ORAL THIN FILM WITH PVA TRIS BUFFER LAYER

Description

[0001] The present invention relates to an oral thin film (also known as oral thin film or by the abbreviation OTF) comprising at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane in an amount of 15 to 70 wt.%, based on the total weight of the at least one layer, and to this oral thin film for use as a medicament.

[0002] WO 2009 / 124096 A1 discloses a patch, a system and a method for delivering a permeation composition to a patient.

[0003] Polyvinyl alcohol (PVA) is well-known and widely used as a matrix polymer in oral thin films because it is well-suited as a matrix polymer for foam formulations or other film-like OTF formulations. However, PVA can only be processed well in solutions with low ionic strength. At high salt concentrations, e.g. high buffer concentrations, the PVA easily precipitates or clumps. A uniform coating pattern is then no longer possible. For many applications, such as adjusting the pH of saliva to an optimal pH value for drug permeation and oral hygiene, etc., the use of stronger buffers, i.e. a higher buffer concentration, is necessary to adjust a specific pH value in the saliva or to maintain it at a certain pH value, as is advantageous, for example, for constant drug absorption.

[0004] The object of the present invention is to eliminate the aforementioned disadvantages of the prior art. In particular, the object of the present invention is to provide an oral thin film which comprises PVA and which contains the highest possible amount of at least one buffer substance, wherein the formulation should simultaneously be easy to process and the PVA should not precipitate and / or clump. At the same time, a formulation should be found which can be foamed well and which can form a film with the highest possible optical homogeneity. Furthermore, the oral thin film should make it possible to adjust the pH value in the patient's saliva over the widest possible range and at the same time be as stable as possible. For this purpose, it should be possible to incorporate as much buffer substance as possible into the PVA.

[0005] In addition, the oral thin film should be as easy to produce as possible and also allow the simplest possible construction of multilayer oral thin films.

[0006] The above object is achieved by a multilayer oral thin film according to claim 1, in particular by an oral thin film comprising at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS) in an amount of 15 to 70 wt.%, based on the total weight of the at least one layer.

[0007] An oral thin film comprising at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS) is hereinafter also referred to as TRIS-PVA layer or TRIS buffer layer.

[0008] Such an oral thin film 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.

[0009] The TRIS-PVA compositions can be easily foamed and form a film of high optical homogeneity.

[0010] Layers with a very high TRIS loading can also be produced, preferably with up to 50 wt.% TRIS. In addition, a wider pH range can be covered by adjustment with acid (e.g., HCl). A further advantage is that, in some embodiments, these oral thin films can be laminated together without the need for additional adhesives, i.e., it is possible to produce relatively thick multilayer films by laminating together several layers of TRIS-PVA layers. The TRIS buffer layers can be administered together with drug-containing OTFs to maintain a suitable pH value in the oral cavity. This can be done either by sequential administration of a TRIS buffer layer and a drug-containing OTF (or vice versa), or the TRIS buffer layer is combined with a drug layer (e.g., lamination to form multilayer OTFs), or the TRIS buffer layer itself contains at least one pharmaceutically active ingredient.In particular, with ketamine as a pharmaceutically active ingredient, systems could be created that are advantageous for clinical reproducibility (compensates for fluctuations in the mouth / saliva pH) and buffer the oral cavity to a favorable pH for permeation.

[0011] In this document, "comprehensive" may also mean "consisting of".

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] According to the present invention, polyvinyl alcohols having an average molecular weight of about 31,000 (4-88) to about 205,000 (40-88) g / mol are particularly suitable.

[0017] Furthermore, according to the present invention, polyvinyl alcohols having a viscosity of from 3.4-4.6 mPas (4-88) to 34-46 mPas (40-88) mPas in a 40 g / l aqueous solution, determined by "falling ball method" (Ph.Eur. 2.2.49), are particularly suitable, or mixtures of two or more different PVA types.

[0018] The oral thin film according to the invention is preferably characterized in that polyvinyl alcohol is contained in the at least one 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 at least one layer.

[0019] The oral thin film according to the invention is further preferably characterized in that polyvinyl alcohol is contained in the at least one layer in an amount of 20 to 50 wt.%, preferably 25 to 45 wt.% and very particularly preferably 30 to 40 wt.%, based on the total weight of the at least one layer.

[0020] The oral thin film according to the invention is further preferably characterized in that polyvinyl alcohol is contained in the at least one layer in an amount of 60 to 85% by weight, preferably 65 to 80% by weight and very particularly preferably 65 to 75% by weight, based on the total weight of the at least one layer.

[0021] The oral thin film according to the invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in the at least one layer in an amount of 25 to 55 wt.%, based on the total weight of the at least one layer.

[0022] The oral thin film according to the invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in the at least one layer in an amount of 15 to 45 wt.% or 15 to 40 wt.%, based on the total weight of the at least one layer.

[0023] The oral thin film according to the invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in the at least one layer in an amount of 20 to 55% by weight or 20 to 50% by weight or 20 to 45% by weight or 20 to 40% by weight, based on the total weight of the at least one layer.

[0024] The oral thin film according to the invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in the at least one layer in an amount of 25 to 55% by weight or 25 to 50% by weight or 25 to 45% by weight or 25 to 40% by weight, based on the total weight of the at least one layer.

[0025] The oral thin film according to the invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in the at least one layer in an amount of about 15% by weight or about 16.7% by weight or about 25% by weight or about 25.5% by weight or about 40% by weight or about 50% by weight, based on the total weight of the at least one layer.

[0026] Preferably, the oral thin film according to the invention contains no buffer substances other than TRIS, in particular no phosphates, carbonates and / or citric acid.

[0027] The oral thin film according to the invention is further preferably characterized in that the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS) does not contain any buffer substances other than TRIS, in particular no phosphates, carbonates and / or citric acid.

[0028] The at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS) preferably does not contain any polymers other than PVA.

[0029] The oral thin film according to the invention is further preferably characterized in that the at least one layer comprises at least one pharmaceutically active ingredient.

[0030] Embodiments of the oral thin film according to the invention are also conceivable in which the oral thin film does not contain a pharmaceutically active ingredient, but is used merely as a "buffer thin film".

[0031] The at least one pharmaceutically active ingredient is in principle not subject to any restrictions, but is preferably selected from all pharmaceutically active ingredients that are suitable for oral and / or transmucosal administration.

[0032] According to the present invention, the pharmaceutically active ingredient also includes all pharmaceutically acceptable salts and solvates of the respective pharmaceutically active ingredient.

[0033] 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.

[0034] Particularly preferably, the at least one pharmaceutically active ingredient is ketamine and / or a pharmaceutically acceptable salt or solvate thereof, preferably ketamine HCl.

[0035] Ketamine is understood here as (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.

[0036] 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.

[0037] The active ingredient content in the at least one layer can vary within relatively wide limits. A suitable content range is 10 to 60 wt.%, based on the dry weight of the at least one layer. In another embodiment, the active ingredient content in the at least one layer is more likely to be in the range of 25 to 35 wt.%, or in the range of 25 to 45 wt.%, or in the range of 25 to 55 wt.%.

[0038] The oral thin film according to the invention is further preferably characterized in that the at least one layer comprises at least one excipient selected from the group comprising dyes, flavorings, sweeteners, plasticizers, taste masking agents, emulsifiers, enhancers, humectants, preservatives and / or antioxidants.

[0039] Each of these auxiliaries is preferably contained in this 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 at least one layer.

[0040] After drying or removing the solvent, it is preferred that the content of residual solvent in the oral thin film is in the range of 0.2 to 15 wt.%, preferably in the range of 0.8 to 7 wt.%, based on the total weight of the oral thin film.

[0041] Preferably, the oral thin film has at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active ingredient.

[0042] In this case, it is a multi-layered oral thin film.

[0043] The at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane may contain at least one pharmaceutically active agent, or in another embodiment, may not contain any pharmaceutically active agent.

[0044] If the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane does not contain a pharmaceutically active ingredient, it is preferred that at least one of the further layers contains at least one pharmaceutically active ingredient.

[0045] In such a case, the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane serves merely as a buffer layer which causes the adjustment of a desired pH value in the patient's mouth.

[0046] An oral thin film according to the invention, which has at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active ingredient, is preferably characterized in that the at least one polymer is a water-soluble polymer selected from the group comprising 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.

[0047] 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.

[0048] All active ingredients listed also include pharmaceutically acceptable salts and / or solvates thereof.

[0049] An oral thin film according to the invention, which has at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active ingredient, is preferably characterized in that the at least one pharmaceutically active ingredient is 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, wherein the at least one pharmaceutically active ingredient preferably comprises ketamine, particularly preferably (S)-ketamine.

[0050] In one embodiment, the multilayer oral thin film according to the invention is characterized in that the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane and / or the at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent are laminated directly to one another.

[0051] In another embodiment, the multilayer oral thin film according to the invention is characterized in that the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane and / or the at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active ingredient or at least one flavoring agent are connected to one another by an intermediate adhesive layer.

[0052] An adhesive layer is defined as a layer that can act as an adhesive, as defined in DIN EN 923:2016-03. A non-adhesive layer cannot therefore 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 relevant content of which is hereby incorporated in full.

[0054] Such 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 preferably comprises shellac, a vinylpyrrolidone / vinyl acetate copolymer, a polyvinylcaprolactam / polyvinyl acetate / polyethylene glycol copolymer, hydroxypropylcellulose or hydroxypropylmethylcellulose and / or polyvinylpyrrolidone, and wherein the at least one plasticizer in the at least one water-soluble adhesive layer preferably comprises glycerol, polyethylene glycol, in particular polyethylene glycol 200, and / or tributyl citrate.

[0055] 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 90 to 50 to about 10 to 50, preferably about 85 to 50 to about 15 to 50.

[0056] Such an adhesive layer, which contains at least one water-soluble polymer and at least one plasticizer, can act as an intermediate water-soluble adhesive layer to firmly bond two further layers, which are not sticky per se, together and thus enable the construction of multi-layered oral films without multiple coatings, which would mean increased drying times and increased temperature stress for the active ingredients and excipients contained therein.

[0057] In another embodiment, the multilayer oral thin film according to the invention is characterized in that the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane and / or the at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active ingredient or at least one flavoring agent are interconnected by an intermediate separating layer.

[0058] A layer comprising at least one polyethylene glycol is preferably used as the separating layer.

[0059] Polyethylene glycols (PEG) are compounds of the general formula:

[0060] 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.

[0061] 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 from 40,000 g / mol to 500,000 g / mol, particularly preferably from 95,000 g / mol to 105,000 g / mol, in particular of about 100,000 g / mol.

[0062] The molecular weight is derived from the rheology measurements described below.

[0063] The at least one polyethylene glycol preferably has a viscosity of 30 mPas to 50 mPas, measured at 25°C.

[0064] 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.

[0065] Particularly preferred is a polyethylene glycol known under the trade name POLYOX WSR N-10 (Dow Chemical).

[0066] The at least one polyethylene glycol is preferably contained in the at least one separating layer in an amount of 60 to 100 wt.%, preferably in an amount of 80 to 100 wt.%, based on the total weight of the at least one separating layer.

[0067] The separating layer preferably 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.

[0068] The use of such a separating layer 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. When heated and / or subjected to 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.

[0069] 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.

[0070] The separating 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.

[0071] The multilayer oral thin film according to the invention is not subject to any restrictions with regard to its structure.

[0072] Thus, embodiments are grateful in which the multilayer oral thin film comprises a TRIS buffer layer which does not contain a pharmaceutically active agent and a further layer which contains at least one matrix polymer and at least one pharmaceutically active agent.

[0073] These two layers can be laminated directly to each other or bonded together with an intermediate adhesive layer or release layer, preferably as defined above.

[0074] Embodiments are also conceivable in which the multilayer oral thin film consists of a TRIS buffer layer which does not contain a pharmaceutically active agent and a further layer which contains at least one matrix polymer and at least one pharmaceutically active agent.

[0075] These two layers can be laminated directly to each other or bonded with an intermediate adhesive layer, preferably as defined above.

[0076] Embodiments are also conceivable in which the multilayer oral thin film comprises a TRIS buffer layer which does not contain a pharmaceutically active agent and a further layer which contains at least one matrix polymer and at least one pharmaceutically active agent, these two layers being connected by an adhesive layer or a separating layer as defined above.

[0077] Embodiments are also conceivable in which the multilayer oral thin film consists of a TRIS buffer layer which does not contain a pharmaceutically active ingredient and a further layer which contains at least one matrix polymer and at least one pharmaceutically active ingredient, these two layers being connected by an adhesive layer or a separating layer as defined above.

[0078] Other multilayered oral thin films are conceivable, which, for example, have the following layer structure: TRIS buffer layer - layer containing at least one matrix polymer and at least one pharmaceutically active ingredient, - TRIS, buffer layer.

[0079] In this embodiment, the two TRIS buffer layers form outer sides of the multilayer oral thin film.

[0080] These three layers can either be laminated directly to each other or bonded together with an intermediate adhesive layer, preferably as defined above.

[0081] In principle, a modular system can be provided with any arrangement of TRIS buffer layers and other layers.

[0082] In all the embodiments described above, the TRIS buffer layer preferably does not contain any pharmaceutically active ingredient. However, embodiments are also conceivable in which at least one pharmaceutically active ingredient is contained in each of the TRIS buffer layers in the multilayer thin film.

[0083] The oral thin film according to the invention is further preferably characterized in that the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane and / or the at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active ingredient is (are) in the form of a solidified foam having cavities.

[0084] 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.

[0085] In the case of a rapidly absorbed active ingredient, the rapid dissolution of the matrix layer can also improve transmucosal absorption. Furthermore, the wall thickness of these cavities is preferably small, as these represent, for example, solidified blisters, allowing rapid dissolution or destruction of these cavities.

[0086] 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.

[0087] Preferably, the 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, argon or a mixture of at least two of these gases.

[0088] 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.

[0089] Preferably, the aforementioned cavities have a volume fraction of 5 to 98%, preferably 50 to 80%, based on the total volume of the respective layer. This favorably influences the intended effect of accelerating the dissolution of the active ingredient-containing matrix layer.

[0090] 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.

[0091] Another parameter that influences the properties of the dosage form according to the invention is the diameter of the cavities or bubbles. The bubbles or cavities are preferably created using a foaming machine, with which the diameter of the bubbles can be adjusted over a wide range, almost arbitrarily. Thus, the diameter of the bubbles or cavities can be in the range from 1 to 350 µm. Particularly preferably, the diameter is in the range from 30 to 200 µm.

[0092] The oral thin film according to the invention preferably has an area of ​​0.5 cm 2< to about 10 cm 2< , particularly preferably of 1.5 cm 2< to about 9 cm 2< .

[0093] The oral thin film according to the invention is preferably characterized in that the basis weight of the oral thin film is 10 to 500 g / m 2< , preferably 100 to 400 g / m 2< .

[0094] The basis weight of the TRIS buffer layer and any further layer that may be present is 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 , most preferably 50 to 250 g / m 2 .

[0095] Preferably, the TRIS buffer layer and any further layer that may be present each have a layer thickness of preferably 10 µm to 500 µm, particularly preferably 20 µm to 300 µm.

[0096] If the TRIS buffer layer is in the form of a foam, the TRIS buffer layer has a layer thickness of preferably 10 µm to 3000 µm, particularly preferably 90 µm to 2000 µm.

[0097] The oral thin film according to the invention is further preferably characterized in that the oral thin film produces a pH value (at 37°C) of 6 to 9, preferably of 6 to 8, in the mouth of a patient, preferably a human.

[0098] The oral thin film according to the invention is further preferably characterized in that the oral thin film produces a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer or water.

[0099] The oral thin film according to the invention is further preferably characterized in that the oral thin film comprises a TRIS buffer layer and a further layer containing S-ketamine HCl and produces a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer or water.

[0100] The oral thin film according to the invention is further preferably characterized in that the oral thin film comprises a TRIS buffer layer and a further layer containing 16.3 mg of S-ketamine HCl and produces a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer or water.

[0101] The oral thin film according to the invention is further preferably characterized in that the oral thin film comprises a TRIS buffer layer and a further layer containing 32.2 mg of S-ketamine HCl and produces a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer or water.

[0102] The present invention also relates to a kit comprising at least a first oral thin film comprising at least one layer comprising at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and at least a second oral thin film comprising at least one matrix polymer and at least one pharmaceutically active agent, wherein the first and second oral thin films are preferably different. Preferably, in this kit, the first oral thin film does not contain a pharmaceutically active agent.

[0103] The above statements for the TRIS buffer layer and the further layer apply analogously to the first and second oral thin films present in the kit according to the invention.

[0104] The oral thin film according to the invention can be prepared according to methods known to those skilled in the art.

[0105] Known manufacturing methods include providing a solution comprising PVA and TRIS, then spreading and drying this solution to obtain a film.

[0106] If a multilayer oral thin film is to be produced, a known production method comprises providing a first solution comprising PVA and TRIS, subsequently spreading and drying this solution to obtain a film and providing a second solution comprising the at least one matrix polymer and at least one pharmaceutically active agent to obtain a second film.

[0107] In principle, these two films can be joined using methods familiar to those skilled in the art. For example, a second film can be applied to a first film by means of a coating, regardless of which film is coated onto which. Furthermore, the two layers can be bonded together using an adhesive layer, as described above.

[0108] The present invention further relates to an oral thin film obtainable by the method described above.

[0109] Furthermore, the present invention relates to an oral thin film as described above, obtainable by the method described above or the kit described above as a medicament.

[0110] The present invention further relates to an oral thin film as described above, obtainable by the method described above or the kit described above, wherein ketamine, preferably S-ketamine (optionally as a pharmaceutically acceptable salt or ion pair), is used as a pharmaceutically active ingredient, as a medicament 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 an adjunct to regional anesthesia and / or as an analgesic.

[0111] The present invention is explained in more detail below in some non-limiting examples. Examples Example 1:

[0112] Influence of pH on the permeation of (S)-ketamine HCI Acidic buffer: 80 g / l Na 2 HPO 4 x2H 2 O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=4.99 at 22°C. Neutral buffer: 80 g / l Na 2 HPO 4 x2H 2 O dissolved in water; pH adjusted with aqueous 1M HCI solution to pH=7.46 at 22°C. Basic buffer: 80 g / l Na 2 HPO 4 x2H 2 O dissolved in water; pH adjusted with aqueous 1M HCI solution to pH=8.33 at 22°C.

[0113] The pH values ​​of this series of experiments are summarized in Table 1. Table 1: Buffer pH at 22°C Buffer pH at 37°C Buffer + (S)-Ketamine HCl pH at 22°C Acid buffer 4,99 5,09 4,92 Neutral buffer 7,46 7,48 6,64 Basic buffer 8,33 7,91 7,81

[0114] The permeated amount of (S)-ketamine was determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) using porcine esophageal mucosa and a Franz diffusion cell. The mucosa was prepared with a dermatome to a thickness of 400 µm and a surface area of ​​1.145 cm², ensuring intact barrier function for all transmucosal therapeutic systems.

[0115] The acceptor medium was 4 mL PBS buffer with a pH of 7.4 at 37°C.

[0116] 2.77 mg of (S)-ketamine HCl was applied to the mucosa, and the mucosa containing the drug was brought into contact with the respective buffer solution on the upper side. The underside of the mucosa was in contact with the acceptor medium. The permeated amount of S-ketamine in the receptor medium at a temperature of 37 ± 1°C was measured. The results are shown in Figure 1 shown.

[0117] From the permeation results obtained, it can be concluded that the permeation of S-ketamine is best in neutral buffer, followed by basic buffer. The lowest permeation rate was observed with acidic buffer. Example 2:

[0118] Influence of pH on the permeation of (S)-ketamine HCI from an oral thin film.

[0119] An oral thin film of the composition shown in Table 2 was prepared. Table 2: material Formulation 1 [wt%] PVA 4-88 39.1 TRIS -- Saccharin Na 1,0 Sucralose 2,0 Cherry Flavor M55394 3,0 Glycerol 4,5 S-Ketamine HCI 50,0 FD&C Red No. 40 0,4 Kollidon VA 64 -- solvent Purified Water Basis weight (incl. residual moisture): 199 g / m 2 PVA 4-88: Polyvinyl alcohol Flavor: MANE Cherry Flavor M55394 Color: FD&C Red No. 40

[0120] The oral thin film with the formulation according to Table 2 is produced by mass production techniques known to the person skilled in the art, e.g. by stirring / mixing the components contained using a stirring motor and suitable stirring tools.

[0121] Gas is added to the resulting mass by stirring, e.g. using a foaming machine.

[0122] The foamy mass is coated onto a coating carrier in a constant layer thickness using suitable equipment (roller applicator, doctor blade, coating box, etc.).

[0123] Any temperature-stable, sheet-like material from which the dry film can be removed can serve as a coating substrate. This can be ensured by the material selection of the coating substrate (different surface tensions between the foam mass and the substrate) or by applying suitable dehesive coatings to the coating substrate, for example, silicones or fluoropolymers.

[0124] The processing solvent(s), usually water or mixtures of water and organic, water-miscible solvents, are removed by drying. The resulting solid foam layer can be cut or punched into the appropriate size for oral thin films. Acidic buffer: 80 g / l Na 2 HPO 4 x2H 2 O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=4.99 at 22°C. Neutral buffer: 80 g / l Na 2 HPO 4 x2H 2 O dissolved in water; pH adjusted with aqueous 1M HCI solution to pH=7.46 at 22°C. Basic buffer: 80 g / l Na 2 HPO 4 x2H 2 O dissolved in water; pH adjusted with aqueous 1M HCI solution to pH=8.33 at 22°C.

[0125] The pH values ​​of this series of experiments are summarized in Table 3. Table 3: Buffer pH at 22°C Buffer pH at 27°C Buffer + OTF pH at 22°C Buffer + OTF pH at 37°C Acid buffer 4,99 5,09 4,92 5,05 Neutral buffer 7,46 7,48 6,88 6,72 Basic buffer 8,33 7,91 7,91 7,50

[0126] 0.287 cm 2< OTF (equivalent to 2.77 mg (S)-ketamine) of S-ketamine HCI formulation 1 was applied to the mucosa and 70 µL of buffer solution was added.

[0127] The permeation was measured similarly to Example 1.

[0128] The permeated amount of (S)-ketamine was determined by in vitro experiments according to the OECD guideline (adopted on April 13, 2004) using porcine esophageal mucosa and a Franz diffusion cell. The mucosa was prepared with a dermatome to a thickness of 400 µm, ensuring intact barrier function for all transmucosal therapeutic systems.

[0129] Punches with an area of ​​0.287 cm 2 were punched out of the OTFs, applied to the mucosa, and the mucosa with the OTFs on top was brought into contact with the respective buffer (the bottom side was in contact with the acceptor medium and the top side was sealed off to a mucosal area of ​​1.145 cm 2).

[0130] The permeated amount of S-ketamine in the receptor medium (phosphate buffer solution pH 7.4) at a temperature of 37 ± 1°C was measured. The results are shown in Figure 2 shown.

[0131] The in vitro experiments using different buffers as donor media showed a permeation behavior of S-ketamine that was dependent on the pH of the buffer used. The pH of the donor medium including drug is shown in Table 2 (buffer + OTF).

[0132] From the permeation results obtained, it can be concluded that the permeation of S-ketamine is best in basic buffer, followed by neutral buffer. The lowest permeation rate was observed with acidic buffer. Example 3:

[0133] Table 4: Formulations (amounts in wt.%) material 2 3 4 5 6 7 8 PVA 4-88 36,15 69,30 59,50 64,00 74,50 39,50 39,0 PVA 40-88 36,15 -- -- --- -- -- -- TRIS 20,00 20,00 30,00 25,50 15,00 50,00 50,00 Saccharin Na 1,00 1,00 1,00 1,00 1,00 1,00 1,00 Sucralose 2,00 2,00 2,00 2,00 2,00 2,00 2,00 Flavoring - 3,0 3,00 3,00 3,00 3,00 3,00 Glycerol 4,50 4,50 4,50 4,50 4,50 4,50 4,50 dye 0,20 0,20 -- -- -- -- -- Aerosil -- -- -- -- -- -- 0,5 Process solvents: Water Water Water Water Water Water Water Gas for foaming Nitrogen Air Air Air Air Air Air pH 3.34 cm 2< OTF in 2 mL water pH=9.0 (36 °C) --- --- 3.34 cm 2< OTF in 2 mL water --- 3.34 cm 2< OTF in 2 mL water pH=9.61 (22 °C) --- pH=9.65 (21 °C) 3.34 cm 2< OTF in 2 mL Glandosane pH=9.01 (21 °C) PVA 4-88: Polyvinyl alcohol PVA 40-88: Polyvinyl alcohol Flavor: MANE Cherry Flavor M55394 Color: FD&C Red No. 40 Aerosil 200: Hydrophilic fumed silica with a specific surface area of ​​200 m 2 / g (EVONIK) Glandosane: artificial saliva

[0134] Oral thin films with the formulations shown in Table 3 were prepared according to Example 2.

[0135] The oral thin films formulated according to Table 4 are characterized by high flexibility and a pleasant feel ("mouthfeel"). Furthermore, the resulting oral thin films dissolve very quickly in the mouth, despite their potentially high basis weight and thickness. Due to the thin layers of the gas bubble walls, very gentle drying is possible (e.g., 20 minutes at 70°C for 200 g / m²). Example 4:

[0136] Table 5: material Formulation 9 [wt%] PVA 4-88 39,5 TRIS 16,7 Saccharin Na 1,0 Sucralose 2,0 Flavoring 3,0 Glycerol 4,50 S-Ketamine 33,3 Gas: Air (alternatively nitrogen) Process solvents Water Basis weight (incl. residual moisture) 2x 141 g / m 2< laminated together pH 3.34 cm 2< OTF in 2 mL Aqua purificata: pH=7.5 (22 °C) pH=7.2 (33 °C) 3.34 cm 2< OTF in 2 mL human saliva: pH=7.45 (22°C) pH=7.28 (33.5 °C) PVA 4-88: Polyvinyl alcohol Flavoring: MANE Cherry Flavor M55394

[0137] The preparation of an oral thin film of the formulation according to Table 5 is carried out by mass production techniques known to the person skilled in the art, e.g. by stirring / mixing the components contained by means of a stirring motor and suitable stirring tools.

[0138] Gas is then introduced into the resulting mass by stirring, e.g., using a foaming machine. The foamed mass is then coated onto a coating substrate in a constant layer thickness using suitable equipment (roller applicator, doctor blade, coating box, etc.).

[0139] Any temperature-stable web-like material from which the dry film can be removed can serve as a coating substrate. This can be ensured by the material selection of the coating substrate (different surface tensions between the foam mass and the substrate) or by applying suitable dehesive coatings to the coating substrate, for example, silicones or fluoropolymers. The process solvent(s) contained in the coating substrate, usually water or mixtures of water and organic, water-miscible solvents, are removed by drying.

[0140] The two laminates were then heated to 70°C and laminated together. The resulting two-layer laminate can be cut or punched into the appropriate size to produce oral thin films.

[0141] This two-layer oral thin film is characterized by its high layer thickness and loading. The process can be repeated as often as required, thus creating multilayer laminates (e.g., laminating three or four laminates together), or multiple laminates can be laminated together in a single step (e.g., heating three laminates to 70 °C and laminating them together). Example 5

[0142] Table 6: Formulation (amount in wt%) material Formulation 10 Formulation 11 Formulation 9 PVA 4-88 37,5 39,5 39,5 TRIS 2,0 25,0 16,7 Saccharin Na 1,0 1,0 1,0 Sucralose 2,0 2,0 2,0 Flavoring 3,0 3,0 3,0 Glycerol 4,5 4,5 4,5 S-Ketamine HCI 50,0 25,0 33,3 Gas: Air (alternatively nitrogen) Air (alternatively nitrogen) Air (alternatively nitrogen) Process solvents Water Water Water Basis weight (incl. residual moisture) 223 g / m 2 175 g / m 2 2x141 g / m 2< laminated together pH 3.34 cm 2< OTF in 2 mL Aqua purificata pH=6.0 (22°C) 3.34 cm 2< OTF in 2 mL Aqua purificata pH=8.26 (24 °C) 3.34 cm 2< OTF in 2 mL Aqua purificata: pH=7.5 (22 °C) 3.34 cm 2< OTF in 2 mL Glandosane pH=5.9 (25 °C) 3.34 cm 2< OTF in 2 mL Glandosane pH=7.40 (26.5 °C) pH=7.2 (33 °C) 3.34 cm 2< OTF in 2 mL human saliva pH=6.0 (25 °C) 3.34 cm 2< OTF in 2 mL human saliva: pH=7.45 (22°C) pH=7.28 (33.5°C)

[0143] The oral thin films with the formulations according to Table 6 were prepared analogously to Example 2 and Example 3. Example 6

[0144] Table 7: Formulation 12 [wt%] Formulation 13 [wt%] PVA 4-88 39,5 36,15 PVA 40-88 --- 36,15 (S)-Ketamine HCl 50,0 --- Sodium saccharin 1,0 1,0 Sucralose 2,0 2,0 Cherry Flavor 3,0 --- Glycerol 4,5 4,5 TRIS --- 20,0 FD&C red 40 --- 0,2 Basis weight / size 193 g / m 2 < 3.34 cm 2 < 160 g / m 2 gas Nitrogen Nitrogen Process solvents Water Water

[0145] An oral thin film was prepared according to the formulations in Table 7. The preparation was carried out analogously to Example 1 and Example 2.

[0146] The oral thin films were dissolved individually in water or in Glandosan (artificial saliva), and the pH of the respective solution was determined. Furthermore, both films were dissolved together in water or in Glandosan, and the pH of the solution was determined (see Table 8). Table 8: pH in water (2 mL) pH in Glandosan (2mL) KetamineOTF 5,85 5,11 TRIS-OTF 9,65 8,91 KetamineOTF+TRIS-OTF 7,13 6,94 Example 7

[0147] Table 9: Formulation (amount in wt%) material Formulation 1 active ingredient layer Formulation 7 Buffer layer Formulation 14 Adhesive layer PVA 4-88 39,1 39,5 --- TRIS --- 50,0 --- Saccharin Na 1,0 1,0 --- Sucralose 2,0 2,0 --- Flavoring 3,0 3,0 Glycerol 4,5 4,5 20,0 S-Ketamine HCI 50,0 --- --- dye 0,4 --- --- Kollidon VA 64 --- --- 80,0 gas Air (alternatively nitrogen) Air (alternatively nitrogen) - (not foamed) Process solvents Water Water Ethanol Basis weight (incl. moisture content) 190.0 g / m 2 2 x 113.0 g / m 2 2 x 63.1 g / m 2 PVA 4-88: Polyvinyl alcohol Flavor: MANE Cherry Flavor M55394 Color: FD&C Red Kollidon VA 64: Vinylpyrrolidone-vinyl acetate copolymer

[0148] Thin films were prepared as the active ingredient layer, buffer layer, and adhesive layer as follows. The layers were prepared as described in Example 1 and Example 2, respectively. The composition is described in the corresponding tables.

[0149] From this, a multilayer oral thin film was produced with the following structure: buffer layer, adhesive layer, drug layer, adhesive layer, buffer layer. An adhesive layer was laminated to both sides of a ketamine laminate. After peeling off the carrier film, a TRIS buffer layer was then laminated to both sides.

[0150] The result was a homogeneous foam composite with good haptic properties and a good dissolution rate for the thickness.

[0151] A pH measurement showed: 3.34 cm2< OTF in 2 mL water: pH=8.07 (at 35.5 °C). pH in 2 mL human saliva: pH=8.04 (at 36.3 °C). Example 8

[0152] Table 10: Formulation (amount in wt%) material Formulation 1 active ingredient layer Formulation 7 Buffer layer Formulation 14 Adhesive layer PVA 4-88 39,1 39,5 --- TRIS --- 50,0 --- Saccharin Na 1,0 1,0 --- Sucralose 2,0 2,0 --- Flavoring 3,0 3,0 Glycerol 4,5 4,5 20,0 S-Ketamine HCI 50,0 --- --- dye 0,4 --- --- Kollidon VA 64 --- --- 80,0 gas Air (alternatively nitrogen) Air (alternatively nitrogen) - (not foamed) Process solvents Water Water Ethanol PVA 4-88: Polyvinyl alcohol Flavor: MANE Cherry Flavor M55394 Color: FD&C Red Kollidon VA 64: Vinylpyrrolidone-vinyl acetate copolymer

[0153] Thin films were prepared as the active ingredient layer, buffer layer, and adhesive layer as described in Examples 1, 2, and 7. The composition is described in the corresponding tables.

[0154] From this, a multilayer oral thin film with a buffer layer, adhesive layer, and drug layer structure was produced as follows. An adhesive layer was laminated onto a ketamine foam. After removing the adhesive layer's backing film, a TRIS foam was laminated onto it.

[0155] The result was a homogeneous foam composite with good haptic properties and a good dissolution rate for the thickness.

[0156] A pH measurement showed: 3.34 cm 2< OTF in 2 mL water: pH=7.97 (at 36.3 °C) Example 9

[0157] Table 11 Formulation (amount in wt%) material Formulation 1 active ingredient layer Formulation 5 Buffer layer Formulation 14 Adhesive layer PVA 4-88 39,1 64,0 --- TRIS --- 25,5 --- Saccharin Na 1,0 1,0 --- Sucralose 2,0 2,0 --- Flavoring 3,0 3,0 Glycerol 4,5 4,5 20,0 S-Ketamine HCI 50,0 --- --- dye 0,4 --- --- Kollidon VA 64 --- --- 80,0 gas Air (alternatively nitrogen) Air (alternatively nitrogen) - (not foamed) Process solvents Water Water Ethanol Basis weight (incl. residual moisture) 187.2 g / m 2 216.9 g / m 2 78.4 g / m 2 PVA 4-88: Polyvinyl alcohol Flavor: MANE Cherry Flavor M55394 Color: FD&C Red Kollidon VA 64: Vinylpyrrolidone-vinyl acetate copolymer

[0158] Thin films were prepared as the active ingredient layer, buffer layer, and adhesive layer as described in Examples 1, 2, and 7. The composition is described in the corresponding tables.

[0159] From this, a multilayer oral thin film with a buffer layer, adhesive layer, and drug layer structure was produced as follows. An adhesive layer was laminated onto a ketamine foam. After removing the adhesive layer's backing film, a TRIS foam was laminated onto it.

[0160] The result was a homogeneous foam composite with good haptic properties and a good dissolution rate for the thickness. Example 10

[0161] Table 12 Formulation (amount in wt%) material Formulation 1 active ingredient layer Formulation 15 Buffer layer Formulation 14 Adhesive layer PVA 4-88 39,1 69,5 --- TRIS --- 20,0 --- Saccharin Na 1,0 1,0 --- Sucralose 2,0 2,0 --- Flavoring 3,0 3,0 Glycerol 4,5 4,5 20,0 S-Ketamine HCI 50,0 --- --- dye 0,4 --- --- Kollidon VA 64 --- --- 80,0 gas not foamed not foamed not foamed Process solvents Water Water Ethanol Basis weight (incl. residual moisture) 187.2 g / m 2 216.9 g / m 2 78.4 g / m 2 PVA 4-88: Polyvinyl alcohol Flavor: MANE Cherry Flavor M55394 Color: FD&C Red Kollidon VA 64: Vinylpyrrolidone-vinyl acetate copolymer

[0162] Thin films were prepared as the active ingredient layer, buffer layer, and adhesive layer as described in Examples 1, 2, and 7, omitting the foaming step. The compositions are described in the corresponding tables.

[0163] From this, a multilayer oral thin film with a buffer layer, adhesive layer, and drug layer structure was produced as follows. An adhesive layer was laminated onto a ketamine foam. After removing the adhesive layer's backing film, a TRIS foam was laminated onto it.

[0164] The result was a homogeneous foam composite with good haptic properties and a good dissolution rate for the thickness.

[0165] A pH measurement showed: 3.34 cm 2< OTF in 2 mL water: pH=6.33 (at 32 °C). Example 11

[0166] Table 13: Formulation (amount in wt%) material Formulation 12 active ingredient layer Formulation 3 Buffer layer Formulation 16 Adhesive layer PVA 4-88 39,5 69,3 30,0 TRIS --- 20,0 --- Saccharin Na 1,0 1,0 --- Sucralose 2,0 2,0 --- Flavoring 3,0 3,0 --- Glycerol 4,5 4,5 10,0 S-Ketamine HCI 50,0 --- --- Kollidon VA 64 --- --- 28,0 Sorbitol --- --- 22,0 Isomalt --- --- 10,0 gas Air (alternatively nitrogen) Air (alternatively nitrogen) Air (alternatively nitrogen) Process solvents Water Water Water PVA 4-88: Polyvinyl alcohol Flavor: MANE Cherry Flavor M55394 Color: FD&C Red

[0167] Thin films were prepared as the active ingredient layer, buffer layer, and adhesive layer as described in Examples 1, 2, and 7. The composition is described in the corresponding tables.

[0168] From this, a multilayer oral thin film with a buffer layer, adhesive layer, and drug layer structure was produced as follows. An adhesive layer was laminated onto a ketamine foam. After removing the adhesive layer's backing film, a TRIS foam was laminated onto it.

[0169] The result was a homogeneous foam composite with good haptic properties and a good dissolution rate for the thickness. Example 12

[0170] Table 14: Formulation (amount in wt%) material 17 18 19 20 21 PVA 4-88 39,50 35,2 57,7 70,2 63,6 caffeine 21,83 --- --- --- --- Citric acid 10,05 --- --- --- --- Sodium citrate dihydrate 18,12 --- --- --- --- Trisodium citrate --- 54,3 --- --- --- Dipotassium hydrogen phosphate --- --- 31,8 --- --- Di-sodium hydrogen phosphate --- --- --- --- 25,9 Sodium carbonate --- --- --- 19,6 --- Saccharin Na 1,00 1,00 1,00 1,00 1,00 Sucralose 2,00 2,00 2,00 2,00 2,00 Flavoring 3,00 3,00 3,00 3,00 3,00 Glycerol 4,50 4,50 4,50 4,50 4,50 gas Air Mass not foamable Mass not foamable Mass not foamable Mass not foamable Process solvents Water Water Water Water Water PVA 4-88: Polyvinyl alcohol Flavoring agent: MANE Cherry Flavor M55394

[0171] The oral thin films with the formulations according to Table 14 were prepared as described in Examples 1, 2 and 7.

[0172] The oral thin films with the formulations listed in Table 14 exhibited the following disadvantages: Lumps and inhomogeneities formed within the mass. The mass could not be spread evenly and was therefore unsuitable for the production of thin films. PVA, as a matrix polymer, is incompatible with the salts / buffers listed in Table 14. Example 13

[0173] Table 15: Formulation (amount in wt%) material 22 23 24 25 Kollicoat Smart Seal 34,0 35,0 41,0 40,0 Triethyl citrate 5,0 --- 6,0 7 TRIS 50,0 50,0 40,0 40,0 Saccharin Na 2,0 1,0 1,0 --- Sucralose 1,0 2,0 3,0 3,5 Flavoring 3,0 3,0 2,0 2,0 Glycerol --- 7,0 --- --- HPC EF 5,0 --- 5,5 5,5 HPMC 90SH4000 --- 20, --- --- Cremophor RH40 --- --- 1,5 --- Polyoxyethylene (23) lauryl ether --- --- --- 2,0 Characteristics No coatable mass Laminate brittle; no homogeneous film Mass not homogeneous; laminate brittle Phase separation in the mass; not coatable

[0174] The oral thin films with the formulations according to Table 15 were prepared as described in Examples 1, 2 and 7.

[0175] The oral thin films with the formulations according to Table 15 showed the adverse properties listed in Table 15.

[0176] The aqueous polymer dispersion (Smart Seal) was initially introduced, and plasticizers, flavorings, and surfactants were added sequentially. Then the second polymer was added. Finally, the buffer salt was stirred in.

[0177] The mass was foamed, coated and dried using standard methods. Example 14

[0178] Co-administration of Formulation 2 and Formulation 12 (two separate OTFs each 3.34 cm 2 OTF): pH in 2 mL water at 36.5 °C: pH= 7.15

[0179] Co-administration of Formulation 5 and Formulation 12 (two separate OTFs each 3.34 cm 2 OTF): For water: pH in 2 mL water Formulation 12 at 21 °C: pH= 5.85 pH in 2 mL water Formulation 5 at 21 °C: pH= 9.65 pH in 2 mL water Formulation 12 + Formulation 5 at 21 °C: pH= 7.13

[0180] For Glandosane (artificial saliva) pH in 2 mL Glandosane Formulation 12 at 21 °C: pH= 5.33 pH in 2 mL Glandosane Formulation 5 at 21 °C: pH= 8.91 pH in 2 mL Glandosane Formulation 12 + Formulation 5 at 21 °C: pH= 6.94

[0181] Co-administration of Formulation 7 and Formulation 12 (two separate OTFs each 3.34 cm 2 < OTF): For water: pH in 2 mL water Formulation 12 at 21 °C: pH= 5.85 pH in 2 mL water Formulation 7 at 22 °C: pH= 9.61 pH in 2 mL water Formulation 12 + Formulation 7 at 22 °C: pH= 7.67

[0182] For Glandosane (artificial saliva) pH in 2 mL Glandosane Formulation 12 at 21 °C: pH= 5.33 pH in 2 mL Glandosane Formulation 7 at 21 °C: pH= 9.01 pH in 2 mL Glandosane Formulation 12 + Formulation 7 at 21 °C: pH= 7.24 Example 15

[0183] Co-administration of Formulation 13 and Formulation 26 (Formulation 13 OTF 2.27 cm2< OTF and 2.27 cm2< Formulation 26): The composition of Dextromethorphan OTF: Formulation 26 is shown in Table 16. Table 16 material Formulation 26 [wt%] Dextromethorphan 43,78 % PVA 4-88 38,00 % Saccharin Na 1,00 % Sucralose 2,00 % Glycerol 4,54 % Flavor 6,00 % Amberlite IRP64 4,48 % FD&C Red 40 0,20 % Trometamol (TRIS) -- solvent Purified water Basis weight 188 g / cm 2

[0184] An oral thin film with the formulation according to Table 16 was prepared as described in Examples 1, 2 and 7.

[0185] A pH measurement showed: pH in 2 mL water at 35 °C: pH= 7.63. Example 16

[0186] Co-administration of Formulation 13 and Formulation 27 (Formulation 13 OTF 2.27 cm2< OTF and 2.27 cm2< Formulation 27): The composition of Paracetamol (Acetaminophen) OTF Formulation 27 is given in Table 17. Table 17 material Formulation 27 [wt%] Paracetamol 20,00 % PVA 4-88 72,50 % Saccharin Na 0,50 % Sucralose 1,00 % Glycerol 4,50 % Flavor 1,50 % Trometamol (TRIS) -- solvent Purified water Basis weight 103 g / cm 2

[0187] An oral thin film with the formulation according to Table 17 was prepared as described in Examples 1, 2 and 7.

[0188] A pH measurement showed: pH in 2 mL water at 33 °C: pH= 8.17. Example 18:

[0189] Co-administration of formulation 13 OTF 2.72 cm 2 OTF and commercial BEMA Fentanyl OTF (strength 200 µg): pH measurement showed: pH in 2 mL water at 22 °C: pH= 8.67. Example 19

[0190] Determination of the influence of pH on the permeation of protonatable / deprotonatable drugs. Adjusting the pH using a buffer OTF can reduce interindividual pH variance and bring the pH into a permeation-preferred range. Multilayer OTFs can influence the release profile through a longer disintegration / dissolution time.

[0191] Ketamine OTFs with buffer substances achieve significantly better permeations (more than 18x higher) than ketamine HCl (without OTF).

[0192] The results are in Figure 3 summarized.

Claims

1. An oral thin film, comprising at least one layer, which contains at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane in an amount of from 15 to 70 wt.% in relation to the total weight of the at least one layer.

2. The oral thin film according to claim 1, characterised in that polyvinyl alcohol is contained in the at least one layer in an amount of from 20 to 90 wt.% in relation to the total weight of the at least one layer.

3. The oral thin film according to any one of the preceding claims, characterised in that tris(hydroxymethyl)aminomethane is contained in the at least one layer in an amount of from 25 to 55 wt.% in relation to the total weight of the at least one layer.

4. The oral thin film according to any one of the preceding claims, characterised in that the at least one layer comprises at least one pharmaceutically active agent.

5. The oral thin film according to any one of the preceding claims, characterised in that the at least one layer comprises at least one pharmaceutically active agent which 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, the at least one pharmaceutically active agent preferably comprising ketamine, especially preferably (S)-ketamine, or pharmaceutically acceptable salts thereof.

6. The oral thin film according to any one of the preceding claims, characterised in that< / b> the at least one layer comprises at least one auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, plasticisers, taste-masking agents, emulsifiers, enhancers, humectants, an acid or a base (or a salt thereof), preservatives and / or antioxidants.

7. The oral thin film according to any one of the preceding claims, characterised in that the oral thin film has at least one further layer which comprises at least one matrix polymer and at least one pharmaceutically active agent.

8. The oral thin film according to claim 7, characterised in that the at least one polymer is a water-soluble polymer which 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.

9. The oral thin film according to claim 7 or 8, characterised in that< / b> 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, the at least one pharmaceutically active agent preferably comprising ketamine, especially preferably (S)-ketamine, or pharmaceutically acceptable salts thereof.

10. The oral thin film according to any one of the preceding claims, characterised in that the at least one layer which contains at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or the at least one further layer which comprises at least one matrix polymer and at least one pharmaceutically active agent is present (are present) in the form of a solidified foam having voids.

11. The oral thin film according to claim 10, characterised in that the voids are isolated from one another and are preferably present in the form of bubbles, the voids being 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.

12. The oral thin film according to claim 10 or 11, characterised in that the voids are connected to one another and preferably form a channel system penetrating the matrix layer.

13. The oral thin film according to any one of claims 10 to 12, characterised in that said voids 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.

14. The oral thin film according to any one of claims 7 to 13, characterised in that the at least one layer which contains at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or the at least one further layer which comprises at least one matrix polymer and at least one pharmaceutically active agent are laminated directly on one another or are connected to one another by an intermediate adhesive layer or separation layer.

15. The oral thin film according to any one of the preceding claims, characterised in that the oral thin film in the mouth of a patient produces a pH value (at 37°C) of from 6 to 9, preferably of from 6 to 8.

16. The oral thin film according to any one of the preceding claims for use as a medicament.