Intraoral film formulations having a smooth fused film

Abstract

The present invention relates to an oral film formulation comprising a polymer matrix and at least one water-insoluble particulate pharmaceutically active ingredient dispersed in the polymer matrix, wherein the matrix polymer is poly(ethylene oxide) having a melting point of at least 55°C, and the amount of the poly(ethylene oxide) having a melting point of at least 55°C is at least 40% by weight based on the total weight of the oral film formulation, and the oral film formulation is obtainable by a process comprising the following steps: a) preparing a suspension comprising the matrix polymer, the at least one water-insoluble particulate pharmaceutically active ingredient, and a solvent which is water or a mixture of water and one or more organic solvents; b) casting the obtained suspension onto a support or into a mold; and c) drying the suspension at a temperature higher than the melting temperature of the poly(ethylene oxide).

Description

[Technical Field]

[0001] The present invention relates to an oral film formulation containing a water-insoluble particulate pharmacoactive ingredient suitable as a pharmaceutical for oral administration. [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] The most common dosage form of the drug is a tablet. For example, ulipristal acetate is a well-known emergency contraceptive ("morning-after pill"), which is administered as a tablet ("EllaOne®") containing 30 mg of micronized 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. Patent Document 1 discloses the pharmaceutically active ingredient ulipristal acetate.

[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] Patent Document 2 relates to a film incorporating a high amount of pharmaceutical agent and polymer, and a method for producing the same. Examples of polymers described include, in particular, polyethylene oxide. The film can be formed by a controlled drying process to achieve uniformity of the film. Preferably, the film contains a pharmaceutically active agent with an active agent variation of 10% or less per unit area of ​​the film. In the example, a film having a grain-like taste is obtained.

[0006] To achieve high patient compliance for the administration of oral film formulations, a polymer matrix is ​​needed that binds the pharmaceutically active ingredient (e.g., ulipristal acetate), creates a pleasant sensation in the oral cavity during administration (a pleasant "mouthfeel"), and adheres well to the mucous membrane.

[0007] Since pharmacoactive ingredients are often highly sensitive to environmental conditions, some form of protection or stabilization is desirable. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] EP422100B1 [Patent Document 2] WO2008 / 089151A2 [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Therefore, the object of the present invention was to provide an oral film formulation that stably encapsulates a pharmaceutically active ingredient and creates a pleasant mouthfeel with little to no foreign body sensation. In addition, the oral film formulation should adhere well to the oral mucosa. [Means for solving the problem]

[0010] 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 at least one water-insoluble particulate pharmaceutically active ingredient dispersed in the polymer matrix, wherein the matrix polymer is poly(ethylene oxide) having a melting point of at least 55°C, and the amount of poly(ethylene oxide) having a melting point of at least 55°C (DSC melting point (peak) temperature) is at least 40% by weight based on the total weight of the intraoral film formulation, and the intraoral film formulation is comprised of the following steps: a) A step of preparing a suspension comprising a matrix polymer, at least one water-insoluble particulate pharmaceutically active ingredient, and a solvent which is water or a mixture of water and one or more organic solvents. b) A step of casting or coating the obtained suspension onto a support, a coating liner, or into a mold, and c) A process to obtain an intraoral film formulation by drying the suspension at a temperature higher than the melting point of poly(ethylene oxide). This relates to an intraoral film formulation obtained by a process including the following.

[0011] It has been found that drying a suspension containing a poly(ethylene oxide) matrix polymer and the pharmaceutically active ingredient leads to a short-term melting of the polymer during the drying period, along with the pharmaceutically active ingredient dispersed within the polymer. As a result, the pharmaceutically active ingredient (e.g., ulipristal acetate) is densely embedded in the polymer matrix and protected from external influences.

[0012] Furthermore, these processes create a surface for the intraoral film formulation that is extremely smooth (similar to smooth plastic foil), which provides a pleasant mouthfeel during oral ingestion. At the same time, the intraoral film formulation adheres well to the mucous membrane due to the low glass transition temperature of poly(ethylene oxide).

[0013] API is a common abbreviation for pharmaceutically active ingredients. As shown, orthooral film formulations are commonly known and abbreviated as OTF. Oral film formulations that dissolve readily in the oral cavity are also commonly referred to as orally dispersible films. [Modes for carrying out the invention]

[0014] 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.

[0015] The OTF of the present invention comprises a polymer matrix and at least one water-insoluble particulate pharmaceutically active ingredient dispersed in the polymer matrix.

[0016] In this specification, a water-insoluble API refers to an API having a water solubility of 1.0 g / L or less, preferably 0.3 g / L or less, at a temperature of 25°C.

[0017] Generally, APIs are lipophilic APIs. In this specification, a lipophilic API refers to an API having a log P (n-octanol / water partition coefficient) greater than 1.5, preferably greater than 2.5, at a temperature of 25°C.

[0018] Suitable APIs include, as a result, inter alia, agents for treating infections; virus growth inhibitors; analgesics such as fentanyl, sufentanil, buprenorphine; anesthetics; anorectics; active ingredients for treating arthritis and asthma such as terbutaline; anticonvulsants; antidepressants; antidiabetic agents; antihistamines; antidiarrheals; agents for treating migraine, pruritus, pathological conditions and nausea; antiemetics such as scopolamine and ondansetron; Parkinson's drugs; antipsychotics; antipyretics, antispasmodics, anticholinergics, agents for treating ulcers such as ranitidine; sympathomimetics; calcium channel blockers such as nifedipine; beta blockers; beta agonists such as dobutamine; antiarrhythmics; antihypertensives; ACE inhibitors; benzodiazepine agonists such as flumazenil; coronary, peripheral and cerebral vasodilators; stimulants for the central nervous system; hormones; hypnotics; immunosuppressants; muscle relaxants; N-methyl D-aspartate (NMDA) receptor antagonists; parasympatholytics; parasympathomimetics; prostaglandins; psychostimulants; sedatives; tranquilizers; antitussives such as dextromethorphan.

[0019] In a preferred embodiment, at least one water-insoluble particulate API is selected from hormones, terpenes, hormone analogs, opioids, non-steroidal anti-inflammatory drugs (NSAIDs), dopamine receptor agonists, antipsychotics, anticholinergics, synthetic opioids and / or imidazolines, preferably hormones.

[0020] Examples of suitable hormones are steroid hormones or prostaglandins. Examples of NSAIDs are ibuprofen and ketoprofen.

[0021] In a preferred embodiment, at least one water-insoluble particulate pharmaceutical active ingredient is selected from ulipristal acetate, ibuprofen or ketoprofen. In a particularly preferred embodiment, at least one water-insoluble particulate pharmaceutical active ingredient is ulipristal acetate. Ulipristal acetate is preferably micronized ulipristal acetate.

[0022] Ulipristal acetate is 17α-acetoxy-11α-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione having the following chemical formula: [Chemical formula]

[0023] The particulate water-insoluble API is dispersed in the polymer matrix. The API is preferably in a crystalline form. The particles are firmly attached to the polymer matrix. According to optical evaluation, APIs such as ulipristal acetate are embedded in the matrix in such a way that a homogeneous OTF is obtained (not "API pieces").

[0024] The amount of at least one water-insoluble particulate API in the oral film formulation is preferably from 8% to 60% by weight, more preferably from 15% to 40% by weight, based on the total weight of the oral film formulation.

[0025] The polymer of the matrix of the oral film formulation is poly(ethylene oxide) having a melting point of at least 55°C. Poly(ethylene oxide) is a water-soluble polymer. One, two or more types of poly(ethylene oxide) can be used, but preferably one type of poly(ethylene oxide) is used. Generally, suitable poly(ethylene oxide) has a melting point in the range of 55°C to 75°C.

[0026] The melting point as used herein is defined as the melting peak temperature as measured by differential scanning calorimetry (DSC). DSC was performed on a DSC 204 FI Phoenix (registered trademark) (Netzsch) applying a heating rate of 10 K / min (two heating cycles) from a starting temperature of -60°C to a final temperature of +210°C under a nitrogen atmosphere (20 ml / min of nitrogen) in an aluminum crucible.

[0027] The poly(ethylene oxide) used as the water-soluble polymer preferably has a molecular weight in the range of 50,000 to 180,000 daltons, more preferably 75,000 to 150,000 daltons. A particularly preferred poly(ethylene oxide) is poly(ethylene oxide) WSR N-10 (PEO WSR N-10), which has a molecular weight of about 100,000 daltons and a melting point of about 65°C. PEO WSR N-10 is commercially available from Dow Chemical Company as Polyox® WSR N-10 or Polyox® WSR N-10 NF, respectively.

[0028] The amount of poly(ethylene oxide), preferably PEO WSR N-10, having a melting point of at least 55°C, is at least 40% by weight based on the total weight of the intraoral film formulation, and this amount is preferably 40% to 85% by weight, or 50% to 85% by weight, and more preferably 55% to 82% by weight, based on the total weight of the intraoral film formulation.

[0029] In a preferred embodiment, the weight ratio of the matrix polymer to at least one water-insoluble particulate pharmaceutically active ingredient (PEO / API) is in the range of 1 / 1 to 10 / 1, preferably 1.6 / 1 to 2.8 / 1, and more preferably 1.8 / 1 to 2.4 / 1.

[0030] Along with a drying process at a temperature higher than the melting point of the polymer matrix, the high proportion of poly(ethylene oxide) matrix and the high PEO / API ratio in the intraoral film formulation according to the present invention allow for improved protection of the API against external influences by densely embedding the API within the polymer matrix, respectively. This is advantageous in terms of storage stability and inhibition of degradation reactions, respectively.

[0031] In a particularly preferred embodiment, the oral layer further comprises one or more plasticizers. Examples of suitable plasticizers include polyols, e.g., glycerin, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, or glycerin monoesters with fatty acids, and glycerin triesters, e.g., triacetin; esters of citrate, e.g., triethyl citrate, acetyl tributyl citrate; water, ethanol, α-tocopherol, benzyl benzoate, butyl stearate, chlorobutanol, dibutyl phthalate, dimethyl phthalate, diethyl phthalate, dibutyl sebacate, stearic acid, and tricaprylin. The plasticizer is preferably glycerin and / or triacetin.

[0032] Plasticizers primarily contribute to lowering the melting point and reducing the glass transition temperature. The addition of plasticizers enhances the mucosal adhesion properties of intraoral film formulations. A further benefit is that tactilely flexible OTFs can be obtained through the addition of plasticizers.

[0033] If present, the total amount of plasticizers, preferably glycerin and / or triacetin, is typically in the range of 0.5% to 20% by weight, preferably 3% to 7% by weight, based on the total weight of the oral film formulation.

[0034] The oral film may further contain one or more additional excipients common in this 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. Examples of sweeteners include sodium saccharin and sucralose.

[0035] The total amount of optional additional excipients, such as sweeteners, is usually 15% by weight or less, preferably 5% by weight or less, based on the total weight of the oral film formulation.

[0036] Examples of antioxidants include sodium metabisulfite, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid, and tocopherol.

[0037] The residual solvent content in the obtained intraoral film formulation, i.e., after drying step c), 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 intraoral film formulation. The residual solvent contained may be water or water and one or more organic solvents.

[0038] Oral film formulations are produced through the following process: a) A step of preparing a suspension comprising a matrix polymer, at least one water-insoluble particulate pharmaceutically active ingredient, and a solvent which is water or a mixture of water and one or more organic solvents. b) A step of casting or coating the obtained suspension onto a support, a coating liner, or into a mold, and c) A process to obtain an intraoral film formulation by drying the suspension at a temperature higher than the melting point of poly(ethylene oxide). It is obtained by a process that includes this.

[0039] The materials and appropriate proportions of the oral film formulation to be manufactured are discussed above and should be referenced.

[0040] First, a suspension is prepared containing a matrix polymer, at least one water-insoluble particulate API, and a solvent which is water or a mixture of water and one or more organic solvents. In the suspension, at least one water-insoluble particulate API is suspended in the solvent. The matrix polymer is generally dissolved in the solvent.

[0041] The solvent used is water or a mixture of water and one or more organic solvents, where water is preferred. Examples of suitable organic solvents are organic solvents that are miscible with water, such as alcohols, especially ethanol and ethylene glycol, or ketones, especially acetone, or ethers, especially tetrahydrofuran and 1,4-dioxane. When a mixture of water and one or more organic solvents is used, the weight ratio of water to organic solvent, preferably ethanol, may be in the range of, for example, 95 / 5 to 30 / 70.

[0042] In a preferred embodiment, one or more plasticizers, preferably glycerin and / or triacetin, are incorporated into the suspension. Optionally, one or more additional excipients, such as sweeteners, may be added in any order.

[0043] Any order in which the components for preparing the suspension are combined is appropriate. For example, the suspension can be prepared by dissolving the matrix polymer in a solvent and then adding at least one water-insoluble particulate API. One or more plasticizers and / or one or more further excipients may be added before, during, or after the addition of at least one API.

[0044] 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".

[0045] In the production of foamed OTF (foamed film), the suspension is generally foamed with gas. Foaming is generally carried out before casting step b). Examples of suitable gases for foaming are air, argon, N2, or CO2.

[0046] The resulting suspension is cast or coated onto a support, coating liner, or in a mold. The suspension can diffuse on its own, and / or the suspension is diffused to a desired wet thickness. The preparation and casting or coating of the suspension and optional diffusion are common process steps known to those skilled in the art.

[0047] The suspension, cast onto a support or in a mold and optionally diffused, is dried at a temperature higher than the melting point of poly(ethylene oxide). During the drying process, the solvent evaporates to obtain an intraoral film formulation. The resulting film can be cut into pieces of the desired size.

[0048] In a preferred embodiment, the suspension is dried at a temperature at least 2°C higher, preferably at least 4°C higher, than the melting temperature of poly(ethylene oxide). Alternatively, or in addition, the suspension is preferably dried at a temperature 30°C or less higher, preferably 20°C or less, than the melting temperature of poly(ethylene oxide). The suspension is preferably dried at a temperature in the range of 60°C to 80°C, preferably 65°C to 75°C.

[0049] The heat treatment to dry the suspension can be carried out for, for example, 4 to 60 minutes, preferably 8 to 30 minutes.

[0050] For example, in a preferred embodiment in which PEO WSR N10 (Polyox® WSR N10), which has a melting point of approximately 65°C, is used, it is appropriate to dry the suspension at a temperature of approximately 70°C.

[0051] In this invention, poly(ethylene oxide) with a melting point lower than the drying temperature of the suspension was used. This ensured rapid fusion of the film matrix during drying. As a result, a very smooth film is produced that stably encapsulates APIs, such as ulipristal acetate. The resulting intraoral film formulation, having a very smooth surface (similar to smooth plastic foil), provides a good mouthfeel when administered orally. Since the API is suspended during the melting of the polymer matrix, a dense encapsulation of the API into the polymer matrix is ​​achieved, resulting in enhanced protection of the API against external influences after solidification.

[0052] Therefore, it is preferable that the surface roughness Ra on both sides of the intraoral film formulation is less than 1 μm, preferably less than 0.8 μm, and more preferably less than 0.4 μm, and / or that the surface roughness Ra on at least one side of the intraoral film formulation is less than 0.3 μm.

[0053] Furthermore, the poly(ethylene oxide) used has a glass transition temperature lower than body temperature (<37°C), ensuring good adhesion within the oral cavity. The intraoral film formulation provides good adhesion to the mucous membrane.

[0054] The present invention relates to a method for producing an oral film formulation according to the present invention, comprising a polymer matrix and at least one water-insoluble particulate pharmaceutically active ingredient dispersed in the polymer matrix, wherein the matrix polymer is poly(ethylene oxide) having a melting point of at least 55°C, and the amount of poly(ethylene oxide) having a melting point of at least 55°C is at least 40% by weight based on the total weight of the oral film formulation, and the method comprises the following steps: a) A step of preparing a suspension comprising a matrix polymer, at least one water-insoluble particulate pharmaceutically active ingredient, and a solvent which is water or a mixture of water and one or more organic solvents. b) A step of casting or coating the obtained suspension onto a support, a coating liner, or into a mold, and c) A step of obtaining an oral film preparation by drying the suspension at a temperature higher than the melting temperature of poly(ethylene oxide). It also relates to a method comprising the above.

[0055] Details regarding the materials used, their appropriate proportions and process steps have been discussed above and are hereby incorporated by reference.

[0056] The present invention also relates to an oral film preparation according to the present invention for use as a medicament. If the API contains ulipristal acetate, the oral film preparation is suitable for use as an emergency contraceptive, i.e., for preventing pregnancy after sexual intercourse, particularly after unprotected sexual intercourse.

[0057] The oral film is administered in the oral cavity, where rapid disintegration of the film is achieved along with the release of the API. The addition of drinking water is not necessary.

[0058] The present invention will now be described more specifically by reference to the following examples, which are presented for purposes of illustration of the invention and are not intended to be limiting thereof.

Examples

[0059] In all examples using ulipristal acetate as the API, ulipristal acetate having the following particle size distribution 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%. [[ID=P38]]

[0060] Example 1 PEO-based OTF using ulipristal acetate as the API 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 (water) 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 extracted into OTFs of appropriate size. Polyox WSR N10 was used as a preliminary solution (Polyox WSR N10: 21% in water).

[0061] Oral film formulations having the following formulations (specified on a dry weight basis) were manufactured as suspension formulations using water as the process solvent (30% solids) and a drying temperature of 70°C: [Table 1]

[0062] We have achieved a tear-resistant intraoral film formulation. Tactile and optical evaluation of the obtained OTF revealed a very smooth film surface and good embedding of the API in the polymer matrix.

[0063] Example 2 PEO-based OTF using ulipristal acetate as the API and an alternative process solvent mixture. 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 (ethanol / water 10% / 90% mixture) 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 extracted into OTFs of appropriate size.

[0064] An intraoral film formulation having the following formulation (specified as a dry composition) was prepared as a suspension formulation using water as the process solvent (30% solids) and a drying temperature of 70°C: [Table 2]

[0065] We have achieved a tear-resistant intraoral film formulation. Tactile and optical evaluation of the obtained OTF revealed a very smooth film surface and good embedding of the API in the polymer matrix.

[0066] The table below shows the melting points (peak temperatures) of the OTF samples from Example 1 (three measurements). Residual moisture and / or plasticizers are still present in the film. This can lower the melting point compared to a pure polymer (melting point depression).

[0067] [Table 3]

[0068] Figure 1 shows the DSC of the OTF from Example 1, which displays the melt peak (peak 1) of the Polyox WSR N10 matrix polymer and the melt peak (peak 2) of API ulipristal acetate. As described above, the decrease in melting point can be caused by moisture / plasticizer residue.

[0069] Example 3 PEO-based OTF using ibuprofen as the API. 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 extracted into OTFs of appropriate size. Polyox WSR N10 was used as a preliminary solution (Polyox WSR N10: 21% in water).

[0070] An intraoral film formulation having the following formulation (specified as a dry composition) was prepared as a suspension formulation using water as the process solvent (24% solids) and a drying temperature of 70°C: [Table 4]

[0071] We have achieved a tear-resistant intraoral film formulation. Tactile and optical evaluation of the obtained OTF revealed a very smooth film surface and good embedding of the API in the polymer matrix.

[0072] Example 4 PEO-based OTF using ketoprofen as the API. 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 extracted into OTFs of appropriate size. Polyox WSR N10 was used as a preliminary solution (Polyox WSR N10: 21% in water).

[0073] An intraoral film formulation having the following formulation (specified as a dry composition) was prepared as a suspension formulation using water as the process solvent (35% solids) and a drying temperature of 70°C: [Table 5]

[0074] We have achieved a tear-resistant intraoral film formulation. Tactile and optical evaluation of the obtained OTF revealed a very smooth film surface and good encapsulation of the API within the polymer matrix.

[0075] Example 5 Surface morphology measurement Surface morphological measurements were performed using a KLA Tencor P15 surface profiler with a stylus tip radius of 2 μm. Surface scans were performed on 2 mm × 2 mm areas on both sides of the OTF in Example 1. Three different line scans were measured on this area, and the amplitude parameters Ra (arithmetic mean deviation of the determined profile), Rq (root mean square), Rp (maximum peak height), and Rv (maximum valley depth) for surface roughness were determined and illustrated in Tables A and B below. The values ​​indicate that both sides are very smooth, and the Ra value is comparable to that of very smooth materials such as polished steel.

[0076] OTF Side A: [Table 6]

[0077] OTF Side B: [Table 7]

[0078] Comparative Example 1 - PVA-based OTF An intraoral film formulation having the following formulation (specified as a dry composition) was prepared as a suspension formulation using water as the process solvent (40% solids content), air was used for foaming, and a temperature of 70°C was applied for drying. The polymer used was PVA 4-88 (water-soluble polymer, molecular weight approximately 31,000 daltons, degree of hydrolysis approximately 86.7-88.7 mol%, melting point / decomposition higher than 180°C). PVA 4-88 was used as a preliminary solution (PVA 4-88: 35% in water).

[0079] [Table 8]

[0080] Tactile and optical assessment of the obtained OTF revealed a rough film surface.

[0081] OTF Side A: [Table 9]

[0082] OTF Side B: [Table 10]

[0083] Comparative Example 2 - Kollicoat® IR-based formulation An intraoral film formulation having the following formulation (specified as a dry composition) was prepared as a suspension formulation using water as the process solvent (solids content 33.7%) and a drying temperature of 70°C. The polymer used was Kollicoat® IR (BASF, water-soluble polyvinyl alcohol / polyethylene glycol copolymer (melting point approximately 208°C)).

[0084] [Table 11]

[0085] A brittle intraoral film formulation was achieved. Tactile and optical evaluation of the obtained OTF revealed an uneven and discontinuous film surface, as well as insufficient embedding of the API in the polymer matrix.

[0086] Comparative Example 3 - PEO-based OTF using ulipristal acetate as the API, dried below its melting point. 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 (water) 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 extracted into OTFs of appropriate size. Polyox WSR N10 was used as a preliminary solution (Polyox WSR N10: 33% in water).

[0087] Oral film formulations having the following formulations (specified on a dry weight basis) were prepared as suspension formulations using water as the process solvent (30% solids) and a drying temperature of 50°C (lower than the melting point of Polyox WSR N10): [Table 12]

[0088] We have developed a tear-resistant intraoral film formulation. Tactile and optical evaluation of the obtained OTF revealed a matte film surface with aggregated APIs.

[0089] Tactile and optical assessment of the obtained OTF revealed a smooth surface on one side (side B) and a rough, matte film surface on the other side (side A).

[0090] OTF Side A: [Table 13]

[0091] OTF Side B: [Table 14]

[0092] Comparative Example 4 - HPMC-based OTF having ulipristal acetate as the API, dried below its melting point. 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 API, matrix polymers (hydroxypropyl methylcellulose (HPMC) 603 and hydroxypropyl methylcellulose (HPMC) 60SH50) and excipients in a process solvent (water) 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 extracted into OTFs of appropriate size.

[0093] Oral film formulations having the following formulations (specified on a dry weight basis) were prepared as suspension formulations using water as the process solvent (32% solids) and a drying temperature of 70°C (lower than the melting point of Polyox WSR N10): [Table 15]

[0094] We have developed a tear-resistant intraoral film formulation. Tactile and optical evaluation of the obtained OTF revealed a matte film surface with aggregated APIs.

[0095] Tactile and optical analysis of the obtained OTF revealed a matte surface on one side (side A) and a rough film surface on the other side (side B).

[0096] OTF Side A: [Table 16]

[0097] OTF Side B: [Table 17]

[0098] Example 2 Stability testing The stability tests for OTF of Example 1 and Comparative Example 1 were performed by storing the OTF samples at a temperature of 40°C and a relative humidity of 75%. After storage, the samples were tested by HPLC for degradation products of ulipristal acetate. The main degradation product detected was N-demethylulipristal acetate (DMUA). Tables 1 and 2 below 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.

[0099] N-Demethylulipristal acetate (DMUA) has the following formula: [ka]

[0100] The formulation of Example 1 was found to be more stable than the formulation of Comparative Example 1. This demonstrates the beneficial effect of PEO as a matrix polymer, where the API was more densely embedded during the manufacturing process.

[0101] [Table 18]

[0102] [Table 19] [Brief explanation of the drawing]

[0103] [Figure 1] Figure 1 shows the DSC of the OTF from Example 1, which shows the melt peak of the Polyox WSR N10 matrix polymer (peak 1) and the melt peak of API ulipristal acetate (peak 2).

Claims

1. An intraoral film formulation comprising a polymer matrix, one or more plasticizers, and at least one water-insoluble particulate pharmaceutically active ingredient dispersed in the polymer matrix, wherein the matrix polymer is poly(ethylene oxide) having a melting point of at least 55°C, the amount of poly(ethylene oxide) having a melting point of at least 55°C is 55% to 85% by weight based on the total weight of the intraoral film formulation, the weight ratio of the matrix polymer to at least one water-insoluble particulate pharmaceutically active ingredient (PEO / API) is in the range of 1.8 / 1 to 2.4 / 1, and the intraoral film formulation is produced by the following steps: a) A step of preparing a suspension comprising a matrix polymer, at least one water-insoluble particulate pharmaceutically active ingredient, and a solvent which is water or a mixture of water and one or more organic solvents. b) A step of casting or coating the obtained suspension onto a support, a coating liner, or into a mold, and c) A process to obtain an intraoral film formulation by drying the suspension at a temperature higher than the melting point of poly(ethylene oxide). Obtained by a process including, The surface roughness Ra on both sides of the oral film formulation is less than 1 μm, and / or The surface roughness Ra of at least one side of the aforementioned intraoral film formulation is less than 0.3 μm. The suspension is dried at a temperature in the range of 60°C to 75°C. The aforementioned intraoral film formulation.

2. The oral film formulation according to claim 1, wherein at least one water-insoluble particulate pharmaceutically active ingredient is selected from hormones, opioids, nonsteroidal anti-inflammatory drugs, dopamine receptor agonists, antipsychotics, anticholinergics, synthetic opioids, terpenes, hormone analogs and / or imidazolines.

3. The oral film formulation according to claim 1 or 2, wherein at least one water-insoluble particulate pharmaceutically active ingredient is selected from ulipristal acetate.

4. The oral film formulation according to any one of claims 1 to 3, wherein the amount of at least one water-insoluble particulate pharmaceutically active ingredient is 8% to 60% by weight, based on the total weight of the oral film formulation.

5. Poly(ethylene oxide) having a melting point of at least 55°C, having a molecular weight in the range of 50,000 daltons to 180,000 daltons, An intraoral film formulation according to any one of claims 1 to 4.

6. The oral film formulation according to any one of claims 1 to 5, wherein the poly(ethylene oxide) having a melting point of at least 55°C is poly(ethylene oxide) WSR N-10.

7. The amount of poly(ethylene oxide) having a melting point of at least 55°C is between 55% and 82% by weight, based on the total weight of the oral film formulation. An oral film formulation according to any one of claims 1 to 6.

8. An oral film formulation according to any one of claims 1 to 7, wherein one or more plasticizers are glycerin and / or triacetin.

9. The oral film formulation according to claim 8, wherein the amount of one or more plasticizers is 0.5% by weight to 20% by weight, based on the total weight of the oral film formulation.

10. The oral film formulation according to any one of claims 1 to 9, wherein the solvent is a mixture of water and alcohol, where the weight ratio of water to organic solvent is in the range of 95 / 5 to 30 / 70.

11. The suspension is dried at a temperature at least 2°C higher than the melting point of poly(ethylene oxide). An intraoral film formulation according to any one of claims 1 to 10.

12. The oral film formulation according to any one of claims 1 to 11, wherein the suspension is foamed with gas before step b).

13. A method for producing an intraoral film formulation comprising a polymer matrix, one or more plasticizers, and at least one water-insoluble particulate pharmaceutically active ingredient dispersed in the polymer matrix, wherein the matrix polymer is poly(ethylene oxide) having a melting point of at least 55°C, the amount of poly(ethylene oxide) having a melting point of at least 55°C is 55% to 85% by weight based on the total weight of the intraoral film formulation, and the weight ratio of the matrix polymer to at least one water-insoluble particulate pharmaceutically active ingredient (PEO / API) is in the range of 1.8 / 1 to 2.4 / 1, and the method comprises the following steps: a) a step of producing a suspension comprising the matrix polymer, at least one water-insoluble particulate pharmaceutically active ingredient, and a solvent which is water or a mixture of water and one or more organic solvents. b) A step of casting or coating the obtained suspension onto a support, a coating liner, or into a mold, and c) A process to obtain an intraoral film formulation by drying the suspension at a temperature higher than the melting point of poly(ethylene oxide). Includes, The surface roughness Ra on both sides of the oral film formulation is less than 1 μm, and / or The surface roughness Ra of at least one side of the aforementioned intraoral film formulation is less than 0.3 μm. The suspension is dried at a temperature in the range of 60°C to 75°C. , the aforementioned method.

14. The method according to claim 13, wherein the oral film formulation and / or method steps are as defined in any one of claims 1 to 12.

15. An oral film formulation according to any one of claims 1 to 12, for use as a pharmaceutical.

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