Oral thin film

Abstract

A method for producing a multi-layer oral film is described, comprising the steps of: a) providing a solution, emulsion, foam or suspension comprising at least one first polymer; b) obtaining a first polymer film by processing the solution, emulsion, foam or suspension from step a); c) applying a powder comprising at least one second substance, preferably different from the first polymer, to the polymer film; d) forming a composite between the polymer film and the powder applied in step c). Further described are the multi-layer oral films obtainable by this method and the use of the multi-layer oral films obtained by this method as a medicament.

Description

Technical Field

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

Background Art

[0002] An oral thin film (OTF) is a thin film generally containing at least one pharmaceutically active agent that is placed directly in the oral cavity or against the oral mucosa and dissolved in situ. Such oral thin films can be configured as single-layer or multilayer systems. The pharmaceutically active agent can be in a dissolved, emulsified or dispersed state in the film. However, oral thin films are not limited to the administration of drugs, but can also be used in the food sector, for dental care, or as oral fresheners.

[0003] In various scenarios, the OTF may need to have a long residence time in the patient's oral cavity. However, due to the continuous flow of saliva and movement in the oral cavity, the OTF is constantly exposed to erosion. To prevent this, it is possible to provide the OTF with one or more slowly soluble or insoluble support layers.

[0004] However, there may also be cases where it is necessary to apply rapidly soluble substances such as flavorings, buffering substances, salts or sweeteners as support layers to the OTF.

[0005] In the case of multilayer OTFs known from the prior art, such support layers are applied using double or multiple coatings, or are attached using an adhesive layer.

[0006] The disadvantages of these known methods are that the support layer has to be produced separately and then joined to the film body by double coating or attached to the film body via an adhesive layer. Applying a double or multiple coating leads to an increase in thermal stress, especially the thermal stress to which the contained pharmaceutically active agent is subjected, and often also leads to poor adhesion of the composite material. During the application of a double or multiple coating, the solvent often diffuses into the lower layer of the film, resulting in the solvent having to be removed by drying again at great expense.

[0007] To join different layers, it is also necessary to produce the support layer separately and then join it. In particular, for use in a support layer that is desired to dissolve slowly during application, a polymer that is not only difficult to dissolve but also has a high viscosity in the polymer solution has to be selected. This results in a low solids content and thus a long drying time. Furthermore, the film has to be extremely thin so as not to be felt as an interference, and for this reason, such films are delicate and difficult to handle.

Summary of the Invention

Problems to be Solved by the Invention

[0008] The object of the present invention is to overcome the above-mentioned disadvantages of the prior art. In particular, the object of the present invention is to provide a method for manufacturing a multilayer oral thin film, which does not require the individual layers to be produced separately and does not require the individual layers to be integrated into a composite material by laminating the individually dried layers. Furthermore, it is also intended to provide a multilayer oral thin film in which the individual layers are not preferably joined and integrated by an independent adhesive layer. In addition, the thermal stress on the contained pharmaceutically active agent should be avoided as much as possible.

Means for Solving the Problems

[0009] The above object is achieved by a method for manufacturing a multilayer, preferably bilayer, oral thin film according to claim 1, i.e., a method for manufacturing a multilayer oral thin film, comprising a) preparing a solution, emulsion, foam or suspension comprising at least one first polymer; b) obtaining a polymer film by processing the solution, emulsion, foam or suspension resulting from step a); c) applying to the polymer film a powder comprising at least one second substance, preferably different from the first polymer; d) forming a composite material from the polymer film and the powder applied in step c) and dealing with it by a method.

Embodiments for Carrying out the Invention

[0010] Preferably, the powder comprising at least one second polymer, preferably different from the first polymer, is applied to the polymer film in step c) before the first polymer is completely dry.

[0011] The powder applied in step c) preferably comprises a second polymer, where the second polymer is preferably different from the first polymer.

[0012] The polymer applied in step c) can also contain non-polymeric substances such as sweeteners, flavorings, buffering substances, salts or even pharmaceutically active agents.

[0013] The advantage of this method is that it is not necessary here to produce the different layers separately. It is only necessary to produce the first polymer film and apply a second substance, preferably a second polymer, thereon, preferably before the first polymer film is completely dry.

[0014] Such incompletely dried polymer films are preferably differentiated in that they have a certain tackiness, whereby a second substance, preferably a second polymer, is adhered to the polymer film to form a composite. By subsequently drying the composite, a multilayer oral thin film can be obtained as a result. Thus, a multilayered oral thin film can be obtained that does not require the individual layers to be made separately and then integrated by bonding or lamination. In addition, this multilayer oral thin film has not been subjected to excessive thermal stress.

[0015] It should be understood that the polymer film that is not completely dried is a polymer film having a residual solvent content of from 0.1 to 10% by weight.

[0016] When the residual solvent content in the film is too low, sufficient moisture can be ensured on the film surface by additionally spraying the film with a solvent.

[0017] However, preferably, no further treatment is performed on the polymer film prior to the application of the second substance, in particular, no further treatment is performed by applying another substance, such as an adhesive, that promotes the adhesion of the second substance.

[0018] Solutions, emulsions, foams or suspensions are processed by conventional methods such as spreading, extrusion or printing.

[0019] The method according to the invention is further preferably differentiated in that forming the composite comprises drying the composite by heating the two-layer composite to a temperature above the melting point of the first and / or second substance, preferably the second polymer.

[0020] The composite material does not necessarily have to be dried (in the sense of solvent removal). It may be sufficient to heat or melt the second substance, preferably the second polymer, sprinkled on the surface, or to reach the glass transition temperature. Pressurizing the second substance, preferably the second polymer, sprinkled on the surface is also envisaged.

[0021] This has the advantage that at least one of at least two different substances or polymers softens or melts, and as a result, a more stable composite material formed from multiple layers is obtained.

[0022] In an alternative embodiment of the method according to the invention, it may be sufficient to heat the composite material to a temperature below the melting point of the polymer used in order to bring the composite material into a state where stabilization has already been achieved. 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 in cases where the melting point of the first or second substance, preferably the polymer, is very high and heating to a temperature above these melting points would damage further raw materials of the multilayer oral thin film, especially if a pharmaceutically active substance is present.

[0023] The method according to the invention is further preferably differentiated in that the polymer film has a residual moisture content of from about 0.1 to 10% by weight at the time of application of the second substance, preferably at least one second polymer. It should be understood that the residual moisture means the content of the solvent expressed as % by weight.

[0024] If the residual moisture in the polymer film is low, the second substance, preferably at least one second polymer different from the first polymer, will no longer adhere well enough to the polymer film.

[0025] Also, it is also preferable that the polymer film has a certain adhesiveness. If the film can act as an adhesive or a pressure-sensitive adhesive as defined in DIN EN 923:2016-03, it is an adhesive film. The film having adhesiveness helps at least one second polymer different from the first polymer to adhere to the surface of the polymer film.

[0026] The method according to the present invention is also differentiated in that preferably at least one second polymer is applied as a powder. This powder is preferably dry, that is, the residual moisture defined above is less than 10% by weight.

[0027] Preferably, this powder is preferably a dry powder and has an average particle size determined by the dynamic light scattering method of less than 500 μm, preferably less than 200 μm.

[0028] The method according to the present invention is further differentiated in that at least one first polymer contains a water-soluble and / or water-swellable polymer.

[0029] Water-soluble polymers include chemically very different natural or synthetic polymers, but the common feature of these polymers is that they are soluble in water or an aqueous medium. The essential condition for this is that these polymers have a sufficient number of hydrophilic groups to be water-soluble and are not crosslinked. The hydrophilic groups can be nonionic, anionic, cationic and / or zwitterionic.

[0030] A water-swellable polymer is a polymer that increases its volume by the penetration of water.

[0031] The method according to the invention is further differentiated in that at least one first polymer is selected from starch and starch derivatives, dextran, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.

[0032] These polymers have the advantage of being compatible with a wide range of pharmaceutically active agents and being almost harmless to the patients for whom the multilayer oral thin films according to the invention are used for treatment.

[0033] These polymers additionally have the advantage that they form stable thin films when dry, but dissolve upon application to the mucosa or in the oral cavity, thereby releasing the active agent. This has the advantage that the active agent can be utilized promptly and no administered active agent remains.

[0034] The method according to the invention further preferably is characterized in that at least one second polymer comprises a water-insoluble polymer.

[0035] The method according to the invention further preferably may be characterized in that at least one second polymer comprises a polymer that is slowly water-soluble or a water-soluble polymer.

[0036] Water-soluble polymers include chemically very different natural or synthetic polymers, but the common feature of these polymers is that they are soluble in water or aqueous media. The essential condition is that these polymers have a sufficient number of hydrophilic groups to be water-soluble and are not cross-linked. The hydrophilic groups can be non-ionic, anionic, cationic, and / or zwitterionic.

[0037] The water-soluble polymer preferably has a solubility in water of more than 100 g / L at 25°C.

[0038] Preferably, at least one second polymer includes polyethylene oxide with an average molecular weight preferably of about 7,000,000 g / mol.

[0039] The use of such water-insoluble or poorly water-soluble polymers has the advantage that a layer is formed on one side of the multilayer oral thin film, and this layer protects the multilayer oral thin film from erosion or rapid dissolution.

[0040] The method according to the present invention preferably further features that the polymer film additionally contains at least one plasticizer in addition to at least one first polymer.

[0041] The plasticizer is a liquid or solid neutral organic substance, preferably with a low vapor pressure, and preferably can physically interact with the polymeric substance without chemical reactions, through its dissolution and swelling properties, but possibly without such properties, and can form a homogeneous system containing itself. The plasticizer imparts certain desired physical properties to the construct or coating made with itself, such as a decrease in the freezing temperature, a decrease in the glass transition temperature, an enhancement of the shape change ability, an enhancement of the elastic properties, a decrease in the hardness, and possibly an enhancement of the adhesion. The plasticizer belongs to the group of plastic additives.

[0042] At least one plasticizer preferably includes glycerin, triacetin, polyethylene glycol, particularly polyethylene glycol 200, sorbitol, water, ethanol and / or tributyl citrate.

[0043] This is particularly advantageous since many water-soluble polymers can be made tacky by the addition of a plasticizer.

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

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

[0046] If too little or too much plasticizer is used, for example, a non-tacky mixture results, or a compound that can actually be used cannot be obtained in the first place.

[0047] Using a polymer film made tacky by the addition of at least one plasticizer has the advantage that a second substance, preferably a second polymer, 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 glycerin as the plasticizer, preferably in a ratio of about 80:20% by weight.

[0049] The method according to the invention preferably further features that the polymer film contains at least one pharmaceutically active agent and / or at least one pharmaceutically active agent is applied to the polymer film alone or together with at least one second polymer.

[0050] When at least one pharmaceutically active agent is contained in the polymer film, the at least one pharmaceutically active agent is preferably present in the polymer film in a dissolved, emulsified or suspended state.

[0051] When at least one pharmaceutically active agent is applied to the polymer film alone or together with at least one second polymer, the active agent is preferably applied in powder form. The at least one pharmaceutically active agent is preferably present as a dry powder. That is, this pharmaceutically active agent has a residual moisture content of less than 10% by weight as defined above.

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

[0053] The at least one pharmaceutically active agent is not limited and includes all pharmaceutically active agents that can be administered using an OTF.

[0054] Suitable pharmaceutically active agents are preferably selected from the group consisting of analgesics, hormones, hypnotics, sedatives, anti-epileptic drugs, analeptics, psychoneurotropic drugs, neuromuscular blocking agents, anti-convulsants, antihistamines, anti-allergy drugs, cardiotonics, anti-arrhythmic drugs, diuretics, antihypertensive drugs, vasopressor drugs, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, anti-diabetic drugs, anti-tumor active agents, antibiotics, chemotherapeutic agents and narcotics.

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

[0056] Alternatively, a buffering substance, a sweetening agent 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 material on which the second substance, preferably the second polymer, is not applied.

[0058] Such application can be carried out by conventional methods known to those skilled in the art, such as lamination and / or bonding. This at least one further layer can contain the same and further pharmaceutically active agents, or buffer substances, sweeteners, flavorings or salts. Furthermore, a special mucoadhesive polymer can be used in this layer to increase the adhesion of the multilayer oral thin film to the mucosa of the patient.

[0059] The method according to the invention is preferably characterized in that the polymer film additionally contains at least one auxiliary substance selected from the group consisting of colorants, flavorings, sweeteners, taste correctors, surfactants, enhancers, pH adjusters, preservatives and / or antioxidants, and / or at least one of these auxiliary substances is applied to the polymer film together with at least one second polymer.

[0060] When at least one additional auxiliary substance is applied to the polymer film together with the second substance, preferably the second polymer, the auxiliary substance is preferably applied in powder form. At least one auxiliary substance is preferably present as a dry powder. That is, the auxiliary substance has a residual moisture content of less than 10% by weight as defined above.

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

[0062] The method according to the invention preferably further comprises that the multilayer oral thin film has a density per unit area of from 50 to 400 g / m 2 up to.

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

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

[0065] The present invention will be described below by way of non-limiting examples.

Example

[0066] A polymer film according to Formulation 1 was applied to a silicon-treated coating carrier. The polymer used, polyvinylpyrrolidone, had the property that when used together with the plasticizer glycerin, it also obtained adhesiveness itself. Immediately after spreading, finely sieved (<160 μm) polyethylene oxide (Polyox VVSR-303; molecular weight 7,000,000) was sprayed onto the surface. The excess powdered polymer was brushed off and then the film was dried. Finally, the film was heated for 5 minutes to a temperature above the melting points of both polymers. The resulting composite could be easily removed from the silicon-treated coating substrate and further processed. Optionally, the composite could be roll onto another laminate. As a result, a composite was obtained having a mucoadhesive layer on one side and a layer protecting the film from erosion on the opposite side.

[0067]

Table 1

Example

[0068] The present invention is illustrated below by showing three different categories. 1. An example where Kollicoat MAE100 was sprayed directly onto the compound as a powder and then dried. 2. This is an example using an adhesive layer. In this example, an adhesive layer was fabricated and laminated onto a pre-prepared foamed laminate. Subsequently, the powdered material was surface-sprayed, covered, and pressed with a roller. 3. This is an example using Polyox. In this example, a polyox laminate was fabricated, the powder was applied, and then it was heated above the melting point of polyox.

[0069] Category 1: Fabrication of the base film + Powder application: Compounds were fabricated according to Table 2 below, and the powdered material was immediately surface-sprayed. Subsequently, drying was carried out in a drying cabinet.

[0070] [Table 2] The weight was determined using test pieces. 2 Test pieces were used for determination. Coating thickness: 150 μm Coating carrier: 75 μm PET AB1 on AB Drying: 15 minutes at 70 °C Density per unit area: 46.5 cm / m 2

[0071] Nine different powdered materials were surface-sprayed according to Table 3 below.

[0072] [Table 3]

[0073] Category 2: Fabrication of the adhesive laminate + Powder application: An adhesive layer was fabricated and laminated onto a pre-prepared foamed laminate. The compositions of the adhesive layer and the foamed laminate were summarized in Table 4. Subsequently, the powdered material was surface-sprayed, covered, and pressed with a roller. Samples were obtained in the same manner as in the case of Category 1.

[0074] [Table 4]

[0075] Eight different powdered materials were surface-sprayed according to Table 5 below.

[0076]

Table 5

[0077] Category 3: Production of polyox laminate + powder application: The compound according to Table 6 was coated and dried. After drying, the powdered material was surface-sprayed, the product was covered, placed on a tray, and weighted from above with another tray. Then, the product was placed between trays in a drying cabinet and melted at 120 °C. After cooling, the sample was obtained in the same manner as in the case of Category 1.

[0078]

Table 6

[0079] Eight different powdered materials were surface-sprayed according to Table 7 below.

[0080]

Table 7

Claims

Claim 1 A method for producing a multilayer oral film, wherein the polymer film has a residual moisture content of from 0.1% to 10% by weight at the time of application of at least one second substance, a) preparing a solution, emulsion, foam or suspension comprising at least one first polymer; b) obtaining a polymer film by processing the solution, emulsion, foam or suspension resulting from step a); c) applying a powder comprising at least one second substance different from the first polymer to the polymer film; d) forming a composite material from the polymer film and the powder applied in step c), the step of forming the composite material comprising heating the composite material to a temperature above the melting point of the first and / or second substance, the method. Claim 2 The method according to claim 1, wherein at least one second substance comprises at least one second polymer different from the first polymer as a powder having a particle size of less than 500 μm and as a dry powder. Claim 3 The method according to claim 1 or 2, wherein at least one first polymer comprises a water-soluble or water-swellable polymer. Claim 4 At least one first polymer is starch and starch derivatives, dextran, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and / or natural gum, the method according to any one of claims 1 to 3. Claim 5 The method according to any one of claims 1 to 4, wherein at least one second substance comprises a water-insoluble polymer. Claim 6 The method according to any one of claims 1 to 5, wherein at least one second polymer comprises polyethylene oxide having an average molecular weight of 7,000,000 g / mol. Claim 7 The method according to any one of claims 1 to 6, wherein the polymer film additionally contains at least one plasticizer. **Claim 8** The method according to any one of claims 1 to 7, wherein the polymer film contains at least one pharmaceutically active agent and / or at least one pharmaceutically active agent is applied to the polymer film as a second substance, wherein the pharmaceutically active agent is selected from the group consisting of analgesics, hormones, hypnotics, sedatives, anti-epileptic drugs, analeptics, psychotropic drugs, neuromuscular blocking agents, anti-convulsants, antihistamines, anti-allergy drugs, cardiotonics, anti-arrhythmic drugs, diuretics, antihypertensive drugs, vasopressor drugs, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, anti-diabetic drugs, anti-tumor active agents, antibiotics, chemotherapeutic agents and narcotics. **Claim 9** The method according to any one of claims 1 to 8, further comprising applying at least one additional layer, a further polymer layer, to the side of the composite material on which the second polymer is not applied. **Claim 10** The method according to any one of claims 1 to 9, wherein the polymer film additionally contains at least one auxiliary substance selected from the group consisting of colorants, flavoring agents, sweeteners, flavor correctives, surfactants, enhancers, pH adjusters, preservatives and / or antioxidants, and / or at least one of said auxiliary substances is applied to the polymer film together with at least one second polymer. **Claim 11** The method according to any one of claims 1 to 10, wherein the multilayer oral film has a density per unit area of from 50 to 400 g / m ２ 2.

Images