Oral film with low water activity

Abstract

An oral film comprising epinephrine or a pharmaceutically acceptable salt thereof and at least one polymer, characterized in that the oral film has a water activity of less than 0.6. Process for the preparation of said oral film comprising the steps of: a) preparing a solution, dispersion or melt comprising adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer and b) spreading the solution, dispersion or melt from step a) or the optionally foamed solution, dispersion or melt from step al) in order to obtain an oral film, and (c) drying the oral film obtained in step (b) so as to obtain an oral film having a water activity of less than 0.6. The oral film is useful as a medicament, in particular for use as a medicament for 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 ingredient, 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 at least one active ingredient, 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 administering adrenaline, especially in dissolved form, is that only the L-enantiomer of adrenaline is pharmaceutically active. However, due to the influence of oxygen and water, pure L-adrenaline racemates rapidly, whereby the pharmaceutical activity of known dosage forms decreases rapidly. Therefore, attempts are made to counteract this racemization by adding antioxidants. Sodium metabisulfite is commonly used as an antioxidant, often in a ratio of 1:1 to adrenaline. However, this has the disadvantage that adrenaline reacts with sodium metabisulfite to form undesirable adrenaline sulfonate.

[0004] Although the degradation of epinephrine to adrenochrome results in intense coloration, the degradation mechanism to form D-epinephrine and epinephrine 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. Sodium metabisulfite is used in large quantities in existing commercial products (regarding sodium metabisulfite:epinephrine, in ratio of 1:1 in , and 1.7:1 in Epipene) leads to sulfite (SO3 2- ) and pyrosulfite (S2O5 2- ) and adrenaline reaction (S N 1 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] 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 a dosage form of adrenaline in which degradation and / or racemization of the pharmaceutically active L-adrenaline is prevented to the greatest possible extent without requiring the use of large amounts of antioxidants, in particular sodium metabisulfite. In addition, the dosage form should also be as stable as possible with respect to possible growth of the microorganisms concerned, without requiring the use of large amounts of antimicrobial additives. Furthermore, the preparation of the dosage form should be as easy and cost-effective as possible.

[0007] This problem is solved by an oral film according to claim 1, comprising epinephrine or a pharmaceutically acceptable salt thereof and at least one polymer, wherein the water activity of the oral film is less than 0.6.

[0008] Such a dosage form overcomes the disadvantages described above. Due to the polymer matrix of the oral film, the active ingredient adrenaline is protected from oxygen and external moisture. At the same time, the extremely low water activity prevents the racemization of L-adrenaline to a large extent, and even the use of large amounts of antioxidants, especially sodium metabisulfite, is not necessary. Since microbial growth no longer occurs at a water activity of less than 0.6, antimicrobial additives are basically not required in the oral film.

[0009] Water activity is a parameter comparing aqueous solutions and solids (such as pharmaceuticals or foods) that relates to the availability of water for chemical, biochemical and microbiological reactions.

[0010] Water activity is expressed as a w The water activity is the quotient of the water concentration in the vapor phase in the space above a substance and the water concentration in the space above pure water at a given temperature. The water activity corresponds to 1 / 100 of the relative equilibrium humidity (RGF).

[0011] The relationship between the water content and water activity of a substrate is represented by its adsorption isotherm. Reducing the water activity first slows down microbial growth, followed by enzymatic reactions and finally non-enzymatic reactions.

[0012] Since the water requirements of various organisms are well known, a w The value can be used to determine the shelf life. It is well established that a w Matrices with values ​​below 0.60 were considered to have unlimited shelf life.

[0013] The oral film according to the present invention has a water activity of less than 0.6, preferably less than 0.55, preferably less than 0.50, preferably less than 0.45, preferably less than 0.40 and more preferably less than 0.35.

[0014] Generally, water activity can be measured as follows: a sample (here, an oral film) is placed in a sealed container and after equilibrium (eg, with a hygrometer) the relative humidity occurring in the container is measured. The water activity corresponds to 1 / 100 of the relative equilibrium humidity (RGF).

[0015] In particular, the water activity of the oral film was determined using a Novasina LabMaster-aw neo G00572. For equilibration purposes, the device was started at least one day before the measurement. The three samples were placed together in a Novasina sample cup (P / N 2601518) and analyzed immediately afterwards.

[0016] Preferably, the oral film according to the invention can also be completely free of water and thus have zero water activity.

[0017] Epinephrine 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).

[0018] Epinephrine, also known as adrenaline, has the systematic IUPAC name 4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol. Only the L-enantiomer is pharmaceutically active.

[0019] Therefore, a preferred feature of the oral film according to the invention is that adrenaline or a pharmaceutically acceptable salt thereof is present as the L-enantiomer.

[0020] Epinephrine is preferably present as epinephrine bitartrate, especially as L-epinephrine bitartrate.

[0021] The oral film according to the invention is preferably characterized in that the at least one polymer comprises at least one water-soluble polymer.

[0022] 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.

[0023] 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.

[0024] Particularly preferred are hydroxypropylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone / polyvinyl acetate copolymers, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol copolymers and / or pectin (pullulan).

[0025] The oral film according to the present invention is preferably characterized in that the oral film 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 the oral film.

[0026] Commonly used known antioxidants or stabilizers include, in particular, tocopherols and their esters, sesamol from sesame oil, coniferyl benzoate from benzoin resin, nordihydroguaiaretic resin and nordihydroguaiaretic acid (NDGA), gallic acid esters (in particular methyl, ethyl, propyl, amyl, butyl, lauryl gallate), butylated hydroxyanisole (BHA / BHT, i.e. 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.

[0027] The absence of antioxidants to a large extent 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.

[0028] 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.

[0029] 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.

[0030] The oral film according to the present invention is preferably characterized in that it 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 the oral film.

[0031] 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.

[0032] Known antimicrobial substances include, in particular, plant extracts.

[0033] Therefore, the oral film according to the present invention is preferably characterized in that it 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 the oral film.

[0034] 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 oral film.

[0035] To determine the water content, the oral films were analyzed via coulometric Karl Fischer titration after dissolution in 5 mL of dimethyl sulfoxide (by shaking on a laboratory shaker at approximately 1200 rpm for 10 minutes).

[0036] However, the oral film according to the present invention may contain up to 10% by weight, preferably up to 4% by weight, of an organic solvent, such as ethanol and / or acetone.

[0037] The oral film of the present invention is preferably characterized in that it contains at least 30% by weight, preferably at least 45% by weight 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 the oral film.

[0038] 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 the oral film.

[0039] The oral film of the present invention is preferably characterized in that it 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 the oral film.

[0040] It is also possible to use a blend of several polymers. In this case, the sum of all polymers used is preferably at least 30% by weight to 60% by weight, preferably at least 35% by weight to 55% by weight, preferably at least 38% by weight to 51% by weight, preferably at least 39% by weight to 50% by weight, based on the total weight of the oral film.

[0041] 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, penetration enhancers, pH regulators, humectants and / or preservatives.

[0042] The excipients may each be present in the oral film in an amount of about 0.001 to 10% by weight, preferably 0.01 to 5% by weight, preferably 0.01 to 2% by weight, based on the total weight of the oral film.

[0043] In one embodiment, the oral thin film according to the present invention is in the form of a substantially smooth film.

[0044] In yet another embodiment, the oral film is in the form of a solidified foam comprising voids.

[0045] The cavities of the membrane and the associated larger surface area promote, among other things, the entry of water, saliva or other body fluids into the interior of the membrane and thereby accelerate dissolution of the dosage form and release of the active ingredient.

[0046] In the case of rapidly absorbed drugs, transmucosal absorption can also be improved by rapid dissolution of the oral film.

[0047] Furthermore, the wall thickness of the voids mentioned is preferably small, since they represent, for example, solidified gas bubbles, so that rapid dissolution or destruction of these voids occurs.

[0048] A further advantage of this embodiment is that despite the relatively high weight per unit area, faster drying can be achieved by converting the oral film into a foam compared to a non-foamed oral film.

[0049] Preferably, the oral film according to the invention is characterized in that the voids are separated from one another and preferably exist in the form of bubbles, wherein the voids are preferably filled with air or a gas, preferably an inert gas, particularly preferably nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

[0050] In yet another embodiment, the cavities can be interconnected, preferably by forming a continuous channel system that penetrates the oral film.

[0051] Preferably, the mentioned voids have a volume percentage of 5 to 98%, preferably 50 to 80%, based on the total volume of the oral film. In this way, the advantageous effect of accelerating the dissolution of the oral film is advantageously influenced.

[0052] Surface active agents and surfactants, respectively, can be added to the oral film to form the foam or can be added to the obtained foam before or after drying to improve the stability of the foam before or after drying.

[0053] Another parameter that influences the properties of the oral film according to the invention is the diameter of the cavities or bubbles. The bubbles or cavities are preferably produced by means of a foam whipping machine, with which the bubble diameter can be adjusted in a wide range (almost at will). Thus, the diameter of the bubbles or cavities can be in the range of 0.01 to 60 μm. A particularly preferred diameter is in the range of 10 to 50 μm.

[0054] The oral film according to the present invention is preferably characterized in that the oral film has a density of 20 to 400 g / m 2 , preferably 100 to 350 g / m 2 area weight.

[0055] A further preferred feature of the oral film according to the invention is that the oral film comprises at least one substance which acts as a seed crystal for adrenaline.

[0056] The oral film according to the present invention is preferably characterized in that the substance serving as the seed of adrenaline comprises small particles which are insoluble in the final oral film environment and insoluble in agglomerates during the preparation of the oral film.

[0057] In this context, small is understood to mean an average particle size of 5 to 100 μm, preferably 20 to 50 μm, the average particle size being able to be taken from the product data sheets of the respective manufacturer valid on the filing date.

[0058] The oral film according to the invention is particularly preferably characterized in that the substance serving as adrenaline seed crystals comprises amorphous fumed silicon dioxide.

[0059] Amorphous fumed silica (SiO2) is a synthetically produced colloidal silica. It consists essentially entirely of amorphous silica particles aggregated into larger units.

[0060] Suitable amorphous fumed silicas are known, for example, from Evonik under the trade name series.

[0061] Also suitable as substances capable of acting as seeds are TiO2, various oxides of iron, silicates, aluminum oxide and / or magnesium stearate.

[0062] The oral film according to the invention is also preferably characterized in that after storage at 40° C. for six months, less than 3% of the adrenaline contained in the oral film has been degraded and / or less than 2.5% of the adrenaline contained has been racemized.

[0063] The present invention also relates to a method for preparing an oral film according to the present invention. The method comprises the following steps:

[0064] a) preparing a solution, dispersion or melt comprising adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, and

[0065] a1) foaming the solution, dispersion or melt from step a), optionally by introducing a gas or a gas mixture, by chemical gas generation or by expanding a dissolved gas,

[0066] b) spreading the solution, dispersion or melt from step a) or the optionally foamed solution, dispersion or melt from step a1) in order to obtain an oral film, and

[0067] (c) drying the oral film obtained in step (b) to obtain an oral film. The obtained oral film may advantageously have a water activity of less than 0.6.

[0068] It is clear to the person skilled in the art that step a1) is only necessary if the oral film is to be in the form of a solidified foam comprising voids.

[0069] All preferred embodiments described above for the oral film apply analogously to the method according to the invention.

[0070] Water or organic solvents such as ethanol, acetone and mixtures thereof are suitable solvents to be used in the process of the present invention.

[0071] A water activity of less than 0.6 can be achieved in particular by extensive drying of the formulation, in particular the foam formulation. Due to the porous structure, OTF can be dried thoroughly and a low water proportion / water activity can be achieved.

[0072] In addition, organic solvents preferably serve as process solvents. In addition, low water activity can be maintained by storage in suitable packaging materials. In addition, auxiliary substances and / or polymers with low hygroscopicity are preferably selected.

[0073] Particularly preferred are polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol copolymers and / or hydroxypropylcellulose.

[0074] The drying conditions for solvent evaporation can be, for example, in the range of 40 to 100° C., more preferably 50 to 80° C., most preferably 50 to 75° C. It is also possible to carry out drying by applying a temperature gradient.

[0075] The oral film is preferably dried for at least 10 minutes, preferably 13 to 25 minutes.

[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 treating or allergic reactions, for treating shock conditions, for use in emergency medicine (e.g. for resuscitation), for treating respiratory diseases and / or for local vasoconstriction.

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

[0080] An oral film having the composition listed in Table 1 was prepared as follows:

[0081] Preparation of foam formulations: 197Adr0086, 197Adr0078, 197Adr0091 and 197Adr0084

[0082] 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.

[0083] 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 a coating support in a constant layer thickness by means of suitable equipment (roller coater, doctor blade, coating box, etc.).

[0084] 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-sticky coating of the coating carrier with, for example, silicone or fluoropolymers.

[0085] 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.

[0086] Drying is achieved by drying the layer in a ventilated drying oven or by moving the coated layer through a ventilated drying tunnel. In the case of a drying tunnel, the drying temperature is defined by the layer speed and the drying tunnel length (and thus the duration of the layer in the drying tunnel). The drying tunnel can be operated with a gradient of different temperature zones. In process control, for example, the determination of the water content (e.g. by Karl Fischer titration) can be accomplished to evaluate the success of the drying step.

[0087] Preparation of suspension formulation 197Adr0100

[0088] The preparation can be carried out by mass preparation techniques known to those skilled in the art, such as stirring / mixing the contained components by means of a stirrer motor and suitable stirring means.

[0089] The mass obtained in this way is applied to a coating support in a constant layer thickness by means of suitable equipment (roller coater, doctor blade, coating box, etc.).

[0090] All temperature-stable web materials from which the dried 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 mass and the substrate) or by suitable non-stick coating of the coating carrier with, for example, silicones or fluoropolymers.

[0091] The process solvent contained in the coating is removed by drying.

[0092] Drying is achieved by drying the layer in a ventilated drying oven or by moving the coated layer through a ventilated drying tunnel. In the case of a drying tunnel, the drying temperature is defined by the layer speed and the drying tunnel length (and thus the duration of the layer in the drying tunnel). The drying tunnel can be operated with a gradient of different temperature zones. In process control, for example, the determination of the water content (e.g. by Karl Fischer titration) can be accomplished to evaluate the success of the drying step.

[0093] From the solid laminated layer thus obtained, the oral film can be cut or punched to the appropriate size. Alternatively, several layers can be combined into a thicker layer by lamination. This can be achieved by heating, high pressure or using adhesive lamination.

[0094] Table 1:

[0095]

[0096] 1： Polyvinyl alcohol / polyethylene glycol copolymer (from BASF)

[0097] 2： Polyvinyl alcohol 4-88 (from Merck)

[0098] 3： Polyvinyl pyrrolidone / polyvinyl acetate copolymer (from BASF)

[0099] 4： Hydroxypropyl cellulose (from Ashland)

[0100] 5： Carbomer / Pulpyrolactone (from Henkel)

[0101] For the prepared oral films, the water content and water activity were measured. The results are summarized in Table 2.

[0102] To determine the water content, each OTF was analyzed via coulometric Karl Fischer titration after being dissolved in 5 mL of dimethyl sulfoxide (by shaking on a laboratory shaker at about 1200 rpm for 10 minutes).

[0103] The water activity of OTF was determined with a Novasina LabMaster-aw neo G00572. For equilibration purposes, the device was started at least one day before the measurement. The three samples were placed together in a Novasina sample cup (P / N 2601518) and analyzed immediately afterwards.

[0104] Table 2:

[0105]

[0106] Additionally, the degradation and racemization of epinephrine after storage at 25°C and 40°C were measured by HPLC and by comparing the relative peak sizes of the peaks due to the L-enantiomer and the D-enantiomer, respectively.

[0107] The results are summarized in Tables 3 and 4.

[0108]

[0109]

[0110] After storing OTF in sealed aluminum bags at 40°C, the amount of adrenaline decreased only slightly after 5 months (values ​​refer to the change relative to the initial value):

[0111] 197Adr0100: 0.09% adrenaline reduction, of which 0.03% racemized

[0112] 197Adr0086: 1.32% adrenaline reduction, of which 0.83% racemized

[0113] 197Adr0078: 1.89% adrenaline reduction, of which 1.18% racemized

[0114] 197Adr0084: 1.79% adrenaline reduction, of which 1.27% was racemized.

Claims

1. An oral film comprising epinephrine or a pharmaceutically acceptable salt thereof and at least one polymer, characterized in that The water activity of the oral film is less than 0.

6.

2. The oral film according to claim 1, characterized in that The adrenaline or a pharmaceutically acceptable salt thereof exists as an L-enantiomer.

3. The oral film according to any one of the preceding claims, characterized in that The at least one polymer comprises at least one water-soluble polymer.

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 the oral film.

6. The oral film according to any one of the preceding claims, characterized in that The oral film contains less than 5% by weight of antimicrobial material, based on 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 less than 10% by weight of water, 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 contains at least 30% by weight of epinephrine or a pharmaceutically acceptable salt thereof, based on the total weight of the oral film.

9. 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.

10. 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.

11. The oral film according to any one of the preceding claims, characterized in that The oral film has a thickness of 20 to 400 g / m 2 surface weight.

12. The oral film according to any one of the preceding claims, characterized in that After storage for six months at 40° C., less than 3% of the epinephrine contained in the oral film had been degraded and / or less than 2.5% of the epinephrine contained had been racemized.

13. A method for preparing an oral film according to any one of claims 1 to 12, comprising the steps of: a) preparing a solution, dispersion or melt comprising adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, and a1) foaming the solution, dispersion or melt from step a), optionally by introducing a gas or a gas mixture, by chemical gas generation or by expanding a dissolved gas, b) spreading the solution, dispersion or melt from step a) or the optionally foamed solution, dispersion or melt from step a1) in order to obtain an oral film, and (c) drying the oral thin film obtained in step (b) to obtain an oral thin film having a water activity of less than 0.

6.

14. An oral thin film obtainable by a process according to claim 13.

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

Images