Multilayer Oral Thin Film

Abstract

The present invention relates to a multi-layer oral article film comprising at least one matrix layer comprising at least one polymer and at least one backing layer comprising a pharma- ceutical active ingredient and at least one polyethylene glycol. The present invention also relates to a method for producing the thin film and the use of such a thin film as a pharmaceutical product.

Description

Technical Field

[0001] The present invention relates to multilayer oral thin films, a method for producing the same, and use of such oral thin films as pharmaceuticals.

Background Art

[0002] An oral thin film is a thin film containing at least one pharmaceutically active agent, which is directly placed in the oral cavity or on the oral mucosa, where it dissolves or softens, thereby delivering the active agent. These films are, in particular, thin single-layer or multilayer active agent-containing polymer films, which can directly deliver the active agent therein when applied to the mucosa, especially the oral mucosa. The extremely good blood supply to the oral mucosa ensures the rapid transfer of the active agent into the bloodstream. This administration system has the advantage of avoiding the first-pass effect that occurs in the case of the dosage form of the active agent of conventional tablets, since most of the active agent is absorbed from the mucosa. The active agent can be dissolved, emulsified or dispersed in the film.

[0003] Oral thin films known from the prior art have the disadvantage that they are subject to permanent erosion when intended to remain at a point on the patient's mucosa for a long time. For this reason, most of the material is swallowed, and as a result, it does not remain at the application site for the desired period. However, the residence time can be of considerable importance for the transmucosal transport of the pharmaceutically active agent. Furthermore, many active agents have an unpleasant taste and are particularly felt uncomfortably when in contact with the tongue.

[0004] The back protective layer can prevent liquid from penetrating into the formulation and the formulation from dissolving rapidly, so that the active agent remains at the application site for the maximum time and achieves maximum possible penetration or sustained release into the mucosa. Another effect of the backing layer is to prevent the administered film from peeling off from the application site and adhering to other places such as teeth. Furthermore, the unpleasant taste caused by the active agent can be hidden by the backing layer.

[0005] As materials for such a backing layer, insoluble or slowly dissolving polymers and polymer films are often used. However, they have the drawback that they must be removed or swallowed after application.

[0006] A backing layer made of a slowly dissolving polymer also has the drawback that it is based on long-chain high molecular weight polymers. These are difficult to process due to their high viscosity (long drying time, irregular films). Furthermore, they tend to increase the viscosity of saliva in the oral cavity, resulting in a slimy feeling.

[0007] A further problem is that the adhesion of the part composed of the active agent-containing layer and the backing layer is often insufficient. For example, if they show different reactions to air humidity, there is a risk of peeling between the two during storage.

Summary of the Invention

Problems to be Solved by the Invention

[0008] The object of the present invention is to overcome the above-mentioned drawbacks of the prior art. In particular, the object of the present invention is to provide a multilayer oral thin film having at least one backing layer, the backing layer having a particularly low melting point, a safe toxicity profile, and a smooth surface. Furthermore, the backing layer dissolves as slowly as possible, thus protecting the applied film from being swallowed, protecting the tongue from direct contact with the active agent, and thus preventing or reducing the unpleasant taste resulting from the active agent. The active agent must also be protected from additional saliva, which is particularly advantageous when the active agent or the penetration of the active agent is pH-sensitive and the pH value changes as a result of too much saliva.

[0009] Furthermore, by providing a method for manufacturing such a film, a fixed bond between the active agent-containing layer and the backing layer in the oral thin film is ensured.

Means for Solving the Problems

[0010] The above object is addressed by a multilayer oral thin film according to claim 1, in particular a multilayer oral thin film comprising a matrix layer containing at least one polymer and at least one pharmaceutically active agent, and at least one backing layer, wherein at least one backing layer contains at least one polyethylene glycol.

[0011] Such a multilayer oral thin film has the advantage that a layer containing polyethylene glycol is well-suited as the backing layer of the oral thin film due to its smooth surface, low melting point and safe toxicity profile. The layer containing polyethylene glycol dissolves slowly in the mouth (more slowly than the active agent layer), thus protecting the applied oral thin film from being swallowed, further protecting the tongue from direct contact with the active agent, and preventing or reducing the unpleasant taste arising from the active agent. Furthermore, the active agent is protected from additional saliva, which is advantageous, for example, when the active agent or the penetration of the active agent is pH-sensitive and the pH value changes as a result of too much saliva. The different roughnesses of the two layers (the layer containing polyethylene glycol is slightly smoother and the active agent-containing layer is slightly rougher in comparison) can be used to determine which side of the oral thin film the patient applies towards the mucosa. Due to the difference in roughness, the patient can also perceive as a sensation in the mouth whether the oral thin film is facing the correct side up in the mouth.

[0012] Furthermore, better visibility can be obtained by coloring the backing layer with a colorant.

[0013] Furthermore, it is also possible to incorporate a flavoring agent to improve the taste upon application, which is a great advantage over known films.

[0014] In this specification, the word "comprising" can also mean "consisting of".

[0015] The term "backing layer" is understood to mean a layer of a multilayer oral thin film that is one of the outermost layers of the multilayer oral thin film.

[0016] Polyethylene glycol (PEG) has the general formula:

Chemical formula

[0017] Higher molecular weight solid polyethylene glycol (melting temperature of about 65 °C) is often also called polyethylene oxide or polyoxyethylene (abbreviated as PEO or more rarely PEOX) or polywax. In this specification, the terms "polyethylene glycol", "polyethylene oxide" and "polyox" are used equivalently.

[0018] The multilayer oral thin film according to the present invention is preferably characterized in that the matrix layer contains at least one water-soluble polymer.

[0019] Water-soluble polymers include chemically quite different natural or synthetic polymers, but their common characteristic is solubility in water or an aqueous medium. As a prerequisite, these polymers have a sufficient number of hydrophilic groups to be water-soluble and are not cross-linked. The hydrophilic groups may be nonionic, anionic, cationic and / or zwitterionic.

[0020] The water-soluble polymer preferably has a solubility in water exceeding 100 g / L at 25 °C.

[0021] At least one water-soluble polymer is preferably selected from the group consisting of starch and starch derivatives, dextran, for example carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, cellulose derivatives such as ethyl or propyl cellulose, polyacrylic acid, polyacrylate, polyvinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural rubber, and polyvinyl alcohol is particularly preferred.

[0022] The multilayer oral thin film according to the present invention is preferably characterized in that at least one polymer, preferably a water-soluble polymer, is provided in the active pharmaceutical ingredient-containing matrix layer of the multilayer oral thin film in an amount of 10 to 90 wt%, preferably 20 to 60 wt%, particularly preferably 30 to 50 wt% based on the total weight of the active pharmaceutical ingredient-containing matrix layer.

[0023] 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.

[0024] According to the present invention, all pharmaceutically acceptable salts and solvates of a specific pharmaceutically active agent are also included in the pharmaceutically active agent.

[0025] Preferred active agents are selected from the group comprising analgesics, hormonal agents, hypnotics, sedatives, anti-epileptic agents, central nervous system stimulants, psychotropic agents, neuromuscular blocking agents, antispasmodics, antihistamines, anti-allergy agents, cardiotonics, antiarrhythmic agents, diuretics, antihypertensive agents, hypertensive agents, antidepressants, antitussives, expectorants, thyroid hormone agents, sex hormone agents, antidiabetic agents, anti-tumor active agents, antibiotics, chemotherapeutic agents and narcotics, which are classifications of active agents, but this group is not exhaustive.

[0026] At least one pharmaceutically active agent is particularly preferably ketamine and / or its pharmaceutically active salt or solvate, preferably ketamine HCl.

[0027] 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 racemate (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

[0028] (S)-Ketamine or its pharmaceutically acceptable salt, particularly (S)-ketamine HCl, is particularly preferably present as a single stereoisomer of ketamine since the analgesic and anesthetic potency of (S)-ketamine is about 3 times higher than that of the (R) form.

[0029] The active agent content in the matrix layer can be varied within a relatively wide range. It can be said that a range of 10 to 60 wt% is suitable with respect to the dry weight of the matrix layer. In one embodiment, the proportion of the active agent in the matrix layer is rather in a lower range, for example, when the active agent has a strong unpleasant taste and it has to be supplemented with a larger amount of taste masking agent. In this case, a range of 10 to 40 wt% can be cited as an appropriate active agent fraction. In another embodiment, the proportion of the active agent in the dosage form according to the invention is rather in a higher range, and it can be stated that contents of 40 to 60 wt%, particularly 45 to 55 wt% are particularly preferred.

[0030] (S)-Ketamine or a pharmaceutically acceptable salt thereof is particularly preferably present in the matrix layer in an amount of 45 to 55 wt% based on the dry weight of the active agent-containing matrix layer.

[0031] The multilayer oral thin film according to the present invention is more preferably characterized in that the matrix layer contains at least one auxiliary agent selected from the group consisting of a colorant, a flavoring agent, a sweetening agent, a plasticizer, a taste masking agent, an emulsifier, a strengthening agent, a pH adjuster, a wetting agent, a preservative and / or an antioxidant.

[0032] Each of these auxiliary agents is preferably contained in the matrix layer in an amount of 0.1 to 40 wt%, preferably 0.1 to 30 wt%, particularly preferably 0.1 to 15 wt%, very particularly preferably 0.1 to 10 wt%, or 0.1 to 5 wt% based on the total weight of this layer.

[0033] At least one polyethylene glycol preferably has an average molecular weight of at least 20,000 g / mol to 7,000,000 g / mol, preferably 40,000 g / mol to 500,000 g / mol, particularly preferably 95,000 g / mol to 105,000 g / mol, particularly about 100,000 g / mol.

[0034] The molecular weight is derived from the rheology measurement described below.

[0035] The multilayer oral thin film according to the present invention is more preferably characterized in that at least one polyethylene glycol has a viscosity of 30 mPa·s to 50 mPa·s as measured at 25°C.

[0036] In each case, the viscosity described refers to a 5 wt% aqueous solution of polyethylene glycol and is measured at 50 rpm, temperature 25°C with a Brookfield viscometer, model RVF, spindle No. 1.

[0037] Particularly preferred is polyethylene glycol known under the trade name Polyox (POLYOX) WSR N-10 (Dow Chemical Company).

[0038] More preferably, in the multilayer oral thin film according to the present invention, at least one polyethylene glycol is contained in at least one backing layer in an amount of 60 to 100 wt%, preferably 80 to 100 wt%, based on the total weight of at least one backing layer.

[0039] More preferably, in the multilayer oral thin film according to the present invention, at least one polyethylene glycol is contained in at least one backing layer in an amount of 65 to 100 wt%, or 70 to 100 wt%, or 85 to 100 wt%, or 90 to 100 wt%, or 95 to 100 wt%, based on the total weight of at least one backing layer.

[0040] More preferably, in the multilayer oral thin film according to the present invention, at least one polyethylene glycol is contained in at least one backing layer in an amount of 60 to 97.5 wt%, or 65 to 97.5 wt%, or 70 to 97.5 wt%, or 80 to 97.5 wt%, or 85 to 97.5 wt%, or 90 to 97.5 wt%, or 95 to 97.5 wt%, based on the total weight of at least one backing layer.

[0041] More preferably, in the multilayer oral thin film according to the present invention, at least one polyethylene glycol is contained in at least one backing layer in an amount of 60 to 97.5 wt%, or 65 to 97.5 wt%, or 70 to 97.5 wt%, or 80 to 97.5 wt%, or 85 to 97.5 wt%, or 90 to 97.5 wt%, or 95 to 97.5 wt%, based on the total weight of at least one backing layer, and further contains 2 to 2.5 wt% of at least one plasticizer, preferably glycerin.

[0042] The multilayer oral thin film according to the present invention is preferably characterized in that at least one backing layer contains at least one auxiliary agent selected from the group consisting of a colorant, a flavoring agent, a sweetening agent, a taste masking agent, an emulsifier, a strengthening agent, a pH adjuster, a wetting agent, a preservative and / or an antioxidant.

[0043] Each of these auxiliary agents is preferably contained in the backing layer in an amount of 0.1 to 10 wt%, preferably 0.1 to 5 wt%, particularly preferably 0.1 to 2.5 wt% based on the total weight of this layer.

[0044] The multilayer oral thin film according to the present invention is preferably characterized in that at least one backing layer contains at least one plasticizer, preferably glycerin, in an amount of preferably 0.5 to 5 wt%, particularly preferably 2 to 2.5 wt% based on the total weight of at least one backing layer.

[0045] In principle, there is no limitation on the number of layers contained in the multilayer oral thin film according to the present invention.

[0046] For example, embodiments in which the multilayer oral thin film has a plurality of active pharmaceutical ingredient-containing matrix layers are also conceivable.

[0047] Embodiments in which the multilayer oral thin film has two backing layers on opposite sides of the multilayer oral thin film are also conceivable.

[0048] In particular, in order to join at least one matrix layer and at least one backing layer to each other as firmly as possible, at least one adhesive layer can be provided between at least one matrix layer and at least one backing layer.

[0049] The adhesive layer means a layer that can act as an adhesive as defined in DIN EN923:2016-03. Therefore, the non-adhesive layer cannot act as an adhesive as defined above.

[0050] A suitable adhesive coating is, in particular, a water-soluble adhesive coating as described in German Patent Application Publication No. 10 2014 127452, the content of which is hereby incorporated in its entirety.

[0051] A suitable adhesive layer contains at least one water-soluble polymer and at least one plasticizer. At least one water-soluble polymer in at least one water-soluble adhesive layer includes shellac, vinyl pyrrolidone / vinyl acetate copolymer, polyvinyl caprolactam / polyvinyl acetate / polyethylene glycol copolymer, hydroxypropyl cellulose or hydroxypropyl methylcellulose and / or polyvinyl pyrrolidone. At least one plasticizer in at least one water-soluble adhesive layer includes glycerin, polyethylene glycol, particularly polyethylene glycol 200, and / or tributyl citrate. The weight ratio of at least one water-soluble polymer to at least one plasticizer in at least one adhesive layer is preferably about 85-50 to about 15-50.

[0052] Such an adhesive layer containing at least one water-soluble polymer and at least one plasticizer can, as an intermediate water-soluble adhesive layer, firmly bond two further layers that are not sticky by themselves to each other, and as a result, a multilayer oral film can be constructed without performing a plurality of overcoat operations.

[0053] The multilayer oral thin film according to the present invention preferably consists of exactly two layers, specifically, a matrix layer containing at least one polymer and at least one pharmaceutically active agent, and a backing layer containing at least one polyethylene glycol.

[0054] In one embodiment, the active agent-containing matrix layer can be a smooth film.

[0055] The multilayer oral thin film according to the present invention is preferably characterized in that the matrix layer exists in the form of a solidified foam having voids.

[0056] The voids in the film and the associated large surface area make it particularly easy for water or saliva or other body fluids to enter the interior of the dosage form, and as a result, promote the dissolution of the dosage form and the release of the active drug.

[0057] In the case of rapidly absorbed active drugs, trans-mucosal absorption is also improved by the rapid dissolution of the matrix layer.

[0058] On the other hand, the wall thickness of the voids is preferably small so that rapid dissolution or destruction of these voids occurs, for example, to represent solidified bubbles.

[0059] A further advantage of this embodiment is that, despite the relatively high areal density, faster drying can be achieved by formulating as a foam rather than using an equivalent non-foamed composition.

[0060] The multilayer oral thin film according to the present invention preferably has voids that are isolated from each other, preferably present in the form of bubbles, and the voids are filled with air or gas, preferably an inert gas, particularly preferably nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

[0061] According to another embodiment, it is provided that the voids are connected to each other, preferably by forming a continuous channel system that penetrates the matrix.

[0062] The voids preferably have a volume fraction of 5 to 98%, preferably 50 to 80%, based on the total volume of the matrix layer. In this way, the advantageous effect of promoting the dissolution of the matrix layer is preferably affected.

[0063] Furthermore, in order to improve the stability of the foam before or after drying, a surfactant or a surface-active agent can be added to the matrix polymer or polymer matrix for foam formation, or to the foam obtained before or after drying.

[0064] Another parameter that affects the properties of the dosage form according to the present invention is the diameter of the voids or air bubbles. The air bubbles or voids are preferably created using a foaming machine that can adjust the diameter of the air bubbles over a wide range, almost as desired. Therefore, the average diameter of the air bubbles or voids can be measured, for example, by microtomography or microscopy and can range from 1 to 350 μm. Particularly preferably, the diameter ranges from 40 to 200 μm.

[0065] The multilayer oral thin film according to the present invention preferably has a rough surface with an average roughness Ra greater than 2.0 μm and a smooth surface with an average roughness Ra less than 1.0 μm.

[0066] In another embodiment, the multilayer oral thin film according to the present invention is characterized in that the multilayer oral thin film has a rough surface and a smooth surface, and the rough surface has an average roughness Ra that is 1.0 μm greater than that of the smooth surface.

[0067] The roughness can here be measured, for example, with a KLA Tencor P15 profilometer equipped with a measuring stylus with a radius of 2 μm. For this purpose, for example, both sides of the oral thin film are surface scanned over an area of 2 mm × 2 mm. Three line scans are randomly selected from the 2 mm × 2 mm scan area, and the roughness parameters Ra, Rq, Rp, and Rv are determined.

[0068] For the evaluation of the samples, the following roughness parameters can be determined: Ra: Average roughness. Specifies the average distance of the measurement points from the center line. Rq: Root mean square roughness (also RMS roughness); calculated from the mean of the squares of the deviations and corresponding to the root mean square. Rp: Peak height, the distance between the center line and the maximum measured value. Rv: Valley depth, the distance between the center line and the minimum measured value.

[0069] The multilayer oral thin film according to the present invention is more preferably characterized in that the release of at least one pharmaceutically active agent from the matrix layer alone without a backing layer is at least 30% slower.

[0070] This means that the presence of a backing layer on the matrix layer can delay the release of at least one pharmaceutically active agent by at least 30%.

[0071] The oral thin film according to the present invention preferably has an area of 0.5 cm 2 ~10 cm 2 and particularly preferably 1 cm 2 ~8 cm 2 in area.

[0072] The oral thin film according to the present invention preferably has an areal density of the multilayer oral thin film of 10 - 500 g / m 2 and preferably 70 - 400 g / m 2 characterized in that.

[0073] The areal density of the matrix layer is preferably at least 10 g / m 2 more preferably at least 20 g / m 2 or at least 30 g / m 2 or most preferably at least 50 g / m 2 or 400 g / m 2 or less, more preferably 350 g / m 2 or less, or 300 g / m 2 or less, or most preferably 150 g / m 2 less than. Preferably, the areal density is 10 - 400 g / m 2 more preferably 20 - 350 g / m 2 or 30 - 300 g / m 2 and most preferably 50 - 150 g / m 2 is.

[0074] The areal density of the backing layer is important for protecting the active agent from dissolving in saliva and for controlling the dissolution behavior and the function of the backing layer. To ensure sufficient protection of the active agent and sufficient dissolution time, a certain thickness is required, which should usually be at least as long as the active penetration requirement, and thus is the dissolution time of the matrix layer.

[0075] Therefore, the backing layer has an areal density of at least 10 g / m 2 , more preferably at least 20 g / m 2 , or at least 30 g / m 2 , most preferably at least 50 g / m 2 or an areal density of 400 g / m 2 or less, more preferably 350 g / m 2 or less, or 300 g / m 2 or less, or most preferably 150 g / m 2 or less, or an areal density of 10 - 400 g / m 2 , more preferably 20 - 350 g / m 2 , or 30 - 300 g / m 2 , most preferably 50 - 150 g / m 2 and preferably has an areal density.

[0076] Preferably, the matrix layer and at least one backing layer each have a layer thickness of about 10 μm to about 500 μm, particularly preferably about 20 μm to about 300 μm.

[0077] In particular, the backing layer may be equal in size to the matrix layer or larger than the matrix layer. Thus, in certain embodiments, the backing layer is the same size as the active agent-containing matrix layer, while in other embodiments, the backing layer is larger than the surface area of the matrix layer. A layered structure in which the backing layer and the matrix layer are the same size is easy to manufacture because a layered structure can be provided by punching out a two-layer sheet. On the other hand, a layered structure in which the backing layer is larger than the matrix layer is more difficult to manufacture, but it also has the advantage of covering the edges of the matrix layer with the carrier layer, reducing the risk of leakage of the active agent.

[0078] The present invention also relates to a method for manufacturing a multilayer oral thin film according to the present invention, the method comprising the following steps: a) producing and spreading a solution or suspension comprising at least one polyethylene glycol to obtain a film comprising at least one polyethylene glycol, and then drying the spread solution or suspension; b) producing a solution, dispersion or melt comprising at least one polymer and at least one pharmaceutically active agent; b1) optionally, foaming the solution, dispersion or melt from step b) by introducing a gas or gas mixture by chemical gas generation or expansion of dissolved gas; c) spreading the solution, dispersion or melt from step b), or optionally the foamed solution, dispersion or melt from step b1), onto the film obtained in step a) comprising at least one polyethylene glycol to obtain a composite; d) drying the composite obtained in step c) to obtain a multilayer oral thin film.

[0079] Steps a) and b) may be carried out in any order.

[0080] It will be apparent to those skilled in the art that step b1) is only necessary when the active agent-containing matrix layer is present in the form of a solidified foam having voids.

[0081] In step c), there may also be additional layers, such as an adhesive layer, present on the matrix layer.

[0082] The joining of the two films from steps a) and b) can in principle be carried out by methods known to those skilled in the art. For example, another film can be applied to the first film by coating. If the backing layer forms one of the outermost layers, it is in principle irrelevant which film is coated onto which film. Furthermore, the two layers can be joined to each other by an adhesive layer as described above.

[0083] Preferably, the layers are joined to each other by heat. For this purpose, the drying in step d) is carried out at a temperature higher than the melting temperature of the matrix layer and / or the backing layer. As a result, the matrix layer and / or the backing layer, for example, begin to melt, and as a result, a strong joining of the two layers is ensured during subsequent cooling.

[0084] A suitable temperature is 40 to 100 °C, preferably 55 to 80 °C. The drying is preferably carried out for 10 to 60 minutes.

[0085] In a further embodiment, the method according to the invention is characterized in that steps c) and d) described above are replaced by the following steps c2) spreading a solution, dispersion or melt from step b), or optionally a foamed solution, dispersion or melt from step b1), to obtain a film comprising at least one polymer and at least one pharmaceutically active agent, and d2) joining the films obtained in steps a) and c2) by lamination, preferably by exposing them to heat above the melting point of one of the polymers comprised in the film, to obtain a multilayer oral thin film. characterized by being replaced by.

[0086] By an improved method, embodiments of multilayer oral thin films in which both sides of the active agent-containing matrix layer are covered with a layer composed of at least one polyethylene glycol can also be easily manufactured. Such multilayer oral thin films dissolve very slowly.

[0087] The present invention further relates to a multilayer oral thin film obtained by the above method.

[0088] The present invention further relates to a multilayer oral thin film as a pharmaceutical product as described above or obtained by the above method.

[0089] The present invention further relates to a multilayer oral thin film as described above or obtained by the above method, wherein ketamine, preferably S-ketamine, is used as a pharmaceutically active agent for the treatment of pain and / or depression, particularly to reduce the risk of suicide, and / or as a general anesthetic, preferably for initiating and performing general anesthesia, or as an adjunct in the case of local anesthesia, and / or for use as an analgesic.

[0090] The preferred embodiments described above for the multilayer oral thin film according to the present invention are also applicable to the method according to the present invention, the multilayer oral thin film obtained by this method, and the use as a pharmaceutical product.

Embodiments for Carrying Out the Invention

[0091] Hereinafter, the present invention will be described in more detail based on non-limiting examples.

Examples

[0092] Formulation example in which a polyethylene glycol (Polyox) backing layer and an S-ketamine-containing matrix layer are formed in a foam-like state.

[0093]

Table 1

[0094] The multilayer oral thin film with the above composition was manufactured as follows.

[0095] The raw materials for the backing layer were processed using known metering and stirring techniques, with appropriate stirring tools and motors, to obtain a homogeneous mass. This was coated onto a web-shaped substrate (having a constant areal density) using a coating tool (e.g., a film applicator). The wet film was dried at 70°C for 15 minutes using a drying cabinet.

[0096] Similarly, the raw materials for the active pharmaceutical ingredient-containing matrix layer were processed using known metering and stirring techniques, also with appropriate stirring tools and motors, to obtain a homogeneous mass. This mass was then foamed using a stirring technique, and the resulting foam was coated onto the dried backing layer. This was also carried out using a coating tool (e.g., a film applicator). The film composed of the obtained backing layer and matrix layer was dried again at 70°C for 15 minutes using a drying cabinet.

[0097] After drying, this multilayer film can be converted into the form of smaller oral thin films.

Example

[0098] In a formulation example formed from a polyethylene glycol (polyox) backing layer and a foamy S-ketamine-containing matrix layer, the layers were individually manufactured and then joined to each other by lamination.

[0099]

Table 2

[0100] The raw materials of the backing layer were processed using known metering and stirring techniques, with appropriate stirring tools and motors, to obtain a homogeneous mass. This was coated onto a web-shaped substrate (having a constant areal density) using a coating tool (e.g., a film applicator). The wet film was dried at 70 °C for 15 minutes using a drying cabinet.

[0101] Similarly, the raw materials of the active agent-containing matrix layer were processed using known metering and stirring techniques, also with appropriate stirring tools and motors, to obtain a homogeneous mass. This mass was then foamed using a stirring technique, and the resulting foam was coated onto a web-shaped substrate. This was also done using a coating tool (e.g., a film applicator). The wet film was dried at 70 °C for 15 minutes using a drying cabinet.

[0102] The two layers were joined by lamination. For this purpose, the backing layer was temporarily heated to 70 °C and joined to the active agent-containing matrix layer by lamination.

[0103] This multilayer film can be converted into the form of smaller oral thin films.

[0104] In this multilayer oral thin film, a polyox layer that does not contain an active agent functions as the backing layer for the actual active agent-containing matrix layer of the oral thin film. This protective layer can mask the taste of the active agent and avoid the rapid swallowing of the active agent, so that the oral mucosa bioavailability can be enhanced. Specifically, the oral thin film according to the present invention is remarkable in that an active agent streak can be directly coated onto the polyox layer during the manufacturing process.

[0105] By drying at a temperature above the melting point of polyox, the active agent-containing matrix layer and the backing layer are bonded to form a strong bond. Therefore, an adhesive layer is not necessary.

[0106] Furthermore, the patient can identify which side of the OTF should be applied to the mucosa based on the different roughness of the layers (the polyox-containing backing layer is very smooth or film-like, and the active agent-containing matrix layer in the form of a foam is very rough), and whether the correct side has been applied in this way (the feel in the mouth varies depending on which layer is on top or bottom).

[0107] Disintegration time characteristics: The disintegration time of the multilayer oral thin film (with a backing layer) of the composition according to Table 2 was compared with the disintegration time of the single-layer oral thin film (without a backing layer) of the composition according to Table 3. The production was carried out in the same manner as the above-described method for the oral thin film having the composition according to Table 2 (with a backing layer).

[0108]

Table 3

[0109] The disintegration time of the oral thin film was measured in accordance with USP701 using a tablet disintegration apparatus (Pharma-Test DIST-3 triple basket tablet disintegration tester, 30 strokes per minute at a distance of 55 mm, in 1 l of pH 6.8 phosphate buffer). A 2.72 cm 2 sized oral thin film was placed in a basket (sinker) and placed in a glass tube fixed to the apparatus. Finally, the time until only the residue of the oral thin film remained in the basket was measured.

[0110]

Table 4

[0111] Release of the active agent: The in vitro release of the active agent from the oral thin films using the compositions according to Tables 2 and 3 was also measured as follows:

[0112] Release method: In vitro release, S-ketamine was released from S-ketamine HCl oral thin film (OTF) and measured. The active drug was released in phosphate buffer pH 6.8 USP and then measured by gradient reverse phase HPLC method. Quantification was performed against an external standard. Release was carried out using Dissolution Apparatus 2-(Paddle over sinker) according to USP <711>.

[0113] [Table 5]

[0114] [Table 6] [Examples]

[0115] Multilayer oral thin films with the composition according to Table 6 were manufactured, where the active drug-containing matrix layer was covered with backing layers from both sides.

[0116] [Table 7]

[0117] The raw materials of the two backing layers were processed using known metering and stirring techniques, using appropriate stirring tools and motors, to obtain a homogeneous mass. This was coated onto a web-like substrate (having a constant areal density) using a coating tool (e.g., film applicator). The wet film was dried at 70 °C for 15 minutes using a drying cabinet.

[0118] The raw materials of the active agent-containing matrix layer were similarly processed by known metering and stirring techniques, and using appropriate stirring tools and motors to obtain a homogeneous mass. This mass was then foamed using a stirring technique, and the resulting foam was coated onto a web-shaped substrate. This was also done using a coating tool (e.g., a film applicator). The wet film was dried at 70 °C for 15 minutes using a drying cabinet.

[0119] The two backing layers and the intermediate active agent layer were joined by lamination. For this purpose, the backing layer was temporarily heated to 70 °C and then joined to the active agent-containing matrix layer by lamination. Next, the second backing layer was temporarily heated to 70 °C and laminated onto the free surface of the active agent-containing matrix layer of the previous laminate. In this way, a laminate of the composition backing layer - active agent-containing matrix layer - backing layer was obtained.

[0120] The resulting laminate can be converted into the form of smaller oral thin films.

Example

[0121] A multilayer oral thin film with the composition according to Table 7 was manufactured in the same manner as in Example 2. In this case, the active agent-containing matrix layer was not foamed.

[0122]

Table 8

[0123] The HPMC used had different viscosities in a 2% aqueous solution: 603 was 3 mPaS, while 60SH50 was 50 mPaS.

[0124] The two layers were manufactured separately and joined to each other by lamination by heating to 70 °C. After cooling, the two layers were firmly joined.

Example

[0125] The TA morphological surface inspection was performed using a KLA Tencor P15 profilometer equipped with a measurement stylus with a radius of 2 μm. Both sides of the OTF of Example 1 were surface scanned over an area of 2 mm × 2 mm. Three line scans were randomly selected from the 2 mm × 2 mm scan area, and the roughness parameters Ra, Rq, Rp, and Rv were measured.

[0126] For the evaluation of the samples, the following roughness parameters were measured: Ra: Average roughness. It indicates the average distance of the measurement points from the center line. Rq: Root mean square roughness (also known as RMS roughness); calculated from the mean of the squares of the deviations and corresponding to the root mean square. Rp: Peak height, the distance between the center line and the maximum measured value. Rv: Valley depth, the distance between the center line and the minimum measured value.

[0127] The roughness parameters indicate that the OTF has two different rough surfaces. The side of the backing layer is very smooth and comparable to a smooth material like polished steel. In contrast, the side of the active agent layer containing the matrix is quite rough. Due to the different roughnesses of the two OTF sides, patients can distinguish by touch which side is the backing layer and which side is the active agent-containing side. For example, the correct position of the OTF in the mouth can be identified (e.g., the rough side facing downwards towards the oral mucosa and the smooth backing layer on the upper side).

[0128] OTF on the backing layer side

[0129]

Table 9

[0130] OTF on the active agent-containing matrix side

[0131]

Table 10

Example

[0132] Further release measurements were carried out with profile dissolution and higher time dissolution than in Table 5.

[0133] The following were compared: · Active pharmaceutical ingredient-containing matrix layer (Table 3) · Active pharmaceutical ingredient-containing matrix layer with a backing layer on one side (Table 2) · Active pharmaceutical ingredient-containing matrix layer with backing layers on both sides (Table 7)

[0134] For this purpose, S-ketamine was released from S-ketamine HCl oral thin films (OTFs) and measured. The active pharmaceutical ingredient was released in phosphate buffer pH 6.8 USP and then measured by gradient reverse-phase HPLC. Quantification was performed against an external standard. Release was carried out using Dissolution Apparatus 2 (paddle over sinker) according to USP <711>.

[0135] [Table 11]

[0136] The results are shown in Figure 1. It can be seen by those skilled in the art that the release profile of the matrix layer can be changed by the backing layer. [Brief Description of the Drawings]

[0137]

Figure 1

Claims

1. A multilayer oral thin film comprising a matrix layer containing at least one polymer and at least one pharmaceutically active agent, and at least one backing layer, wherein the at least one backing layer contains at least one polyethylene glycol in an amount of 60 to 100 wt% based on the total weight of the at least one backing layer, and the at least one backing layer contains at least one plasticizer, said multilayer oral thin film.

2. The multilayer oral thin film according to claim 1, wherein the matrix layer contains at least one water-soluble polymer.

3. The at least one water-soluble polymer is selected from the group consisting of 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, vinyl pyrrolidone / vinyl acetate copolymer, polyvinyl alcohol, polyethylene oxide polymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural rubber. The multilayer oral thin film according to claim 2.

4. The at least one pharmaceutically active agent is selected from the group consisting of analgesics, hormonal drugs, hypnotics, sedatives, anti-epileptic drugs, central nervous stimulants, psychotropic drugs, neuromuscular blocking agents, antispasmodics, antihistamines, anti-allergy drugs, cardiotonics, antiarrhythmic drugs, diuretics, antihypertensive drugs, vasopressor drugs, antidepressants, antitussives, expectorants, thyroid hormone drugs, sex hormone drugs, antidiabetic drugs, antitumor active drugs, antibiotics, chemotherapeutic drugs, and narcotics, which are classifications of active drugs. The multilayer oral thin film according to any one of claims 1 to 3.

5. The at least one pharmaceutically active agent is ketamine. The multilayer oral thin film according to any one of claims 1 to 4. described.

6. The matrix layer further comprises at least one auxiliary agent selected from the group consisting of a coloring agent, a flavoring agent, a sweetening agent, a plasticizer, a taste masking agent, an emulsifier, a strengthening agent, a pH adjuster, a wetting agent, a preservative and / or an antioxidant, the multilayer oral thin film according to any one of claims 1 to 5.

7. The at least one polyethylene glycol has an average molecular weight of 20,000 g / mol to 7,000,000 g / mol, the multilayer oral thin film according to any one of claims 1 to 6.

8. The at least one polyethylene glycol has a viscosity of 30 mPa·s to 50 mPa·s as measured in a 5 wt% aqueous solution at 25°C, the multilayer oral thin film according to any one of claims 1 to 7.

9. The at least one polyethylene glycol is contained in at least one backing layer in an amount of 80 to 100 wt% based on the total weight of the at least one backing layer, the multilayer oral thin film according to any one of claims 1 to 8.

10. The at least one plasticizer is glycerin, the multilayer oral thin film according to any one of claims 1 to 9.

11. The multilayer oral thin film according to any one of claims 1 to 10, wherein the multilayer oral thin film consists of exactly two layers, specifically, a matrix layer containing at least one polymer and at least one pharmaceutically active agent, and a backing layer containing at least one polyethylene glycol.

12. The matrix layer is present in the form of a solidified foam having voids, the multilayer oral thin film according to any one of claims 1 to 11.

13. The voids are isolated from each other and filled with air or gas, the multilayer oral thin film according to claim 12.

14. The voids are connected to each other, the multilayer oral thin film according to claim 12 or 13.

15. The voids in the matrix layer occupy a volume fraction of 5 to 98% with respect to the total volume of the layer, the multilayer oral thin film according to any one of claims 12 to 14.

16. The oral thin film has a rough surface with an average roughness Ra greater than 2.0 μm and a smooth surface with an average roughness Ra less than 1.0 μm, the multilayer oral thin film according to any one of claims 1 to 15.

17. The oral thin film has a rough side and a smooth side, and the average roughness Ra of the rough side is 1.0 μm greater than that of the smooth side. The multilayer oral thin film according to any one of claims 1 to 16.

18. The multilayer oral thin film has at least 30% slower release of at least one pharmaceutically active agent than the matrix layer alone without a backing layer. The multilayer oral thin film according to any one of claims 1 to 17.

19. A method for manufacturing the multilayer oral thin film according to any one of claims 1 to 18, comprising: a) preparing a solution or suspension containing at least one polyethylene glycol, spreading it, and then drying the spread solution or suspension to obtain a film containing at least one polyethylene glycol. b) preparing a solution, dispersion or melt containing at least one polymer and at least one pharmaceutically active agent. c) introducing a solution, dispersion or melt from step b), or a gas or gas mixture by chemical gas generation or dissolution gas expansion, onto the film obtained in step a) containing at least one polyethylene glycol, and spreading the foamed solution, dispersion or melt obtained by foaming the solution, dispersion or melt from step b) to obtain a composite. d) drying the composite obtained in step c) to obtain a multilayer oral thin film. The method as described above.

20. Steps c) and d) are the following steps: c2) introducing a solution, dispersion or melt from step b), or a gas or gas mixture by chemical gas generation or dissolution gas expansion, and spreading the foamed solution, dispersion or melt obtained by foaming the solution, dispersion or melt from step b) to obtain a film containing at least one polymer and at least one pharmaceutically active agent. d2) joining the films obtained in steps a) and c2) to obtain a multilayer oral thin film. The method according to claim 19, characterized in that it is replaced by the above.

21. The multilayer oral thin film according to any one of claims 1 to 18, for use as a medicine.

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