MULTI-LAYER ORAL THIN FILM

Description

[0001] The present invention relates to a multilayer oral thin film, a method for producing the same, and the multilayer oral thin film for use as a medicament.

[0002] Oral thin films are thin films containing at least one pharmaceutically active ingredient. They are placed directly into the oral cavity or applied to the oral mucosa, where they dissolve or swell, releasing the active ingredient. These are, in particular, thin, single- or multi-layer, polymer-based, active-ingredient films that, when applied to the mucosa, especially the oral mucosa, can release the active ingredient directly into it. The excellent blood flow of the oral mucosa ensures rapid transfer 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 delivery. The active ingredient can be dissolved, emulsified, or dispersed in the film.

[0003] Multilayer oral thin films can offer several advantages over "conventional" single-layer oral thin films. For example, combining multiple layers allows for a high basis weight, and different layers can be combined, such as a drug layer with a pH-regulating layer, or a drug layer with a protective backing layer.

[0004] 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.

[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 recent developments in the field of oral thin films as a new delivery system for oral drug administration.

[0006] WO 2009 / 124096 A1 discloses a patch, a system and a method for administering a permeant composition into a subject via at least one formed pathway through a biological membrane of the subject.

[0007] Multilayered oral thin films can in principle be produced in various ways, such as by multiple coating or by gluing or laminating prefabricated layers together.

[0008] Multiple coatings have several disadvantages. For example, multiple coating coats subject the active ingredient to greater thermal stress. Furthermore, the bond between the layers is often weak and can delaminate. Furthermore, defects in the coating (basis weight) propagate into the subsequent layers.

[0009] Joining multiple layers together by gluing also has disadvantages. Conventional adhesive layers often have a high density of functional groups, such as -OH groups, which promote the migration of active ingredients or excipients such as buffer salts through the adhesive layer. Furthermore, conventional adhesive layers are often poorly soluble in water and thus exhibit poor dissolution behavior in the patient's mouth (poor mouthfeel). Furthermore, conventional adhesive layers often require the use of large amounts of plasticizers (e.g., 20% glycerin), which can migrate into the other layers of the oral thin film and alter its physical properties (e.g., lowering the glass transition temperature).

[0010] The object of the present invention was to overcome the disadvantages known from the prior art. In particular, a multilayer oral thin film is to be provided in which the individual layers are firmly bonded together, eliminating the need for the known adhesive layers and / or the need for superimposing layers. Furthermore, migration of substances between the individual layers is to be largely prevented. Furthermore, the multilayer oral thin film is to be manufactured as easily and cost-effectively as possible.

[0011] These objects have now been achieved by an oral thin film according to claim 1, ie by a multilayer oral thin film comprising a first and a second matrix layer, each containing at least one polymer, and a separating layer located between the first and the second matrix layer, wherein the separating layer comprises at least one polyethylene glycol having a molecular weight of 8000 g / mol to 7,000,000 g / mol in an amount of 60 to 100 wt.%.

[0012] Such a multilayer oral thin film has the advantage, among other things, that polyethylene glycol films, due to their smooth surface, low melting or glass transition temperature, non-toxicity, and water solubility, are well suited as separating / bonding layers / adhesive layers in multilayer oral thin films. By heating and / or applying high pressure, polyethylene glycol adhesive layers are particularly suitable for bonding two additional layers together. For example, a drug-containing layer and a pH-regulating buffer layer can be bonded together.

[0013] In principle, several laminates, even with different active ingredients / excipients, can be combined to form a "sandwich OTF".

[0014] Furthermore, the polyethylene glycol layer is suitable as a barrier layer, which prevents or minimizes the migration of active ingredients or excipients (e.g. buffer salts) between the individual layers.

[0015] The polyethylene glycol adhesive layer also requires no or only small amounts of excipients such as plasticizers (e.g. 2-3% glycerol) and thus reduces the risk of migration of the adhesive layer components into the other layers of the oral thin film.

[0016] In this document, "comprehensive" may also mean "consisting of".

[0017] In the following, the terms "separation layer", "bonding layer" and "adhesive layer" are to be understood as equivalent.

[0018] Polyethylene glycols (PEG) are compounds of the general formula:

[0019] Higher molecular weight solid polyethylene glycols (melting point approximately 65 °C) are often referred to as polyethylene oxides or polyoxyethylenes (abbreviated PEO or, less frequently, PEOX) or polywaxes. In this document, the terms "polyethylene glycol," "polyethylene oxide," and "polyOx" are used interchangeably.

[0020] The following definitions regarding the first and second matrix layers always apply analogously to both the first and second matrix layers.

[0021] In principle, the first and second matrix layers can have the same composition or a different composition.

[0022] The multilayer oral thin film according to the invention is preferably characterized in that the first and / or the second matrix layer comprises at least one water-soluble polymer.

[0023] Water-soluble polymers include chemically very diverse natural or synthetic polymers whose common characteristic is their solubility in water or aqueous media. These polymers must possess a sufficient number of hydrophilic groups for water solubility and be non-crosslinked. The hydrophilic groups can be non-ionic, anionic, cationic, and / or zwitterionic.

[0024] Water-soluble is preferably understood to mean a solubility of greater than 100 g / L in water at 25°C.

[0025] 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.

[0026] 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 respective matrix layer 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 first and / or the second matrix layer.

[0027] The first and / or second matrix layer preferably contains at least one pharmaceutically active ingredient.

[0028] The first and second matrix layers may contain the same or different pharmaceutically active ingredients.

[0029] The at least one pharmaceutically active ingredient is in principle not subject to any restriction, but is preferably selected from all pharmaceutically active ingredients that are suitable for oral and / or transmucosal administration.

[0030] According to the present invention, the pharmaceutically active ingredient also includes all pharmaceutically acceptable salts and solvates of the respective pharmaceutically active ingredient.

[0031] Preferably, active ingredients are selected from the group comprising the active ingredient classes of analgesics, hormones, hypnotics, sedatives, antiepileptics, stimulants, psychoneurotropic agents, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutics and narcotics, whereby this group is not exhaustive.

[0032] Particularly preferably, the at least one pharmaceutically active ingredient is ketamine and / or a pharmaceutically acceptable salt or solvate thereof, preferably ketamine HCl.

[0033] Ketamine is understood to mean (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, (R)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, and the racemate (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

[0034] Particularly preferably, (S)-ketamine or a pharmaceutically acceptable salt thereof, in particular (S)-ketamine HCl, is present as the only stereoisomer of ketamine, since the analgesic and anesthetic potency of (S)-ketamine is about three-fold higher than that of the (R) form.

[0035] The active ingredient content in the first and / or second matrix layer can vary within relatively wide limits. A range of 10 to 60 wt.%, based on the dry weight of the respective matrix layer, can be specified as suitable. In one embodiment, the proportion of active ingredient in the respective matrix layer is towards the lower range, e.g. if the active ingredient has a strongly unpleasant taste that must be compensated for with a larger amount of taste-masking agents. In this case, a range of 10 to 40 wt.% can be specified as a suitable active ingredient proportion. In another embodiment, the proportion of active ingredient in the dosage form according to the invention is towards the upper range, with a content of 40 to 60 wt.% and in particular a content of 45 to 55 wt.% being specified as particularly preferred.

[0036] Particularly preferably, (S)-ketamine or a pharmaceutically acceptable salt thereof is present in the respective matrix layer in an amount of 45 to 55 wt.%, based on the dry weight of the first and / or second matrix layer.

[0037] The multilayer oral thin film according to the invention is further preferably characterized in that the first and / or the second matrix layer comprises at least one excipient selected from the group comprising dyes, flavorings, sweeteners, plasticizers, taste masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0038] Each of these excipients is preferably contained in the respective matrix layer in an amount of 0.1 to 40 wt.%, preferably 0.1 to 30 wt.%, particularly preferably 0.1 to 15 wt.%, very particularly preferably 0.1 to 10 wt.% or 0.1 to 5 wt.%, based on the total weight of the first and / or second matrix layer.

[0039] The at least one polyethylene glycol preferably has an average molecular weight of at least 8,000 to 7,000,000 g / mol, from 8,000 g / mol to 300,000 g / mol, preferably from 95,000 g / mol to 105,000 g / mol, in particular from about 100,000 g / mol, or particularly preferably from 195,000 g / mol to 205,000 g / mol, in particular from about 200,000 g / mol.

[0040] The molecular weight is derived from the rheology measurements described below.

[0041] 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 or of 65 mPa s to 115 mPa s, measured at 25°C.

[0042] 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.

[0043] Particularly preferred are polyethylene glycols, which are known, for example, under the trade names POLYOX WSR N-10 or POLYOX WSR N-80 (Dow Chemical).

[0044] Furthermore, the polyethylene glycols PEG 2000, PEG 4000, PEG 6000, PEG 8000, PEG 10000 or PEG 20000 can be used.

[0045] 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 separating layer in an amount of 80 to 100 wt.%, based on the total weight of the at least one separating layer.

[0046] 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 separating layer 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 separating layer.

[0047] 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 separating layer 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 separating layer.

[0048] 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 separating layer 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 separating layer.

[0049] The multilayer oral thin film according to the invention is preferably characterized in that the at least one separating layer comprises at least one excipient selected from the group comprising dyes, flavorings, sweeteners, taste masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0050] Each of these auxiliaries 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 separating layer.

[0051] The multilayer oral thin film according to the invention is preferably characterized in that the at least one separating 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 separating layer.

[0052] The multilayer oral thin film according to the invention is further preferably characterized in that the first and / or the second matrix layer contains at least one water-soluble polymer, preferably a polyvinyl alcohol, and tris(hydroxymethyl)aminomethane (TRIS).

[0053] TRIS is an abbreviation for tris(hydroxymethyl)aminomethane (THAM), also known as tromethamine, trometamol (INN), and TRIS buffer. Chemically, it is a primary amine with three alcoholic hydroxy groups.

[0054] TRIS is used as a buffer substance for biochemical, molecular biological, microbiological, and pharmaceutical purposes. With a pKa of 8.2 (at 20 °C), TRIS has a good buffering capacity between pH 7.2 and 9.0.

[0055] A matrix layer containing at least one water-soluble polymer, preferably a polyvinyl alcohol, and tris(hydroxymethyl)aminomethane (TRIS) is hereinafter also referred to as a TRIS buffer layer or, if polyvinyl alcohol is used, as a TRIS-PVA layer.

[0056] In particular, the water-soluble polymer in such a TRIS buffer layer comprises polyvinyl alcohol.

[0057] Such a layer has the advantage that TRIS can be incorporated with the highest percentage and molar ratio of buffer / PVA. However, with other salts / buffers (phosphates, carbonates, citric acid, etc.), clumping or precipitation of PVA occurs.

[0058] The TRIS-PVA compositions can be easily foamed and form a film of high optical homogeneity.

[0059] Polyvinyl alcohols (abbreviated PVA or PVAL, occasionally PVOH) are polymers with the general structure which in small proportions (about 2 %) also contain structural units of the type They belong to the group of vinyl polymers.

[0060] Commercially available polyvinyl alcohols, which are offered as white-yellowish powders or granules with degrees of polymerization ranging from approximately 500 to 2500 (molar masses of approximately 20,000 to 100,000 g / mol), generally have degrees of hydrolysis of 98 to 99 or 87 to 89 mol%, respectively, thus still containing a residual amount of acetyl groups. Manufacturers characterize polyvinyl alcohols by specifying the degree of polymerization of the starting polymer, the degree of hydrolysis, the saponification number, or the solution viscosity.

[0061] According to the present invention, polyvinyl alcohols having an average molecular weight of about 31,000 (PVA 4-88) to about 205,000 (PVA 40-88) g / mol are particularly suitable in the TRIS buffer layer.

[0062] Furthermore, according to the present invention, polyvinyl alcohols with a viscosity of 3.4-4.6 mPa s (PVA 4-88) to 34-46 mPa s (PVA 40-88) in a 40 g / l aqueous solution, determined by the "falling ball method" (Ph. Eur. 2.2.49), are particularly suitable in the TRIS buffer layer, or mixtures of two or more different PVA types

[0063] The oral thin film according to the invention is preferably characterized in that polyvinyl alcohol is contained in the TRIS buffer layer in an amount of 20 to 90 wt.%, preferably 40 to 80 wt.% and very particularly preferably 50 to 75 wt.%, based on the total weight of the TRIS buffer layer.

[0064] The oral thin film according to the invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in the TRIS buffer layer in an amount of 3 to 70 wt.%, preferably 10 to 55 wt.% and most preferably 15 to 50 wt.%, based on the total weight of the TRIS buffer layer.

[0065] Preferably, the multilayer oral thin film according to the invention, in particular in the TRIS buffer layer, contains no buffer substances other than TRIS, in particular no phosphates, carbonates and / or citric acid.

[0066] The TRIS buffer layer preferably does not contain any polymers other than PVA.

[0067] Preferably, the multilayer oral thin film according to the invention is characterized in that the first and / or the second matrix layer is in the form of a solidified foam having cavities.

[0068] The cavities and the associated larger surface area of ​​the films facilitate the access of water, saliva or other body fluids into the interior of the dosage form, thus accelerating the dissolution of the dosage form and the release of the active ingredient.

[0069] In the case of a rapidly absorbing active ingredient, transmucosal absorption can also be improved by the rapid dissolution of the matrix layer.

[0070] On the other hand, the wall thickness of the said cavities is preferably small, since these represent, for example, solidified bubbles, so that a rapid dissolution or destruction of these cavities takes place.

[0071] A further advantage of this embodiment is that, despite the comparatively high basis weight, the foam formulation allows for faster drying than with a comparable non-foamed composition.

[0072] Preferably, the multilayer oral thin film according to the invention is characterized in that the cavities are isolated from one another and are preferably in 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.

[0073] According to another embodiment, it is provided that the cavities are connected to one another, preferably by forming a coherent channel system penetrating the matrix.

[0074] Preferably, said cavities have a volume fraction of 5 to 98%, preferably 50 to 80%, based on the total volume of the matrix layer. This favorably influences the beneficial effect of accelerating the dissolution of the matrix layer.

[0075] Furthermore, surface-active substances or surfactants can be added to the matrix polymer or 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.

[0076] Another parameter that influences the properties of the dosage form according to the invention is the diameter of the cavities or bubbles.

[0077] The bubbles or cavities are preferably created using a foaming machine, which allows the bubble diameter to be adjusted almost arbitrarily within a wide range. Thus, the diameter of the bubbles or cavities can be in the range of 0.01 to 350 µm. Particularly preferred is a diameter in the range of 10 to 200 µm.

[0078] The multilayer oral thin film according to the invention is in principle not limited in the number of layers it contains.

[0079] Thus, embodiments are conceivable in which the multilayer oral thin film comprises additional matrix layers in addition to the first and second matrix layers. The above definitions apply analogously to the additional matrix layers. These additional matrix layers are connected to one another analogously to the first and second matrix layers by an intermediate separating layer, as defined above.

[0080] In one embodiment, the multilayer oral thin film comprises a first matrix layer containing ketamine, preferably (S)-ketamine, as pharmaceutically active ingredient, and a TRIS buffer layer as second matrix layer, which are connected to a separating layer, wherein the first and second matrix layers and separating layer are to be understood as defined above.

[0081] In one embodiment, the multilayer oral thin film consists of a first matrix layer containing ketamine, preferably (S)-ketamine, as pharmaceutically active ingredient, and a TRIS buffer layer as second matrix layer, which are connected to a separating layer, wherein the first and second matrix layers and separating layer are to be understood as defined above.

[0082] The oral thin film according to the invention preferably has an area of ​​0.5 cm 2< to 10 cm 2< , particularly preferably 2 cm 2< to 8 cm 2< .

[0083] 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 / m 2< , preferably 70 to 400 g / m 2< .

[0084] The basis weight of the first matrix layer, the second matrix layer or any TRIS buffer layer that may be present and any further layer that may be present is each preferably at least 10 g / m 2< , more preferably at least 20 g / m 2< or at least 30 g / m 2< or most preferably at least 50 g / m 2< or less than or equal to 400 g / m 2< , more preferably less than or equal to 350 g / m 2< or less than or equal to 300 g / m 2< or most preferably less than 250 g / m 2< . Preferably, the basis weight is 10 to 400 g / m 2< , more preferably 20 to 350 g / m 2< or 30 to 300 g / m 2< and most preferably 50 to 250 g / m 2< .

[0085] Preferably, each of the layers present has a layer thickness of preferably 10 µm to 500 µm, particularly preferably 20 µm to 300 µm.

[0086] If the respective layers are in the form of a solidified foam, it is preferred that each of the layers present as a foam has a layer thickness of preferably 10 µm to 3000 µm, particularly preferably 90 µm to 2000 µm.

[0087] The oral thin film according to the invention can be prepared according to methods known to those skilled in the art.

[0088] However, the oral thin film according to the invention is preferably produced by a process comprising the following steps: a) preparing and spreading a solution or suspension comprising the at least one polyethylene glycol, and then drying the spread solution or suspension to obtain a film comprising the at least one polyethylene glycol, b) providing a first and a second matrix layer, each comprising at least one polymer, c) positioning the film obtained in step a) on the first matrix layer and positioning the second matrix layer on the film obtained in step a) such that the film obtained in step a) lies between the first and the second matrix layer to form a loose composite and d) forming a solid composite by heating and / or applying pressure to the loose composite from step c).

[0089] In step d) the temperature is preferably from 30 to 200, preferably from 50 to 90.

[0090] In step d), the pressure applied is preferably from 0.001 bar to 20 bar, preferably from 0.01 bar to 8 bar.

[0091] The first and / or second matrix layer is preferably provided by a method comprising the following steps: a1) preparing a solution, dispersion or melt comprising at least one polymer, aa1) optionally foaming the solution, dispersion or melt from step a1) by introducing a gas or gas mixture, by chemical gas generation or by decompressing a dissolved gas, b) spreading the solution, dispersion or melt from step a) or the optionally foamed solution, dispersion or melt from step aa1) to obtain a first and / or second matrix layer.

[0092] It is clear to the person skilled in the art that step aa1) is only necessary if the first and / or the second matrix layer is to be in the form of a solidified foam having cavities.

[0093] The present invention further relates to a multilayer oral thin film obtainable by the method described above.

[0094] Furthermore, the present invention relates to a multilayer oral thin film as described above or obtainable by the method described above as a medicament.

[0095] 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, or a pharmaceutically acceptable salt thereof, is used as pharmaceutically active ingredient in the first and / or the second matrix layer, 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 inducing and conducting general anesthesia or as a supplement to regional anesthesia and / or as an analgesic.

[0096] 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 medicament.

[0097] The invention is explained in more detail below using non-limiting examples. Examples: Example 1:

[0098] Production of a first matrix layer with PolyOx cover layer:

[0099] Example formulation of a PolyOx layer (non-foamed) and a first matrix layer containing S-ketamine (in the form of a foam) by multiple coating: Table 1: material 1 [wt.%] (S)-Ketamine HCl 50.00 % PVA 4-88 41.70 % PVA 40-88 -- Saccharin Na 1.00 % Sucralose 2.00 % Glycerol 2.30 % Flavoring 1 1.00 % Flavoring 2 2.00 % Polyox WSR N10 97.50 % Glycerol 2.3 % FD&C Red 40 (dye) 0.20 % solvent Purified water Basis weight (dry) 1. Matrix layer: 118.7 g / cm 2 Separating layer: 100 g / cm 2 Coating weight (incl. residual water) 1. Matrix layer: 121.9 g / cm 2 Separating layer 101.5 g / cm 2 Production:

[0100] Formulation 1 is a two-layer formulation, with a first Polyox layer forming a drug-free release layer, which is prepared first. This layer is then coated with a drug-containing matrix layer containing 50% (S)-ketamine HCl in a polyvinyl alcohol (PVA) 4-88 foam matrix. The dry basis weight for the Polyox release layer is defined as 100.0 g / m², resulting in a coating weight of 101.5 g / m² including 1.5% residual water. The dry basis weight for the drug-containing matrix layer is defined as 118.7 g / m², resulting in a coating weight of 123.6 g / m² including 4% residual water (expected value). Example 2:

[0101] Example formulation of a PolyOx release layer (non-foamed) and a S-ketamine-containing first matrix layer (foamed) and a TRIS buffer layer as a second matrix layer, bonded by lamination: Table 2: S-ketamine-containing 1st matrix layer 2 [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 % solvent Purified water Basis weight (dry) 117.3 g / m" PolyOx separating layer 3 [wt.%] Polyox WSR N10 97,50 % Glycerol 2,3 % FD&C Red 40 (dye) 0,20 % solvent Purified water Basis weight (dry) 98.2 g / m" 2. Matrix layer (TRIS buffer layer) 4 [wt.%] PVA 4-88 36,15 PVA 40-88 36,15 TRIS 20,00 Saccharin Na 1,00 Sucralose 2,00 Glycerol 4,50 FD&C Red No. 40 (dye) 0,20 solvent Purified water Area weight (dry) 192.8 g / m 2 Coating weight (incl. residual water) 200.6 g / m 2

[0102] The three layers were produced separately, and the resulting laminates were heated to 70 °C and bonded together by lamination. After cooling, the laminates were firmly bonded. pH measurement

[0103] The pH value of the individual layers from Table 2 as well as of the composites of these layers was measured. Table 3: sample Temperature medium pH TRIS layer 4 33.3°C 2 mL water 8,54 Kea layer 2 33.4°C 2 mL water 5,71 PolyOx layer 3 33.3 °C 2 mL water 7,58 TRIS / Polyox / Kea (3-layer OTF) 33.6°C 2 mL water 7,24 TRIS layer 4 30.3°C 2 mL Glandosane 1< 8,48 Kea layer 2 33.7°C 2 mL Glandosane 1< 5,46 PolyOx layer 3 32.6 2 mL Glandosane 1< 6,02 TRIS / Polyox / Kea (3-layer OTF) 31.8°C 2 mL Glandosane 1< 7,06 1< :Glandosane = artificial saliva Example 3:

[0104] The migration of substances between individual layers of a multilayer oral thin film was investigated, with the individual layers being bonded together using various methods. 1. Bilayer oral thin film (OTF1) - connection of the layers by a suture.

[0105] The two layers of the OTF1 have a composition according to the following Tables 4 and 5 respectively. Table 4: material [Wt.%] PVA 4-88 39,50 Saccharin Na 1,0 Sucralose 2,0 Raspberry flavor 2,0 Masking flavor 1,0 Glycerol 4,5 S-Ketamine HCl 50,0 Basis weight 121.9 g / m 2 Table 5: material [Wt.%] PVA 4-88 36,15 PVA 40-88 36,15 TRIS 20,00 Saccharin Na 1,00 Sucralose 2,00 Glycerol 4,50 FD&C Red No. 40 0,20 Basis weight 200.6 g / m 2

[0106] Two single layers with a composition according to Tables 4 and 5, respectively, and an area of ​​2.72 cm2 were prepared and sewn by hand using a 0.2 mm thick PVA thread (Vis Extrusion GmbH, Hohberg, Germany).

[0107] 2. Two-layer oral thin film (OTF2) - connection of the layers by a seal.

[0108] The two layers of the OTF2 have a composition according to Tables 4 and 5 above.

[0109] Two individual layers with a composition according to Tables 4 and 5, respectively, and an area of ​​2.72 cm² were produced and sealed together. A hand-held sealer (Polystar 100 GEW at Level 9 and with a feeler gauge pitch of 850 µm) was used for this purpose.

[0110] 3. Three-layer oral thin film (OTF3) - Connection of the layers by a PolyOx interlayer.

[0111] The three layers of the OTF3 have a composition according to Table 5 above and Tables 6 and 7 below. Table 6: material Foam formulation [wt%] PVA 4-88 41,70 Saccharin Na 1,00 Sucralose 2,00 Glycerol 2,30 Masking Flavor PHL-131985 1,00 Raspberry Flavor PHL-097336 2,00 S-Ketamine HCl 50,00 Basis weight 121.9 g / m 2 Table 7: material [Wt.%] Polyethylene oxide MW 100,000 97,50 Glycerol 2,30 FD&C Red No. 40 0,20 Basis weight 101.5 g / m 2

[0112] A three-layer oral thin film was prepared, the three layers having a composition according to Table 5 above and Tables 6 and 7.

[0113] For this purpose, the individual layers were arranged into a loose composite with the PolyOx layer (Table 7) in the center. Heating the loose composite to approximately 70°C melts the PolyOx, and the layers of the loose composite bond together.

[0114] The OTFs of all three formulations were sealed in 60x60 mm COC bags and stored in a 40°C laboratory cabinet. Migration tests were scheduled after 3 and 6 weeks of storage with n=3. Due to a misunderstanding, all 6 OTFs of the three formulations were removed from storage after 3 weeks, but only 3 OTFs were analyzed. This allowed the remaining 3 OTFs to be reintroduced into the 40°C cabinet after 3 weeks of storage at room temperature. After another 3 weeks at 40°C, the 6-week test point (3 weeks at 40°C + 3 weeks at room temperature + 3 weeks at 40°C) was analyzed.

[0115] The migration of substances between the individual layers was investigated. Table 8: pH values ​​(n=3) in the unstored active ingredient-containing layers Not stored Sample 1 Sample 2 Sample 3 Ø OTF1 sewn 5,75 5,75 5,75 5,75 OTF2 sealed 5,75 5,75 5,75 5,75 OTF3 PolyOx 6,12 6,13 6,14 6,13 Table 9: pH values ​​(n=3) in the active ingredient-containing layers 3 weeks 6 weeks Sample 1 Sample 2 Sample 3 Ø Sample 1 Sample 2 Sample 3 Ø OTF1 sewn 6,47 6,43 6,48 6,46 6,53 6,46 6,45 6,48 OTF2 sealed 6,44 6,54* 6,54* 6,51 6,44* 6,42* 6,45* 6,44 OTF3 PolyOx 6,23 6,19 6,18 6,20 6,32 6,29 6,28 6,30 * Seal seam rejected Table 10: pH differences in the active ingredient-containing layers storage Not stored 3 weeks 6 weeks OTF1 sewn --- +0,71 +0,73 OTF2 sealed --- +0,76* +0,69* OTF3 PolyOx --- +0,07 +0,17 * Seal seam rejected Table 11: Active ingredient content in the buffer-containing layers 3 weeks 6 weeks Content mg % LC % by weight Content mg % LC % by weight OTF1 sewn 1.0 6.2 1.9 1.0 6.1 1.8 OTF2 sealed t 0.9 5.3 2.0 0.4 2.7 1.1 OTF3 PolyOx 0.6 3.8 1.0 0.8 4.8 1.4 LC = lable claim 16.1mg / OTF n=3

[0116] The lowest pH values ​​and drug concentrations were found in the PolyOx formulation. Therefore, the OTF3 formulation appears to be the best way to combine the two layers with lower drug migration.

Claims

1. A multi-layer oral thin film comprising a first and a second matrix layer, which each contain at least one polymer, and a separation layer located between the first and the second matrix layer, wherein the separation layer comprises at least one polyethylene glycol with a molecular weight of from 8,000 g / mol to 7,000,000 g / mol in an amount of from 60 to 100 wt.%.

2. The multi-layer oral thin film according to claim 1, wherein the first and / or the second 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 first and / or the second matrix layer comprise at least one pharmaceutically active agent, wherein the at least one pharmaceutically active agent is preferably 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 first and / or the second 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 8,000 g / mol to 300,000 g / mol, preferably from 95,000 g / mol to 105,000 g / mol, especially of about 100,000 g / mol, or especially preferably from 195,000 g / mol to 205,000 g / mol, especially of 200,000 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 separation layer in an amount of from 80 to 100 wt.%, in relation to the total weight of the separation layer.

9. The multi-layer oral thin film according to any one of the preceding claims, wherein the first and / or the second matrix layer contains at least one water-soluble polymer, preferably a polyvinyl alcohol and tris(hydroxymethyl)aminomethane.

10. The multi-layer oral thin film according to claim 9, wherein the water-soluble polymer, preferably the polyvinyl alcohol, is contained in the first and / or second matrix layer in an amount of from 20 to 90 wt.%, in relation to the total weight of this layer.

11. The multi-layer oral thin film according to claim 9 or claim 10, wherein tris(hydroxymethyl)aminomethane is contained in the first and / or second matrix layer in an amount of from 3 to 70 wt.%, in relation to the total weight of this layer.

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

13. The multi-layer oral thin film according to claim 12, 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.

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

15. The multi-layer oral thin film according to any one of claims 12 to 14, wherein the voids in the particular matrix layer have for a volume fraction of from 5 to 98%, preferably from 50 to 80%, in relation to the total volume of the particular matrix layer.

16. A method for producing a multi-layer oral thin film according to any one of claims 1 to 15, 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) providing a first and a second matrix layer, which each comprise at least one polymer; c) positioning the film obtained in step a) on the first matrix layer and positioning the second matrix layer on the film obtained in step a) so that the film obtained in step a) lies between the first and the second matrix layer in order to form a loose grouping, and d) forming a firm bond by heating and / or by applying pressure to the loose grouping from step c).

17. The method according to claim 16, wherein the first and / or second matrix layer is provided by a method comprising the following steps: a1) producing a solution, dispersion or melt comprising at least one polymer, aa1) optionally foaming the solution, dispersion or melt from step a1) by introducing a gas or gas mixture by chemical gas generation or by expansion of a dissolved gas, b) spreading the solution, dispersion or melt from step a) or the optionally foamed solution, dispersion or melt from step aa1) in order to obtain a first and / or second matrix layer.

18. Multi-layer oral thin film according to any one of claims 1 to 15 or of a multi-layer oral thin film obtained by the method according to claim 16 or 17 for the use as a medicament.