Oral thin films containing a PVA-Tris buffer layer

Abstract

The present invention relates to oral thin films comprising at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and the use of such oral thin films as medicaments.

Description

[Technical Field]

[0001] The present invention relates to oral thin films (also known by the abbreviation OTF) comprising at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and the use of such oral thin films as pharmaceuticals. [Background technology]

[0002] Polyvinyl alcohol (PVA) is well-suited as a matrix polymer for foams and other oral thin-film formulations, and is therefore widely used and well-known as a matrix polymer for oral thin films. However, PVA can only be processed well in solutions with low ionic strength. At high salt concentrations, e.g., high buffer concentrations, PVA easily precipitates or aggregates. In such cases, a uniform coating appearance is no longer possible. For many applications, such as adjusting the pH of oral saliva to an optimal pH value for active agent penetration and oral hygiene, the use of stronger buffers, i.e., higher buffer concentrations, is required to adjust or maintain a certain pH value in saliva, for example, to favor the absorption of certain active agents. Summary of the Invention [Problem to be solved by the invention]

[0003] The object of the present invention is to overcome the aforementioned drawbacks of the prior art. In particular, the object of the present invention is to provide an oral thin film containing PVA and containing the largest possible amount of at least one buffering substance, while at the same time ensuring that the formulation is easy to process and that the PVA does not precipitate and / or aggregate. At the same time, it is desirable to find a formulation that can foam well and form the most optically homogeneous film possible. Furthermore, the oral thin film must be as stable as possible while also being able to adjust the pH value of the patient's saliva over as wide a range as possible. To this end, it must be possible to incorporate as many buffering substances as possible into the PVA.

[0004] Additionally, oral thin films should be as easy as possible to manufacture, and multi-layer oral thin films should be as simple to construct as possible. [Means for solving the problem]

[0005] The above object is addressed by a multi-layer oral thin film according to claim 1, in particular by an oral thin film comprising at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (tris).

[0006] Oral thin films comprising at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (Tris) are hereinafter also referred to as Tris-PVA layers or Tris buffer layers.

[0007] Such oral thin films have the advantage that Tris can be incorporated at the highest buffer / PVA ratio in terms of percentage and moles, whereas other salts / buffers (phosphate, carbonate, citrate, etc.) cause PVA to aggregate or precipitate.

[0008] The Tris-PVA composition can be foamed well to form films with high optical homogeneity.

[0009] Layers with very high Tris loadings, preferably up to 50 wt% Tris, can also be produced. Additionally, a wide pH range can be accommodated by adjusting with acid (e.g., HCl). Another advantage is that, in some embodiments, these oral thin films can be laminated together without additional adhesives, i.e., relatively thick multilayer films can be produced by laminating multiple Tris-PVA layers together. The Tris buffer layer may be administered in conjunction with an active agent-containing OTF to maintain a suitable pH in the oral cavity. This can be achieved by sequentially administering the Tris buffer layer and the active agent OTF (or vice versa), or the Tris buffer layer may be combined with the active agent layer (e.g., laminated to form a multilayer OTF), or the Tris buffer layer itself may contain at least one pharmaceutically active agent. In particular, systems may be formed with ketamine as the pharmaceutically active agent, for example, which is advantageous for clinical reproducibility (compensating for variations in oral / saliva pH) and neutralizing the oral cavity to a pH favorable for penetration.

[0010] As used herein, "comprising" can also mean "consisting of."

[0011] Tris is an abbreviation for tris(hydroxymethyl)aminomethane (THAM), also known as tromethamine, trometamol (INN), and Tris buffer. Chemically, Tris is a primary amine with three alcoholic hydroxy groups.

[0012] Tris is used as a buffer for biochemistry, molecular biology, microbiology, and medicine. At pH 8.2 (at 20°C), Tris has good buffering capacity at pH 7.2-9.0.

[0013] 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:

[0014] They belong to the group of vinyl polymers.

[0015] Commercially available polyvinyl alcohols, supplied as off-white powders or granular materials with degrees of polymerization ranging from about 500 to 2,500 (molar masses of about 20,000 to 100,000 g / mol), usually have degrees of hydrolysis of 98-99 or 87-89 mol%, i.e., they still contain a residual content of acetyl groups. Polyvinyl alcohols are characterized by the manufacturer by specifying the degree of polymerization, degree of hydrolysis, saponification number, and / or solution viscosity of the starting polymer.

[0016] According to the invention, polyvinyl alcohols having an average molecular weight of about 31,000 (4-88) to about 205,000 (40-88) g / mol are particularly suitable.

[0017] Furthermore, polyvinyl alcohols having a viscosity of 3.4-4.6 mPas (4-88) to 34-46 mPas (40-88) in a 40 g / l aqueous solution, determined by the falling ball method (European Pharmacopoeia 2.2.49), or mixtures of two or more different PVA types, are particularly suitable according to the invention.

[0018] The oral thin film according to the invention is preferably characterized in that polyvinyl alcohol is contained in at least one layer in an amount of 20 to 90 wt. %, preferably 40 to 80 wt. %, very particularly preferably 50 to 75 wt. %, relative to the total weight of the at least one layer.

[0019] The oral thin film according to the invention is further preferably characterized in that polyvinyl alcohol is contained in at least one layer in an amount of 20 to 50 wt. %, preferably 25 to 45 wt. %, very particularly preferably 30 to 40 wt. %, relative to the total weight of the at least one layer.

[0020] The oral thin film according to the invention is further preferably characterized in that polyvinyl alcohol is contained in at least one layer in an amount of 60 to 85 wt. %, preferably 65 to 80 wt. %, very particularly preferably 65 to 75 wt. %, relative to the total weight of the at least one layer.

[0021] The oral thin film according to the invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in at least one layer in an amount of 3 to 70 wt %, preferably 10 to 55 wt %, very particularly preferably 15 to 50 wt %, relative to the total weight of the at least one layer.

[0022] The oral thin film according to the present invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in at least one layer in an amount of 10 to 50 wt %, or 15 to 45 wt %, or 15 to 40 wt %, based on the total weight of the at least one layer.

[0023] The oral thin film according to the present invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in at least one layer in an amount of 20 to 55 wt%, or 20 to 50 wt%, or 20 to 45 wt%, or 20 to 40 wt%, based on the total weight of the at least one layer.

[0024] The oral thin film according to the present invention is further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in at least one layer in an amount of 25 to 55 wt%, or 25 to 50 wt%, or 25 to 45 wt%, or 25 to 40 wt%, based on the total weight of the at least one layer.

[0025] Oral thin films according to the present invention are further preferably characterized in that tris(hydroxymethyl)aminomethane is contained in at least one layer in an amount of about 15 wt%, or about 16.7 wt%, or about 25 wt%, or about 25.5 wt%, or about 40 wt%, or about 50 wt%, based on the total weight of the at least one layer.

[0026] Preferably, oral thin films according to the present invention do not contain any buffering substances other than Tris, particularly phosphate, carbonate and / or citrate.

[0027] The oral thin films according to the present invention are further preferably characterized in that no buffer substances other than Tris, in particular phosphate, carbonate and / or citric acid, are contained in at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (Tris).

[0028] Preferably, no polymers other than PVA are contained in the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (tris).

[0029] Oral thin films according to the present invention are further preferably characterized in that at least one layer comprises at least one pharmaceutically active agent.

[0030] Embodiments of oral thin films according to the present invention are also contemplated in which the oral thin films do not contain a pharmaceutically active agent, but are used simply as "buffer thin films."

[0031] 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.

[0032] According to the present invention, pharmaceutically active agents also include all pharmaceutically acceptable salts and solvates of the pharmaceutically active agent in question.

[0033] Preferred active agents are selected from the group comprising the following classes of active agents: analgesics, hormonal agents, hypnotics, sedatives, antiepileptics, central nervous system stimulants, psychotropic agents, neuromuscular blocking agents, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmic agents, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormone agents, sex hormone agents, antidiabetic agents, antitumor active agents, antibiotics, chemotherapeutic agents and narcotics, but this group is not exhaustive.

[0034] The at least one pharmaceutically active agent is particularly preferably ketamine and / or a pharmaceutically active salt or solvate thereof, preferably ketamine HCl.

[0035] In the present case, ketamine is understood to mean (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, (R)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one and racemic (RS)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

[0036] Because the analgesic and anesthetic potency of (S)-ketamine is approximately three times higher than that of (R)-ketamine, (S)-ketamine or a pharmaceutically acceptable salt thereof, particularly (S)-ketamine HCl, is particularly preferably present as a single stereoisomer of ketamine.

[0037] The active agent content in the at least one layer can vary within relatively wide limits. A content range of 10 to 60 wt. % relative to the dry weight of the at least one layer can be specified as suitable. In other embodiments, the active agent content in the at least one layer tends to be in the range of 25 to 35 wt. %, or in the range of 25 to 45 wt. %, or in the range of 25 to 55 wt. %.

[0038] The oral thin films according to the present invention are further preferably characterized in that at least one layer comprises at least one auxiliary substance selected from the group comprising colorants, flavoring agents, sweeteners, plasticizers, taste masking agents, emulsifiers, enhancers, humectants, preservatives and / or antioxidants.

[0039] These auxiliary substances are preferably contained in at least one 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. %, each relative to the total weight of this layer.

[0040] After drying or removing the solvent, the content of the residual solvent in the oral thin film is preferably in the range of 0.2 to 15 wt %, more preferably in the range of 0.8 to 7 wt %, based on the total weight of the oral thin film.

[0041] Preferably, the oral thin film has at least one additional layer comprising at least one matrix polymer and at least one pharmaceutically active agent.

[0042] In this case, the oral thin film is therefore a multi-layer oral thin film.

[0043] At least one layer comprising at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane may contain at least one pharmaceutically active agent, or in another embodiment, may be free of a pharmaceutically active agent.

[0044] If at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane does not contain a pharmaceutically active agent, it is preferred that at least one of the further layers contains at least one pharmaceutically active agent.

[0045] In such cases, the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane functions solely as a buffer layer to provide the desired pH adjustment in the patient's mouth.

[0046] Oral thin films according to the present invention having at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent are preferably characterized in that the at least one polymer is a water-soluble polymer selected from the group comprising 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, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.

[0047] 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.

[0048] All mentioned active agents further include pharmaceutically acceptable salts and / or solvates thereof.

[0049] Oral thin films according to the present invention having at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent are preferably characterized in that the at least pharmaceutically active agent is selected from the group comprising the following classes of active agents: analgesics, hormonal agents, hypnotics, sedatives, antiepileptics, central nervous system stimulants, psychotropic agents, neuromuscular blocking agents, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmic agents, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormone agents, sex hormone agents, antidiabetics, antitumor active agents, antibiotics, chemotherapeutic agents and narcotics, and the at least one pharmaceutically active agent preferably comprises ketamine, particularly preferably (S)-ketamine.

[0050] In one embodiment, the multilayer oral thin film according to the present invention is characterized in that at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent, are laminated directly to one another.

[0051] In another embodiment, the multilayer oral thin film according to the present invention is characterized in that at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or at least one additional layer comprising at least one matrix polymer and at least one pharmaceutically active agent or at least one flavoring agent, are connected to each other by intermediate adhesive layers.

[0052] An adhesive layer means a layer that can act as an adhesive as defined in DIN EN 923:2016-03. A non-adhesive layer is therefore not capable of acting as an adhesive as defined above.

[0053] Suitable adhesive coatings are in particular water-soluble adhesive coatings as described in DE 10 2014 127 452 A1, the content of which is incorporated herein in its entirety.

[0054] Such adhesive layers comprise at least one water-soluble polymer and at least one plasticizer, wherein the at least one water-soluble polymer in at least one water-soluble adhesive layer comprises shellac, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl caprolactam / polyvinyl acetate / polyethylene glycol copolymer, hydroxypropyl cellulose or hydroxypropyl methylcellulose and / or polyvinylpyrrolidone, and the at least one plasticizer in the at least one water-soluble adhesive layer preferably comprises glycerin, polyethylene glycol, in particular polyethylene glycol 200 and / or tributyl citrate.

[0055] The weight ratio of the at least one water-soluble polymer to the at least one plasticizer in the at least one adhesive layer is preferably about 90:50 to about 10:50, more preferably about 85:50 to about 15:50.

[0056] Such an adhesive layer containing at least one water-soluble polymer and at least one plasticizer can act as an intermediate water-soluble adhesive layer to firmly bond two additional layers that are not themselves sticky to each other, thereby allowing the construction of a multi-layer oral film without multiple overcoating operations, which would mean increased drying times and increased temperature stresses for the active agents and auxiliary substances contained therein.

[0057] In another embodiment, the multilayer oral thin film according to the present invention is characterized in that at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent or at least one flavoring agent, are connected to each other by an intermediate separating layer.

[0058] Preferably, a layer containing at least one polyethylene glycol is used as the separating layer.

[0059] Polyethylene glycol (PEG) has the general formula: [ka] is a compound of

[0060] High molecular weight solid polyethylene glycol (melting temperature about 65°C) is often also called polyethylene oxide or polyoxyethylene (PEO or, more rarely, PEOX) or polywax. In this specification, the terms "polyethylene glycol," "polyethylene oxide," and "polyox" are used equivalently.

[0061] The 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, in particular about 100,000 g / mol.

[0062] The molecular weight is obtained from the rheological measurements described below.

[0063] The at least one polyethylene glycol preferably has a viscosity measured at 25°C of between 30 mPas and 50 mPas.

[0064] The viscosities stated in each case refer to a 5 wt % solution of polyethylene glycol in water and are measured on a Brookfield viscometer model RVF with a No. 1 spindle at 50 rpm and a temperature of 25°C.

[0065] Particularly preferred is polyethylene glycol known under the trade name POLYOX WSR N-10 (Dow Chemical).

[0066] The at least one polyethylene glycol is preferably contained in the at least one separating layer in an amount of 60 to 100 wt %, preferably 80 to 100 wt %, based on the total weight of the at least one separating layer.

[0067] The separating layer preferably contains at least one plasticizer, preferably glycerin, preferably in an amount of 0.5 to 5 wt %, particularly preferably in an amount of 2 to 2.5 wt %, relative to the total weight of the at least one separating layer.

[0068] One advantage of using such a separating layer is that polyethylene glycol membranes are well suited as separating / connecting / adhesive layers in multilayer oral thin films due to their smooth surface, low melting point or glass transition temperature, safety toxicity profile, and water solubility. A polyethylene glycol adhesive layer is particularly suitable for connecting two other layers together under heat and / or high pressure. For example, it may connect an active agent-containing layer and a pH-adjusting buffer layer together.

[0069] 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.

[0070] The separating layer also requires no or very little auxiliary substances such as plasticizers (eg, 2-3% glycerin), thus reducing the risk of migration of adhesive layer components to other layers of the oral thin film.

[0071] The multi-layer oral thin film according to the present invention is not subject to any restrictions regarding its structure.

[0072] Thus, embodiments are contemplated in which the multi-layer oral thin film comprises a Tris buffer layer that does not contain a pharmaceutically active agent, and another layer that contains at least one matrix polymer and at least one pharmaceutically active agent.

[0073] These two layers may be laminated directly to each other or, preferably, connected to an intermediate adhesive or separating layer as defined above.

[0074] Also contemplated are embodiments in which the multi-layer oral thin film comprises a Tris buffer layer that does not contain a pharmaceutically active agent, and another layer that contains at least one matrix polymer and at least one pharmaceutically active agent.

[0075] These two layers may be laminated directly to each other or, preferably, connected to an intermediate adhesive layer as defined above.

[0076] Also contemplated are embodiments in which the multi-layer oral thin film comprises a Tris buffer layer that does not contain a pharmaceutically active agent, and another layer that contains at least one matrix polymer and at least one pharmaceutically active agent, with these two layers connected by an adhesive or separation layer as defined above.

[0077] Also contemplated are embodiments in which the multi-layer oral thin film consists of a Tris buffer layer containing no pharmaceutically active agent, and another layer containing at least one matrix polymer and at least one pharmaceutically active agent, with these two layers connected by an adhesive or separation layer as defined above.

[0078] Other multi-layer oral thin films are contemplated, for example, having the following layer structure: Tris buffer layer - layer containing at least one matrix polymer and at least one pharmaceutically active agent - Tris buffer layer.

[0079] In this embodiment, two Tris buffer layers form the exterior of the multi-layer oral thin film.

[0080] These three layers may be laminated directly to each other or, preferably, connected to an intermediate adhesive layer as defined above.

[0081] In principle, a modular system can be provided, more particularly a modular system with any configuration of TRIS buffer layers and further layers.

[0082] In all of the above embodiments, the Tris buffer layers preferably do not contain a pharmaceutically active agent, however, embodiments are contemplated in which at least one pharmaceutically active agent is also contained in each Tris buffer layer of the multilayer thin film.

[0083] The oral thin films according to the present invention are further preferably characterized in that at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent, is present in the form of a solidified foam having voids.

[0084] The porosity and associated large surface area of ​​the membrane particularly facilitates access of water or saliva or other bodily fluids to the interior of the dosage form, thus accelerating dissolution of the dosage form and release of the active agent.

[0085] In the case of rapidly absorbed active agents, transmucosal absorption can also be improved by the rapid dissolution of the matrix layer. On the other hand, the wall thickness of the voids is preferably small so that rapid dissolution or destruction of these voids occurs, e.g., due to solidification of gas bubbles.

[0086] A further advantage of this embodiment is that despite the relatively high surface density, by formulating it as a foam, it can achieve faster drying than comparable non-compositions.

[0087] The oral thin film according to the invention is preferably characterized in that the voids are isolated from one another and are preferably present in the form of bubbles, which voids are filled with air or a gas, preferably an inert gas, particularly preferably nitrogen, carbon dioxide, helium, argon or a mixture of at least two of these gases.

[0088] According to another embodiment, it is provided that the voids are connected to one another, preferably by forming a continuous channel system that passes through the matrix.

[0089] The voids preferably have a volume fraction of 5 to 98%, preferably 50 to 80%, relative to the total volume of the layer in question. In this way, the intended effect of accelerating the dissolution of the active agent-containing matrix layer is favorably influenced.

[0090] Additionally, surface active agents or surfactants may be added to the matrix polymer or polymer matrix for foam formation or to the resulting foam before or after drying to improve the stability of the foam before or after drying.

[0091] Another parameter that influences the properties of the dosage form according to the present invention is the diameter of the voids or bubbles. The bubbles or voids are preferably formed by a whisk, which allows the diameter of the bubbles to be adjusted in a wide range almost arbitrarily. Thus, the diameter of the bubbles or voids may be in the range of 1 to 350 μm. Particularly preferably, the diameter is in the range of 30 to 200 μm.

[0092] The oral thin film of the present invention is 0.5 cm 2 ~about 10cm 2 , particularly preferably 1.5 cm 2 ~about 9cm 2 Preferably, the area of ​​the surface is .gtoreq.1.0.times.1 ...

[0093] The oral thin film according to the present invention has an areal density of 10 to 500 g / m 2 , preferably 100 to 400 g / m 2 It is preferably characterized in that:

[0094] The areal density of the TRIS buffer layer and any other layers that may be present 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 2or less, or most preferably 250 g / m 2 Preferably, the surface density is 10 to 400 g / m 2 , more preferably 20 to 350 g / m 2 , or 30 to 300 g / m 2 , and most preferably 50 to 250 g / m 2 is.

[0095] Preferably, the Tris buffer layer and any other layers that may be present each have a layer thickness of preferably 10 μm to 500 μm, particularly preferably 20 μm to 300 μm.

[0096] When the TRIS buffer layer is in the form of a foam, the TRIS buffer layer preferably has a layer thickness of 10 μm to 3,000 μm, particularly preferably 90 μm to 2,000 μm.

[0097] The oral thin films according to the present invention are further preferably characterized in that the oral thin film in the mouth of a patient, preferably a human, has a pH value (at 37° C.) of 6-9, preferably 6-8.

[0098] The oral thin film according to the present invention is further preferably characterized by having a pH value of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer solution, or water (at 37° C.).

[0099] Oral thin films according to the present invention are further preferably characterized in that the oral thin film comprises a Tris buffer layer and another layer containing S-ketamine HCl, and has a pH value of 6-8 in 2 mL of human saliva, artificial saliva, PBS buffer, or water (at 37°C).

[0100] The oral thin film according to the present invention is further preferably characterized in that the oral thin film comprises a Tris buffer layer and another layer containing 16.3 mg of S-ketamine HCl, which has a pH value of 6-8 in 2 mL of human saliva, artificial saliva, PBS buffer, or water (at 37°C).

[0101] The oral thin film according to the present invention is further preferably characterized in that the oral thin film comprises a Tris buffer layer and another layer containing 32.2 mg of S-ketamine HCl, and has a pH value of 6-8 in 2 mL of human saliva, artificial saliva, PBS buffer, or water (at 37°C).

[0102] The present invention also relates to a kit comprising at least one first oral thin film comprising at least one layer comprising at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and at least one second oral thin film comprising at least one matrix polymer and at least one pharmaceutically active agent, wherein the first and second oral thin films are preferably different. Preferably, in this kit, the first oral thin film does not comprise a pharmaceutically active agent.

[0103] The above description of the Tris buffer layer and additional layers applies analogously to the first and second oral thin films present in the kit according to the present invention.

[0104] Oral thin films according to the present invention can be manufactured according to methods known to those skilled in the art.

[0105] A known manufacturing method involves providing a solution containing PVA and Tris, then spreading and drying the solution to obtain a membrane.

[0106] When a multi-layer oral thin film is to be produced, a known manufacturing method includes providing a first solution containing PVA and Tris, then spreading and drying said solution to obtain a membrane, and providing a second solution containing at least one matrix polymer and at least one pharmaceutically active agent to obtain a second membrane.

[0107] The joining of these two membranes can be carried out in principle by methods known to those skilled in the art. For example, another membrane can be applied to the first membrane by coating; which membrane is coated on which membrane is not important. Furthermore, the two layers can be connected to each other by the above-mentioned adhesive layer.

[0108] The present invention further relates to oral thin films obtainable by the above process.

[0109] The present invention further relates to the oral thin film as described above as a medicament, obtained by the method or kit described above.

[0110] The present invention further relates to an oral thin film as described above or obtainable by the method or kit described above, wherein ketamine, preferably S-ketamine (optionally as a pharmaceutically acceptable salt or ion pair) is used as the pharmaceutically active agent, as a medicine for use in the treatment of pain and / or the treatment of depression, particularly to reduce the risk of suicide, and / or preferably for use as a general anesthetic for initiating and performing general anesthesia or as an adjuvant in the case of local anesthesia, and / or as an analgesic. DETAILED DESCRIPTION OF THE INVENTION

[0111] The invention will now be described in further detail in some non-limiting examples. [Example]

[0112] Example 1 Effect of pH value on the permeation of (S)-ketamine HCl acidic buffer Na2HPO4×2H2O 80 g / l was dissolved in water; pH adjustment with 1 M aqueous HCl to pH=4.99 at 22 °C.

[0113] neutral buffer Na2HPO4×2H2O 80 g / l was dissolved in water; pH adjustment with 1 M aqueous HCl to pH=7.46 at 22 °C.

[0114] alkaline buffer solution Na2HPO4×2H2O 80 g / l was dissolved in water; pH adjustment with 1 M aqueous HCl to pH=8.33 at 22 °C.

[0115] The pH values ​​of this test system are summarized in Table 1.

[0116] [Table 1]

[0117] The permeation amount of (S)-ketamine was determined in vitro using porcine mucosa (esophageal mucosa) and "Franz diffusion cells" according to OECD guidelines (adopted April 13, 2004). Using a dermatome, the mucosa was divided into 400 μm and 1.145 cm sections with intact barrier function for all transmucosal therapeutic systems. 2 It was manufactured to a thickness of

[0118] The receptor medium was 4 mL of PBS buffer with a pH value of 7.4 at 37°C.

[0119] 2.77 mg of (S)-ketamine HCl was applied to the mucosa, and the upper side of the mucosa containing the active agent was in contact with the buffer solution. The lower side of the mucosa was in contact with the receptor medium. The amount of S-ketamine permeated into the receptor medium was measured at a temperature of 37±1°C. The results are shown in Figure 1.

[0120] From the obtained permeation results, it can be concluded that the permeation of S-ketamine is best in neutral buffer, followed by alkaline buffer. The lowest permeation rate was observed in acidic buffer.

[0121] Example 2 Effect of pH value on the permeation of (S)-ketamine HCl from oral thin films

[0122] Oral thin films having the compositions shown in Table 2 were prepared.

[0123] [Table 2]

[0124] Oral thin films with formulations according to Table 2 were manufactured by bulk manufacturing techniques known to those skilled in the art, such as by stirring / mixing the ingredients with a stirring motor and suitable stirring means.

[0125] Gas was injected into the resulting mass by stirring, for example with a whisk. The foam mass was coated onto the coating substrate with a consistent layer thickness using suitable equipment (roller applicator, squeegee, coating box, etc.).

[0126] Any temperature-stable web-like material from which the dry film can be peeled off again can be used as the coating substrate, which can be ensured by the choice of material of the coating substrate (different surface tensions between the foam mass and the substrate) or by a suitable release coating of the coating substrate, for example with silicone or fluoropolymers.

[0127] The processing solvent contained, usually water or a mixture of water and an organic water-miscible solvent, is removed by drying. Oral thin films are provided in appropriate sizes by cutting or die-cutting from the solid foam layer thus obtained.

[0128] acidic buffer Na2HPO4×2H2O 80 g / l was dissolved in water; pH adjustment with 1 M aqueous HCl to pH=4.99 at 22 °C.

[0129] neutral buffer Na2HPO4×2H2O 80 g / l was dissolved in water; pH adjustment with 1 M aqueous HCl to pH=7.46 at 22 °C.

[0130] alkaline buffer solution Na2HPO4×2H2O 80 g / l was dissolved in water; pH adjustment with 1 M aqueous HCl to pH=8.33 at 22 °C.

[0131] The pH values ​​of this test system are summarized in Table 3.

[0132] [Table 3]

[0133] Formulation 1 S-Ketamine HCl OTF 0.287 cm 2 (equivalent to 2.77 mg of (S)-ketamine) was placed on the mucosa, and 70 μL of buffer solution was added.

[0134] The penetration was measured as in Example 1.

[0135] The amount of (S)-ketamine permeation was determined in vitro using porcine esophageal mucosa and Franz diffusion cells according to OECD guidelines (adopted April 13, 2004). A dermatome was used to prepare the mucosa to a thickness of 400 μm, ensuring an intact barrier function for all transmucosal therapeutic systems.

[0136] 0.287cm 2 A punch with an area of ​​1.145 cm was cut from the OTF and applied to the mucosa, with the upper side of the mucosa bearing the OTF in contact with the buffer (the lower side was in contact with the receptor medium and the upper side was in contact with the buffer). 2 (cut into mucosal areas of 100 mm).

[0137] The permeation amount of S-ketamine in the receptor medium (phosphate buffer pH 7.4) was measured at a temperature of 37±1° C. The results are shown in Figure 2.

[0138] In vitro experiments using various buffer solutions as donor media demonstrated that the permeation behavior of S-ketamine depended on the pH of the buffer solution used. The pH values ​​of the donor media containing the active agent are shown in Table 3 (buffer solution + OTF).

[0139] From the permeation results obtained, it can be concluded that the permeation of S-ketamine is best in alkaline buffer, followed by neutral buffer. The lowest permeation rate was observed in acidic buffer.

[0140] Example 3 [Table 4]

[0141] Oral thin films with formulations according to Table 4 were prepared according to Example 2.

[0142] Oral thin films formulated according to Table 4 are characterized by excellent flexibility and a pleasant sensation ("mouth feel"). Furthermore, the oral thin films produced in this way dissolve very quickly in the mouth despite the highest possible surface density and large thickness. The thin walls of the gas bubbles allow for very gentle drying (e.g., 200 g / m 2 (20 minutes at 70°C).

[0143] Example 4 [Table 5]

[0144] Oral thin films formulated according to Table 5 were manufactured by bulk manufacturing techniques known to those skilled in the art, such as by stirring / mixing the ingredients with a stirring motor and suitable stirring means.

[0145] Gas was injected into the resulting mass by stirring, for example, with a whisk. The foam mass was coated onto a coating substrate with a constant layer thickness using suitable equipment (roller applicator, squeegee, coating box, etc.).

[0146] Any temperature-stable web-like material from which the dried film can be peeled off again can be used as the coating substrate. This can be ensured by the selection of the coating substrate material (different surface tensions between the foam mass and the substrate) or by a suitable release coating of the coating substrate, for example with silicone or fluoropolymer. The contained processing solvent, usually water or a mixture of water and organic water-miscible solvents, is removed by drying.

[0147] The two laminates are then heated to 70° C. and laminated together. Oral thin films can be provided to the appropriate size by cutting or punching the bi-layer laminate thus obtained.

[0148] This bilayer oral thin film is characterized by its high layer thickness and loading. The process may be repeated as often as desired to obtain a multilayer laminate (e.g., laminating three or four laminates), or several laminates may be laminated together in one step (e.g., heating three laminates to 70°C and laminating them together).

[0149] Example 5 [Table 6]

[0150] Oral thin films with formulations according to Table 6 were prepared in the same manner as in Example 2 or Example 3.

[0151] Example 6 [Table 7]

[0152] In each case, oral thin films were prepared according to the formulations in Table 7. Preparation was similar to Example 1 or Example 2.

[0153] The oral thin film was dissolved alone in water or in glandosane (artificial saliva) to determine the pH of the solution. Additionally, both films were dissolved together in water or in glandosane to determine the pH of the solution (see Table 8).

[0154] [Table 8]

[0155] Example 7 [Table 9]

[0156] Thin films were prepared as follows: activator layer, buffer layer, and adhesive layer. The layers were prepared as described in Example 1 and Example 2, respectively. The compositions are listed in the corresponding tables.

[0157] From this, a multi-layer oral thin film having a buffer layer-adhesive layer-active agent layer-adhesive layer-buffer layer structure was prepared as follows: adhesive layers were laminated on both sides of the ketamine laminate, and after removing the carrier membrane, Tris buffer layers were then laminated on both sides.

[0158] The result was a homogeneous foam composite with good tactile properties and good dissolution rate relative to thickness.

[0159] pH measurement is: OTF 3.34 cm in 2 mL of water 2 pH = 8.07 (at 35.5°C) pH of 2 mL of human saliva: pH = 8.04 (at 36.3°C) showed.

[0160] Example 8 [Table 10]

[0161] Thin films were prepared with activator, buffer and adhesive layers as described in Examples 1, 2 and 7, respectively, with compositions listed in the corresponding tables.

[0162] From this, a multi-layer oral thin film having a buffer layer-adhesive layer-active agent layer structure was prepared as follows: The adhesive layer was laminated onto the ketamine foam, and after removing the carrier film of the adhesive layer, the Tris foam was laminated.

[0163] The result was a homogeneous foam composite with good tactile properties and good dissolution rate relative to thickness.

[0164] pH measurement: 3.34 cm of OTF in 2 mL of water 2 : pH = 7.97 (at 36.3°C).

[0165] Example 9 [Table 11]

[0166] Thin films were prepared with activator, buffer and adhesive layers as described in Examples 1, 2 and 7, respectively, with compositions listed in the corresponding tables.

[0167] From this, a multi-layer oral thin film having a buffer layer-adhesive layer-active agent layer structure was prepared as follows: The adhesive layer was laminated onto the ketamine foam, and after removing the carrier film of the adhesive layer, the Tris foam was laminated.

[0168] The result was a homogeneous foam composite with good tactile properties and good dissolution rate relative to thickness.

[0169] Example 10 [Table 12]

[0170] Thin films were prepared with the active agent layer, buffer layer, and adhesive layer as described in Examples 1, 2, and 7, respectively, but the foaming step was omitted. The compositions are listed in the corresponding tables.

[0171] From this, a multi-layer oral thin film having a buffer layer-adhesive layer-active agent layer structure was prepared as follows: The adhesive layer was laminated onto the ketamine foam, and after removing the carrier film of the adhesive layer, the Tris foam was laminated.

[0172] The result was a homogeneous foam composite with good tactile properties and good dissolution rate relative to thickness.

[0173] pH measurement: 3.34 cm of OTF in 2 mL of water 2 : pH = 6.33 (at 32°C).

[0174] Example 11 [Table 13]

[0175] Thin films were prepared with activator, buffer and adhesive layers as described in Examples 1, 2 and 7, respectively, with compositions listed in the corresponding tables.

[0176] From this, a multi-layer oral thin film having a buffer layer-adhesive layer-active agent layer structure was prepared as follows: The adhesive layer was laminated onto the ketamine foam, and after removing the carrier film of the adhesive layer, the Tris foam was laminated.

[0177] The result was a homogeneous composite with good tactile properties and good dissolution rate relative to thickness.

[0178] Example 12 [Table 14]

[0179] Oral thin films with formulations according to Table 14 were prepared as described in Examples 1, 2 and 7.

[0180] Oral thin films formulated according to Table 14 showed the following drawbacks: Lumps and inhomogeneities occur in the mass. The mass does not spread uniformly and is therefore not suitable for thin film production. PVA as a matrix polymer is not compatible with the salts / buffers listed in Table 14.

[0181] Example 13 [Table 15]

[0182] Oral thin films with formulations according to Table 15 were prepared as described in Examples 1, 2 and 7.

[0183] Oral thin films formulated according to Table 15 exhibited the adverse properties listed in Table 15.

[0184] An aqueous polymer dispersion (Smart Seal) was provided, and the plasticizer, flavoring agent, and surfactant were added in sequence. The second polymer was then added, and finally, buffer salts were added and stirred in.

[0185] The mass was coated and dried in the usual manner.

[0186] Example 14 Formula 2 and Formula 12 were administered together (two separate OTFs, each OTF 3.34 cm 2 ): pH in 2 mL of water at 36.5°C: pH = 7.15

[0187] Formula 5 and Formula 12 were administered together (two separate OTFs, each OTF 3.34 cm 2 ): About water: pH of Formulation 12 in 2 mL of water at 21°C: pH = 5.85 pH of Formulation 5 in 2 mL of water at 21°C: pH = 9.65 pH of Formula 12 + Formula 5 in 2 mL of water at 21°C: pH = 7.13 About glandosane (artificial saliva): pH of 2 mL of glandosane in formulation 12 at 21°C: pH = 5.33 pH of 2 mL of glandosane in formulation 5 at 21°C: pH = 8.91 pH of 2 mL of glandosane (Formulation 12 + Formulation 5) at 21°C: pH = 6.94

[0188] Formula 7 and Formula 12 were administered together (two separate OTFs, each OTF 3.34 cm 2 ): About water: pH of Formulation 12 in 2 mL of water at 21°C: pH = 5.85 pH of Formulation 7 in 2 mL of water at 22°C: pH = 9.61 pH of Formula 12 + Formula 7 in 2 mL of water at 22°C: pH = 7.67 About glandosane (artificial saliva): pH of 2 mL of glandosane in formulation 12 at 21°C: pH = 5.33 pH of 2 mL of glandosane in formulation 7 at 21°C: pH = 9.01 pH of 2 mL of glandosane (Formulation 12 + Formulation 7) at 21°C: pH = 7.24

[0189] Example 15 Formula 13 and Formula 26 were administered together (OTF of Formula 13 was OTF 2.27 cm 2 and prescription 26 is 2.27 cm 2 ): Dextromethorphan-containing OTF: Formulation 26 is specified in Table 16.

[0190] [Table 16]

[0191] Oral thin films with formulations according to Table 16 were prepared as described in Examples 1, 2 and 7.

[0192] pH measurement showed pH = 7.63 in 2 mL of water at 35°C.

[0193] Example 16 Formula 13 and Formula 27 were administered together (OTF of Formula 13 was OTF 2.27 cm 2 and prescription 27 is 2.27 cm 2 ):

[0194] Formulation 27 of paracetamol (acetaminophen)-containing OTF is shown in Table 17.

[0195] [Table 17]

[0196] Oral thin films with formulations according to Table 17 were prepared as described in Examples 1, 2 and 7.

[0197] pH measurement showed pH = 8.17 in 2 mL of water at 33°C.

[0198] Example 18 Prescription 13 OTF, OTF 2.72cm 2 and commercially available BEMA fentanyl OTF (200 μg strength) were administered together.

[0199] pH measurement showed pH = 8.67 in 2 mL of water at 22°C.

[0200] Example 19 Determining the effect of pH on the permeation of protonatable / deprotonatable active agents. Adjusting the pH using a buffered OTF can reduce pH variability between individuals and bring the pH into a favorable range for permeation. Multilayered OTFs can affect the release profile by increasing disintegration / dissolution time.

[0201] Ketamine OTF with buffer achieved significantly better penetration (over 18-fold higher) than ketamine HCl (without OTF).

[0202] The results are summarized in FIG. [Brief explanation of the drawings]

[0203] [Figure 1] 1 is a graph showing the amount of permeation of an active agent (S-ketamine) in neutral (pH 7.4), alkaline (pH 8.3), and acidic (pH 5.0) buffer solutions. [Figure 2] 1 is a graph showing the permeation amount of OTF containing an active agent (S-ketamine) in alkaline (pH 8.3), neutral (pH 7.4), and acidic (pH 5.0) buffer solutions. [Figure 3] 1 is a graph showing the amount of permeation of an active agent (S-ketamine) (without OTF) and an OTF containing an active agent (S-ketamine) in alkaline (pH 8.3) and neutral (pH 7.4) buffer solutions.

Claims

1. An oral thin film comprising at least one layer, wherein the at least one layer contains at least one type of polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and the tris(hydroxymethyl)aminomethane is contained in an amount of 15 to 70 wt% relative to the total weight of the at least one layer.

2. The oral thin film of claim 1, wherein tris(hydroxymethyl)aminomethane is contained in at least one layer in an amount of 25 to 55 wt % based on the total weight of the at least one layer.

3. 3. The oral thin film of claim 1, wherein at least one layer comprises at least one pharmaceutically active agent.

4. 4. The oral thin film according to claim 1, wherein at least one layer comprises at least one pharmaceutically active agent selected from the group consisting of classes of active agents: analgesics, hormonal drugs, hypnotics, sedatives, antiepileptics, central nervous system stimulants, psychotropic drugs, neuromuscular blocking drugs, antispasmodics, antihistamines, antiallergic drugs, cardiotonics, antiarrhythmic drugs, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormone drugs, sex hormone drugs, antidiabetic drugs, antitumor active agents, antibiotics, chemotherapeutic drugs and narcotics.

5. The oral thin film of any one of claims 1 to 4, wherein at least one layer comprises at least one pharmaceutically active agent which is (S)-ketamine.

6. 6. The oral thin film of any one of claims 1 to 5, wherein at least one layer comprises at least one auxiliary substance selected from the group comprising colorants, flavoring agents, sweeteners, plasticizers, taste-masking agents, emulsifiers, enhancers, humectants, acids or bases (or their salts), preservatives and / or antioxidants.

7. The oral thin film according to claim 1, characterized in that it has at least one additional layer comprising at least one matrix polymer and at least one pharmaceutically active agent.

7. The oral thin film according to any one of claims 1 to 6.

8. 8. The oral thin film of claim 7, wherein the at least one polymer is a water-soluble polymer selected from the group consisting of starch, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propylcellulose, polyacrylic acid, polyacrylate, polyvinylpyrrolidone, vinylpyrrolidone / 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 gum.

9. 9. The oral thin film of claim 7 or 8, wherein the at least one pharmaceutically active agent is selected from the group comprising the following classes of active agents: analgesics, hormonal agents, hypnotics, sedatives, antiepileptics, central nervous system stimulants, psychotropic agents, neuromuscular blocking agents, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmic agents, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormone agents, sex hormone agents, antidiabetics, antitumor active agents, antibiotics, chemotherapeutics and narcotics.

10. 10. The oral thin film of claim 9, wherein the at least one pharmaceutically active agent is (S)-ketamine.

11. 11. The oral thin film of claim 1, wherein at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent, is present in the form of a solidified foam having voids.

12. 12. The oral thin film of claim 11, wherein the voids are isolated from each other.

13. The oral thin film of claim 11 , wherein the voids are interconnected.

14. 14. The oral thin film of claim 11, wherein the voids occupy a volume fraction of 5 to 98% of the total volume of at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and / or at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent, present in the form of a voided solidified foam.

15. 15. The oral thin film according to any one of claims 7 to 14, characterized in that at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane and / or at least one further layer comprising at least one matrix polymer and at least one pharmaceutically active agent are laminated directly to each other or connected to each other by an intermediate adhesive or separating layer.

16. The oral thin film of any one of claims 1 to 15, wherein the oral thin film in the patient's mouth has a pH value of 5 to 8 (at 37°C).

17. The oral thin film of any one of claims 1 to 16 for use as a medicine.

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