Oral Thin Film

Abstract

Disclosed are oral thin films comprising a polymer matrix, the oral thin film comprising an active pharmaceutical ingredient, a first polymer and a second polymer, the first polymer being different from the second polymer, the active pharmaceutical ingredient and the second polymer being a combination of a cationic active pharmaceutical ingredient and an anionic polymer, or a combination of an anionic active pharmaceutical ingredient and a cationic polymer, methods for the production thereof, and medical uses of the oral thin film.

Description

[Technical field]

[0001] The present invention relates to oral films comprising at least one active pharmaceutical agent, methods for preparing the same, and the use of such oral films as medicaments, particularly for use as emergency contraceptives. [Background technology]

[0002] Oral thin films are films that contain at least one pharma- ceutically active agent and are placed directly in the oral cavity or on the oral mucosa, where they dissolve or disintegrate, releasing the active agent, which is then absorbed transmucosally or in the gastrointestinal tract after swallowing. The active agent can be dissolved, emulsified, or dispersed in the film.

[0003] As will be explained in more detail further below, the oral thin film according to the present invention preferably comprises ulipristal acetate as the pharma- ceutical active agent, and is preferably used as an emergency contraceptive.

[0004] When administering some pharma- ceutical active ingredients via oral thin films, it may be desirable to have the pharma- ceutical active ingredient released quickly, which is usually achieved by a fast disintegration time of the oral thin film.

[0005] However, in other cases, when administering some pharma- ceutical active ingredients via oral thin films, it may be desirable to release the pharma- ceutical active ingredient slowly and / or to delay the release of the pharma- ceutical active ingredient in order to prevent or at least minimize transmucosal absorption in favor of gastrointestinal absorption.

[0006] This is usually achieved by increasing the thickness and / or areal weight of the oral film so that it disintegrates more slowly, resulting in a slower release of the pharma- ceutical active ingredient.

[0007] However, in certain applications, a thick oral film is undesirable, nor is it desirable to increase or delay the disintegration time of the oral film after oral application.

[0008] Thus, there is a need for an oral thin film by which an active pharmaceutical ingredient can be administered, which has a reasonably rapid disintegration time, preferably less than 30 seconds, but where the release of the active pharmaceutical ingredient is decoupled from the disintegration time and can be delayed independently of the disintegration time.

[0009] In addition, it should be possible to produce such oral films as easily and economically as possible. Summary of the Invention [Problem to be solved by the invention]

[0010] Furthermore, it was a particular objective to provide an oral thin film, in particular an oral thin film comprising ulipristal acetate as the active pharmaceutical ingredient, which is preferably non-mucoadhesive and bioequivalent to the commercially available EllaOne® tablet. The film should therefore exhibit disintegration and release properties that prevent or at least minimize transmucosal absorption of ulipristal acetate and allow gastrointestinal absorption.

[0011] It was therefore a specific objective to develop an oral thin film that has a delayed in vitro drug release and therefore a higher comparability than previously known ulipristal acetate oral thin films to the in vitro release of the commercially available ulipristal acetate tablet EllaOne®. At the same time, the oral thin film should still exhibit rapid disintegration, so that it can be swallowed quickly and no discomfort occurs in the mouth (caused for example by a bitter taste of the active ingredient or a foreign body sensation due to membrane residues) and transmucosal absorption is prevented. [Means for solving the problem]

[0012] Usually, the release of active ingredient in oral thin film can be delayed by reducing disintegration time.This can be achieved by increasing thickness or areal weight, or by selecting a polymer with lower solubility in water or saliva.This makes oral thin film disintegrate slower, resulting in slower release of active ingredient.However, this approach is not suitable, because oral thin film should not have too large disintegration time.

[0013] Based on the principle of the long-known commercial product "Theraflu Thin Strips Long acting cough", the possibility of binding ulipristal acetate to ionic components of the membrane matrix by ion-pair bonds was considered, such that the membrane would disintegrate quickly, but the active ingredient would be released from the ion-pair bonds only after a longer period of time and would therefore be absorbed with a delayed effect.

[0014] In the case of Theraflu Thin Strips Long acting cough, an ion pair bond is created between the cationic group of the basic active ingredient dextromethorphan HBr and the anionic carboxylic acid group of the ion exchange resin (e.g. Amberlite IRP64). The formation of the ion pair bond reduces the bitter taste of dextromethorphan because the cationic tertiary amine that causes the bitter taste is not present free in the mouth. A side effect is that the ion pair bond is not completely broken by the acidic stomach pH until swallowed into the stomach, resulting in delayed drug release.

[0015] In the first test, the anionic ion exchange resin Amberlite IRP64 was tested for ion pairing with the cationic tertiary amine of ulipristal acetate. The high required dosage, preferably 30 mg of ulipristal acetate, which must only be present in suspension in the membrane, did not allow the use of powdered Amberlite IRP64 as the counterion. Amberlite IRP64 was in powder form and insoluble in water, the solvent used. Typically, the active ingredient and the corresponding ion exchange resin are used in a ratio of about 1:1, so that in addition to the 30 mg of undissolved ulipristal acetate already present, an additional 30 mg of Amberlite IRP64 was present undissolved in each dose. This resulted in a total of 60 mg of powdered solids to be incorporated into the OTF with a target total weight of 90 mg. The high solids content did not allow the production of membranes flexible enough for commercial applications.

[0016] It was therefore another object of the present invention to overcome the above mentioned drawbacks of known commercial products.

[0017] The above mentioned objects surprisingly include a polymer matrix comprising an active pharmaceutical ingredient, a first polymer and a second polymer, the first polymer being different from the second polymer, the active pharmaceutical ingredient and the second polymer being a combination of a cationic active pharmaceutical ingredient and an anionic polymer, or Combination of anionic active pharmaceutical ingredient and cationic polymer This problem has been solved by the oral thin film according to claim 1,

[0018] Preferred embodiments are set forth in the dependent claims.

[0019] The advantage of using such a combination of polymer and active pharmaceutical ingredient is that a larger amount of the active ingredient can be bound or incorporated without the membrane losing flexibility, as compared to water-insoluble ion exchange resins.

[0020] The use of these combinations also allows the areal weight to be kept low, which has a positive effect on disintegration time, so that disintegration times of less than 30 seconds can be achieved.

[0021] The use of ion exchange resins instead of polymers is only possible by significantly increasing the amount of membrane-forming polymer in the formulation, which requires an increase in areal weight if the membrane size is to remain the same, leading to longer disintegration times.

[0022] Although this finding is based on the development of oral thin films with ulipristal acetate, the overall concept of combining a cationic active pharmaceutical ingredient and an anionic polymer, or an anionic active pharmaceutical ingredient and a cationic polymer, is applicable to all potential active pharmaceutical ingredients.

[0023] Depending on the main components of the film composition, the use of anionic or cationic polymers for sustained release is not limited to water-soluble polymers, but can also be extended to water-insoluble polymers.

[0024] The following specification provides some embodiments of the present invention and is not intended to limit the scope, applicability, or form of the invention or embodiments. Various changes can be made in the function and arrangement of elements without departing from the scope of the invention as set forth herein.

[0025] The terminology used in the description of the present disclosure herein is only for describing specific embodiments and is not intended to limit the subject matter. As used in this specification and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term "and / or" as used herein refers to and includes any and all possible combinations of one or more of the associated listed items. It should further be understood that the terms "includes", "including", "comprises" and / or "comprising" as used herein can also be understood as "consisting of".

[0026] Terms such as first, second, etc. may be used herein to describe various elements, but it should be understood that these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first object or step may be referred to as a second object or step, and similarly, a second object or step may be referred to as a first object or step. Although a first object or step and a second object or step are both objects or steps, respectively, they should not be considered to be the same object or step.

[0027] The present invention provides oral thin films comprising a polymer matrix, the thin films comprising an active pharmaceutical ingredient, a first polymer and a second polymer, the first polymer being different from the second polymer, and the active pharmaceutical ingredient and the second polymer being a combination of a cationic active pharmaceutical ingredient and an anionic polymer, or a combination of an anionic active pharmaceutical ingredient and a cationic polymer.

[0028] The polymer matrix can also be understood as a matrix layer or a polymer layer.

[0029] In the context of the present invention, a cationic polymer refers to a polymer that has a positive charge, in particular a net charge, at a pH of 6-9 and a temperature of 20°C.

[0030] The cationic polymer preferably has a pK a It has a value of 8.5 to 10.5.

[0031] In the context of the present invention, anionic polymers refer to polymers which have a negative charge, in particular a net charge, at a pH of 3.5 to 8 and a temperature of 20°C.

[0032] The anionic polymer preferably has a pK a It has a value of 3.5 to 6.5.

[0033] In the context of the present invention, a cationic active pharmaceutical ingredient refers to an active pharmaceutical ingredient that has a positive charge, especially a net charge, at a pH of 6-8 and a temperature of 20°C.

[0034] The cationic active pharmaceutical ingredient preferably has a pK a It has a value of 8.5 to 10.5.

[0035] In the context of the present invention, anionic active pharmaceutical ingredients refer to active pharmaceutical ingredients which have a negative charge, in particular a net charge, at a pH of 6-8 and at a temperature of 20°C.

[0036] The anionic active pharmaceutical ingredient preferably has a pK a It has a value of 3.5 to 6.5.

[0037] The first and second polymers are different.

[0038] The first polymer is preferably present to form the scaffold of the polymer matrix (film-forming polymer) and the second polymer is preferably present to form an ion pair with the active pharmaceutical ingredient, and thus act as a release retardant.

[0039] Therefore, it is preferred that the amount of the first polymer in the polymer matrix is ​​greater than the amount of the second polymer in the polymer matrix.

[0040] In a preferred embodiment, the first polymer is a water-soluble polymer.

[0041] By water solubility is preferably intended a solubility in water at 25° C. of more than 10 g / L, preferably more than 50 g / L, in particular 100 g / L.

[0042] In a preferred embodiment, the first polymer is uncharged, has film-forming ability, and preferably sufficient solubility in water or an aqueous medium.

[0043] Water-soluble polymers, which are also meant to encompass water-swellable polymers herein, include chemically very diverse natural or synthetic polymers, the common feature of which is their solubility or ability to swell in water or aqueous media. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for solubility in water and are not crosslinked. The hydrophilic groups may be non-ionic.

[0044] By water solubility is preferably intended a solubility in water at 25° C. of more than 10 g / L, preferably more than 50 g / L, in particular 100 g / L.

[0045] Preferably, the first polymer is a water-soluble or water-swellable polymer selected from the group consisting of starch and starch derivatives, dextran, cellulose derivatives, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose or propyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, pullulan, tragacanth, arabinogalactan, galactomannan, agar, agarose, carrageenan and / or natural gums.

[0046] Polyvinyl alcohol is preferred herein.

[0047] Further, a mixture of two or more polyvinyl alcohols is preferred.

[0048] Typical commercial polyvinyl alcohols are available in the form of white to yellow powders or granules and generally have a degree of hydrolysis of 98-99 or 87-89 mol %, i.e. also a residual content of acetyl groups. Polyvinyl alcohols are usually characterized by the manufacturer by the specification of the degree of polymerization of the starting polymer, or the average molecular weight, the degree of hydrolysis, the saponification number or the solution viscosity.

[0049] The oral thin film according to the present invention is preferably characterized in that the at least one polyvinyl alcohol comprises a polyvinyl alcohol having an average molecular weight of about 25,000 to about 250,000 g / mol.

[0050] The oral thin film according to the present invention is preferably characterized in that the at least one polyvinyl alcohol comprises a polyvinyl alcohol having an average molecular weight of approximately 25,000 to approximately 35,000 g / mol and / or a polyvinyl alcohol having an average molecular weight of approximately 200,000 to 210,000 g / mol.

[0051] According to the invention, polyvinyl alcohols having an average molecular weight of about 31,000 (4-88) to about 205,000 (40-88) g / mol are particularly suitable.

[0052] According to the invention, polyvinyl alcohols having an average molecular weight of about 31,000 (4-88) to about 205,000 (40-88) g / mol are particularly suitable.

[0053] Also preferred are mixtures of the above-mentioned 4-88 and 40-88, preferably in weight ratios of 20:1-5:1 or 15:1-7:1.

[0054] The active pharmaceutical ingredient is not limited to, but may be selected from the group consisting of analgesics, hormones, hypnotics, sedatives, antiepileptics, psychostimulants, psychotropic agents, neuromuscular blocking agents, antispasmodics, antihistamines, antiallergics, cardiac inotropes, antiarrhythmics, diuretics, antihypertensives, antihypotensives, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, contraceptives, antidiabetic agents, antitumor active ingredients, antibiotics, chemotherapeutic agents and / or narcotics.

[0055] In a preferred embodiment, the active pharmaceutical ingredient comprises an active pharmaceutical ingredient that is preferably somewhat water insoluble, having a solubility in water of less than 100 g / L, preferably less than 50 g / L, especially less than 10 g / L (all at 20° C.).

[0056] In a preferred embodiment, the active pharmaceutical ingredient comprises a somewhat lipophilic active pharmaceutical ingredient, preferably having a logP greater than 1, preferably greater than 2, particularly greater than 3, especially greater than 4, but less than 10, or less than 8, preferably less than 7, especially less than 6.

[0057] In a preferred embodiment, the active pharmaceutical ingredient comprises a somewhat lipophilic active pharmaceutical ingredient, preferably with a logP of 3-5, preferably 3.6-4.7.

[0058] In one preferred embodiment, the active pharmaceutical ingredient comprises ulipristal acetate.

[0059] Ulipristal acetate is 7α-acetoxy-11α-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione), which has the following chemical formula: [ka]

[0060] Ulipristal acetate is a well-known emergency contraceptive ("morning-after pill"). It is administered as a tablet ("EllaOne®") containing 30 mg micronized ulipristal acetate and further ingredients lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate. EllaOne® was approved in the European Union in 2009.

[0061] Tablets such as EllaOne® are typically taken with water to facilitate swallowing. Thus, in areas where clean drinking water is not readily available, taking tablets can be difficult, especially for certain patient groups who have difficulty swallowing medicines, i.e., suffer from dysphagia. Administration of oral thin films that dissolve quickly when applied in the oral cavity does not require additional water and is therefore advantageous.

[0062] At pH 6-8, ulipristal acetate exists in a protonated, positively charged form.

[0063] In a preferred embodiment, the second polymer is a water insoluble polymer, meaning that it has a solubility in water of less than 10 g / L at 25°C.

[0064] Preferably, the second polymer is an anionic polymer comprising a polymer backbone and side chains, the side chains preferably comprising anionic groups, such as sulfone, carboxylate and / or phosphate, preferably at pH 6-8.

[0065] In particular, the anionic polymers include polyacrylic acid, carboxylate-modified cellulose, pectin and / or alginate.

[0066] Carboxylate-modified celluloses are particularly preferred, including celluloses bearing carboxylic acid groups, preferably as alkali metal salts.

[0067] In particular, an alkali salt of a carboxyalkylcellulose, such as carboxymethylcellulose or carboxyethylcellulose, is preferred.

[0068] Particularly preferred are the sodium salts of carboxymethylcellulose or carboxyethylcellulose.

[0069] Sodium carboxymethylcellulose is particularly preferred.

[0070] A suitable sodium carboxymethylcellulose is known under the name "Blanose 7LP."

[0071] Another preferred anionic polymer comprises polyacrylic acid.

[0072] Suitable polyacrylic acids are known under the names "Carbopol 934" or "Carbopol 971". Carbopol 934 has a molecular weight of about 3 Mio g / mol, Carbopol 971 has a molecular weight of about 1.25 Mio g / mol.

[0073] In a preferred embodiment, the combination of cationic active pharmaceutical ingredient and anionic polymer comprises sodium carboxymethylcellulose and ulipristal acetate.

[0074] In another preferred embodiment, the combination of cationic active pharmaceutical ingredient and anionic polymer comprises polyacrylic acid and ulipristal acetate.

[0075] In a preferred embodiment, the combination of cationic active pharmaceutical ingredient and anionic polymer comprises sodium carboxymethylcellulose and ulipristal acetate, and the first polymer comprises polyvinyl alcohol or a mixture of two polyvinyl alcohols.

[0076] In another preferred embodiment, the combination of cationic active pharmaceutical ingredient and anionic polymer comprises polyacrylic acid and ulipristal acetate, and the first polymer comprises polyvinyl alcohol or a mixture of two polyvinyl alcohols.

[0077] Preferably, the second polymer as a cationic polymer comprises a polymer backbone and side chains, which preferably contain cationic groups, such as amines, preferably at pH 6-8.

[0078] Further suitable cationic polymers include polyethyleneimine, chitosan and / or poly(L-lysine).

[0079] In a preferred embodiment, the first polymer is included in the polymer matrix in an amount of 10 to 60% by weight, preferably 20 to 40% by weight, based on the total weight of the polymer matrix.

[0080] In another preferred embodiment, the first polymer comprises a mixture of two polymers that are contained in total in the polymer matrix in an amount of 10-60% by weight, preferably 20-40% by weight, based on the total weight of the polymer matrix.

[0081] In a preferred embodiment, the first polymer comprises polyvinyl alcohol contained in the polymer matrix in an amount of 10 to 60% by weight, preferably 20 to 40% by weight, based on the total weight of the polymer matrix.

[0082] In another preferred embodiment, the first polymer comprises a mixture of two polyvinyl alcohols which are present in total in the polymer matrix in an amount of 10 to 60% by weight, preferably 20 to 40% by weight, in particular 24 to 32% by weight, based on the total weight of the polymer matrix.

[0083] In a preferred embodiment, the second polymer is contained in the polymer matrix in an amount of 1 to 30% by weight, preferably 2 to 15% by weight, in particular 4 to 8% by weight, based on the total weight of the polymer matrix.

[0084] In another preferred embodiment, the second polymer comprises polyacrylic acid and is present in the polymer matrix in an amount of 1 to 30% by weight, preferably 2 to 15% by weight, in particular 4 to 8% by weight, based on the total weight of the polymer matrix.

[0085] In another preferred embodiment, the second polymer comprises sodium carboxymethylcellulose and is present in the polymer matrix in an amount of 1 to 30% by weight, preferably 2 to 15% by weight, in particular 4 to 8% by weight, based on the total weight of the polymer matrix.

[0086] In a preferred embodiment, the weight ratio of the first polymer to the second polymer is from 15:1 to 2:1, preferably from 12:1 to 2:1, in particular from 10:1 to 2:1, more particularly from 8:1 to 2:1, or from about 7:1 to 2:1, or from about 6:1 to 2:1, or from about 5:1 to 2:1, or from about 4:1 to 2:1, or from about 3:1 to 2:1.

[0087] In particular, the preferred weight ratio of the first polymer to the second polymer is from 7:1 to 2:1 or from 7:1 to 2.5:1.

[0088] Another preferred weight ratio of the first polymer to the second polymer is from 4.5:1 to 3.5:1 or from 7.5:1 to 6.5:1.

[0089] In a preferred embodiment, the active pharmaceutical ingredient is contained in the polymer matrix in an amount of 0.1-50% by weight, preferably 0.5-50% by weight, preferably 1-50% by weight, preferably 5-50% by weight, preferably 10-50% by weight, preferably 20-50% by weight, preferably 35-45% by weight, in particular 37-40% by weight or 40-44% by weight or 37-44% by weight, based on the total weight of the polymer matrix.

[0090] In a preferred embodiment, the active pharmaceutical ingredient comprises ulipristal acetate, which is present in the polymer matrix in an amount of 20-50% by weight, preferably 35-45% by weight, in particular 37-40% by weight or 40-44% by weight or 37-44% by weight, based on the total weight of the polymer matrix.

[0091] In a preferred embodiment, the active pharmaceutical ingredient comprises ulipristal acetate, which is present in the oral film in a total amount of 0.1 to 100 mg, preferably 1 to 100 mg, preferably 10 to 100 mg, preferably 10 to 50 mg, particularly 20 to 40 mg, in particular about 30 mg.

[0092] The oral thin film according to the invention is preferably also characterized in that the polymer matrix further comprises at least one auxiliary substance selected from the group comprising colorants, flavorants, sweeteners, softeners, taste masking agents, emulsifiers, enhancers, pH adjusters, humectants, preservatives and / or antioxidants.

[0093] Each of these auxiliary substances is preferably contained in an amount of 0.1 to 15% by weight, preferably 0.1 to 10% by weight or 0.1 to 5% by weight, relative to the total weight of the polymer matrix in each case.

[0094] The oral thin film according to the present invention is not subject to any restrictions regarding its structure.

[0095] Thus, the oral thin film according to the invention may be provided in the form of a single layer oral thin film and therefore may consist only of the polymer matrix as defined above.

[0096] In another embodiment, the oral thin film according to the present invention may be provided in the form of a multi-layer oral thin film and thus may comprise further layers in addition to the polymer matrix defined above.

[0097] The layers may be laminated directly onto one another or may be joined with an adhesive layer disposed therebetween.

[0098] An adhesive layer is understood to mean a layer capable of acting as an adhesive as defined in DIN EN923:2016-03. A non-adhesive layer is therefore not capable of acting as an adhesive as defined above.

[0099] In particular, the water-soluble adhesive layers described in DE 10 2014 127 452 A1 are suitable as adhesive layers, the content of which document in this regard is hereby expressly incorporated in its entirety into the present disclosure.

[0100] For example, a buffer layer to determine the pH value, or a slowly dissolving or insoluble layer to protect the oral membrane from premature erosion can be provided as an additional layer.

[0101] Alternatively, further layers may be provided which contain other active pharmaceutical ingredients or flavourings or taste-masking agents.

[0102] In one embodiment, the oral thin film according to the invention is characterized in that the polymer matrix is ​​in the form of a smooth film, meaning that the polymer matrix is ​​not provided in the form of, for example, a foam.

[0103] The smooth membrane is preferably characterized in that it has a volume fraction of 0-5% based on the total volume of the polymer matrix, bubbles or voids. The voids here are preferably filled with air or gas, preferably with an inert gas, particularly preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases. The diameter of the bubbles or voids generally lies in the range of 0.01-350 μm. The diameter of the bubbles or voids particularly preferably lies in the range of 10-200 μm.

[0104] In another embodiment, the oral thin film according to the invention is characterized in that the polymer matrix is ​​in the form of a foamed (solidified) film having voids.

[0105] In particular, the infiltration of water or saliva or other body fluids into the interior of the dosage form is driven by the increase in the voids and the associated membrane surface area, thus accelerating the disintegration of the dosage form.

[0106] On the one hand, the wall thickness of the voids is preferably small, since these are, for example, solidified gas bubbles and therefore these voids dissolve or break down quickly.

[0107] A further advantage of this embodiment is that the formulation as a foam can provide faster drying than a comparable non-foamed composition, despite the relatively high areal density.

[0108] The oral thin film according to the invention is preferably characterized in that the cavities are separated from one another and are preferably formed in the form of bubbles, the cavities being filled with air or a gas, preferably an inert gas, particularly preferably nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

[0109] According to another embodiment, the voids are interconnected, preferably by forming a coherent channel system that permeates the matrix.

[0110] The voids preferably have a volume fraction of 5-98%, preferably 50-80%, relative to the total volume of the polymer matrix, in this way the beneficial effect of accelerating the dissolution of the polymer matrix is ​​advantageously influenced.

[0111] Additionally, surface active materials or surfactants can be added to the polymer matrix for foam formation or to the resulting foam before or after drying to improve the stability of the foam before and after drying.

[0112] A further variable that influences the properties of the dosage form according to the invention is the diameter of the voids or bubbles. The bubbles or bubbles are preferably produced using a foaming machine, which allows the bubble diameter to be set almost arbitrarily within a wide range. The diameter of the bubbles or bubbles can therefore be in the range of 0.01 to 350 μm. The diameter is preferably in the range of 10 to 200 μm.

[0113] Oral thin films according to the present invention preferably have an area of ​​0.5 cm 2 ~10cm 2 , particularly preferably 2 cm 2 ~8cm 2 , or 6 cm 2 ~8cm 2 has.

[0114] The area weight of the polymer matrix or of the further layers optionally provided is in each case 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 50 g / m 2 , or 400 g / m 2 Less than 350 g / m 2 or less than 300g / m 2 Less than or most preferably 250 g / m 2 The area weight is preferably 10 to 400 g / m 2 , more preferably 20 to 350 g / m 2 , or 30 to 300 g / m 2 and most preferably 50 to 250 g / m 2 It is.

[0115] In another embodiment, the area weight is preferably 90 to 130 g / m 2 , more preferably 95 to 125 g / m 2 It is.

[0116] The provided polymer matrices or layers, in particular each of the polymer matrices, preferably have a layer thickness in each case preferably between 10 μm and 500 μm, more preferably between 20 μm and 300 μm.

[0117] If the various layers, and in particular the polymer matrix, are present in the form of a solidified foam, it is therefore preferred that each of the layers provided as a foam has a layer thickness in each case preferably between 10 μm and 3000 μm, more preferably between 90 μm and 2000 μm.

[0118] Oral thin films according to the present invention preferably have an (in vitro) disintegration time of less than 30 seconds, preferably less than 27 seconds and especially 25 seconds or less, the (in vitro) disintegration time being determined as described in the Examples section.

[0119] In another embodiment, the oral thin films according to the present invention preferably have an (in vitro) disintegration time of less than 10 seconds, preferably less than 7 seconds and in particular 6 seconds or less, 5 seconds or less, or 3 seconds or less, the (in vitro) disintegration time being determined as described in the Examples section.

[0120] Oral films according to the present invention can be produced by conventional methods.

[0121] The above definitions relating to oral thin films apply equally to the method according to the present invention.

[0122] The method for producing an oral thin film according to the present invention comprises the steps: a) a combination of a cationic active pharmaceutical ingredient and an anionic polymer, comprising an active pharmaceutical ingredient, a first polymer and a second polymer, the first polymer being different from the second polymer, the active pharmaceutical ingredient and the second polymer being in water, in an organic solvent and / or in a mixture thereof; or Combination of anionic active pharmaceutical ingredient and cationic polymer producing a solution, suspension and / or dispersion, b) applying or coating the solution, suspension and / or dispersion obtained in step a) onto a support, coating liner, or mold to spread the solution, suspension and / or dispersion; and c) Evaporating the solvent to obtain an oral thin film Includes.

[0123] The solvent used comprises or consists of water or a mixture of water and one or more organic solvents, the use of water being preferred. Examples of suitable organic solvents are alcohols, in particular ethanol. The weight ratio of water to the organic solvent, preferably ethanol, when used, may be, for example, in the range of 95 / 5 to 5 / 95, preferably in the range of 95 / 5 to 80 / 20.

[0124] In step a), the components are mixed with each other to obtain a solution, a suspension and / or a dispersion. Some components may be soluble in the selected solvent, while others are not, so that the mixture obtained in step a) may be simultaneously a solution, a suspension and / or a dispersion.

[0125] The components may be combined in any order.

[0126] When preparing effervescent oral films, the suspension is generally foamed with a gas. The foaming is preferably carried out before the injection step b). Examples of gases suitable for foaming are air, N2, argon or CO2.

[0127] After evaporation of the solvent, a solid oral film is achieved.

[0128] Evaporation of the solvent is typically achieved by drying the spread solution, suspension and / or dispersion after step b) at a temperature up to 130° C. for about 5 minutes to 1 hour.

[0129] Drying conditions for solvent evaporation may be, for example, in the range of 40 to 130° C., more preferably 50 to 80° C., and most preferably 50 to 75° C. Drying can also be performed by applying a temperature gradient.

[0130] After solvent evaporation, the residual solvent content in the resulting oral film is preferably in the range of 0.2-10% by weight, preferably 0.8-6% by weight, based on the total weight of the oral film. The residual solvents present may be water, or water and one or more organic solvents, such as water and ethanol.

[0131] The resulting membrane can be cut and / or punched into pieces of desired dimensions.

[0132] The present invention further relates to an oral thin film obtainable by the method described above.

[0133] The above definitions relating to oral films apply equally to oral films obtained by the methods described above.

[0134] The present invention further relates to the oral thin film described above for use as a medicament.

[0135] The present invention further relates to the oral thin film as described above for use as a contraceptive, in particular for use as an emergency contraceptive, i.e. in the prevention of pregnancy after sexual intercourse, in particular after unprotected sexual intercourse. The oral film is administered into the oral cavity. No addition of drinking water is required. The active agent ulipristal acetate is swallowed mostly in solid form into the gastrointestinal tract so that bioequivalence to the approved ulipristal acetate tablets ("EllaOne®") is achieved.

[0136] The above definitions relating to oral films apply equally to the medical uses of oral films described above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0137] The present invention will now be more particularly described with reference to the following examples, which are given for the purpose of illustrating the present invention and are not intended to limit the present invention. EXAMPLES

[0138] Oral thin films of the composition shown in Table 1 were prepared according to the following protocol:

[0139] Examples A1 to A3 Ulipristal acetate, Carbopol, and sodium chloride were weighed out separately.

[0140] The total amount of water required was then added. The mixture was stirred for approximately 2 hours to allow the Carbopol to dissolve and form an ion pair with the ulipristal acetate. All remaining excipients were then added in any order. The mass was stirred for an additional 2 hours.

[0141] The mass was then coated onto the polyethylene coated side of a paper intermediate release liner. Coating was performed using a coating knife with a defined coating gap to obtain the required final areal weight.

[0142] The coated mass was dried at a maximum temperature of 60° C. for 30 minutes.

[0143] Examples B1 to B2 Ulipristal acetate and NaCMC were weighed in.

[0144] The total amount of water required was then added. The mixture was stirred for approximately 2 hours to allow the NaCMC to dissolve and form an ion pair with the ulipristal acetate. All remaining excipients were then added in any order. The mass was stirred for an additional 2 hours.

[0145] The mass was then coated onto the polyethylene coated side of a paper intermediate release liner. Coating was performed using a coating knife with a defined coating gap to obtain the required final areal weight.

[0146] The coated mass was dried at a maximum temperature of 60° C. for 30 minutes.

[0147] The dried film was die-cut into pieces with an area of ​​7.04 cm2 each containing 30 mg of ulipristal acetate. 2 obtained.

[0148] [Table 1]

[0149] In vitro release study: In vitro release studies of the previously described examples were carried out using a fiber optic dissolution tester G00668. Detection was carried out by UV / Vis. Wavelength: 310nm (path length 10mm) Test medium: 900ml of 0.1M HCL, simulating the pH of an empty stomach Mixing: 50 rpm Release: 1 device, USP sinker (12 turns) Release time: 15 minutes Test Interval: 12x5 seconds (4 scan rates per test) 4x every 15 seconds (scan rate 4 per test) 13 x 60 seconds (4 scan rates per test) Temperature: 37℃ (±0,5℃) n:3 (number of tests per formulation)

[0150] The results of the in vitro release experiments are given in FIG. 1 and FIG.

[0151] The experiments show that the release of ulipristal acetate can be delayed to a greater extent with increasing carbopol content, especially compared to a reference example without modified drug release.

[0152] The higher the carbopol content, the closer the profile is to that of EllaOne.

[0153] Higher concentrations of carbopol could potentially be incorporated into the OTF to achieve even greater delay in drug release, if necessary, but this was not tested since the solubility of the OTF decreased rapidly early on from 10% carbopol, which would lead to a longer residence time in the mouth, which could lead to an unpleasant sensation in the mouth.

[0154] Furthermore, the experiments show that a delay in drug release could be achieved by adding 7.5% NaCMC (Blanose7LP).

[0155] Higher NaCMC concentrations could potentially be incorporated to achieve even greater delay in drug release, however higher NaCMC concentrations would again lead to slower disintegration, which is undesirable.

[0156] The experiments further show that the retardation of drug release is most effective when the pH of the NaCMC formulation is not modified (Example B2).

[0157] The principle of ion pair bonding in the formulation is based on the fact that the carboxylic acids of the polymer protonate the basic groups (tertiary amines) of the active ingredient, thus forming ionic bonds.

[0158] In formulations A1-A3, the current theory is that the formulations already had sufficient amount of acidic groups due to the presence of carbopol, which resulted in protonation of the active ingredient, which led to ion pair binding.

[0159] However, formulation B1 used NaCMC. The polymer exists as a salt. Thus, some of the carboxylic acid groups exist as deprotonated carboxylate ions. According to the current theory, thus, the acidic groups / proton donors to protonate ulipristal acetate and allow ion-pairing were lost in the system. For this reason, formulation B1 was adjusted to pH 4.5 during preparation to allow ion-pairing between CMC and the drug.

[0160] However, the experiments showed that formulation B1 could only result in a negligible reduction in drug release.

[0161] In contrast, formulation B2 showed delayed drug release compared to formulation B1. In this formulation, NaCMC (Blanose7LP) was mixed with ulipristal acetate in the formulation without further pH adjustment. The measured pH of the final mass was about 7.

[0162] A possible explanation for this observation is that in the case of NaCMC, and in our particular case Blanose7LP, only a portion of the carboxylic acid groups are "salted" with sodium, while the majority of the carboxylic acids are still free. Thus, despite its description as a sodium salt, Blanose7LP has a sufficient amount of acidic groups to form ion-pair bonds with the active ingredient. Hence, further acidification would be counterproductive, as too many carboxylic acid groups would be reprotonated and therefore no longer available for ion-pair bonds.

[0163] In vitro disintegration experiment: Disintegration was measured for the reference formulation and for representative formulations A2 and B2.

[0164] The tests were carried out with a Pharma Test PTZ Auto 2 EZ test device using an ODF basket. The test medium was 800 ml of demineralized water at a temperature of 37±2° C.

[0165] The preparation was sized 7.04 cm 2 The formulation was tested in a rectangular shape of 1. One side of the formulation was clamped to the top of the ODF basket and a metal clamp was attached to the other side of the formulation as a weight.

[0166] The membrane was then placed in the conditioned water bath of the test device and the measurement was initiated. Disintegration time is defined in this test as the time required for the formulation to lose its integrity to such an extent that the membrane shreds and the underside to which the metal clamp is attached sinks to the bottom of the test device, closing the electrical circuit and signaling that the test is complete.

[0167] The following disintegration times were determined for the three formulations: The test was performed with n=3. Reference formulation: mean value 7s (min 7s, max 8s). Formulation A2: mean value 25s (minimum 25s, maximum 25s). Formulation B2: mean value 5s (min 3s, max 6s). [Brief description of the drawings]

[0168] [Figure 1] 1 is a graph showing the results of an in vitro release experiment. [Diagram 2] 1 is a graph showing the results of an in vitro release experiment.

Claims

1. an oral thin film comprising a polymer matrix, the active pharmaceutical ingredient, a first polymer, and a second polymer, the first polymer being different from the second polymer, and the active pharmaceutical ingredient and the second polymer being a combination of a cationic active pharmaceutical ingredient and an anionic polymer; or an oral thin film that is a combination of an anionic active pharmaceutical ingredient and a cationic polymer.

2. 10. The oral thin film of claim 1, wherein the first polymer is a water-soluble or water-swellable polymer.

3. 2. The oral thin film of claim 1, wherein the first polymer is a water-soluble or water-swellable polymer selected from the group consisting of starch and starch derivatives, dextran, cellulose derivatives, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamide, polyethylene glycol, gelatin, collagen, pullulan, tragacanth, arabinogalactan, galactomannan, agar, agarose, carrageenan, and / or natural gum.

4. 2. The oral thin film of claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of analgesics, hormones, hypnotics, sedatives, antiepileptics, psychostimulants, psychotropic agents, neuromuscular blocking agents, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, antihypertensives, antihypotensives, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, contraceptives, antidiabetic agents, antitumor active ingredients, antibiotics, chemotherapeutic agents and / or narcotics.

5. 10. The oral thin film of claim 1, wherein the active pharmaceutical ingredient comprises ulipristal acetate.

6. 10. The oral thin film of claim 1, wherein the anionic polymer comprises a polymer backbone and pendant anionic groups, such as sulfone, carboxylate, and / or phosphate.

7. The anionic polymer may be polyacrylic acid and / or carboxylate-modified cellulose. The oral thin film of claim 1 comprising

8. 10. The oral thin film of claim 1, wherein the cationic polymer comprises a polymer backbone and pendant cationic groups, such as amines.

9. 2. The oral thin film of claim 1, wherein the first polymer is included in the polymer matrix in an amount of 10 to 60% by weight, preferably 20 to 40% by weight, based on the total weight of the polymer matrix.

10. 2. The oral thin film of claim 1, wherein the second polymer is included in the polymer matrix in an amount of 1 to 30% by weight, preferably 2 to 15% by weight, based on the total weight of the polymer matrix.

11. 10. The oral thin film of claim 1, wherein the weight ratio of the first polymer to the second polymer is from 15:1 to 2:

1.

12. 10. The oral thin film of claim 1, wherein the active pharmaceutical ingredient is contained in the polymer matrix in an amount of 20 to 50% by weight, preferably 35 to 45% by weight, based on the total weight of the polymer matrix.

13. 10. The oral thin film of claim 1 having a disintegration time of less than 30 seconds.

14. A method for producing an oral thin film according to any one of claims 1 to 13, comprising the steps of: a) a combination of a cationic active pharmaceutical ingredient and an anionic polymer, comprising an active pharmaceutical ingredient, a first polymer, and a second polymer, wherein the first polymer is different from the second polymer, and the active pharmaceutical ingredient and the second polymer are in water, an organic solvent, and / or a mixture thereof; or Combination of anionic active pharmaceutical ingredient and cationic polymer preparing a solution, suspension and / or dispersion, b) applying or coating the solution, suspension and / or dispersion obtained in step a) onto a support, a coating liner, or a mold to spread the suspension; and c) Evaporating the solvent to obtain an oral film A method comprising:

15. An oral thin film according to any one of claims 1 to 13 for use as a medicament, in particular for use as an emergency contraceptive.

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