Oral thin film agent having a low water activity

Abstract

An oral thin film agent comprising adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, the oral thin film agent having a water activity of less than 0.6. A method for producing the oral thin film agent, comprising: a) producing 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 optionally the foamed solution, dispersion or melt from step a1), to obtain an oral thin film; and (c) drying the oral thin film obtained in step (b) to obtain an oral thin film agent having a water activity of less than 0.6. The oral thin film agent for use as a medicament, particularly for use as a medicament in the treatment of allergic reactions.

Description

Technical Field

[0001] The present invention is directed to an oral thin film agent, a method for producing the same, and its use as a medicament.

Background Art

[0002] An oral thin film agent (OTF) is a thin film agent that contains at least one pharmaceutically active substance, is directly placed in the oral cavity or applied to the oral mucosa, and dissolves therein. In particular, these are polymer-based thin film agents containing at least one active ingredient, and when applied to the mucosa, particularly the oral mucosa, the active ingredient is released directly into the oral mucosa. The very good blood circulation of the oral mucosa ensures the rapid transfer of the active ingredient into the blood circulation. This administration system has the advantage of avoiding the "first-pass effect" associated with the tablet form, which is a conventional dosage form of the active ingredient, since most of the active ingredient is absorbed through the mucosa.

[0003] The problem associated with adrenaline administration, particularly 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 rapidly racemizes, thereby rapidly reducing the pharmaceutical activity of known dosage forms. Therefore, attempts have been made to counteract this racemization by adding antioxidants. Sodium metabisulfite is usually used as an antioxidant and is often in a 1:1 ratio to adrenaline. However, this has the disadvantage that adrenaline reacts with sodium metabisulfite to form undesirable adrenaline sulfonic acid.

[0004] The decomposition of adrenaline to adrenochrome leads to strong coloring, but the decomposition mechanisms to D-adrenaline and adrenaline sulfonic acid are responsible for the quantitatively largest decomposition. This is planar sp 2The transition state occurs through being stabilized by an activated aromatic. The reaction of the transition state with water leads to the formation of D - adrenaline and L - adrenaline in a ratio of 1:1, and in the long term, to the racemization of the starting material. In current commercial products (Adrenaline (registered trademark) is in a 1:1 ratio with sodium metabisulfite for adrenaline, and Epipene is in a 1.7:1 ratio), a large amount of sodium metabisulfite is used, leading to the reaction of sulfite (SO3 2- ) and metabisulfite (S2O5 2- ) with adrenaline (S N 1 reaction). Therefore, at the end of the quality retention period, known commercial products contain up to 15% of adrenaline sulfonic acid.

[0005] Patent Document 1 discloses a pharmaceutical composition for adrenaline administration in which adrenaline is partially dissolved in the composition.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] The problem underlying the present invention is to overcome the disadvantages of the aforementioned prior art. In particular, the problem of the present invention is to provide a dosage form of adrenaline that prevents the decomposition and / or racemization of pharmaceutically active L - adrenaline to the greatest possible extent without the need to use a large amount of antioxidants, especially sodium metabisulfite. Furthermore, this dosage form should be as stable as possible with respect to the possibility of microbial growth without the need to use a large amount of antibacterial additives. Also, this dosage form should be easy to manufacture and as inexpensive as possible.

Means for Solving the Problems

[0008] This problem is solved by the orally disintegrating film agent according to claim 1, which contains adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, and has a water activity of less than 0.6.

[0009] Such a dosage form overcomes the above disadvantages. Due to the polymer matrix of the orally disintegrating film agent, the active ingredient adrenaline is protected from oxygen and exogenous moisture. At the same time, due to the extremely low water activity, it is not even necessary to use a large amount of antioxidants, especially sodium metabisulfite, and the racemization of L - adrenaline is generally prevented. Since microbial growth does not occur at a water activity of less than 0.6, antibacterial additives are not essentially required in this orally disintegrating film agent.

Mode for Carrying Out the Invention

[0010] Water activity is a parameter for comparing aqueous solutions and solids (such as drugs or foods) with respect to the water that can be utilized in chemical, biochemical, and microbial reactions.

[0011] Water activity is represented by the a w value and is defined as the ratio of the water concentration in the vapor phase of the space above the substance at a given temperature to the water concentration in the space above pure water. Water activity corresponds to 1 / 100 of the relative equilibrium humidity (RGF).

[0012] The relationship between the water content of the substrate and the water activity is represented by its sorption isotherm. When the water activity is decreased, initially the growth of microorganisms decelerates, followed by enzyme reactions and finally non - enzyme reactions decelerating.

[0013] Since the water requirements of various organisms are well - known, the a w value can be used to determine the quality retention period. It has been proven that substrates with an a w value of less than 0.60 have an infinite quality retention period.

[0014] The oral thin film agent 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, more preferably less than 0.35.

[0015] Generally, the water activity can be measured by putting a sample, here an oral thin film agent, in a container sealed airtight and measuring the relative humidity generated in the container after equilibration using, for example, a hygrometer. The water activity corresponds to 1 / 100 of the relative equilibrium humidity (RGF).

[0016] Thereby, in particular, the water activity of the oral thin film agent is determined using Novasina's LabMaster-aw neo G00572. At the latest one day before the measurement, the device is switched on for equilibration reasons. Three samples are put together in Novasina's sample cup (P / N2601518) and analyzed immediately afterwards.

[0017] Preferably, the oral thin film agent according to the present invention contains no water at all, and thus the water activity is zero.

[0018] Adrenaline is a hormone produced in the adrenal medulla and belongs to the group of catecholamines. Adrenaline is also found in the central nervous system, where it exists as a neurotransmitter in adrenaline neurons. Adrenaline mediates its effects by activating the adrenaline receptor, which is a G protein-coupled receptor.

[0019] Adrenaline is also known as epinephrine and has the IUPAC systematic name 4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol. Only the L-enantiomer is pharmaceutically active.

[0020] Therefore, the oral thin film agent according to the present invention is preferably characterized in that adrenaline or a pharmaceutically acceptable salt thereof is present as the L-enantiomer.

[0021] Adrenaline preferably exists as adrenaline bitartrate, especially L - adrenaline bitartrate.

[0022] The oral thin film agent according to the present invention preferably comprises at least one polymer containing at least one water - soluble polymer.

[0023] Water - soluble polymers include chemically different, natural or synthetic polymers that share the common feature of solubility in water or an aqueous medium. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for water solubility and are not cross - linked. The hydrophilic groups can be non - ionic, anionic, cationic and / or zwitterionic.

[0024] Preferably, at least one polymer in the oral thin film agent of the present invention is selected from the group consisting of starch and starch derivatives, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl pyrrolidone / polyvinyl acetate copolymer, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, polyvinyl alcohol / polyethylene glycol copolymer, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, natural rubber and mixtures thereof.

[0025] Particularly preferred are hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl pyrrolidone / polyvinyl acetate copolymer, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol copolymer and / or pectin (amylopectin).

[0026] The oral thin film agent according to the present invention preferably contains an antioxidant in an amount of less than 1% by weight, preferably less than 0.5% by weight, more preferably less than 0.1% by weight, based on the total weight of the oral thin film agent.

[0027] As the commonly used known antioxidants or stabilizers, in particular, tocopherols and their esters, sesamol derived from sesame oil, coniferous tree benzoate derived from benzoin resin, nordihydroguaiaretic resin and nordihydroguaiaretic acid (NDGA), gallic acid esters (especially 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 (isoascorbic acid) and its salts and esters, monothioglycerol, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, sodium sulfite, potassium metabisulfite, butylhydroxyanisole, butylhydroxytoluene (BHT) and / or propionic acid can be mentioned.

[0028] Generally, the absence of antioxidants has the advantage that there is no possibility that the antioxidant reacts with the active ingredient to form undesirable compounds. Furthermore, antioxidants can cause allergic reactions. Therefore, the absence or reduction of antioxidants is advantageous.

[0029] In particular, it is advantageous that the oral thin film agent of the present invention contains a metabisulfite such as sodium metabisulfite or potassium metabisulfite in an amount of less than 1% by weight, preferably less than 0.5% by weight, more preferably less than 0.1% by weight, based on the total weight of the oral thin film agent.

[0030] In particular, sodium metabisulfite can cause allergic reactions and can react with adrenaline to form sulfonic acid adrenaline. Therefore, it is advantageous that the amount of sodium metabisulfite is small or it is not even contained.

[0031] The oral thin film agent according to the present invention preferably 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, more preferably less than 0.1% by weight of an antibacterial substance based on the total weight of the oral thin film agent.

[0032] Since antibacterial substances can be toxic to patients or cause allergic reactions, the absence of antibacterial substances has advantages. By omitting antibacterial substances as much as possible, this risk is reduced.

[0033] Known antibacterial substances include, in particular, plant extracts.

[0034] Therefore, the oral thin film agent according to the present invention preferably 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, more preferably less than 0.1% by weight of a plant extract based on the total weight of the oral thin film agent.

[0035] The oral thin film agent according to the present invention preferably 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, more preferably less than 3% by weight of water based on the total weight of the oral thin film agent.

[0036] For the purpose of determining the water content, the oral thin film agent is analyzed by the Karl Fischer coulometric titration method after dissolving it by shaking with an experimental shaker at about 1200 rpm for 10 minutes in 5 mL of dimethyl sulfoxide.

[0037] However, the oral thin film agent according to the present invention can contain up to 10% by weight, preferably up to 4% by weight of an organic solvent such as ethanol and / or acetone.

[0038] The oral thin film agent of the present invention preferably contains at least 30% by weight, preferably at least 45% by weight, 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 thin film agent.

[0039] Preferably, the oral thin film agent according to the present invention contains 40% to 65% by weight, preferably 45% to 60% by weight, 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 thin film agent.

[0040] The oral thin film agent of the present invention preferably contains at least one polymer in an amount of 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 based on the total weight of the oral thin film agent.

[0041] Combinations of several polymers can also be used. In this case, the total of all polymers used is preferably at least 30% to 60% by weight, preferably at least 35% to 55% by weight, preferably at least 38% to 51% by weight, preferably 39% to 50% by weight based on the total weight of the oral thin film agent.

[0042] The oral thin film agent according to the present invention preferably further contains at least one excipient selected from the group consisting of a dye, a flavoring agent, a sweetening agent, a taste masking agent, an emulsifier, a penetration enhancer, a pH adjuster, a humectant and / or a preservative.

[0043] Each excipient can be present in the oral thin film agent 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 thin film agent.

[0044] In one embodiment, the oral thin film agent according to the present invention essentially exists in the form of a smooth film.

[0045] In another embodiment, the oral thin film agent exists in the form of a solidified foam containing cavities.

[0046] The cavities and the accompanying increase in the surface area of the film particularly facilitate the entry of water, saliva, or other body fluids into the interior of the film, thereby accelerating the dissolution of the dosage form and the release of the active ingredient.

[0047] In the case of an immediate absorption drug, transmucosal absorption can also be improved by the rapid dissolution of the oral thin film agent.

[0048] Furthermore, the wall thickness of the mentioned cavities is preferably thin because they become, for example, solidified bubbles, resulting in the rapid dissolution or disintegration of these cavities.

[0049] A further advantage of this embodiment is that, despite the relatively large weight per unit area, by converting the oral thin film agent into a foam, it is possible to achieve a faster drying compared to a non-foam type oral thin film agent.

[0050] Preferably, the oral thin film agent according to the present invention has cavities that are isolated from each other, preferably existing in the form of bubbles, where the cavities are preferably filled with air or gas, preferably an inert gas, particularly preferably nitrogen, carbon dioxide, helium, or a mixture of at least two of these gases.

[0051] In another embodiment, the cavities can communicate with each other, preferably by forming a continuous channel system that penetrates the oral thin film agent.

[0052] Preferably, the mentioned cavities have a volume percentage of 5 to 98%, preferably 50 to 80%, based on the total volume of the oral thin film agent. In this way, the advantageous effect of promoting the dissolution of the oral thin film agent is favorably affected.

[0053] Surfactants and detergents can each be added to the oral thin film agent for the purpose of forming a foam, or added to the obtained foam before or after drying to improve the stability of the foam before or after drying.

[0054] Another parameter that affects the properties of the oral thin film agent according to the present invention is the diameter of the cavities or bubbles. The bubbles or cavities are preferably produced with the aid of a foaming machine that can adjust the diameter of the bubbles substantially as desired over a wide range. Thus, the diameter of the bubbles or cavities can range from 0.01 to 60 μm. Particularly preferred is a diameter in the range of 10 to 50 μm.

[0055] The oral thin film agent according to the present invention preferably has a basis weight of 20 to 400 g / m 2 , preferably 100 to 350 g / m 2 and is characterized by having a basis weight per unit area.

[0056] The oral thin film agent according to the present invention is more preferably characterized by containing at least one material that can be used as a seed for adrenaline crystallization.

[0057] The oral thin film agent according to the present invention is preferably characterized in that the material that can be used as a seed for adrenaline crystallization contains small particles that are also insoluble in the mass during the production of the finished oral thin film agent and around the oral thin film agent.

[0058] In this context, small is understood to mean an average particle size of 5 to 100 μm, preferably 20 to 50 μm, where the average particle size can be obtained from the respective manufacturer's product data sheet valid at the filing date.

[0059] The oral thin film agent according to the present invention is particularly preferably characterized in that the material that can be used as a seed for adrenaline crystallization contains amorphous fumed silica.

[0060] Amorphous fumed silica (SiO2) is colloidal silica produced by synthesis. Amorphous fumed silica essentially consists entirely of amorphous silica particles aggregated into large units.

[0061] Suitable amorphous fumed silicas are known, for example, those of the "Aerosil"® series from Evonik.

[0062] Other materials suitable as crystallization seeds are TiO2, iron oxide, silicate, aluminum trioxide and / or magnesium stearate.

[0063] The oral thin film agent according to the present invention is more preferably characterized in that after storage at 40 °C for 6 months, less than 3% of the adrenaline contained in the oral thin film agent is decomposed and / or less than 2.5% of the adrenaline contained is racemized.

[0064] The present invention also relates to a method for producing an oral thin film agent according to the present invention. The method comprises the steps: a) producing a solution, dispersion or melt comprising adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer a1) optionally foaming the solution, dispersion or melt from step a) by introducing a gas or gas mixture, by chemical gas generation or by expansion of dissolved gas, b) spreading the solution, dispersion or melt from step a), or optionally the foamed solution, dispersion or melt from step a1), to obtain an oral thin film, and c) drying the oral thin film obtained in step (b) to obtain an oral thin film agent The resulting oral thin film agent may advantageously have a water activity of less than 0.6.

[0065] It will be apparent to those skilled in the art that step a1) is only necessary when the oral thin film agent is in the form of a solidified foam containing cavities.

[0066] All of the above preferred embodiments for the oral thin film agent are similarly applicable to the method according to the present invention.

[0067] Water or organic solvents such as ethanol, acetone and mixtures thereof are suitable solvents used in the method of the present invention.

[0068] A water activity of less than 0.6 can be achieved in particular by sufficiently drying the formulation, especially the foam formulation. Due to the porous structure, the OTF is sufficiently dried and a low water ratio / water activity is achieved.

[0069] Furthermore, organic solvents are preferred as process solvents. In addition, a low water activity can be maintained by storage in a suitable packaging material. In addition, the selection of auxiliary materials and / or polymers with lower hygroscopicity is preferred.

[0070] Particularly preferred are polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol copolymers and / or hydroxypropyl cellulose.

[0071] The drying conditions for solvent evaporation can be in the range of, for example, 40 to 100 °C, more preferably 50 to 80 °C, and most preferably 50 to 75 °C. It is also possible to achieve drying by applying a temperature gradient.

[0072] The oral thin film agent is preferably dried for at least 10 minutes, preferably 13 to 25 minutes.

[0073] The present invention also relates to an oral thin film agent obtainable by the aforementioned method.

[0074] All of the above preferred embodiments of the oral thin film agent and the method for obtaining the oral thin film agent are similarly applicable to the oral thin film agent obtainable by the method according to the present invention.

[0075] The present invention further relates to the use of an oral thin film agent obtained by the above or the above method as a medicament, particularly in the treatment or alleviation of allergic reactions, in the treatment of shock states, in emergency medicine, for example for resuscitation, and in the treatment of respiratory diseases and / or local vasoconstriction.

[0076] The present invention will be further illustrated by non-limiting examples.

Example

[0077] An oral thin film agent containing the composition listed in Table 1 was produced as follows:

[0078] Production of foam formulation: 197Adr0086, 197Adr0078, 197Adr0091 and 197Adr0084 The production of the oral thin film agent can be carried out by mass production techniques known to those skilled in the art, for example by stirring / mixing the components contained using an agitator motor and a suitable stirring tool.

[0079] Subsequently, gas was added to the obtained mass by stirring using, for example, a foaming machine. The foamed mass can then be coated on a coating carrier with a constant layer thickness using a suitable instrument (roller applicator, doctor blade, coating box, etc.).

[0080] A fully temperature-stable mesh material from which the dry film can be removed can be used as the coating carrier. This can be achieved by the material selection of the coating carrier (different surface tensions between the foamed mass and the substrate) or by a suitable non-adhesive coating of the coating carrier using, for example, silicone or fluoropolymer.

[0081] The process solvent contained, usually water or a mixture of water and an organic water-miscible solvent, is removed by drying. From the fixed foam layer thus obtained, the oral thin film agent can be cut or die-cut into an appropriate size. Drying is achieved either by drying the laminate in a ventilated drying oven or by moving the coated laminate through a ventilated drying channel. In the case of the drying channel, the drying temperature is defined by the laminating speed and the length of the drying channel, i.e., the period of lamination within the drying channel. The drying channel can be operated using a gradient of different temperature zones. In the process, control can be carried out, such as determination of the water content, via, for example, Karl Fischer titration, to evaluate the success of the drying process.

[0082] Manufacture of suspension formulation 197Adr0100 Manufacture can be carried out by mass production techniques known to those skilled in the art, for example, by stirring / mixing the components contained using an agitator motor and a suitable stirring tool.

[0083] The mass thus obtained is coated onto a coating carrier with a constant layer thickness using a suitable instrument (roller applicator, doctor blade, coating box, etc.).

[0084] A reticular material with total temperature stability from which the dried film can be removed can be used as a coating carrier. This can be achieved by the material selection of the coating carrier (different surface tensions between the mass and the substrate) or by a suitable non-adhesive coating of the coating carrier using, for example, silicone or fluoropolymer.

[0085] The process solvent contained in the coating is removed by drying. Drying is achieved either by drying the laminate in a ventilated drying oven or by moving the coated laminate through a ventilated drying channel. In the case of the drying channel, the drying temperature is defined by the lamination speed and the length of the drying channel, i.e., the period of lamination within the drying channel. The drying channel can be operated using a gradient of different temperature zones. In the process, control can be carried out, such as the determination of the water content, for example via Karl Fischer titration, to evaluate the success of the drying process. From the solid laminate layer thus obtained, the oral thin film agent can be cut or die-cut into an appropriate size. Alternatively, several laminates can be laminated and combined into a thicker laminate. This can be achieved by heating, using high pressure or an adhesive laminate.

[0086]

Table 1

[0087] For the manufactured oral thin film agent, the water content and water activity were measured. The results are summarized in Table 2.

[0088] To determine the water content, each OTF was analyzed by Karl Fischer coulometric titration after dissolving it in 5 mL of dimethyl sulfoxide by shaking on a laboratory shaker at about 1200 rpm for 10 minutes.

[0089] The water activity of the OTF was determined using a Novasina LabMaster-aw neo G00572. The device was switched on at least one day before the measurement for equilibration reasons. Three samples were placed together in a Novasina sample cup (P / N 2601518) and analyzed immediately.

[0090]

Table 2

[0091] Furthermore, the degradation and racemization of adrenaline after storage at 25 °C and 40 °C were measured by HPLC and by comparing the relative peak sizes of the peaks arising from the L - enantiomer and the D - enantiomer, respectively.

[0092] The results are summarized in Tables 3 and 4.

[0093]

Table 3

[0094]

Table 4

[0095] When the OTF in the sealed aluminum pouch is stored at 40 °C, the amount of adrenaline after 5 months only decreases slightly (the values show the change relative to the initial value): 197Adr0100: 0.09% decrease in adrenaline, of which 0.03% is racemization 197Adr0086: 1.32% decrease in adrenaline, of which 0.83% is racemization 197Adr0078: 1.89% decrease in adrenaline, of which 1.18% is racemization 197Adr0084: 1.79% decrease in adrenaline, of which 1.27% is racemization

Claims

1. An oral thin film agent containing adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer, wherein the water activity is less than 0.

6.

2. The oral thin film agent according to Claim 1, wherein adrenaline or a pharmaceutically acceptable salt thereof is present as the L-enantiomer.

3. The oral thin film agent according to Claim 1 or 2, wherein the at least one polymer contains at least one water-soluble polymer.

4. The at least one polymer is selected from the group consisting of starch and starch derivatives, dextran, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl pyrrolidone / polyvinyl acetate copolymer, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, polyvinyl alcohol / polyethylene glycol copolymer, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, natural rubber, and mixtures thereof. The oral thin film agent according to any one of Claims 1 to 3.

5. The oral thin film agent according to any one of Claims 1 to 4, containing an antioxidant of less than 1% by weight, particularly metabisulfite of less than 1% by weight, based on the total weight of the oral thin film agent.

6. The oral thin film agent according to any one of Claims 1 to 5, containing an antibacterial substance of less than 5% by weight, based on the total weight of the oral thin film agent.

7. The oral thin film agent according to any one of Claims 1 to 6, containing water of less than 10% by weight, based on the total weight of the oral thin film agent.

8. The oral thin film agent according to any one of Claims 1 to 7, containing at least 30% by weight of adrenaline or a pharmaceutically acceptable salt thereof, based on the total weight of the oral thin film agent.

9. The oral thin film agent according to any one of claims 1 to 8, containing at least 35% by weight of at least one polymer based on the total weight of the oral thin film agent.

10. The oral thin film agent according to any one of claims 1 to 9, further comprising at least one excipient selected from the group consisting of a coloring agent, a flavoring agent, a sweetening agent, a taste masking agent, an emulsifier, an enhancer, a pH adjuster, a humectant and / or a preservative.

11. 20 to 400 g / m ２ The orally disintegrating film agent according to any one of claims 1 to 10, having a basis weight of

12. The oral thin film agent according to any one of claims 1 to 11, wherein less than 3% of the adrenaline contained in the oral thin film agent is decomposed and / or less than 2.5% of the adrenaline contained is racemized after storage at 40°C for 6 months.

13. A method for producing the oral thin film agent according to any one of claims 1 to 12, comprising: a) a step of producing a solution, dispersion or melt containing adrenaline or a pharmaceutically acceptable salt thereof and at least one polymer; a1) optionally, a step of foaming the solution, dispersion or melt from step a) by introducing a gas or gas mixture, by chemical gas generation, or by expansion of a dissolved gas; b) a step of spreading the solution, dispersion or melt from step a), or optionally the foamed solution, dispersion or melt from step a1), to obtain an oral thin film; and c) a step of drying the oral thin film obtained in step (b) to obtain an oral thin film agent having a water activity of less than 0.6 A method comprising.

14. An oral thin film agent obtainable by the method according to claim 13.

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

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