Oral Microneedle Patch

Abstract

The present invention relates to oral thin films comprising a matrix layer containing at least one polymer, wherein a microneedle system is applied to at least one side of the oral thin film, a method for making such oral thin films, a composite comprising such oral thin films and an application aid for oral thin films comprising at least one polymer, wherein the oral thin film and the application aid are firmly linked to each other, a method for making the oral thin film, a method for making the composite, and the oral thin film and the composite for use as a pharmaceutical.

Description

[Technical field]

[0001] The present invention relates to an oral film, a method for preparing such an oral film, a complex comprising said oral film and an application aid, a method for preparing said complex, and said oral film or said complex for use as a medicament. [Background technology]

[0002] Oral thin films are usually thin films containing active pharmaceutical ingredients, which are placed directly in the oral cavity or applied to the oral mucosa, where they dissolve. Specifically, these oral thin films are polymer-based thin films containing active ingredients, which release the active ingredients directly into the mucosa when applied to the mucosa, especially the oral mucosa. These oral thin films are generally not sticky on the outside. Good blood circulation in the oral mucosa ensures that the active ingredients are rapidly absorbed into the bloodstream. This administration system has the advantage that the active ingredients are absorbed mostly through the mucosa, thus avoiding the "first-pass metabolism" that occurs in conventional administration forms of active ingredients in tablet form, which are usually taken with a liquid, which can be disadvantageous. The active ingredient is dissolved, emulsified, or dispersed in the membrane. Suitable active ingredients can also be swallowed after the oral thin film dissolves in the mouth, and thus absorbed through the digestive tract.

[0003] However, there are many active pharmaceutical ingredients that cannot be applied through the oral mucosa due to their size or other properties such as hydrophobicity, which form an insurmountable barrier for these active pharmaceutical ingredients.

[0004] The present invention was therefore based on the problem of providing an oral thin film which overcomes these disadvantages, by means of which active principles which were previously inaccessible by this administration route can also be applied via the oral mucosa.

[0005] This problem is solved by an oral thin film according to claim 1. Such an oral thin film is characterized in that it comprises a matrix layer containing at least one polymer and that a microneedle system is applied to at least one side of the oral thin film, which microneedle system is applied to at least one side of the oral thin film by means of an adhesive layer.

[0006] The microneedles are able to penetrate the oral mucosa, thus reducing its resistance so that the active pharmaceutical ingredient can penetrate this mucosa more easily.

[0007] Application of oral thin films can be problematic.Due to the shape, size, characteristics and intended application site of oral thin films, and also due to the user's obstacles, difficulties may occur in applying oral thin films to desired sites.Especially for oral thin films with microneedles on one side to increase the active ingredient flux, it is important that these microneedles are not damaged before any application.

[0008] These disadvantages are eliminated by the oral thin film application aid.

[0009] Conventional application aids can ameliorate this problem, but these application aids usually require difficult removal from the oral film and / or have complex structures. There is also a risk that the user may inadvertently swallow the application aid. Summary of the Invention [Problem to be solved by the invention]

[0010] The present application was therefore also based on the problem of providing an application aid for oral thin films which overcomes the above mentioned disadvantages. The application aid should have high haptic stability in order to apply the oral thin film to the desired site. Furthermore, the risk of swallowing the application aid should be minimized in general and the risk of the user destroying or damaging the oral thin film before application should be minimized. [Means for solving the problem]

[0011] This problem is surprisingly solved by a composite according to claim 9, i.e. a composite comprising an oral thin film according to the invention and an application aid for oral thin films, which comprises at least one polymer, characterized in that the oral thin film and the application aid are firmly bonded to each other.

[0012] The advantage of such bonding is that the user does not need to touch the oral thin film itself to apply it. Contact is preferably only via the application aid. Moreover, in a preferred embodiment, the application aid is designed to dissolve in the oral cavity of the user. Due to the strong bond with the application aid, the oral thin film with microneedles on one side is advantageously applied.

[0013] All features of one embodiment may be combined with the features of another embodiment, unless the features of the different embodiments are incompatible.

[0014] The terminology used in the description of this disclosure is intended to describe specific embodiments only and should not be construed as limiting the subject matter. When used in the present specification and claims, unless otherwise clearly indicated by the context, the singular forms "a" and "an" are to be understood to include the plural. This also applies vice versa, i.e., the plural also includes the singular. As used herein, the term "and / or" is also understood to refer to and include all possible combinations of one or more of the associated listed items. Furthermore, it is also to be understood that the terms "include", "including", "comprise", and / or "comprising", when used in the present specification and claims, specify the presence of certain features, steps, elements, and / or components, but do not exclude the presence or addition of one or more other features, steps, elements, components, and / or groups thereof.

[0015] In this specification and claims, the terms "include", "comprise" and / or "comprising" can also mean "consisting of", i.e., excluding the presence or addition of one or more other features, steps, elements, components and / or groups.

[0016] The oral thin film according to the present invention comprises at least one polymer-containing matrix layer, and a microneedle system is applied to at least one side of said oral thin film.

[0017] In a preferred embodiment, the oral thin film according to the present invention consists of a matrix layer and a microneedle system.

[0018] Microneedle systems, also known as microneedle arrays, preferably include systems comprising a plurality of microneedles on a support.

[0019] The support preferably comprises at least one polymer.

[0020] The needle preferably has a length of 5 μm to 1000 μm.

[0021] The density of the needle is cm 2 It is preferable that the number of needles per unit area is 50 to 1000, and particularly 100 to 600.

[0022] The microneedle system is preferably applied to at least one, preferably exactly one, face of the oral membrane.

[0023] The surface to which the microneedle system is applied is preferably the largest surface of the oral membrane.

[0024] In one embodiment, the microneedle system is larger than the oral membrane.

[0025] In one embodiment, the microneedle system is smaller than the oral membrane.

[0026] In one embodiment, the microneedle system and the oral membrane are approximately the same size.

[0027] In a preferred embodiment, the at least one polymer comprises a water-soluble polymer.

[0028] Water-soluble polymers include natural or synthetic polymers that are chemically quite different, 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 may be nonionic, anionic, cationic and / or zwitterionic.

[0029] Water soluble is preferably understood to mean a solubility of more than 100 g / L in water at 25°C.

[0030] Preferably, the at least one water-soluble polymer is selected from the group comprising starch, starch derivatives, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, cellulose derivatives such as ethylcellulose or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and / or natural gum.

[0031] The oral thin film according to the present invention is preferably characterized in that at least one polymer, preferably a water-soluble polymer, is present in the matrix layer in an amount of 10 to 100% (w / w), or 30 to 95% (w / w), preferably 60 to 90% (w / w), particularly preferably 70 to 90% (w / w), based on the total weight of said matrix layer.

[0032] In one embodiment, the oral thin film according to the present invention is further preferably characterized in that the matrix layer contains at least one active pharmaceutical ingredient.

[0033] In one embodiment, the oral thin film according to the present invention is further preferably characterized in that the microneedle system comprises at least one active pharmaceutical ingredient.

[0034] In one embodiment, the oral thin film according to the invention is further characterized in that the matrix layer and / or the microneedle system contain at least one active pharmaceutical ingredient. In this embodiment, the matrix layer and the microneedle system may contain the same active pharmaceutical ingredient or they may each contain a different active pharmaceutical ingredient.

[0035] The amount of the at least one active pharmaceutical ingredient is preferably 1-60% (w / w), preferably about 1-40% (w / w), based on the total weight of the matrix layer.

[0036] The absolute amount of at least one active pharmaceutical ingredient is preferably 1 μg to 100 mg, particularly preferably 1 μg to 10 mg.

[0037] The at least one active pharmaceutical ingredient is in principle not limited.

[0038] Preferably, the at least one active pharmaceutical ingredient is selected from the group comprising the following classes of active ingredients: analgesics, hormones, hypnotics, sedatives, antiepileptics, amphetamines, psychourotropic agents, neuromuscular blocking agents, antispasmodics, antihistamines, antiallergic agents, cardiac inotropes, antiarrhythmics, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antineoplastics, antibiotics, vaccines, chemotherapeutics and / or narcotics.

[0039] 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, granisetron, insulin, insulin nanoparticles, insulin / GLP-1 nanoparticles, ketamine, ketoprofen, ketotifen, caffeine, levocetirizine, lopeparidine, Lamido, loratadine, meclizine, methylphenidate, midazolam, mirodenafil, montelukast, multimeric-001, naloxone, nicotine, nitroglycerin, olanzapine, olopatadine, ondansetron, oxybutynin, pectin, pectin / menthol, pectin / ascorbic acid, pediaSUNAT (artesunate and amodialysis) In some embodiments, the active ingredient in the composition is benzodiazepine, benzodiazepine, benzoyl peroxidase ...

[0040] The active pharmaceutical ingredient may also be a mixture of different active ingredients.

[0041] In one embodiment, the oral thin film, particularly the matrix layer, is in the form of a smooth membrane.

[0042] A smooth film is preferably characterized in that it is not in the form of a foam and does not show any significant irregularities when analyzed optically without aids or amplification. Films are produced, for example, by spreading and drying a polymer-containing solution, a polymer-containing emulsion, a polymer-containing suspension, or a polymer-containing melt.

[0043] In another embodiment, the oral thin film, particularly the matrix layer, is in the form of a solidified foam having cavities.

[0044] The membrane cavities and associated large surface area facilitate the access of water or saliva or other bodily fluids to the interior of the dosage form, thus accelerating dissolution of the dosage form and release of the active ingredient.

[0045] In the case of rapidly absorbed active ingredients, transmucosal absorption is also improved by rapid dissolution.

[0046] On the other hand, since these cavities represent solidified bubbles, it is preferred that the wall thickness of the mentioned cavities is low, so that, for example, these cavities dissolve or collapse quickly.

[0047] A further advantage of this embodiment is that production as a foam results in faster dry times than with comparable non-foamed compositions, despite the relatively high weight per unit area.

[0048] The oral membrane is preferably characterized in that the cavities are isolated from one another, preferably in the form of a bubble, and 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.

[0049] According to another embodiment, it is provided that the cavities are interconnected, preferably by forming a connected channel system through the matrix.

[0050] The aforementioned cavities preferably have a volume fraction of 5-98%, preferably 50-80%, relative to the total volume of the matrix layer, in this way the beneficial effect of accelerating the dissolution of the matrix layer is advantageously influenced.

[0051] Additionally, surface active substances or surfactants may be added to the matrix layer for foam formation or to the resulting foam before or after drying to improve the stability of the foam before or after drying.

[0052] Another parameter influencing 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 using a foam whipping machine, with which the diameter of the bubbles can be adjusted in a wide range almost at will. The diameter of the bubbles or cavities can therefore range from 0.01 to 350 μm. It is particularly preferred that the diameter is in the range from 10 to 200 μm.

[0053] The oral thin film according to the invention, more precisely the matrix layer, is 0.5 cm 2 ~10cm 2 , particularly preferably 1.5 cm 2 ~7.5cm 2 It is preferred that the surface area of ​​the substrate is 100 mm or less.

[0054] The oral thin film, more precisely the matrix layer, according to the present invention has a weight per unit area of ​​10 to 500 g / m 2 , preferably 100 to 400 g / m 2 It is preferable that the present invention is characterized in that

[0055] The weight per unit area of ​​the oral thin film, more precisely the matrix layer, is preferably at least 10 g / m 2 , more preferably at least 20 g / m 2 , or at least 30 g / m 2 , or most preferably at least 50 g / m 2 or 400 g / m 2Less than 350 g / m 2 or less than 300g / m 2 or less, or most preferably 150 g / m 2 The weight per unit area of ​​the oral thin film, or more precisely the 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 It is preferable that:

[0056] The oral thin film or matrix layer preferably has a layer thickness of about 20 μm to about 500 μm, particularly preferably about 50 μm to about 300 μm.

[0057] The microneedle system preferably includes microneedles having a length of 10 to 1000 μm, preferably 100 μm to 600 μm, and particularly preferably 250 μm to 350 μm.

[0058] Furthermore, the microneedle system is preferably based on starch, starch derivatives, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, cellulose derivatives such as ethylcellulose or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, polyvinyl alcohol, poly(lactide-co-glycolide), hyaluronic acid, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and / or natural rubber, this group is not exhaustive.

[0059] Preferably, the microneedles comprise a polymer that is also present in the support.

[0060] The microneedles preferably comprise a polymer that is also present in the oral film, particularly the matrix layer.

[0061] The support for the microneedles preferably comprises a polymer that is also present in the oral film, particularly the matrix layer.

[0062] The microneedles and their supports preferably comprise a polymer that is also present in the oral film, particularly the matrix layer.

[0063] In specific embodiments, the microneedle system may also be made of ceramic, steel, polymer, and / or SiO 2 It can also be made from materials such as

[0064] In a preferred embodiment, the oral thin film and / or microneedle system further comprises at least one additive selected from the group including colorants, flavorants, sweeteners, plasticizers, taste-masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives, and / or antioxidants.

[0065] Each of these additives is preferably contained in the oral thin film or microneedle system in an amount of 0.1 to 30.0% (w / w).

[0066] In one embodiment, the oral film having microneedles is also manufactured by using a negative mold of the microneedles during the manufacture of the oral film, such that the oral film and the microneedles are integral.

[0067] Alternatively, the microneedle system may be manufactured separately and attached to the oral membrane using any suitable attachment means.

[0068] The microneedle system and the oral membrane are joined, for example, by an adhesive layer, preferably a water-soluble adhesive layer, and / or by sealing, preferably heat sealing.

[0069] Sealing includes, but is not limited to, bonding by embossing and / or heat sealing.

[0070] Heat sealing refers to bonding the microneedle system and the oral membrane by applying heat and pressure in a punctiform manner. The punctiform heating softens or melts at least one polymer present in the microneedle system or the oral membrane, which results in a strong bond after recooling. The temperature is preferably increased punctiformly to a temperature above the melting temperature or glass transition temperature of each polymer.

[0071] The usual temperature for heat sealing is about 50°C to 200°C.

[0072] Heat sealing is preferably carried out at a temperature of about 50° C. to 200° C. for about 5 seconds, more preferably about 3 seconds, and most preferably for about 2 seconds or less.

[0073] The microneedle system is applied to at least one side of the oral membrane by means of an adhesive layer, in particular a water-soluble adhesive layer.

[0074] Water solubility is herein to be understood as defined above.

[0075] Water-soluble adhesive layers are particularly suitable as adhesive layers, as described in DE 10 2014 127 452 A1, the entire relevant content of which is hereby incorporated herein.

[0076] Suitable adhesive layers include at least one water-soluble polymer and at least one plasticizer, where the at least one water-soluble polymer in the at least one water-soluble adhesive layer includes shellac, vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer, hydroxypropyl cellulose or hydroxypropyl methylcellulose, and / or polyvinylpyrrolidone, and the at least one plasticizer in the at least one water-soluble adhesive layer includes 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 85:50 to about 15:50.

[0077] Such an adhesive layer containing at least one water-soluble polymer and at least one plasticizer can act as an intermediate water-soluble adhesive layer to firmly bond two further layers that are not themselves tacky to one another, thus making it possible to form a multilayer composite.

[0078] In principle, an oral film is not limited in the number of layers it can contain.

[0079] Thus, embodiments are contemplated in which the oral thin film comprises additional layers, and the above definitions apply analogously to the other layers.

[0080] The present invention further relates to a complex comprising an oral thin film as described above and an application aid for the oral thin film.

[0081] The application aid comprises at least one polymer and is firmly bonded to the oral film.

[0082] It is to be understood that the application aid is bonded to the oral film on the side where the microneedle system is not applied.

[0083] The term "application aid" is understood herein in the broadest possible sense.

[0084] The application aid preferably comprises a flat structure, to the surface of which the oral thin film is firmly adhered, 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.

[0085] The application aid can be of any shape, for example, the application aid can be round, oval, or elliptical in shape.

[0086] However, the application aid can also be triangular or rectangular, with rounded corners if desired. Other polygonal shapes, conceivable with rounded corners if desired, are also possible.

[0087] Mixed forms are also possible, such that the application aid has a shape generally resembling that of a tennis racquet, e.g., having a first circular, oval, or elliptical region and a second region, e.g., a strip, triangle, or square (as well as polygon) attached to the first region, the second region preferably functioning herein as a "handle" and the first region functioning to hold the oral film.

[0088] In this case, "strongly bonded" means that the application aid and the oral membrane are bonded to one another such that the user cannot separate the bond without disrupting the membrane. The bond should also remain intact upon storage for longer periods.

[0089] The complex according to the invention is preferably characterised in that the application aid comprises a first region and a second region.

[0090] The oral thin film is preferably disposed in a first region of the application aid.

[0091] The second area of ​​the application aid is preferably designed to allow the user to access the application aid in a manner that does not allow access to the oral film.

[0092] The oral film is preferably adhered to the first third or first half of the face of the application aid, leaving the last two thirds or last half of the application aid free to act as a "handle" for application of the oral film.

[0093] The complex according to the invention is preferably characterized in that the application aid has a surface area at least 2 times greater than the surface area of ​​the oral thin film, preferably 2 to 10 times or 2 to 4 times greater.

[0094] In a possible embodiment, the application aid is 1 cm 2 ~30cm 2 , preferably 2 cm 2 ~15cm 2 , or 2 cm 2 ~10cm 2 has a surface area of

[0095] In a possible embodiment, the oral membrane is 0.3 cm 2 ~10cm 2 , preferably 0.5 cm 2 ~7cm 2 has a surface area of

[0096] In a possible embodiment, the application aid has a length of 1 cm to 10 cm, preferably 2 cm to 5 cm.

[0097] In a possible embodiment, the application aid has a width of 0.5 cm to 5 cm, preferably 1 cm to 3 cm.

[0098] In a possible embodiment, the oral film has a length of 0.5 cm to 5 cm, preferably 1 cm to 4 cm.

[0099] In a possible embodiment, the oral membrane has a width of 0.5 cm to 4 cm, preferably 1 cm to 4 cm.

[0100] In a possible embodiment, 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.

[0101] In a possible embodiment, 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.

[0102] In a possible embodiment, the application aid is 20 g / m 2 ~800g / m 2 , more specifically 20 g / m 2 ~500g / m 2 It has a weight per unit area of

[0103] In a possible embodiment, the oral thin film is 10 g / m 2 ~600g / m 2 , preferably 10 g / m 2 ~400g / m 2 It has a weight per unit area of

[0104] The application aid may be formulated as a single layer or multiple layers.

[0105] The complex according to the invention is preferably characterized in that the application aid comprises at least one water-soluble polymer.

[0106] Water-soluble polymers include natural or synthetic polymers that are chemically quite different, 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 may be nonionic, anionic, cationic and / or zwitterionic.

[0107] Water soluble is preferably understood to mean a solubility of more than 100 g / L in water at 25°C.

[0108] The at least one water-soluble polymer is preferably selected from the group consisting of starch and starch derivatives, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, cellulose derivatives such as ethylcellulose or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and / or natural gums, with polyvinyl alcohol being particularly preferred.

[0109] The complex according to the invention is preferably characterized in that at least one polymer, preferably a water-soluble polymer, is present in the matrix layer in an amount of 10 to 100% (w / w), or 10 to 95% (w / w), preferably 60 to 90% (w / w), particularly preferably 80 to 90% (w / w), based on the total weight of the application aid.

[0110] The complex according to the invention is preferably characterized in that the application auxiliaries are generally water-soluble, where water-soluble is also preferably understood to mean a solubility of more than 100 g / L in water at 25° C.

[0111] The complex according to the invention is preferably characterized in that the application aid comprises an aroma, a taste masking agent and / or an anaesthetic or local anaesthetic agent.

[0112] As anesthetics or local anesthetics, aminoamides such as lidocaine, aminoesters such as procaine, homocaine, quinisocaine, or cyclonine are preferred herein.

[0113] These anesthetics or local anesthetics are preferably contained in an amount of 0.1 to 10% (w / w) or 0.1 to 5% (w / w) based on the total weight of the application adjuvant.

[0114] The complex according to the invention is preferably characterized in that the application aid further comprises at least one additive selected from the group comprising colorants, sweeteners, plasticizers, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0115] Each of these additives is preferably present in an amount of 0.1 to 40% (w / w), particularly preferably 0.1 to 30% (w / w), more particularly preferably 0.1 to 15% (w / w), and even more preferably 0.1 to 10% (w / w) or 0.1 to 5% (w / w), relative to the total weight of the application aid.

[0116] Specifically, the stability of the application aid is controlled by the plasticizer content.

[0117] Suitable plasticizers include, for example, glycerin.

[0118] The plasticizer is preferably present in an amount of 0.1 to 15% (w / w), most preferably 0.1 to 10% (w / w), or 0.1 to 5% (w / w), especially about 5% (w / w), based on the total weight of the application aid.

[0119] The complex according to the invention is preferably characterized in that the application aid is in the form of a film which is as smooth as possible.

[0120] In another embodiment, the complex according to the invention is characterized in that the application aid is in the form of a solidified foam having cavities.

[0121] The larger cavities and associated surface area of ​​the application aid particularly facilitate the access of water or saliva or other body fluids to the interior of the application aid, thus accelerating dissolution of the application aid.

[0122] On the other hand, since these cavities represent solidified bubbles, it is preferred that the wall thickness of the mentioned cavities is low, so that, for example, these cavities dissolve or collapse quickly.

[0123] A further advantage of this embodiment is that production as a foam results in faster dry times than with comparable non-foamed compositions, despite the relatively high weight per unit area.

[0124] The composite according to the invention is preferably characterized in that the cavities are isolated from one another, preferably in the form of bubbles, and 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.

[0125] According to another embodiment, it is provided that the cavities are interconnected, preferably by forming a connected channel system through the matrix.

[0126] The aforementioned cavities preferably have a volume fraction of 5-98%, preferably 50-80%, relative to the total volume of the application aid, in this way the solution of the application aid is influenced in a favorable manner.

[0127] Additionally, surface active substances or surfactants are added to the application aid for foam formation or to the resulting foam before or after drying to improve the stability of the foam before or after drying.

[0128] 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 produced using a foam whipping machine, with which the diameter of the bubbles can be adjusted in a wide range almost at will. The diameter of the bubbles or cavities can therefore range from 0.01 to 350 μm. It is particularly preferred that the diameter is in the range from 10 to 200 μm.

[0129] The complex according to the invention is preferably characterized in that the application aid and the oral film are joined to one another by an adhesive layer, preferably a water-soluble adhesive layer, and / or by a seal, preferably a heat seal.

[0130] An adhesive layer is understood as a layer which can act as an adhesive, as defined in DIN EN923:2016-03.

[0131] Water-soluble adhesive layers are particularly suitable as adhesive layers, as described in DE 10 2014 127 452 A1, the entire relevant content of which is hereby incorporated herein.

[0132] Suitable adhesive layers include at least one water-soluble polymer and at least one plasticizer, where the at least one water-soluble polymer in the at least one water-soluble adhesive layer includes shellac, vinylpyrrolidone-vinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer, hydroxypropyl cellulose or hydroxypropyl methylcellulose, and / or polyvinylpyrrolidone, and the at least one plasticizer in the at least one water-soluble adhesive layer includes 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 85:50 to about 15:50.

[0133] Such an adhesive layer containing at least one water-soluble polymer and at least one plasticizer can act as an intermediate water-soluble adhesive layer to firmly bond two further layers that are not themselves tacky to one another, thus making it possible to form a multilayer composite.

[0134] Sealing is understood to mean any possible way in which the application aid and the oral membrane are joined to one another, however, this concludingly does not include joining by embossing and / or heat sealing.

[0135] Heat sealing refers to bonding the application aid and the oral thin film by spot-wise heating and pressure. Spot-wise heating melts at least one polymer present in the application aid or the oral thin film, resulting in a strong bond after recooling. The temperature is preferably raised punctiformly to a temperature above the melting temperature or glass transition temperature of each polymer.

[0136] The usual temperature for heat sealing is about 50°C to 200°C.

[0137] The heat sealing is preferably carried out at a temperature of about 50° C. to 200° C. for about 5 seconds, preferably about 3 seconds, and particularly preferably for about 2 seconds or less.

[0138] The complex according to the present invention is further preferably characterized in that the application aid dissolves in the patient's oral cavity within 10 seconds to 5 minutes, preferably within 30 seconds to 3 minutes.

[0139] It is further preferred that the complex according to the invention is characterized in that the application aid and the oral thin film dissolve in the patient's oral cavity within 10 seconds to 5 minutes, preferably within 30 seconds to 2 minutes.

[0140] The present invention also provides a method for producing an oral thin film as described above, comprising the steps of: - providing an oral thin film comprising at least one polymer and at least one active pharmaceutical ingredient; - providing a microneedle system; - A process for firmly bonding the microneedle system and the oral membrane, comprising the steps of: - applying an adhesive layer to a surface of the oral membrane; - applying a microneedle system to this adhesive layer; - drying the adhesive layer to obtain a strong composite. A process including The present invention also relates to a method, comprising:

[0141] All the above embodiments and definitions regarding the oral thin film, the microneedle system, and the adhesive layer apply analogously to the manufacturing method of such oral thin film.

[0142] It does not matter whether a microneedle system or an oral thin film is prepared in the first step.

[0143] If the oral thin film is in the form of a foam, the method also includes the step of effervescently foaming the solution, emulsion, melt, or suspension by introducing a gas or mixture of gases, by generating a chemical gas, or by expanding a dissolved gas.

[0144] In this case, "strongly bonded" preferably means that the microneedle system and the oral membrane are bonded together such that the user cannot separate the bond without disrupting the membrane. The bond should also remain intact upon storage for longer periods.

[0145] In particular, an alternative method for manufacturing such an oral membrane comprises the steps of: - heating the oral film to a temperature above the softening temperature of at least one polymer; - applying a microneedle system to the surface of the heated oral membrane to obtain a loose composite; - cooling the loose composite to obtain a strong composite. It is preferred that the compound contains

[0146] Heating preferably involves heating to a temperature of 50-100° C. for a period of preferably about 0.5-5 minutes.

[0147] The present invention further relates to an oral thin film obtainable by the above process.

[0148] The present invention also provides a method for preparing a complex comprising an oral thin film as described above and an application aid for the oral thin film as described above, comprising: - providing an application aid; - providing an oral thin film; - firmly attaching the application aid to the oral membrane; The present invention also relates to a method, comprising:

[0149] All embodiments defined above for the complex, the oral film and the application aid apply analogously to the method according to the invention.

[0150] It does not matter whether the application aid or the oral film is prepared in the first step.

[0151] The application aid and / or oral film are preferably prepared by a process which includes producing a solution, emulsion, dissolution or suspension containing all the components of the application aid or oral film, respectively, followed by spreading and drying the solution, emulsion, dissolution or suspension.

[0152] Any suitable shape may be cut or punched from these dried solutions, emulsions, melts, or suspensions.

[0153] If the application aid and / or oral film is present in the form of a foam, the method also includes the step of foaming the solution, emulsion, dissolution, or suspension by introducing a gas or mixture of gases, by generating a chemical gas, or by expanding a dissolved gas.

[0154] The method for preparing such a composite includes the following steps to form a strong bond between the application aid and the oral membrane: - heating the oral film and / or the application aid to a temperature above the softening temperature of the at least one respective polymer; - applying an oral thin film to the surface of the application aid to obtain a loose complex; - cooling the loose composite to obtain a strong composite. It is preferred that the compound contains

[0155] As used herein, heating preferably includes heating to a temperature of 50-100° C., preferably for about 0.5-5 minutes.

[0156] An alternative method for preparing such a composite, to form a strong bond between the application aid and the oral membrane, is as follows: - applying an adhesive layer to a surface of the oral film or to a surface of an application aid; - joining the oral membrane and the application aid with said adhesive layer; - drying the adhesive layer to obtain a strong composite. It is preferred that the compound contains

[0157] An adhesive layer is to be understood as defined above.

[0158] Furthermore, the present invention also relates to an oral film as described above or obtainable by the method described above as a medicament.

[0159] Furthermore, the present invention also relates to a conjugate as described above or obtainable by the method described above as a medicament.

[0160] All the embodiments defined above for the complex, the oral film and the application aids apply analogously to the medical uses according to the invention. [Brief description of the drawings]

[0161] [Figure 1] 1 shows a possible design of an oral thin film. [Diagram 2] An oral membrane (7) with a microneedle system (8) is shown. [Diagram 3] 1 shows possible embodiments of an oral thin film and a complex including an application aid for an oral thin film. [Figure 4] Another possible embodiment of the oral thin film and the complex including an application aid for the oral thin film is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0162] Description of the drawings: Figure 1: Figure 1 shows a possible design of an oral membrane. The membrane is an oral membrane (3) onto which microneedles (5) are applied. These microneedles (5) are applied to the oral membrane with an adhesive layer (4) or are glued onto the oral membrane using alternative adhesive means.

[0163] Figure 2: Figure 2 shows an oral membrane (7) with a microneedle system (8), where the oral membrane is larger than the microneedle system.

[0164] Figure 3: 3 shows a possible embodiment of a composite comprising an oral thin film and an application aid for the oral thin film. The composite has a first region of the application aid where the oral thin film is placed, and a second region of the application aid that is designed to allow the user to touch the application aid without touching the oral thin film.

[0165] An adhesive layer (2) is applied to the application aid (1) and an oral film (3) is applied to a first area thereof. Optionally, pieces of application aid (1a) are reapplied to the adhesive layer in a second area such that the user does not have to touch the adhesive layer.

[0166] The oral film optionally comprises microneedles (5). These microneedles (5) are applied to the oral film with a separate adhesive layer (4) or are attached to the oral film using alternative adhesive means.

[0167] Figure 4: 4 shows another possible embodiment of a composite comprising an oral thin film and an application aid for the oral thin film, where the composite has a first region of the application aid where the oral thin film is placed, and a second region of the application aid designed to allow the user to touch the application aid such that the oral thin film is not touched. The user is represented by a stylized hand (9).

[0168] The oral film (7) is applied to an area of ​​the application aid (6) that is distinct from the area that the user will touch with his hand (9). The oral film (7) may be equipped with microneedles (8). EXAMPLES

[0169] The invention is explained in more detail below with reference to non-limiting examples. EXAMPLES

[0170] Oral thin films were prepared using a microneedle system.

[0171] The microneedle system had a composition according to Table 1 below.

[0172] [Table 1]

[0173] All components were dissolved in process solvent water. The mass was then dispensed onto a silicone matrix (the "negative", which defines the number, shape, and length of the needles) and dried. The dried microneedle system was demolded from the matrix and packaged.

[0174] The oral film had the composition according to Table 2 below.

[0175] [Table 2]

[0176] The raw material was dissolved in water, coated onto a liner, and then dried in a drying oven. 2 A membrane having a weight per unit area of

[0177] Two variants were selected for microneedle application.

[0178] Both variants used a low melting point such that the Polyox in this formulation remained soft and tacky at the 70°C dry temperature.

[0179] Variant 1: Immediately after the drying time had elapsed, the microneedles were placed on their backs with the film still at 70° C. Since the polyethylene oxide film was still soft, the microneedles would adhere to it. After cooling, the film solidified and the microneedles were "welded" together.

[0180] Variant 2: The microneedles were applied with a cold, hard polyethylene oxide membrane on their backside. This membrane was then heated to 70° C. to fix the microneedles in place. After cooling, the microneedles were then welded to the membrane. EXAMPLES

[0181] The microneedles were adhered onto the oral membrane by an adhesive layer. The microneedle system corresponds to the microneedles of Example 1.

[0182] For this purpose, an adhesive layer having the composition shown in Table 3 was used.

[0183] [Table 3]

[0184] The raw materials were dissolved in ethanol, coated onto a siliconized liner, and then dried. The resulting adhesive layer had a weight of 47 g / m2 The weight per unit area was 1.01 kg / m.

[0185] For the oral thin film, a dissolving composition according to Table 4 below was used.

[0186] [Table 4]

[0187] The polymer was dissolved in a water / ethanol mixture, then the other ingredients were stirred and homogenized. The mass was spread onto a siliconized liner and dried. This resulted in a mass of 48 g / m 2 A membrane having a weight per unit area of

[0188] The prepared adhesive layer was then used to bond the microneedles and the oral membrane together. EXAMPLES

[0189] An oral membrane with microneedles was prepared with polyvinyl alcohol foam as an application aid. The microneedle system corresponds to that of Example 1.

[0190] The application aid had the following formula:

[0191] [Table 5]

[0192] A pre-solution of polyvinyl alcohol was prepared in water. The other ingredients were then stirred into this pre-solution and dissolved. The foam used here was then foamed using a foaming machine and dried in a pilot plant.

[0193] The oral film was applied to the application aid using an adhesive layer (similar to Example 2).

[0194] A stable complex was obtained. A very thin oral film could be applied that was prone to wrinkling. The presence of the microneedles made proper application especially necessary, as improper application would result in the microneedles breaking.

Claims

1. An oral thin film comprising a matrix layer containing at least one polymer, wherein a microneedle system is applied to at least one side of the oral thin film, and wherein the microneedle system is applied to at least one side of the oral thin film by an adhesive layer.

2. 2. The oral thin film of claim 1, wherein the at least one polymer comprises a water-soluble polymer preferably selected from the group comprising starch, starch derivatives, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, cellulose derivatives such as ethylcellulose or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and / or natural gums.

3. The oral thin film of claim 1 , wherein the matrix layer and / or the microneedle system contains at least one active pharmaceutical ingredient.

4. 10. The oral thin film of claim 1, wherein the at least one active pharmaceutical ingredient is selected from the group comprising the following classes of active ingredients: analgesics, hormones, hypnotics, sedatives, antiepileptics, amphetamines, psychotropic drugs, neuromuscular blocking drugs, antispasmodics, antihistamines, antiallergic drugs, cardiac inotropes, antiarrhythmic drugs, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antineoplastics, antibiotics, chemotherapeutics, and / or narcotics.

5. 10. The oral thin film of claim 1, which is in the form of a solidified foam having cavities.

6. 2. The oral thin film of claim 1, wherein the microneedle system comprises microneedles having a length of 10 to 1000 μm, preferably having a length of 100 μm to 600 μm, and particularly preferably having a length of 250 μm to 350 μm.

7. 2. The oral thin film of claim 1, wherein the microneedle system is a microneedle system based on starch, starch derivatives, dextran, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, cellulose derivatives such as ethylcellulose or propylcellulose, polyacrylic acid, polyacrylates, polyvinylpyrrolidone, polyvinyl alcohol, poly(lactide-co-glycolide), hyaluronic acid, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, and / or natural gum.

8. 10. The oral thin film of claim 1, wherein the oral thin film and / or the microneedle system further comprises at least one additive selected from the group comprising colorants, flavorants, sweeteners, plasticizers, taste masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives, and / or antioxidants.

9. A composite comprising an oral thin film according to any one of claims 1 to 8 and an application aid for an oral thin film, the composite comprising at least one polymer, wherein the oral thin film and the application aid are firmly bonded to each other.

10. The complex of claim 9, wherein the application aid has a surface area at least 2 times greater, preferably 2 to 10 times greater, than the surface area of ​​the oral thin film.

11. Application aid: 1 cm ２ ~30cm ２ 10. The composite of claim 9 having a surface area of

12. 10. The complex of claim 9, wherein 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 an oral thin film comprising at least one polymer and at least one active pharmaceutical ingredient; - providing a microneedle system; - A process for firmly bonding the microneedle system and the oral membrane, comprising the steps of: - applying an adhesive layer to the surface of the oral membrane; - applying a microneedle system to this adhesive layer; drying the adhesive layer to obtain a strong composite. A process including A method comprising:

14. A method for producing a complex comprising the oral thin film and an oral thin film application aid according to claim 9, comprising: - providing an application aid; - providing an oral thin film; - firmly attaching the application aid to the oral membrane; A method comprising:

15. The tight bonding of the oral membrane and application aids is as follows: - heating the oral film and / or the application aid to a temperature above the softening temperature of the at least one respective polymer; - applying an oral film onto the surface of the application aid to obtain a loose complex; - cooling the loose composite to obtain a strong composite.

15. The method of claim 14, comprising:

16. The application aid and the oral membrane are firmly bonded to each other by the following: - applying an adhesive layer to the surface of the oral film or to the surface of the application aid; - joining the application aid and the oral membrane by means of said adhesive layer; drying the adhesive layer to obtain a strong composite.

15. The method of claim 14, comprising:

17. An oral thin film according to any one of claims 1 to 8 for use as a medicament.

18. The conjugate of claim 9 for use as a medicament.

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