SOLUBLE BACKING FOR OTF

Description

[0001] The present invention relates to a multilayer oral thin film, a process for its production, 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 a mucous membrane, particularly 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] State-of-the-art oral thin films have the disadvantage that, if they are intended to remain in one place on a patient's mucosa for an extended period, they are subject to permanent erosion. This leads to a large portion of the material being swallowed and thus not remaining at the application site for the desired duration. However, the retention time can be crucial for the transmucosal transport of the pharmaceutically active ingredient.

[0004] A protective layer on the backing layer prevents liquid from penetrating the formulation and dissolving it too quickly, allowing the active ingredient to remain at the application site for maximum time to achieve maximum permeation through the mucosa or delayed release. Another effect of the backing layer is that it prevents the administered film from detaching from the application site and adhering to another site, such as the teeth.

[0005] Insoluble or very slowly soluble polymers or polymer films are often used as materials for such backing layers. However, these have the disadvantage that they must be removed or swallowed after application.

[0006] Backing layers made of slowly soluble polymers also have the disadvantage of being based on long-chain, high-molecular-weight polymers. These are difficult to process due to their high viscosity (long drying times, irregular films). Furthermore, they tend to increase the viscosity of saliva in the mouth, creating a slimy feeling in the mouth.

[0007] Masek Josef et al. (Journal of Controlled Release, Elsevier, Amsterdam, NL; Vol. 249, July 25, 2016, pages 183-195) disclose a multilayer oral thin film containing a matrix layer and a backing layer, wherein the backing layer consists of an orally soluble polymer that protects the matrix layer from erosion.

[0008] The object of the present invention is to remedy the aforementioned disadvantages of the prior art. In particular, the object of the present invention is to provide a multilayer oral thin film comprising at least one backing layer whose dissolution time can be varied and thus adjusted, and which can be dissolved without residue and without producing an unpleasant mouthfeel.

[0009] The above object is achieved by a multilayer oral thin film according to claim 1, which comprises a matrix layer containing at least one polymer and at least one pharmaceutically active ingredient and at least one backing layer, wherein the at least one backing layer has a layer thickness of 10 µm to 500 µm and comprises at least one polymer which has free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer which comprises free carboxyl groups are present in neutralized form as a salt, and wherein the at least one polymer which comprises free carboxyl groups is present in the backing layer in an amount of 10 to 99% by weight, based on the total weight of the backing layer.

[0010] Such a multilayer oral thin film has the advantage that, by specifically adjusting the degree of neutralization of the at least one polymer containing free carboxyl groups, a backing layer can be provided that dissolves without residue after the desired time. Because the polymer is preferably water-insoluble in the unneutralized state and highly water-soluble in the fully neutralized state, the dissolution rate can be adjusted as desired, from insoluble to rapidly soluble. The backing layer thus reliably protects the applied film through slow solubility for the desired duration.

[0011] Even stroking with the tongue cannot achieve increased erosion, since the dissolution cannot be accelerated mechanically but depends on the buffer capacity of the existing saliva and the subsequently produced saliva.

[0012] Furthermore, it is advantageous that due to its good solubility in the neutralized state, the backing layer does not cause an unpleasant mouthfeel.

[0013] Additionally, the backing layer can be colored with dye to achieve better visibility.

[0014] Furthermore, it is possible to incorporate flavorings to improve the mouthfeel during use, which is a major advantage over films.

[0015] In the present description of the oral thin film, "comprising" may also mean "consisting of".

[0016] The backing layer is understood to be a layer of the multilayer oral thin film that represents one of the outermost layers of the multilayer oral thin film.

[0017] The at least one polymer comprising free carboxyl groups is preferably a sparingly soluble, very sparingly soluble or practically insoluble polymer in water according to the following table.

[0018] Solubility at 15 °C to 25 °C: Designation V(solvent) in ml per g substance g·l -1< solvent very easily soluble < 1 >1000 easily soluble 1 to 10 100 to 1000 soluble 10 to 30 33 to 100 slightly soluble 30 to 100 10 to 33 difficult to dissolve 100 to 1000 1 to 10 very difficult to dissolve 1000 to 10000 0.1 to 1 practically (almost) insoluble > 10000 < 0,1

[0019] It has been shown that the solubility of polymers containing free carboxyl groups in water can be varied by partial neutralization or the addition of at least one base. Applied to the backing layer of the multilayer oral thin film, this means that the disintegration time of the backing layer in the patient's mouth can be varied.

[0020] The multilayer oral thin film according to the invention is characterized in that at least 10%, particularly preferably from 15 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt.

[0021] Preferably, 15 to 100% or 20 to 100% or 25 to 100% or 30 to 100% or 35 to 100% or 40 to 100% or 45 to 100% or 50 to 100% or 60 to 100% or 70 to 100% or 80 to 100% or 90 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt.

[0022] According to the invention, 10 to 100%, preferably 15 to 100% or 20 to 95% or 25 to 90% or 30 to 85% or 35 to 80% or 40 to 75% or 45 to 70% or 50 to 65% or 55 to 60% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized as a salt.

[0023] If, contrary to the invention, 0% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer is preferably insoluble. If approximately 10% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of approximately 4 and is thus very slowly soluble.

[0024] If about 15% to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are neutralized, the polymer preferably has a pH of about 4.6 to 7.

[0025] The multilayer oral thin film according to the invention is further preferably characterized in that the at least one backing layer has a pH of 3.5 to 7.5, preferably of 4 to 7, especially 4.5 to 6.5.

[0026] The pH of the backing layer corresponds to the pH of the solution or suspension of an aqueous solution of all ingredients of the backing layer at 20°C. The aqueous solution can contain only water as the solvent, but also mixtures of water with organic solvents. In principle, all water-miscible organic solvents are suitable as organic solvents. Preferred are ketones, alcohols, and / or esters, especially acetone or ethanol.

[0027] If more than one polymer containing free carboxyl groups is present in the backing layer, the values ​​given for the degree of neutralization of the free carboxyl groups refer to the sum of all carboxyl groups present.

[0028] The multilayer oral thin film according to the invention is further characterized in that the at least one polymer comprising free carboxyl groups is present in the backing layer in an amount of 10 to 99 wt.%, preferably 20 to 95 wt.%, particularly preferably 25 to 90 wt.%, based on the total weight of the backing layer.

[0029] Mixtures of several polymers comprising free carboxyl groups can also be used. The sum of all polymers comprising free carboxyl groups is in an amount of 10 to 99 wt.%, preferably 20 to 95 wt.%, particularly preferably 25 to 90 wt.%, based on the total weight of the backing layer.

[0030] The multilayer oral thin film according to the invention is further preferably characterized in that the content of free carboxyl groups in the polymer comprising free carboxyl groups is 10 to 40 wt.%, preferably 15 to 35 wt.%, particularly preferably 20 to 30 wt.%, based on the average polymer mass.

[0031] If more than one polymer containing free carboxyl groups is present in the backing layer, these values ​​refer to the sum of all carboxyl groups present.

[0032] The at least one polymer comprising free carboxyl groups preferably comprises a polymer based on (meth)acrylic acid and / or based on a copolymer of (meth)acrylic acid and (meth)acrylic acid esters.

[0033] Most preferably, the at least one polymer comprising free carboxyl groups comprises a copolymer of (meth)acrylic acid and (meth)acrylic acid esters, most preferably a (meth)acrylic acid / ethyl acrylate copolymer.

[0034] Suitable polymers are available, for example, under the trade names Kollicoat L100, Kollicoat L100-55, Kollicoat MAE Kollicoat Smart Seal (from BASF) or Eudragit L, Eudragit S (Evonic) or Acryl-EZE (Colorcon).

[0035] These polymers have the advantage of being virtually insoluble in water, and their solubility can be easily varied by adding at least one base. Some of these polymers are already pre-neutralized by the manufacturer.

[0036] The multilayer oral thin film according to the invention is further preferably characterized in that the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralized by adding at least one base.

[0037] The type of base is not limited; in principle, any pharmaceutically acceptable base can be used. The base particularly preferably comprises a hydroxide, especially an alkali or alkaline earth metal hydroxide. NaOH is especially preferred.

[0038] The added amount of the at least one base is preferably such that the equivalence ratio of the base to the free carboxyl groups of the at least one polymer comprising free carboxyl groups is 1:10 to 2:1, preferably 1:10 to 1:1.

[0039] If NaOH is added as a base, the amount added can preferably be such that 0.5 to 15 wt.% NaOH, based on the weight of the at least one polymer comprising free carboxyl groups, is added.

[0040] The multilayer oral thin film according to the invention is further preferably characterized in that the backing layer comprises at least one plasticizer.

[0041] Suitable plasticizers include citric acid esters, alpha tocopherol, benzyl benzoate, butyl stearate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, diethyl phthalate, dimethyl phthalate, dipropylene glycol, glycerin, glycerol monostearate, polyethylene glycol, propylene glycol, stearic acid, triacetin and / or tricaprylin, particularly preferably triethyl citrate.

[0042] The multilayer oral thin film according to the invention is preferably characterized in that the at least one plasticizer is present in the back layer of the multilayer oral thin film in an amount of 1 to 20 wt.%, preferably 5 to 15 wt.%, particularly preferably 8 to 12 wt.%, based on the total weight of the back layer.

[0043] The multilayer oral thin film according to the invention is further preferably characterized in that the matrix layer comprises at least one water-soluble polymer.

[0044] 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.

[0045] Water-soluble polymers preferably have a solubility in water according to the table above of at least "soluble".

[0046] The at least one water-soluble polymer is preferably selected from the group consisting of starch and starch derivatives, dextrans; cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propylcellulose; polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinylpyrrolidone / vinyl acetate copolymer, 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. Particularly preferably, the at least one water-soluble polymer comprises vinylpyrrolidone / vinyl acetate copolymer

[0047] The multilayer oral thin film according to the invention is preferably characterized in that the at least one polymer, preferably the water-soluble polymer, is present in the matrix layer of the multilayer oral thin film in an amount of 5 to 95 wt.%, preferably 10 to 80 wt.%, based on the total weight of the matrix layer.

[0048] Embodiments of the multilayer oral thin film according to the invention are also possible, wherein the at least one polymer, preferably the water-soluble polymer, is present in the matrix layer of the multilayer oral thin film in an amount of 5 to 50 wt.%, preferably 10 to 40 wt.%, based on the total weight of the matrix layer.

[0049] 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.

[0050] According to the present invention, the pharmaceutically active ingredient also includes all pharmaceutically acceptable salts and solvates of the respective pharmaceutically active ingredient.

[0051] Preferably, active ingredients are selected from the group consisting of 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.

[0052] Particularly preferably, the at least one pharmaceutically active ingredient is ketamine and / or a pharmaceutically acceptable salt or solvate thereof, preferably ketamine HCl.

[0053] 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.

[0054] However, it is particularly preferred that (S)-ketamine or a pharmaceutically acceptable salt thereof, in particular (S)-ketamine HCl, is 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.

[0055] The multilayer oral thin film according to the invention is further preferably characterized in that the at least one pharmaceutically active ingredient, preferably ketamine, is present in the matrix layer in an amount of 1 to 50 wt.%, preferably 10 to 40 wt.%, particularly preferably 25 to 35 wt.%, based on the total weight of the matrix layer.

[0056] The multilayer oral thin film according to the invention is further preferably characterized in that the matrix layer further 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.

[0057] Each of these excipients is preferably contained in this layer in an amount of about 0.1 to 40% by weight, preferably from 0.1 to 30% by weight, particularly preferably from 0.1 to 15% by weight, based on the total weight of the matrix layer.

[0058] The multilayer oral thin film according to the invention is further preferably characterized in that the backing layer further comprises at least one excipient selected from the group comprising dyes, flavorings, sweeteners, taste masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0059] Each of these auxiliaries is preferably contained in this layer in an amount of about 0.1 to 40 wt.%, preferably from 0.1 to 30 wt.%, particularly preferably from 0.1 to 15 wt.%, based on the total weight of the backing layer.

[0060] The oral thin film according to the invention preferably has an area of ​​about 0.5 cm 2< to about 10 cm 2< , more preferably about 2 cm 2< to about 8 cm 2< .

[0061] The oral thin film according to the invention is preferably characterized in that the basis weight of the oral thin film is about 10 to 500 g / m 2< , preferably about 100 to 400 g / m 2< .

[0062] The basis weight of the backing layer is important for controlling dissolution behavior and the backing layer's function in protecting the active ingredient from dissolving in saliva. A certain thickness is required to ensure adequate protection of the active ingredient as well as a sufficient dissolution time, which should normally be at least as long as the active permeation requirement and thus the dissolution time of the matrix layer.

[0063] In addition, it is also difficult to coat, especially very thin layers, with sufficient accuracy. On the other hand, thick layers can not only cause an unpleasant feeling in the oral cavity, but can also be difficult to produce and result in the layer taking too long to dissolve for the desired (e.g. overnight) application. Overall, it is preferred that the backing layer has a basis weight of at least 10 g / m 2< , more preferably at least 20 g / m 2< or most preferably at least 30 g / m 2< or a basis weight of less than or equal to 400 g / m 2< , more preferably less than or equal to 350 g / m 2< or most preferably less than or equal to 300 g / m 2< or a basis weight of 10 to 400 g / m 2< , more preferably from 20 to 350 g / m 2< or most preferably from 30 to 300 g / m 2<.

[0064] According to the invention, this corresponds to a layer thickness of 10 µm to 500 µm, particularly preferably of about 20 µm to about 300 µm.

[0065] The oral thin film according to the invention is preferably characterized in that the carrier layer, in certain embodiments, dissolves in 5 minutes or more, preferably in 10 minutes or more, and more preferably in 15 minutes or more, or in 12 hours or less, preferably in 8 hours or less, and more preferably in 4 hours or less, or in 5 minutes or 12 hours, preferably in 10 minutes or 8 hours, and more preferably in 15 minutes or 4 hours after administration of the oral thin film to a patient.

[0066] It is also preferred that the backing layer dissolves in water, in artificial or natural saliva, or in any other aqueous medium, preferably in a buffered aqueous medium, at 37°C and 150 rpm, in 5 minutes or more, preferably in 10 minutes or more, preferably in 15 minutes or more, and more preferably in 30 minutes or more, and in 15 hours or less, preferably in 12 hours or less, and more preferably in 10 hours or less, or in 10 minutes or 15 hours, preferably in 15 minutes or 12 hours, and more preferably in 30 minutes or 10 hours. In particular, the backing layer can be the same size as or larger than the matrix layer. Thus, in certain embodiments, the size of the backing layer and the size of the matrix layer are the same, while in other embodiments, the backing layer is larger than the surface area of ​​the matrix layer and increases in size.While a layered structure with the same size backing and matrix layers is easier to manufacture because a two-layer sheet can be die-cut to provide the layered structure, a layered structure with a backing layer that is larger than the matrix layer is more difficult to manufacture but also offers the advantage of reducing the risk of active leakage because the edge of the matrix layer is also covered by the carrier layer.

[0067] The present invention further relates to a process for producing the oral thin film according to the invention. The process comprises the steps: a) Providing at least one active ingredient-containing matrix layer comprising the steps a1) Preparing a solution or suspension comprising the at least one polymer and the at least one pharmaceutically active ingredient and a2) Spreading and drying the solution or suspension obtained according to step a1); b) Providing at least one backing layer with a layer thickness of 10 µm to 500 µm, comprising the steps b1) Preparing a solution or suspension comprising at least one polymer which comprises free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer which comprises free carboxyl groups are present in neutralized form as a salt; wherein the at least one polymer which comprises free carboxyl groups is present in an amount of 10 to 99% by weight.-%, based on the total weight of the backing layer, is present in the backing layer; b2) spreading and drying the solution obtained according to step b1); c) combining the active ingredient-containing matrix layer obtained according to a) and the backing layer obtained according to b) to obtain a multilayer oral thin film.

[0068] The polymer used in step b) can be at least partially neutralized by adding at least one base, as described above. Alternatively, a polymer pre-neutralized by the manufacturer can be used.

[0069] The two films can be joined together using methods familiar to those skilled in the art. For example, a second film can be applied to a first film by coating, whereby it is irrelevant which film is coated onto which film, as long as the backing layer forms one of the outermost layers. Furthermore, the two layers can be bonded together using an adhesive layer. Furthermore, the two layers can be bonded together using heat.

[0070] The present invention further relates to a multilayer oral thin film obtainable by the method described above.

[0071] Furthermore, the present invention relates to a multilayer oral thin film as described above or obtainable by the method described above for use as a medicament.

[0072] The present invention further relates to a multilayer oral thin film as described above or obtainable by the method described above, 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.

[0073] The preferred embodiments listed above for the multilayer oral thin film according to the invention also apply to the process according to the invention, the multilayer oral thin film obtained by this process and its use as a medicament.

[0074] Description of the characters: Figure 1 : Dissolution times of formulations without backing layer, with PET backing layer and a backing layer according to the invention.

[0075] The invention is explained in more detail below using non-limiting examples. Examples: Example 1:

[0076] A backing layer is prepared as follows: Formulation Composition: Table 1: Ingredient function Portion [%] Kollicoat MAE 100-55 polymer 42 Kollocoat MAE 100 P polymer 42 Triethyl citrate plasticizers 10 Sucralose Taste correction 3 Saccharin Na Taste correction 2 Cherry Flavor Taste correction 1 Solvent: Ethanol:Water 80:20 Target basis weight: approx. 50 g / m2 Manufacturing sequence: The solvents are placed together, and the plasticizer and flavoring are added. Then, the sweeteners are dissolved one after the other, and the polymers are sprinkled in and dissolved. The mixture is then allowed to rest until it is free of bubbles.

[0077] The result is a homogeneous, slightly cloudy mass. Coating / drying:

[0078] The mass is applied to a siliconized liner and the resulting film is dried.

[0079] The result is a thin, stable, clear film. Further processing:

[0080] The resulting coating can now be further processed. For example, another film, such as the matrix layer, can be applied to this backing layer by coating, gluing, or heat treatment. Example 2:

[0081] In an initial study, three formulation variants were tested. Formulation 1 was the base without a backing layer. A formulation with a PET backing (insoluble, 2) and the inventive dissolving backing layer (3) was then formed from the same mass. Table 2: material 1 2 3 Matrix layer S-Ketamine HCl 30.0 % 30.0 % 30.0 % Kollidon VA 64 1< 20.5 % 20.5 % 20.5 % Kollicoat MAE 2< 35.0 % 35.0 % 35.0 % NaOH 1.0 % 1.0 % 1.0 % accharin Na 2.0 % 2.0 % 2.0 % Sucralose 1.0 % 1.0 % 1.0 % Cherry Flavor 3.0 % 3.0 % 3.0 % Glycerin 7.5 % 7.5 % 7.5 % solvent Purified water / ethanol Purified water / ethanol Purified water / ethanol Backing layer - - PET backing layer - FO PET 15µm tsp. Kollicoat MAE backing layer - - Kollicoat MAE backing layer: Kollicoat MAE 100-55 - - 42.0 % Kollicoat MAE 100 P - - 42.0 % Triethyl citrate - - 10.0 % Cherry EU - - 3.0 % Saccarin Na - - 2.0 % Sucralose - - 1.0 % solvent - - Purified water / ethanol 1< : Vinylpyrrolidone / vinyl acetate copolymer 2< : (Meth)acrylic acid / ethyl acrylate copolymer Table 3: formulation Decay time [s] Fully resolved* [s] 1 341 425 2 773 1122 3 Not recognizable 742 * The full dissolution time refers to the dissolution of the matrix layer containing at least one pharmaceutically active ingredient.

[0082] The disintegration rate and the release of the active ingredient were tested.

[0083] The disintegration time was tested using a standard dissolution tester with a sinker, which is well known and described in pharmacopoeias. The active ingredient was released using a standard dissolution tester using the "rotating cylinder" method. For this purpose, the OTFs were glued to a cylinder, which rotated in the release medium. Analysis was performed by HPLC.

[0084] The tests confirmed that the backing layer of the inventive formulation 3 dissolved and significantly slowed down the disintegration and drug release compared to the reference (1). The results are also shown in Figure 1 shown.

[0085] The polymer is neutralized by adding sodium hydroxide solution (preferably as a solution in the corresponding solvent used for the polymer solution) dropwise, while stirring, to a polymer suspended in water or dissolved in a mixture of organic solvent and water (here, Kollicoat L100-55). The increasing neutralization reduces the solubility in the organic solvent and increases the solubility in water.

[0086] It is preferable that a certain amount of water is present, otherwise phase separation occurs and the polymer can precipitate as a solid component.

[0087] Since the proportion of added sodium hydroxide solution becomes very high at higher concentrations, a blend of pre-neutralized polymer (Kollicoat MAE 100P pre-neutralized by the manufacturer using NaOH) and non-neutralized polymer (Kollicoat MAE 100-55) was also used (see Table 4). The pH value of the polymer mixtures summarized in Table 4 is in Figure 2 shown. Table 4 Recipe Kollicoat MAE 100-55 Kollicoat MAE 100P Relationship NaOH [%] PH value 1 72.21 72.21 / 13.14 13,14 7,61 2 71.9 71.9 / 12.1 12,1 6,93 3 74 74.0 / 10.0 10 6,76 4 73.2 73.2 / 10.8 10,8 6,64 5 72.4 72.4 / 11,6 11,6 6,51 6 82.5 82.5 / 1.5 1,5 5,9 7 100 100+0.25 0,25 6,04 8 0 100 0 / 100 0 6,2 9 17 83 17 / 83 0 6 10 25 75 25 / 75 0 5,9 11 50 50 50 / 50 0 5,6 12 75 25 75 / 25 0 5,3 13 79 21 79 / 21 0 4,9 14 85 15 85 / 15 0 4,6 15 100 0 100 / 0 0 3,5 Example 3:

[0088] In a further experiment, the differences between different pH values ​​were demonstrated. For this purpose, an active ingredient film with a similar composition to that used in previous experiments was coated with backing layers with different degrees of neutralization (pH values). The compositions (in wt. %) are summarized in Table 5. Table 5: formulation 1 2 3 4 Matrix layer S-Ketamine HCl 30.0 % 30.0 % 30.0 % 30.0 % Kollidon VA 64 20.5 % 20.5 % 20.5 % 20.5 % Kollicoat MAE 35.0 % 35.0 % 35.0 % 35.0 % NaOH 1.0 % 1.0 % 1.0 % 1.0 % Saccharin Na 2.0 % 2.0 % 2.0 % 2.0 % Sucralose 1.0 % 1.0 % 1.0 % 1.0 % Cherry Flavor 3.0 % 3.0 % 3.0 % 3.0 % Glycerin 7.5 % 7.5 % 7.5 % 7.5 % solvent Purified water / ethanol Purified water / ethanol Purified water / ethanol Purified water / ethanol Kollicoat MAE backing layer Kollicoat MAE pH 3.5: Collie coat MAE pH 5.0: Kollicoat MAE pH 6.0: Kollicoat MAE pH 7.0: Kollicoat MAE 100-55 84.0 % 66.4 % 14.3 % -- Kollicoat MAE 100 P -- 17.6 % 69.7 % 71.9 % Triethyl citrate 10.0 % 10.0 % 10.0 % 10.0 % Cherry EU 3.0 % 3.0 % 3.0 % 3.0 % Saccarin Na 2.0 % 2.0 % 2.0 % 2.0 % Sucralose 1.0 % 1.0 % 1.0 % 1.0 % NaOH -- -- -- 12.1 % solvent Purified water / ethanol Purified water / ethanol Purified water / ethanol Purified water / ethanol

[0089] The release was tested in two setups using the "paddle over disk" (TTS holder). In the first version, the OTF was tested with a USP 5 TTS holder, mesh size 40 (35 mm diameter), with the API side facing a PET film and the backing layer facing the release medium. This allowed the effectiveness of the backing layer to be tested. The measurement results are shown in Figure 3 summarized.

[0090] In a second variation, the setup was essentially the same, with the difference that the backing layer of the OTF was applied to the PET side to show the release profiles of the API matrix. The measurement results are shown in Figure 4 summarized. Example 5:

[0091] Oral thin films containing agomelatine as the pharmaceutically active ingredient were also prepared with the compositions shown in Tables 6 and 7. Table 6: Agomelatine-containing matrix layer Ingredient Example 3a Examples 3b, 3c and 3d Quantity [g] Solids [%] Quantity [g] Solids [%] Agomelatine 0.50 9.96 3.50 9.98 Eucalyptol 0.04 0.83 0.17 0.49 menthol 0.05 1.00 0.35 1.00 Methyl salicylate 0.03 0.52 0.18 0.51 Novamint Fresh Peppermint 0.18 3.52 1.24 3.52 Kolliphor RH 40 (Cremophor) 0.12 2.43 0.72 2.06 FD&C Red #40 0.004 0.09 0.04 0.10 Sucralose 0.03 0.50 0.18 0.50 Polyvinylpyrrolidone (Povidone K90) 4.00 79.14 27.98 79.80 Polysorbate 80 (Tween 80) 0.10 2.02 0.71 2.03 Ethanol 21.89 - 155.60 - Total 26.94 100.01 190.67 99.99 Basis weight [g / m 2< ] 55.4 50.0 Agomelatine content [µg / cm 2 ] 551.6 499.2 Size of the OTF [cm 2 ] 0.522 Backing layer Ex. 3a Ex. 3b Ex. 3c Ex. 3d Ingredient Quantity [g] Fixed [%] FO-PET 15µm Ethylcellulose N50F 5.22 65.09 castor oil 2.80 34.91 Ethanol 45.33 - Total 53.35 100.00 Basis weight [g / m 2< ] 12.3 Size of the OTF [cm 2 ] 0.522 Table 7: Agomelatine-containing matrix layer Ingredient Example 3e - 3h Quantity [g] Solids [%] Agomelatine 3.50 9.98 Eucalyptol 0.17 0.49 menthol 0.35 1.00 Methyl salicylate 0.18 0.51 Novamint Fresh Peppermint 1.24 3.52 Kolliphor RH 40 (Cremophor) 0.72 2.06 FD&C Red #40 0.04 0.10 Sucralose 0.18 0.50 Polyvinylpyrrolidone(Povidone K90) 27.98 79.80 Polysorbate 80 (Tween 80) 0.71 2.03 Ethanol 155.60 Total 190.67 99.99 Basis weight [g / m 2< ] 50.0 Agomelatine content[µg / cm 2< ] 499.2 Size of the OTF [cm 2 ] 0.522 Backing layer Example 3e Example 3f Example 3g Example: 3 hours Ingredient Quantity [g] Fixed [%] Quantity [g] Fixed [%] Quantity [g] Fixed [%] Quantity [g] Fixed [%] Kollidon VA 64 9.29 46.36 9.31 39.63 8.40 42.11 8.50 42.50 Eudragit L100-55 9.22 46.01 9.21 39.21 8.40 42.11 8.50 42.50 Glycerol (99.5%) 1.54 7.63 1.51 6.39 1.55 7.72 3.02 15.00 NaOH 0.1N - - 3.47 14.77 1.61 8.07 - - Ethanol 22.49 - 22.53 - 22.5 - 22.49 - Purified water 7.50 - 7.55 - 7.52 - 7.56 - Total 50.04 100.00 53.58 100.00 49.98 100.01 50.07 100.00 Basis weight [g / m 2< ] 26.8 26.0 20.5 22.9 pH 3.75 5.01 4.46 3.62 Size of the OTF [cm 2 ] 0.522

[0092] For Example 3a, a beaker was loaded with agomelatine. Ethanol, eucalyptol, menthol, methyl salicylate, Novamint Fresh Peppermint, Kolliphor RH 40, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was then stirred. The polyvinylpyrrolidone was added with stirring, and after approximately 2.5 hours of stirring, a clear, red solution was obtained.

[0093] For Examples 3b to 3h, the same coating composition was used for the agomelatine-containing layer, which was prepared as follows: A beaker was filled with agomelatine. Ethanol, menthol, eucalyptol, methyl salicylate, Kolliphor RH 40, FD&C Red #40, sucralose, and polysorbate 80 were added, and the mixture was then stirred. A clear solution was obtained. The polyvinylpyrrolidone was added, and after further stirring, the Novamint Fresh Peppermint was added dropwise with stirring to obtain a clear, red solution. Preparation of a second coating composition (backing layer):

[0094] For Example 3c, a beaker was loaded with ethylcellulose. Ethanol was added, and the mixture was then stirred. Castor oil was added with stirring to obtain a slightly opaque mixture.

[0095] For Examples 3e to 3h, a beaker was charged with ethanol. Purified water and Kollidon were added, and the mixture was stirred to obtain a solution. Eudragit and glycerin were added with stirring, resulting in a clear mixture.

[0096] For Examples 3f and 3g, sodium hydroxide solution was added to obtain a pH value as indicated in Table 7.

[0097] The resulting second coating composition of Examples 3c and 3e to 3h was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 µm thick, which can function as a release layer) and dried for approximately 10 minutes at room temperature and 20 minutes at 70°C (Ex. 3c) and for approximately 5 minutes at room temperature, 10 minutes at 35°C, and 2 minutes at 80°C (Ex. 3e to 3h). The layer thickness resulted in a basis weight of 12.3 g / m 2 (Ex. 3c), 26.8 g / m 2 (Ex. 3e), 26.0 g / m 2 (Ex. 3f), 20.5 g / m 2 (Ex. 3g), and 22.9 g / m 2 (Ex. 3h), respectively.

[0098] For example 3d, a commercially available polyethylene terephthalate film with a thickness of 15 µm was used as the carrier layer.

[0099] The resulting agomelatin-containing first coating composition of Examples 3a and 3b was applied to a polyester film (polyethylene terephthalate film, siliconized on one side, 75 µm thick, which can act as a release layer) and dried for approximately 15 minutes at room temperature and 5 minutes at 70 °C (Ex. 3a) or for approximately 5 minutes at room temperature, 10 minutes at 50 °C, and 2 minutes at 90 °C (Ex. 3b). For Examples 3a and 3b, the dried film represents the final agomelatin-containing layer structure.

[0100] The resulting agomelatin-containing first coat compositions of Examples 3c and 3e to 3h were applied to the dried carrier layer and dried for about 5 min at room temperature, 10 min at 50 °C and 2 min at 90 °C (Examples 3c and 3e to 3h).

[0101] The coating thickness resulted in a basis weight of 55.4 g / m² (Example 3a) and 50.0 g / m² (Example 3b, 3c, and 3e to 3h). The coating process of Example 3d was identical to that of Examples 3b, 3c, and 3e to 3h, except that the coating composition was applied to a 15 μm thick polyethylene terephthalate film, resulting in an OTF with a carrier layer (made of a polyethylene terephthalate film).

[0102] The OTFs of Examples 3b, 3c, and 3e to 3h were prepared by laminating the support layers to the agomelatin-containing layers. The release liner was removed prior to lamination. Measurement of mucosal permeation rate:

[0103] The permeate quantity and the corresponding mucosal permeation rates of the OTFs prepared according to Examples 3a to 3h were determined by in vitro experiments using porcine mucosa (esophageal mucosa) according to the OECD guideline (adopted on April 13, 2004). Using a dermatome, the mucosa was prepared to a thickness of 400 µm with an intact barrier function. The OTFs were applied to the mucosa with an area of ​​0.522 cm², and the mucosa, with the OTF on top, was immersed in artificial saliva (the bottom side is in contact with the receptor medium, the top side is divided into a mucosal area of ​​1.145 cm²). The amount of agomelatin permeated into the receptor medium (phosphate buffer solution pH 7.4) at a temperature of 37 ± 1°C was measured, and the corresponding mucosal permeation rate was calculated. The results are presented in Tables 8 and 9 and Figures 3a and 3b.In this example, the standard deviation (SD) was calculated using the n-method. Table 8: Time [h] Bsp. 3a (n = 3) Bsp. 3b (n = 3) Bsp. 3c (n = 3) Bsp. 3d (n = 3) Rate SD Rate SD Rate SD Rate SD 0.5 23.19 5.57 55.30 46.92 17.07 6.03 5.44 3.18 1 91.36 7.68 131.57 84.76 63.94 8.91 29.20 12.09 2 105.02 3.93 115.97 51.31 75.98 11.34 45.16 9.80 4 64.60 0.46 45.71 15.35 59.38 0.99 37.46 2.22 6 34.53 1.21 32.42 6.60 37.75 1.01 35.10 3.86 Table 9: Zeit [h] Bsp. 3e (n = 3) Bsp. 3f (n = 3) Bsp. 3g (n = 3) Bsp. 3h (n = 3) Rate SD Rate SD Rate SD Rate SD 0.5 24.26 1.05 12.66 7.08 11.06 3.42 17.28 7.68 1 61.51 2.48 41.72 12.24 35.91 4.34 47.51 11.58 2 63.17 1.45 50.58 6.03 44.57 3.58 53.13 7.70 4 58.15 2.65 52.93 3.42 46.19 2.17 50.98 4.52 6 43.26 3.14 45.01 0.75 37.46 2.54 45.56 2.35 Uses of agomelatine:

[0104] Agomelatine utilization at 6 hours was calculated based on the cumulative permeate amount at 6 hours and the initial agomelatine content. The results are presented in Table 10. Table 10: Verwendung von Agomelatin nach 6 Stunden [%] Bsp. 3a (n = 3) Bsp. 3b (n = 3) Bsp. 3c (n = 3) Bsp. 3d (n = 3) Bsp. 3e (n = 3) Bsp. 3f (n = 3) Bsp. 3g (n = 3) Bsp. 3h (n = 3) 65.4 68.9 62.3 41.6 61.9 54.8 47.2 55.8

[0105] The in vitro experiments demonstrate good mucosal permeation rates and good drug utilization. Examples 3c to 3h, compared to Examples 3a and 3b, demonstrate that even with the use of a backing layer, lower but still good permeation can be achieved.

Claims

1. A multi-layer oral thin film comprising a matrix layer, which contains at least one polymer and at least one pharmaceutically active agent, and at least one backing layer, wherein the at least one backing layer has a layer thickness of from 10 µm to 500 µm and comprises at least one polymer containing free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are present in a neutralised form as a salt, and wherein the at least one polymer comprising free carboxyl groups is provided in the backing layer in an amount of 10 to 99 wt.%, in relation to the total weight of the backing layer.

2. The multi-layer oral thin film according to claim 1, wherein the at least one backing layer has a pH of 3.5 to 7.

3. The multi-layer oral thin film according to any one of the preceding claims, wherein the content of free carboxyl groups in the polymer comprising free carboxyl groups is 10 to 40 wt.%, in relation to the mean polymer mass.

4. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polymer comprising free carboxyl groups comprises a polymer based on (meth)acrylic acid and / or based on a copolymer of (meth)acrylic acid and (meth)acrylates.

5. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polymer comprising free carboxyl groups comprises a (meth)acrylic acid / ethyl acrylate copolymer.

6. The multi-layer oral thin film according to any one of the preceding claims, wherein the free carboxyl groups of the at least one polymer comprising free carboxyl groups have been neutralised by addition of at least one base, preferably NaOH.

7. The multi-layer oral thin film according to any one of the preceding claims, wherein the backing layer comprises at least one plasticiser, preferably triethyl citrate.

8. The multi-layer oral thin film according to any one of the preceding claims, wherein the matrix layer comprises at least one water-soluble polymer.

9. The multi-layer oral thin film according to claim 9, wherein the at least one water-soluble polymer is selected from the group consisting of 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 copolymer, 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.

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

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

12. A method for producing a multi-layer oral thin film according to any one of claims 1 to 11, comprising the steps of: a) providing at least one active agent-containing matrix layer, comprising the steps of a1) producing a suspension or suspension comprising the at least one polymer and the at least one pharmaceutically active agent, and a2) spreading out and drying the solution or suspension obtained in accordance with step a1); b) providing at least one backing layer with a layer thickness of from 10 µm to 500 µm, comprising the steps of b1) producing a solution or suspension comprising at least one polymer comprising free carboxyl groups, wherein 10 to 100% of the free carboxyl groups of the at least one polymer comprising free carboxyl groups are present in a neutralised form as a salt, wherein the at least one polymer comprising free carboxyl groups is provided in the backing layer in an amount of 10 to 99 wt.%, in relation to the total weight of the backing layer; b2) spreading out and drying the solution obtained in accordance with step b1); c) joining together the active agent-containing matrix layer obtained in accordance with a) and the backing layer obtained in accordance with b) in order to obtain a multi-layer oral thin film.

13. A multi-layer oral thin film obtainable by the method according to claim 12.

14. A multi-layer oral thin film according to any one of claims 1 to 11 or 13 for the use as a medicament.