Ulipristal acetate OTF

Abstract

The present invention relates to an oral film formulation comprising a polymer matrix and ulipristal acetate as an active agent, wherein the ulipristal acetate is dispersed in the polymer matrix, and the polymer matrix is ​​a matrix of a water-soluble polymer selected from poly(ethylene oxide), poly(vinyl alcohol), or hydroxypropyl methylcellulose. The oral film formulation is suitable as an emergency contraceptive and can be administered to the oral cavity without water. It disintegrates rapidly in the oral cavity, and the active agent, ulipristal acetate, is swallowed in a largely undissolved form and absorbed in the gastrointestinal tract.

Description

[Technical Field]

[0001] This invention relates to an oral film formulation containing ulipristal acetate as an active agent. [Background technology]

[0002] Oral film formulations (OTFs) are thin, flexible films based on a polymer matrix, loaded with active substances for drug delivery. Oral film formulations are taken orally and dissolve immediately in the mouth or applied to the mucous membrane. They are placed on or under the tongue or buccally, where they then dissolve or disintegrate.

[0003] Patent Document 1 discloses the active drug ulipristal acetate. Ulipristal acetate is a well-known emergency contraceptive ("morning-after pill"). It is administered as a tablet ("EllaOne®") containing 30 mg of microparticle ulipristal acetate, as well as lactose monohydrate, povidone, croscarmellose sodium, and magnesium stearate as further ingredients. EllaOne® was approved in the European Union in 2009.

[0004] Tablets like EllaOne® are typically taken with water to facilitate swallowing. Taking tablets in places without immediate access to clean drinking water can therefore be difficult, especially for certain patient groups who have difficulty swallowing medications, i.e., those suffering from dysphagia. The administration of oral film formulations that dissolve rapidly in the mouth is advantageous because they do not require additional water.

[0005] To achieve high patient compliance for the administration of intraoral film formulations, a polymer matrix is ​​needed that integrates the active substance (e.g., ulipristal acetate), creates a pleasant sensation in the oral cavity during administration (a pleasant "mouthfeel"), and rapidly dissolves and / or disintegrates without the addition of drinking water.

[0006] Patent Document 2 relates to a comicronized product containing an active ingredient selected from a selective progesterone receptor modulator or its metabolite, such as ulipristal acetate, and an N-vinyl-2-pyrrolidone-based polymer, as well as a pharmaceutical composition comprising the comicronized product and excipients. Examples of dosage forms for the described pharmaceutical composition include, among others, orally dispersible films. A method for producing the comicronized product comprises the steps of mixing the active ingredient with a polymer and comicronizing the resulting mixture. According to Patent Document 2, the comicronization method significantly improves the in vitro solubility profile of ulipristal acetate, which should correlate with enhanced in vivo bioavailability. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] EP 422100 B1 [Patent Document 2] US 20150258118 A1 [Overview of the project] [Problems that the invention aims to solve]

[0008] The object of the present invention was to provide an oral film formulation that can be administered orally without the addition of drinking water and has the pharmaceutically active ingredient ulipristal acetate, which is bioequivalent to the approved ulipristal acetate tablet ("EllaOne®"), and that has minimal transmucosal uptake and release of ulipristal acetate in the gastrointestinal tract, similar to the already approved EllaOne tablet. In other words, the goal is an oral film formulation in which the active drug ulipristal acetate is swallowed in an insoluble form and absorbed into the gastrointestinal tract by rapidly disintegrating in the oral cavity. [Means for solving the problem]

[0009] An intraoral film formulation as defined in claim 1 can achieve this objective. Accordingly, the present invention relates to an intraoral film formulation comprising a polymer matrix and ulipristal acetate as an active agent, wherein the ulipristal acetate is dispersed in the polymer matrix, and the polymer matrix is ​​a matrix of a water-soluble polymer selected from poly(ethylene oxide), poly(vinyl alcohol), or hydroxypropyl methylcellulose.

[0010] Water-soluble polymers selected from poly(ethylene oxide), poly(vinyl alcohol), and hydroxypropyl methylcellulose have been shown to form solid API-matrix combinations (APIs = pharmaceutically active ingredients) that are sufficiently stable for storage and administration when combined with ulipristal acetate. After application in the oral cavity (or in in vitro tests using the addition of water, buffer, or artificial saliva), the oral film formulations of the present invention disintegrate very rapidly, releasing the active ingredient ulipristal acetate.

[0011] The manufactured formulations are characterized by the fact that they rapidly disintegrate into readily swallowable components such as dissolved polymers and released ulipristal acetate.

[0012] Rapid decomposition and a short residual time in the oral cavity minimize the absorption of the active agent by the mucous membrane. The active agent, ulipristal acetate, is swallowed mostly in solid form, preferably crystalline form, and absorbed into the gastrointestinal tract. Therefore, bioequivalence with ulipristal acetate tablets EllaOne® can be achieved. This can be achieved by using the water-soluble polymer described above, which also generally exhibits hygroscopic properties. Therefore, the moisture in the oral cavity is sufficient for dissolution.

[0013] For rapidly decomposing OTFs, meaning rapid dissolution or disintegration in the oral cavity and rapid swallowing, the selected polymers have good and rapid solubility in water, as well as generally hygroscopic properties, and therefore absorb enough water from the oral cavity to disintegrate. This means that drinking water is not required for convenient administration, which is an advantage over tablets. The oral film formulations of the present invention are also particularly advantageous for patients who do not like to take tablets or have difficulty swallowing them, i.e., patients suffering from dysphagia.

[0014] As indicated, intraoral film formulations are commonly known and abbreviated as OTF. Intraoral film formulations that dissolve easily in the oral cavity are also commonly referred to as intraoral dispersible films. [Modes for carrying out the invention]

[0015] The OTF of the present invention is, for example, 0.3 cm 2 20cm 2 Preferably 1 cm 2 10cm 2 The OTF has a size within the range of [specify size range]. The thickness of the OTF may be, for example, in the range of 10 μm to 1000 μm, preferably 40 μm to 400 μm. The OTF of the present invention can take the form of a single-layer film or a multilayer film, with a single-layer film being preferred.

[0016] The OTF of the present invention may be a non-foaming film or a non-porous film. Alternatively, the OTF may include a matrix that exists in the form of solidified foam having spaces or cavities filled with gas, a gas mixture, a liquid, or a liquid mixture. Such OTFs are commonly referred to as "foam-OTFs".

[0017] Ulipristal acetate has the following chemical formula: 17α-acetoxy-11α-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione: [ka]

[0018] The OTF of the present invention contains a polymer matrix and ulipristal acetate as an active agent. The active agent ulipristal acetate is dispersed in the polymer matrix. In the polymer matrix, ulipristal acetate exists as particles in a solid form, particularly in a crystalline form. The particles are firmly adhered to the polymer matrix. Optical evaluation indicates that the solid or crystalline ulipristal acetate is embedded in the matrix in such a way that a homogeneous OTF is obtained (there were no visible "API pieces").

[0019] In a preferred embodiment, the ulipristal acetate is micronized ulipristal acetate.

[0020] The particle size of the micronized ulipristal acetate can range, for example, from 0.2 μm to 100.0 μm, preferably from 0.5 μm to 40.0 μm. The particle size refers to the volume-weighted particle size d90 and can be measured, for example, by laser diffraction analysis, dynamic light scattering, or sieve analysis. The volume-weighted particle size d90 refers to the volume-weighted particle size where 90% of the distribution has a smaller particle size and 10 percent has a larger particle size, as is known to those skilled in the art.

[0021] The amount of ulipristal acetate is preferably from 10% to 60% by weight, more preferably from 20% to 43% by weight, based on the total weight of the oral film formulation.

[0022] When the water-soluble polymer is selected from poly(ethylene oxide) or poly(vinyl alcohol), the amount of ulipristal acetate is preferably 10% to 60% by weight, more preferably 20% to 43% by weight, and even more preferably 25% to 35% by weight, based on the total weight of the intraoral film formulation. When the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of ulipristal acetate is preferably 20% to 60% by weight, more preferably 20% to 43% by weight, or 35% to 43% by weight, based on the total weight of the intraoral film formulation.

[0023] The polymer matrix in which ulipristal acetate is dispersed is a matrix of a water-soluble polymer selected from poly(ethylene oxide), poly(vinyl alcohol), or hydroxypropyl methylcellulose. These polymers are film-forming polymers.

[0024] Furthermore, these polymers are generally hygroscopic.

[0025] In this specification, a water-soluble polymer refers to a polymer having a water solubility of at least 10 g / L, preferably at least 50 g / L, at a temperature of 25°C.

[0026] The water-soluble polymer is preferably selected from poly(ethylene oxide), poly(vinyl alcohol), or hydroxypropyl methylcellulose. One, two, or more types of poly(ethylene oxide), one, two, or more types of poly(vinyl alcohol), or one, two, or more types of hydroxypropyl methylcellulose may be used.

[0027] The amount of water-soluble polymer is preferably 20% to 90% by weight, more preferably 40% to 70% by weight, based on the total weight of the oral film formulation.

[0028] When the water-soluble polymer is selected from poly(ethylene oxide) and / or poly(vinyl alcohol), the amount of the water-soluble polymer is preferably 25% to 90% by weight, more preferably 35% to 70% by weight, based on the total weight of the intraoral film formulation. When the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of the water-soluble polymer is preferably 30% to 70% by weight, more preferably 40% to 60% by weight, based on the total weight of the intraoral film formulation.

[0029] The poly(ethylene oxide) (PEO) used as the water-soluble polymer preferably has a molecular weight in the range of 50,000 to 200,000 daltons, and more preferably 75,000 to 150,000 daltons. Particularly preferred poly(ethylene oxide) is poly(ethylene oxide) WSR N-10 (PEO WSR N-10), which is commercially available from Dow Chemical Company as Polyox® WSR N-10 or Polyox® WSR N-10 NF, respectively, and yields a molecular weight of approximately 100,000 daltons.

[0030] The poly(vinyl alcohol) (PVA) used as the water-soluble polymer preferably has a molecular weight in the range of 20,000 to 40,000 daltons, preferably 25,000 to 35,000 daltons, and / or a degree of hydrolysis of 84 mol-% to 92 mol-%, preferably 86 mol-% to 90 mol-%. Particularly preferred is poly(vinyl alcohol) 4-88 (PVA 4-88), which is commercially available from Merck KGaA, for example as Mowiol® 4-88, and yields a molecular weight of about 31,000 daltons and a degree of hydrolysis of about 86.7 to 88.7 mol%.

[0031] Hydroxypropyl methylcellulose (HPMC), used as a water-soluble polymer, preferably has a labeled viscosity in the range of 1 mPas to 100 mPas, more preferably 2 mPas to 75 mPas. The labeled viscosity is based on the 2012 (USP = US Pharmacopoeia) USP Research. <911> This refers to the viscosity as measured according to Method 1. Hydroxypropyl methylcellulose (HPMC) is preferably substituted type 2910 according to USP: degree of substitution: methoxy 28-30%, hydroxypropoxy 7-12%.

[0032] Particularly preferred hydroxypropyl methylcelluloses are hydroxypropyl methylcellulose 603 (HPMC 603) (labeled viscosity of 3 mPas and substitution type 2910) and hydroxypropyl methylcellulose 60SH50 (HPMC 60SH50) (labeled viscosity of 50 mPas and substitution type 2910), which are commercially available from Shin-Etsu Chemical Co., Ltd., for example, as Pharmacoat® 603 or Pharmacoat® 603W and Metronos® 60SH-50, respectively.

[0033] In a preferred embodiment, the mixture of two hydroxypropyl methylcelluloses is used as a mixture of water-soluble polymers, preferably HPMC 603 and HPMC 60SH50, for example, in a weight ratio of HPMC 603 to HPMC 60SH50 of 3 / 1 to 1 / 1, preferably 2 / 1 to 1.5 / 1.

[0034] In a preferred embodiment, the oral cavity thin layer further comprises one or more plasticizers, which are also suitable for reducing the melting temperature and glass transition temperature. Examples of suitable plasticizers include triacetin, triethyl citrate, acetyl tributyl citrate, water, ethanol, polyalcohols, such as glycerin, diethylene glycol, polyethylene glycol, propylene glycol, or glycerin monoester with a fatty acid, with glycerin being preferred.

[0035] If present, the total amount of plasticizer, preferably glycerin, is typically in the range of 0.5% to 20% by weight, preferably 3% to 15% by weight, based on the total weight of the intraoral film formulation. When the water-soluble polymer is selected from poly(ethylene oxide) and / or poly(vinyl alcohol), the total amount of plasticizer, preferably glycerin, if present, is preferably 0.5% to 15% by weight, more preferably 3% to 11% by weight, based on the total weight of the intraoral film formulation. When the water-soluble polymer is selected from hydroxypropyl methylcellulose, the total amount of plasticizer, preferably glycerin, if present, is preferably 3% to 15% by weight, more preferably 4% to 13% by weight, based on the total weight of the intraoral film formulation.

[0036] The oral film may further contain one or more additional excipients common in the art. Examples of suitable excipients include flavoring agents, sweeteners, flavoring agents, lubricants, pigments, colorants, stabilizers, fillers, salivary stimulants, emulsifiers, surfactants, enhancers, pH adjusters, buffers, release regulators, softeners, humectants, mold release agents, adhesives, anti-adhesion agents, and antioxidants. Preferably, one or more sweeteners are used in the oral film formulation. The total amount of optional additional excipients, such as sweeteners, may be 15% by weight or less, preferably 5% by weight or less, based on the total weight of the oral film formulation.

[0037] Examples of antioxidants include sodium metabisulfite, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid, and tocopherol.

[0038] The advantage of the oral film formulation of the present invention is its storage stability. The main degradation product of ulipristal acetate is N-demethylulipristal acetate (DMUA), which has the following formula. [ka]

[0039] In a preferred embodiment, the oral film formulation is characterized in that, after storing the oral film formulation for 6 months at a temperature of 40°C and a relative humidity of 75%, the amount of the degradation product N-demethylulipristal acetate (DMUA) is less than 1% by weight, based on the initial amount of ulipristal acetate in the oral film formulation before storage.

[0040] The present invention also relates to an intraoral film formulation comprising a polymer matrix and ulipristal acetate as an active agent, wherein the ulipristal acetate is dispersed in the polymer matrix, and after storing the intraoral film formulation at a temperature of 40°C and 75% relative humidity for 6 months, the amount of the degradation product N-demethylulipristal acetate (DMUA) is less than 1% by weight based on the initial amount of ulipristal acetate in the intraoral film formulation before storage.

[0041] The present invention involves the following steps: a) A step of obtaining a suspension in which the water-soluble polymer is dissolved in the solvent and the ulipristal acetate is suspended in the solvent by mixing a solvent containing or consisting of water or a mixture of water and one or more organic solvents, and solid ulipristal acetate, preferably micronized ulipristal acetate. b) A step of diffusing the obtained suspension by casting or coating it onto a support, a coating liner, or into a mold, and c) Evaporation of the solvent The present invention also relates to a method for manufacturing and preparing oral thin film intraoral film formulations as described above, including the above.

[0042] The water-soluble polymer is typically selected from poly(ethylene oxide), poly(vinyl alcohol), or hydroxypropyl methylcellulose.

[0043] The solvent used includes or consists of water or a mixture of water and one or more organic solvents, with the use of water being preferred. Examples of suitable organic solvents are alcohols, particularly ethanol. If used, the weight ratio of water to organic solvent, preferably ethanol, may be, for example, in the range of 95 / 5 to 5 / 95, preferably in the range of 95 / 5 to 80 / 20.

[0044] In step a), the water-soluble polymer, solvent, and solid ulipristal acetate components are mixed together to obtain a suspension. The order in which the components are combined is at the discretion of the user. For example, the water-soluble polymer may be dissolved in the solvent first, followed by the addition of the solid ulipristal acetate, or alternatively, the solid ulipristal acetate may be provided first, followed by the addition of the solvent and polymer.

[0045] One or more plasticizers, preferably glycerin, are preferably incorporated into the suspension. This addition can be carried out at any time prior to step b). Optionally, one or more additional excipients, such as sweeteners, may be added in any order.

[0046] In the production of foamed OTF (foamed film), the suspension is generally foamed with gas. Foaming is generally carried out before the pouring step b).

[0047] Examples of suitable gases for foaming include air, N2, argon, or CO2.

[0048] After evaporation of the solvent, a solid API-polymer matrix combination is realized, with ulipristal acetate particulate matter dispersed in the polymer matrix. Firm adhesion of the ulipristal acetate particulate matter to the matrix is ​​achieved. The resulting film can be cut and / or drawn into pieces of the desired size.

[0049] The drying conditions for solvent evaporation can be, for example, in the range of 40°C to 100°C, more preferably 50°C to 80°C, and most preferably 50°C to 75°C. Drying can also be carried out by applying a temperature gradient.

[0050] After solvent evaporation, the residual solvent content in the obtained oral film formulation is preferably in the range of 0.2% to 10% by weight, preferably 0.8% to 6% by weight, based on the total weight of the oral film formulation. The residual solvent contained can be water or water and one or more organic solvents, such as water and ethanol.

[0051] The present invention also relates to an oral film formulation according to the present invention as described above for use as an emergency contraceptive, i.e., for use in preventing pregnancy after sexual intercourse, particularly after unprotected sexual intercourse. The oral film is to be administered orally. The addition of drinking water is not necessary. The active agent ulipristal acetate is mostly taken up in the gastrointestinal tract in solid form, achieving biological equivalence to the approved ulipristal acetate tablets ("EllaOne®").

[0052] The present invention will be described more specifically with reference to the following examples, which are shown for purposes of illustration of the invention and are not intended to be limiting thereof.

Examples

[0053] In all examples, ulipristal acetate having the following particle size distribution as measured by laser diffraction was used: d 10 = 1.48 μm ± 11.20%; d 50 = 3.64 μm ± 8.71%; d 90 = 6.73 μm ± 10.40%; d 95 = 7.86 μm ± 11.08%; d 99 = 10.52 μm ± 16.30%.

[0054] OTF laminates were prepared by standard laboratory methods (stirrer, glass container, coating tool, drying oven). The formulation was prepared as a suspension formulation by mixing the API, matrix polymer and excipient in a process solvent for a suitable time, then coating the prepared mass onto a suitable liner, and subsequently drying in a drying oven. This process yielded laminate pieces, which were then cut to a suitable size (approximately 7 cm). 2 The solution was extracted into OTF (Oral-to-Fluid) water. PVA 4-88 and Polyox WSR N10 were used as pre-solutions (PVA 4-88: 35% in water, Polyox WSR N10: 21% in water). For foam production, the suspension obtained in step b) was foamed using air or nitrogen gas with a whisk or turbine agitator. [Examples]

[0055] PEO-based OTF Oral film formulations having the following formulations (calculated on a dry weight basis) were manufactured as suspension formulations using water as the process solvent (30.4% solids). Alternatively, ethanol / water 10 / 90 is suitable as the process solvent (33% solids): [Table 1]

[0056] PEO WSR N-10 (Polyox® WSR N10) was found to be a suitable matrix polymer for ulipristal acetate OTF formulations. A 30% ulipristal acetate content was found to result in tactilely and optically good OTF films. [Examples]

[0057] PVA-based OTF foam An intraoral film formulation having the following formulation (calculated as a dry composition) was manufactured as a suspension formulation using water as the process solvent (40% solids content), and air was used to create foam: [Table 2]

[0058] PVA 4-88 was found to be a suitable polymer for formulating ulipristal acetate OTF as foam. An API loaded with 30% ulipristal acetate was found to be suitable. The PVA formulation as OTF foam using 30% ulipristal acetate loading exhibited good optical and tactile properties.

[0059] Tests using higher loadings of 40% ulipristal acetate resulted in fracture-resistant but slightly brittle OTF. Formulations using 30% API as described above yielded better OTF.

[0060] Furthermore, formulations using a 23.7% API load and nitrogen gas as the foaming gas were found to be suitable, resulting in tear-resistant films:

[0061] The formulation uses water as the process solvent (40% solids content) along with PVA 4-88 as the matrix polymer and a 23.7% API load, with nitrogen used for foaming: [Table 3] [Examples]

[0062] PVA-based OTF (non-foamed) An intraoral film formulation having the following formulation (calculated as a dry composition) was manufactured as a suspension formulation using water as the process solvent (40% solids): [Table 4]

[0063] PVA 4-88 was found to be a suitable polymer for formulating ulipristal acetate OTF. An API loaded with 30% ulipristal acetate was found to be suitable. The PVA formulation as a film with a 30% ulipristal acetate loading had good optical and tactile properties.

[0064] Tests using a higher load of 40% ulipristal acetate resulted in fracture-resistant but slightly brittle OTF. Formulations using 30% API yielded better OTF. [Examples]

[0065] HPMC-based OTF An intraoral film formulation having the following formulation (calculated as a dry composition) was prepared as a suspension formulation using water as the process solvent (solids content 31.9%). Alternatively, ethanol / water 20 / 80 is suitable as the process solvent (solids content 32%): [Table 5]

[0066] HPMC was found to be a suitable polymer for formulating ulipristal acetate OTF. A 40% API load was found to yield a stable and tactilely good film. To improve tactile properties and tear resistance, the glycerin content was set to 10%. A process solvent mixture of 20% ethanol and 80% water (32% solids) was found to be most suitable for production.

[0067] Tests using loadings of 30% and 40% ulipristal acetate resulted in acceptable films, but formulations using 26.63% API showed improved OTF:

[0068] An intraoral film formulation having the following formulation (calculated as a dry composition) was manufactured as a suspension formulation using water as the process solvent (32% solids): [Table 6]

[0069] Comparative Example - Kollicoat® IR-based formulation Kollicoat® IR from BASF, a water-soluble polyvinyl alcohol / polyethylene glycol copolymer, was tested for the production of ulipristal acetate OTF. Different ulipristal acetate loadings, including 50%, 30%, and 20% ulipristal acetate in the formulations, were investigated. However, these formulations were brittle and lacked sufficient fracture resistance. As a result, Kollicoat® IR was not found to be a suitable polymer for formulating ulipristal acetate OTF. [Examples]

[0070] Penetration survey The penetration of OTF prepared according to Examples 1, 2, 3, and 4 was measured by in vitro experiments using porcine mucosa (esophageal mucosa) in accordance with OECD guidelines (adopted April 13, 2004). Using dermatographs, a 400 pm thick mucosa with intact barrier function against all transmucosal treatment systems was prepared. 0.524 cm 2 A die-cut with the specified area was removed from the OTF and applied to the mucosa, and the mucosa with the OTF was immersed on top of artificial saliva (the bottom side was in contact with the receptor medium, and the top side was 0.985 cm). 2 (The area is divided into sections corresponding to the mucosal surface area.) The permeability of ulipristal acetate in the receptor medium (phosphate buffer solution pH 7.4) at a temperature of 37±1°C was measured. The results are shown in Figure 1.

[0071] In vitro experiments showed that the four test formulations exhibited very slow, almost undetectable penetration of ulipristal acetate (the high standard deviation of measurements was due to the low amount of penetration ulipristal acetate, which was within the detection limit). Within the first five minutes, no detectable amounts of ulipristal acetate were found in any of the four formulations.

[0072] Even after 120 minutes, the amount was still extremely small (<0.15 μg / cm³). 2 Only ) was found. Since the film disintegrates quickly (Example 6), ulipristal acetate is swallowed before a relevant amount can penetrate, and therefore it can be concluded that PEO, PVA, and HPMC are suitable matrix polymers for immediate release products, and ulipristal acetate is swallowed and absorbed via the gastrointestinal tract. [Examples]

[0073] Collapse survey The disintegration time of OTFs prepared according to Examples 1, 2, 3, and 4 was measured in accordance with USP 701 using a tablet disintegration device (Pharma-Test DIST-3 Triple Basket Tablet Disintegration Tester, 30 strokes per minute over a distance of 55 mm in 1 l ELGA Water (RWSx002)). 7.04 cm 2 Die-cut pieces of OTF of a certain size were placed in a basket ("sinker") and positioned inside a glass tube attached to the instrument. Finally, time was allowed to pass until only the residue of OTF remained inside the basket.

[0074] The times shown in the table below refer to the point when only OTF residue remains inside the basket: [Table 7]

[0075] These studies indicate that the tested polymers dissolve quickly and are suitable for releasing APIs through rapid disintegration in the mouth. [Examples]

[0076] Stability testing The stability of OTFs prepared according to Examples 1, 2, and 4 was measured by storing OTF samples at a temperature of 40°C and 75% relative humidity. OTF samples were analyzed for degradation products by HPLC at fixed time intervals of 1, 2, 3, and 6 months. The main degradation product detected was N-demethylulipristal acetate (DMUA). Tables 1, 2, and 3 show the amount of DMUA and the total amount of detected degradation products (sum) in wt% based on the initial amount of ulipristal acetate in the OTF before storage. The test formulations were found to be stable, with only small amounts of degradation products.

[0077] [Table 8]

[0078] [Table 9]

[0079] [Table 10] [Brief explanation of the drawing]

[0080] [Figure 1] This graph shows the results of in vitro experiments using porcine mucosa (esophageal mucosa) to measure the penetration amount of OTF produced according to Examples 1, 2, 3, and 4.

Claims

1. An oral film formulation comprising a polymer matrix and ulipristal acetate as an active agent, wherein ulipristal acetate is dispersed in the polymer matrix, and the polymer matrix is ​​a matrix of a water-soluble polymer selected from poly(ethylene oxide), poly(vinyl alcohol), or hydroxypropyl methylcellulose, where, When the water-soluble polymer is selected from poly(ethylene oxide) or poly(vinyl alcohol), the amount of the water-soluble polymer is 25% to 90% by weight, and / or based on the total weight of the intraoral film formulation. When the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of the water-soluble polymer is 30% to 70% by weight, based on the total weight of the oral film formulation. The aforementioned intraoral film formulation.

2. The oral film formulation according to claim 1, wherein ulipristal acetate is micronized ulipristal acetate.

3. The oral film formulation according to claim 1 or 2, wherein the amount of ulipristal acetate is 10% to 60% by weight based on the total weight of the oral film formulation.

4. The oral film formulation according to any one of claims 1 to 3, wherein the water-soluble polymer is selected from poly(ethylene oxide) or poly(vinyl alcohol), and the amount of ulipristal acetate is 10% to 60% by weight based on the total weight of the oral film formulation, and / or the water-soluble polymer is selected from hydroxypropyl methylcellulose, and the amount of ulipristal acetate is 20% to 60% by weight based on the total weight of the oral film formulation.

5. The oral film formulation according to any one of claims 1 to 4, wherein the amount of water-soluble polymer is 40% to 70% by weight based on the total weight of the oral film formulation.

6. When the water-soluble polymer is selected from poly(ethylene oxide) or poly(vinyl alcohol), the amount of the water-soluble polymer is 35% to 70% by weight, and / or based on the total weight of the intraoral film formulation. When the water-soluble polymer is selected from hydroxypropyl methylcellulose, the amount of the water-soluble polymer is 40% to 60% by weight, based on the total weight of the oral film formulation. An intraoral film formulation according to any one of claims 1 to 5.

7. Poly(ethylene oxide) (PEO) has a molecular weight in the range of 50,000 daltons to 200,000 daltons. Poly(vinyl alcohol) (PVA) has a molecular weight in the range of 20,000 daltons to 40,000 daltons and / or a degree of hydrolysis of 84 mol-% to 92 mol-%; and / or hydroxypropyl methylcellulose (HPMC) has a labeled viscosity in the range of 1 mPas to 100 mPas. An oral film formulation according to any one of claims 1 to 6.

8. The oral film formulation according to any one of claims 1 to 7, wherein the water-soluble polymer is selected from poly(ethylene oxide) WSR N-10, poly(vinyl alcohol) 4-88, hydroxypropyl methylcellulose 603, hydroxypropyl methylcellulose 60SH50, or a mixture of hydroxypropyl methylcellulose 603 and hydroxypropyl methylcellulose 60SH50.

9. An intraoral film formulation according to any one of claims 1 to 8, further comprising one or more plasticizers.

10. The oral film formulation according to any one of claims 1 to 9, wherein the oral film formulation is a non-foaming film or a foaming film.

11. The oral film formulation according to any one of claims 1 to 10, wherein, after storing the oral film formulation at a temperature of 40°C and a relative humidity of 75% for six months, the amount of the degradation product N-demethylulipristal acetate (DMUA) is less than 1% by weight based on the initial amount of ulipristal acetate in the oral film formulation before storage.

12. The following steps: a) A step of mixing a water-soluble polymer, a solvent containing or consisting of water or a mixture of water and one or more organic solvents, and solid ulipristal acetate to obtain a suspension in which the water-soluble polymer is dissolved in the solvent and the ulipristal acetate is suspended in the solvent. b) A step of diffusing the obtained suspension by casting or coating it onto a support, a coating liner, or into a mold, and c) Step of evaporating the solvent A method for producing an oral film formulation according to any one of claims 1 to 11, including the method described in any one of claims 1 to 11.

13. The method according to claim 12, wherein one or more plasticizers are added in mixing step a).

14. The method according to claim 12 or 13, wherein the suspension is foamed with gas before step b).

15. An oral film formulation according to any one of claims 1 to 11, for use as an emergency contraceptive.

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