-containing matrix layer by lamination.

[0104] This multilayered film can be packaged into smaller oral thin films.

[0105] In this multilayered oral thin film, a drug-free polyox layer serves as a backing layer for the actual drug-containing matrix layer of the oral thin film. This protective layer can mask the taste of the active ingredient and prevent rapid swallowing, thus increasing oromucosal bioavailability. Specifically, the inventive oral thin film is characterized by the fact that the drug coating can be applied directly to the polyox layer during manufacturing.

[0106] By drying above the melting point of polyoxymethylene (POX), the active ingredient-containing matrix layer and the backing layer bond together to form a solid composite. An adhesive layer is therefore unnecessary.

[0107] Furthermore, the patient can recognize which side of the OTF should be placed on the mucosa and whether the correct side has been applied by the different roughness of the layers (the polyox-containing backing layer is very smooth or film-like and the active ingredient-containing matrix layer in the form of a foam is very rough) (different mouth sensation depending on which layer is on top or bottom). Properties Decay time:

[0108] The disintegration time of a multilayer oral thin film (with backing layer) with a composition according to Table 2 was compared with the disintegration time of a single-layer oral thin film with a composition according to Table 3 (without backing layer). The preparation was carried out analogously to the procedure described above for the oral thin film (with backing layer) with a composition according to Table 2. Table 3: Drug-containing matrix layer Quantity [wt.%] (S)-Ketamine HCl 50,00 % PVA 4-88 41,70 % Saccharin Na 1,00 % Sucralose 2,00 % Glycerol 2,30 % Flavoring 1 1,00 % Flavoring 2 2,00 % Process solvents Purified water Basis weight (dry) 117.3 g / m² Basis weight (incl. residual solvent) 121.9 g / m²

[0109] The disintegration times of the prepared oral thin films were measured according to USP 701 using a tablet disintegration tester (Pharma-Test DIST-3 Triple Basket Tablet Disintegration Tester, 30 strokes per minute over a distance of 55 mm, in 1 L pH 6.8 phosphate buffer). Oral thin films with a surface area of ​​2.72 cm² were placed in a basket ("sinker") and positioned in a glass tube attached to the instrument. Finally, the time until only remnants of the oral thin films remained in the basket was determined. Table 4: Oral thin film Decay time only active ingredient-containing matrix layer (Table 3) 3 s active ingredient-containing matrix layer with backing layer (Table 2) 44 s Drug release:

[0110] Furthermore, the in vitro release of the active ingredient from the oral thin films with the compositions according to Tables 2 and 3 was determined as follows: Release method:

[0111] In the in vitro release assay, S-ketamine is released from S-ketamine HCl oral thin films (OTF) and quantified. The drug is released into phosphate buffer pH 6.8 USP and then determined by gradient reversed-phase HPLC. Quantification was performed against an external standard.

[0112] The release is carried out using Dissolution Apparatus 2 - (Paddle over sinker) according to USP <711> carried out. Sinker: Stainless Steel Capsule Sinker with 10 Spirals, 31.0 x 11.0 mm Capacity (Sotax Style) Stirring speed: 50 rpm Distance between the vessel floor and the bottom edge of the paddle: 25 mm ± 2 mm Temperature: 37°C ± 0.5°C Release medium: Phosphate buffer pH 6.8 USP Volume of release medium: 900 mL Sampling times: 1, 3.5, 10 and 15 min Sample volume: 5.0 mL Table 5: In vitro release [% of LC*] only active ingredient-containing matrix layer (Table 3) active ingredient-containing matrix layer with backing layer (Table 2) after 1 minute Mean 101 60 Min 96 47 Max 106 75 RSD [%] 4,2 19,9 after 3 minutes Mean 103 102 Min 100 97 Max 108 111 RSD [%] 3,6 4,7 after 5 minutes Mean 104 104 Min 100 100 Max 109 105 RSD [%] 4,0 1,9 after 10 minutes Mean 104 103 Min 100 101 Max 109 105 RSD [%] 3,9 1,4 after 15 minutes Mean 103 104 Min 100 101 Max 108 106 RSD [%] 3,9 1,9 *Label Claim = Target Salary Example 3:

[0113] A multilayer oral thin film with a composition according to Table 6, wherein an active ingredient-containing matrix layer is covered on both sides with a backing layer, was produced. Table 6: material Quantity [wt.%] Drug-containing matrix layer S-Ketamine HCl 50,00 PVA 4-88 41,70 Saccharin Na 1,00 Sucralose 2,00 Glycerol 2,30 Flavoring 1 1,00 Flavoring 2 2,00 Process solvents Water 2 x back layer (each) Polyox WSR N10 97,50 Glycerol 2,30 dye 0,20 Process solvents Water Basis weight (dry) Drug-containing matrix layer: 118.7 g / m² Back layer: 100 g / m²< Coating weight (including residual water) Drug-containing matrix layer: 121.9 g / m² Back layer: 101.5 g / m²< S-ketamine base in mg / oral thin film 14 mg / 2.72 cm² Equivalent to 16.1 mg S-ketamine HCl

[0114] The raw materials for the two backing layers are processed into a homogeneous mass using established weighing and stirring techniques, as well as suitable mixing tools and motors. This mass is then applied to a web-shaped substrate (with a specific basis weight) using coating tools (e.g., film drawing machines). The wet film is then dried in a drying oven at 70°C for 15 minutes.

[0115] The raw materials for the active ingredient-containing matrix layer are processed into a homogeneous mass using established weighing and stirring techniques, as well as suitable stirring tools and motors. This mass is then foamed using stirring techniques, and the resulting foam is coated onto a web-shaped substrate. This is again done using coating tools (e.g., film forming machines). The moist film is then dried in a drying oven at 70°C for 15 minutes.

[0116] The two backing layers and the intervening active ingredient layer were joined by lamination. For this purpose, one backing layer was briefly heated to 70 °C and then bonded to the active ingredient-containing matrix layer by lamination. A second backing layer was then briefly heated to 70 °C and subsequently laminated to the exposed side of the active ingredient-containing matrix layer of the previous laminate. This resulted in a laminate with the composition backing layer - active ingredient-containing matrix layer - backing layer.

[0117] The resulting laminate can be prepared into smaller oral thin films. Example 4

[0118] A multilayered oral thin film with a composition according to Table 7 was prepared analogously to Example 2. The drug-containing matrix layer was not foamed. Table 7: Back shift Quantity [wt.%] Polyox WSR N10 97,50 % Glycerol 2,3 % dye 0,20 % Process solvents Purified water Basis weight (dry) 98.2 g / m² basis weight (incl. residual process solvents) 101.5 g / m²< Drug-containing matrix layer Quantity [wt.%] HPMC 2910 (603) 39,5 HPMC 2910 (60SH50) 10,0 S-Ketamine 41,0 Saccharin Na 2,0 Sucralose 1,0 Glycerol 3,5 Flavoring 3,0 Process solvents Purified water Basis weight (dry) 175 g / m² basis weight (incl. residual process solvents) 184.5 g / m² remark Not foamed HPMC 2910 (603): Hydroxypropylmethylcellulose 2910 (603) HPMC 2910 (60SH50): Hydroxypropylmethylcellulose 2910 (60SH50) The HPMCs used differ in the viscosity of a 2% aqueous solution: 603: 3 mPaS vs. 60SH50: 50 mPaS

[0119] The two layers were produced separately and bonded together by lamination after heating to 70 °C. After cooling, the two layers were firmly bonded. Example 5

[0120] A morphological surface analysis was performed on a KLA Tencor P15 profilometer with a 2 µm radius probe tip. A surface scan was performed on both sides of an OTF (Optical Surface Terrain) from Example 1, covering an area of ​​2 mm x 2 mm. Three line scans were randomly selected within this 2 mm x 2 mm scan area, and the roughness parameters Ra, Rq, Rp, and Rv were determined.

[0121] The following roughness parameters were determined to evaluate the sample: Ra: Mean roughness, indicates the average distance of a measurement point from the center line. Rq: Quadratic roughness (also RMS roughness), is calculated from the mean of the squared deviations and corresponds to the root mean square. Rp: Peak height, distance between the center line and the highest measurement. Rv: Valley depth, distance between the center line and the lowest measurement.

[0122] The roughness parameters show that the OTF has two differently rough sides. The backing layer is very smooth, comparable to smooth materials like polished steel. The side containing the drug matrix, on the other hand, is significantly rougher. Due to the different roughness of the two OTF sides, a patient can distinguish by touch which side is the backing layer and which is the drug-containing side. This allows, for example, the patient to determine the correct orientation of the OTF in the mouth (e.g., rough side facing down towards the oral mucosa, smooth backing layer facing up). OTF on the back-shift side:

[0123] measurement Ra / µm Rq / µm Rp / µm Rv / µm 1 0,76 1,06 4,85 1,40 2 0,55 0,86 5,54 0,87 3 0,74 1,15 6,64 2,09 mean 0,68 1,02 5,68 1,45 OTF on the side of the drug-containing matrix layer:

[0124] measurement Ra / µm Rq / µm Rp / µm Rv / µm 1 3,17 3,89 11,64 11,15 2 2,73 3,84 11,59 19,96 3 3,84 4,74 10,61 12,07 mean 3,24 4,16 11,28 14,39 Example 6:

[0125] Further release measurements were carried out with profifil dissolution and a higher temporal resolution than shown in Table 5.

[0126] The following were compared: active ingredient matrix layer (Table 3) active ingredient matrix layer with backing layer on one side (Table 2) active ingredient matrix layer with backing layer on both sides (Table 7)

[0127] S-ketamine was released from S-ketamine HCl oral thin films (OTF) and quantified. The drug was released into phosphate buffer pH 6.8 USP and then determined by gradient reversed-phase HPLC. Quantification was performed against an external standard.

[0128] The release is carried out using Dissolution Apparatus 2 - (Paddle over sinker) according to USP <711> carried out. Sinker: Stainless Steel Capsule Sinker with 10 Spirals, 31.0 x 11.0 mm Capacity (Sotax Style) Stirring speed: 50 rpm Distance between the vessel floor and the bottom edge of the paddle: 25 mm ± 2 mm Temperature: 37°C ± 0.5°C Release medium: Phosphate buffer pH 6.8 USP Volume of release medium: 900 mL Sampling times: 1, 3.5, 10 and 15 min Sample volume: 5.0 mL

[0129] The results are in Figure 1 As illustrated. A person skilled in the art can see that the release profile of the matrix layer can be varied by the backing layer.

Claims

1. A multi-layer oral thin film comprising a matrix layer, which contains at least one polymer and at least one pharmaceutically active agent, and at least one backing layer, wherein the at least one backing layer comprises at least one polyethylene glycol in an amount of from 60 to 100 wt.%, in relation to the total weight of the at least one backing layer.

2. The multi-layer oral thin film according to claim 1, wherein the matrix layer comprises at least one water-soluble polymer.

3. The multi-layer oral thin film according to claim 2, wherein the at least one water-soluble polymer is selected from the group comprising starch and starch derivatives, dextrans, cellulose derivatives, such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinyl pyrrolidone / vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatines, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural gums.

4. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one pharmaceutically active agent is selected from the group comprising the active agent classes of analgesics, hormones, hypnotics, sedatives, antiepiletics, analeptics, psychoneurotropic drugs, neuro-muscle blockers, antspasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumour active agents, antibiotics, chemotherapeutics and narcotics, wherein the at least one pharmaceutically active agent preferably comprises ketamine, especially preferably (S)-ketamine.

5. The multi-layer oral thin film according to any one of the preceding claims, wherein the matrix layer further comprises at least one auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, plasticisers, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

6. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polyethylene glycol has a mean molecular weight of from 20,000 g / mol to 7,000,000 g / mol, preferably from 40,000 g / mol to 500,000 g / mol, especially preferably from 95,000 g / mol to 105,000 g / mol, especially of about 100,000 g / mol.

7. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polyethylene glycol has a viscosity of from 30 mPa s to 50 mPa s, measured in 5 wt.% aqueous solution at 25°C.

8. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polyethylene glycol is contained in the at least one backing layer in an amount of from 80 to 100 wt.%, in relation to the total weight of the at least one backing layer.

9. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one backing layer contains at least one plasticiser, preferably glycerol, preferably in an amount of from 0.5 to 5 wt.% in relation to the total weight of the at least one backing layer.

10. The multi-layer oral thin film according to any one of the preceding claims, wherein the multi-layer oral thin film consists of exactly two layers, specifically the matrix layer containing at least one polymer and at least one pharmaceutically active agent and the backing layer containing at least one polyethylene glycol.

11. The multi-layer oral thin film according to any one of the preceding claims, wherein the matrix layer is present in the form of a solidified foam that has voids.

12. The multi-layer oral thin film according to claim 11, wherein the voids are isolated from one another and are preferably present in the form of bubbles, wherein the voids are filled with air or a gas, preferably with an inert gas, especially preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

13. The multi-layer oral thin film according to any one of claims 11 or 12, wherein the voids are connected to one another and preferably form a channel system penetrating the matrix layer.

14. The multi-layer oral thin film according to any one of claims 11 to 13, wherein the voids in the matrix layer account for a volume fraction of from 5 to 98%, preferably from 50 to 80%, in relation to the total volume of the layer in question.

15. The multi-layer oral thin film according to any one of the preceding claims, wherein the oral thin film has a rough side with an average roughness Ra greater than 2.0 µm and a smooth side with an average roughness Ra less than 1.0 µm.

16. The multi-layer oral thin film according to any one of the preceding claims, wherein the oral thin film has a rough side and a smooth side, wherein the rough side has an average roughness Ra of 1.0 µm more than the smooth side.

17. The multi-layer oral thin film according to any one of the preceding claims, wherein the multi-layer oral thin film has an at least 30% slower release of the at least one pharmaceutically active agent than the matrix layer alone without backing layer.

18. A method for producing a multi-layer oral thin film according to any one of claims 1 to 17, comprising the steps of: a) producing and spreading a solution or suspension comprising the at least one polyethylene glycol, and then drying the spread solution or suspension in order to obtain a film comprising the at least one polyethylene glycol, b) producing a solution, dispersion or melt which at least comprises the at least one polymer and the at least one pharmaceutical active agent, b1) optionally foaming the solution, dispersion or melt from step b) by introducing a gas or gas mixture by chemical gas generation or by expansion of a dissolved gas, c) spreading the solution, dispersion or melt from step b) or the optionally foamed solution, dispersion or melt from step b1) onto the film obtained in step a) comprising the at least one polyethylene glycol in order to obtain a composite, d) drying the composite obtained in step c) in order to obtain a multi-layer oral thin film.

19. The method according to claim 18, characterised in that steps c) and d) are replaced by the following steps: c2) spreading the solution, dispersion or melt from step b) or the optionally foamed solution, dispersion or melt from step b1) in order to obtain a film comprising the at least one polymer and the at least one pharmaceutical active agent, d2) connecting the films obtained in step a) and c2), preferably by lamination by exposure to heat above the melting point of one of the polymers contained in the films in order to obtain a multi-layer oral thin film.

20. Multi-layer oral thin film according to any one of claims 1 to 17 or of a multi-layer oral thin film obtained by the method according to claim 18 or 19 for the use as a medicament.