Oral film comprising epinephrine

Abstract

An oral film comprising one or more layers wherein at least one layer contains epinephrine or a pharmaceutically acceptable salt thereof and at least one polymer, characterized in that said epinephrine is substantially insoluble in said at least one polymer. Process for the preparation of said oral film comprising the steps of: a) preparing a solution comprising said at least one polymer and a solvent in which epinephrine or a pharmaceutically acceptable salt thereof is substantially insoluble, (b) adding epinephrine, (c) spreading and drying the suspension obtained in step (b) in order to obtain a single-layer oral film, and the oral film is used as a medicament, and is used as a medicament in the treatment of allergic reactions.

Description

[0001] The present invention relates to an oral film, a method for its preparation and its use as a medicament.

[0002] Oral thin films (OTF) are films containing at least one pharmaceutically active substance, which are placed directly in the oral cavity or applied to the oral mucosa and dissolve there. In particular, they are polymer-based films containing active ingredients, which, when applied to the mucosa, in particular the oral mucosa, release the active ingredient directly thereto. The good blood circulation of the oral mucosa ensures a rapid transfer of the active ingredient into the blood circulation. This dosing system has the advantage that the active ingredient is largely absorbed through the mucosa, thereby avoiding the "first-pass metabolism" that occurs with conventional dosage forms of the active ingredient in tablet form.

[0003] A problem with the administration of adrenaline, especially in dissolved form in an oral film, is that the active ingredient initially dissolves or partially dissolves during the preparation of the oral film and partially recrystallizes when the solvent evaporates. However, recrystallization is undesirable because it leads to morphological changes in the active ingredient and can also have a negative effect on the chemical stability of the active ingredient. In particular, an uneven appearance on the surface can occur, which appears as spots and / or macroscopically visible crystals / crystal accumulations. In addition, recrystallization can also have a negative effect on the mechanical properties of the oral film.

[0004] Although the degradation of epinephrine to adrenochrome results in a strong coloration, the degradation mechanism to form D-epinephrine and adrenaline sulfonate is responsible for the largest amount of degradation. This occurs via the planar sp 2 - transition state occurs. The reaction of the transition state with water results in the formation of D- and L-epinephrine in a 1:1 ratio, which in the long term leads to racemization of the starting material. The large-scale use of sodium metabisulfite in existing market products leads to the formation of sulfite (SO3 2- ) and adrenaline reaction (S N 1 reaction). At the end of the shelf life, known commercial products therefore contain up to 15% of adrenaline sulfonate.

[0005] US2018 / 0125977 A1 discloses a pharmaceutical composition for administering epinephrine, wherein the epinephrine is partially dissolved in the composition.

[0006] Other oral film formulations are disclosed in WO 2022 / 195521 A1 and WO 2021 / 001461 A1. Foam film formulations are disclosed in WO 2018 / 224591 A1.

[0007] The problem on which the present invention is based is to overcome the aforementioned disadvantages of the prior art. In particular, the problem of the present invention is to provide an oral film for administering adrenaline or a pharmaceutically acceptable salt thereof, wherein uncontrolled recrystallization of adrenaline or a pharmaceutically acceptable salt thereof is largely prevented. In addition, adrenaline or a pharmaceutically acceptable salt thereof should also be present in the oral film in a largely chemically stable state, thereby preventing degradation or racemization of the pharmaceutically active L-adrenaline without the need to use large amounts of antioxidants, in particular sodium metabisulfite. In addition, the preparation of the oral film should be easy and inexpensive.

[0008] This problem is solved by an oral film according to claim 1, comprising one or more layers, wherein at least one layer contains adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, characterized in that the adrenaline is substantially (essentially) insoluble in the at least one polymer.

[0009] This dosage form makes it possible to eliminate the above-mentioned disadvantages. In particular, adrenaline is crystalline during the entire production process, so that uncontrolled or partial recrystallization does not occur during the oral film production or storage, which would cause the above-mentioned disadvantages.

[0010] Due to the polymer matrix of the oral film, the active ingredient adrenaline is also well protected from oxygen and external moisture. Since adrenaline in crystalline form is also chemically very stable, this largely prevents the racemization of L-adrenaline, even without the need for large amounts of antioxidants, especially sodium metabisulfite.

[0011] Essentially undissolved means that more than 95% by weight, preferably more than 98% of the adrenaline is present in undissolved, ie crystalline, form.

[0012] Preferably, adrenaline is at least poorly soluble in the at least one polymer at a temperature of 15°C to 25°C.

[0013] Definitions of the different solubility grades are provided below.

[0014] the term <![CDATA[g·l -1 Solvents]]> Very soluble ＞1000 Soluble 100 to 1000 Soluble 33 to 100 Not easily soluble 10 to 33 Poorly soluble 1 to 10 Almost insoluble 0.1 to 1 Insoluble <0.1

[0015] The adrenaline is thus preferably present as a solid suspension in at least one polymer. That is, the adrenaline is present as particles, which are dispersed in the oral film matrix / polymer. As further disclosed herein, the oral film may comprise one or more layers, wherein at least one layer contains adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, characterized in that the adrenaline or a pharmaceutically acceptable salt thereof is in the form of micronized particles, preferably the micronized particles have a particle size distribution with d(99) <10 μm.

[0016] Epinephrine or adrenaline is a hormone produced in the adrenal medulla that belongs to the catecholamine class. Epinephrine is also present in the central nervous system, where it exists as a neurotransmitter in adrenergic nerve cells. Epinephrine mediates its effects by activating G-protein-coupled receptors (adrenaline receptors).

[0017] Epinephrine is also known by the systematic IUPAC name 4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol. Only the L-enantiomer is pharmaceutically active.

[0018] Therefore, the oral film according to the present invention is preferably characterized in that adrenaline or a pharmaceutically acceptable salt thereof is present as the L-enantiomer, ie the film comprises L-adrenaline or a pharmaceutically acceptable salt thereof.

[0019] Epinephrine is particularly preferably epinephrine bitartrate, in particular L-epinephrine bitartrate, also named L-epinephrine bitartrate. Another possible salt may be L-epinephrine hydrochloride.

[0020] The oral film according to the present invention is further preferably characterized in that the adrenaline or a pharmaceutically acceptable salt thereof is in the form of micronized particles in the oral film. The micronized particles may be characterized by having a particle size distribution with d(99) < 10 μm. Since the particle size distribution is preferably determined by laser diffraction by determining a volume-based particle size distribution such as dv(99), the micronized particles may have a particle size distribution with dv(99) < 10 μm.

[0021] The characteristic d(99) or dv(99) means that 99% of the particles are smaller than 10 μm. Optionally, dv(99) can be smaller, such as <9 μm, <8 μm, <5 μm or even in the low micron range such as <3 μm, <2 μm, <1 μm.

[0022] The particle size distribution of epinephrine or a pharmaceutically acceptable salt thereof may be controlled / determined by laser diffraction techniques prior to being suspended in at least one polymer.

[0023] Alternatively, the size and shape of the adrenaline particles can be determined by light microscopy.This method can also be used to control the particle size of adrenaline or its pharmaceutically acceptable salt in an oral film.

[0024] The particle size distribution can also be determined according to the European Pharmacopoeia (Ph. Eur.), 10th edition.

[0025] The particle size distribution is preferably such that the largest particle does not exceed a size of 12 μm and does not fall below a size of 0.5 μm.

[0026] The use of micronized active ingredients on the one hand increases the dissolution rate in the final film (which can be advantageous for absorption) and on the other hand makes processing to form a homogeneous film possible.

[0027] The oral film according to the invention is further preferably characterized in that the at least one polymer comprises at least one water-soluble polymer.

[0028] Water-soluble polymers include chemically different, natural or synthetic polymers whose common feature is their solubility in water or aqueous media. It is a prerequisite that these polymers have a sufficient number of hydrophilic groups for water solubility and are not cross-linked. The hydrophilic groups can be nonionic, anionic, cationic and / or zwitterionic.

[0029] Preferably, the at least one polymer in the oral film of the present invention is selected from starch and starch derivatives, dextran, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidone, polyvinyl alcohols, polyvinylpyrrolidone / polyvinyl acetate copolymers, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, polyvinyl alcohol / polyethylene glycol copolymers, gelatin, collagen, alginates, pectins, pullulan, tragacanth, chitosan, alginic acid, arabinogalactans, galactomannans, agar, agarose, carrageenan, natural gums and mixtures thereof.

[0030] Hydroxypropylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone / polyvinyl acetate copolymers, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol copolymers and / or pectin (pullulan) are particularly preferred.

[0031] The most preferred polymers are hydroxypropylcellulose and polyvinylpyrrolidone / polyvinyl acetate copolymers.

[0032] The oral film according to the present invention is preferably characterized in that it contains less than 1% by weight, preferably less than 0.5% by weight, more preferably less than 0.1% by weight of antioxidants, based on the total weight of each layer of the oral film or the total weight of the oral film.

[0033] Known antioxidants or stabilizers used include, in particular, tocopherols and their esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, gallic acid esters (including methyl, ethyl, propyl, amyl, butyl, lauryl gallate), butylated hydroxyanisole (BHA / BHT, also known as butyl-p-cresol), ascorbic acid and its salts and esters (e.g. ascorbyl palmitate), erythorbic acid (isomeric ascorbic acid) and its salts and esters, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene (BHT) and / or propionic acid.

[0034] The absence of antioxidants to a large extent or completely has the advantage that the antioxidants cannot react with the active ingredients and produce undesirable compounds. In addition, antioxidants can trigger allergic reactions. Therefore, the absence of antioxidants or reduced antioxidants is advantageous.

[0035] In particular, it is advantageous that the oral film of the present invention contains less than 1% by weight, preferably less than 0.5% by weight, more preferably less than 0.1% by weight of a pyrosulfite, such as sodium pyrosulfite or potassium pyrosulfite, based on the total weight of the oral film layers or based on the total weight of the oral film, respectively.

[0036] In particular, low amounts of sodium metabisulfite or even its absence is advantageous since sodium metabisulfite can cause allergic reactions and can react with adrenaline to form adrenaline sulfonate.

[0037] The oral film according to the present invention is preferably characterized in that the oral film contains less than 5% by weight, preferably less than 4% by weight, preferably less than 3% by weight, preferably less than 2% by weight, preferably less than 1% by weight, preferably less than 0.5% by weight and more preferably less than 0.1% by weight of antimicrobial substances, based on the total weight of each layer of the oral film or based on the total weight of the oral film.

[0038] The absence of antimicrobial substances has the advantage that antimicrobial substances can also be toxic to the patient or can cause allergic reactions. This risk is reduced by not using antimicrobial substances as much as possible.

[0039] Known antimicrobial substances include, in particular, plant extracts.

[0040] Therefore, the oral film according to the present invention is preferably characterized in that the oral film contains less than 5% by weight, preferably less than 4% by weight, preferably less than 3% by weight, preferably less than 2% by weight, preferably less than 1% by weight, preferably less than 0.5% by weight and more preferably less than 0.1% by weight of plant extract, based on the total weight of each layer of the oral film or based on the total weight of the oral film.

[0041] The oral film according to the present invention is preferably characterized in that it contains less than 10% by weight, preferably less than 9% by weight, preferably less than 8% by weight, preferably less than 7% by weight, preferably less than 6% by weight, preferably less than 5% by weight and more preferably less than 3% by weight of water, based on the total weight of the layers of the oral film or on the total weight of the oral film, respectively.

[0042] To determine the water content, the oral films are analyzed via coulometric Karl Fischer titration, typically after dissolution in 5 mL of dimethyl sulfoxide (by shaking on a laboratory shaker at about 1200 rpm for 10 minutes). Thus, the water content can be determined by Karl Fischer titration.

[0043] However, the oral film according to the present invention may contain up to 10 wt%, preferably up to 4 wt% of organic solvents such as ethanol and / or acetone, based on the total weight of the oral film layers or on the total weight of the oral film, respectively.

[0044] The oral film according to the present invention is preferably characterized in that it contains at least 40% by weight, preferably at least 45% and more preferably at least 50% by weight of adrenaline or a pharmaceutically acceptable salt thereof (as defined above), based on the total weight of each layer of the oral film or based on the total weight of the oral film, respectively.

[0045] Preferably, the oral film according to the present invention is characterized in that it contains 40% to 65% by weight, preferably 45% to 60% by weight and more preferably 50% to 56% by weight of adrenaline or a pharmaceutically acceptable salt thereof (as defined above), based on the total weight of each layer of the oral film or on the total weight of the oral film, respectively.

[0046] The oral film of the present invention is preferably characterized in that the oral film contains at least 30% to 60% by weight, preferably 33% to 55% by weight, preferably 35% to 50% by weight, preferably 38% to 44% by weight of at least one polymer, based on the total weight of each layer of the oral film or based on the total weight of the oral film.

[0047] It is also possible to use a blend of several polymers. In this case, the sum of all polymers used is preferably 30% to 60% by weight, preferably 35% to 55% by weight, preferably 38% to 51% by weight, preferably 39% to 50% by weight, based on the total weight of the oral film layers or on the total weight of the oral film, respectively.

[0048] A preferred feature of the oral film according to the present invention is that the oral film further comprises at least one excipient selected from the group consisting of dyes, flavoring agents, sweeteners, taste masking agents, emulsifiers, enhancers, pH regulators, humectants and / or preservatives.

[0049] The excipients may each be present in the oral film in an amount of about 0.001 to 10 wt%, preferably 0.01 to 5 wt%, preferably 0.01 to 2 wt%, based on the total weight of each layer of the oral film or the total weight of the oral film, respectively.

[0050] The oral film according to the present invention is also preferably characterized in that the oral film has a density of 20 to 400 g / m 2 , preferably 100 to 350 g / m 2 The quality of unit area.

[0051] A preferred feature of the oral film according to the invention is that the oral film comprises at least two layers.

[0052] The two layers are preferably identical, but can also have different compositions.

[0053] It is also possible that the oral film according to the invention has more than two layers. Again, the composition of the individual layers is identical or varies.

[0054] Preferably, the oral film of the present invention is characterized in that the oral film comprises at least two layers, wherein the at least two layers each contain adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, and characterized in that adrenaline is substantially insoluble in each of the at least one polymer.

[0055] The oral film according to the invention is also preferably characterized in that the plurality of layers are coupled by a pharmaceutically acceptable adhesive.

[0056] Several layers (preferably two layers) can also be joined by other methods familiar to the person skilled in the art. These include, for example, sealing or heat sealing, direct coating or lamination of the first layer with the second layer.

[0057] A preferred feature of the oral film according to the invention is that the multiple layers are linked by a pharmaceutically acceptable adhesive, which preferably comprises at least one water-soluble polymer and at least one plasticizer.

[0058] The multilayer oral film according to the invention is also preferably characterized in that at least one water-soluble polymer in the binder comprises shellac, vinylpyrrolidone / vinyl acetate copolymer, polyvinylcaprolactam / polyvinyl acetate / polyethylene glycol copolymer, hydroxypropylcellulose or hydroxypropylmethylcellulose and / or polyvinylpyrrolidone.

[0059] Preferably, the oral film according to the invention is characterized in that the at least one plasticizer in the binder comprises glycerol, polyethylene glycol, in particular polyethylene glycol 200, sorbitol and / or tributyl citrate.

[0060] In particular, the at least one plasticizer in the adhesive comprises glycerol, polyethylene glycol 200 and / or tributyl citrate.

[0061] The use of at least one water-soluble polymer and at least one plasticizer, preferably as a mixture, results in a viscous mixture which, preferably after drying, can be used as an adhesive layer in an oral film according to the invention.

[0062] Preferably, the weight ratio of the at least one water-soluble polymer to the at least one plasticizer in the adhesive is about 85 to 50: about 15 to 50, preferably 85 to 65: about 15 to 35, more preferably about 80 to 60: about 20 to 40, more preferably about 80 to 50: about 20 to 50, more preferably about 82 to 68: about 18 to 32 and most preferably about 80 to 70: about 20 to 30.

[0063] If too little or too much plasticizer is used, the mixture will either not be cohesive or the mixture will be impossible to handle.

[0064] It has been shown that even special mixtures of two polymers are sufficiently cohesive so that they can be used as adhesives. In this case, mixtures of 5 to 15% by weight of polyvinylpyrrolidone / polyvinyl acetate copolymer and 35 to 45% by weight of hydroxypropylcellulose have proven useful.

[0065] The present invention also relates to a method for preparing an oral film according to the present invention. The method comprises the following steps:

[0066] a) preparing a solution comprising said at least one polymer and a solvent in which adrenaline or a pharmaceutically acceptable salt thereof is substantially insoluble,

[0067] (b) adding epinephrine or a pharmaceutically acceptable salt thereof,

[0068] (c) spreading and drying the suspension obtained in step (b) to obtain a single-layer oral film.

[0069] If a multilayer oral film is to be prepared, the above process further comprises the following steps:

[0070] d) coating the first layer obtained in c) with a pharmaceutically acceptable binder and applying a further layer, preferably a second layer identical to the first layer, in order to obtain a double-layer oral film.

[0071] Similarly, additional layers can of course be applied to achieve an oral film having any number of layers.

[0072] All preferred embodiments described above for the oral film apply analogously to the method according to the invention.

[0073] The solvent in which adrenaline or a pharmaceutically acceptable salt thereof is substantially insoluble preferably comprises ethanol, ethyl acetate, methanol, propanol and / or isopropanol.

[0074] These solvents have the advantage that the common polymer is sufficiently soluble in them, whereas adrenaline is essentially insoluble.

[0075] Essentially insoluble is understood to mean a solubility in the at least one polymer that is at least poorly soluble (as defined in Table 4 above) at a temperature of 15°C to 25°C.

[0076] The present invention also relates to an oral thin film obtainable by the aforementioned process.

[0077] All preferred embodiments described above for the oral film and the method for obtaining the oral film apply analogously to the oral film obtainable by the method according to the invention.

[0078] The invention also relates to an oral film as described above or obtainable by the above process for use as a medicament, in particular for the treatment of allergic reactions, for the treatment of shock conditions, for use in emergency medicine (e.g. for resuscitation), for the treatment of respiratory diseases and / or for local vasoconstriction.

[0079] The present invention is further explained by means of non-limiting examples. Example

[0080] Embodiment 1:

[0081] Oral thin films containing micronized epinephrine were prepared using the excipients listed in Table 1.

[0082] Table 1:

[0083] substance Function Amount [wt%] Epinephrine bitartrate* Active ingredients 50.0 <![CDATA[Kollidon VA 64 1 ]]> polymer 39.9 <![CDATA[HPC 2 ]]> polymer 10.0 Sodium metabisulfite Stabilizer / Antioxidant 0.1

[0084] 1 : Polyvinyl pyrrolidone / polyvinyl acetate copolymer (from BASF)

[0085] 2： Hydroxypropyl cellulose (from Ashland)

[0086] *: Epinephrine bitartrate has a particle size distribution of D(99) = 8.76 μm

[0087] HPC was dissolved in ethanol as process solvent. Subsequently, Kollidon VA 64, sodium metabisulfite and adrenaline bitartrate were added.

[0088] The suspension was applied to a siliconized pad and dried.

[0089] An adhesive having the ingredients listed in Table 2 was also prepared.

[0090] Table 2:

[0091] substance Function Amount [wt%] Kollidon VA 64 polymer 80.0 glycerin polymer 20.0

[0092] For this purpose, Kollidon VA 64 was dissolved in ethanol as process solvent. Glycerol was then added.

[0093] The coating is applied onto a siliconized liner and then dried to obtain an adhesive layer.

[0094] A multilayer oral film is then prepared. For this purpose, a laminate of an adhesive layer is applied to a laminate of an active ingredient layer, and another laminate of an active ingredient layer is applied to the other side of the adhesive layer.

[0095] Advantages of the multilayer oral film include better stability of epinephrine (see also Example 2), no acetate odor (as often occurs in formulations containing dissolved epinephrine), and no uncontrolled recrystallization.

[0096] Embodiment 2:

[0097] A single layer oral film 197Adr0100 was prepared similar to Example 1.

[0098] Formulations 197Adr0086, 197Adr0078, 197Adr0091 and 197Adr0084 were prepared as follows:

[0099] Preparation of the oral film can be carried out by mass preparation techniques known to those skilled in the art, such as stirring / mixing the components by means of a stirrer motor and suitable stirring tools.

[0100] Gas is then added to the resulting mass by stirring, for example using a foam whipping machine. The foamed mass can then be applied to the coating support with a constant layer thickness by suitable equipment (roller coater, doctor blade, coating box, etc.). The resulting foam contains voids.

[0101] All temperature-stable web materials from which the dry film can be removed can serve as coating carriers. This can be achieved by material selection of the coating carrier (different surface tensions between the foam mass and the substrate) or by suitable non-stick coating of the coating carrier with, for example, silicone or fluoropolymers.

[0102] The contained process solvent (usually water or a mixture of water and a water-miscible organic solvent) is removed by drying. From the solid foam layer thus obtained, the oral film can be cut or punched out to appropriate dimensions.

[0103] Table 3:

[0104]

[0105] 1： Polyvinyl alcohol / polyethylene glycol copolymer (from BASF)

[0106] 2： Polyvinyl alcohol 4-88 (from Merck)

[0107] 3： Polyvinyl pyrrolidone / polyvinyl acetate copolymer (from BASF)

[0108] 4： Hydroxypropyl cellulose (from Ashland)

[0109] 5： Carbomer / Pulpyrolactone (from Henkel)

[0110] *: Epinephrine bitartrate has a particle size distribution of D(99) = 8.76 μm

[0111] Formulation 197Adr0100 corresponds to the oral film according to the invention.

[0112] The other formulations correspond to prototype formulations in which the active ingredient is partially dissolved.

[0113] The degradation of L-epinephrine and the racemization to form D-epinephrine after storage at 25° C. and 40° C. were measured by HPLC, respectively. The results are summarized in Tables 4 and 5. The measurements by HPLC were performed and the relative peak sizes of the peaks due to the L-enantiomer and the D-enantiomer, respectively, were compared.

[0114]

[0115]

[0116] After storing OTF in sealed aluminum bags at 40°C for 5 months, the amount of adrenaline decreased only slightly (values ​​refer to the change relative to the initial value)

[0117] 197Adr0100: 0.09% adrenaline reduction, of which 0.03% racemized

[0118] 197Adr0086: 1.32% adrenaline reduction, of which 0.83% racemized

[0119] 197Adr0078: 1.89% adrenaline reduction, of which 1.18% racemized

[0120] 197Adr0084: 1.79% adrenaline reduction, of which 1.27% racemized

[0121] It has been shown that the OTF according to the present invention has minimal degradation and racemization.

Claims

1. An oral film comprising one or more layers, wherein at least one layer contains adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, characterized in that The epinephrine is substantially insoluble in the at least one polymer.

2. The oral film according to claim 1, characterized in that The adrenaline or a pharmaceutically acceptable salt thereof is present in a micronized form having a particle size distribution of d(99)<10 μm.

3. The oral film according to any one of the preceding claims, characterized in that The adrenaline or a pharmaceutically acceptable salt thereof exists as an L-enantiomer.

4. The oral film according to any one of the preceding claims, characterized in that The at least one polymer is selected from starch and starch derivatives, dextran, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinyl pyrrolidone, polyvinyl alcohols, polyvinyl pyrrolidone / polyvinyl acetate copolymers, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, polyvinyl alcohol / polyethylene glycol copolymers, gelatin, collagen, alginates, pectins, pullulan, tragacanth, chitosan, alginic acid, arabinogalactans, galactomannans, agar, agarose, carrageenan, natural gums and mixtures thereof.

5. The oral film according to any one of the preceding claims, characterized in that The oral film contains less than 1% by weight of antioxidants, especially less than 1% by weight of pyrosulfite, based on the total weight of each layer of the oral film or the total weight of the oral film.

6. The oral film according to any one of the preceding claims, characterized in that The oral film contains at least 40% by weight of adrenaline or a pharmaceutically acceptable salt thereof, based on the total weight of each layer of the oral film or the total weight of the oral film.

7. The oral film according to any one of the preceding claims, characterized in that The oral film contains at least 35% by weight of the at least one polymer, based on the total weight of the oral film.

8. The oral film according to any one of the preceding claims, characterized in that The oral film further comprises at least one excipient selected from the group consisting of dyes, flavoring agents, sweeteners, taste masking agents, emulsifiers, enhancers, pH adjusters, humectants and / or preservatives.

9. The oral film according to any one of the preceding claims, characterized in that The oral film comprises at least two layers, wherein each of the at least two layers contains adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, wherein the adrenaline is substantially insoluble in each of the at least one polymer.

10. The oral film according to any one of the preceding claims, characterized in that The multiple layers are coupled by a pharmaceutically acceptable adhesive, wherein the pharmaceutically acceptable adhesive preferably comprises at least one water-soluble polymer and at least one plasticizer.

11. A method for preparing an oral film according to any one of claims 1 to 11, comprising the steps of: a) preparing a solution comprising said at least one polymer and a solvent in which adrenaline or a pharmaceutically acceptable salt thereof is substantially insoluble, (b) adding epinephrine or a pharmaceutically acceptable salt thereof, (c) spreading and drying the suspension obtained in step (b) to obtain a single-layer oral film, and d) Optionally coating the first layer obtained in c) with a pharmaceutically acceptable binder and applying a further layer, preferably a second layer identical to the first layer, in order to obtain a double-layer oral film.

12. An oral thin film obtainable by a process according to claim 11.

13. An oral film according to any one of claims 1 to 10 or 12 for use as a medicament.

14. An oral film according to any one of claims 1 to 10 or 12 for use as a medicament in the treatment of allergic reactions.

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