Multilayer oral thin film

Abstract

The present invention relates to a multi-layer oral thin film comprising a first and a second matrix layer, each containing at least one polymer, and a separating layer located between the first and second matrix layers, the separating layer comprising at least one polyethylene glycol. The present invention also relates to a method for producing said thin film, and its use as a medicament.

Description

[Technical Field]

[0001] The present invention relates to multi-layer oral films, methods for their preparation, and the use of said oral films as medicaments. [Background technology]

[0002] Oral thin film is a thin film containing at least one pharmaceutically active agent, which is placed directly in the oral cavity or against the oral mucosa and dissolves or macerates in situ, thereby delivering the active agent.Oral thin film is particularly a single-layer or multi-layer thin film based on an active agent-containing polymer, which can be applied to mucosa, especially the oral mucosa, and deliver the active agent directly into the mucosa.The abundant blood supply to the oral mucosa ensures that the active agent is rapidly transported into the bloodstream.This dosage system has the advantage that most of the active agent is absorbed by the mucosa, thus avoiding the first-pass effect that occurs in the conventional dosage form of active agent, i.e., in tablet form.The active agent can be dissolved, emulsified or dispersed in the film.

[0003] Multilayer oral films can offer various advantages over "typical" single layer oral films, such as the ability to achieve high density per unit area through the combination of several layers, and the ability to combine different layers, such as an active agent layer with a pH adjusting layer, or an active agent layer with a protective backing layer.

[0004] Multilayer oral films can be produced in principle in a variety of ways, such as by multiple coatings or by adhesively or laminating prefabricated layers together.

[0005] However, multiple coatings have various drawbacks. For example, the active agent is subjected to greater thermal stresses with multiple coating operations. Furthermore, such bonds between layers often lack strength and can delaminate back to their original state. In addition, any errors in the coating (density per unit area) are reproduced in subsequent layers.

[0006] The use of adhesives to unite multiple layers also has drawbacks. Known adhesive layers often have a high density of functional groups, such as -OH groups, which facilitate the migration of active agents and / or auxiliary substances, such as buffer salts, through the adhesive layer. In addition, known adhesive layers are often poorly water-soluble, resulting in poor dissolution behavior in the patient's mouth (poor palatability). In addition, known adhesive layers often require the use of large amounts of plasticizers (e.g., 20% glycerin), which can migrate into layers other than the adhesive layer of the oral thin film and alter its physical properties in situ (e.g., lowering the glass transition temperature). Summary of the Invention [Problem to be solved by the invention]

[0007] The object of the present invention was to overcome the drawbacks known from the prior art. In particular, a multi-layer oral thin film should be provided in which the individual layers are firmly integrated, allowing known adhesive layers and / or coatings to be dispensed with. Furthermore, migration of substances between the individual layers should be largely prevented. In addition, the multi-layer oral thin film should be as easy and cost-effective to manufacture as possible. [Means for solving the problem]

[0008] These objects have now been addressed by an oral thin film as claimed in claim 1, i.e. a multi-layer oral thin film comprising first and second matrix layers each containing at least one polymer and a separating layer located between the first and second matrix layers, wherein the separating layer comprises at least one polyethylene glycol. DETAILED DESCRIPTION OF THE INVENTION

[0009] One advantage of using such a multi-layer oral thin film is that polyethylene glycol film is suitable as a separating / connecting / adhesive layer in the multi-layer oral thin film due to its smooth surface, low melting point or glass transition temperature, benign toxicity profile, and water solubility. By heating and / or high pressure treatment, the polyethylene glycol adhesive layer becomes particularly suitable for connecting two other layers together. For example, an active agent-containing layer and a pH-adjusting buffer layer can be connected together.

[0010] In principle, it is also possible to combine multiple laminates with different activators / auxiliaries to form a "sandwich OTF."

[0011] Additionally, the polyethylene glycol layer is suitable as a barrier layer to prevent or minimize migration of active agents or auxiliary substances (eg, buffer salts) between individual layers.

[0012] Additionally, polyethylene glycol adhesive layers require little or no auxiliary substances such as plasticizers (e.g., 2-3% glycerin), thus reducing the risk of components of the adhesive layer migrating into other layers of the oral thin film.

[0013] In this document, the word "including" can also mean "consisting of."

[0014] Hereinafter, the terms "separation layer," "tie layer," and "adhesive layer" should be understood as synonyms.

[0015] Polyethylene glycol (PEG) has the general formula: [ka] is a compound of

[0016] Polyethylene glycol, a high molecular weight solid (melting temperature about 65°C), is often called polyethylene oxide or polyoxyethylene (abbreviated as PEO or, less frequently, PEOX) or polywax. In this document, the terms "polyethylene glycol," "polyethylene oxide," and "polyox" are used interchangeably.

[0017] The following definitions regarding the first and second matrix layers always apply equally to both the first and second matrix layers.

[0018] In principle, the first and second matrix layers can have the same composition or different compositions.

[0019] The multi-layer oral thin film according to the present invention is preferably characterized in that the first and / or second matrix layer comprises at least one water-soluble polymer.

[0020] Water-soluble polymers include natural or synthetic polymers that vary widely chemically, but the common feature of these polymers is that they are soluble in water or aqueous media. The essential requirement 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.

[0021] The water-soluble polymer preferably has a solubility in water of greater than 100 g / L at 25°C.

[0022] The at least one water-soluble polymer is preferably selected from the group consisting of starch and starch derivatives, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, cellulose derivatives such as ethyl or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gum, with polyvinyl alcohol being particularly preferred.

[0023] The multi-layer oral thin film according to the invention is preferably characterized in that at least one polymer, preferably a water-soluble polymer, is present in a particular matrix layer in an amount of from 10 to 90% by weight, preferably from 20 to 60% by weight, particularly preferably from 30 to 50% by weight, based on the total weight of the first and / or second matrix layer.

[0024] The first and / or second matrix layers preferably contain at least one pharmaceutically active agent.

[0025] The first and second matrix layers can contain the same or different pharmaceutically active agents.

[0026] The at least one pharmaceutically active agent is in principle not subject to any restrictions but is preferably selected from all pharmaceutically active agents suitable for oral and / or transmucosal application.

[0027] In accordance with the present invention, all pharmaceutically acceptable salts and solvates of a particular pharmaceutically active agent are also encompassed by pharmaceutically active agent.

[0028] Preferred active agents are selected from the group comprising active agents classified as analgesics, hormones, hypnotics, sedatives, antiepileptics, analgesics, psychotropic agents, neuromuscular blocking agents, anticonvulsants, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetic agents, antitumor active agents, antibiotics, chemotherapeutics and narcotics, but this group is not exhaustive.

[0029] The at least one pharmaceutically active agent is particularly preferably ketamine and / or a pharmaceutically active salt or solvate thereof, preferably ketamine HCl.

[0030] Ketamine is understood to mean (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, (R)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one and the racemic compound (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

[0031] (S)-ketamine or a pharmaceutically acceptable salt thereof, particularly (S)-ketamine HCl, is particularly preferably present as a single stereoisomer of ketamine because the analgesic and anesthetic potency of (S)-ketamine is approximately three-fold greater than that of the (R) form.

[0032] The active agent content in the first and / or second matrix layer can vary within relatively wide limits. A range of 10 to 60% by weight, based on the dry weight of a particular matrix layer, is suitable. In one embodiment, for example, if the active agent has a strong, unpleasant taste that needs to be compensated for by a larger amount of flavoring agent, the active agent content in a particular matrix layer is somewhat lower. In this case, a range of 10 to 40% by weight is suitable. In another embodiment, the active agent content in a dosage form according to the present invention is somewhat higher, with a content of 40 to 60% by weight, and particularly 45 to 55% by weight, being particularly preferred.

[0033] (S)-ketamine or a pharmaceutically acceptable salt thereof is particularly preferably present in a particular matrix layer in an amount of from 45 to 55% by weight, based on the dry weight of the first and / or second matrix layer.

[0034] The multi-layer oral thin film according to the present invention is further preferably characterized in that the first and / or second matrix layer comprises at least one auxiliary substance selected from the group comprising colorants, flavors, sweeteners, plasticizers, taste masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives and / or antioxidants.

[0035] Each of these auxiliary substances is preferably contained in a particular matrix layer in an amount of from 0.1 to 40% by weight, preferably from 0.1 to 30% by weight, particularly preferably from 0.1 to 15% by weight, and most particularly preferably from 0.1 to 10% by weight or from 0.1 to 5% by weight, relative to the total weight of the first and / or second matrix layer.

[0036] The at least one polyethylene glycol preferably has an average molecular weight of at least 2,000 g / mol to 7,000,000 g / mol, or 8,000 g / mol to 7,000,000 g / mol, preferably 8,000 g / mol to 300,000 g / mol, particularly preferably 95,000 g / mol to 105,000 g / mol, in particular about 100,000 g / mol, or 195,000 g / mol to 205,000 g / mol, in particular about 200,000 g / mol.

[0037] The molecular weight is derived from the rheological measurements described below.

[0038] The multi-layer oral thin film according to the present invention is further preferably characterized in that the at least one polyethylene glycol has a viscosity measured at 25°C of from 30 mPas to 50 mPas, or from 65 mPas to 115 mPas.

[0039] The viscosities mentioned here refer in all cases to a 5% by weight aqueous solution of polyethylene glycol, measured using a Brookfield viscometer, model RVF, spindle number 1, at 50 rpm and a temperature of 25°C.

[0040] Polyethylene glycols known, for example, under the trade names POLYOX WSR N-10 or POLYOX WSR N-80 (Dow Chemical) are particularly preferred.

[0041] Additionally, polyethylene glycols PEG2000, PEG4000, PEG6000, PEG8000, PEG10000 or PEG20000 can also be used.

[0042] The multi-layer oral thin film according to the invention is further preferably characterized in that at least one polyethylene glycol is contained in at least one separating layer in an amount of from 60 to 100% by weight, preferably from 80 to 100% by weight, based on the total weight of the at least one separating layer.

[0043] The multi-layer oral thin film according to the present invention is further preferably characterized in that at least one polyethylene glycol is contained in at least one separating layer in an amount of from 65 to 100% by weight, or from 70 to 100% by weight, or from 85 to 100% by weight, or from 90 to 100% by weight, or from 95 to 100% by weight, based on the total weight of the at least one separating layer.

[0044] The multi-layer oral thin film according to the present invention is further preferably characterized in that at least one polyethylene glycol is contained in at least one separating layer in an amount of from 60 to 97.5% by weight, or from 65 to 97.5% by weight, or from 70 to 97.5% by weight, or from 80 to 97.5% by weight, or from 85 to 97.5% by weight, or from 90 to 97.5% by weight, or from 95 to 97.5% by weight, based on the total weight of the at least one separating layer.

[0045] The multi-layer oral thin film according to the present invention is further preferably characterized in that at least one polyethylene glycol is contained in at least one separating layer in an amount of from 60 to 97.5% by weight, or from 65 to 97.5% by weight, or from 70 to 97.5% by weight, or from 80 to 97.5% by weight, or from 85 to 97.5% by weight, or from 90 to 97.5% by weight, or from 95 to 97.5% by weight, relative to the total weight of the at least one separating layer, additionally together with 2 to 2.5% by weight of at least one plasticizer, preferably glycerin.

[0046] The multi-layer oral thin film according to the present invention is preferably characterized in that at least one separate layer comprises at least one auxiliary substance selected from the group comprising colorants, flavors, sweeteners, taste masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives and / or antioxidants.

[0047] Each of these auxiliary substances is preferably contained in the separating layer in an amount of from 0.1 to 10% by weight, preferably from 0.1 to 5% by weight, particularly preferably from 0.1 to 2.5% by weight, relative to the total weight of the separating layer.

[0048] The multi-layer oral thin film according to the invention is preferably characterized in that at least one separating layer contains at least one plasticizer, preferably glycerin, preferably in an amount of from 0.5 to 5% by weight, particularly preferably from 2 to 2.5% by weight, relative to the total weight of the at least one separating layer.

[0049] The multi-layer oral thin film according to the present invention is further preferably characterized in that the first and / or second matrix layer contains at least one water-soluble polymer, preferably polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS).

[0050] TRIS is an abbreviation for tris(hydroxymethyl)aminomethane (THAM), also known as tromethamine, trometamol (INN), or TRIS buffer. Chemically, TRIS is a primary amine with three alcoholic hydroxy groups.

[0051] TRIS is used as a buffer substance for biochemical, molecular biological, microbiological, and pharmaceutical purposes. With a pK value of 8.2 (at 20°C), TRIS has good buffering capacity between pH 7.2 and 9.0.

[0052] The matrix layer containing at least one water-soluble polymer, preferably polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS), will hereinafter also be referred to as a TRIS buffer layer, or, if polyvinyl alcohol is used, as a TRIS-PVA layer.

[0053] In particular, water-soluble polymers used in such TRIS buffer layers include polyvinyl alcohol.

[0054] This type of layer has the advantage that TRIS can be incorporated at the highest buffer / PVA ratios, both percentage and molar, whereas with other salts / buffers (phosphates, carbonates, citrate, etc.), the PVA will aggregate or precipitate.

[0055] The TRIS-PVA composition foams well and can form films with high optical uniformity.

[0056] Polyvinyl alcohol (PVA or PVAL, sometimes abbreviated as PVOH) has the general structure [ka] It is a polymer of which a small proportion (about 2%) [ka] It may also contain structural units of the type:

[0057] They belong to the group of vinyl polymers.

[0058] Commercially available polyvinyl alcohol is supplied as a white to yellowish powder or granular material with a degree of polymerization ranging from about 500 to 2,500 (molar mass from about 20,000 to 100,000 g / mol) and often a degree of hydrolysis ranging from 98 to 99 mol% or even 87 to 89 mol%. This means that such commercially available polyvinyl alcohol still contains residual acetyl groups. Polyvinyl alcohol is characterized by manufacturers' specifications for the degree of polymerization of the starting polymer, the degree of hydrolysis, the saponification number, and / or the solution viscosity.

[0059] In accordance with the present invention, polyvinyl alcohols having an average molecular weight of about 31,000 g / mol (PVA4-88) to about 205,000 g / mol (PVA40-88) are particularly suitable for use in the TRIS buffer layer.

[0060] Furthermore, according to the present invention, polyvinyl alcohols having a viscosity in aqueous solution of 40 g / l, determined by the falling ball method (Ph.Eur.2.2.49), of 3.4-4.6 mPas (PVA4-88) to 34-46 mPas (PVA40-88) are particularly suitable for use in TRIS buffer layers, or in mixtures of two or more different PVA types.

[0061] The oral thin film according to the present invention is preferably characterized in that polyvinyl alcohol is contained in the TRIS buffer layer in an amount of 20 to 90% by weight, preferably 40 to 80% by weight, and particularly preferably 50 to 75% by weight, based on the total weight of the TRIS buffer layer.

[0062] The oral thin film according to the present invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in the TRIS buffer layer in an amount of 3 to 70% by weight, preferably 10 to 55% by weight, and particularly preferably 15 to 50% by weight, based on the total weight of the TRIS buffer layer.

[0063] Preferably, the multi-layer oral thin film according to the invention, in particular in the TRIS buffer layer, does not contain any other buffer substances other than TRIS, in particular does not contain any phosphate, carbonate and / or citric acid.

[0064] Preferably, no polymers other than PVA are contained in the TRIS buffer layer.

[0065] The multi-layer oral thin film according to the present invention is preferably characterized in that the first and / or second matrix layer is present in the form of a voided solidified foam.

[0066] The voids and associated increased membrane surface area facilitate, inter alia, the access of water or saliva or other bodily fluids to the interior of the dosage form, thus accelerating the dissolution of the dosage form and the release of the active agent.

[0067] For rapidly absorbed active agents, transmucosal absorption can also be enhanced by rapid dissolution of the matrix layer.

[0068] On the other hand, it is preferable that the wall thickness of the aforementioned voids is small, since the voids are like solidified bubbles, and therefore, voids with small wall thickness will quickly dissolve or collapse.

[0069] A further advantage of this embodiment is that, despite having a higher density per unit area compared to a comparable non-foaming composition, by being formulated as a foaming agent, it can achieve faster drying than a non-foaming composition.

[0070] The multi-layer oral thin film according to the invention is preferably characterized in that the voids are separated from one another and are preferably present in the form of bubbles, which voids are filled with air or a gas, preferably with an inert gas, particularly preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

[0071] According to another embodiment, a multi-layer oral film is provided in which the voids are interconnected, preferably by forming a continuous channel system through the matrix.

[0072] The aforementioned voids preferably have a volume fraction of 5 to 98%, preferably 50 to 80%, relative to the total volume of the matrix layer, in order to favorably influence the advantageous effect of accelerating the dissolution of the matrix layer.

[0073] Additionally, the stability of the foam before or after drying can be improved by adding a surface active agent or surfactant to the matrix polymer or polymer matrix for foam formation, or to the resulting foam, before or after drying.

[0074] Another parameter that influences the properties of the dosage form according to the present invention is the size of the voids or bubbles. The bubbles or voids are preferably created using a foaming machine, which allows for almost any desired adjustment of the bubble size within a wide range. Thus, the size of the bubbles or voids can be in the range of 0.01 to 350 μm. Particularly preferably, the size is in the range of 10 to 200 μm.

[0075] The multi-layer oral thin film according to the present invention may, in principle, contain any number of layers.

[0076] Thus, embodiments are envisioned in which the multilayer oral thin film has additional matrix layers in addition to the first and second matrix layers. The above definitions apply equally to such additional matrix layers. Like the first and second matrix layers, such additional matrix layers are connected to one another by intermediate separating layers, as defined above.

[0077] In one embodiment, the multi-layer oral thin film comprises a first matrix layer containing ketamine, preferably (S)-ketamine, as the pharmaceutically active agent and a TRIS buffer layer as a second matrix layer connected to a separating layer, wherein the first and second matrix layers and the separating layer are understood to be as defined above.

[0078] In one embodiment, the multi-layer oral thin film consists of a first matrix layer containing ketamine, preferably (S)-ketamine, as the pharmaceutically active agent and a TRIS buffer layer as a second matrix layer connected to a separating layer, wherein the first and second matrix layers and the separating layer are understood to be as defined above.

[0079] Oral thin films according to the present invention preferably have an area of ​​0.5 cm 2 10cm from 2 up to 2 cm, particularly preferably 2 From 8cm 2 This is up to now.

[0080] Oral films according to the present invention preferably have a density per unit area of ​​the multi-layer oral film of 10 to 500 g / m 2 , preferably 70 to 400 g / m 2 It is characterized in that:

[0081] The density per unit area of ​​the first matrix layer, the second matrix layer or the TRIS buffer layer which may be present and any other layers which may be present is preferably at least 10 g / m 2 , more preferably at least 20 g / m 2 Or at least 30g / m 2 , or most preferably at least 50 g / m 2 or 400g / m 2 or less, more preferably 350 g / m 2 or less or 300g / m 2 or less, or most preferably 250 g / m 2 Preferably, the density per unit area is 10 to 400 g / m 2 , more preferably 20 to 350 g / m 2 , or 30 to 300 g / m 2 , most preferably 50 to 250 g / m 2 is.

[0082] Preferably, the layer thickness of each of the layers provided is preferably from 10 to 500 μm, particularly preferably from 20 to 300 μm.

[0083] Thus, when the various layers are present in the form of solidified foams, each of the layers present as a foam preferably has a layer thickness of from 10 μm to 3,000 μm, in particular from 90 μm to 2,000 μm.

[0084] Oral thin films according to the present invention can be prepared according to methods known to those skilled in the art.

[0085] However, oral thin films according to the present invention preferably comprise: a) preparing and spreading a solution or suspension containing at least one polyethylene glycol, and then drying the spread solution or suspension to obtain a membrane containing at least one polyethylene glycol; b) providing first and second matrix layers, each comprising at least one polymer; c) placing the membrane obtained in step a) on a first matrix layer and a second matrix layer on the membrane obtained in step a), so that the membrane obtained in step a) is placed between the first matrix layer and the second matrix layer, forming a loose grouping; d) applying heat and / or pressure to the unbonded assembly from step c) to form a strong bond; It is produced by a method comprising:

[0086] In step d), the heating is preferably carried out at a temperature of from 30 to 200 degrees, preferably from 50 to 90 degrees.

[0087] In step d) a pressure of from 0.001 bar to 20 bar, preferably from 0.01 bar to 8 bar, is preferably applied.

[0088] The first and / or second matrix layer preferably comprises: a1) preparing a solution, dispersion or melt comprising at least one polymer; aa1) optionally foaming the solution, dispersion or melt from step a1) by inducing a gas or gas mixture by chemical gas generation or by dissolved gas expansion; b) obtaining a first and / or second matrix layer by spreading the solution, dispersion or melt from step a) or the optionally foamed solution, dispersion or melt from step aa1); The method is prepared by a method comprising:

[0089] It will be clear to those skilled in the art that step aa1) is only necessary if the first and / or second matrix layer is intended to be present in the form of a solidified foam having voids.

[0090] The present invention further relates to a multi-layer oral thin film obtainable by the method described above.

[0091] The invention additionally relates to a multi-layer oral thin film as described above or obtainable by the method described above as a medicament.

[0092] The present invention additionally relates to a multi-layer oral thin film as described above or obtainable by the method described above, wherein the pharmaceutically active agent in the first and / or second matrix layer is ketamine, preferably S-ketamine or a pharmaceutically acceptable salt thereof, for use in the treatment of pain and / or depression, in particular to reduce the risk of suicide, and / or as a general anesthetic, preferably as a supplement for use during the induction and administration of general anesthetic or for local anesthetics, and / or as an analgesic.

[0093] The preferred embodiments described above for the multi-layer oral film according to the invention are also applicable to the method according to the invention, the multi-layer oral film obtainable by this method and its use as a medicament.

[0094] The invention will now be explained in more detail on the basis of non-limiting examples. [Example]

[0095] Preparation of the first matrix layer with a polyox top layer: The prototype was formed by multi-coating a polyox layer (not foamed) and a first matrix layer (in the form of a foam) containing S-ketamine.

[0096] [Table 1]

[0097] Fabrication: Formulation 1 was a two-layer formulation in which a first polyox layer formed the active agent-free separation layer that was created first. This layer was then coated with an active agent-containing matrix layer consisting of 50% (S)-ketamine HCl in a polyvinyl alcohol (PVA) 4-88 foam matrix. The dry density of the polyox separation layer was 100.0 g / m². 2 This results in a coating weight of 101.5 g / m2 containing 1.5% residual water. 2 The density per unit area of ​​the active agent-containing matrix layer when dry was 118.7 g / m 2 This results in a coating weight of 123.6 g / m2 containing 4% residual water. 2 (Expected value). [Example]

[0098] The prototype consisted of a polyox separator layer (not foamed), a first matrix layer (foamed) containing S-ketamine, and a TRIS buffer layer as the second matrix layer, joined by lamination:

[0099] [Table 2]

[0100] The three layers were prepared separately and the resulting laminate was heated to 70°C and joined by lamination. After cooling, the laminate was firmly joined.

[0101] pH measurement The pH values ​​of the individual layers shown in Table 2 were measured, as well as the pH values ​​of the composites formed from these layers.

[0102] [Table 3] [Example]

[0103] The transport of substances between the individual layers of multilayer oral films, in which the individual layers were connected to each other by various methods, was investigated.

[0104] 1. Two-layer oral film (OTF1) - layers connected by seams. The two layers of OTF1 had the compositions set forth in Tables 4 and 5 below, respectively.

[0105] [Table 4]

[0106] [Table 5]

[0107] Each has the composition shown in Table 4 and Table 5 and has an area of ​​2.72 cm 2 Two individual layers of were prepared and manually sutured with 0.2 mm thick PVA thread (Vis Extrusion GmbH, Hohberg, Germany).

[0108] 2. Two-layer oral thin film (OTF2) - Layers connected by sealing. The two layers of OTF2 had the compositions set forth in Tables 4 and 5, respectively.

[0109] Each has the composition shown in Table 4 and Table 5 and has an area of ​​2.72 cm 2 Two individual layers of 1000 MPa were prepared and connected by sealing. For this purpose, a portable sealing device (Polystar 100 GEW with level 9 and feeler gauge spacing of 850 μm) was used.

[0110] 3. Three-layer oral film (OTF3) - Layers connected by a polyox intermediate layer. The three layers of OTF3 had the compositions set forth in Table 5 above and Tables 6 and 7 below.

[0111] [Table 6]

[0112] [Table 7]

[0113] Three-layer oral thin films were prepared in which the three layers had the compositions set forth in Tables 5, 6 and 7, supra.

[0114] For this purpose, the individual layers were arranged in the form of an unbonded assembly with a polyox layer (Table 7) in the middle. By heating the unbonded assembly to approximately 70°C, the polyox began to melt and the layers that made up the unbonded assembly bonded together.

[0115] All three formulations of OTF were sealed in 60 x 60 mm COC bags and stored in a laboratory cabinet at 40°C. Migration tests were planned to be performed in triplicate after 3 and 6 weeks of storage. Due to misinterpretation, a total of six OTFs of the three formulations were removed from storage after 3 weeks, but only three OTFs were analyzed. Therefore, the remaining three OTFs could be returned to the 40°C cabinet after 3 weeks of room temperature storage. After an additional 3 weeks at 40°C, analysis was performed at the 6-week test time point (3 weeks at 40°C + 3 weeks at room temperature + 3 weeks at 40°C).

[0116] The transport of materials between the individual layers was investigated.

[0117] [Table 8]

[0118] [Table 9]

[0119] [Table 10]

[0120] [Table 11]

[0121] The lowest pH values ​​and active agent contents were found in the polyox formulations, therefore formulation OTF3 appeared to be the best option when combining two layers with lower active agent migration rates.

Claims

1. 1. A multi-layer oral thin film comprising first and second matrix layers each containing at least one polymer, and a separating layer located between the first and second matrix layers, wherein the separating layer comprises at least one polyethylene glycol having a molecular weight of from 8,000 g / mol to 7,000,000 g / mol in an amount of from 60 to 100% by weight.

2. 10. The multi-layer oral thin film of claim 1, wherein the first and / or second matrix layer comprises at least one water-soluble polymer.

3. 3. The multilayer oral thin film of claim 2, wherein the at least one water soluble polymer is selected from the group comprising starch, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propylcellulose, polyacrylic acid, polyacrylate, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural gum.

4. The multi-layer oral thin film of any one of claims 1 to 3, wherein the first and / or second matrix layer comprises at least one pharmaceutically active agent.

5. 5. The multilayer oral thin film of any one of claims 1 to 4, wherein the first and / or second matrix layer further comprises at least one auxiliary substance selected from the group comprising colorants, flavors, sweeteners, plasticizers, taste masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives and / or antioxidants.

6. 6. The multi-layer oral thin film of any one of claims 1 to 5, wherein the at least one polyethylene glycol has a viscosity of from 30 mPa s to 50 mPa s measured at 25°C using a 5% by weight aqueous solution.

7. The multi-layer oral thin film according to any one of claims 1 to 6, wherein the at least one polyethylene glycol is contained in at least one separating layer in an amount of from 80 to 100% by weight, based on the total weight of the separating layer.

8. The multi-layer oral thin film of any one of claims 1 to 7, wherein the first and / or second matrix layer contains at least one water-soluble polymer.

9. 9. The multi-layer oral thin film of claim 8, wherein the water-soluble polymer is contained in the first and / or second matrix layer in an amount of from 20 to 90% by weight, based on the total weight of the first and / or second matrix layer.

10. 10. The multi-layer oral thin film of claim 8 or 9, wherein tris(hydroxymethyl)aminomethane is contained in the first and / or second matrix layer in an amount of from 3 to 70 wt % based on the total weight of the first and / or second matrix layer.

11. The multi-layer oral thin film of any one of claims 1 to 10, wherein the first and / or second matrix layer is in the form of a voided solidified foam.

12. 12. The multi-layer oral thin film of claim 11, wherein the voids are isolated from one another.

13. 12. The multi-layer oral thin film of claim 11, wherein the voids are interconnected.

14. The multi-layer oral thin film according to any one of claims 11 to 13, wherein the voids in a particular matrix layer have a volume fraction of from 5 to 98% relative to the total volume of the particular matrix layer.

15. A method for producing a multi-layer oral thin film according to any one of claims 1 to 14, comprising the steps of: a) preparing and spreading a solution or suspension containing at least one polyethylene glycol, and then drying the spread solution or suspension to obtain a membrane containing at least one polyethylene glycol; b) providing first and second matrix layers, each comprising at least one polymer; c) placing the membrane obtained in step a) on a first matrix layer and a second matrix layer on the membrane obtained in step a), so that the membrane obtained in step a) is placed between the first matrix layer and the second matrix layer to form an unbonded assembly; d) applying heat and / or pressure to the unbonded assembly from step c) to form a strong bond; A method comprising:

16. The first and / or second matrix layer may comprise: b1-1) preparing a solution, dispersion or melt containing at least one polymer; or b1-2) foaming the solution, dispersion or melt from step b1-1) by inducing a gas or gas mixture by chemical gas generation or by dissolved gas expansion; b2) obtaining a first and / or second matrix layer by spreading the solution, dispersion or melt from step b1-1) or the foamed solution, dispersion or melt from step b1-2); 16. The method of claim 15, prepared by a method comprising:

17. A multilayer oral thin film according to any one of claims 1 to 14 for use as a medicament.

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