ORAL THIN FILMS

Description

[0001] The present invention relates to a process for producing a multilayer oral thin film, an oral thin film obtainable by this process and its use as a medicament.

[0002] Oral thin films (OTFs) are thin films, usually containing at least one pharmaceutically active ingredient, that are placed directly into the oral cavity or applied to the oral mucosa, where they dissolve. These thin oral films can be constructed as single- or multi-layer systems. The pharmaceutically active ingredient can be dissolved, emulsified, or dispersed within the film. However, oral thin films are not limited to the administration of drugs; they also find applications in the food sector, as well as in dental care and as mouth fresheners.

[0003] In certain cases, it may be necessary for an OTF to remain in the patient's mouth for a long time. However, due to constant salivation and movement in the mouth, the films are subject to permanent erosion. To prevent this, the OTF can be coated with one or more slowly dissolving or insoluble backing layers.

[0004] However, it may also be necessary to use rapidly soluble substances, such as

[0005] Applying flavors, buffering agents, salts or sweeteners as backing layer(s) to the OTF.

[0006] In the multilayer OTFs known from the prior art, these backing layers are applied by a double or multiple coating or adhered using an adhesive layer. Some compositions for oral thin films are disclosed in US 2005 / 136096 A1, US 2014 / 335153 A1, WO 2007 / 102817 A1, US 2020 / 146997 A1, and WO 2015 / 195605 A1.

[0007] A disadvantage of these known processes is that the backing layer must be produced separately and then bonded to the actual film by double coating or adhesive. Double or multiple coating leads to increased thermal stress, particularly for the pharmaceutically active ingredient contained within, and often results in poorly bonded bonds. Due to the diffusion of the solvent into the lower film during double or multiple coating, the solvent often has to be dried out again, which is a laborious process.

[0008] Bonding the various layers also requires the backing layer to be produced separately and then bonded. Especially for backings that are intended to dissolve slowly during application, polymers must be selected that, in addition to their poor solubility, also exhibit high viscosity in the polymer solution. This leads to low solids contents and thus long drying times. Furthermore, the films must be very thin to avoid being perceived as distracting, which makes them delicate and difficult to handle.

[0009] The object of the present invention is to remedy the aforementioned disadvantages of the prior art. In particular, the object of the present invention is to provide a process for producing a multilayer oral thin film in which the individual layers do not have to be produced separately and do not have to be joined together to form a composite by laminating individual, separately dried layers. Furthermore, a multilayer oral thin film is to be provided in which the individual layers are preferably also not bonded to one another by a separate adhesive layer. Furthermore, thermal stress on the pharmaceutically active ingredient contained therein is to be avoided as far as possible.

[0010] The above object is achieved by a method for producing a multilayer, preferably two-layer, oral thin film according to claim 1, ie by a method for producing a multilayer oral thin film comprising the steps a) Providing a solution, an emulsion, a foam or a suspension comprising at least a first polymer and at least one plasticizer, b) Processing the solution, the emulsion, the foam or the suspension from step a) to obtain a polymer film, wherein the amount of the at least one plasticizer is 0.1 to 50 wt. %, based on the total weight of the polymer film, c) Applying a powder comprising at least one second substance different from the first polymer to the polymer film, wherein the at least one second substance comprises polyethylene oxide with an average molecular weight of 7,000,000 g / mol, and d) Forming a composite between the polymer film and the powder applied in step c).

[0011] Preferably, the powder comprising at least a second polymer different from the first is applied to the polymer film in step c) before it has completely dried.

[0012] The powder applied in step c) comprises a second polymer, wherein the second polymer is different from the first polymer.

[0013] The polymer applied in step c) may also comprise non-polymeric substances, such as sweeteners, flavorings, buffer substances, salts or pharmaceutically active ingredients.

[0014] An advantage of this process is that it eliminates the need for separate production of different layers. Only a first polymer film is produced, onto which a second substance, preferably a second polymer, is applied, preferably before the first polymer film is completely dry.

[0015] Such an incompletely dried polymer film is preferably characterized by having a certain tackiness, which causes the second substance, comprising the second polymer, to adhere to the polymer film and form a composite. Subsequent drying of the composite thus makes it possible to provide a multilayer oral thin film. Thus, a multilayer oral thin film can be provided, whereby the individual layers do not have to be manufactured separately and bonded together by gluing or lamination. Furthermore, the multilayer oral thin film is not subjected to excessive thermal stress.

[0016] A polymer film that is not completely dried is understood to mean a polymer film that has a residual solvent content of 0.1 to 10 wt.%.

[0017] If the residual solvent content in the film is too low, the film can be additionally sprayed with solvent to achieve sufficient moisture on the surface of the film.

[0018] Preferably, however, the polymer film is not further treated before the application of the second substance, in particular not by applying another substance that promotes the adhesion of the second substance, such as an adhesive.

[0019] The processing of the solution, emulsion, foam or suspension is carried out using the usual methods, such as spreading, extruding or printing.

[0020] The method according to the invention is further preferably characterized in that the formation of the composite comprises drying the composite by heating the two-layer composite to a temperature above the melting temperature of the first and / or the second substance, preferably the second polymer.

[0021] The composite does not necessarily need to be dried (in the sense of removing solvent). Heating or melting the sprinkled-on second material, preferably the second polymer, or reaching the glass transition temperature may also be sufficient. Pressing the sprinkled-on second material, preferably the second polymer, onto the composite is also conceivable.

[0022] This has the advantage that at least one of the at least two different substances or polymers softens or melts, thus resulting in a more stable bond between the layers.

[0023] In an alternative embodiment of the method according to the invention, it may also be sufficient to heat the composite to a temperature below the melting point of the polymers used in order to stabilize the composite. Suitable temperatures are, for example, from about 50°C to about 120°C, preferably up to about 100°C, particularly preferably up to about 80°C. This is preferred if the melting point of the first or second substance, preferably the polymer, is so high that heating to a temperature above these melting points impairs the other ingredients of the multilayer oral thin film, in particular any pharmaceutically active ingredient present.

[0024] The process according to the invention is further preferably characterized in that the polymer film has a residual moisture content of approximately 0.1 to 10 wt.% upon application of the second substance comprising the at least one second polymer. Residual moisture is understood to mean the solvent content in wt.%.

[0025] If there is less residual moisture in the polymer film, the second substance, preferably the at least one second polymer different from the first, no longer adheres well enough to the polymer film.

[0026] It is further preferred that the polymer film has a certain stickiness.

[0027] A film is tacky if it can act as an adhesive or pressure-sensitive adhesive, as defined in DIN EN 923:2016-03. This helps at least one second polymer, different from the first, to adhere to the surface of the polymer film.

[0028] The process according to the invention is characterized in that the at least one second polymer is applied as a powder. The powder is preferably dry, i.e., it has a residual moisture content, as defined above, of less than 10 wt. %.

[0029] Preferably, this powder, which is preferably a dry powder, has an average particle size of less than 500µm, preferably less than 200µm, determined by dynamic light scattering.

[0030] The process according to the invention is further preferably characterized in that the at least one first polymer comprises a water-soluble and / or water-swellable polymer.

[0031] Water-soluble polymers include chemically very diverse natural or synthetic polymers whose common characteristic is their solubility in water or aqueous media. The prerequisite for this is that these polymers possess 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.

[0032] Water-swellable polymers are polymers that increase their volume when water penetrates them.

[0033] The method according to the invention is further preferably characterized in that the at least one first polymer is selected from starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propylcellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.

[0034] These polymers have the advantage that they are compatible with a variety of pharmaceutically active ingredients and are also largely safe for a patient for whose treatment the multilayer oral thin film according to the invention is used.

[0035] These polymers also have the advantage that, when dried, they form a thin, stable film that dissolves upon application to the mucous membrane or in the oral cavity, releasing the active ingredient. This has the advantage of rapid availability of the active ingredient and residue-free administration.

[0036] The process according to the invention is also preferably characterized in that the at least one second polymer comprises a water-insoluble polymer.

[0037] The process according to the invention can also preferably be characterized in that the at least one second polymer comprises a slowly water-soluble polymer or a water-soluble polymer. Water-soluble polymers include chemically very different, natural or synthetic polymers whose common feature is their solubility in water or aqueous media. The prerequisite is that these polymers possess 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.

[0038] Water-soluble is preferably understood to mean a solubility of greater than 100 g / L in water at 25°C.

[0039] The at least one second polymer comprises polyethylene oxide, with an average molecular weight of approximately 7,000,000 g / mol. The use of such a water-insoluble or sparingly water-soluble polymer has the advantage of forming a layer on one side of the multilayer oral thin film that protects the multilayer oral thin film from erosion or rapid dissolution.

[0040] The process according to the invention is further characterized in that the polymer film, in addition to the at least one first polymer, additionally contains at least one plasticizer.

[0041] Plasticizers are liquid or solid, inert organic substances, preferably with low vapor pressure, which, without chemical reaction, primarily due to their solvency and swelling properties, but under certain circumstances also without such, can physically interact with high-polymer materials and form a homogeneous system with them. Plasticizers impart certain desired physical properties to the structures or coatings produced with them, such as a reduced glass transition temperature, increased formability, increased elastic properties, reduced hardness, and possibly increased adhesion. They are classified as plastics additives.

[0042] It is preferred that the at least one plasticizer comprises glycerol, triacetin, polyethylene glycol, in particular polyethylene glycol 200, sorbitol, water, ethanol and / or tributyl citrate.

[0043] This is particularly advantageous since many water-soluble polymers can be made sticky by adding plasticizers.

[0044] Since a plasticizer is present in the polymer film, it is preferred that the amount of the at least one first polymer in the polymer film is about 25 to 90 wt.%, preferably about 35 to 85 wt.%, particularly preferably about 40 to 80 wt.%, based on the total weight of the polymer film.

[0045] The amount of at least one plasticizer in the polymer film is 0.1 to 50 wt.%, preferably about 0.5 to 25 wt.%, based on the total weight of the polymer film.

[0046] If too little or too much plasticizer is used, the mixture will either not be sticky or a workable mass cannot be provided from the outset.

[0047] The use of a polymer film which has been made tacky by the addition of at least one plasticizer has the advantage that the second substance, comprising the second polymer, which is applied to the polymer film, adheres particularly well.

[0048] Particularly preferred is a mixture of polyvinyl alcohol and / or polyvinylpyrrolidone as the first water-soluble polymer and glycerol as a plasticizer, preferably in a ratio of about 80:20 wt.%

[0049] The method according to the invention is further preferably characterized in that the polymer film comprises at least one pharmaceutically active ingredient, and / or wherein at least one pharmaceutically active ingredient is applied to the polymer film either alone or together with the at least one second polymer.

[0050] If the at least one pharmaceutically active ingredient is contained in the polymer film, the at least one pharmaceutically active ingredient is preferably dissolved, emulsified or suspended therein.

[0051] If the at least one pharmaceutically active ingredient is applied to the polymer film alone or together with the at least one second polymer, it is preferably applied in powder form. The at least one pharmaceutically active ingredient is preferably in the form of a dry powder, i.e., it has a residual moisture content, as defined above, of less than 10 wt.%.

[0052] Preferably, the powdered at least one pharmaceutically active ingredient has an average particle size of less than 500 µm, preferably less than 200 µm, measured by means of dynamic light scattering.

[0053] The at least one pharmaceutically active ingredient is not limited, but includes all pharmaceutically active ingredients that can be administered via an OTF.

[0054] Suitable pharmaceutically active ingredients are preferably selected from the group consisting of analgesics, hormones, hypnotics, sedatives, antiepileptics, stimulants, psychoneurotropic agents, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutics and narcotics.

[0055] In a further alternative embodiment of the multilayer oral thin film, the at least one pharmaceutically active ingredient is applied as a second substance to the polymer film.

[0056] Alternatively, a buffering substance, a sweetener and / or a salt is applied.

[0057] The method according to the invention is preferably characterized in that at least one further layer, preferably a further polymer layer, is applied to the side of the two-layer composite on which the second substance, preferably the second polymer, has not been applied.

[0058] This can be achieved using conventional methods known to those skilled in the art, such as lamination and / or bonding. This additional at least one layer can comprise the same or additional pharmaceutically active ingredients or buffer substances, sweeteners, flavorings, or salts. Furthermore, special mucoadhesive polymers can be used to increase the adhesion of the multilayer oral thin film to the patient's mucosa.

[0059] The method according to the invention is preferably characterized in that the polymer film additionally contains at least one excipient selected from the group comprising dyes, flavorings, sweeteners, taste masking agents, surfactants, enhancers, pH regulators, preservatives and / or antioxidants and / or at least one of these excipients is applied to the polymer film together with the at least one second polymer.

[0060] If the additional at least one auxiliary substance is applied to the polymer film together with the second substance, preferably the second polymer, it is preferably applied in powder form. The at least one auxiliary substance is preferably in the form of a dry powder, i.e., it has a residual moisture content, as defined above, of less than 10 wt.%.

[0061] It is also possible to apply a superabsorbent as a second substance to the polymer film, either alone or together with the at least one second substance. This also allows for the application of liquids absorbed by the superabsorbent.

[0062] The method according to the invention is further preferably characterized in that the multilayer oral thin film has a basis weight of 50 to 400 g / m 2<.

[0063] The present invention further relates to a multilayer oral thin film obtainable by the method described above.

[0064] The present invention further relates to a multilayer oral thin film obtainable by the above-described process for use as a medicament.

[0065] The invention is explained below using non-limiting examples. Examples Example 1

[0066] A polymer film according to recipe 1 was applied to a siliconized coating substrate. The polymer used, polyvinylpyrrolidone, has the property of being tacky when treated with the plasticizer glycerin. Immediately after coating, the surface was sprinkled with finely sieved (<160 µm) polyethylene oxide (Polyox VVSR-303; molecular weight 7,000,000). The excess powdered polymer was brushed off with a brush, and the film was then dried. Finally, the film was heated for 5 minutes to a temperature above the melting point of both polymers. The resulting composite could be easily removed from the siliconized coating substrate and further processed. If desired, the composite can be rolled onto another laminate. This creates a composite with a mucoadhesive layer on one side and a layer that protects the film from erosion on the other. Table 1 with recipe 1: material Proportion (wt% dry) Description PVP VA64 80 polymer Glycerin 20 plasticizers Reference example 2

[0067] Below, three different categories for representing the invention are shown. 1. Examples where Kollicoat MAE 100 powder was sprinkled directly onto a mass and then dried. 2. Examples with an adhesive layer, where an adhesive layer was prepared and laminated onto a pre-prepared foam laminate. The powdered materials were then sprinkled on, covered, and pressed down with a roller. 3. Examples with Polyox, where a Polyox laminate was prepared, powder was applied, and then heated above the melting point of Polyox. Category 1:

[0068] Preparation of the base film + powder application: The mixture according to Table 2 below was prepared and the powdered materials were immediately sprinkled on. The coating was then dried in a drying cabinet. Table 2: Composition: Starting material function Percentage mg / m 2< Portion % Kollicoat MAE100-55 polymer 9,742 20,95 Kollicoat MAE 100 P polymer 29,272 62,95 Triethyl citrate plasticizers 4,650 10 Cherry US aroma 1,395 3 Saccharin NA Sweeteners 0,930 2 Sucralose Sweeteners 0,465 1 menthol aroma 0,047 0,1 sum 46,5 100

[0069] The weight was determined using a 10 cm2< test specimen. Coating thickness: 150 µm Coating carrier: 75 µm PET AB1 on AB Drying: 15 min at 70°C Basis weight: 46.5 cm / m 2<

[0070] Nine different powdered materials were sprinkled according to the following Table 3. Table 3: powder Basic film Technology function material Total weight [g / m 2< ] Powder weight [g / m 2< ] Kollicoat MAE 100 Film Basis weight 46.5 [g / m 2< ] Sprinkled before drying Superabsorbent Kelkogel 75,8 29,30 Ion exchanger Amberlite IRP64 75,8 29,30 aroma Firmenich Peach 93,7 47,20 Masking Mane Bitter Masking 98,1 51,60 buffer Trisodium citrate 417,1 370,60 Sweeteners Sucralose 66,9 20,40 Polymer (mucoadhesive) Kollidon VA 64 108,8 62,30 API Caffeine 77 30,50 API mixture Mixture for melting 143,4 96,90 Category 2:

[0071] Production of an adhesive laminate + powder application: An adhesive layer was produced and laminated onto a pre-prepared foam laminate. The composition of the adhesive layer and the foam laminate is summarized in Table 4. The powdered materials were then sprinkled on, covered, and pressed down with a roller. Sampling was carried out analogously to Category 1. Table 4: composition Starting material function Percentage mg / m 2< Portion % Foam laminate* PVA 4-88 polymer 77,60 52,33 100 g / m 2 FD&C red no. 40 dye 0,40 0,27 Saccharin NA Sweeteners 2,00 1,35 Sucralose Sweeteners 4,00 2,70 Glycerin plasticizers 9,00 6,07 Cherry US aroma 6,00 4,05 menthol aroma 1,00 0,67 Adhesive layer: Vinyl alcohol (VA64) polymer 38,64 26,06 48.3 g / m 2 Glycerin plasticizers 9,66 6,51 sum 148,3 100,00 *Foamed with ambient air; alternatively, foaming with nitrogen is possible. Coating thickness: 150 µm Coating carrier: 75 µm PET AB1 on AB Drying: 10 min at room temperature and 8 min at 70°C Basis weight: 148.3 cm / m 2

[0072] Eight different powdered materials were sprinkled according to the following Table 5. Table 5: powder Basic film Technology function material Total weight [g / m 2 ] Powder weight [g / m 2< ] Foam + adhesive layer basis weight 148.3 g / cm 2< Pressed onto adhesive layer Superabsorbent Kelkogel 161,9 13,60 Ion exchanger Amberlite IRP64 155,1 6,80 aroma Firmenich Peach 159,1 10,80 Masking Mane Bitter Masking 173,4 25,10 buffer Trisodium citrate 403,2 254,90 Polymer (mucoadhesive) Kollidon VA 64 164,1 15,80 API Caffeine 149,1 0,80 API mixture Mixture for melting 154 5,70 Category 3:

[0073] Production of a Polyox laminate + powder coating: The mixture according to Table 6 was coated and dried. After drying, the powdered materials were sprinkled on, the coatings were covered, placed on a metal sheet, and weighted down with another metal sheet. The coatings were then placed between the metal sheets in a drying cabinet and melted at 120°C. After cooling, samples were taken as described in Category 1. Table 6: composition Starting material function Percentage mg / m 2< Portion % Polyox polymer 92,63 97,5 Glycerol plasticizers 2,19 2,3 FD&C red no. 40 dye 0,19 0,2 sum 95,00 100 Coating thickness: 300 µm Coating carrier: 100 µm PET TSP Drying: 15 min at 70°C Basis weight: 95 cm / m 2<

[0074] Melting step: Cover film: 75 µm PET AB1 on AB Melting: 10 min at 120°C

[0075] Eight different powdered materials were sprinkled according to the following Table 7. Table 7: powder Basic film Technology function material Total weight [g / m 2 ] Powder weight [g / m 2< ] Polyox basis weight 95 g / m 2< Melted down Superabsorbent Kelkogel 119,8 73,30 Ion exchanger Amberlite IRP64 94,2 47,70 aroma Firmenich Peach 168,4 121,90 Masking Mane Bitter Masking 146 99,50 buffer Trisodium citrate 482,3 435,80 Polymer (mucoadhesive) Kollidon VA 64 159,9 113,40 API Caffeine 196,7 150,20 API mixture Mixture for melting 96,6 50,10

Claims

1. A method for producing a multi-layer oral thin film comprising the steps of a) providing a solution, an emulsion, a foam or a suspension comprising at least one first polymer and at least one plasticiser, b) processing the solution, the emulsion, the foam or the suspension from step a) in order to obtain a polymer film, wherein the amount of the at least one plasticiser is 0.1 to 50 wt.%, in relation to the total weight of the polymer film, c) applying a powder comprising at least one second substance, to the polymer film, wherein the at least one second substance comprises polyethylene oxide, with an average molecular weight of 7,000,000 g / mol, and d) forming a composite between the polymer film and the powder applied in step c).

2. The method according to claim 1, wherein the forming of the composite comprises the heating of the composite to a temperature above the melting point of the first and / or the second substance.

3. The method according to any one of the preceding claims, wherein the polymer film has a residual moisture of from 0.1% to 10 wt.% at the time of application of the at least one second substance.

4. The method according to any one of the preceding claims, wherein the at least one second substance comprises at least one second polymer, which differs from the first polymer, as dry powder, preferably with a particle size of less than 500 µm.

5. The method according to any one of the preceding claims, wherein the at least one first polymer comprises a water-soluble or water-swellable polymer.

6. The method according to any one of the preceding claims, wherein the at least one first polymer is selected from starch and starch derivatives, dextrans, cellulose derivatives, such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatines, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and / or natural gums.

7. The method according to any one of the preceding claims, wherein the polymer film contains at least one plasticiser in an amount of from 0.5 to 25 wt.%, in relation to the total weight of the polymer film.

8. The method according to any one of the preceding claims, wherein the polymer film comprises at least one pharmaceutically active agent, and / or wherein at least one pharmaceutically agent is applied as second substance to the polymer film, wherein the pharmaceutically active agent is preferably selected from the group consisting of analgesics, hormones, hypnotics, sedatives, antiepiletics, analeptics, psychoneurotropic drugs, neuro-muscle blockers, antspasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumour active agents, antibiotics, chemotherapeutics and narcotics.

9. The method according to any one of the preceding claims, further comprising the application of at least one further layer to the side of the composite to which the second polymer has not been applied.

10. The method according to claim 9, wherein the further layer is a polymer layer.

11. The method according to any one of the preceding claims, wherein the polymer film additionally contains at least one auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, taste-masking agents, surfactants, enhancers, pH regulators, preservatives and / or antioxidants, and / or at least one of these auxiliary substances is applied together with the at least one second polymer to the polymer film.

12. The method according to any one of the preceding claims, wherein the multi-layer oral thin film has an area density of from 50 to 400 g / m2.

13. A multi-layer oral thin film obtainable by the method according to any one of claims 1 to 12.

14. The multi-layer oral thin film according to claim 13 for use as a medicament.