HK40097188B - Multi-layer oral thin film - Google Patents

Description

The present invention relates to a multi-layered oral thin film, a method for its production, as well as the multi-layered oral thin film for use as a medicament.

Oral thin films are thin films containing at least one pharmaceutically active ingredient, which are placed directly in the oral cavity or applied to the mucous membranes of the mouth and there dissolve or swell, releasing the active ingredient. These are particularly thin, single- or multi-layered, polymer-based films containing the active ingredient, which can directly deliver the active substance into the mucous membranes, especially the oral mucosa, when applied. The very good blood circulation of the oral mucosa ensures a rapid transfer of the active ingredient into the bloodstream. This dosage form has the advantage that the active ingredient is mostly absorbed through the mucous membranes, thereby avoiding the "first-pass metabolism" which occurs with conventional dosage forms such as tablets. The active ingredient can be dissolved, emulsified, or dispersed in the film.

Mašek Josef, et al. Multi-layered nanofibrous mucoadhesive films for buccal and sublingual administration of drug-delivery and vaccination nanoparticles - an important step towards effective mucosal vaccines. J Control Release. March 10, 2017; pages 183-195, describes nanofiber-based mucoadhesive films developed for the oral mucosal delivery of nanoparticle carriers for drugs and vaccines.

Prajapati Vipul et al. Pullulan-based oral thin film formulation of zolmitriptan: Development and optimization using factorial design. Int J Biol Macromol., February 1, 2018; pp. 2075-2085, describes a study on the formulation and characterization of pullulan-based oral thin films (OTF) of zolmitriptan using a solvent casting method.

Yogyata S Pathare et al., "Polymers Used for Fast Disintegrating Oral Films: A Review," International Journal of Pharmaceutical Sciences Review and Research, July 1, 2013, pp. 169-178, describes the current developments in the field of oral thin films as a new delivery system for the oral administration of medications.

Oral thin films known from the prior art have the disadvantage that, if they are intended to remain at a specific location on a patient's mucosa for a longer period of time, they are subject to constant erosion. This leads to a large portion of the material being swallowed and thus not remaining at the application site for the desired duration. However, the residence time can indeed be of crucial importance for the transmucosal transport of the pharmaceutical active ingredient. Furthermore, many active ingredients have a bad taste and are perceived as unpleasant, especially when in contact with the tongue.

A protective layer on the back side can prevent liquid from penetrating the formulation and dissolving it too quickly, allowing the active ingredient to remain at the application site for a longer period of time, thus achieving maximum permeation through the mucosa or a delayed release. Another effect of the backing layer is that it prevents the applied film from detaching from the application site and sticking to other areas, such as the teeth. Furthermore, the unpleasant taste caused by the active ingredient can be masked by the backing layer.

As materials for such backcoats, insoluble or slowly soluble polymers or polymer films are often used. However, they have the disadvantage that they must be removed or swallowed after the application is completed.

Moreover, coatings made from slowly soluble polymers have the disadvantage of being based on long-chain, high-molecular-weight polymers. These are difficult to process due to their high viscosity (long drying time, uneven films). Furthermore, they tend to increase the viscosity of saliva in the oral cavity, causing a slimy sensation.

Another problem is an often insufficient connection between the parts of the active ingredient layer and the backing layer. There is a risk that the two parts may separate from each other during storage, for example, if they react differently to humidity.

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 a multi-layered oral thin film having at least one backing layer, wherein the backing layer should particularly have a low melting temperature, an innocuous toxicity and a smooth surface. Furthermore, the backing layer should dissolve as slowly as possible, thus protecting the applied film from being swallowed and the tongue from direct contact with the active ingredient, thereby preventing or reducing an unpleasant taste caused by the active ingredient. Moreover, the active ingredient should be protected from additional saliva, which is particularly advantageous when the active ingredient or its permeation is pH-sensitive and the pH would change due to excessive saliva.

Furthermore, a manufacturing process for such a film should be provided, ensuring a firm bond between the active ingredient-containing layer and the backing layer in the oral thin film.

The above object is solved by a multilayered oral thin film according to claim 1, particularly by a multilayered oral thin film comprising at least one matrix layer containing at least one polymer and at least one pharmaceutically active ingredient, and at least one backing layer, wherein the at least one backing layer comprises at least polyethylene glycol in an amount of 60 to 100 wt.-%, based on the total weight of the at least one backing layer.

Such a multi-layered oral thin film has the advantage that the layer comprising polyethylene glycol is well suited as a backing layer for oral thin films due to its smooth surface, low melting temperature and non-toxicity. The layer comprising polyethylene glycol dissolves slowly in the mouth (slower than the active ingredient layer) and thus protects the applied oral thin film from being swallowed and also protects the tongue from direct contact with the active ingredient, thereby preventing or reducing an unpleasant taste caused by the active ingredient. Furthermore, the active ingredient is protected from additional saliva, which can be advantageous, for example, if the active ingredient or its permeation is pH-sensitive and the pH would change due to excessive saliva. The different roughness of the two layers (the layer containing polyethylene glycol is rather smooth and the active ingredient-containing layer is rather very rough) can be used by the patient to determine which side of the oral thin film is applied towards the mucosa. Due to the different roughness, the patient can also recognize by the feeling in the mouth whether the oral thin film is correctly oriented in the mouth.

Additionally, the backing layer can be dyed with a dye to achieve better visibility.

Furthermore, it is possible to incorporate flavoring agents to improve the mouthfeel during application, which is a significant advantage over known foils.

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

Under the term "back layer" is understood a layer of the multi-layered oral thin film, which represents one of the outermost layers of the multi-layered oral thin film.

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

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

The multi-layered oral thin film according to the invention is preferably characterized in that the matrix layer comprises at least one water-soluble polymer.

Water-soluble polymers include chemically very different natural or synthetic polymers, whose common characteristic is their solubility in water or aqueous media. The prerequisite is that these polymers possess a sufficient number of hydrophilic groups to ensure water solubility and are not cross-linked. The hydrophilic groups can be non-ionic, anionic, cationic, and/or zwitterionic.

Water-soluble preferably refers to a solubility greater than 100 g/L in water at 25°C.

The at least one water-soluble polymer is preferably 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, polyvinylpyrrolidones, vinylpyrrolidone/vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageen and natural gums, with polyvinyl alcohols being particularly preferred.

The invention's multilayered oral thin film is preferably characterized in that at least one polymer, preferably the water-soluble polymer, is present in an amount of 10 to 90 wt.%, preferably 20 to 60 wt.%, particularly preferably 30 to 50 wt.%, based on the total weight of the active ingredient-containing matrix layer, in the active ingredient-containing matrix layer of the multilayered oral thin film.

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 transmucosal administration.

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

Preferred are active ingredients selected from the group including the following classes of drugs: analgesics, hormones, hypnotics, sedatives, antiepileptics, psychostimulants, psychotropic agents, neuromuscular blockers, antispasmodics, antihistamines, anti-allergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antineoplastic agents, antibiotics, chemotherapeutics, and narcotics, although 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.

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 the matrix layer can vary within relatively wide limits. A range of 10 to 60 wt.%, based on the dry weight of the matrix layer, can be considered suitable. In one embodiment, the amount of active ingredient in the matrix layer is rather in the lower range, for example, when the active ingredient has a strong unpleasant taste that must be compensated by a larger quantity of taste-masking agents. In this case, a suitable active ingredient content can be between 10 and 40 wt.%. In another embodiment, the amount of active ingredient in the dosage form according to the invention is rather in the upper range, with a content of 40 to 60 wt.%, and particularly a content of 45 to 55 wt.%, being especially preferred.

Particularly preferred is (S)-ketamine or a pharmaceutically acceptable salt thereof in an amount of 45 to 55 wt.%, based on the dry weight of the active ingredient-containing matrix layer, present in the matrix layer.

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

Each of these additives 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 matrix layer, within this layer.

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.

The multilayered oral thin film according to the invention is further preferably characterized in that the at least one polyethylene glycol has a viscosity of 30 to 50 mPa·s, measured at 25°C.

The indicated 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 one known under the trade name POLYOX WSR N-10 (Dow Chemical).

The inventive multilayered oral thin film is further preferably characterized in that at least one polyethylene glycol is present in an amount of 80 to 100 wt.%, based on the total weight of the at least one back layer, which is contained in the at least one back layer.

The inventive multilayer oral thin film is further preferably characterized in that at least one polyethylene glycol is present in an amount of 65 to 100 wt.-% or 70 to 100 wt.-% or 85 to 100 wt.-% or 90 to 100 wt.-% or 95 to 100 wt.-%, based on the total weight of the at least one back layer, which contains the at least one back layer.

The inventive multilayered oral thin film is further preferably characterized in that at least one polyethylene glycol is present in an amount of 60 to 97.5 wt.-% or 65 to 97.5 wt.-% or 70 to 97.5 wt.-% or 80 to 97.5 wt.-% or 85 to 97.5 wt.-% or 90 to 97.5 wt.-% or 95 to 97.5 wt.-%, based on the total weight of the at least one backing layer, which contains the at least one backing layer.

The invention's multi-layered oral thin film is furthermore preferably characterized in that at least one polyethylene glycol is present in an amount of 60 to 97.5 wt.-% or 65 to 97.5 wt.-% or 70 to 97.5 wt.-% or 80 to 97.5 wt.-% or 85 to 97.5 wt.-% or 90 to 97.5 wt.-% or 95 to 97.5 wt.-%, and additionally 2 to 2.5 wt.-% of at least one plasticizer, preferably glycerol, based on the total weight of the at least one backing layer, which contains the at least one backing layer.

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

Each of these additives is preferably present in an amount of 0.1 to 10 wt.%, preferably 0.1 to 5 wt.%, particularly preferably 0.1 to 2.5 wt.%, based on the total weight of the back layer, within this layer.

The multi-layered oral thin film according to the invention is preferably characterized in that the at least one backing layer contains at least one plasticizer, preferably glycerol, preferably in an amount of 0.5 to 5 weight-%, particularly preferably in an amount of 2 to 2.5 weight-%, based on the total weight of the at least one backing layer.

The invention's multi-layered oral thin film is, in principle, not limited in the number of layers it contains.

Thus, embodiments are conceivable in which the multilayered oral thin film comprises several active ingredient-containing matrix layers.

Also, embodiments are conceivable in which the multilayered oral thin film has two backing layers on opposite sides of the multilayered oral thin film.

In particular, at least one adhesive layer can be present between the at least one matrix layer and the at least one backing layer, in order to connect the at least one matrix layer and the at least one backing layer as firmly as possible.

A bonding layer is understood to be a layer 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.

Suitable adhesive layers include 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 comprises shellac, a vinylpyrrolidone/vinyl acetate copolymer, a polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer, hydroxypropyl cellulose or hydroxypropyl methylcellulose and/or polyvinylpyrrolidone, and wherein the at least one plasticizer in the at least one water-soluble adhesive layer comprises glycerin, polyethylene glycol, in particular polyethylene glycol 200, and/or tributyl citrate. 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 85 to 50 to about 15 to 50.

Such an adhesive layer containing 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 production of multi-layered oral films without requiring multiple overlapping coating steps.

The inventive multilayer oral thin film is preferably characterized in that the multilayer oral thin film consists of exactly two layers, namely a matrix layer containing at least one polymer and at least one pharmaceutical active ingredient, and a backing layer containing at least one polyethylene glycol.

The active ingredient-containing matrix layer can, in one embodiment, represent a smooth film.

Preferably, the multilayered oral thin film according to the invention is characterized in that the matrix layer is in the form of a solid foam having cavities.

Due to the cavities 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.

In addition, a rapidly resorbable active ingredient can improve transmucosal absorption through the rapid dissolution of the matrix layer.

Furthermore, the wall thickness of the aforementioned cavities is preferably small, as these may represent solidified bubbles, so that a rapid dissolution or destruction of these cavities occurs.

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

Preferably, the multilayered 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, or a mixture of at least two of these gases.

According to another embodiment, it is provided that the cavities are in communication with 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 matrix layer. In this way, the advantageous effect of accelerating the dissolution of the 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 adjusted over a wide range, almost arbitrarily. Thus, the average diameter, for example determined by microtomography or microscopy of the bubbles or cavities, can range from 1 to 350 µm. Particularly preferred is a diameter in the range of 40 to 200 µm.

The inventive multilayer oral thin film preferably has a rough side with an average roughness Ra greater than 2.0 µm and a smooth side with an average roughness Ra less than 1.0 µm.

In another embodiment, the inventive multilayer oral thin film is characterized in that the multilayer oral thin film has a rough side and a smooth side, wherein the rough side has a mean roughness Ra of more than 1.0 µm compared to the smooth side.

The measurement of roughness can, for example, be performed using a KLA Tencor P15 profilometer with a measuring tip of 2 µm radius. For this purpose, for example, a surface scan is conducted on both sides of an oral thin film over an area of 2 mm x 2 mm. On the scanning area of 2 mm x 2 mm, three random line scans are selected and the roughness parameters Ra, Rq, Rp, and Rv are determined.

For evaluating the sample, the following roughness parameters can be determined: Ra: Average roughness, indicating the average distance of a measurement point from the centerline. Rq: Root mean square roughness (also called RMS roughness), calculated as the mean of the squared deviations and corresponds to the root mean square. Rp: Peak height, the distance between the centerline and the highest measured value. Rv: Valley depth, the distance between the centerline and the lowest measured value.

The inventive multilayer oral thin film is furthermore preferably characterized in that the multilayer oral thin film exhibits a release of at least one pharmaceutical active ingredient that is at least 30% slower than that of the matrix layer alone without a backing layer.

This means that the presence of the back layer on the matrix layer can delay the release of at least one pharmaceutically active ingredient by at least 30%.

The inventive oral thin film preferably has an area of 0.5 cm² to 10 cm², particularly preferably from 1 cm² to 8 cm².

The orally administered thin film according to the invention is preferably characterized in that the grammage of the multi-layered oral thin film is 10 to 500 g/m², preferably 70 to 400 g/m².

The basis weight of the matrix 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 or equal to 150 g/m². Preferably, the basis weight is between 10 and 400 g/m², more preferably between 20 and 350 g/m² or between 30 and 300 g/m², and most preferably between 50 and 150 g/m².

The weight per unit area of the backing layer is important for controlling the dissolution behavior and ensuring the function of the backing layer, which protects the active ingredient from dissolving in saliva. A certain thickness is meaningful to ensure sufficient protection of the active ingredient as well as a sufficient dissolution time, which should normally be at least as long as the active permeation requirement and thus the dissolution time of the matrix layer.

It is therefore preferred that the back coating has a grammage of at least 10 g/m², preferably at least 20 g/m² or at least 30 g/m², most preferably at least 50 g/m², or a grammage less than or equal to 400 g/m², preferably less than or equal to 350 g/m² or less than or equal to 300 g/m², most preferably less than or equal to 150 g/m², or a grammage of 10 to 400 g/m², preferably 20 to 350 g/m² or 30 to 300 g/m², most preferably 50 to 150 g/m².

Preferably, the matrix layer and each of the at least one back layer have a thickness of approximately 10 µm to about 500 µm, particularly preferably from about 20 µm to about 300 µm.

The backing layer can, with respect to size, be particularly the same size or larger than the matrix layer. Thus, in certain embodiments, the size of the backing layer and the size of the active ingredient-containing matrix layer are equal, whereas in other embodiments, the backing layer is larger than the surface area of the matrix layer. While a layer structure with equal sizes of backing and matrix layers is easier to produce, since a two-layer sheet can be punched to provide the layer structure, a layer structure with a backing layer larger than the matrix layer is more difficult to manufacture, but has the advantage that the risk of active substance leakage is lower, as even the edge of the matrix layer is covered by the support layer.

The present invention also relates to a method for producing the multi-layered oral thin film according to the invention, comprising the steps of: a) preparing and spreading a solution or suspension comprising at least one polyethylene glycol, followed by drying the spread solution or suspension to obtain a film comprising at least one polyethylene glycol, b) preparing a solution, dispersion or melt comprising at least one polymer and at least one pharmaceutical active ingredient, b1) optionally foaming the solution, dispersion or melt from step b) by introducing a gas or gas mixture, by chemical gas generation, or by releasing a dissolved gas, c) spreading the solution, dispersion or melt from step b) or the optionally foamed solution, dispersion or melt from step b1) onto the film obtained in step a), comprising at least one polyethylene glycol, to obtain a composite, d) drying the composite obtained in step c) to obtain a multi-layered oral thin film.

Steps a) and b) can be performed in any order.

To the expert, it is clear that step b1) is only necessary if the active ingredient-containing matrix layer is to be in the form of a rigid foam with hollow spaces.

In step c), further layers, such as an adhesive layer, can also be present on the matrix layer.

The combination of the two films from step a) and b) can generally be carried out using conventional methods known to experts. For example, a second film can be applied to a first film by coating, and it is essentially irrelevant which film is coated onto which, as long as the backside layer forms one of the outer layers. Furthermore, the two layers can be connected together by an adhesive layer, as described above.

Usually, the layers are joined together by means of heat. For this purpose, the drying in step d) is carried out at a temperature higher than the melting temperature of the matrix layer and/or the backing layer. This results in the matrix layer and/or the backing layer partially melting, thus ensuring a solid connection between the two layers during subsequent cooling.

Suitable temperatures range from 40 to 100 °C, preferably from 55 to 80 °C. Preferably, drying is carried out for a duration of 10 to 60 minutes.

In a further embodiment, the method according to the invention is characterized in that the aforementioned steps c) and d) are replaced by the following steps: c2) Spreading the solution, dispersion or melt from step b), or optionally the foamed solution, dispersion or melt from step b1), to obtain a film comprising at least one polymer and at least one pharmaceutical active ingredient, and d2) joining the films obtained in step a) and c2), preferably by laminating using heat treatment above the melting point of one of the polymers contained in the films, to obtain a multi-layered oral thin film.

Due to the modified process, embodiments of the multilayer oral thin film, wherein both sides of the active ingredient-containing matrix layer are covered by a layer comprising at least one polyethylene glycol, can be easily manufactured. Such multilayer oral thin films dissolve very slowly.

The present invention also relates to a multi-layered oral thin film obtainable by the aforementioned method.

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

The present invention also relates to a multi-layered oral thin film as described above or obtainable by the aforementioned method, wherein ketamine, preferably S-ketamine, is used as the pharmaceutical active ingredient, 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 initiating and conducting general anesthesia or as an adjunct in regional anesthesia and/or as an analgesic.

The preferred embodiments listed above for the invention's multi-layered oral film also apply to the invention's method, the multi-layered oral film obtained by this method, and its use as a medicinal product.

The invention will now be explained in more detail with reference to non-limiting examples.

Example 1:

Example formulation from a polyethylene glycol (Polyox) backing layer and an S-ketamine containing matrix layer in the form of a foam. Tabelle 1:

Material	Menge [Gew.-%]
S-Ketamin·HCl	50,00
PVA 4-88	41,70
Saccharin Na	1,00
Sucralose	2,00
Glycerol	2,30
Geschmacksstoff 1	1,00
Geschmacksstoff 2	2,00
Prozesslösungsmittel	Wasser

Tabelle 1:

Polyox WSR N10	97,50
Glycerol	2,30
Farbstoff	0,20
Prozesslösungsmittel	Wasser
Flächengewicht (trocken)	Wirkstoffhaltige Matrixschicht:
	Rückschicht:
	Beschichtungsgewicht (inkl. Restwasser)	Wirkstoffhaltige Matrixschicht:
		Rückschicht:
S-Ketamin Base in mg/oralem Dünnfilm
		Entspricht 17,2 mg S-Ketamin·HCl

Tabelle 1:

PVA 4-88: Polyvinylakohol Polyox WSR N10: Polyethylenglycol mit einem MW von 100,000 g/mol von Dow Chemical

The multi-layered oral thin film according to the above composition was prepared as follows.

The raw materials of the backcoat are processed into a homogeneous mass using well-known weighing and mixing techniques, along with suitable mixing tools and motors. This mixture is then coated onto a web-shaped carrier using coating tools (e.g., film casting devices) to a specific grammage. The wet film is dried in a drying oven at 70°C for 15 minutes.

The raw materials of the active ingredient-containing matrix layer are also processed into a homogeneous mass using well-known weighing and mixing techniques, as well as suitable mixing tools and motors. This mass is then foamed using stirring techniques, and the resulting foam is coated onto the dry backing layer. This is done again with the aid of coating tools (e.g., film casting devices). The resulting film, consisting of the backing layer and the matrix layer, is dried once more in a drying cabinet at 70°C for 15 minutes.

This multi-layered film can be processed into smaller oral thin films after drying.

Example 2:

Example formulation from a polyethylene glycol (Polyox) backing layer and an S-ketamine containing matrix layer in the form of a foam, wherein the layers are produced individually and finally connected to each other by laminating. Tabelle 2:

(S)-Ketamin HCl	50,00 %
PVA 4-88	41,70 %
Saccharin Na	1,00 %
Sucralose	2,00 %
Glycerol	2,30 %
Geschmacksstoff 1	1,00 %
Geschmacksstoff 2	2,00 %
Prozesslösungsmittel	Aqua purificata
Flächengewicht (tocken)
Flächengewicht (incl. res. Lösungsmittel)

Tabelle 2:

Polyox WSR N10	97,50 %
Glycerol	2,3 %
Farbstoff	0,20 %
Prozesslösungsmittel	Aqua purificata
Flächengewicht (trocken)
Flächengewicht (incl. res. Lösungsmittel)

The raw materials of the back coating are processed into a homogeneous mass using well-known weighing and mixing techniques, along with suitable mixing tools and motors. This mixture is then coated onto a web-shaped carrier using coating tools (e.g., film casting equipment) to a specific grammage. The wet film is dried in a drying oven at 70°C for 15 minutes.

The raw materials of the active ingredient-containing matrix layer are also processed into a homogeneous mass using well-known weighing and mixing techniques, along with suitable mixing tools and motors. This mass is then foamed using stirring techniques, and the resulting foam is coated onto a web-shaped carrier. This is done again with the aid of coating tools (e.g., film casting devices). The wet film is dried in a drying oven at 70°C for 15 minutes.

The two layers were combined by laminating. For this, the backing layer was briefly heated to 70 °C and then connected to the active ingredient-containing matrix layer by laminating.

This multi-layered film can be packaged into smaller oral thin films.

In this multilayered oral thin film, a drug-free polyox layer serves as a backing layer for the actual drug-containing matrix layer of the oral thin film. The protective layer can mask the taste of the active ingredient and prevent rapid swallowing of the active substance, thereby increasing its oro-mucosal bioavailability. In particular, the inventive oral thin film is characterized in that the active ingredient coating can be directly applied to the polyox layer during production.

By drying above the melting point of polyox, the active ingredient-containing matrix layer and the backing layer bond together into a solid composite. Therefore, an adhesive layer is not necessary.

Furthermore, the patient can recognize which side of the OTF should be applied to the mucosa and whether the correct side was actually applied (different tactile sensations depending on which layer is on top or bottom), due to the different roughness of the layers (the polyox-containing backing layer is very smooth or film-like, while the active ingredient-containing matrix layer in the form of a foam is very rough).

Properties Decay time:

The dissolution time of a multilayered oral thin film (with backing layer) having a composition according to Table 2 was compared with the dissolution time of a single-layered oral thin film having a composition according to Table 3 (without backing layer). The preparation was carried out analogously to the previously described method for the oral thin films (with backing layer) having a composition according to Table 2. Tabelle 3:

(S)-Ketamin HCl	50,00 %
PVA 4-88	41,70 %
Saccharin Na	1,00 %
Sucralose	2,00 %
Glycerol	2,30 %
Geschmacksstoff 1	1,00 %
Geschmacksstoff 2	2,00 %
Prozesslösungsmittel	Aqua purificata
Flächengewicht (trocken)
Flächengewicht (incl. res. Lösungsmittel)

The disintegration times of the prepared oral films were measured according to USP 701 using a tablet disintegration apparatus (Pharma-Test DIST-3 Triple Basket Tablet Disintegration Tester, 30 strokes per minute over a distance of 55 mm, in 1 l of pH 6.8 phosphate buffer). Oral films with a size of 2.72 cm² were placed into a basket ("sinker") and positioned in a glass tube attached to the instrument. Finally, the time until only remnants of the oral films remained in the basket was determined. Tabelle 4:

Oraler Dünnfilm	Zerfallszeit
nur wirkstoffhaltige Matrixschicht (Tabelle 3)	3 s
wirkstoffhaltige Matrixschicht mit Rückschicht (Tabelle 2)	44 s

Active ingredient release:

Furthermore, the in vitro release of the active ingredient from the oral films with the compositions according to Table 2 and 3 was determined as follows:

Release method:

In the in vitro release study, S-ketamine is released from S-ketamine HCl oral thin films (OTF) and determined. The drug is released in phosphate buffer pH 6.8 USP and then quantified using a gradient reversed-phase HPLC method. Quantification was performed against an external standard.

The release is performed using Dissolution Apparatus 2 - (Paddle over sinker) according to USP <711>.

Sinker:	Stainless Steel Capsule Sinker with 10 Spirals, 31.0 x 11.0 mm Capacity (Sotax Style)
Rührgeschwindigkeit:	50 rpm
Abstand zwischen dem Vesselboden und der Unterkante des Paddle:	25 mm ± 2 mm
Temperatur:	37°C ± 0.5°C
Freisetzungsmedium:	Phosphatpuffer pH 6.8 USP
Volumen Freisetzungsmedium:	900 mL
Probennahmezeitpunkte:	1, 3,5 10 und 15 min
Probenvolumen:	5,0 mL

Tabelle 5:

In-vitro Freisetzung [% von LC*]		nur wirkstoffhaltige Matrixschicht (Tabelle 3)	wirkstoffhaltige Matrixschicht mit Rückschicht (Tabelle 2)
nach 1min	Mean	101	60
	Min	96	47
	Max	106	75
	RSD [%]	4,2	19,9
nach 3min	Mean	103	102
	Min	100	97
	Max	108	111
	RSD [%]	3,6	4,7
nach 5min	Mean	104	104
	Min	100	100
	Max	109	105
	RSD [%]	4,0	1,9
nach 10min	Mean	104	103
	Min	100	101
	Max	109	105
	RSD [%]	3,9	1,4
nach 15min	Mean	103	104
	Min	100	101
	Max	108	106
	RSD [%]	3,9	1,9

Tabelle 5:

*Label Claim = Sollgehalt

Example 3:

A multi-layered oral thin film with a composition according to Table 6, wherein an active ingredient-containing matrix layer is covered on both sides with a backing layer, was produced. Tabelle 6:

Material	Menge [Gew.-%]
S-Ketamin·HCl	50,00
PVA 4-88	41,70
Saccharin Na	1,00
Sucralose	2,00
Glycerol	2,30
Geschmacksstoff 1	1,00
Geschmacksstoff 2	2,00
Prozesslösungsmittel	Wasser

Tabelle 6:

Polyox WSR N10	97,50
Glycerol	2,30
Farbstoff	0,20
Prozesslösungsmittel	Wasser
Flächengewicht (trocken)	Wirkstoffhaltige Matrixschicht:
	Rückschicht:
	Beschichtungsgewicht (inkl. Restwasser)	Wirkstoffhaltige Matrixschicht:
		Rückschicht:
S-Ketamin Base in mg/oralem Dünnfilm
		Entspricht 16,1 mg S-Ketamin·HCl

The raw materials of both backcoatings are processed into a homogeneous mass using well-known weighing and mixing techniques, along with suitable mixing tools and motors. This mixture is then coated onto a continuous carrier (with a specific grammage) using coating tools (e.g., film casting units). The wet film is dried in a drying oven at 70°C for 15 minutes.

The raw materials of the active ingredient-containing matrix layer are also processed into a homogeneous mass by means of well-known weighing and mixing techniques, as well as with suitable mixing tools and motors. This mass is then foamed using stirring techniques, and the resulting foam is coated onto a web-shaped carrier. This is done again using coating tools (e.g., film casting devices). The wet film is dried in a drying oven at 70°C for 15 minutes.

The two backing layers and the intermediate active ingredient layer were combined by laminating. For this purpose, one backing layer was briefly heated to 70 °C and then laminated with the active ingredient-containing matrix layer. Subsequently, a second backing layer was briefly heated to 70 °C and then laminated onto the free side of the active ingredient-containing matrix layer of the previous laminate. Thus, a laminate having the composition backing layer - active ingredient-containing matrix layer - backing layer was obtained.

The received laminate can be processed into smaller oral films.

Example 4

A multilayered oral thin film with a composition according to Table 7 was prepared analogously to Example 2. The active ingredient-containing matrix layer was not foamed. Tabelle 7:

Polyox WSR N10	97,50 %
Glycerol	2,3 %
Farbstoff	0,20 %
Prozesslösungsmittel	Aqua purificata
Flächengewicht (trocken)
Flächengewicht (incl. res. Prozesslösungsmittel )

Tabelle 7:

HPMC 2910 (603)	39,5
HPMC 2910 (60SH50)	10,0
S-Ketamin	41,0
Saccharin Na	2,0
Sucralose	1,0
Glycerol	3,5
Geschmacksstoff	3,0
Prozesslösungsmittel	Aqua purificata
Flächengewicht (trocken)
Flächengewicht (incl. res. Prozesslösungsmittel )
Bemerkung	Nicht geschäumt

Tabelle 7:

HPMC 2910 (603): Hydroxypropylmethylcellulose 2910 (603) HPMC 2910 (60SH50): Hydroxypropylmethylcellulose 2910 (60SH50) Die eingesetzten HPMCs unterscheiden sich in der Viskosität einer 2% wässrigen Lösung: 603: 3 mPaS vs. 60SH50: 50 mPaS

The two layers were produced separately and connected together by laminating at 70°C. After cooling, the two layers were firmly bonded.

Example 5

A morphological surface examination was conducted using a KLA Tencor P15 profilometer with a measuring tip of 2 µm radius. A surface scan was performed on a 2 mm x 2 mm area on both sides of the OTF from Sample 1. On the 2 mm x 2 mm scanning area, three random line scans were selected and the roughness parameters Ra, Rq, Rp, and Rv were determined.

For the evaluation of the sample, the following roughness parameters were determined: Ra: Average roughness, indicating the average distance of a measurement point from the centerline. Rq: Root mean square roughness (also called RMS roughness), calculated as the mean of the squared deviations and corresponds to the root mean square value. Rp: Peak height, the distance between the centerline and the highest measured value. Rv: Valley depth, the distance between the centerline and the lowest measured value.

The roughness parameters indicate that the OTF has two different rough sides. The side of the backing layer is very smooth, comparable to smooth materials such as polished steel. In contrast, the side of the drug-containing matrix layer is significantly rougher. Due to the different roughness of the two OTF sides, a patient can recognize which side is the backing layer and which side is the drug-containing layer by touch. This allows, for example, the correct placement of the OTF in the mouth to be identified (e.g., the rough side facing downward toward the oral mucosa, and the smooth backing layer facing upward).

OTF on the back side:

Messung	Ra/µm	Rq/µm	Rp/µm	Rv/µm
1	0,76	1,06	4,85	1,40
2	0,55	0,86	5,54	0,87
3	0,74	1,15	6,64	2,09
Mittelwert	0,68	1,02	5,68	1,45

OTF on the active ingredient-containing matrix layer:

Messung	Ra/µm	Rq/µm	Rp/µm	Rv/µm
1	3,17	3,89	11,64	11,15
2	2,73	3,84	11,59	19,96
3	3,84	4,74	10,61	12,07
Mittelwert	3,24	4,16	11,28	14,39

Example 6:

Additional release measurements were conducted using profile dissolution and a higher temporal resolution than in Table 5.

Compared were: active ingredient-containing matrix layer (Table 3), active ingredient-containing matrix layer with a backing layer on one side (Table 2), active ingredient-containing matrix layer with a backing layer on both sides (Table 7)

For this purpose, S-ketamine is released from oral thin films (OTF) of S-ketamine HCl and determined. The active pharmaceutical ingredient is released in phosphate buffer pH 6.8 USP and then quantified using a gradient reversed-phase HPLC method. Quantification was performed against an external standard.

The release is performed using Dissolution Apparatus 2 - (Paddle over sinker) according to USP <711>.

Sinker:	Stainless Steel Capsule Sinker with 10 Spirals, 31.0 x 11.0 mm Capacity (Sotax Style)
Rührgeschwindigkeit:	50 rpm
Abstand zwischen dem Vesselboden und der Unterkante des Paddle:	25 mm ± 2 mm
Temperatur:	37°C ± 0.5°C
Freisetzungsmedium:	Phosphatpuffer pH 6,8 USP
Volumen Freisetzungsmedium:	900 mL
Probennahmezeitpunkte:	1, 3,5 10 und 15 min
Probenvolumen:	5,0 mL

The results are shown in Figure 1. The expert can recognize that the release profile of the matrix layer can be varied with the backcoat.

Claims (20)

1. A multi-layer oral thin film comprising a matrix layer, which contains at least one polymer and at least one pharmaceutically active agent, and at least one backing layer, wherein the at least one backing layer comprises at least one polyethylene glycol in an amount of from 60 to 100 wt.%, in relation to the total weight of the at least one backing layer.
2. The multi-layer oral thin film according to claim 1, wherein the matrix layer comprises at least one water-soluble polymer.
3. The multi-layer oral thin film according to claim 2, wherein the at least one water-soluble polymer 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.
4. The multi-layer oral thin film according to any one of the preceding claims, wherein 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, wherein the at least one pharmaceutically active agent preferably comprises ketamine, especially preferably (S)-ketamine.
5. The multi-layer oral thin film according to any one of the preceding claims, wherein the matrix layer further comprises at least one auxiliary substance selected from the group comprising colouring agents, flavourings, sweeteners, plasticisers, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or antioxidants.
6. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polyethylene glycol has a mean molecular weight of from 20,000 g/mol to 7,000,000 g/mol, preferably from 40,000 g/mol to 500,000 g/mol, especially preferably from 95,000 g/mol to 105,000 g/mol, especially of about 100,000 g/mol.
7. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polyethylene glycol has a viscosity of from 30 mPa s to 50 mPa s, measured in 5 wt.% aqueous solution at 25°C.
8. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one polyethylene glycol is contained in the at least one backing layer in an amount of from 80 to 100 wt.%, in relation to the total weight of the at least one backing layer.
9. The multi-layer oral thin film according to any one of the preceding claims, wherein the at least one backing layer contains at least one plasticiser, preferably glycerol, preferably in an amount of from 0.5 to 5 wt.% in relation to the total weight of the at least one backing layer.
10. The multi-layer oral thin film according to any one of the preceding claims, wherein the multi-layer oral thin film consists of exactly two layers, specifically the matrix layer containing at least one polymer and at least one pharmaceutically active agent and the backing layer containing at least one polyethylene glycol.
11. The multi-layer oral thin film according to any one of the preceding claims, wherein the matrix layer is present in the form of a solidified foam that has voids.
12. The multi-layer oral thin film according to claim 11, wherein the voids are isolated from one another and are preferably present in the form of bubbles, wherein the voids are 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.
13. The multi-layer oral thin film according to any one of claims 11 or 12, wherein the voids are connected to one another and preferably form a channel system penetrating the matrix layer.
14. The multi-layer oral thin film according to any one of claims 11 to 13, wherein the voids in the matrix layer 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.
15. The multi-layer oral thin film according to any one of the preceding claims, wherein the oral thin film has a rough side with an average roughness Ra greater than 2.0 µm and a smooth side with an average roughness Ra less than 1.0 µm.
16. The multi-layer oral thin film according to any one of the preceding claims, wherein the oral thin film has a rough side and a smooth side, wherein the rough side has an average roughness Ra of 1.0 µm more than the smooth side.
17. The multi-layer oral thin film according to any one of the preceding claims, wherein the multi-layer oral thin film has an at least 30% slower release of the at least one pharmaceutically active agent than the matrix layer alone without backing layer.
18. A method for producing a multi-layer oral thin film according to any one of claims 1 to 17, comprising the steps of:

    a) producing and spreading a solution or suspension comprising the at least one polyethylene glycol, and then drying the spread solution or suspension in order to obtain a film comprising the at least one polyethylene glycol,

    b) producing a solution, dispersion or melt which at least comprises the at least one polymer and the at least one pharmaceutical active agent,

    b1) optionally foaming the solution, dispersion or melt from step b) by introducing a gas or gas mixture by chemical gas generation or by expansion of a dissolved gas,

    c) spreading the solution, dispersion or melt from step b) or the optionally foamed solution, dispersion or melt from step b1) onto the film obtained in step a) comprising the at least one polyethylene glycol in order to obtain a composite,

    d) drying the composite obtained in step c) in order to obtain a multi-layer oral thin film.
19. The method according to claim 18, characterised in that steps c) and d) are replaced by the following steps:

    c2) spreading the solution, dispersion or melt from step b) or the optionally foamed solution, dispersion or melt from step b1) in order to obtain a film comprising the at least one polymer and the at least one pharmaceutical active agent,

    d2) connecting the films obtained in step a) and c2), preferably by lamination by exposure to heat above the melting point of one of the polymers contained in the films in order to obtain a multi-layer oral thin film.
20. Multi-layer oral thin film according to any one of claims 1 to 17 or of a multi-layer oral thin film obtained by the method according to claim 18 or 19 for the use as a medicament.