EP4436545A1

EP4436545A1 - Oral microneedle patch

Info

Publication number: EP4436545A1
Application number: EP22822909.2A
Authority: EP
Inventors: Markus Müller; Anna SCHLÜTER; Michael Linn
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2021-11-25
Filing date: 2022-11-25
Publication date: 2024-10-02
Also published as: DE102021130954A1; CN118510494A; WO2023094637A1; CA3240159A1

Abstract

The invention relates to an oral thin film, comprising a matrix layer containing at least one polymer, wherein a microneedle system is applied to at least one surface of the oral thin film, to a method for producing such an oral thin film, to a composite, comprising such a thin film, and to an application aid, which comprises at least one polymer, for the oral thin film, wherein the oral thin film and the application aid are firmly connected to each other, to a method for producing the oral thin film, to a method for producing the composite, and to the oral thin film and to the composite for use as medicinal products.

Description

ORAL MICRONEEDLE PATCH

Description

The invention relates to an oral thin film, a method for producing such an oral thin film, a composite comprising the oral thin film and an application aid, a method for producing this composite and the oral thin film or composite for use as a medicament.

Oral thin films are thin films, usually containing a pharmaceutically active ingredient, which are placed directly in the oral cavity or applied to the oral mucosa and dissolve there. These are, in particular, thin polymer-based films containing active substance which, when applied to a mucous membrane, in particular the oral mucosa, release the active substance directly into the latter. These oral thin films are typically non-tacky to the outside. The very good blood circulation in the oral mucosa ensures that the active substance enters the bloodstream quickly. This administration system has the advantage that the active ingredient is largely absorbed through the mucous membrane and thus the "first-pass metabolism" that occurs with the conventional administration form of an active ingredient in tablet form, which is usually taken with liquid, which can be disadvantageous The active ingredient can be dissolved, emulsified or dispersed in the film. Suitable active ingredients can also be swallowed after the oral thin film has dissolved in the mouth and thus be absorbed via the gastrointestinal tract. However, among the pharmaceutically active ingredients there are a large number of molecules which cannot be applied through the oral mucosa due to their size or other properties, such as hydrophobicity. For these, the oral mucosa forms an insurmountable barrier.

The object of the present invention was therefore to provide an oral thin film which overcomes these disadvantages and with which active ingredients can also be administered via the oral mucosa for which this route of administration was previously inaccessible.

This object was solved by an oral thin film according to claim 1. Such an oral thin film comprises a matrix layer containing at least one polymer and is characterized in that a microneedle system is applied to at least one surface of the oral thin film, the microneedle system being applied to the at least one surface of the oral thin film by means of an adhesive layer.

The microneedles can penetrate into the oral mucosa and thus reduce its resistance, so that a pharmaceutically active substance can penetrate into it more easily.

The application of oral thin films can be problematic. Difficulties can arise in applying the oral thin film as desired at the appropriate point due to the shape, size, properties and intended application site of the oral thin film, but also due to impairments of the user. In the case of oral thin films in particular, which are equipped with microneedles on a surface to increase the lux of active substance, it is important that these microneedles are not damaged before application.

These disadvantages can be eliminated by an application aid for the oral thin film.

Although conventional application aids can bring about improvement, they usually have to be laboriously detached from the oral thin film and/or have a complicated structure. There is also a risk that the user will accidentally swallow the application aid. The present application was therefore also based on the object of providing an application aid for the oral thin film which overcomes the above disadvantages. The application aid should have high haptic stability in order to apply the oral thin film at the desired location. In addition, the risk of the application aid being swallowed as a whole should be minimized and the risk of the user destroying or damaging the thin oral film before application should be minimized.

This object is surprisingly achieved with a composite according to claim 9, i. H. by a composite comprising the oral thin film according to the invention and an application aid which comprises at least one polymer for the oral thin film, which is characterized in that the oral thin film and the application aid are firmly connected to one another.

Such a connection has the advantage that the user does not have to touch the oral thin film himself in order to apply it. The contact is preferably exclusively via the application aid. Furthermore, in a preferred embodiment, the application aid can be designed in such a way that it dissolves itself in the oral cavity of the user. Due to the firm connection with the application aid, particularly those oral thin films that are equipped with microneedles on one surface can be advantageously applied.

All features of one embodiment can be combined with features of another embodiment if the features of the different embodiments are not incompatible.

The terminology used in the description of the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting of the subject matter. As used in the present specification and claims, the singular forms "a", "an" and "the" should be understood to include the plural forms as well, unless the context clearly dictates otherwise. This also applies vice versa, ie the plural forms also include the singular forms. It is also to be understood that the term "and/or" as used herein refers to and includes all possible combinations of one or more of the associated listed items. It goes without saying that the terms "includes,""including,""comprises," and/or "comprising" when used in the present specification and claims specify the presence of the specified features, steps, elements, and/or components, but not exclude the presence or addition of any other feature, step, element, component and/or group thereof.

In the present description and claims, the terms "includes", "comprises" and/or "comprising" can also mean "consisting of", i.e. the presence or addition of one or more other features, steps, elements, components and/or groups is excluded.

The oral thin film according to the invention comprises a matrix layer containing at least one polymer, with a microneedle system being applied to at least one surface of the oral thin film.

In a preferred embodiment, the oral thin film according to the invention consists of the matrix layer and the microneedle system.

A microneedle system, also referred to as a microneedle array, preferably comprises a system comprising a multiplicity of microneedles on a carrier.

The carrier preferably comprises at least one polymer.

The needles preferably have a length of 5 μm to 1000 μm.

The density of the needles is preferably from 50 to 1000, in particular from 100 to 600 needles per cm ² .

The microneedle system is preferably applied to at least one, preferably exactly to one surface of the oral thin film.

The surface on which the microneedle system is applied is preferably the largest surface of the oral thin film.

In one embodiment, the microneedle system is larger than the oral thin film. In one embodiment, the microneedle system is smaller than the oral thin film.

In one embodiment, the microneedle system and the oral thin film are approximately the same size.

In a preferred embodiment, the at least one polymer comprises a water-soluble polymer.

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

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

The at least one water-soluble polymer is preferably selected from the group comprising starch, starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acid, 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, carrageenan and/or natural gums.

The oral thin film according to the invention is further preferably characterized in that the at least one polymer, preferably the water-soluble polymer, is present in an amount of 10 to 100% by weight or 30 to 95% by weight, preferably 60 to 90% by weight. , particularly preferably from 70 to 90% by weight, based on the total weight of the matrix layer, is present in the matrix layer. In one embodiment, the oral thin film according to the invention is preferably further characterized in that the matrix layer contains at least one pharmaceutically active substance.

In one embodiment, the oral thin film according to the invention is further preferably characterized in that the microneedle system contains at least one pharmaceutically active ingredient.

In one embodiment, the oral thin film according to the invention is further preferably characterized in that the matrix layer and the microneedle system contain at least one pharmaceutically active ingredient. In this embodiment, the same pharmaceutically active substance can be contained in the matrix layer and the microneedle system, or different pharmaceutically active substances can be contained in each case.

The amount of the at least one pharmaceutically active substance is preferably 1% by weight to 60% by weight, in particular from 1% by weight to 40% by weight, based on the total weight of the matrix layer.

The absolute amount of the at least one pharmaceutically active substance is preferably 1 pg to 100 mg, in particular from 1 pg to 10 mg.

In principle, the at least one pharmaceutically active ingredient is not limited.

The at least one pharmaceutically active ingredient is preferably selected from the group comprising the active ingredient classes of analgesics, hormones, hypnotics, sedatives, antiepileptics, waking amines, psychoneurotropics, neuromuscular blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors , antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antitumor agents, antibiotics, vaccines, chemotherapeutic agents and/or narcotics.

Specific examples include acetaminophen, adrenaline, alprazolam, amlodipine,

Anastrozole, Apomorphine, Aripiprazole, Atorvastatin, Baclofen, Benzocaine, Benzocaine/Menthol, Benzydamine, Buprenorphine, Buprenorphine/Naloxone, Buprenorphine/Naloxone/Cetirizine, Cetirizine, Chlorpheniramine, Clomipramine, Dexamethasone, Dextromethorphan, Dextromethorphan/Phenylephrine, Diclofenac, Diphenhydramine, Diphenhydramine/Phenylephrine, Donepezil Dronabinol, Epinephrine, Escitalopram, Famotidine, Fentanyl, Glimepiride, GLP-1 Peptides, Granise tron, insulin, Insulin Nanoparticles, Insulin/GLP-1 Nanoparticles, Ketamine, Ketoprofen, Ketotifen, Caffeine, Levocetirizine, Loperamide, Loratadine, Medicine, Methylphenidate, Midazolam, Mirodenafil, Montelukast, Multimeric-001, Naloxone, Nicotine, Nitroglycerin, Olanzapine, Olopatadine, Ondansetron, Oxybutynin, pectin, pectin/menthol, pectin/ascorbinic acid, pediasunate (artesunate and amodiaquin), piroxicam, phenylephrin, prednisolone, pseudoephedrin, risperidon, rivastigmine, rizatriptan, Selegiline, Senna Glykoside, sildenafil zitrat, Simethic, Simethic on, sumatriptan, tadalafil, testosterone, triamcinolone acetonide, triptan, tropicamide, voglibose, zolmitriptan, zolpidem and/or pharmaceutically acceptable salts of these compounds.

The pharmaceutical active ingredient can also be a mixture of different active ingredients.

In one embodiment, the oral thin film, particularly the matrix layer, is in the form of a smooth film.

A smooth film is preferably characterized in that it is not in the form of a foam and does not have any significant unevenness when analyzed optically without aids or magnification. A film can be produced, for example, by spreading and drying a polymer-containing solution, emulsion, suspension or melt.

In another embodiment, the oral thin film, particularly the matrix layer, is in the form of a voided solidified foam.

The cavities and the associated larger surface area of the films make it easier for water or saliva or other body fluids to enter the interior of the dosage form, thus accelerating the dissolution of the dosage form and the release of the active ingredient.

In the case of a rapidly absorbing active substance, the rapid dissolution can also improve transmucosal absorption. On the other hand, the wall thickness of the cavities mentioned is preferably small, since these represent, for example, solidified bubbles, so that these cavities are rapidly dissolved or destroyed.

A further advantage of this embodiment is that, despite the comparatively high basis weight, the packaging as a foam allows faster drying than with a comparable non-foamed composition.

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

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

The cavities mentioned preferably have a volume fraction of 5 to 98%, preferably 50 to 80%, based on the total volume of the matrix layer. In this way, the beneficial effect of accelerating the dissolution of the matrix layer is favorably influenced.

Furthermore, surface-active substances or surfactants can be added to the matrix for foam formation or to the resulting foam before or after drying in order to improve the stability of the foam before or after drying.

Another parameter that influences the properties of the dosage form according to the invention is the diameter of the cavities or bubbles. The bubbles or cavities are preferably produced with the aid of a foam whipping machine with which the diameter of the bubbles can be adjusted over a wide range, almost at will. Thus, the diameter of the bubbles or cavities can range from 0.01 to 350 µm. The diameter is particularly preferably in the range from 10 to 200 μm. The oral thin film or matrix layer according to the invention preferably has an area of 0.5 cm ² to 10 cm ² , particularly preferably 1.5 cm ² to 7.5 cm ² .

The oral thin film or the matrix layer according to the invention is preferably characterized in that the basis weight of the oral thin film or the matrix layer is 10 to 500 g/m ² , preferably 100 to 400 g/m ² .

The basis weight of the oral thin film or matrix layer is preferably at least 10 g/m ² , more preferably at least 20 g/m ² or at least 30 g/m ² or most preferably at least 50 g/m ² or less than or equal to 400 g /m ² , more preferably less than or equal to 350 g/m ² , or less than or equal to 300 g/m ² , or most preferably less than or equal to 150 g/m ² . Preferably the basis weight of the oral thin film or matrix layer is 10 to 400 g/m ² , more preferably 20 to 350 g/m ² or 30 to 300 g/m ² and most preferably 50 to 150 g/m ² .

The oral thin film or the matrix layer preferably has a layer thickness of about 20 μm to about 500 μm, particularly preferably from about 50 μm to about 300 μm.

The microneedle system preferably comprises microneedles with a length of 10 to 1000 μm, preferably with a length of 100 μm to 600 μm, particularly preferably of 250 μm to 350 μm.

Furthermore, the microneedle system is preferably a microneedle system based on starch, starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinylpyrrolidones, polyvinyl alcohols, poly (lactide-co-glycoid), hyaluronic acid, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and/or natural gums, this group is not conclusive. Preferably, the microneedles comprise a polymer that is also present in the carrier.

Preferably, the microneedles comprise a polymer that is also present in the oral thin film, particularly in the matrix layer.

Preferably, the carrier of the microneedles comprises a polymer that is also present in the oral thin film, particularly in the matrix layer.

Preferably, the microneedles and their carriers comprise a polymer that is also present in the oral thin film, particularly in the matrix layer.

In particular embodiments, the microneedle system can also consist of materials such as ceramics, steel, polymers and/or SiCh.

In a preferred embodiment, the oral thin film and/or the microneedle system further comprise at least one excipient selected from the group comprising colorants, flavorings, sweeteners, plasticizers, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or antioxidants.

These adjuvants are preferably contained in the oral thin film or in the microneedle system in an amount of 0.1 to 30.0% by weight.

In one embodiment, the oral thin film with microneedles can also be manufactured by using a negative mold of the microneedles in the manufacture of the oral thin film, so that the oral thin film and the microneedles are monolithic.

Alternatively, the microneedle system can be manufactured separately and attached to the oral thin film with any suitable attachment means.

The microneedle system and oral thin film can be connected, for example, by means of an adhesive layer, preferably a water-soluble adhesive layer, and/or by means of a seal, preferably a heat seal. A seal includes, for example but not limited to, connections by embossing and/or heat sealing.

Heat sealing means a connection of the microneedle system and the oral thin film through selective heating and pressing. The at least one polymer that is present in the microneedle system or in the oral thin film softens or melts as a result of the selective heating, which leads to a firm connection after cooling again. Preference is given to heating at specific points to a temperature which is above the melting temperature or glass transition temperature of the respective polymer.

Typical temperatures for a heat seal are about 50°C to 200°C.

The heat sealing is preferably performed for about 5 seconds, more preferably about 3 seconds, and most preferably about 2 seconds or less at a temperature of about 50°C to 200°C.

The microneedle system is applied to at least one surface of the oral thin film by means of an adhesive layer, in particular a water-soluble adhesive layer.

Water-soluble is understood here as defined above.

Water-soluble adhesive layers are particularly suitable as adhesive layers, as are described in DE 10 2014 127 452 A1, the relevant content of which is hereby incorporated in its entirety.

Suitable adhesive layers comprise at least one water-soluble polymer and at least one plasticizer, the at least one water-soluble polymer in the at least one water-soluble adhesive layer being 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 comprises glycerol, 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, which contains at least one water-soluble polymer and at least one plasticizer, can, as an intermediate water-soluble adhesive layer, firmly bond two further layers that are not tacky per se and thus enable the construction of multilayer composites.

In principle, the oral thin film is not limited in the number of layers it contains.

Thus, embodiments are conceivable in which the oral thin film comprises additional layers. The above definitions apply analogously to the other layers.

The present invention further relates to a composite comprising an oral thin film as described above and an application aid for the oral thin film.

The application aid comprises at least one polymer and is firmly connected to the oral thin film.

It goes without saying that the application aid is connected to the oral thin film on the surface on which the microneedle system is not applied.

The term "application aid" can be understood here as broadly as possible.

The application aid preferably comprises a flat structure with a preferred thickness of 0.1 mm to 4 mm, in particular 0.1 mm to 2 mm, or 0.5 mm to 2 mm or 100 μm to 500 μm on the oral surface Thin film is firmly attached.

The application aid can have all possible forms. For example, the application aid can be essentially round, oval or elliptical. However, the application aid can also be triangular or square, optionally with rounded corners. Furthermore, shapes in other possible polygons, possibly with rounded corners, are possible.

Mixed forms are also possible, with the application aid having, for example, a first round, oval or elliptical area and a second area attached thereto, which is for example strip-shaped, triangular or square (also polygonal), so that the application aid as a whole has a shape that resembles the shape of a tennis racquet, with the second region preferably serving as the 'handle' and the first region for receiving the oral thin film.

"Firmly connected" is understood here to mean that the application aid and the oral thin film are connected to one another in such a way that the user cannot separate the connection without destroying the film. This connection should not be impaired as far as possible, even over a longer period of storage.

The composite according to the invention is preferably characterized in that the application aid comprises a first area and a second area.

The oral thin film is preferably arranged in the first area of the application aid.

The second area of the application aid is preferably designed in such a way that a user can touch the application aid in such a way that the oral thin film is not touched.

Preferably, the oral thin film is attached to a first third or a first half of the area of the application aid. In this way, two thirds or a second half of the application aid remain free and can serve as a "handle" for applying the oral thin film.

The composite according to the invention is preferably characterized in that the application aid has an area that is at least twice as large, preferably 2 to 10 times or 2 to 4 times as large as the area of the oral thin film. In possible embodiments, the application aid has an area of 1 cm ² to 30 cm ² , preferably 2 cm ² to 15 cm ² or 2 cm ² to 10 cm ² .

In possible embodiments, the oral thin film has an area of 0.3 cm ² to 10 cm ² , preferably 0.5 cm ² to 7 cm ² .

In possible embodiments, the application aid has a length of 1 cm to 10 cm, preferably 2 cm to 5 cm.

In possible embodiments, the application aid has a width of 0.5 cm to 5 cm, preferably 1 cm to 3 cm.

In possible embodiments, the oral thin film has a length of 0.5 cm to 5 cm, preferably 1 cm to 4 cm.

In possible embodiments, the oral thin film has a width of 0.5 cm to 4 cm, preferably 1 cm to 4 cm.

In possible embodiments, the application aid has a thickness of 0.1 mm to 4 mm, preferably 0.1 mm to 2 mm or 100 μm to 500 μm.

In possible embodiments, the oral thin film has a thickness of 0.01 mm to 2 mm, preferably 0.05 mm to 1 mm or 100 μm to 400 μm.

In possible embodiments, the application aid has a weight per unit area of from 20 g/m ² to 800 g/m ² , preferably from 20 g/m ² to 500 g/m ² .

In possible embodiments, the oral thin film has a basis weight of from 10 g/m ² to 600 g/m ² , preferably from 10 g/m ² to 400 g/m ² .

The application aid can have a single layer or multiple layers.

The composite according to the invention is preferably characterized in that the application aid comprises at least one water-soluble polymer. Water-soluble polymers include chemically very different, natural or synthetic polymers whose common feature is their solubility in water or aqueous media. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for water solubility and are not crosslinked. The hydrophilic groups can be non-ionic, anionic, cationic and/or zwitterionic.

The at least one water-soluble polymer is preferably selected from the group consisting of starch, starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates, polyvinyl pyrrolidone, vinyl pyrrolidone / Vinyl acetate copolymers, polyvinyl alcohols, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and/or natural gums, polyvinyl alcohols being particularly preferred.

The composite according to the invention is preferably characterized in that the at least one polymer, preferably the water-soluble polymer, in an amount of 10 to 100% by weight or 10 to 95% by weight, preferably 60 to 90% by weight, particularly preferably from 80 to 90% by weight, based on the total weight of the application aid.

The composite according to the invention is preferably characterized in that the application aid is water-soluble as a whole. Here, too, water-soluble is preferably understood as meaning a solubility of greater than 100 g/l in water at 25.degree.

The composite according to the invention is preferably characterized in that the application aid comprises aromas, taste-masking agents and/or narcotics or local anesthetics. For example, aminoamides such as lidocaine, amino esters such as procaine, fomocaine, quinisocaine or cyclonine are suitable as narcotics or local anesthetics.

These are preferably present in an amount of 0.1 to 10% by weight or 0.1 to 5% by weight, based on the total weight of the application aid.

The composite according to the invention is preferably characterized in that the application aid also comprises at least one auxiliary selected from the group comprising dyes, sweeteners, plasticizers, emulsifiers, enhancers, pH regulators, humectants, preservatives and/or antioxidants.

Each of these excipients is preferably present in an amount of from 0.1 to 40% by weight, more preferably from 0.1 to 30% by weight, most preferably from 0.1 to 15% by weight, and even more preferably from 0.1 to 10% by weight or 0.1 to 5% by weight, based on the total weight of the application aid.

The stability of the application aid can be adjusted in particular via the content of plasticizer.

Suitable plasticizers include, for example, glycerin.

The plasticizer(s) is/are preferably in an amount of 0.1 to 15% by weight, most preferably 0.1 to 10% by weight or 0.1 to 5% by weight, especially about 5% by weight, based on the total weight of the application aid.

The composite according to the invention is preferably characterized in that the application aid is in the form of a film that is as smooth as possible.

In another embodiment, the composite according to the invention is characterized in that the application aid is in the form of a solidified foam having cavities. The cavities and the associated larger surface area of the application aid make it easier for water or saliva or other body fluids to enter the interior of the application aid and thus accelerate the dissolution of the application aid.

On the other hand, the wall thickness of the cavities mentioned is preferably small, since these represent, for example, solidified bubbles, so that these cavities are rapidly dissolved or destroyed.

The composite according to the invention is preferably characterized in that the cavities are isolated from one another and are preferably in the form of bubbles, the cavities being 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 are filled.

The cavities mentioned preferably have a volume fraction of 5 to 98%, preferably 50 to 80%, based on the total volume of the application aid. In this way, the solution of the application aid is influenced in a favorable manner.

Furthermore, application aids for foam formation or surface-active substances or surfactants can be added to the foam obtained before or after drying in order to improve the stability of the foam before or after drying.

Another parameter that influences the properties of the application aid according to the invention is the diameter of the cavities or bubbles. The bubbles or cavities are preferably using a foam whipping machine, with which the diameter of the bubbles can be adjusted in a wide range, almost arbitrarily. Thus, the diameter of the bubbles or cavities can range from 0.01 to 350 µm. The diameter is particularly preferably in the range from 10 to 200 μm.

The composite according to the invention is preferably characterized in that the application aid and the oral thin film are connected to one another by means of an adhesive layer, preferably a water-soluble adhesive layer and/or by means of a seal, preferably a heat seal.

Adhesive layer means a layer that can act as an adhesive as defined in DIN EN 923:2016-03.

Such an adhesive layer, which contains at least one water-soluble polymer and at least one plasticizer, can, as an intermediate water-soluble adhesive layer, firmly bond two further layers that are not tacky per se and thus enable the construction of multilayer composites. Sealing is understood to mean any possible way in which the application aid and the oral thin film can be connected to one another. This includes, for example but not limited to, connections by embossing and/or heat sealing.

Heat sealing means connecting the application aid and the oral thin film by means of selective heating and pressing. The at least one polymer that is present in the application aid or in the oral thin film melts as a result of the selective heating, which leads to a firm connection after cooling again. Preference is given to heating at specific points to a temperature which is above the melting temperature or glass transition temperature of the respective polymer.

Typical temperatures for a heat seal are about 50°C to 200°C.

The heat sealing is preferably performed for about 5 seconds, preferably about 3 seconds, and more preferably about 2 seconds or less at a temperature of about 50°C to 200°C.

The composite according to the invention is also preferably characterized in that the application aid dissolves in the oral cavity of a patient within 10 s to 5 min, preferably from 30 s to 3 min.

The composite according to the invention is also preferably characterized in that the application aid and the oral thin film dissolve in the oral cavity of a patient within 10 s to 5 min, preferably from 30 s to 2 min.

The present invention also relates to a method for producing an oral thin film as described above, comprising the steps

- providing an oral thin film comprising at least one polymer and at least one pharmaceutically active agent,

- Providing a microneedle system and

- fixed connection of the microneedle system and the oral thin film, the fixed connection comprising the following steps

- applying an adhesive layer to a surface of the oral thin film, - applying the microneedle system to this adhesive layer and - drying the adhesive layer in order to obtain a firm bond. All the embodiments and definitions described above for the oral thin film, the microneedle system and for the adhesive layer apply analogously to the method for producing an oral thin film as described above.

It is irrelevant whether the microneedle system or the oral thin film is provided in a first step.

When the oral thin film is in the form of a foam, the method further includes the step of foaming the solution, emulsion, melt or suspension by introducing a gas or gas mixture, by chemical gas generation, or by expanding a dissolved gas.

"Firmly connected" is preferably understood here to mean that the microneedle system and the oral thin film are connected to one another in such a way that the user cannot separate the connection without destroying the film. This connection should not be impaired as far as possible, even over a longer period of storage.

An alternative method for producing an oral thin film, in particular as described above, preferably comprises the following steps for forming a permanent connection between the microneedle system and the oral thin film:

- heating the oral thin film to a temperature above the softening point of the at least one polymer,

- applying the microneedle system to a surface of the heated oral thin film to obtain a loose bond, and

- Cooling of the loose bond to obtain a solid bond.

The heating preferably comprises heating at a temperature of 50 to 100°C, preferably for about 0.5 to 5 minutes.

The present invention further relates to an oral thin film obtainable by the method described above. The present invention also relates to a method for producing a composite comprising an oral thin film as described above and an application aid for the oral thin film as described above, comprising the steps:

-Providing an application help,

- providing an oral thin film and

-firmly connecting the application aid to the oral thin film.

All the embodiments defined above for the composite, the oral thin film and the application aid apply analogously to the method according to the invention.

It is irrelevant whether the application aid or the oral thin film is provided in the first step.

The application aid and/or the oral thin film is preferably provided by a method that involves the preparation of a solution, emulsion, melt or suspension comprising all the ingredients of the application aid or oral thin film, followed by spreading out and drying the solution, emulsion, melt or suspension.

All suitable shapes can be cut out or stamped from these dried solutions, emulsions, melts or suspensions.

If the application aid and/or the oral thin film is in the form of a foam, the method also includes the step of foaming the solution, emulsion, melt or suspension by introducing a gas or gas mixture, by chemical gas generation or by expanding a dissolved gas.

The method for producing a composite, as described above, preferably comprises the following steps for forming a firm connection between the application aid and the oral thin film:

- heating the oral thin film and/or the application aid to a temperature above the softening point of the respective at least one polymer, - applying the oral thin film to a surface of the application aid to obtain a loose bond, and

- Cooling of the loose bond to obtain a solid bond.

The heating here preferably comprises heating at a temperature of 50 to 100°C, preferably for about 0.5 to 5 minutes.

An alternative method for producing a composite, as described above, preferably comprises the following steps for forming a firm connection between the application aid and the oral thin film:

- applying an adhesive layer to a surface of the oral thin film or to a surface of the application aid,

-connecting the oral thin film and the application aid via this adhesive layer and

-Drying the adhesive layer to obtain a solid bond.

The adhesive layer is understood as defined above.

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

Furthermore, the present invention relates to a composite as described above, or obtainable by the method described above as a medicament.

All the embodiments defined above for the composite, the oral thin film and the application aid apply analogously to the medical use according to the invention. Description of the figures:

Figure 1:

FIG. 1 shows a possible embodiment of the oral thin film. This has an oral thin film (3) on which microneedles (5) are applied. These microneedles (5) can either be attached to the oral thin film with an adhesive layer (4) or attached there by means of alternative attachment measures.

Figure 2:

Figure 2 shows an oral thin film (7) equipped with a microneedle system (8). The oral thin film is larger than the microneedle system

Figure 3:

FIG. 3 shows a possible configuration of the composite, comprising an oral thin film and an application aid for the oral thin film. The composite has a first area of the application aid on which the oral thin film is arranged and a second area of the application aid that is designed such that a user can touch the application aid in such a way that the oral thin film is not touched.

An adhesive layer (2) is applied to an application aid (1), to which the oral thin film (3) is applied in a first area. So that the user does not have to touch the adhesive layer, a piece of the application aid (1a) can optionally be applied again in a second area on the adhesive layer.

The oral thin film is fitted with microneedles (5). These microneedles (5) can either be applied to the oral thin film with a further adhesive layer (4) or attached there by means of alternative fastening measures. FIG. 4: FIG. 4 shows a further possible embodiment of the composite, comprising an oral thin film and an application aid for the oral thin film. The composite has a first area of the application aid, on which the oral thin film is arranged, and a second area of the application aid that is designed such that a user can touch the application aid in such a way that the oral thin film is not touched. The user is represented by the stylized hand (9).

An oral thin film (7) is applied to an application aid (6) in an area that differs from the area that the user touches with his hand (9). The oral thin film (7) can be equipped with microneedles (8).

examples

The invention is explained in more detail below using non-limiting examples.

Example 1:

An oral thin film was prepared using a microneedle system.

The microneedle system has a composition according to Table 1 below.

polyvinylpyrrolidone

All components are dissolved in the process solvent water. The mass is then dosed onto silicone matrices ("negative mold", specifies the number, shape and length of the needles) and dried. The dried microneedle systems are demoulded from the matrices and packaged.

The oral thin film has a composition as shown in Table 2 below.

Table 2:

1: Polyethylene oxide with a molecular weight of about 100,000.

2: dye The raw materials were dissolved in water, coated onto a liner and then dried in a drying cabinet. A film with a basis weight of 96 g/m ² resulted. Two variants were chosen for the application of the microneedles.

Both variants take advantage of the low melting point at which the polyox in this formulation is in a soft, sticky state at the drying temperature of 70°C.

Version 1:

Immediately after the drying time, the microneedles with the

placed on the back of the still 70 °C warm film. Because of that

If the polyethylene oxide film is still soft, the microneedles will stick. After cooling, the film solidifies and the microneedles are "welded".

Variant 2:

Microneedles are attached to a cold, solid polyethylene oxide film

applied to the back. The film is then heated to 70°C to fix the microneedles. After cooling, they are then welded to the film.

Example 2:

Microneedles were fixed to an oral thin film by means of an adhesive layer. The microneedle system corresponds to that of example 1.

An adhesive layer with the composition shown in Table 3 was used for this purpose.

Table 3: 1: Polyvinylpyrrolidone-vinyl acetate copolymer

The raw materials were dissolved in ethanol, coated onto a siliconized liner and then dried. The resulting adhesive layer had a basis weight of 47 g/m ² .

As an oral thin film, a soluble composition shown in Table 4 below was used.

Table 4:

1 : (Meth)acrylic ethyl acrylate copolymer

2: (Meth)acrylic ethyl acrylate copolymer

The polymers were dissolved in a water/ethanol mixture, then the other raw materials were stirred in and homogenized. The mass was spread out on a siliconized liner and dried. A film with a basis weight of 48 g/m ² resulted

Subsequently, the microneedles and the oral thin film were bonded to each other using the prepared adhesive layer.

Example 3:

An oral thin film with microneedles was fitted with polyvinyl alcohol foam as an application aid. The microneedle system corresponds to that of example 1.

The application aid shows the following recipe.

Table 5: A pre-solution of the polyvinyl alcohol in water was prepared. The other raw materials were then stirred into this preliminary solution and dissolved. The foam used here was then foamed using a foam machine and dried in a pilot plant. The oral thin film was applied to the application aid by means of an adhesive layer (similar to example 2).

A stable bond is obtained. The very thin oral thin film, which tends to wrinkle, could be applied. Especially due to the presence of Proper application is necessary for microneedles, since improper application leads to the breakage of the microneedles.

Claims

32 claims

1. Oral thin film comprising a matrix layer containing at least one polymer, characterized in that a microneedle system is applied to at least one surface of the oral thin film, the microneedle system being applied to the at least one surface of the oral thin film by means of an adhesive layer.

2. Oral thin film according to claim 1, characterized in that the at least one polymer comprises a water-soluble polymer which is preferably selected from the group comprising starch, starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropylethyl cellulose, Sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidones, 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 , carrageenan and/or natural gums.

3. Oral thin film according to any one of the preceding claims, characterized in that the matrix layer and/or the microneedle system contain at least one pharmaceutically active ingredient.

4. Oral thin film according to any one of the preceding claims, characterized in that the at least one pharmaceutically active ingredient is selected from the group comprising the drug classes of analgesics, hormones, hypnotics, sedatives, antiepileptics, wakeful amines, psychoneurotropics, neuromuscle blockers, antispasmodics, Antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, 33

Antidiabetics, antitumor agents, antibiotics, chemotherapeutic agents and/or narcotics.

5. An oral thin film according to any one of the preceding claims characterized in that the oral thin film is in the form of a voided solidified foam.

6. Oral thin film according to any one of the preceding claims, characterized in that the microneedle system comprises microneedles with a length of 10 to 1000 μm, preferably with a length of 100 μm to 600 μm and particularly preferably with a length of 250 μm to 350 μm .

7. Oral thin film according to any one of the preceding claims, characterized in that the microneedle system is a microneedle system based on starch, starch derivatives, dextrans, cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose, polyacrylic acids, polyacrylates , polyvinylpyrrolidones, polyvinyl alcohols, poly(lactide-co-glycoid), hyaluronic acid, polyethylene oxide polymers, polyacrylamides, polyethylene glycols, gelatin, collagen, alginates, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and/or is natural gums.

8. Oral thin film according to any one of the preceding claims, characterized in that the oral thin film and / or the microneedle system further at least one excipient selected from the group comprising dyes, flavorings, sweeteners, plasticizers, taste-masking agents, emulsifiers, enhancers, pH regulators , humectants, preservatives and/or antioxidants.

9. Composite comprising an oral thin film according to any one of claims 1 to 8 and an application aid comprising at least one polymer for the oral thin film, characterized in that the oral thin film and the application aid are firmly connected to one another.

10. Composite according to claim 9, characterized in that the application aid has an area which is at least twice as large, preferably 2 to 10 times as large as the area of the oral thin film.

11. Composite according to any one of the preceding claims 9 or 10, characterized in that the application aid has an area of 1 cm ² to 30 cm ² .

12. Composite according to any one of the preceding claims 9 to 11, characterized in that the application aid comprises at least one water-soluble polymer.

13. A method for producing an oral thin film according to any one of claims 1 to 8, comprising the steps of

- Providing a microneedle system and

- applying an adhesive layer to a surface of the oral thin film, - applying the microneedle system to this adhesive layer and - drying the adhesive layer in order to obtain a firm bond.

14. A method of making a composite comprising an oral thin film and an oral thin film application aid according to any one of claims 9 to 12, comprising the steps of: -Providing an application help,

- providing an oral thin film and

-firmly connecting the application aid to the oral thin film.

15. The method according to claim 14, characterized in that the fixed connection of the oral thin film and the application aid comprises the following steps

- heating the oral thin film and/or the application aid to a temperature above the softening point of the respective at least one polymer,

- applying the oral thin film to a surface of the application aid to obtain a loose bond, and

- Cooling of the loose bond to obtain a solid bond.

16. The method according to claim 14, characterized in that the fixed connection of the application aid and the oral thin film comprises the following steps

-connecting the application aid and the oral thin film via this adhesive layer and

-Drying the adhesive layer to obtain a solid bond.

17. Oral thin film according to any one of claims 1 to 8 or obtainable by the method according to claim 13 for use as a medicament.

18. A composite according to any one of claims 9 to 12 or obtainable by the process according to any one of claims 15 or 16 for use as a medicament.