ORAL THIN FILM

Description

[0001] The present invention relates to an oral thin film, a process for its preparation and the use of such an oral thin film 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] Prajapati Vipul D. at al.: "Pullulan based oral thin film formulation of zolmitriptan: Development and optimization using factorial design", International Journal of Biological Macromolecules, Vol. 107, 1 February 2018 (2018-02-01), pages 2075-2085 investigates the formulation and characterization of pullulan-based oral thin films (OTF) of zolmitriptan using solvent casting method.

[0004] WO 2009 / 124096 A1 discloses a patch, a system and a method for administering a permeable composition to a subject.

[0005] Josef Mašek et al.: "Multi-layered nanofibrous mucoadhesive films for buccal and sublingual administration of drug-delivery and vaccination nanoparticles - important step towards effective mucosal vaccines", Journal of controlled release, Elsevier, Vol. 249, 25 July 2016, pages 183-195, investigates mucoadhesive films based on nanofibers for the oromucosal delivery of drugs and vaccines.

[0006] Oral thin films in foam form can, in principle, contain a high loading of pharmaceutically active ingredients. These highly loaded oral thin films in foam form generally exhibit a very rapid disintegration time, which is advantageous for many applications.

[0007] In other cases, however, it may be desirable for the highly loaded oral thin films in the form of a foam to remain in the oral cavity for a longer period, for example, to provide the pharmaceutically active ingredient for transmucosal absorption for a longer period.

[0008] A typical problem in the production of slow-release oral thin films of the pharmaceutically active ingredient is that the polymers typically used for this purpose form highly viscous aqueous solutions and thus reduce the solid content of a drug solution, which, among other things, significantly increases the drying time.

[0009] The objective of the present invention was to provide an oral thin film comprising a polymer matrix in the form of a solidified foam containing cavities, whose disintegration rate can be controlled as widely as possible. Furthermore, the oral thin film should be as simple and quick to produce as possible. In particular, highly viscous solutions and long drying times should be avoided.

[0010] This object was surprisingly achieved by an oral thin film according to claim 1. Such an oral thin film is characterized in that it contains a polymer matrix in the form of a solidified foam having cavities, wherein the polymer matrix contains at least one pharmaceutically active ingredient, at least one first polymer comprising a water-soluble polymer, and at least one second polymer comprising a mucoadhesive polymer having a number-average molecular weight of equal to or greater than 100,000 g / mol.

[0011] By adding a mucoadhesive polymer with a number-average molecular weight of 100,000 g / mol or greater, a foam formulation can be created that has a longer retention time in the oral cavity. Furthermore, the addition of a mucoadhesive polymer with a number-average molecular weight of 100,000 g / mol or greater achieves increased mucoadhesiveness, allowing the foam to adhere better to the mucosa and retain the active ingredient at the site of absorption.

[0012] The oral thin film can be produced in principle in the same way as previously known oral thin films, since the added mucoadhesive polymer with a number-average molecular weight of 100,000 g / mol or greater has only a minor influence on the physical behavior during suspension and drying. Since even a very small amount of mucoadhesive polymer with a number-average molecular weight of 100,000 g / mol or greater can cause delayed dissolution, the potential drug loading is virtually unaffected.

[0013] In this document, "comprehensive" may also mean "consisting of".

[0014] 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.

[0015] Water-soluble is preferably understood to mean a solubility of greater than 100 g / L in water at 25°C.

[0016] The mucoadhesion process is primarily influenced by the properties of the polymers used, such as the degree of cross-linking, chain length, and various functional groups in the polymer structure. Mucoadhesive systems are used in many mucosal organelles for the delivery of drugs with local or systemic effects.

[0017] Mucoadhesion can be defined as a phenomenon of molecular attraction forces at the interfaces between the surfaces of the mucosa, here the oral mucosa, and the mucoadhesive polymers, which enables the polymers to adhere to the mucosa for a prolonged period of time.

[0018] The second polymer, which comprises at least one mucoadhesive polymer, has a number-average molecular weight of equal to or greater than 100,000 g / mol, preferably greater than 200,000 g / mol or greater than 300,000 g / mol or greater than 400,000 g / mol or greater than 500,000 g / mol or greater than 600,000 g / mol or greater than 700,000 g / mol or greater than 800,000 g / mol or greater than 900,000 g / mol.

[0019] Also particularly preferred are mucoadhesive polymers having a number-average molecular weight of equal to or greater than 1,000,000 g / mol or 2,000,000 g / mol or 3,000,000 g / mol or 4,000,000 g / mol or 5,000,000 g / mol or 6,000,000 g / mol or 7,000,000 g / mol.

[0020] The molecular weight is determined according to methods known to the person skilled in the art, such as gel permeation chromatography.

[0021] Preferably, the second polymer, which comprises at least one mucoadhesive polymer having a number average molecular weight equal to or greater than 100,000 g / mol, is a water-soluble polymer as defined above.

[0022] The oral thin film according to the invention is further preferably characterized in that the first polymer comprises a polymer having a number-average molecular weight of less than 100,000 g / mol, preferably less than 80,000 or less than 60,000.

[0023] The molecular weight is determined according to methods known to the person skilled in the art, such as gel permeation chromatography.

[0024] The first polymer, which comprises a water-soluble polymer, is preferably 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 / or natural gums, with polyvinyl alcohols being particularly preferred.

[0025] The oral thin film according to the invention is further preferably characterized in that the second polymer, which comprises a mucoadhesive polymer having a number-average molecular weight of equal to or greater than 100,000 g / mol, is selected from the group consisting of poly(ethylene) oxide polymers, starch derivatives, polyacrylic acids, amylopectins and / or polyvinyl alcohols, in particular mixtures of polyacrylates or polyacrylic acids and amylopectins.

[0026] Suitable second polymers are, for example, poly(ethylene) oxide polymers, such as polyethylene glycols, with a number-average molecular weight of about 1,000,000 g / mol or about 7,000,000 g / mol, which are available, for example, under the trade name "Polyox WSR N12" or "Polyox WSR 303".

[0027] Other suitable second polymers are mixtures of polyacrylate or polyacrylic acids and amylopectin, which are available under the trade name "Proloc 15".

[0028] Long-chain polyvinyl alcohols are also suitable as a second polymer. For example, a polyvinyl alcohol with a number-average molecular weight of approximately 200,000 g / mol, which is available under the trade name "PVA 40-88," for example, is suitable.

[0029] The oral thin film according to the invention is further preferably characterized in that the first polymer is contained in the oral thin film in an amount of 40 to 95 wt.%, preferably 45 to 85 and particularly preferably 48 to 80, based on the total weight of the oral thin film.

[0030] Preferably, the second polymer is present in the oral thin film in an amount of 0.1 to 20 wt.%, preferably 2 to 18 and particularly preferably 5 to 15 based on the total weight of the oral thin film.

[0031] 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.

[0032] 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.

[0033] Particularly preferably, the at least one pharmaceutically active ingredient is ketamine.

[0034] 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.

[0035] Particularly preferred is (S)-ketamine as the only stereoisomer of ketamine, since the analgesic and anesthetic potency of (S)-ketamine is about three times higher than that of the (R) form.

[0036] The active ingredient content in the oral thin film can vary within relatively wide limits. A range of 10 to 60 wt.%, based on the total weight (total dry weight) of the oral thin film, can be specified as suitable. In one embodiment, the proportion of active ingredient in the oral thin film 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.

[0037] The active ingredient content per dosage unit is up to 100 mg, preferably up to 50 mg, particularly preferably up to 40 mg, and most preferably up to 35 mg. On the other hand, the minimum active ingredient content per dosage unit should preferably be 5 mg, more preferably 10 mg, and most preferably 15 mg. Depending on the application, the active ingredient content can also be in the upper range of the above specifications, for example, in the range of 50 to 100 mg. A material content of 30 to 50 mg may also be suitable.

[0038] The oral thin film according to the invention is further preferably characterized in that the oral thin film 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.

[0039] Each of these excipients is preferably contained in an amount of 0.1 to 40 wt.%, preferably 0.1 to 30 wt.%, particularly preferably 0.1 to 15 wt.%, most preferably 0.1 to 10 wt.% or 0.1 to 5 wt.%, based on the total weight of the oral thin film.

[0040] The multilayer oral thin film according to the invention is in principle not limited in the number of layers it contains.

[0041] Thus, embodiments are conceivable in which the oral thin film according to the invention has several active substance-containing layers.

[0042] The oral thin film according to the invention is characterized in that it is in the form of a solidified foam containing cavities.

[0043] An 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.

[0044] 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 or a mixture of at least two of these gases.

[0045] 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.

[0046] 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 oral thin film.

[0047] Furthermore, surface-active substances or surfactants can be added to the oral thin film 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.

[0048] Another parameter that influences the properties of the oral thin film according to the invention is the diameter of the cavities or bubbles. The bubbles or cavities are preferably created using a foam-forming 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 of 0.01 to 60 µm. Particularly preferably, the diameter is in the range of 10 to 50 µm.

[0049] 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< .

[0050] The basis weight of the oral thin film according to the invention 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 or equal to 150 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 200 g / m 2 .

[0051] Preferably, the oral thin film according to the invention has a thickness of about 10 µm to about 1000 µm, particularly preferably about 20 µm to about 500 µm.

[0052] The pharmaceutically active ingredient released from the oral thin film is preferably absorbed either at the site of application, i.e. via the oral mucosa, or it is transported further and absorbed at another site (e.g., after swallowing the active ingredient released in the oral cavity, in the gastrointestinal tract).

[0053] The residence time of the oral thin film according to the invention at the application site (e.g. oral cavity) or the disintegration time is preferably in the range of 10 seconds to 10 minutes, more preferably in the range of 30 seconds to 8 minutes and most preferably in the range of 1 minute to 5 minutes.

[0054] The present invention also relates to a process for producing an oral thin film as described above, comprising the steps: a) preparing a solution, dispersion or melt comprising at least the first polymer, the second polymer and the at least one pharmaceutical active ingredient; b) foaming the solution, dispersion or melt by introducing a gas or gas mixture, by chemical gas generation, or by decompressing a dissolved gas, optionally after prior addition of a foam-stabilising agent; c) spreading the foamed solution, dispersion or melt onto a coating substrate; and d) solidifying the spread solution, dispersion or melt by drying and removing the solvent or by cooling.

[0055] "Drying" means removing solvent, especially water, from the oral thin film. It is not necessary to remove all solvent, such as water, from the oral thin film; rather, it is sufficient if the significant portion of solvent is removed from the oral thin film, allowing the foam to solidify. The oral thin film may therefore contain a residual water content after drying.

[0056] Solvent removal causes the foam to solidify during drying, giving the resulting cavities a permanent structure. Oral thin films with desired surface dimensions or geometric shapes can be obtained by pouring the foamed mass into appropriate molds before drying, or by punching the individual oral thin films out of a larger piece of material.

[0057] The shape, number, and size of the created cavities can be influenced by various process parameters, e.g., the type and concentration of the polymers, the viscosity of the polymer mass, the control of the foaming process, the selection of foam-stabilizing agents, etc.

[0058] As an alternative to the method described above, it is possible to produce the oral thin film according to the invention by a method in which the formation of the cavities inside the polymer matrix is ​​carried out by introducing a hydrophobic solvent which is immiscible with the solvent used for the preparation of said solution or dispersion.

[0059] This creates an emulsion which contains the hydrophobic solvent in the form of finely distributed droplets.

[0060] The removal of solvents during subsequent drying leaves droplet- or bubble-shaped cavities in the polymer matrix.

[0061] Furthermore, in a modification of the process described above, the creation of the aforementioned cavities can occur by adding auxiliaries to the solution or dispersion containing the polymer and active ingredient, which form a gas or gases, thereby foaming the mass. This foaming through gas evolution can occur either during the production of the polymer mass or during the coating of this mass onto the substrate, or only during the subsequent drying process. Substances or mixtures of substances suitable for gas generation are known to the person skilled in the art. Foaming can also be brought about by expanding the pressure of a previously dissolved gas. The gas used can in particular be an inert gas, such as nitrogen, carbon dioxide or helium, or a mixture thereof.

[0062] Alternatively, the oral thin film according to the invention can be produced from a melt of the matrix polymer or polymer mixture. Processing is generally similar to that of prior art hot-melt coating materials.

[0063] A gas or gas mixture is introduced into the polymer melt using one of the methods mentioned above to cause the melt to foam. The melt is then spread onto a suitable support, extruded, or poured into a mold, and then allowed to cool or solidify. Processing from the melt is not an option if the intended active ingredient is unstable or volatile at the melting temperature of the polymer melt. If necessary, additives can be added to the polymer melt to lower the melting point.

[0064] According to a further modification of the manufacturing process described above, the polymer matrix is ​​initially produced in the form of a block. The desired dosage form is then separated from this block by cutting, i.e., after drying or solidification.

[0065] This means that in this embodiment, the steps c) and d) described above are replaced by the following steps c2) and d2): c2) producing a block from the solution, dispersion or melt; d2) cutting the solidified block to obtain sheet-like shapes.

[0066] The present invention also relates to an oral thin film obtainable according to the method described above.

[0067] Furthermore, the present invention relates to an oral thin film as described above or obtainable by the method described above, as a medicament.

[0068] The present invention further relates to an 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 present as pharmaceutically active ingredient, 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 or conducting general anesthesia or as an adjunct to regional anesthesia and / or as an analgesic.

[0069] The preferred embodiments listed above for the multilayer oral thin film also apply to the process according to the invention, the multilayer oral thin film obtained by this process and its use as a medicament.

[0070] The invention is explained in more detail below using non-limiting examples. Examples

[0071] The following polymers are used in the following examples. PVA 4-88: Polyvinyl alcohol (MW < 100,000) PVA 40-88: Polyvinyl alcohol (MW > 100,000) Polyox WSR N12: Poly(ethylene) oxide polymer (MW approximately 1,000,000) Polyox WSR 303: Poly(ethylene) oxide polymer (MW approximately 7,000,000) Proloc 15: Mixture of polyacrylate and amylopectin (MW > 100,000) Example 1

[0072] Foamed oral thin films with the compositions shown in Tables 1 to 5 without pharmaceutically active ingredient were prepared as follows.

[0073] The individual oral thin films were produced using mass production techniques known to those skilled in the art, e.g., by stirring / mixing the components using a stirring motor and suitable stirring tools. Gas is then injected into the resulting mass by stirring, e.g., using a foam-forming machine. The foamy mass is coated onto a coating carrier using suitable equipment (roller applicator, doctor blade, coating box, etc.) in a constant layer thickness. Any temperature-stable web-like material from which the dry film can be removed can serve as the coating carrier. This can be ensured by the material selection of the coating carrier (different surface tensions between the foamy mass and the substrate) or by suitable non-adhesive coatings of the coating carrier, e.g., silicones or fluoropolymers.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. Table 1: Ingredient function Amount [wt%] PVA 4-88 polymer 74,6 Polyox WSR N12 Polymer (decay retarder) 2,2 FD&C Red 40 dye 0,4 Saccharin Na Sweeteners 2,0 Sucralose Sweeteners 4,0 Glycerin plasticizers 9,0 menthol aroma 2,0 Cherry Flavor aroma 6,0 Table 2: Ingredient function Amount [wt%] PVA 4-88 polymer 81,1 Polyox WSR 303 Polymer (decay retarder) 0,5 FD&C Red 40 dye 0,4 Saccharin Na Sweeteners 2,0 Sucralose Sweeteners 4,0 Glycerin plasticizers 9,0 Cherry Flavor aroma 6,0 Table 3: Ingredient function Amount [wt%] PVA 4-88 polymer 80,6 Polyox WSR 3032 Polymer (decay retarder) 1,0 FD&C Red 40 dye 0,4 Saccharin Na Sweeteners 2,0 Sucralose Sweeteners 4,0 Glycerin plasticizers 9,0 menthol aroma 2,0 Cherry Flavor aroma 6,0 Table 4: Ingredient function Amount [wt%] PVA 4-88 polymer 79,6 Polyox WSR 3032 Polymer (decay retarder) 2,0 FD&C Red 40 dye 0,4 Saccharin Na Sweeteners 2,0 Sucralose Sweeteners 4,0 Glycerin plasticizers 9,0 menthol aroma 2,0 Cherry Flavor aroma 6,0 Table 5: Ingredient function Amount [wt%] PVA 4-88 polymer 79,6 Proloc 15 Polymer (decay retarder) 2,0 FD&C Red 40 dye 0,4 Saccharin Na Sweeteners 2,0 Sucralose Sweeteners 4,0 Glycerin plasticizers 9,0 menthol aroma 2,0 Cherry Flavor aroma 6,0

[0074] The oral thin films with the compositions shown in Tables 1 to 6 showed significantly longer disintegration times than compositions that did not contain a polymer with a MW greater than 100,000 g / mol. Example 2

[0075] Foamed oral thin films with the compositions shown in Tables 6 and 7 were prepared with (S)-ketamine HCl as the active ingredient as described above. Table 6: Ingredient function Amount per dose [m / 1.67 cm 3< ) Amount [wt%] (S)-Ketamine HCl Active ingredient 16,1 55,00 PVA 4-88 polymer 5,1 17,25 PVA 40-88 Polymer (decay retarder) 5,1 17,25 Saccarin Na Sweeteners 0,3 1,00 Sucralose Sweeteners 0,6 2,00 Glycerol plasticizers 1,3 4,50 Flavor PHL-131985 aroma 0,3 1,00 Flavor PHL-097336 aroma 0,6 2,00 Decay time 31 seconds Table 7: Ingredient function Amount per dose [m / 1.67 cm 3< ) Amount [wt%] (S)-Ketamine HCl Active ingredient 16,1 50,00 PVA 4-88 polymer 12,8 39,50 Saccarin Na Sweeteners 0,3 1,00 Sucralose Sweeteners 0,6 2,00 Glycerol plasticizers 1,4 4,50 Cherry Flavor aroma 1,0 3,00 Decay time about 9 seconds

[0076] The oral thin film with the composition shown in Table 6 had a significantly longer disintegration time than the oral thin film with the composition shown in Table 7, which did not contain any polymer with a MW greater than 100,000 g / mol.

[0077] The release rates of the active ingredient were also determined for the foamed oral thin film with the composition shown in Table 6. Release measurement:

[0078] During in vitro release, S-ketamine is released from S-ketamine HCl oral thin films (OTFs) and determined. The drug is released in phosphate buffer pH 6.8 USP and then determined using a gradient reversed-phase HPLC method. Quantification is performed against an external standard.

[0079] The release is carried out using Dissolution Apparatus 2 - (Paddle over sinker) according to USP <711> carried out. Table 8: Sinker: Stainless Steel Capsule Sinker with 10 Spirals, 31.0 x 11.0 mm Capacity (Sotax Style) Stirring speed: 50 rpm Distance between the vessel bottom and the bottom edge of the paddle: 25 mm ± 2 mm Temperature: 37°C ± 0.5°C Release medium: Phosphate buffer pH 6.8 USP Volume of release medium: 900 ml Sampling times: 1, 3, 5, 10 and 15 minutes Sample volume: 5.0 mL

[0080] The determined release rates are summarized in Table 9. Table 9: In vitro release [% of LC*] after 1 minute Mean 57 min 52 Max 59 RSD [%] 5,2 after 3 minutes Mean 101 min 97 Max 105 RSD [%] 2,8 after 5 minutes Mean 104 min 101 Max 110 RSD [%] 2,9 after 10 minutes Mean 104 min 102 Max 108 RSD [%] 2,3 after 15 minutes Mean 104 min 101 Max 109 RSD [%] 2,7 *Lable Claim = Target Salary

[0081] The drug release from an oral thin film according to Table 7 (fast release) was compared with the drug release from an oral thin film characterized by a particularly slow drug release (slow release).

[0082] The composition of the oral slow-release thin film is shown in Table 10. Table 10: Ingredient function Amount [wt%] (S)-Ketamine HCl Active ingredient 30,00 Proloc 15 polymer 10,00 PVA 40-88 Polymer (decay retarder) 49,50 Saccarin Na Sweeteners 1,00 Sucralose Sweeteners 2,00 Glycerol plasticizers 4,50 Cherry Flavor aroma 3,00 Basis weight (dry) 152.9 g / m 2 Basis weight (incl. residual solvent) 156.0 g / m 2

[0083] For the foamed oral thin films with the compositions shown in Table 7 and Table 10, the release rates of the active ingredient were also determined as described above.

[0084] The determined release rates are in Figure 1 shown. Example 3:

[0085] A foamed oral thin film with the composition shown in Table 11 with (S)-ketamine HCl as the active ingredient was prepared as described above. Table 11: Ingredient function Amount per dose [mg / 2.72 cm 3< ) Amount [wt%] (S)-Ketamine HCl Active ingredient 16,1 50,00 PVA 4-88 polymer 12,8 39,50 Saccarin Na Sweeteners 0,3 1,00 Sucralose Sweeteners 0,6 2,00 Glycerol plasticizers 1,5 4,50 Masking Flavor aroma 0,3 1,00 Raspberry Flavor aroma 0,6 2,00 Decay time about 3 seconds

[0086] For the foamed oral thin film with the composition shown in Table 11, the release rate of the active ingredient was also determined as described above.

[0087] The determined release rates are summarized in Table 12. Table 12: In vitro release [% of LC*] after 1 minute Mean 100 min 93 Max 106 RSD [%] 5,0 after 3 minutes Mean 104 min 100 Max 109 RSD [%] 3,4 after 5 minutes Mean 105 min 100 Max 109 RSD [%] 3,6 after 10 minutes Mean 105 min 100 Max 110 RSD [%] 3,8 after 15 minutes Mean 105 Min 101 Max 109 RSD [%] 3,6 *Lable Claim = Sollgehalt

Claims

1. An oral thin film comprising a polymer matrix in the form of a solidified foam having voids, wherein the polymer matrix contains at least one active pharmaceutical ingredient, at least one first polymer which comprises a water-soluble polymer and at least one second polymer which comprises a mucoadhesive polymer having a number-average molecular weight of equal to or greater than 100,000 g / mol.

2. The oral thin film according to claim 1, characterised in that the at least one mucoadhesive polymer comprises a water-soluble polymer.

3. The oral thin film according to any one of the preceding claims, characterised in that the first polymer comprises a polymer having a number-average molecular weight of less than 100,000 g / mol.

4. The oral thin film according to any one of the preceding claims, characterised in that the first 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.

5. The oral thin film according to any one of the preceding claims, characterised in that the second polymer is selected from the group comprising polyethylene oxide polymers, starch derivatives, polyacrylic acids, amylopectins and / or polyvinyl alcohols, especially mixtures from polyacrylates or polyacrylic acids and amylopectins.

6. The oral thin film according to any one of the preceding claims, characterised in that the first polymer is contained in the oral thin film in an amount of 40 to 95 wt.% in relation to the total weight of the oral thin film.

7. The oral thin film according to any one of the preceding claims, characterised in that the second polymer is contained in the oral thin film in an amount of 0.1 to 20 wt.% in relation to the total weight of the oral thin film.

8. The oral thin film according to any one of the preceding claims, characterised in that the at least one active pharmaceutical ingredient is contained in the oral thin film in an amount of 10 to 60 wt.% in relation to the total weight of the oral thin film.

9. The oral thin film according to any one of the preceding claims, 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.

10. The oral thin film according to any one of the preceding claims, characterised in that the voids are connected to one another and preferably form a channel system penetrating the polymer matrix.

11. The oral thin film according to any one of the preceding claims, 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 oral thin film.

12. A method for producing an oral thin film according to any one of claims 1 to 11, characterised by the steps of: a) producing a solution, dispersion or melt which at least comprises the first polymer, the second polymer and the at least one active pharmaceutical ingredient; b) foaming the solution, dispersion or melt by introducing a gas or gas mixture, by chemical gas generation, or by expanding a dissolved gas, optionally after prior addition of a foam-stabilising agent; c) spreading the foamed solution, dispersion or melt onto a coating substrate; and d) solidifying the spread solution, dispersion or melt by drying and removal of the solvent or by cooling.

13. The method according to claim 12, characterised in that steps c) and d) are replaced by the following steps c2) and d2): c2) producing a block, starting from the solution, dispersion or melt; d2) cutting the solidified block in order to obtain planar forms.

14. An oral thin film obtainable by a method according to any one of claims 12 or 13.

15. Oral thin film according to any one of claims 1 to 12 or claim 14 for use as a medicament.