HK40096217B - Oral thin film comprising a pva-tris buffer layer - Google Patents

Description

The present invention relates to an oral thin film (also known as an oral thin film or abbreviated as OTF), comprising at least one layer containing at least polyvinyl alcohol and tris(hydroxymethyl)aminomethane in an amount of 15 to 70 wt.%, based on the total weight of the at least one layer, and this oral thin film for use as a medicinal product.

WO 2009/124096 A1 discloses a patch, a system, and a method for delivering a permeation composition to a patient.

Polyvinyl alcohol (PVA) is known as a matrix polymer in oral thin films and is widely used because PVA is well suited as a matrix polymer for foam formulations or other film-like OTF formulations. However, PVA can only be processed well in solutions with low ionic strength. At high salt concentrations, for example, at high buffer concentrations, PVA tends to precipitate or clump. A uniform coating then becomes impossible. For many applications, such as adjusting the pH of saliva to an optimal pH value for drug permeation and oral hygiene, respectively, the use of stronger buffers, that is, higher buffer concentrations, is necessary to set or maintain a certain pH value in the saliva, which is advantageous, for example, for a constant drug absorption.

The object of the present invention is to eliminate the aforementioned disadvantages of the prior art. In particular, the object of the present invention is to provide an oral thin film comprising PVA which contains as high a quantity as possible of at least one buffering substance, while the formulation should simultaneously be easily processable, and the PVA should not precipitate and/or agglomerate. At the same time, a formulation should be found which can be easily foamed and which is capable of forming a film with as high an optical homogeneity as possible. Furthermore, the oral thin film should enable the adjustment of the pH value in the patient's saliva over as wide a range as possible and be as stable as possible. For this purpose, as much buffering substance as possible should be incorporated into the PVA.

In addition, the oral thin film should be as easy to produce as possible and also allow for a simple construction of multi-layered oral thin films.

The above object is solved by a multilayered oral thin film according to claim 1, particularly by an oral thin film comprising at least one layer containing at least polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS) in an amount of 15 to 70 weight percent, based on the total weight of the at least one layer.

An oral thin film comprising at least one layer containing at least polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS) is hereinafter also referred to as a TRIS-PVA layer or as a TRIS buffer layer.

Such a thin film oral formulation has the advantage that TRIS can be incorporated in the highest proportion of buffer/PVA both on a percentage and molar basis. In contrast, with other salts/buffers (phosphates, carbonates, citric acid, etc.), agglomeration or precipitation of PVA occurs.

The TRIS-PVA compositions can be well foamed and form a film of high optical homogeneity.

It is also possible to produce layers with a very high TRIS loading, preferably up to 50 wt.-% TRIS. Moreover, a broader pH range can be covered by adjusting with acid (e.g., HCl). Another advantage is that these oral thin films can be laminated together without additional adhesives in certain embodiments, meaning it is possible to produce relatively thick multi-layered films by laminating several TRIS-PVA layers. The TRIS buffer layers can be administered together with drug-containing OTFs to achieve an appropriate pH in the oral cavity. This can either be done by sequentially administering a TRIS buffer layer and a drug OTF (or vice versa), or the TRIS buffer layer can be combined with a drug layer (e.g., laminating to multi-layered OTFs), or the TRIS buffer layer itself contains at least one pharmaceutically active ingredient. In particular, systems were produced using ketamine as the pharmaceutically active ingredient, which are advantageous for clinical reproducibility (compensating for fluctuations in oral/saliva pH) and buffer the oral cavity to a beneficial pH for permeation.

In the present text, "umfassend" can also mean "consisting of."

TRIS is an abbreviation for Tris(hydroxymethyl)aminomethane (THAM), also known as Tromethamine, Trometamol (INN), and TRIS buffer. Chemically, it is a primary amine with three alcoholic hydroxyl groups.

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

Polyvinyl alcohols (abbreviated as PVA or PVAL, occasionally also PVOH) are polymers of the general structure that can also contain structural units of the type in small amounts (approximately 2%). They belong to the group of vinyl polymers.

Commercially available polyvinyl alcohols are usually supplied as white-yellowish powders or granules with polymerization degrees ranging from about 500 to 2500 (molecular weights of approximately 20,000 to 100,000 g/mol). They generally have hydrolysis degrees of 98 to 99 or 87 to 89 mol-%, meaning that they still contain a residual amount of acetyl groups. The polyvinyl alcohols are characterized by the manufacturers by specifying the polymerization degree of the starting polymer, the degree of hydrolysis, the saponification number, or the solution viscosity.

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

Furthermore, according to the present invention, polyvinyl alcohols having a viscosity of 3.4-4.6 mPa·s (4-88) to 34-46 mPa·s (40-88) in a 40 g/l aqueous solution, determined by the "falling ball method" (Ph.Eur. 2.2.49), are particularly suitable, or mixtures of two or more different PVA types.

The inventive oral thin film is preferably characterized in that polyvinyl alcohol is present in an amount of 20 to 90 wt.%, preferably 40 to 80 wt.%, and particularly preferably 50 to 75 wt.%, based on the total weight of the at least one layer in which it is contained.

The inventive oral thin film is furthermore preferably characterized in that polyvinyl alcohol is present in an amount of 20 to 50 wt.%, preferably 25 to 45 wt.%, and particularly preferably 30 to 40 wt.%, based on the total weight of the at least one layer in which it is contained.

The inventive oral thin film is also preferably characterized in that polyvinyl alcohol is present in an amount of 60 to 85 wt.%, preferably 65 to 80 wt.%, and particularly preferably 65 to 75 wt.%, based on the total weight of the at least one layer in which it is contained.

The inventive oral thin film is further preferably characterized in that tris(hydroxymethyl)aminomethane is present in an amount of 25 to 55 wt.%, based on the total weight of the at least one layer, which is contained in the at least one layer.

The inventive oral thin film is furthermore preferably characterized in that tris(hydroxymethyl)aminomethane is present in an amount of 15 to 45 wt.% or 15 to 40 wt.%, based on the total weight of the at least one layer, which contains the at least one layer.

The inventive oral thin film is also preferably characterized in that tris(hydroxymethyl)aminomethane is present 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 at least one layer in which it is contained.

The inventive oral thin film is also preferably characterized in that tris(hydroxymethyl)aminomethane is present 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 at least one layer in which it is contained.

The inventive oral thin film is furthermore preferably characterized in that tris(hydroxymethyl)aminomethane is present in an amount of approximately 15% by weight or approximately 16.7% by weight or approximately 25% by weight or approximately 25.5% by weight or approximately 40% by weight or approximately 50% by weight, based on the total weight of at least one layer in which it is contained.

The invention's oral thin film preferably contains no other buffer substances besides TRIS, in particular no phosphates, carbonates and/or citric acid.

The inventive oral thin film is further preferably characterized in that in the at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS), no other buffering substances than TRIS are present, in particular no phosphates, carbonates and/or citric acid.

In at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane (TRIS), preferably no other polymers than PVA are present.

The inventive oral thin film is further preferably characterized in that the at least one layer comprises at least one pharmaceutically active ingredient.

Also, embodiments of the invention's oral thin film are conceivable, in which the oral thin film does not contain a pharmaceutical active ingredient, but is used solely as a "buffering thin film."

At least one pharmaceutically active ingredient is generally not subject to any restrictions, but is preferably selected from all pharmaceutically active ingredients that are suitable for oral and/or transmucosal administration.

According to the present invention, all pharmaceutically acceptable salts and solvates of the respective pharmaceutically active ingredient are also included under the pharmaceutically active ingredient.

Preferred are active ingredients selected from the group including the following classes of drugs: analgesics, hormones, hypnotics, sedatives, antiepileptics, stimulants, psychotropic agents, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetic agents, antitumor agents, antibiotics, chemotherapeutics, and narcotics, wherein this group is not exhaustive.

It particularly relates to at least one pharmaceutically active ingredient, which is ketamine and/or a pharmaceutically acceptable salt or solvate thereof, preferably ketamine hydrochloride.

Here, ketamine refers to (S)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, (R)-(±)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, as well as the racemate (RS)-(+)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one.

Particularly preferred is (S)-ketamine or a pharmaceutically acceptable salt thereof, especially (S)-ketamine hydrochloride, as the single stereoisomer of ketamine, since the analgesic and anesthetic potency of (S)-ketamine is about three times higher than that of the (R)-form.

The active ingredient content in at least one layer can vary within relatively wide limits. A suitable concentration range of 10 to 60 wt.%, based on the dry weight of at least one layer, can be specified. In another embodiment, the proportion of active ingredient in at least one layer is more likely 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.%.

The inventive oral thin film is furthermore preferably characterized in that the at least one layer comprises at least one excipient selected from the group consisting of colorants, flavoring agents, sweeteners, plasticizers, taste-masking agents, emulsifiers, enhancers, humectants, preservatives and/or antioxidants.

Each of these auxiliaries is preferably present 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 the at least one layer, contained in this layer.

After drying or removal of the solvent, it is preferred that the residual solvent content in the oral film is in the range of 0.2 to 15 wt.%, preferably in the range of 0.8 to 7 wt.%, based on the total weight of the oral film.

Preferably, the oral thin film has at least one additional layer comprising at least one matrix polymer and at least one pharmaceutically active ingredient.

In this case, it is therefore a multilayered oral thin film.

The at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane may contain at least one pharmaceutically active ingredient, or in another embodiment, this layer may also not contain any pharmaceutically active ingredient.

If the composition contains at least one layer containing at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and no pharmaceutical active ingredient, it is preferred that at least one of the further layers contains at least one pharmaceutical active ingredient.

In such a case, the at least one layer containing at least polyvinyl alcohol and tris(hydroxymethyl)aminomethane serves merely as a buffer layer, which causes the adjustment of a desired pH value in the patient's mouth.

An inventive oral thin film comprising at least one further layer, which comprises at least one matrix polymer and at least one pharmaceutically active ingredient, is preferably characterized in that the at least one polymer is a water-soluble polymer selected from the group consisting of starch and starch derivatives, dextrans, cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl- or propylcellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageen and natural gums.

At least one pharmaceutically active ingredient is generally not subject to any restriction, but is preferably selected from all pharmaceutically active ingredients suitable for oral and/or mucosal administration.

All the listed active ingredients additionally include pharmaceutically acceptable salts and/or solvates thereof.

An inventive oral thin film comprising at least one further layer containing at least one matrix polymer and at least one pharmaceutically active ingredient is preferably characterized in that the at least one pharmaceutically active ingredient is selected from the group consisting of the drug classes of analgesics, hormones, hypnotics, sedatives, anticonvulsants, stimulants, psychotropic agents, neuromuscular blockers, antispasmodics, antihistamines, anti-allergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antitumor agents, antibiotics, chemotherapeutics, and narcotics, wherein the at least one pharmaceutically active ingredient preferably comprises ketamine, particularly preferably (S)-ketamine.

In one embodiment, the inventive multi-layered oral thin film is characterized in that at least one layer containing at least polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and/or at least one further layer comprising at least a matrix polymer and at least one pharmaceutically active ingredient, are directly laminated onto each other.

In another embodiment, the inventive multi-layered oral thin film 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 ingredient or at least one flavoring substance, are connected to each other by an intermediate adhesive layer.

Under the term "adhesive layer," a layer is understood that can act as an adhesive, as defined in DIN EN 923:2016-03. Therefore, a non-adhesive layer cannot act as an adhesive as defined above.

In particular, water-soluble adhesive layers are suitable, such as those described in DE 10 2014 127 452 A1, the relevant content of which is fully incorporated herein.

Such adhesive layers comprise at least one water-soluble polymer and at least one plasticizer, wherein the at least one water-soluble polymer in the at least one water-soluble adhesive layer preferably comprises shellac, a vinylpyrrolidone/vinyl acetate copolymer, a polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer, hydroxypropylcellulose or hydroxypropylmethylcellulose and/or polyvinylpyrrolidone, and wherein 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.

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

Such an adhesive layer, which contains at least one water-soluble polymer and at least one plasticizer, can firmly bond two further layers that are not sticky by themselves, thus enabling the construction of multi-layered oral films without the need for multiple overlapping coating steps, which would otherwise result in increased drying times and higher temperature stress for the active and auxiliary substances contained.

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

As a separating layer, a layer comprising at least one polyethylene glycol is preferably used.

Polyethylene glycols (PEGs) are compounds of the general formula:

High molecular weight solid polyethylene glycols (melting temperature approximately 65 °C) are also often referred to as polyethylene oxides or polyoxyethylene (abbreviation PEO, or less commonly PEOX) or polywaxes. In the present text, the terms "polyethylene glycol," "polyethylene oxide," and "PolyOx" are used interchangeably.

It preferably has a mean molecular weight of at least 20,000 g/mol to 7,000,000 g/mol, preferably from 40,000 g/mol to 500,000 g/mol, particularly preferably from 95,000 g/mol to 105,000 g/mol, especially about 100,000 g/mol.

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

It preferably has a viscosity of 30 to 50 mPa·s, measured at 25°C.

The specified viscosities refer to a 5 weight-% solution of polyethylene glycol in water and are measured on a Brookfield viscometer, model RVF, with spindle No. 1 at 50 rpm and at a temperature of 25°C.

A polyethylene glycol particularly preferred is known under the trade name POLYOX WSR N-10 (Dow Chemical).

At least one polyethylene glycol is preferably present in an amount of 60 to 100 weight-%, preferably in an amount of 80 to 100 weight-%, based on the total weight of the at least one separating layer, which contains the at least one separating layer.

The separating layer preferably contains at least one plasticizer, preferably glycerol, preferably in an amount of 0.5 to 5 wt.%, particularly preferably in an amount of 2 to 2.5 wt.%, based on the total weight of the at least one separating layer.

The use of such a separating layer has, among other advantages, the benefit that polyethylene glycol films are well suited as separating layers/interlayers/adhesive layers in multi-layered oral thin films due to their smooth surface, low melting or glass transition temperature, generally acceptable toxicity, and water solubility. When heated and/or under high pressure, polyethylene glycol adhesive layers are particularly suitable for bonding two additional layers together. For example, an active ingredient-containing layer and a pH-regulating buffer layer can be connected to each other.

Furthermore, the polyethylene glycol layer serves as a barrier layer, preventing or minimizing the migration of active substances or excipients (e.g., buffer salts) between the individual layers.

The separation layer also requires no or only small amounts of additives such as plasticizers (e.g., 2–3% glycerin) and thus reduces the risk of migration of the adhesive layer components into the other layers of the oral film.

The invention's multi-layered oral thin film is not subject to any limitations regarding its structure.

Thus, embodiments are grateful in which the multi-layered oral thin film comprises a TRIS buffer layer containing no pharmaceutically active ingredient, and another layer containing at least one matrix polymer and at least one pharmaceutically active ingredient.

These two layers can be directly laminated onto each other or connected with an intermediate adhesive layer or release layer, preferably as defined above.

Also, embodiments are conceivable in which the multi-layered oral thin film consists of a TRIS buffer layer containing no pharmaceutical active ingredient, and a further layer containing at least one matrix polymer and at least one pharmaceutical active ingredient.

These two layers can be directly laminated onto each other or connected with an intermediate adhesive layer, preferably as defined above.

Also, embodiments are conceivable in which the multi-layered oral thin film comprises a TRIS buffer layer containing no pharmaceutical active ingredient, and another layer containing at least one matrix polymer and at least one pharmaceutical active ingredient, wherein these two layers are connected by an adhesive layer or a separating layer, as defined above.

Also, embodiments are conceivable in which the multi-layered oral thin film consists of a TRIS buffer layer that does not contain a pharmaceutically active ingredient, and another layer containing at least one matrix polymer and at least one pharmaceutically active ingredient, wherein these two layers are connected by an adhesive layer or a separating layer as defined above.

Further multilayered oral thin films are conceivable, for example, having the following layer structure: TRIS buffer layer - layer containing at least one matrix polymer and at least one pharmaceutically active ingredient - TRIS, buffer layer.

In this embodiment, the two TRIS buffer layers form the outer sides of the multi-layered oral thin film.

These three layers can either be laminated directly onto each other or connected with an intermediate adhesive layer, preferably as defined above.

In principle, such a modular system can be provided, with any arrangements of TRIS buffer layers and additional layers.

In all the embodiments described above, the TRIS buffer layer preferably contains no pharmaceutically active ingredient. However, embodiments are also conceivable in which, in the multilayer thin film, each TRIS buffer layer contains at least one pharmaceutically active ingredient.

The inventive oral thin film is further preferably characterized in that the at least one layer containing at least polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and/or the at least one further layer comprising at least one matrix polymer and at least one pharmaceutical active ingredient, is present in the form of a rigid foam having cavities.

Due to the hollow spaces and the resulting larger surface area of the films, the access of water or saliva or other body fluids into the interior of the dosage form is facilitated, thereby accelerating the dissolution of the dosage form and the release of the active ingredient.

With a rapidly resorbable active ingredient, the transmucosal absorption can also be improved by the rapid dissolution of the matrix layer. On the other hand, the wall thickness of the aforementioned cavities is preferably thin, as these may represent solidified bubbles, thus allowing for a rapid dissolution or destruction of these cavities.

Another advantage of this embodiment is that, despite the relatively high grammage, a faster drying process can be achieved through the foaming configuration compared to a comparable non-foamed composition.

Preferably, the oral thin film according to the invention is characterized in that the cavities are isolated from each other and preferably are in the form of bubbles, wherein the cavities are filled with air or a gas, preferably with an inert gas, particularly preferably with nitrogen, carbon dioxide, helium, argon, or a mixture of at least two of these gases.

According to another embodiment, it is provided that the cavities are connected to each other, preferably by forming a continuous channel system penetrating the matrix.

Preferably, the mentioned voids have a volume fraction of 5 to 98%, preferably 50 to 80%, relative to the total volume of the respective layer. In this way, the intended effect of accelerating the dissolution of the active ingredient-containing matrix layer is favorably influenced.

Furthermore, surfactants or tensides can be added to the matrix polymer or the polymer matrix for foaming or to the resulting foam before or after drying, in order to improve the stability of the foam before or after drying.

Another parameter influencing the properties of the inventive dosage form is the diameter of the cavities or bubbles. The bubbles or cavities are preferably produced using a foaming machine, which allows the bubble diameter to be set over a wide range, almost arbitrarily. Thus, the diameter of the bubbles or cavities can range from 1 to 350 µm. Particularly preferred is a diameter in the range of 30 to 200 µm.

The inventive oral thin film preferably has an area of 0.5 cm² to about 10 cm², particularly preferably from 1.5 cm² to about 9 cm².

The inventive oral thin film is preferably characterized in that the surface weight of the oral thin film is 10 to 500 g/m², preferably 100 to 400 g/m².

The areal weight of the TRIS buffer layer and each possibly further layer is preferably at least 10 g/m², more preferably at least 20 g/m² or at least 30 g/m², or most preferably at least 50 g/m² or less than or equal to 400 g/m², more preferably less than or equal to 350 g/m² or less than or equal to 300 g/m², or most preferably less than 250 g/m². Preferably, the areal weight is between 10 and 400 g/m², more preferably between 20 and 350 g/m² or between 30 and 300 g/m², most preferably between 50 and 250 g/m².

Preferably, the TRIS buffer layer and any further possibly present layer each have a thickness of preferably 10 µm to 500 µm, particularly preferably 20 µm to 300 µm.

If the TRIS buffer layer is present in the form of a foam, the TRIS buffer layer has a thickness preferably from 10 µm to 3000 µm, particularly preferably from 90 µm to 2000 µm.

The inventive oral thin film is further preferably characterized in that the oral thin film generates a pH value (at 37°C) of 6 to 9, preferably of 6 to 8, in the mouth of a patient, preferably a human.

The inventive oral thin film is furthermore preferably characterized in that the oral thin film produces a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer, or water.

The inventive oral thin film is further preferably characterized in that the oral thin film comprises a TRIS buffer layer and another layer containing S-ketamine HCl, and generates a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer, or water.

The inventive oral thin film 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, and produces a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer, or water.

The inventive oral thin film 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 produces a pH value (at 37°C) of 6 to 8 in 2 mL of human saliva, artificial saliva, PBS buffer, or water.

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

The above explanations for the TRIS buffer layer and the subsequent layer apply analogously to the first and second oral films present in the inventive kit.

The inventive oral thin film can be produced using methods known to those skilled in the art.

Known manufacturing processes include providing a solution containing PVA and TRIS, followed by spreading and drying this solution to obtain a film.

If a multi-layered oral thin film is to be produced, a known manufacturing process comprises providing a first solution containing PVA and TRIS, then spreading and drying this solution to obtain a film, and providing a second solution containing at least one matrix polymer and at least one pharmaceutically active ingredient to obtain a second film.

Combining these two films can generally be done using methods familiar to experts. For example, a second film can be applied to a first film by coating, regardless of which film is coated onto which. Furthermore, the two layers can be connected together by an adhesive layer, as described above.

The present invention also relates to an oral thin film, obtainable by the method described above.

In addition, the present invention relates to an oral thin film as described above, obtainable by the aforementioned method or the aforementioned kit as a medicament.

The present invention also relates to an oral thin film as described above, obtainable according to the aforementioned method or the aforementioned kit, wherein ketamine, preferably S-ketamine (optionally as a pharmaceutically acceptable salt or ion pair), is used as the pharmaceutically active ingredient, as a medicinal product for use in the treatment of pain and/or depression, particularly for reducing the risk of suicide and/or for use as a general anesthetic, preferably for inducing and conducting general anesthesia or as an adjunct in regional anesthesia and/or as an analgesic.

The present invention will now be explained in some non-limiting examples.

Examples Example 1:

Effect of pH on the permeation of (S)-Ketamine HCl Acidic buffer: 80 g/l Na2HPO4·2H2O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=4.99 at 22°C. Neutral buffer: 80 g/l Na2HPO4·2H2O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=7.46 at 22°C. Basic buffer: 80 g/l Na2HPO4·2H2O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=8.33 at 22°C.

The pH values of this series of experiments are summarized in Table 1. Tabelle 1:

Puffer pH bei 22°C	Puffer pH bei 37°C	Puffer + (S)-Ketamin HCI pH bei 22°C
Saurer Puffer	4,99	5,09	4,92
Neutraler Puffer	7,46	7,48	6,64
Basischer Puffer	8,33	7,91	7,81

The permeated amount of (S)-ketamine was determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004), using porcine mucosa (Mucosa oesophagus) and a "Franz diffusion cell". The mucosa was prepared with a dermatome to a thickness of 400 µm and an area of 1.145 cm², maintaining intact barrier function for all transmucosal therapeutic systems.

As the receiving medium, 4 mL of PBS buffer with a pH of 7.4 at 37°C was used.

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

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

Example 2:

Effect of pH on the permeation of (S)-Ketamine HCl from an oral thin film.

An oral thin film of the composition according to Table 2 was prepared. Tabelle 2:

PVA 4-88	39.1
TRIS	--
Saccharin Na	1,0
Sucralose	2,0
Cherry Flavor M55394	3,0
Glycerol	4,5
S-Ketamin HCI	50,0
FD&C Red No. 40	0,4
Kollidon VA 64	--
Lösungsmittel	Aqua Purificata
Flächengewicht (incl. Restfeuchtigkeit):

Tabelle 2:

PVA 4-88: Polyvinylalkohol Geschmacksstoff: MANE Cherry Flavor M55394 Farbstoff: FD&C Red No. 40

The oral thin film formulation according to Table 2 is produced using well-known techniques for mass production, such as stirring/mixing the contained components with a stirrer motor and appropriate stirring tools.

The resulting mass is aerated by stirring, for example using a foam generator.

The foamy mass is applied to a coating substrate using appropriate equipment (roller applicator, squeegee, doctor blade, etc.) in a constant layer thickness.

As a coating carrier, all temperature-stable sheet-like materials can be used, from which the dry film can be removed again. This can be ensured by selecting the appropriate material for the coating carrier (different surface tensions between the foam mass and the substrate), or by using suitable degradable coatings on the coating carrier, such as silicones or fluoropolymers.

The process solvents contained, usually water or mixtures of water and water-miscible organic solvents, are removed by drying. From the resulting solid foam layer, the oral thin films can be cut or punched into the appropriate size. Acetic buffer: 80 g/l Na2HPO4·2H2O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=4.99 at 22°C. Neutral buffer: 80 g/l Na2HPO4·2H2O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=7.46 at 22°C. Basic buffer: 80 g/l Na2HPO4·2H2O dissolved in water; pH adjusted with aqueous 1M HCl solution to pH=8.33 at 22°C.

The pH values of this series of experiments are summarized in Table 3. Tabelle 3:

Puffer pH bei 22°C	Puffer pH bei 27°C	Puffer + OTF pH bei 22°C	Puffer + OTF pH bei 37°C
Saurer Puffer	4,99	5,09	4,92	5,05
Neutraler Puffer	7,46	7,48	6,88	6,72
Basischer Puffer	8,33	7,91	7,91	7,50

0.287 cm² OTF (equivalent to 2.77 mg (S)-ketamine) of the (S)-ketamine HCl formulation was applied to the mucosa, and 70 µL of buffer solution was added.

Permeation was measured similarly to Example 1.

The permeated amount of (S)-ketamine was determined by in vitro experiments according to the OECD guidelines (adopted on April 13, 2004), using pig esophageal mucosa (Mucosa oesophagus) and a "Franz diffusion cell". The mucosa was prepared with a dermatome to a thickness of 400 µm, maintaining an intact barrier function for all transmucosal therapeutic systems.

From the OTFs, punches with an area of 0.287 cm² were punched out, applied to the mucosa, and the mucosa with the OTFs on top was brought into contact with the respective buffer (the bottom side was in contact with the acceptor medium, while the top side was isolated to a mucosal area of 1.145 cm²).

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

In vitro experiments with different buffers as the donor medium showed a permeation behavior of S-ketamine that depended on the pH of the buffer used. The pH of the donor medium including the active ingredient is shown in Table 2 (buffer + OTF).

From the obtained permeation results, it can be concluded that the permeation of S-ketamine is best in a basic buffer, followed by a neutral buffer. The lowest permeation rate was observed with an acidic buffer.

Example 3:

Tabelle 4:

Formulierungen (Mengen in Gew.-%)
Material	2	3	4	5	6	7	8
PVA 4-88	36,15	69,30	59,50	64,00	74,50	39,50	39,0
PVA 40-88	36,15	--	--	---	--	--	--
TRIS	20,00	20,00	30,00	25,50	15,00	50,00	50,00
Saccharin Na	1,00	1,00	1,00	1,00	1,00	1,00	1,00
Sucralose	2,00	2,00	2,00	2,00	2,00	2,00	2,00
Geschmacksstoff	-	3,0	3,00	3,00	3,00	3,00	3,00
Glycerol	4,50	4,50	4,50	4,50	4,50	4,50	4,50
Farbstoff	0,20	0,20	--	--	--	--	--
Aerosil	--	--	--	--	--	--	0,5
Prozesslösemittel:	Wasser	Wasser	Wasser	Wasser	Wasser	Wasser	Wasser
Gas für Schäumung	Stickstoff	Luft	Luft	Luft	Luft	Luft	Luft
pH		---	---		---		---
pH=9,65 (21 °C)

Tabelle 4:

Oral thin films with the formulations according to Table 3 were prepared according to Example 2.

The oral thin films with the formulations according to Table 4 are characterized by high flexibility and a pleasant tactile sensation ("mouth feel"). Furthermore, the resulting oral thin films dissolve very quickly in the mouth, despite potentially large area weight and thickness. Due to the thin layers of the gas bubble walls, a very gentle drying process is possible (e.g., 20 minutes at 70°C for 200 g/m²).

Example 4:

Tabelle 5:

Material	Formulierung 9 [Gew.-%]
PVA 4-88	39,5
TRIS	16,7
Saccharin Na	1,0
Sucralose	2,0
Geschmacksstoff	3,0
Glycerol	4,50
S-Ketamin	33,3
Gas:	Luft (alternativ Stickstoff)
Prozesslösemittel	Wasser
Flächengewicht (incl. Restfeuchtigkeit)
pH
pH=7.5 (22 °C)
pH=7.2 (33 °C)
pH=7,45 (22°C)
pH=7.28 (33,5 °C)

Tabelle 5:

PVA 4-88: Polyvinylalkohol Geschmacksstoff: MANE Cherry Flavor M55394

The production of an oral thin film formulation according to Table 5 is carried out using techniques known to the expert in the art for mass production, such as stirring/mixing the components contained therein using a stirrer motor and suitable stirring tools.

The resulting mass is aerated by stirring, for example using a foam generator. The foamy mass is applied onto a coating carrier in a constant layer thickness by means of suitable devices (roller applicator, squeegee, doctor blade, etc.).

As a coating carrier, all temperature-stable sheet-like materials can be used, from which the dry film can be removed again. This can be ensured by selecting the appropriate material for the coating carrier (different surface tensions between the foam mass and the substrate), or by using suitable release coatings on the coating carrier, such as silicones or fluoropolymers. The process solvents contained, usually water or mixtures of water and water-miscible organic solvents, are removed by drying.

Subsequently, the two laminates were heated to 70°C and laminated together. From this two-layer laminate, the oral thin films can be cut or punched into the appropriate size.

This two-layered oral thin film is characterized by its high layer thickness and loading. The process can be repeated as often as desired, thus allowing the production of multi-layer laminates (e.g., three laminates combined, or four laminates), or multiple laminates can also be combined in a single step (e.g., three laminates heated to 70°C and then laminated together).

Example 5

Tabelle 6:

Formulierung (Menge in Gew.-%)
Material	Formulierung 10	Formulierung 11	Formulierung 9
PVA 4-88	37,5	39,5	39,5
TRIS	2,0	25,0	16,7
Saccharin Na	1,0	1,0	1,0
Sucralose	2,0	2,0	2,0
Geschmacksstoff	3,0	3,0	3,0
Glycerol	4,5	4,5	4,5
S-Ketamin HCI	50,0	25,0	33,3
Gas:	Luft (alternativ Stickstoff)	Luft (alternativ Stickstoff)	Luft (alternativ Stickstoff)
Prozesslösemittel	Wasser	Wasser	Wasser
Flächengewicht (incl. Restfeuchtigkeit)
pH
			pH=7.2 (33 °C)

The oral thin films with the formulations according to Table 6 were prepared analogously to Example 2 or Example 3.

Example 6

Tabelle 7:

Formulierung 12 [Gew.-%]	Formulierung 13 [Gew.-%]
PVA 4-88	39,5	36,15
PVA 40-88	---	36,15
(S)-Ketamin-HCl	50,0	---
Saccharin-Natrium	1,0	1,0
Sucralose	2,0	2,0
Cherry Flavor	3,0	---
Glycerol	4,5	4,5
TRIS	---	20,0
FD&C red 40	---	0,2
Flächengewicht / Größe
Gas	Stickstoff	Stickstoff
Prozesslösemittel	Wasser	Wasser

An oral thin film was produced according to the formulations in Table 7, respectively. The production was carried out analogously to Example 1 or Example 2.

The oral thin films were each dissolved separately in water or in Glandosan (artificial saliva), and the respective pH value of the solution was determined. Furthermore, both films were dissolved together in water or in Glandosan, and the pH value of the solution was determined (see Table 8). Tabelle 8:

pH in Wasser (2 mL)	pH in Glandosan (2mL)
KetaminOTF	5,85	5,11
TRIS-OTF	9,65	8,91
KetaminOTF+TRIS-OTF	7,13	6,94

Example 7

Tabelle 9:

Formulierung (Menge in Gew.-%)
Material	Formulierung 1 Wirkstoffschicht	Formulierung 7 Pufferschicht	Formulierung 14 Klebeschicht
PVA 4-88	39,1	39,5	---
TRIS	---	50,0	---
Saccharin Na	1,0	1,0	---
Sucralose	2,0	2,0	---
Geschmacksstoff	3,0	3,0
Glycerol	4,5	4,5	20,0
S-Ketamin HCI	50,0	---	---
Farbstoff	0,4	---	---
Kollidon VA 64	---	---	80,0
Gas	Luft (alternativ Stickstoff)	Luft (alternativ Stickstoff)	- (nicht geschäumt)
Prozesslösemittel	Wasser	Wasser	Ethanol
Flächengewicht (incl. Rechstfeuchtigkeit)

Tabelle 9:

PVA 4-88: Polyvinylalkohol Geschmacksstoff: MANE Cherry Flavor M55394 Farbstoff: FD&C Red Kollidon VA 64: Vinylpyrrolidon-Vinylacetat-Copolymer

Each of the thin films was produced as an active ingredient layer, a buffer layer, and as an adhesive layer as follows. The layers were produced as described in Example 1 or Example 2. The composition is described in the corresponding tables.

Thus, a multilayered oral thin film was produced with the following structure: buffer layer-adhesive layer-active ingredient layer-adhesive layer-buffer layer. A layer of adhesive was applied to both sides of a ketamine laminate. After removing the carrier film, a TRIS buffer layer was then applied to both sides.

It resulted in a homogeneous foam composite with good tactile properties and a good resolution speed for its thickness.

A pH measurement showed: 3.34 cm² OTF in 2 mL water: pH = 8.07 (at 35.5 °C). pH in 2 mL human saliva: pH = 8.04 (at 36.3 °C).

Example 8

Tabelle 10:

Formulierung (Menge in Gew.-%)
Material	Formulierung 1 Wirkstoffschicht	Formulierung 7 Pufferschicht	Formulierung 14 Klebeschicht
PVA 4-88	39,1	39,5	---
TRIS	---	50,0	---
Saccharin Na	1,0	1,0	---
Sucralose	2,0	2,0	---
Geschmacksstoff	3,0	3,0
Glycerol	4,5	4,5	20,0
S-Ketamin HCI	50,0	---	---
Farbstoff	0,4	---	---
Kollidon VA 64	---	---	80,0
Gas	Luft (alternativ Stickstoff)	Luft (alternativ Stickstoff)	- (nicht geschäumt)
Prozesslösemittel	Wasser	Wasser	Ethanol

Tabelle 10:

PVA 4-88: Polyvinylalkohol Geschmacksstoff: MANE Cherry Flavor M55394 Farbstoff: FD&C Red Kollidon VA 64: Vinylpyrrolidon-Vinylacetat-Copolymer

Thin films were prepared as active ingredient layer, buffer layer, and as adhesive layer, as described in examples 1, 2, and 7. The composition is described in the corresponding tables.

As a result, a multi-layered oral thin film was produced with the structure of a buffer layer, adhesive layer, and active ingredient layer, as follows. A coating layer was applied onto a ketamine foam. After removing the carrier film of the adhesive layer, a TRIS foam was applied.

It resulted in a homogeneous foam composite with good tactile properties and a good resolution speed for its thickness.

A pH measurement showed: 3.34 cm² OTF in 2 mL water: pH = 7.97 (at 36.3 °C)

Example 9

Tabelle 11

Formulierung (Menge in Gew.-%)
Material	Formulierung 1 Wirkstoffschicht	Formulierung 5 Pufferschicht	Formulierung 14 Klebeschicht
PVA 4-88	39,1	64,0	---
TRIS	---	25,5	---
Saccharin Na	1,0	1,0	---
Sucralose	2,0	2,0	---
Geschmacksstoff	3,0	3,0
Glycerol	4,5	4,5	20,0
S-Ketamin HCI	50,0	---	---
Farbstoff	0,4	---	---
Kollidon VA 64	---	---	80,0
Gas	Luft (alternativ Stickstoff)	Luft (alternativ Stickstoff)	- (nicht geschäumt)
Prozesslösemittel	Wasser	Wasser	Ethanol
Flächengewicht (incl. Restfeuchtigkeit)

Tabelle 11

PVA 4-88: Polyvinylalkohol Geschmacksstoff: MANE Cherry Flavor M55394 Farbstoff: FD&C Red Kollidon VA 64: Vinylpyrrolidon-Vinylacetat-Copolymer

Thin films were prepared as the active ingredient layer, buffer layer, and as an adhesive layer, as described in examples 1, 2, and 7. The composition is described in the corresponding tables.

As a result, a multi-layered oral thin film was produced with the following structure: buffer layer - adhesive layer - active ingredient layer. A coating layer was laminated onto a ketamine foam. After removing the carrier foil of the adhesive layer, a TRIS foam was laminated.

It resulted in a homogeneous foam composite with good tactile properties and a good resolution speed for its thickness.

Example 10

Tabelle 12

Formulierung (Menge in Gew.-%)
Material	Formulierung 1 Wirkstoffschicht	Formulierung 15 Pufferschicht	Formulierung 14 Klebeschicht
PVA 4-88	39,1	69,5	---
TRIS	---	20,0	---
Saccharin Na	1,0	1,0	---
Sucralose	2,0	2,0	---
Geschmacksstoff	3,0	3,0
Glycerol	4,5	4,5	20,0
S-Ketamin HCI	50,0	---	---
Farbstoff	0,4	---	---
Kollidon VA 64	---	---	80,0
Gas	nicht geschäumt	nicht geschäumt	nicht geschäumt
Prozesslösemittel	Wasser	Wasser	Ethanol
Flächengewicht (incl. Restfeuchtigkeit)

Tabelle 12

PVA 4-88: Polyvinylalkohol Geschmacksstoff: MANE Cherry Flavor M55394 Farbstoff: FD&C Red Kollidon VA 64: Vinylpyrrolidon-Vinylacetat-Copolymer

Thin films were prepared as active ingredient layers, buffer layers, and as adhesive layers, as described in Examples 1, 2, and 7, except that the foaming step was omitted. The composition is described in the corresponding tables.

As a result, a multi-layered oral thin film was produced with the structure of buffer layer-adhesive layer-active ingredient layer. A layer of adhesive was laminated onto a ketamine foam. After removing the carrier film of the adhesive layer, a TRIS foam was laminated.

It resulted in a homogeneous foam composite with good tactile properties and a good resolution speed for its thickness.

A pH measurement showed: 3.34 cm² OTF in 2 mL water: pH = 6.33 (at 32 °C).

Example 11

Tabelle 13:

Formulierung (Menge in Gew.-%)
Material	Formulierung 12 Wirkstoffschicht	Formulierung 3 Pufferschicht	Formulierung 16 Klebeschicht
PVA 4-88	39,5	69,3	30,0
TRIS	---	20,0	---
Saccharin Na	1,0	1,0	---
Sucralose	2,0	2,0	---
Geschmacksstoff	3,0	3,0	---
Glycerol	4,5	4,5	10,0
S-Ketamin HCI	50,0	---	---
Kollidon VA 64	---	---	28,0
Sorbitol	---	---	22,0
Isomalt	---	---	10,0
Gas	Luft (alternativ Stickstoff)	Luft (alternativ Stickstoff)	Luft (alternativ Stickstoff)
Prozesslösemittel	Wasser	Wasser	Wasser

Tabelle 13:

PVA 4-88: Polyvinylalkohol Geschmacksstoff: MANE Cherry Flavor M55394 Farbstoff: FD&C Red

Thin films were prepared as the active ingredient layer, buffer layer, and as an adhesive layer, as described in examples 1, 2, and 7. The composition is described in the corresponding tables.

As a result, a multi-layered oral thin film was produced with the structure of a buffer layer, adhesive layer, and active ingredient layer, as follows. A coating layer was laminated onto a ketamine foam. After removing the carrier film of the adhesive layer, a TRIS foam was laminated.

It resulted in a homogeneous foam composite with good tactile properties and a good dissolution rate for its thickness.

Example 12

Tabelle 14:

Formulierung (Menge in Gew.-%)
Material	17	18	19	20	21
PVA 4-88	39,50	35,2	57,7	70,2	63,6
Koffein	21,83	---	---	---	---
Citronensäure	10,05	---	---	---	---
Natriumcitrat-Dihydrayt	18,12	---	---	---	---
Trinatriumcitrat	---	54,3	---	---	---
Di-Kaliumhydrogenphosphat	---	---	31,8	---	---
Di-Natriumhydrogenphosphat	---	---	---	---	25,9
Natriumcarbonat	---	---	---	19,6	---
Saccharin Na	1,00	1,00	1,00	1,00	1,00
Sucralose	2,00	2,00	2,00	2,00	2,00
Geschmacksstoff	3,00	3,00	3,00	3,00	3,00
Glycerol	4,50	4,50	4,50	4,50	4,50
Gas	Luft	Masse nicht schäumbar	Masse nicht schäumbar	Masse nicht schäumbar	Masse nicht schäumbar
Prozesslösemittel	Wasser	Wasser	Wasser	Wasser	Wasser

Tabelle 14:

PVA 4-88: Polyvinylakohol Geschmacksstoff: MANE Cherry Flavor M55394

The oral thin films with the formulations according to Table 14 were prepared as described in Examples 1, 2, and 7.

The oral thin films with the formulations according to Table 14 showed the following disadvantages: Lumps and inhomogeneities form in the mass. The mass is not uniformly spreadable and therefore unsuitable for the production of thin films. PVA is not compatible as a matrix polymer with the salts/buffers mentioned in Table 14.

Example 13

Tabelle 15:

Formulierung (Menge in Gew.-%)
Material	22	23	24	25
Kollicoat Smart Seal	34,0	35,0	41,0	40,0
Triethylcitrat	5,0	---	6,0	7
TRIS	50,0	50,0	40,0	40,0
Saccharin Na	2,0	1,0	1,0	---
Sucralose	1,0	2,0	3,0	3,5
Geschmacksstoff	3,0	3,0	2,0	2,0
Glycerol	---	7,0	---	---
HPC EF	5,0	---	5,5	5,5
HPMC 90SH4000	---	20,	---	---
Cremophor RH40	---	---	1,5	---
Polyoxyethylen (23) laurylether	---	---	---	2,0
Eigenschaften	Keine beschichtbare Masse	Laminat spröde; kein homogener Film	Masse nicht homogen; Laminat brüchig	Phasentrennung in der Masse; nicht beschichtbar

The oral thin films with the formulations according to Table 15 were prepared as described in Examples 1, 2, and 7.

The oral thin films with the formulations according to Table 15 showed the adverse properties listed in Table 15.

The aqueous polymer dispersion (Smart Seal) was prepared and plasticizers, flavoring agents, and surfactants were added successively. Then the second polymer was added. Finally, the buffer salt was incorporated.

The mass was foamed, coated, and dried using conventional methods.

Example 14

Administration of formulation 2 and formulation 12 together (two separate OTFs each with 3.34 cm2 OTF): pH in 2 mL water at 36.5 °C: pH = 7.15

Combined administration of formulation 5 and formulation 12 (two separate OTFs each with 3.34 cm² OTF): For water: pH in 2 mL water with formulation 12 at 21 °C: pH = 5.85; pH in 2 mL water with formulation 5 at 21 °C: pH = 9.65; pH in 2 mL water with formulation 12 + formulation 5 at 21 °C: pH = 7.13.

For Glandosane (artificial saliva): pH in 2 mL Glandosane formulation 12 at 21 °C: pH = 5.33; pH in 2 mL Glandosane formulation 5 at 21 °C: pH = 8.91; pH in 2 mL Glandosane formulation 12 + formulation 5 at 21 °C: pH = 6.94.

Combined administration of formulation 7 and formulation 12 (two separate OTFs each with an area of 3.34 cm²): For water: pH in 2 mL water with formulation 12 at 21 °C: pH = 5.85; pH in 2 mL water with formulation 7 at 22 °C: pH = 9.61; pH in 2 mL water with formulation 12 + formulation 7 at 22 °C: pH = 7.67.

For Glandosane (artificial saliva): pH in 2 mL Glandosane formulation 12 at 21 °C: pH = 5.33; pH in 2 mL Glandosane formulation 7 at 21 °C: pH = 9.01; pH in 2 mL Glandosane formulation 12 + formulation 7 at 21 °C: pH = 7.24

Example 15

Administration of formulation 13 and formulation 26 together (formulation 13 OTF 2.27 cm2 OTF and 2.27 cm2 formulation 26): The composition of Dextromethorphan OTF: formulation 26 is listed in Table 16. Tabelle 16

Dextromethorphan	43,78 %
PVA 4-88	38,00 %
Saccharin Na	1,00 %
Sucralose	2,00 %
Glycerol	4,54 %
Flavor	6,00 %
Amberlite IRP64	4,48 %
FD&C Red 40	0,20 %
Trometamol (TRIS)	--
Aqua purificata

An oral thin film formulated according to Table 16 was prepared as described in Examples 1, 2, and 7.

A pH measurement showed: pH in 2 mL water at 35 °C: pH = 7.63.

Example 16

Administration of formulation 13 and formulation 27 together (formulation 13 OTF 2.27 cm2 OTF and 2.27 cm2 formulation 27): The composition of Paracetamol (Acetaminophen) OTF formulation 27 is given in Table 17. Tabelle 17

Paracetamol	20,00 %
PVA 4-88	72,50 %
Saccharin Na	0,50 %
Sucralose	1,00 %
Glycerol	4,50 %
Flavor	1,50 %
Trometamol (TRIS)	--
Lösungsmittel	Aqua purificata
Flächengewicht

An oral thin film with the formulation according to Table 17 was prepared as described in Examples 1, 2, and 7.

A pH measurement showed: pH in 2 mL water at 33 °C: pH = 8.17.

Example 18:

Combined administration of formulation 13 OTF 2.72 cm2 OTF and commercial BEMA Fentanyl OTF (strength 200 µg): A pH measurement resulted in: pH in 2 mL water at 22 °C: pH = 8.67.

Example 19

Determination of the influence of pH on the permeation of ionizable/unionizable drugs. Adjusting the pH using a buffer OTF can reduce the variation in pH between individuals and bring the pH into a preferred range for permeation. Multilayer OTFs can influence the release profile due to a higher disintegration/dissolution time.

Ketamine OTFs with buffering agents achieve significantly better permeations (more than 18 times higher) compared to ketamine·HCl (without OTF).

The results are summarized in Figure 3.

Claims (16)

1. An oral thin film, comprising at least one layer, which contains at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane in an amount of from 15 to 70 wt.% in relation to the total weight of the at least one layer.
2. The oral thin film according to claim 1, characterised in that polyvinyl alcohol is contained in the at least one layer in an amount of from 20 to 90 wt.% in relation to the total weight of the at least one layer.
3. The oral thin film according to any one of the preceding claims, characterised in that tris(hydroxymethyl)aminomethane is contained in the at least one layer in an amount of from 25 to 55 wt.% in relation to the total weight of the at least one layer.
4. The oral thin film according to any one of the preceding claims, characterised in that the at least one layer comprises at least one pharmaceutically active agent.
5. The oral thin film according to any one of the preceding claims, characterised in that the at least one layer comprises at least one pharmaceutically active agent which is selected from the group comprising the active agent classes of analgesics, hormones, hypnotics, sedatives, antiepiletics, analeptics, psychoneurotropic drugs, neuro-muscle blockers, antspasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumour active agents, antibiotics, chemotherapeutics and narcotics, the at least one pharmaceutically active agent preferably comprising ketamine, especially preferably (S)-ketamine, or pharmaceutically acceptable salts thereof.
6. The oral thin film according to any one of the preceding claims, characterised in that the at least one layer comprises at least one auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, plasticisers, taste-masking agents, emulsifiers, enhancers, humectants, an acid or a base (or a salt thereof), preservatives and/or antioxidants.
7. The oral thin film according to any one of the preceding claims, characterised in that the oral thin film has at least one further layer which comprises at least one matrix polymer and at least one pharmaceutically active agent.
8. The oral thin film according to claim 7, characterised in that the at least one polymer is a water-soluble polymer which is selected from the group comprising starch and starch derivatives, dextrans, cellulose derivatives, such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, vinyl pyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatines, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and natural gums.
9. The oral thin film according to claim 7 or 8, characterised in that the at least one pharmaceutically active agent is selected from the group comprising the active agent classes of analgesics, hormones, hypnotics, sedatives, antiepiletics, analeptics, psychoneurotropic drugs, neuro-muscle blockers, antspasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sexual hormones, antidiabetics, antitumour active agents, antibiotics, chemotherapeutics and narcotics, the at least one pharmaceutically active agent preferably comprising ketamine, especially preferably (S)-ketamine, or pharmaceutically acceptable salts thereof.
10. The oral thin film according to any one of the preceding claims, characterised in that the at least one layer which contains at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and/or the at least one further layer which comprises at least one matrix polymer and at least one pharmaceutically active agent is present (are present) in the form of a solidified foam having voids.
11. The oral thin film according to claim 10, characterised in that the voids are isolated from one another and are preferably present in the form of bubbles, the voids being filled with air or a gas, preferably with an inert gas, especially preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.
12. The oral thin film according to claim 10 or 11, characterised in that the voids are connected to one another and preferably form a channel system penetrating the matrix layer.
13. The oral thin film according to any one of claims 10 to 12, characterised in that said voids account for a volume fraction of from 5 to 98%, preferably from 50 to 80%, in relation to the total volume of the layer in question.
14. The oral thin film according to any one of claims 7 to 13, characterised in that the at least one layer which contains at least one polyvinyl alcohol and tris(hydroxymethyl)aminomethane, and/or the at least one further layer which comprises at least one matrix polymer and at least one pharmaceutically active agent are laminated directly on one another or are connected to one another by an intermediate adhesive layer or separation layer.
15. The oral thin film according to any one of the preceding claims, characterised in that the oral thin film in the mouth of a patient produces a pH value (at 37°C) of from 6 to 9, preferably of from 6 to 8.
16. The oral thin film according to any one of the preceding claims for use as a medicament.