CN119033737A - Oral films comprising lurasidone - Google Patents

Abstract

The present invention relates to an oral film comprising a matrix layer, wherein the matrix layer comprises lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer and at least one polyvinyl alcohol having an average molecular weight of 20000-250000g/mol, a process for the preparation of the oral film, and the use of such an oral film as a medicament, in particular in the treatment of schizophrenia, depression and/or bipolar disorders.

Description

Oral films comprising lurasidone

Technical Field

The present invention relates to an oral film comprising lurasidone or a pharmaceutically acceptable salt thereof, a process for preparing the same and the use of such an oral film as a medicament, in particular in the treatment of schizophrenia, depression and/or bipolar disorders.

Background

An oral film is a film that contains at least one pharmaceutically active agent, which may be in the form of a smooth film or a foamed film, which is placed directly into the oral cavity or against the oral mucosa (e.g., lingual, sublingual, gingival, buccal) and dissolves or disintegrates there and thereby delivers the active agent over a period of time. In particular, these films are polymer-based films containing an active agent that can be delivered by direct release of the active agent from an oral film to the mucosa, indirect delivery of the active agent via dissolution in saliva for absorption in the gastrointestinal tract (GI), or a combination of both.

The active agent may be dissolved, emulsified or dispersed in the membrane.

As explained in further detail below, the oral film according to the present invention contains lurasidone or a pharmaceutically acceptable salt thereof as a pharmaceutically active agent, and is preferably used for the treatment of schizophrenia, depression and/or bipolar disorder.

Lurasidone is a compound having the following formula (I), the system of which is known as (3 ar,4s,7r,7 as) -2- [ [ (1 r,2 r) -2- [ [4- (1, 2-benzisothiazol-3-yl) -1-piperazinyl ] methyl ] cyclohexyl ] methyl ] hexahydro-4, 7-methylene-2H-isoindole-1, 3-dione, (1 r,2s,6r,7 s) -4- [ (1 s,2 s) -2- [ [4- (1, 2-benzothiazol-3-yl) piperazin-1-yl ] methyl ] cyclohexyl ] methyl ] -4-azatricyclo [5.2.1.02,6] decane-3, 5-dione, or N- (2- (4- (1, 2-benzisothiazol-3-yl) -1-piperazinylmethyl) -1-cyclohexylmethyl) -2, 3-bicyclo (2.2.1-heptanedicarboximide.

Lurasidone was developed by Sumitomo pharmaceutical Co., ltd (Dainippon Sumitomo Pharma) and is under the trade nameThe second generation of anti-schizophrenia drugs sold as oral tablets of 20mg, 40mg, 60mg, 80mg and 120mg are approved by the U.S. Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder, etc. at 10 and 28 days 2010. Subsequently, the FDA has also approved lurasidone for the treatment of major depressive episodes associated with bipolar I disorders in children aged 10-17, as well as for extended indications for the treatment of bipolar depression in adults either alone or in combination with lithium/valproate.

As an atypical antipsychotic, lurasidone has the characteristics of unique action mechanism, definite curative effect, high safety, small influence on body weight and metabolic index, once a day and convenient administration compared with similar medicines. Lurasidone is less likely to cause extrapyramidal symptoms (EPS) than conventional antipsychotics, and has been used as a first-line drug for antipsychotics due to its broader indication, small toxic side effects and ability to improve cognition in patients.

Lurasidone belongs to the chemical class of piperidinyl-benzisoxazole derivatives. It has high affinity for dopamine D2-receptors and 5-hydroxytryptamine energy 5HT2A and 5-HT7 receptors. In addition, it inhibits the alpha 2 c-adrenergic receptor and the alpha 2 a-adrenergic receptor. Lurasidone also exhibits some partial agonism at the 5HT1A receptor. Furthermore, lurasidone does not bind to cholinergic receptors or muscarinic receptors in humans.

Currently, lurasidone is only provided in tablet form, which is difficult to swallow and therefore unsuitable for children and elderly patients. Furthermore, tablets are inconvenient for patients to take without water. Moreover, in the acute phase of schizophrenia, patients often refuse to take medications, which may be hidden in the mouth or vomit out, and thus medication compliance problems are common for schizophrenic patients. Thus, dosage forms such as tablets and capsules are often ineffective, and convenient dosage forms should be considered for patients suffering from schizophrenia. Therefore, it is necessary to provide a new formulation which is convenient to use and has good compliance to solve the above problems.

As described above, the oral film has certain advantages over tablets, and therefore it is an object of the present invention to provide an oral film for administration of lurasidone, which is compatible with commercially available onesTablet bioequivalence.

Due to 40mgThe tablet comprises 40mg of lurasidone hydrochloride in an insoluble form (corresponding to 37.2mg of lurasidone), so the oral film should also be designed in such a way that it is possible to comprise at least 40mg of lurasidone hydrochloride in a monolithic oral film, which is a rather high dose for an oral film, wherein lurasidone is preferably present in the oral film in an insoluble, i.e. suspended, form.

High active loading in oral films is a known problem because it can lead to brittle films or can directly hinder the formation of films from the contained polymer. In particular, the use of hydroxypropyl methylcellulose (HPMC) tends to result in brittle films. In order to still be able to prepare a suitable film with HPMC, large oral films or oral films with very large layer thicknesses are generally required. However, a disadvantage of large or thick oral films is that they cause problems in application, may feel foreign body sensation to the patient, and may exhibit long disintegration times.

However, depending on the application, a long disintegration time is not desirable. For lurasidone, a fast disintegration is preferred to help swallow the disintegrated film in a short time, which will lead to the delivery of the active substance via the oral/GI route. Without wishing to be bound by theory, due to the low solubility of the active substance, it is believed that the release of the active substance is primarily controlled by drug dissolution in the gastrointestinal tract, such that the oral/GI route is responsible for achieving and oral administrationBioequivalence of the tablets is important.

In addition, the higher the active loading, the more film-forming polymer must be included. This results in a greater areal density/areal weight of the film, with the result that the drying time is longer. However, prolonged drying times are uneconomical and may also lead to uneven distribution of the active agent within the oral film.

In addition, unless a suitable polymer is selected, in many cases, also depending on the polymer used, oral films with high areal densities exhibit an unpleasant sensation to the patient when administered into the patient's mouth.

In addition, the use of certain polymers for forming oral films, such as HPMC, enables incorporation of large amounts of active agents. But in that case too, a large amount of HPMC is required to provide an acceptable oral film. If high concentrations of HPMC polymers are used, they exhibit a long lasting sticky feel in the mouth of the patient, which should be avoided.

Thus, despite the advantages of OTF, there are several challenges in formulating an effective oral film of lurasidone. Lurasidone has poor water solubility and bitter taste, and can affect the acceptability and efficacy of the preparation. Ensuring uniform drug distribution within the membrane matrix is another important consideration.

In summary, alternative administration of lurasidone is highly desirable, overcoming the drawbacks of administration in tablet form. As mentioned above, OTF will be able to address these drawbacks.

Thus, there is a need in the art for oral films of lurasidone.

Summary of The Invention

The object of the present invention is to overcome the above-mentioned drawbacks of the prior art. In particular, it is an object of the present invention to provide a pharmaceutical composition for administration of a large amount of lurasidone or a pharmaceutically acceptable salt thereof, and toTablets, in particular with40Mg of tablet bioequivalence oral film. In addition, the oral film should have an acceptable disintegration time and the pharmaceutically active agent should be uniformly distributed in the oral film. Still further, the oral film should preferably have the characteristics of a pleasant and soft texture and thus preferably will not cause a patient's foreign body sensation after administration, particularly should avoid any persistent sticky sensation in the patient's mouth. Moreover, the oral films should be relatively stable, as well as relatively stable over extended shelf lives, such as one month.

It is another object of the present invention to provide an oral film (OTF) formulation that effectively masks the bitter taste of lurasidone, ensuring a pleasant taste to improve patient compliance.

Moreover, it is convenient to carry, has excellent clinical compliance, is particularly suitable for children and elderly patient groups, or for the acute onset of psychosis, and exhibits excellent disintegration properties and high bioavailability.

Furthermore, it would be possible to prepare an oral film with a uniform drug distribution throughout the OTF as easily and economically as possible.

The above object is solved by an oral film comprising a matrix layer, wherein the matrix layer comprises lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 250000g/mol, in particular 20000 to 40000 g/mol.

Such oral film displaysBioequivalence of 40mg of tablet, because oral films with reasonable size and reasonable area density can be used to provide a dose of 40mg of lurasidone hydrochloride (equivalent to 37.2mg of lurasidone).

It has been found that the polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol still have good film forming properties if a large amount of suspended/dispersed active agent is present in the formulation.

This has also been observed in polyvinyl alcohol, where the effect is somewhat even more pronounced. However, films based solely on polyvinyl alcohol are hard and therefore have a texture that is unpleasant for the patient.

In contrast, films based solely on polyvinyl alcohol-polyethylene glycol graft copolymers have a softer texture, as the polymer itself forms a softer film. However, these films are not so stable.

Due to the polyvinyl alcohol-polyethylene glycol graft copolymer and the polyvinyl alcohol having a defined molecular weight, it has been possible to manufacture films featuring high active agent loading, having a soft texture of the polyvinyl alcohol-polyethylene glycol graft copolymer film, and approaching the stability of the polyvinyl alcohol film.

Polyvinyl alcohol having a higher molecular weight is suitable for forming oral films with high active agent loading. However, it was previously reported that polyvinyl alcohol with higher molecular weight results in longer disintegration time, which is not desirable for the oral film according to the present invention.

The inventors have surprisingly found that, contrary to the previous preliminary findings, high molecular weight polyvinyl alcohol can also be used to formulate lurasidone oral films with acceptable disintegration times.

The polyvinyl alcohol-polyethylene glycol graft copolymer preferably forms the basic structure and decisively determines the properties of the film, while polyvinyl alcohol serves as an additional stabilizer.

This allows for high active agent loadings and layer thicknesses and film sizes within acceptable ranges. The disintegration time is also within an acceptable range, which preferably includes values of less than 1 minute, or in particular less than 45 seconds.

Furthermore, the oral film according to the present invention does not cause a sticky feeling in the oral cavity of a patient after administration.

In addition, such oral films are readily accepted by patients, thus ensuring patient compliance with treatment, and can be simply and economically prepared.

Preferred embodiments are described in the dependent claims.

Another aspect of the present invention relates to a method for manufacturing an oral film, comprising the steps of:

a) Preparing a dispersion comprising lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 250000g/mol, in particular 20000 to 40000 g/mol;

b) Spreading the dispersion from step a), and

C) The spread dispersion was dried to give an oral film.

In another aspect, the present embodiment relates to an oral film as described herein and/or as obtained or obtainable by the process disclosed herein for use as a medicament, preferably for the treatment of psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders.

The following description provides some embodiments of the invention and is not intended to limit the scope, applicability, or configuration of the invention or inventions. Various changes may be made in the function and arrangement of elements without departing from the scope of the invention described herein. Some embodiments may be practiced without all of the specific details.

Reference will now be made in detail to embodiments. In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the subject matter herein. It will be apparent, however, to one skilled in the art that the subject matter may be practiced without these specific details. In other instances, well-known methods, procedures, components, and systems have not been described in detail so as not to unnecessarily obscure aspects of the embodiments. In the following description, it should be understood that features of one embodiment may be used in combination with features of another embodiment, where the features of the different embodiments are not incompatible.

Definition of the definition

Within the meaning of the present invention, an "oral film" (OTF) is a drug delivery system comprising a thin flexible film designed to dissolve or disintegrate rapidly when placed in the oral cavity. Different modes of administration of the oral film include sublingual, gingival, buccal, oromucosal and oral administration.

Lingual administration of a drug or therapeutic agent refers to placing it on the tongue. Sublingual administration involves placing the drug under the tongue. Gingival delivery includes application of the drug to the gums. Buccal administration requires placement of the drug between the gums and the inner layer of the cheek. Oral mucosal administration refers to the delivery of a drug or therapeutic agent through the oral mucosa of the mouth. Oral administration involves swallowing the drug, which then passes through the digestive system and is absorbed in the stomach or intestine.

Unless otherwise indicated, the "average molecular weight" of a polymer disclosed herein refers to the weight average molecular weight (M _W), which is the average molecular weight of the polymer calculated by taking the sum of the molecular weights of all individual polymer chains, weighting by mass of each chain, and dividing by the total mass of the polymer. In other cases, "average molecular weight" refers to the number average molecular weight M _N, which is the average molecular weight of a polymer calculated by dividing the total weight of the polymer by the total number of polymer molecules.

Any average molecular weight can be determined by Gel Permeation Chromatography (GPC). In GPC, a polymer sample is dissolved in a suitable solvent and passed through a column packed with a porous gel. The molecules separate based on their size, with larger molecules eluting first because they are less entangled in the pores of the porous gel. The elution profile is detected by appropriate means (e.g., UV-Vis detector) and analyzed to determine the molecular weight distribution, whereby the calibration curves can be used to calculate M _N and M _W.

Within the meaning of the present invention, the term "therapeutically effective amount" refers to an amount of active agent in an oral film that, if administered to a patient via an oral film, is sufficient to provide a similar range (e.g., about 10% to about 1000%, as measured by AUC) of blood levels of lurasidone when compared to blood levels obtained by single administration of 40mg of oral lurasidone. Within the meaning of the present invention, the terms "active", "active agent" and the like as well as the term "lurasidone" refer to lurasidone in any pharmaceutically acceptable chemical and morphological form as well as physical state. These forms include, but are not limited to, lurasidone in free, dissociated, or any associated form, such as a hydrate, solvate, salt, etc., as well as lurasidone in particulate form, which may be in micronized form, in crystalline form, particularly in one of its polymorphic forms and/or in amorphous form, and any of the hybrid types of any of the foregoing forms, or mixtures thereof. When lurasidone is contained in a medium such as a solvent, it may be dissolved or dispersed or partially dissolved and partially dispersed.

When it is mentioned that lurasidone is used in a specific form in the manufacture of OTF, this does not exclude interactions between lurasidone in this form and other components of the OTF, such that the active substance is present in the final OTF in another form. This means that even though lurasidone is contained in the OTF in a free, dissociated form, it may be present in the final OTF in the form of a hydrate or solvate, or if it is contained in the OTF in one of its polymorphic forms, it may be present in the final oral film in an amorphous form.

The lurasidone starting material contained in the oral film may be in the form of particles during the manufacture of the oral film. Lurasidone may be present in OTF, for example, in particulate, dispersed, and/or dissolved form.

Within the meaning of the present invention, the term "particles" refers to solid particulate material comprising individual particles of negligible size compared to the material. In particular, the particles are solids, including plastic/deformable solids, including amorphous and crystalline materials.

Within the meaning of the present invention, the term "dispersed" refers to a step or combination of steps in which the starting material (e.g. lurasidone) is insoluble or incompletely soluble. Dispersion in the sense of the present invention includes dissolution of a portion of the starting material (e.g. lurasidone particles) depending on the solubility of the starting material (e.g. lurasidone in the dispersion). Most preferably, the lurasidone is present in the form of particles during manufacture and in the final oral film.

It will also become apparent herein that terms such as "disintegrate (disintegration)", "disintegrable", "Disintegrate (DISINTEGRATE)", etc. should be understood very broadly for any layer of an oral film (e.g., backing layer, matrix layer) and for polymers such as "disintegrate (disintegration)", when cast (cast) is film-formed, rather than being understood in the strict scientific sense as chemically dissolving the molecule in a solvent. Any transition from the solid state to the liquid state of the relevant layer, such as dispersion, formation of a suspension, gelation of the film and disintegration into smaller gel portions, etc., must be regarded as "disintegration" in the sense of the present invention, provided that the "disintegrated" material is free to move in the liquid (e.g. saliva).

It should be noted that the term "dissolution" with respect to the substance itself, such as the active agent lurasidone or any excipient, will continue to be used in the usual chemical sense of dissolving the molecule in a solvent. For example, the dissolved form of lurasidone obviously does not include lurasidone in a dispersed form. In the manufacture of oral films, the polymer itself may be present in the coating composition in a dissolved form in the general chemical sense (e.g., not dispersed, in the form of small gel portions, etc.), but in the case of polymer cast films, "dissolving" such films also includes gelation and disintegration of the film into smaller gel portions.

The matrix layer is the final cured layer, for example, obtained after coating and drying the spread dispersion (i.e., solvent-containing coating composition). The substrate layer may also be manufactured by laminating two or more such cured layers of the same composition (e.g., dried layers) to provide the desired areal weight. The matrix layer may be mucoadhesive (in the form of a mucoadhesive layer), or the oral film may comprise a mucocontact layer of additional mucoadhesive agent to provide adequate adhesion. Preferably, however, the matrix layer is not a mucoadhesive layer, nor does the OTF comprise such a mucocontact layer.

Within the meaning of the present invention, the term "areal density" refers to the total weight of a particular layer (e.g. matrix layer) provided in g/m ². This value may include a residual amount of process solvent, such as water. The term "areal weight" is used synonymously with the term "areal density". The tolerance of the area weight values is + -10%, preferably + -7.5%, due to manufacturing variability.

If not otherwise indicated, "%" or "wt.%" refers to weight percent based on the total weight of the layer or oral film or the corresponding coating composition used to prepare such layer, e.g., based on the total weight of the matrix layer, or, e.g., based on the total weight of the dispersion.

Within the meaning of the present invention, the term "polymer" generally refers to any substance consisting of repeating units obtained by polymerizing one or more monomers, and includes homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomer. The polymer may have any structure, such as a linear polymer, a star polymer, a comb polymer, a brush polymer, in the case of a copolymer, any arrangement of monomers, such as an alternating copolymer, a statistical copolymer, a block copolymer or a graft polymer. The minimum molecular weight varies according to the type of polymer and is known to those skilled in the art. The molecular weight of the polymer may for example be higher than 2000 daltons, preferably higher than 5000 daltons, more preferably higher than 10000 daltons. Accordingly, compounds having a molecular weight below 2000 daltons, preferably below 5000 daltons or more preferably below 10000 daltons are commonly referred to as oligomers.

In a more specific sense, the term "polymer" in the context of the matrix layer may also be collectively referred to as at least one polyvinyl alcohol-polyethylene glycol graft copolymer and at least one polyvinyl alcohol.

Within the meaning of the present invention, the term "room temperature" refers to the unchanged temperature found in the laboratory where the experiment is carried out, typically within 15 ℃ to 35 ℃, preferably about 18 ℃ to 25 ℃.

Within the meaning of the present invention, the term "patient" refers to a subject who has presented with a clinical manifestation of one or more specific symptoms indicative of a need of treatment, is being treated prophylactically or prophylactically for a disorder, or has been diagnosed with a disorder to be treated.

Within the meaning of the present invention, the term "dispersion" is used synonymously with the term "coating composition" and refers to a composition comprising a matrix layer component in a solvent that can be applied to a backing layer (if present) or a release liner to form a matrix layer upon drying.

Within the meaning of the present invention, the term "dissolving" in the context of preparing a coating composition, for example dissolving a component of the coating composition (such as an active agent), refers to the process of obtaining a solution that is clear and does not contain any macroscopic particles.

Within the meaning of the present invention, the term "solvent" refers to any liquid substance which may be a volatile organic liquid, such as methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, hexane, n-heptane, toluene and mixtures thereof, but is preferably water.

Within the meaning of the present invention, the term "about" refers to an amount of + -10% of the disclosed amount, unless otherwise indicated. In some embodiments, the term "about" refers to an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±2% of the disclosed amount.

The terminology used in the description of the disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting of 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 as well, unless the context clearly indicates otherwise. It will also be understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. It will be further understood that the terms "comprises," "comprising," "includes," and/or "including" when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

The term "comprising" may also be used herein to refer to "consisting of.

Drawings

FIG. 1 OTF and according to formulation AComparison of dissolution times of 40mg tablets at different pH.

FIG. 2 comparison of dissolution times of OTF according to formulation A at different pH.

Detailed Description

Substrate layer

The oral film according to the invention has (at least one) a matrix layer, wherein the matrix layer comprises lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer and at least one polyvinyl alcohol having an average molecular weight of 20000 to 250000g/mol, in particular 20000 to 40000 g/mol.

The oral film according to the present invention comprises lurasidone or a pharmaceutically acceptable salt thereof as an active agent. However, the oral film may further comprise at least one other active agent which may be selected from the active agent classes of analgesics, hormones, hypnotics, sedatives, antiepileptics, stimulants, psychotropic drugs, neuromuscular blockers, spasmolytics, antihistamines, antiallergic agents, cardiotonic agents, antiarrhythmics, diuretics, antihypertensives, vasopressors, antidepressants, antitussives, expectorants, thyroid hormones, sex hormones, antidiabetics, antitumor active agents, antibiotics, chemotherapeutics and anesthetics, although this group is not exhaustive.

Lurasidone (3 ar,4s,7r,7 as) -2- { [ (1 r,2 r) -2- [4- (1, 2-benzisothiazol-3-yl) -piperazin-1-ylmethyl ] cyclohexylmethyl } hexahydro-4, 7-methylene-2H-isoindole-1, 3-dione or a pharmaceutically acceptable salt thereof, e.g. (3 ar,4s,7r,7 as) -2- { [ (1 r,2 r) -2- [4- (1, 2-benzisothiazol-3-yl) -piperazin-1-ylmethyl ] cyclohexylmethyl } hexahydro-4, 7-methylene-2H-isoindol-1, 3-dione hydrochloride is a white to off-white powder.

The active substance is slightly soluble in water, belongs to BCS class II drugs, and its poor oral bioavailability is mainly due to its extremely low solubility and dissolution rate (the absolute bioavailability in humans after a single oral administration is only 9% -19%).

The matrix layer also comprises at least one polyvinyl alcohol.

Polyvinyl alcohol (abbreviated as PVA or PVAL, sometimes also referred to as PVOH) is a polymer having the general structure

It may also contain small amounts (about 2%) of structural units of the type

They belong to the class of vinyl polymers.

Commercially common polyvinyl alcohols are provided in the form of white-yellow powders or granules, generally having a degree of hydrolysis of 98 to 99 mol% or 87 to 89 mol%, that is to say also containing residual amounts of acetyl groups. Manufacturers characterize polyvinyl alcohols by specifying the degree of polymerization or average molecular weight, degree of hydrolysis, saponification value or solution viscosity of the starting polymers.

According to the invention, at least one polyvinyl alcohol has an average molecular weight of 20000 to 250000g/mol, in particular 20000 to 40000 g/mol.

The inventors have found that if the oral film comprises at least one polyvinyl alcohol-polyethylene glycol graft copolymer and at least one polyvinyl alcohol, the average molecular weight of the polyvinyl alcohol can be adjusted over a wide range. However, if the average molecular weight is less than 20000g/mol, the viscosity of at least one polyvinyl alcohol becomes too low, which negatively affects the handling properties of the OTF during manufacture and application. If the average molecular weight is higher than 250000g/mol, the viscosity of the at least one polyvinyl alcohol becomes too high, which negatively affects the handling properties of the OTF, especially during manufacture. Furthermore, outside the claimed scope, the disintegration behaviour of the oral film may be negatively affected.

In another embodiment of the invention, at least one polyvinyl alcohol has an average molecular weight of 20000 to 40000g/mol or greater than 40000 to 250000 g/mol. Preferably, the average molecular weight is 20000 to 40000g/mol. In some embodiments, the average molecular weight is in the range of 20000 to 210000g/mol, and/or greater than 40000 to 210000g/mol, and/or 20000 to 150000g/mol, and/or greater than 40000 to 150000g/mol, and/or 20000 to 100000g/mol, and/or greater than 40000 to 100000g/mol, and/or from 20000 to 75000g/mol, and/or greater than 40000 to 75000 g/mol.

According to a preferred embodiment of the invention, the average molecular weight of the at least one polyvinyl alcohol is 20000 to 40000g/mol. Average molecular weight refers in some embodiments to number average molecular weight. The inventors have found that if at least one polyvinyl alcohol has an average molecular weight within the stated range, the OTF exhibits a desired balance of mechanical properties (in particular foldability, tensile strength and puncture strength) and dissolution behavior.

In a preferred embodiment, the average molecular weight refers to the weight average molecular weight.

Polyvinyl alcohol having an average molecular weight of about 31000 is particularly suitable in accordance with the present invention. Polyvinyl alcohols having an average molecular weight of about 37000g/mol are also particularly suitable. Another specific example of a polyvinyl alcohol suitable for use in the present invention is a polyvinyl alcohol having an average molecular weight of about 205000 g/mol.

The molecular weight can be determined, for example, by gel permeation chromatography.

In a preferred embodiment, the polyvinyl alcohol is partially hydrolyzed polyvinyl alcohol. For the purposes of the present invention, partially hydrolyzed polyvinyl alcohol refers to polymeric materials derived from polyvinyl acetate in which a portion of the acetate groups have been hydrolyzed to form hydroxyl groups, resulting in, for example, polymers having a degree of hydrolysis of from 70% to 95%, preferably from 80 to 92%, more preferably about 88%. The degree of hydrolysis is defined as the percentage of acetate groups that have been converted to hydroxyl groups.

In another embodiment, the polyvinyl alcohol is fully hydrolyzed polyvinyl alcohol having a degree of hydrolysis greater than 95%, such as 97% or greater.

In addition, polyvinyl alcohols having a viscosity of 3.4 to 4.6mPa in 40 g/l of aqueous solution, as determined by the "falling ball method" (Ph. Eur. 2.2.49), are also particularly suitable.

Known by the name of suitable polyvinyl alcohols are polyvinyl alcoholsHas an average molecular weight of about 31,000g/mol and a degree of hydrolysis of about 88%. Further specific examples include(Average molecular weight of about 37000g/mol, degree of hydrolysis of about 88%) and (Average molecular weight about 205000g/mol, degree of hydrolysis about 88%).

In a preferred embodiment, the at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5 to 30wt.%, preferably 10 to 25wt.%, relative to the total weight of the matrix layer. In another embodiment, the at least one polyvinyl alcohol is provided in the matrix layer in an amount of 10 to 20wt.%, preferably 15 to 25wt.%, relative to the total weight of the matrix layer. Thus, in one embodiment, at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5wt.% to less than 10wt.% or 10wt.% to 35wt.%, or in an amount of 10wt.% to less than 15wt.% or 15wt.% to 25wt.% or more than 25wt.% to 30wt.%, each relative to the total weight of the matrix layer.

The matrix layer also comprises at least one polyvinyl alcohol-polyethylene glycol graft copolymer, also abbreviated as PVA-g-PEG.

Graft copolymers are branched polymers containing different monomer units in the main chain and in the branches.

The term "graft copolymer" is a common term.

"Graft polymer" or "graft copolymer" refers to a type of polymer in which the main polymer backbone (also referred to as the graft copolymer backbone) has one or more side chains (also referred to as grafts (grafts)) covalently attached thereto. These side chains are typically composed of one or more monomers that are different from the main polymer backbone and are attached to the backbone by chemical reactions such as free radical polymerization or polycondensation. Grafts may be attached to the backbone at random or specific positions and may vary in their molecular weight, composition and structure.

The polyvinyl alcohol-polyethylene glycol graft copolymers provided herein preferably have a backbone comprising polyethylene glycol onto which polyvinyl alcohol units are grafted.

Preferably, the oral film according to the present invention is further characterized in that at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone onto which polyvinyl alcohol units are grafted.

Preferably, the oral film according to the invention is further characterized in that at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone onto which polyvinyl alcohol units are grafted, wherein the molar ratio of polyethylene glycol to polyvinyl alcohol is 1:3.

Preferably, the oral film according to the invention is further characterized in that at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone onto which polyvinyl alcohol units are grafted, wherein the polyvinyl alcohol-polyethylene glycol graft copolymer has an average molecular weight in the range 40000 to 50000g/mol, preferably about 45000g/mol.

The average molecular weight is in particular the value of the average molecular weight.

Most preferably, the average molecular weight refers to the weight average molecular weight.

The molecular weight can be determined, for example, by gel permeation chromatography.

One suitable and preferred polyvinyl alcohol-polyethylene glycol graft copolymer is known under the trade name Kollicoat IR (BASF).

The at least one polyvinyl alcohol-polyethylene glycol graft copolymer is preferably provided in the matrix layer in an amount of 5 to 35wt.%, preferably 10 to 30wt.%, relative to the total weight of the matrix layer. In another embodiment, the at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 5wt.% to less than 10wt.% or 10wt.% to 35wt.%, preferably in an amount of 10wt.% to less than 15wt.% or 10wt.% to 25wt.% or more than 25wt.% to 30wt.%, each relative to the total weight of the matrix layer.

In a preferred embodiment, the oral film comprises the at least one polyvinyl alcohol-polyethylene glycol graft copolymer and the at least one polyvinyl alcohol are present in a combined amount of 25wt.% to 65wt.%, preferably 30wt.% to 60wt.%, more preferably 30wt.% to 45wt.%, relative to the total weight of the matrix layer.

The oral film according to the invention preferably comprises a substantial amount of lurasidone or a pharmaceutically acceptable salt.

Thus, the oral film according to the present invention comprises a therapeutically effective amount of lurasidone.

When reference is made hereinafter to "lurasidone", it is understood to refer to lurasidone in free form and in pharmaceutically acceptable salt form.

In one embodiment of the invention, the oral film comprises 35 to 55wt.%, preferably 35 to 53wt.%, more preferably 40 to 45wt.% lurasidone, or a pharmaceutically acceptable salt thereof, in the matrix layer relative to the total weight of the matrix layer. As mentioned above, it is particularly advantageous to have a high load of lurasidone in the oral film to achieve a balance between the size and area weight of the OTF. However, if the amount of lurasidone becomes too high, the film may be too brittle to handle adequately during manufacture and use.

The oral film may further comprise 35 to 50wt.% or more than 50 to 55wt.%, preferably 35 to 50wt.% or more than 50 to 53wt.%, more preferably 40 to 45wt.% of lurasidone or a pharmaceutically acceptable salt thereof, relative to the total weight of the matrix layer.

Thus, preferably, the oral film of the present invention is characterized in that lurasidone or a pharmaceutically acceptable salt thereof is provided in the matrix layer in an amount of 35 to 50wt.%, preferably 40 to 45wt.%, relative to the total weight of the matrix layer.

The pharmaceutically acceptable salt of lurasidone may be selected from its halides (i.e. fluoride, chloride, bromide or iodide), sulphates, phosphates, bicarbonates, carbonates and/or carboxylates (e.g. acetate, citrate, lactate, tartrate, succinate, malate, fumarate or maleate).

The preferred pharmaceutically acceptable salt of lurasidone is lurasidone hydrochloride (lurasidone hydrochloride).

The lurasidone in the matrix layer may be (fully) dissolved or the matrix layer may comprise lurasidone particles, preferably consisting of lurasidone hydrochloride, such that the lurasidone is present in a dispersed form. Needless to say, if the lurasidone is present in dispersed form, the matrix layer may still comprise lurasidone in dissolved form, depending on the solubility (e.g. saturation or supersaturation) of the active substance in the matrix layer.

The at least one polyvinyl alcohol-polyethylene glycol graft copolymer and the at least one polyvinyl alcohol together provide sufficient cohesion to the substrate layer as long as the substrate layer remains in a dry state. In addition, these polymers are the main controlling factor of the disintegration behavior of the matrix layer. In particular, the matrix layer should disintegrate long enough for easy administration, but short enough to allow rapid release of the active substance into the oral cavity so that the OTF can be swallowed quickly and cannot be easily removed after administration.

In certain embodiments, this means that if the substrate layer is cast into a film having an areal weight of 150 to 200g/m ² or 185 to 195g/m ², for example about 190g/m ², the substrate layer dissolves in water, artificial or natural saliva or any other aqueous medium at 37 ℃ and 50rpm in less than 2 minutes, preferably less than 1.5 minutes, more preferably less than 1 minute, most preferably less than 45 seconds. If the substrate layer is cast into a film having an areal weight of 150 to 200g/m ² or 185 to 195g/m ², for example about 190g/m ², the substrate layer may also be dissolved in water, artificial or natural saliva or any other aqueous medium at 37 ℃ and 50rpm for a period of more than 5 seconds, preferably more than 10 seconds, most preferably more than 15 seconds. Notably, if the substrate layer is cast into a film having an areal weight of 150 to 200g/m ² or 185 to 195g/m ², for example about 190g/m ², the substrate layer can dissolve for greater than 5 seconds and less than 2 minutes, preferably greater than 10 seconds and less than 1.5 minutes, more preferably greater than 15 seconds and less than 1 minute, most preferably greater than 15 seconds and less than 45 seconds.

The oral films of the present invention may contain other components.

For example, the oral film may comprise additional polymers as film formers. Such film formers include polymers such as polyvinylpyrrolidone (which may be30F commercially available from BASF), methylcellulose (available fromCommercially available from Colorcon), ethylcellulose (available fromCommercially available from Colorcon), hydroxyethyl cellulose (available from250L commercially available from Ashland Industries), hydroxypropyl cellulose (available asCommercially available from Ashland Industries), hydroxypropyl methylcellulose (also known as hypromellose, which may beCommercially available from Shin-Etsu), sodium carboxymethyl cellulose (uncrosslinked sodium salt of carboxymethyl cellulose, also known as CMC or carboxymethyl cellulose, may beCommercially available from Ashland Industries), maltodextrin, graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinyl caprolactam (which may beCommercially available from BASF), polyvinylpyrrolidone-polyvinyl acetate copolymer (also known as copovidone, and may be, for exampleVA64 commercially available from BASF), polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer (which may beAndCommercially available from Evonik) and methacrylic acid-ethyl methacrylate copolymers (available asAndCommercially available from Evonik), and natural film formers such as shellac, pectin, gelatin, alginates, pullulan, and starch derivatives, as well as any mixtures thereof.

Preferably, such film forming agents are present in the matrix layer in an amount of up to 10wt.%, preferably up to 5 wt.%. In view of the undesirable tactile properties of cellulose and in particular the mouthfeel, the film forming agent is preferably not selected from cellulose and cellulose derivatives (i.e. for example methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose). Thus, in a preferred embodiment, the matrix layer does not comprise cellulose and does not comprise a cellulose derivative.

In a particularly preferred embodiment, the matrix layer does not comprise a film former other than at least one polyvinyl alcohol-polyethylene glycol graft copolymer and at least one polyvinyl alcohol.

The matrix layer of the OTF according to the present invention may comprise further excipients or additives selected from the group consisting of fatty acids, sweeteners, flavouring agents (flavoring agents) ("flavouring agents (flavorings)"), colouring agents (colorants) ", solubilisers, plasticisers, disintegrants, emulsifiers, stabilisers and buffering agents.

Such excipients or additives may be present in the matrix layer in an amount of 0.001 to 15wt.% of each additive as matrix layer. In one embodiment, the total amount of all additives is 0.001 to 25wt.% of the matrix layer. Hereinafter, when a range of the amount of a specific additive is given, such range refers to the amount of each individual additive

It should be noted that in pharmaceutical formulations, the formulation components are classified according to their physicochemical and physiological properties and according to their function. This means in particular that substances or compounds belonging to one category are not excluded from belonging to another formulation component category. For example, a certain polymer may be a crystallization inhibitor, but also a tackifier. Some substances may be, for example, typical softeners, but at the same time act as permeation enhancers. The person skilled in the art is able to determine, on the basis of his general knowledge, the type of formulation component or components to which a substance or compound belongs. In the following, details are provided with respect to excipients and additives, however, the details should not be understood as being exclusive. Other substances not explicitly listed in the present description may also be used according to the present invention and in the sense of the present invention the use of substances and/or compounds explicitly listed for one formulation component class as another formulation component is not excluded.

The fatty acid may in particular be a saturated or unsaturated, linear or branched carboxylic acid comprising from 4 to 24 carbon atoms, and may in particular be selected from the group consisting of caprylic acid, myristoleic acid, palmitoleic acid, cis 6-hexadecenoic acid (SAPIENIC ACID), oleic acid, elaidic acid, isooleic acid, linoleic acid, elaidic acid (linoelaidic acid), alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid. Oleic acid or linoleic acid is particularly preferred.

It is generally known in the art that the active-containing layer of an oral film may contain a permeation enhancer. Typical permeation enhancers include compounds selected from the group consisting of diethylene glycol monoethyl ether (transcutol), dipropylene glycol, levulinic acid, 2, 5-dimethyl isosorbide (dottisol), lauryl lactate, lactic acid, dimethylethyleneurea, N-diethyl-m-toluamide (DEET), propylene glycol monocaprylate, 2-methoxy-4- (prop-2-en-1-yl) phenol, laurocapram (laurocapram), bile acids, bile salts, bile acid derivatives, acyl carnitines, sodium dodecyl sulfate, dimethyl sulfoxide, sodium dodecyl sulfate, terpenes, cyclodextrins, cyclodextrin derivatives, saponins, saponin derivatives, chitosan, EDTA, citric acid and salicylates. From the point of view that the oral film of the invention is intended for oral delivery of lurasidone to the gastrointestinal tract, the matrix layer according to the invention preferably does not comprise a permeation enhancer, in particular does not comprise a permeation enhancer selected from the present list.

The matrix layer according to the invention may comprise a pH adjuster. Preferably, the pH adjuster is selected from the group consisting of monobasic and polybasic acids (polytropic acid), monobasic, dibasic and tribasic bases, buffered solutions with mixtures of weak acids and their conjugate bases, amine derivatives, inorganic base derivatives, polymers with basic and acidic functionalities, respectively.

Preferably, the oral film according to the invention is further characterized in that the at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5to 20wt.%, preferably 10 to 15wt.%, relative to the total weight of the matrix layer.

Preferably, the oral film according to the invention is further characterized in that the at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 10 to 35wt.%, preferably 15 to 25wt.%, relative to the total weight of the matrix layer.

The amount of polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer disclosed herein is particularly suitable because it ensures that the oral film can be loaded with a large amount of active agent while maintaining a flexible film that exhibits a pleasant feel in the patient's mouth.

Preferably, the oral film according to the present invention does not comprise any other polymer than polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer.

In particular, the oral film according to the invention does not comprise any cellulose-based polymer such as HPMC.

Preferably, the oral film according to the invention is further characterized in that the matrix layer comprises at least one plasticizer.

The plasticizer is specifically selected from monosaccharides, disaccharides, oligosaccharides and polysaccharides and their derivatives such as sorbitol, glycerol, polyethylene glycol, glyceryl triacetate, triethyl citrate, propylene glycol and medium chain triglycerides.

Preferred plasticizers are selected from glyceryl triacetate, PEG400 and/or glycerin. Glyceryl triacetate (TRIACETIN) (also known as glyceryl triacetate (GLYCERIN TRIACETATE) or 1,2, 3-triacetoxypropane) is particularly preferred. The plasticizers, especially glyceryl triacetate, were found to provide the best results with respect to tactile sensation and OTF flexibility.

The at least one plasticizer is preferably present in the matrix layer in an amount of 1 to 15wt.%, preferably 4 to 10wt.%, most preferably 5 to 10wt.%, based on the total weight of the matrix layer. The at least one plasticizer may also be present in the matrix layer in an amount of 1 to 10wt.% or more than 10 to 15wt.%, or in an amount of 4 to less than 5wt.% or 5 to 10wt.%, each relative to the total weight of the matrix layer.

Furthermore, the at least one plasticizer is preferably present in the matrix layer in an amount of 1 to 10%, preferably 5 to 10%, relative to the total weight of the matrix layer.

Preferably, the oral film according to the invention is further characterized in that the matrix layer comprises at least one emulsifier.

Examples of emulsifiers which can be used are soaps, metal soaps, organic soaps such as ethanolamino oleate or stearates, sulfurized compounds such as sodium lauryl sulfate, quaternary ammonium compounds, fatty alcohols such as lauryl, cetyl, stearyl or palmityl alcohol, partial fatty acid esters of polyhydric alcohols with saturated fatty acids such as glycerol monostearate, pentaerythritol monostearate, ethylene glycol monostearate, propylene glycol monostearate, partial fatty acid esters of polyhydric alcohols with unsaturated fatty acids such as glycerol monooleate, glycerol dioleate, pentaerythritol monooleate, polyoxyethylene esters of further fatty acids such as polyoxyethylene stearate, polymerization products of ethylene oxide and propylene oxide with fatty alcohols such as fatty alcohol polyglycol ethers, or polymerization products of ethylene oxide and propylene oxide with fatty acids such as fatty acid ethoxylates, polysorbates, sorbitan esters, polyglycol glycerol hydroxystearates (macrogolglycerol hydroxystearate), lecithins, mono-or diglycerides and/or polyoxyethylene fatty acid ethers.

Other emulsifiers that may be used include lecithin, polysorbates, sorbitan esters such as polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (23) sorbitan monolaurate, polyoxyethylene fatty acid ethers such as polyoxyethylene (23) lauryl ether or polyoxyethylene (2) stearyl alcohol, polyethylene glycol glycerol hydroxystearate, glycerol monooleate and glycerol dioleate and/or mixtures thereof, such as polysorbate 80 or 60, span 83 or 85, kolliphor RH, tween 20, tween 80, atmos 300, brij S2 and Brij L-23 sold under the trade names.

Further examples include ethoxylated sorbitan esterified with fatty acids, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate and polyoxyethylene sorbitan monooleate (commercially available as tween 80 or polysorbate 80), safflower oleosomes, propylene glycol, polyethoxylated castor oil, soy lecithin, sodium phosphate, mono-and diglycerides of fatty acids, sodium stearoyl lactylate, diacetyl tartaric acid esters and diglycerides of mono-and diglycerides, and polyethoxylated hydrogenated castor oil (commercially available as Cremophor RH 40 from BASF).

Preferred emulsifiers are selected from the group consisting of polysorbate 80, polysorbate 60, diacetyl esters of mono-and diglycerides, in particular polysorbate 80.

Among other functions, the emulsifier improves the dispersion of the lurasidone particles in the polymer matrix. This function becomes particularly important if the OTF contains a higher amount of flavoring agent, which unexpectedly alters the surface tension of the coating composition, resulting in the appearance of holes in the coated film. However, as mentioned above, the presence of a flavoring agent is preferred in view of the bitter taste of lurasidone. Thus, the inventors have recognized that emulsifiers help incorporate a significant amount of flavoring agents into the matrix layer, thereby helping to improve patient compliance.

Furthermore, the at least one emulsifier is preferably present in the matrix layer in an amount of 0.1 to 2wt.%, preferably 0.5 to 1.5wt.%, relative to the total weight of the matrix layer.

The oral film according to the invention is preferably further characterized in that the matrix layer further comprises at least one auxiliary substance selected from the group consisting of colorants, flavors and/or sweeteners.

Each of these auxiliary substances is preferably contained in an amount of 0.005 to 15wt.%, preferably 0.1 to 10wt.% or 0.1 to 5wt.%, relative to the total weight of the matrix layer in each case.

The colorants optionally incorporated into the matrix layer must be safe in terms of toxicity and should be approved by the U.S. Food and Drug Administration (FDA).

Any colorant suitable for use in pharmaceutical/food applications may be included, particularly those approved for use by the U.S. FDA or by European Authority EFSA/EMA or China national drug administration. The colorant may be selected, for example, from the group consisting of titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allure red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin-5 '-phosphate, quinoline yellow, orange yellow S, carmine, carminic acid, azo-carmine, light red (carmoisine), amaranth, erythrosine, ponceau 4R, carmine a, patent blue V, indigo, chlorophyll, chlorophyllin (chlorophyllin), copper complexes of chlorophyll and chlorophyllin, green S, plain caramel, caustic sulfite caramel, ammonia caramel, ammonium sulfite caramel, brilliant black BN, black PN, vegetable carbon black, brown HT, carotene, carmine, norbixin, capsaicin extract, capsaicin, capsanthin, β -apo-8' -aldehyde, lutein, canthaxanthin, betanin, iron carbonate, iron oxide and hydroxide, silver, gold, and silver.

Lurasidone has an unpleasant bitter taste, which should be masked to improve patient compliance. Thus, in a preferred embodiment, the matrix layer further comprises one or more excipients selected from the group consisting of sweetening and flavoring agents.

Flavoring agents that may be used include those known to those skilled in the art, such as natural flavoring agents and artificial flavoring agents. These flavoring agents may be selected from the group consisting of synthetic flavoring oils and flavoring aromatics, and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits and the like, and combinations thereof. Representative flavoring oils include spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage and oil of bitter almonds. Artificial, natural or synthetic fruit flavors such as vanilla, chocolate, coffee, cocoa and citrus oils including lemon, orange, grape, lime and grapefruit, and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and the like are also useful. These flavoring agents may be used alone or in combination. Common flavoring agents include peppermint, such as peppermint, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether employed alone or in combination. Flavoring agents such as aldehydes and esters may also be used, including cinnamyl cinnamaldehyde, citral, diethyl acetal, dihydrocarvyl formate (dihydrocarvyl eugenyl formate), para-methylanisole, and the like. In general, any flavoring or food additive may be used, such as those described in the publications 1274 of the national academy of sciences (the National Academy of Sciences) at pages 63-258 of CHEMICALS USED IN FOOD PROCESSING. Other examples of aldehyde flavors include, but are not limited to, acetaldehyde (apple), benzaldehyde (cherry, almond), cinnamaldehyde (cinnamon), citral, i.e., alpha citral (lemon, lime), neral, i.e., beta citral (lemon, lime), decanal (orange, lemon), ethyl vanillin (vanilla, cream), heliotropin, i.e., piperonal (vanilla, cream), vanillin (vanilla, cream), alpha-amyl cinnamaldehyde (spicy fruit flavor), butyraldehyde (butter, cheese), valeraldehyde (butter, cheese), citronellal (modifiers), types), decanal (citrus fruits), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), 2-ethyl butyraldehyde (berry fruits), hexenal, i.e., trans-2 (berry fruits), tolualdehyde (cherry, almond), veral (vanilla), 2, 6-dimethyl-5-heptenal, i.e., melon aldehyde (melon), 2-6-dimethyloctanal (cherry), and orange, and mixtures thereof.

In a further preferred embodiment, the matrix layer comprises one or more natural or artificial flavors selected from the group consisting of vanillin (vanillin), methyl salicylate, menthol, chamomile (manzanate), diacetyl, levulinyl, acetoin (acetoin), isoamyl acetate, benzaldehyde, cinnamaldehyde (CINNAMALDEHYDE), cherry flavors, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl caproate, ethyl maltol, dimethyl thiomethane (2, 4-DITHIAPENTANE), ethyl vanillin, and eucalyptol, and flavor compositions such as peppermint flavor. Cherry flavoring is particularly preferred.

Sweeteners that may be included are those well known in the art, including natural sweeteners and artificial sweeteners. Suitable sweeteners include, for example, carbohydrates, monosaccharides, disaccharides, oligosaccharides, sucralose, aspartame, cyclamate, saccharin, neohesperidin, thaumatin, stevioside, acesulfame k, and salts thereof.

Maltose, lactose, sucrose, dextrose (glucose) and trehalose, sugar alcohols such as mannitol, sorbitol, xylitol, maltitol and the like. Examples of other carbohydrates are maltodextrin, corn syrup (from corn), soluble starch.

Other exemplary sweeteners include glycyrrhizin, aspartame, glycyrrhizin, saccharin, stevioside, naringin dihydrochalcone, aspartame salts, sucralose, monellin, thaumatin, neohesperidin dihydrochalcone, and neotame.

In certain preferred embodiments, the matrix layer comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin, and sodium saccharin. Particularly preferably, the matrix layer comprises one or more natural or artificial sweeteners selected from sorbitol, sucralose and neotame. Sugar alcohols, such as sorbitol, can also act as humectants.

Sorbitol, sucralose, and/or neotame are preferred.

The oral film according to the invention may further and/or additionally comprise at least one auxiliary substance selected from taste masking agents, enhancers, pH-adjusting agents, humectants, preservatives and/or antioxidants.

Each of these auxiliary substances is preferably contained in an amount of 0.005 to 15wt.%, preferably 0.1 to 10wt.% or 0.1 to 5wt.%, relative to the total weight of the matrix layer in each case.

The matrix layer according to the invention may comprise a wetting agent. Humectants are substances used in formulations to help retain moisture by attracting and retaining water molecules of the surrounding environment. The humectant may be selected from sugar alcohol, glycerol, propylene glycol, sorbitol, urea, hyaluronic acid, lactic acid, panthenol (provitamin b 5), sodium lactate, honey, aloe vera gel, butylene glycol, xylitol, erythritol, maltitol, mannitol, isomalt, lactitol, hydrogenated Starch Hydrolysate (HSH), galactitol (dulcitol), ribitol, arabitol and threitol, preferably the humectant is sorbitol. Sorbitol may also act as a sweetener.

The inventors have found that a humectant can help increase the polarity of the oral film, thereby helping to disintegrate. Thus, the matrix layer may further comprise a humectant in an amount of 2 to 10wt.%, preferably 5 to 10wt.%, wherein the humectant is preferably a sugar alcohol such as sorbitol. One embodiment of the present invention relates to an oral film comprising a matrix layer, wherein the matrix layer comprises lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol or more than 40000 to 250000g/mol, with the proviso that if a polyvinyl alcohol having an average molecular weight of more than 40000 to 250000g/mol is used, the matrix layer of the oral film further comprises 2 to 10wt.%, preferably 5 to 10wt.%, of a humectant, wherein the humectant is preferably a sugar alcohol such as sorbitol.

In addition, the matrix layer of the present invention may contain residual process solvents, such as water. The residual process solvent is preferably contained in the matrix layer in an amount of less than 10wt.%, preferably less than 5 wt.%.

Particularly preferred oral films according to the invention are characterized in that lurasidone or a pharmaceutically acceptable salt thereof is present in particulate form, in particular with a D ₉₀ of 1 to 100 μm, or 3 to 20 μm, preferably 1 to 10 μm. The particles may have a D ₉₀ of 1 to 20 or greater than 20 to 100 μm, or a D ₉₀ of 3 to 20 μm or greater than 20 to 100 μm, preferably 1 to 10 μm.

Preferably, the oral film according to the invention is further characterized in that the lurasidone or a pharmaceutically acceptable salt thereof is present in the form of particles, in particular in the form of particles having a D ₉₀ of 1 to 20 μm, or 3 to 20 μm, preferably 1 to 10 μm.

Additionally or alternatively, D ₅₀ of the microparticles may be in the range 0.1 to 25 μm, preferably 0.5 to 5 μm.

Particle size refers to the volume weighted particle size D ₉₀ (i.e., 90% of all particles by volume have a particle size less than the recited value) and the volume median particle size D ₅₀ (i.e., 50% of all particles by volume have a particle size less than the recited value), and can be determined, for example, by laser diffraction analysis or sieve analysis, particularly laser diffraction analysis.

Preferably, lurasidone, or a pharmaceutically acceptable salt thereof, is present in the form of microparticles having a D ₉₀ of less than 5 μm.

Since the active ingredient is preferably present undissolved, i.e. suspended, the active ingredient is preferably present in a sufficiently small particle size. Too large particles can lead to streaking in the final film and additionally produce a rough, uneven film surface.

Thus, the particle size of the micronized particles may contribute to the beneficial tactile properties of OTF and dissolution behavior in the gastrointestinal tract.

Preferably, the oral film according to the present invention is further characterized in that lurasidone or a pharmaceutically acceptable salt thereof is substantially insoluble in the matrix layer.

By substantially insoluble is meant that more than 95%, preferably more than 98% by weight of the lurasidone, or a pharmaceutically acceptable salt thereof, is rendered insoluble.

Preferably, the oral film according to the invention is further characterized in that the area density (also referred to as area weight) of the oral film is preferably at least 10g/m ², more preferably at least 20g/m ² or at least 30g/m ², most preferably 50g/m ², or less than or equal to 400g/m ², more preferably less than or equal to 350g/m ², or less than or equal to 300g/m ², or most preferably less than 250g/m ².

Preferably, the area density of the oral film is 50 to 300g/m ², preferably 150 to 250g/m ².

The area density is selected so that the OTF can be conveniently handled and administered and disintegrated within a desired time frame. In particular, OTFs with lower areal densities are thinner and disintegrate faster, which is preferred, but also more fragile. Thus, the area density of the oral film may also be 80 to 150g/m ².

In one embodiment, the oral film according to the invention is further characterized in that it comprises lurasidone in the form of lurasidone hydrochloride in a total amount of 15-55mg, preferably 25-55mg, for example about 20mg or about 40 mg. Thus, the oral film according to the present invention may comprise lurasidone hydrochloride in a total amount of 15 to less than 25mg or 25 to 55 mg.

Preferably, the oral film according to the invention is further characterized in that the lurasidone or a pharmaceutically acceptable salt thereof comprises lurasidone hydrochloride in a total amount of 25 to 55mg, preferably about 20mg or about 40 mg.

Thus, in a preferred embodiment, the OTF comprises lurasidone or a pharmaceutically acceptable salt thereof in an amount of 35 to 55wt.%, preferably 35 to 53wt.%, relative to the total weight of the matrix layer, in the matrix layer, and the area density of the oral film is 50 to 300g/m ², preferably 80 to 150g/m ² or 150 to 250g/m ².

The preferred amount and area weight of lurasidone in the matrix layer is selected such that a single dose of lurasidone OTF having an OTF size in the range of 2-6cm ² contains a total amount of lurasidone hydrochloride of 25-55 mg. Particularly preferably, the amount and area weight of lurasidone in the matrix layer is selected such that a single dose of lurasidone OTF having an OTF size of 2.5cm ² comprises a total amount of about 20mg of lurasidone hydrochloride and a single dose of lurasidone OTF having an OTF size of 5cm ² comprises a total amount of about 40mg of lurasidone hydrochloride.

Preferably, the oral film according to the invention is further characterized in that at least 70% or at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after administration at a pH value of 3.8 (mimicking the pH value present in the absorption site of lurasidone-the gastrointestinal tract).

The oral film is also preferably characterized by release of at least 70% or at least 80%, preferably at least 90% of the lurasidone, or a pharmaceutically acceptable salt thereof, within the first 15 minutes after immersion in an aqueous solution having a pH of 3.8 at a temperature of 37±0.5 ℃. The aqueous solution having a pH of 3.8 may be a mixture of disodium hydrogen phosphate buffer and citric acid buffer, more preferably McIlvaine buffer ([ (0.025M citric acid solution+0.05M Na ₂HPO₄ solution (3:2) ]) the pH may be chosen to mimic the pH present in the gastrointestinal tract in the fed state.

Additionally or alternatively, the oral film is characterized by release of at least 70% or at least 80%, preferably at least 90% of the lurasidone, or a pharmaceutically acceptable salt thereof, within the first 15 minutes after immersion in an aqueous solution having a pH of 1.2 at a temperature of 37±0.5 ℃. The aqueous solution having a pH of 1.2 may be a dilute hydrochloric acid solution. The pH may be selected to mimic the pH present in the gastrointestinal tract in a satiated state.

Additionally or alternatively, the oral film is characterized by releasing up to 70% or up to 60% of the lurasidone, or a pharmaceutically acceptable salt thereof, within the first 15 minutes after immersion in an aqueous solution having a pH of 4.5 at a temperature of 37±0.5 ℃. The aqueous solution having a pH of 4.5 may be a mixture of disodium hydrogen phosphate buffer and citric acid buffer.

Additionally or alternatively, the oral film is characterized by releasing up to 15% or up to 10% of the lurasidone, or a pharmaceutically acceptable salt thereof, within the first 15 minutes after immersion in an aqueous solution having a pH of 6.8 at a temperature of 37±0.5 ℃. The aqueous solution having a pH of 6.8 may be a mixture of disodium hydrogen phosphate buffer and citric acid. The pH may be selected to simulate conditions in the oral cavity.

The release profile ensures dissolution of lurasidone in the gastrointestinal tract, but not premature dissolution during administration (e.g., in saliva).

Within the meaning of the present invention, "release" of lurasidone refers to the portion of the total amount of lurasidone present in the OTF that is dissolved in an aqueous solution in USP dissolution apparatus II having an additional settler to fix the OTF on the bottom of the vessel.

Preferably, the release is measured by placing OTF of size 5cm ² in 900mL of aqueous solution in USP dissolution apparatus II with a stirring speed of 50 rpm. Preferably, the aqueous solution is degassed prior to use.

Most preferably, the release of lurasidone is measured according to FDA dissolution methods and parameters.

For the purposes of the present invention, OTF is considered bioequivalent to Latuda if the dissolution profiles substantially match. More specifically, OTF is considered bioequivalent if at least 80% of the lurasidone or a pharmaceutically acceptable salt thereof is released within the first 15 minutes after immersion in an aqueous solution at a pH of 1.2 at a temperature of 37±0.5 ℃ and/or if at least 90% of the lurasidone or a pharmaceutically acceptable salt thereof is released within the first 15 minutes after immersion in an aqueous solution at a pH of 3.8 at a temperature of 37±0.5 ℃.

In another preferred embodiment, the oral film of the present invention has a tensile strength of at least 1N, or at least 2N, preferably at least 5N. Preferably, the oral films of the present invention have a tensile strength of 1 to 15N, preferably 2 to 12N, more preferably 5 to 12N, most preferably 6 to 12N. The tensile strength can be measured by a tensile strength tester. In this method, a single unit of test product is held with two jaws (clamp jaws) spaced 10mm apart from each other. When the sample is fixed, the upper jaw moves up on the 10mm measurement path at a speed of 300 mm/min. The maximum force required to tear an individual cell is determined in newtons (N).

Thus, tensile strength is a measure of the maximum tensile (tensile or traction) stress a material can withstand before breaking or failing. Thus, it is a measure of the durability and mechanical integrity of OTFs. OTFs are subjected to various mechanical stresses during manufacture, packaging, storage and handling. A sufficiently high tensile strength ensures that the film does not tear or break easily, maintaining its structural integrity during these processes. In addition, films with sufficient tensile strength are easier to handle without premature mechanical disintegration. For this reason, high tensile strength may even contribute to better patient compliance by making the film stronger and easier to handle without fear of breakage.

Preferably, the oral films of the present invention do not crack or disintegrate when folded. This property is preferably assessed by folding a single unit in the pouch, rolling a standard 2kg tube over the folded edge and determining if the sample is still one piece or broken into two parts. Similar to tensile strength, good fracture or shatter resistance ensures that the film does not fracture or shatter when produced, removed from the package or placed into the mouth. Thus, they are easier to manufacture, handle and administer, which enhances user experience and compliance.

In a further preferred embodiment, the oral film of the present invention has a puncture strength of 0.02 to 0.2N/mm ², preferably 0.03 to 0.15N/mm ², more preferably 0.03 to 0.1N/mm ². The puncture strength may be determined using standard equipment (e.g., a force measurement device that measures the maximum force applied to the OTF until the OTF breaks or is pierced). Puncture strength refers to the ability of a material to resist penetration by a sharp object. It measures how much force is required to pierce the material. Similar to tensile strength, a sufficiently high puncture strength indicates good mechanical stability of the OTF. For example, OTFs are not easily penetrated by fingers or damaged by sharp objects during handling, nor are they easily damaged by sharp objects during manufacturing.

The oral film according to the present invention is not subject to any limitation in terms of structure.

Thus, the oral film according to the present invention may be provided in the form of a single layer oral film and thus may consist of only the matrix layer as defined above.

Thus, in another embodiment, the oral film according to the present invention may be provided in the form of a multilayer oral film, and thus may contain other layers in addition to the matrix layer defined above.

Each of the plurality of layers provided, in particular the matrix layer, preferably has a layer thickness of preferably 10 μm to 500 μm, particularly preferably 20 μm to 300 μm in each case.

If the individual layers, in particular the matrix layer, are present in the form of a cured foam, it is therefore preferred that each of the plurality of layers provided as foam has a layer thickness of preferably from 10 μm to 3000 μm, particularly preferably from 90 μm to 2000 μm, in each case.

The multiple layers may be laminated directly on top of each other or may be connected to an adhesive layer arranged in between.

The additional layer may be selected from a backing layer, a decorative layer, an adhesive layer, a mucosal contact layer, a mucoadhesive layer, a protective layer, a water soluble adhesive layer, a buffer layer and/or an additional active ingredient layer.

However, in a particularly preferred embodiment, the oral film consists of a matrix layer.

Preferably, the oral film does not comprise a backing layer. As mentioned above, a backing layer in the sense of the present invention is any layer of an oral film that prevents premature dissolution of the active substance contained in the oral film. Thus, in certain embodiments, the backing layer dissolves at least as long as the (bulk) active substance is delivered across the mucosa, e.g. as long as the matrix layer dissolves. Thus, in certain embodiments, the backing layer does not dissolve in less than 2 minutes, less than 1 minute, or less than 45 seconds after the oral film is applied to a human patient. In some embodiments, the backing layer does not dissolve completely in water, artificial or natural saliva, or any other aqueous medium at 37 ℃ and 50rpm in less than 4 minutes, less than 2 minutes, or less than 1 minute.

Within the meaning of the present invention, the term "mucoadhesive" refers in particular to a material capable of adhering to and contacting the mucous membrane, but preferably non-adhesive, which can be touched and handled with the fingers in a dry state, for example applied in the mouth, without accidentally adhering to the skin of the fingers. The mucoadhesive layer is "self-adhesive" when in contact with the mucosa, i.e. provides adhesion to the mucosa, such that no further fixation assistance is typically required. The adhesive strength is preferably strong enough that typical movements in the oral cavity are not sufficient to displace the mucoadhesive layer adhering to the mucosa. The "mucoadhesive" layer structure includes a mucoadhesive layer for mucocontact, which may be provided in the form of a mucoadhesive matrix layer or in the form of an additional layer (i.e. mucoadhesive mucocontact layer). The mucoadhesive coating may still be used to promote adhesion.

Within the meaning of the present invention, the term "mucosal contact layer" refers to a layer comprised in an oral film that is in direct contact with the mucosa of the patient during administration. When the oral film comprises a mucosal contact layer, the other layers do not contact the mucosa and do not necessarily have mucoadhesive properties. The release area is provided by the area of the matrix layer. Mucosal contact layers can be used to enhance adhesion. The dimensions of the additional mucosal contact layer and the matrix layer are typically coextensive (coextensive) and correspond to the release area. Preferably, the oral film of the present invention does not comprise a mucosal contact layer, a mucoadhesive cover layer or a mucoadhesive matrix layer.

As mentioned above, the oral film may also include a decorative layer. In another embodiment, the oral film does not include a decorative layer.

The decorative layer is located on top of the substrate layer, as opposed to the mucosal contact layer. The decorative layer may provide decorative means, such as coloration or imprinting, or may simply prevent the patient from contacting the matrix layer during administration of the oral film. For this protective function, it is preferable that the decorative layer completely covers the substrate layer. Thus, in certain embodiments, the OTF further comprises a decorative layer, and the size of the matrix layer and the size of the decorative layer are coextensive, or the size of the decorative layer is greater than the surface area of the matrix layer and extends the surface area of the matrix layer.

On the other hand, the decorative layer should not be confused with the backing layer. This is not a function of the decorative layer and is indeed undesirable if the decorative layer causes an obstacle to the release of the active substance into saliva. Thus, the decorative layer dissolves fast enough not to impede the dispersion of the active into saliva, and in certain embodiments, the decorative layer dissolves in water, artificial or natural saliva, or any other aqueous medium at 37 ℃ and 150rpm in less than 2 minutes, less than 1 minute, or less than 30 seconds.

However, one elegant solution for oral films is that the matrix layer is the oral film itself, in terms of ease of manufacture and simplicity. In other words, in certain preferred embodiments, the oral film of the present invention comprises neither a mucosal contact layer nor a decorative layer, and in particular, the oral film may simply consist of a matrix layer.

Adhesive layer is understood to mean a layer which can be used as an adhesive, as defined in DIN EN 923:2016-03. Thus, the non-adhesive layer cannot be used as an adhesive as defined above.

In particular, the water-soluble adhesive layer described in DE102017127452A1 is suitable as an adhesive layer, the disclosure of which is expressly incorporated herein in its entirety into the present disclosure.

For example, a buffer layer for setting the pH or a slow dissolving or insoluble layer protecting the oral film from premature attack may be provided as the other layer.

Alternatively, other matrix layers containing other pharmaceutically active agents or flavouring or taste masking agents may be provided.

In one embodiment, the oral film according to the invention is characterized in that the matrix layer is in the form of a smooth film. This means that the matrix layer is not provided, for example, in the form of a foam.

The matrix layer may be in the form of a smooth film (i.e., monolithic film (monolithic film)) or may be in the form of a foamed film. Preferably, the matrix layer is in the form of a smooth film (i.e., a monolithic film). Thus, it is preferred that the matrix layer is not present in the oral film in the form of a foam film. The terms "monolithic film" and "smooth film" are used interchangeably herein. The terms "foam" and "blown film" are also used interchangeably herein.

The smooth film is preferably characterized in that the smooth film has a volume fraction of bubbles or cavities of 0% to 25% relative to the total volume of the matrix layer. These cavities are typically formed during the process of preparing a smooth film and should be avoided to the greatest extent possible when a smooth film is desired.

In another embodiment, the oral film according to the invention is characterized in that the matrix layer is in the form of a solidified foam having cavities.

The chambers may be separated from one another, preferably provided in the form of bubbles, wherein the chambers are filled with air or a gas, preferably with an inert gas, particularly preferably with nitrogen, carbon dioxide, helium or a mixture of at least two of these gases.

According to another embodiment, the defined chambers are preferably connected to each other by a system of interconnecting channels forming a penetrating matrix.

The cavity preferably has a volume fraction of 25% to 98%, preferably 50% to 80%, relative to the total volume of the matrix layer. In this way, the beneficial effect of accelerating the disintegration and/or dissolution of the matrix layer is advantageously affected.

In particular, the cavities and associated large surfaces of the membrane facilitate the penetration of water or saliva or other body fluids into the interior of the dosage form and thus the disintegration and/or dissolution of the dosage form and the release of the active agent.

On the other hand, the wall thickness of the cavities is preferably small, as these represent e.g. solidified bubbles, and thus the cavities dissolve or collapse rapidly.

Another advantage of this embodiment is that it provides faster drying than comparable non-foaming compositions, due to the formulation as a foam, despite the relatively large area density.

In addition, in order to improve the stability of the foam before or after drying, a surfactant or a surfactant may be added to the matrix layer for forming the foam before or after drying or to the obtained foam.

Another parameter affecting the properties of the dosage form according to the invention is the diameter of the cavity or bubble. The bubbles or cavities are preferably produced by means of a foaming machine, which can be used to set the diameter of the bubbles almost arbitrarily within a wide range. Thus, the diameter of the bubbles or cavities may be in the range of 0.01 to 350 μm. The diameter is particularly preferably in the range from 10 to 200. Mu.m.

The oral films according to the present invention are typically stored in seam-sealed pouches without any other means of protection. However, the OTF may also be located on a detachable protective layer (release liner) from which it is removed immediately prior to application to the patient's mouth. Thus, the oral film may or may not further comprise a release liner. Oral films protected by release liners are also typically stored in seam-sealed pouches. The package may be child resistant or child friendly and/or senior friendly.

Preferred formulations of the matrix layer are listed in tables a to H below:

TABLE A preferred matrix layer compositions

Table B. further preferred matrix layer compositions

TABLE C even more preferred matrix layer compositions

Table D. even further preferred matrix layer compositions

TABLE E even further preferred matrix layer compositions

TABLE F even more preferred matrix layer compositions

TABLE G even more preferred matrix layer compositions

TABLE H even more preferred matrix layer compositions

The substrate layer having any of the above formulations I to XXXIV preferably has an areal density of from 50 to 300g/m ², preferably from 150 to 250g/m ² of the oral film.

In a preferred embodiment, the matrix layer with any of the above formulations I to XXXIV is in the form of a smooth film, i.e. not a foamed film.

In a preferred embodiment, the matrix layer

Comprising lurasidone hydrochloride in a total amount of 15mg to 55mg, preferably about 40mg,

Having a formulation according to any of the above formulations I to XXXIV,

The area density of the oral film is 50 to 300g/m ², preferably 150 to 250g/m ², and optionally

In the form of a smooth film.

Thus, in an exemplary embodiment, the substrate layer is characterized by:

comprising lurasidone hydrochloride in a total amount of 15mg to 55mg, preferably about 40mg,

Inclusion of

O 35 to 53wt.% lurasidone,

O 5 to 30wt.% of a polyvinyl alcohol,

O 5 to 35wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

O 4 to 10wt.% of a plasticizer selected from polyethylene glycol, glycerol and/or glyceryl triacetate,

O 0.1 to 2wt.% of an emulsifier selected from the group consisting of polyoxyethylene- (20) -sorbitan monooleate, polyoxyethylene- (20) -sorbitan monostearate and diacetyl esters of mono-and diglycerides,

O 5 to 15wt.% of a sweetener,

O 2.5 to 10wt.% of a flavoring agent,

O 0 to 2wt.% of a colorant, and

The area density of the oral film is 50 to 300g/m ², preferably 150 to 250g/m ².

Thus, in another exemplary embodiment, the substrate layer is characterized by:

comprising lurasidone hydrochloride in a total amount of 15mg to 55mg, preferably about 40mg,

Inclusion of

O 35 to 53wt.% lurasidone,

O 5 to 30wt.% of a polyvinyl alcohol,

O 5 to 35wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

O 4 to 10wt.% of a plasticizer selected from polyethylene glycol, glycerol and/or glyceryl triacetate,

O 0.1 to 2wt.% of an emulsifier selected from polyoxyethylene-

(20) Sorbitan monooleate, polyoxyethylene- (20) -sorbitan monostearate and diacetyl esters of mono-and diglycerides,

O 5 to 15wt.% of a sweetener,

O 2.5 to 10wt.% of a flavoring agent,

O 0 to 2wt.% colorant;

The area density of the oral film is 50 to 300g/m ², preferably 80 to 150g/m ² or 150 to 250g/m ², and

In the form of a smooth film.

In yet another preferred embodiment, the oral film consists of a matrix layer having any of the above formulas I to XXXIV.

In yet another preferred embodiment, the oral film consists of a matrix layer having any of the above formulas I to XXXIV and the area density of the oral film is 50 to 300g/m ², preferably 80 to 150g/m ² or 150 to 250g/m ².

In a further preferred embodiment, the oral film consists of a matrix layer having any of the above formulations I to XXXIV and being in the form of a smooth film, i.e. not a foamed film.

In yet another preferred embodiment, the oral film is composed of a matrix layer

Comprising lurasidone hydrochloride in a total amount of 15mg to 55mg, preferably about 40mg,

Having a formulation according to any of the above formulations I to XXXIV,

The area density of the oral film is 50 to 300g/m ², preferably 80 to 150g/m ² or 150 to 250g/m ², and optionally

In the form of a smooth film.

The oral film according to the invention preferably has an area of 0.5cm ² to 10cm ², particularly preferably 2cm ² to 8cm ² or 4cm ² to 5cm ², in particular 2.5cm ² or 5cm ².

Preferably, the oral film according to the invention is further characterized in that the matrix layer comprises 40 to 45wt.% of lurasidone hydrochloride, 18 to 22wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer, 10 to 15wt.% of a polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol, in particular 31000g/mol, each based on the total weight of the matrix layer.

Preferably, the oral film according to the invention is further characterized in that the matrix layer comprises 42.5wt.% lurasidone hydrochloride, 20.5wt.% polyvinyl alcohol-polyethylene glycol graft copolymer, 13.5wt.% polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol, in particular 31000g/mol, each based on the total weight of the matrix layer.

In a particularly preferred embodiment, the oral film has a formulation according to formulation A, F or G, in particular formulation a, as described in table 1.

In a very particularly preferred embodiment, the oral film comprises

42.535Wt.% of lurasidone hydrochloride, which is preferably micronized to a D ₉₀ (determined by laser diffraction analysis) of 3 to 20 μm, in particular 4 to 5 μm,

20.57Wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer, in particular a polyethylene glycol backbone having polyvinyl alcohol units grafted thereon, wherein the molar ratio of polyethylene glycol to polyvinyl alcohol is 1:3 and/or wherein the average molecular weight of the polyvinyl alcohol-polyethylene glycol graft copolymer is in the range of 40000 to 50000g/mol, preferably about 45000g/mol (determined by gel permeation chromatography),

13.57Wt.% of polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol, in particular 31000g/mol (determined by gel permeation chromatography),

-6.13Wt.% wt.% of (wt.) the preparation method of the glyceryl triacetate comprises the steps of,

-2.33Wt.% wt.% is added with a mixture of the sucralose,

-8.26Wt. -%: is used as a starting material for the sorbitol,

-0.1Wt.% wt.% of neotame, the total content of the composition,

5Wt.% of a first flavoring agent, in particular cherry flavoring agent,

0.5Wt.% of a second flavoring agent, in particular peppermint oil,

0.005Wt.% of a colorant, in particular erythrosine,

-1.00Wt.% wt.% of (wt.) polysorbate 80 is provided in the form of a polysorbate 80,

And optionally residual process solvents, in particular water.

The dry area weight of the oral film is preferably in the range of 180 to 190g/m ², in particular 188g/m ².

The load of lurasidone hydrochloride per oral film is preferably 20mg or 40mg.

The size of the oral film is preferably 2.5cm ² or 5cm ².

In another very particularly preferred embodiment, the oral film comprises

42.535Wt.% of lurasidone hydrochloride, micronized to a D ₉₀ (determined by laser diffraction analysis) of 3 to 20 μm, in particular 4 to 5 μm,

20.57Wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer which is a polyethylene glycol backbone onto which polyvinyl alcohol units are grafted, wherein the molar ratio of polyethylene glycol to polyvinyl alcohol is 1:3 and wherein the average molecular weight of the polyvinyl alcohol-polyethylene glycol graft copolymer is about 45000g/mol (as determined by gel permeation chromatography),

13.57Wt.% of polyvinyl alcohol having an average molecular weight of about 31000g/mol (as determined by gel permeation chromatography),

-6.13Wt.% wt.% of (wt.) the preparation method of the glyceryl triacetate comprises the steps of,

2.33Wt.% of sucralose,

8.26Wt.%, sorbitol is used as a starting material for the food,

-0.1Wt.% is characterized in that the neotame of (a) is a compound of (b),

5Wt.% of a first flavoring agent, which is a cherry flavoring agent,

0.5Wt.% of a second flavoring agent, which is peppermint oil,

0.005Wt.% of a colorant which is erythrosine,

1.00Wt.% polysorbate 80,

And optionally residual process solvents, in particular water.

The dry area weight of the oral film is preferably 188g/m ².

The load of lurasidone hydrochloride per oral film is preferably 20mg or 40mg.

The size of the oral film is preferably 2.5cm ² or 5cm ².

Preparation method

The oral film according to the present invention can be prepared by a conventional method.

The definition above for oral films applies equally to the method according to the invention.

The method for manufacturing the oral film according to the present invention comprises the steps of:

a) Preparing a dispersion comprising lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 250000g/mol, in particular 20000 to 40000 g/mol;

b) Spreading the dispersion from step a), and

C) The spread dispersion was dried to give an oral film.

It will be appreciated that lurasidone, or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol are described hereinabove in the context of the matrix layer.

The process for preparing an oral film according to the invention preferably comprises the steps of:

a) Preparing a solution, dispersion or melt comprising lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000 g/mol;

a1 Optionally foaming the solution, dispersion or melt from step a) by introducing a gas or gas mixture, by chemical gas generation, or by expansion of dissolved gas,

B) Spreading the solution, dispersion or melt from step a) or the optionally foamed solution, dispersion or melt from step a 1),

C) Drying the spread solution, dispersion or melt from step b) to obtain an oral film.

It is clear to the person skilled in the art that step a 1) is only necessary when the matrix layer is to be provided in the form of a solidified foam with cavities.

The bubbles or cavities are preferably produced by means of a foaming machine, which can be used to set the diameter of the bubbles almost arbitrarily within a wide range.

The process solvent in step a) and/or a 1) preferably comprises water or water.

The drying in step C) preferably comprises drying at about 30 to 60 ℃ for about 15 to 60 minutes, in particular 30 minutes.

In a preferred embodiment, the lurasidone of step a), or a pharmaceutically acceptable salt thereof, is subjected to one or more of the steps of milling, deagglomeration and/or micronization prior to performing step a). These methods are well known to the skilled person and may be carried out by any means common in the art, for example by ball milling, jet milling, cryogenic milling, high pressure homogenisation, high shear mixing, wet milling and/or ultrasonic milling.

The oral film comprising the matrix layer may be manufactured using the methods described above using further manufacturing steps as known to those skilled in the art, such as stamping out individual oral films and packages, for example by sealing in a pouch of primary packaging material. These further steps preferably result in a mucoadhesive layer structure or an oral film, as described in the previous section.

The invention also relates to an oral film obtainable by the above method.

The film obtainable by the above-described method may have any or all of the properties as described above in the context of the matrix layer.

Therapeutic method/medical use

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

Furthermore, the present invention relates to an oral film as described above or obtainable by the above method as a medicament for lingual, sublingual and/or buccal administration, in particular for lingual administration. In certain embodiments, the OTF of the invention is administered sublingually and swallowed after rapid disintegration, i.e., in certain embodiments, the OTF is an orodispersible film.

Furthermore, the present invention relates to an oral film as described above or obtainable by the above method for the treatment of psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders.

The invention also relates to the use of an oral film as described above for the preparation of a medicament as described herein.

The invention also relates to a method for treating a patient comprising applying the above oral film, in particular a rapidly disintegrating oral film, to the tongue in the mouth of the patient.

The invention also relates to a method for the treatment of psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders, comprising applying an oral film, in particular a rapidly disintegrating oral film, as described above to the tongue in the mouth of a patient.

In accordance with the above, the present invention also relates to a method of treating a disease comprising administering to a patient in need thereof an oral film as described above or obtainable by the above method. The disease is preferably selected from psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders.

In accordance with the above, the present invention also relates to an oral film as described above or obtainable by the above method for use in a method of treatment. In a related aspect, the invention also relates to an oral film as described above or obtainable by the above method for the treatment of psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders.

The patient is preferably a human patient, more preferably a child, adult or senior.

Examples

A plurality of oral films were prepared by the method according to the invention and further analyzed.

The following methods were used to prepare the oral films of the examples, unless otherwise indicated. The formulation is prepared by appropriate standard laboratory equipment. First, lurasidone hydrochloride is weighed in a mass production vessel. Thereafter, the process solvent is added followed by the remaining excipients. No specific order of excipient addition is required. The material was stirred for at least 4h. Homogenized with UltraTurax homogenizer. The material was degassed at least overnight. The material was coated on the siliconized paper middle release liner using a coating knife with an appropriate gap width. The samples were dried using a heating and drying oven.

"Kollicoat IR" is a polyvinyl alcohol-polyethylene glycol graft copolymer having an average molecular weight of about 45000g/mol and a PEG/PVA monomer unit ratio of about 25:75.

"PVA 4-88" is a partially hydrolyzed polyvinyl alcohol having a degree of hydrolysis of about 88% and an average molecular weight of 31000g/mol.

"PVA 5-88" is a partially hydrolyzed polyvinyl alcohol having a degree of hydrolysis of about 88% and an average molecular weight of 37000g/mol.

"PVA 40-88" is a partially hydrolyzed polyvinyl alcohol having a degree of hydrolysis of about 88% and an average molecular weight of 205000g/mol.

"PEG 400" is polyethylene glycol having an average molecular weight of 400 g/mol.

"Polysorbate 80" is polyoxyethylene (20) sorbitan monooleate.

FD & C Red No.40 is alluring Red AC (disodium 7-hydroxy-5- [ (2-methoxy-5-methyl-4-sulfophenyl) diazenyl ] naphthalene-2-sulfonate).

The composition of these oral films is summarized in table 1.

Example 1 formulations A to G

Formulation a shows the best results because a smooth, non-brittle oral film can be provided in which a large number of APIs can be incorporated.

Oral films according to formulation a were further shown to be near commercialDissolution profile of 40mg tablet.

Preferred are oral films of formula a wherein the API is present in micronized form with the following parameters (as determined by laser diffraction method):

D_0.1 0μm

D₅₀ 2μm

D₉₀ 4.759μm

oral films of formula a in which the API is present in micronized form with the following parameters are less preferred because they exhibit a rougher surface and higher friability (as determined by laser diffraction):

D_0.1 8μm

D₅₀ 56μm

D₉₀ 213μm

Oral films of formulas B, C, D and E exhibited too long a disintegration time due to the use of high molecular weight polyvinyl alcohols 40-88 having an average molecular weight of about 205000 g/mol.

The disintegration time of formulation a was measured according to the european pharmacopoeia (ph.eur.) 2.9.1 as described below. The disintegration time of formulations B, C, D and E was estimated by placing the corresponding OTF in a horizontal bowl filled with water and visually observing.

The oral film of formulation F showed good disintegration time, good flexibility and no brittleness. In addition, the oral film of formulation E can be improved by increasing the amount of plasticizer.

The oral films of formulas F and G showed very similar characteristics to the oral film of formula a.

The incorporation of flavoring agents may alter the surface tension of the composition, which may lead to wetting problems, resulting in a disadvantageous oral film. To overcome this possible disadvantage, emulsifiers such as polysorbate 80 may be added.

Example 2 further characterization of formulation A

According to the method of the present invention, an oral film according to formula a was prepared using water as the process solvent. In a laboratory drying oven, the following parameters were used for drying.

1.30 ℃ For 10 minutes

2. A temperature program from 30 ℃ to 60 ℃ for 10 minutes

3.60 ℃ For 10 minutes

The resulting oral film showed 3.5% residual moisture. The assay was performed by karl fischer titration (KARL FISCHER titration) using a Metrohm 874 oven sample processor and 851KF Titrando.

In addition, the disintegration time of formulation A was determined,

Instrument disintegration measuring device according to European pharmacopoeia (Ph. Eur.) 2.9.1

Buffer solution, phosphate citrate buffer solution, pH 7.1

Temperature of 37+ -2 DEG C

Frequency 29-32 cycles

For the measurement, an oral film of formulation a with an area of 5cm ² was tested. For testing, the oral film was rolled up and placed in a spiral settling basket (e.g., sotax) to avoid floating of the oral film. The sedimentation basket was then placed into the basket support of the disintegration tester (1 sedimentation basket per tube). Then the measurement is started and the decay is visually checked.

Six measurements were made and the results are summarized in table 2:

table 2 results of measurements of disintegration time of oral films of formulation A.

Measurement of	Disintegration time s
		1	46
2	45
		3	45
4	37
		5	40
6	40
		Average of	42
RSD disintegration time	8.7%

For the marketDissolution of the 40mg tablets was measured and summarized in table 3:

Table 3: the dissolution time of a 40mg tablet at different pH values is given as the percentage of lurasidone released in the drug load of the tablet.

As shown by the data in table 3, lurasidone hydrochloride tablets @40 Mg) dissolved rapidly in dissolution medium at pH 1.2 (JP), pH 3.8 (JP) and pH 4.0 (JP), and dissolved slowly in water.

TABLE 4 dissolution times (average) of oral film compositions at different pH values

Performed under the following test conditionsIn vitro dissolution test of tablets and formulation A in vitro release analysis (https:// www.accessdata.fda.gov/scripts/cder/dissolution/index. Cfm (22.04.2022)) was performed according to the lurasidone tablet in vitro release test parameters mentioned in the FDA webpage. USP apparatus II (paddle) was used according to FDA information. However, an additional sinker was included to fix the OTF at the bottom of the container at the beginning of the analysis. The stirring speed was 50 revolutions per minute. Analysis was performed using 900mL of one of the four release media at 37 ± 0.5 ℃.

The following four release mediums were used:

The pH of the release medium is 1.2, the diluted hydrochloric acid solution.

The release medium pH was 3.8, a mixture of disodium hydrogen phosphate buffer and citric acid buffer.

The release medium pH was 4.5, a mixture of disodium hydrogen phosphate buffer and citric acid buffer.

The release medium pH was 6.8, a mixture of disodium hydrogen phosphate buffer and citric acid buffer.

The active agent release at different pH is further shown in FIGS. 1 and 2Release of 40mg tablet and oral film of formulation a.

The data shown in FIG. 1 indicate thatThe oral film according to formulation a had a faster dissolution time at low pH buffer than the 40mg tablet.

Thus, OTF is considered to be bioequivalent to Latuda tablets.

The data shown in fig. 2 demonstrate that oral films according to formulation a show slower dissolution times at higher pH values.

EXAMPLE 3 oral films of the prior art

Comparison of OTF of formulation a with film compositions known in the art.

Table 5 summarizes the film compositions known from Prabhu et al, int J App Pharm, volume 13, stage 1, 2021, 170-177. The disintegration time was determined as described therein by visual inspection in a petri dish with 10mL of phosphate buffer at pH 6.8, i.e. the disintegration time was remembered once the membrane had ruptured and slowly disintegrated.

Film compositions known from Prabhu et al, int J App Pharm, volume 13, phase 1, 2021,170-177 show longer disintegration times than oral films of formula a and have disadvantages in that these films are brittle due to the use of HPMC and in that these films have other disadvantages in that they exhibit an unpleasant (sticky) feel in the mouth of the user. Furthermore, the composition according to Prabhu et al does not correspond toTablets are bioequivalent because the Prabhu et al composition results in a faster achievement of C _max than tablets.

The film compositions from CN112618518a are summarized in table 6. Disintegration time was determined as described herein by wetting the filter paper with purified water and spreading it over a petri dish. The finished film was placed on top of a relatively wet filter paper. The time required for the film to completely disintegrate was recorded.

The film composition known from CN112618518a shows a fast disintegration time. But nevertheless these films have drawbacks in that they are brittle due to the use of HPMC, and in that they have other drawbacks in that they exhibit an unpleasant (sticky) feel in the mouth of the user.

Example 4 formulations J to O

Additional OTFs were prepared according to formulas J to O and compared to formula a. The compositions and results are summarized in table 7.

The folding test was performed by folding a single unit of 5cm ² (2 x 2:5 cm) size in a pouch. Folding the sample represents the worst case in terms of possible physical stresses that can be transferred to the sample. For analysis, the packaging material is folded about 170 ° -180 ° at the location of the individual units of the packaged test article. The standard 2kg tube was then rolled twice over the folded edge. Thereafter, the packaging material is slit. By carefully removing the sample from the packaging material, it is determined whether the sample is still intact or broken into two parts.

The tensile strength was measured according to the method of fixing a single unit of the test product with two jaws in a tensile strength tester. The distance between the upper and lower jaws should be 10mm. When the sample is fixed, the upper clamp moves up on the 10mm measurement path at a speed of 300 mm/min. The maximum force required to tear an individual cell is determined in newtons (N).

The degree of disintegration is determined according to the European pharmacopoeia as described above.

Puncture strength was measured by fixedly mounting a digital dynamometer. The sample (20 x 25 mm) was fixed to the rim and pressed against the test surface of the device (circular test surface with a diameter of 5 mm). The applied force increases until the OTF is pierced. The maximum value of the force (N) acting on the specimen until it is pierced or ruptured is recorded. Measurements were made with n=3 laminated samples per batch.

Formulations N and O show so high brittleness that they break during removal of the intermediate release liner (see table below, indicating that these formulations are not processable), indicating that formulating OTFs with very high loadings of lurasidone hydrochloride is challenging and it may be preferable to limit the concentration of lurasidone hydrochloride to less than 60wt.%, e.g., less than 55wt.% or 53wt.%. Formulations a and J to M show acceptable mechanical properties and disintegration behavior. In particular, formulation a has excellent tensile strength, indicating that this formulation produces OTF with particularly beneficial mechanical properties. For example, formulation J still exhibited acceptable tensile strength. Formulation K shows the highest puncture strength, which further supports that on average, low molecular weight PVA can be advantageously used if particularly high mechanical strength is required. On the other hand, the disintegration time is less affected by the PVA molecular weight, indicating that the mechanical properties can be fine-tuned while maintaining a good disintegration curve.

EXAMPLE 5 stability Studies

Two different sizes of OTFs (2.5 cm ² and 5cm ²) were prepared from formulation A. The test was performed at 40℃/75% RH for 6 months, at 25℃/60% RH for 9 months, and at 30℃/65% RH for 10 months. All measurements were repeated six times. All OTFs stored under all conditions were found to meet the required test parameters. Illustratively, the following test parameters (averages) are determined for 5cm ² OTF stored for 9 months at 25 ℃):

the appearance meets the requirements, the light pink is opaque OTF, and no abnormality exists

Content of 102.7%

According to European pharmacopoeia, the dissolution rate after 2.9.3,45 minutes is 98%

According to the content uniformity of European pharmacopoeia 2.9.40

Degradation products of <0.1% total impurities

Disintegration time of 48s

Water content 5.2%

Folding test of meeting the requirements

Tensile Strength of 8.6N

The invention relates in particular to the following further embodiments:

1. an oral film comprising a matrix layer, wherein the matrix layer comprises lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000 g/mol.

2. The oral film of embodiment 1, wherein lurasidone, or a pharmaceutically acceptable salt thereof, is provided in the matrix layer in an amount of 35 to 50wt.%, preferably 40 to 45wt.%, relative to the total weight of the matrix layer.

3. The oral film of any of the preceding embodiments, wherein at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone with grafted polyvinyl alcohol units thereon.

4. The oral film of any of the preceding embodiments, wherein at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone with grafted polyvinyl alcohol units thereon, wherein the molar ratio of polyethylene glycol to polyvinyl alcohol is 1:3.

5. The oral film of any of the preceding embodiments, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has an average molecular weight ranging from 40000 to 50000g/mol, preferably about 45000g/mol.

6. The oral film according to any of the preceding embodiments, wherein at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5 to 20wt.%, preferably 10 to 15wt.%, relative to the total weight of the matrix layer.

7. The oral film of any of the preceding embodiments, wherein at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 10 to 35wt.%, preferably 15 to 25wt.%, relative to the total weight of the matrix layer.

8. The oral film of any preceding embodiment, wherein the matrix layer comprises at least one plasticizer.

9. The oral film of any preceding embodiment, wherein the matrix layer comprises at least one emulsifier.

10. The oral film of any of the preceding embodiments, wherein the matrix layer further comprises at least one auxiliary substance selected from the group consisting of colorants, flavors, sweeteners, taste masking agents, enhancers, pH modifiers, humectants, preservatives, and/or antioxidants.

11. The oral film according to any of the preceding embodiments, wherein lurasidone or a pharmaceutically acceptable salt thereof is present in particulate form, in particular in particulate form having a D ₉₀ of 1 to 20 μm, preferably 1 to 10 μm.

12. The oral film of any one of the preceding embodiments, wherein lurasidone, or a pharmaceutically acceptable salt thereof, is substantially insoluble in the matrix layer.

13. The oral film according to any of the preceding embodiments, wherein the oral film has an areal density of 50 to 300g/m ², preferably 150 to 250g/m ².

14. The oral film of any one of the preceding embodiments, wherein the lurasidone or a pharmaceutically acceptable salt thereof comprises lurasidone hydrochloride in a total amount of 25 to 55mg, preferably about 40 mg.

15. The oral film of any one of the preceding embodiments, wherein at least 70% or at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after administration at a pH of 3.8.

16. The oral film of any one of the preceding embodiments, wherein the oral film comprises:

42.535wt.% lurasidone hydrochloride,

20.57Wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

13.57Wt.% of a polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol, in particular 31000g/mol,

6.13Wt.% of glyceryl triacetate,

2.33Wt.% of sucralose,

-8.26Wt.% sorbitol is used as a starting material for the food,

0.1Wt.% neotame,

5Wt.% of a first flavoring agent, in particular cherry flavoring agent,

0.5Wt.% of a second flavoring agent, in particular peppermint oil,

0.005Wt.% of a colorant, in particular erythrosine,

1.00Wt.% polysorbate 80,

And optionally residual process solvents, in particular water.

17. A process for preparing an oral film according to any one of the preceding embodiments, comprising the steps of:

a) Preparing a solution, dispersion or melt comprising lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000 g/mol;

a1 Foaming the solution, dispersion or melt from step a) optionally by introducing a gas or gas mixture, by chemical gas generation, or by expansion of dissolved gases,

B) Spreading the solution, dispersion or melt from step a), or the optionally foamed solution, dispersion or melt from step a 1),

C) Drying the spread solution, dispersion or melt from step b) to obtain an oral film.

18. An oral film according to any one of embodiments 1 to 16 or obtainable by the method according to embodiment 17 for use as a medicament.

19. An oral film according to any one of embodiments 1 to 16 or obtainable by a method according to embodiment 17 for use in the treatment of psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders.

The invention relates in particular to the following further items:

1. an oral film comprising a matrix layer, wherein the matrix layer comprises lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000 g/mol.

2. The oral film of item 1, wherein the lurasidone, or a pharmaceutically acceptable salt thereof, is provided in the matrix layer in an amount of from 35 to 55wt.%, preferably from 35 to 53wt.%, more preferably from 40 to 45wt.%, relative to the total weight of the matrix layer.

3. The oral film of item 1 or 2, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone with grafted polyvinyl alcohol units thereon.

4. The oral film of any one of the preceding items, wherein the molar ratio of polyethylene glycol monomer units to polyvinyl alcohol monomer units is 1:3.

5. The oral film of any preceding item, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has an average molecular weight in the range of 40000 to 50000g/mol, preferably about 45000g/mol.

6. The oral film of any preceding item, wherein the at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5 to 30wt.%, preferably 10 to 25wt.%, relative to the total weight of the matrix layer.

7. The oral film of any preceding item, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 5wt.% to 35wt.%, preferably 10wt.% to 30wt.%, relative to the total weight of the matrix layer.

8. The oral film of any preceding item, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer and the at least one polyvinyl alcohol are present in a combined amount of 25 to 65wt.%, preferably 30 to 60wt.%, more preferably 30 to 45wt.%, relative to the total weight of the matrix layer.

9. The oral film of any one of the preceding items, wherein the matrix layer comprises at least one plasticizer, preferably selected from polyethylene glycol, glycerol and glyceryl triacetate, preferably wherein the at least one plasticizer is glyceryl triacetate.

10. The oral film of item 8, wherein the plasticizer is present in an amount of 1 to 15wt.%, preferably 4 to 10wt.%, most preferably 5 to 10 wt.%.

11. The oral film of any preceding item, wherein the matrix layer comprises at least one emulsifier, preferably selected from polyoxyethylene- (20) -sorbitan monooleate, polyoxyethylene- (20) -sorbitan monostearate, monoglycerides and diacetyl esters of diglycerides, most preferably wherein the emulsifier is polyoxyethylene- (20) -sorbitan monooleate.

12. The oral film of any one of the preceding items, wherein the matrix layer comprises at least one emulsifier in an amount of 0.1wt.% to 2wt.%, preferably 0.5wt.% to 1.5wt.%, relative to the total weight of the matrix layer.

13. The oral film of any preceding item, wherein the matrix layer further comprises at least one auxiliary substance selected from the group consisting of colorants, flavors, sweeteners, taste masking agents, enhancers, pH modifiers, humectants, preservatives, and/or antioxidants.

14. The oral film of any one of the preceding items, wherein the lurasidone or a pharmaceutically acceptable salt thereof is present in the form of particles, preferably with

-D ₉₀ is 1 to 100 μm, preferably 1 to 10 μm, and/or

-D ₅₀ is 0.1 to 25 μm, preferably 0.5 to 5 μm.

15. The oral film of any one of the preceding items, wherein the lurasidone, or a pharmaceutically acceptable salt thereof, is substantially insoluble in the matrix layer.

16. The oral film of any preceding claim, wherein the oral film has an areal density of 50 to 300g/m ², preferably 150 to 250g/m ².

17. The oral film of any one of the preceding items, wherein the lurasidone or a pharmaceutically acceptable salt thereof is provided in the matrix layer in an amount of from 35 to 55wt.%, preferably from 35 to 53wt.%, relative to the total weight of the matrix layer, and wherein the oral film has an area density of from 50 to 300g/m ², preferably from 150 to 250g/m ².

18. The oral film of any one of the preceding items, wherein the lurasidone or a pharmaceutically acceptable salt thereof comprises lurasidone hydrochloride in a total amount of 15mg to 55mg, preferably 25mg to 55mg, most preferably about 40 mg.

19. The oral film according to any of the preceding items, having an in vitro disintegration time of from 10 to 120 seconds, preferably from 15 to 60 seconds.

20. The oral film according to any of the preceding items, having a tensile strength of 3 to 15N, preferably 5 to 15N.

21. The oral film of any one of the preceding items, wherein at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after immersion in an aqueous solution having a pH of 1.2 at a temperature of 37±0.5 ℃, and/or at least 90% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after immersion in an aqueous solution having a pH of 3.8 at a temperature of 37±0.5 ℃.

22. The oral film of any one of the preceding items, wherein at least 70% or at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after being immersed in an aqueous solution having a pH of 3.8.

23. The oral film of any one of the preceding items, wherein the oral film comprises:

40 to 45wt.% lurasidone hydrochloride,

10 To 25wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

10 To 25wt.% of a polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol,

4 To 10wt.% of a plasticizer, in particular glyceryl triacetate,

5 To 15wt.% of a sweetener, preferably a mixture of sucralose, sorbitol, and neotame,

2.5 To 7.5wt.% of a first flavoring agent, in particular cherry flavoring agent,

0 To 2.5wt.% of a second flavoring agent, in particular peppermint oil,

0 To 2wt.% of a colorant, in particular erythrosine,

0.5 To 2wt.% of an emulsifier, in particular polyoxyethylene- (20) -sorbitan monooleate, and optionally a residual process solvent, in particular water.

24. The oral film of any one of the preceding items, wherein the oral film is obtainable by drying a coated coating composition comprising lurasidone, polyvinyl alcohol-polyethylene glycol graft copolymer, and water.

25. A method of preparing an oral film comprising:

a) Preparing a dispersion comprising lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000 g/mol;

b) Spreading the dispersion from step a), and

C) Drying the spread dispersion to obtain a matrix layer.

26. The method of item 25, wherein the oral film comprises or consists of the matrix layer.

27. The method of any one of clauses 25 or 26, wherein the lurasidone or a pharmaceutically acceptable salt thereof is provided in the matrix layer in an amount of 35 to 55wt.%, preferably 35 to 53wt.%, more preferably 40 to 45wt.%, relative to the total weight of the matrix layer.

28. The method of any one of clauses 25 to 27, wherein the at least one polyvinyl alcohol has an average molecular weight of 20000 to 40000 g/mol.

29. The method of any one of clauses 25 to 28, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone with grafted polyvinyl alcohol units thereon, preferably wherein the molar ratio of polyethylene glycol monomer units to polyvinyl alcohol monomer units is 1:3.

30. The method of any one of clauses 25 to 29, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has an average molecular weight in the range of 40000 to 50000g/mol, preferably about 45000g/mol.

31. The method of any one of items 25 to 30, wherein the at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5 to 30wt.%, preferably 10 to 25wt.%, relative to the total weight of the matrix layer.

32. The method of any one of clauses 25 to 31, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 5 to 35wt.%, preferably 10 to 30wt.%, relative to the total weight of the matrix layer.

33. The method of any one of clauses 25 to 32, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer and the at least one polyvinyl alcohol are present in a combined amount of 25 to 65wt.%, preferably 30 to 60wt.%, more preferably 30 to 45wt.%, based on the total weight of the matrix layer.

34. The method of any one of clauses 25 to 33, wherein the dispersion comprises at least one plasticizer, preferably selected from the group consisting of polyethylene glycol, glycerol, and glyceryl triacetate, preferably wherein the at least one plasticizer is glyceryl triacetate.

35. The method of clause 34, wherein the plasticizer is present in an amount of 1 to 15wt.%, preferably 4 to 10wt.%, most preferably 5 to 10 wt.%.

36. The method of any of clauses 25 to 35, wherein the dispersion comprises at least one emulsifier, preferably selected from polyoxyethylene- (20) -sorbitan monooleate, polyoxyethylene- (20) -sorbitan monostearate, diacetyl esters of mono-and diglycerides, most preferably wherein the emulsifier is polyoxyethylene- (20) -sorbitan monooleate.

37. The method of item 36, wherein the matrix layer comprises at least one emulsifier in an amount of 0.1 to 2wt.%, preferably 0.5 to 1.5wt.%, relative to the total weight of the matrix layer.

38. The method of any of clauses 25 to 37, wherein the matrix layer further comprises at least one auxiliary substance selected from the group consisting of colorants, flavors, sweeteners, taste masking agents, enhancers, pH modifiers, humectants, preservatives, and/or antioxidants.

39. The method of any one of clauses 25 to 38, wherein lurasidone, or a pharmaceutically acceptable salt thereof, is present in particulate form, preferably having

-D ₉₀ is 1 to 100 μm, preferably 1 to 10 μm, and/or

-D ₅₀ is 0.1 to 25 μm, preferably 0.5 to 5 μm.

40. The method of any one of clauses 25 to 39, wherein said lurasidone or a pharmaceutically acceptable salt thereof is substantially insoluble in said dispersion and said matrix layer.

41. The method of any one of clauses 25 to 40, wherein the oral film has an areal density of 50 to 300g/m ², preferably 150 to 250g/m ².

42. The method of any one of clauses 25 to 41, wherein the lurasidone or a pharmaceutically acceptable salt thereof is provided in the matrix layer in an amount of 35 to 55wt.%, preferably 35 to 53wt.%, relative to the total weight of the matrix layer, and wherein the oral film has an area density of 50 to 300g/m ², preferably 150 to 250g/m ².

43. The method of any one of clauses 25 to 42, wherein the lurasidone or a pharmaceutically acceptable salt thereof comprises lurasidone hydrochloride in a total amount of 15mg to 55mg, preferably 25mg to 55mg, most preferably about 40 mg.

44. The method of any one of items 25 to 43, wherein the oral film has an in vitro disintegration time of 10 to 120 seconds, preferably 15 to 60 seconds.

45. The method of any one of items 25 to 44, wherein the oral film has a tensile strength in the range of 3-15N, preferably 5-15N.

46. The method of any one of clauses 25 to 45, wherein the oral film releases at least 80% of the lurasidone or a pharmaceutically acceptable salt thereof in the first 15 minutes after being immersed in an aqueous solution having a pH of 1.2 at a temperature of 37 ± 0.5 ℃ and/or releases at least 90% of the lurasidone or a pharmaceutically acceptable salt thereof in the first 15 minutes after being immersed in an aqueous solution having a pH of 3.8 at a temperature of 37 ± 0.5 ℃.

47. The method of any one of clauses 25 to 46, wherein at least 70% or at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released in the first 15 minutes after being immersed in the aqueous solution having a pH of 3.8.

48. The method of any one of items 25 to 47, wherein the oral film comprises:

40 to 45wt.% lurasidone hydrochloride,

10 To 25wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

10 To 25wt.% of a polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol,

4 To 10wt.% of a plasticizer, in particular glyceryl triacetate,

5 To 15wt.% of a sweetener, preferably a mixture of sucralose, sorbitol, and neotame,

2.5 To 7.5wt.% of a first flavoring agent, in particular cherry flavoring agent,

0 To 2.5wt.% of a second flavoring agent, in particular peppermint oil,

0 To 2wt.% of a colorant, in particular erythrosine,

0.5 To 2wt.% of an emulsifier, in particular polyoxyethylene- (20) -sorbitan monooleate, and optionally a residual process solvent, in particular water.

49. The method of any one of clauses 25 to 48, wherein said oral film is obtainable by drying a spread dispersion comprising lurasidone, polyvinyl alcohol-polyethylene glycol graft copolymer, and water.

50. The oral film according to any one of items 1 to 24 or obtainable by the method of any one of items 25 to 49 for use as a medicament, preferably for the treatment of psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders.

51. Use of an oral film according to any one of items 1 to 24 or obtainable by a method according to any one of items 25 to 49 in the manufacture of a medicament, preferably for the treatment of a psychotic disorder, in particular schizophrenia, depression and/or bipolar disorder.

52. A method of treatment comprising administering to a patient in need thereof the oral film of any one of items 1 to 24 or an oral film obtainable by the method of any one of items 25 to 49.

53. The method of treatment of item 52, wherein the method of treatment is a method of treating a psychotic disorder, particularly schizophrenia, depression and/or bipolar disorder.

54. The oral film for use of item 50, the use of item 51 in the manufacture of a medicament, or the method of treatment of any one of items 52 or 53, wherein the lurasidone, or a pharmaceutically acceptable salt thereof, is provided in the matrix layer in an amount of 35 to 55wt.%, preferably 35 to 53wt.%, more preferably 40 to 45wt.%, relative to the total weight of the matrix layer.

55. The oral film for use of item 50 or 54, the use of item 51 or 54 in the manufacture of a medicament, or the method of treatment of any one of items 52, 53, or 54, wherein the at least one polyvinyl alcohol has an average molecular weight of 20000 to 40000 g/mol.

56. The oral film for use according to any one of items 50, 54 and 55, the use of any one of items 51, 54 and 55 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 55, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone with grafted polyvinyl alcohol units thereon, preferably wherein the molar ratio of polyethylene glycol monomer units to polyvinyl alcohol monomer units is 1:3.

57. The oral film for use according to any one of items 50 and 54 to 56, the use of any one of items 51 and 54 to 56 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 56, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has an average molecular weight in the range 40000 to 50000g/mol, preferably about 45000g/mol.

58. The oral film for use according to any one of items 50 and 54 to 57, the use of any one of items 51 and 54 to 57 in the manufacture of a medicament or the method of treatment of any one of items 52 to 57, wherein the at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5 to 30wt.%, preferably 10 to 25wt.%, relative to the total weight of the matrix layer.

59. The oral film for use according to any one of items 50 and 54 to 58, the use of any one of items 51 and 54 to 58 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 58, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 5 to 35wt.%, preferably 10 to 30wt.%, relative to the total weight of the matrix layer.

60. The oral film for use of any one of items 50 and 54-59, the use of any one of items 51 and 54-59 in the manufacture of a medicament, or the method of treatment of any one of items 52-59, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer and the at least one polyvinyl alcohol are present in a combined amount of 25 to 65wt.%, preferably 30 to 60wt.%, more preferably 30 to 45wt.%, based on the total weight of the matrix layer.

61. The oral film for use according to any one of items 50 and 54 to 60, the use of any one of items 51 and 54 to 60 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 60, wherein the matrix layer comprises at least one plasticizer, preferably selected from polyethylene glycol, glycerol and glyceryl triacetate, preferably wherein the at least one plasticizer is glyceryl triacetate.

62. The oral film for use according to item 61, the use of the oral film according to item 61 in the manufacture of a medicament, or the method of treatment according to item 61, wherein the plasticizer is present in an amount of 1 to 15wt.%, preferably 4 to 10wt.%, and most preferably 5 to 10 wt.%.

63. The oral film for use according to any one of items 50 and 54 to 62, the use of any one of items 51 and 54 to 62 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 62, wherein the matrix layer comprises at least one emulsifier, preferably selected from polyoxyethylene- (20) -sorbitan monooleate, polyoxyethylene- (20) -sorbitan monostearate, diacetyl esters of monoglycerides and diglycerides, most preferably wherein the emulsifier is polyoxyethylene- (20) -sorbitan monooleate.

64. The oral film for use according to any one of items 50 and 54 to 63, the use of any one of items 51 and 54 to 63 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 63, wherein the matrix layer comprises at least one emulsifier in an amount of 0.1 to 2wt.%, preferably 0.5 to 1.5wt.%, based on the total weight of the matrix layer.

65. The oral film for use according to any one of items 50 and 54 to 64, the use of any one of items 51 and 54 to 64 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 64, wherein the matrix layer further comprises at least one auxiliary substance selected from the group consisting of colorants, flavourings, sweeteners, taste masking agents, enhancers, pH-adjusting agents, humectants, preservatives and/or antioxidants.

66. The oral film for use according to any one of items 50 and 54 to 65, the use of any one of items 51 and 54 to 65 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 65, wherein the lurasidone or a pharmaceutically acceptable salt thereof is present in particulate form, preferably with

-D ₉₀ is 1 to 100 μm, preferably 1 to 10 μm, and/or

-D ₅₀ is 0.1 to 25 μm, preferably 0.5 to 5 μm.

67. The oral film for use of any one of items 50 and 54 to 66, the use of any one of items 51 and 54 to 66 in the manufacture of a medicament, or the method of treatment of any one of items 52 to 66, wherein lurasidone, or a pharmaceutically acceptable salt thereof, is substantially insoluble in the matrix layer.

68. The oral film for use of any one of items 50 and 54 to 67, the use of any one of items 51 and 54 to 67 in the manufacture of a medicament or the method of treatment of any one of items 52 to 67, wherein the oral film has an areal density of 50 to 300g/m ², preferably 150 to 250g/m ².

69. The oral film for use of any one of items 50 and 54 to 68, the use of any one of items 51 and 54 to 68 in the manufacture of a medicament, or the method of treatment of any one of items 52 to 68, wherein the lurasidone, or a pharmaceutically acceptable salt thereof, is provided in the matrix layer in an amount of 35 to 55wt.%, preferably 35 to 53wt.%, relative to the total weight of the matrix layer, and wherein the oral film has an areal density of 50 to 300g/m ², preferably 150 to 250g/m ².

70. The oral film for use of any one of items 50 and 54 to 69, the use of any one of items 51 and 54 to 69 in the manufacture of a medicament or the method of treatment of any one of items 52 to 69, wherein the lurasidone or a pharmaceutically acceptable salt thereof comprises lurasidone hydrochloride in a total amount of 15mg to 55mg, preferably 25mg to 55mg, most preferably about 40 mg.

71. The oral film for use according to any one of items 50 and 54 to 70, the use of any one of items 51 and 54 to 70 in the manufacture of a medicament or the method of treatment according to any one of items 52 to 70, wherein the oral film has an in vitro disintegration time of from 10 to 120 seconds, preferably from 15 to 60 seconds.

72. The oral film for use of any one of items 50 and 54 to 71, the use of any one of items 51 and 54 to 71 in the manufacture of a medicament or the method of treatment of any one of items 52 to 71, wherein the oral film has a tensile strength of 3-15N, preferably 5-15N.

73. The oral film for use of any one of items 50 and 54 to 72, the use of any one of items 51 and 54 to 72 in the manufacture of a medicament, or the method of treatment of any one of items 52 to 72, wherein the oral film releases at least 80% of the lurasidone or a pharmaceutically acceptable salt thereof within the first 15 minutes after immersion in an aqueous solution having a pH of 1.2 at a temperature of 37±0.5 ℃ and/or releases at least 90% of the lurasidone or a pharmaceutically acceptable salt thereof within the first 15 minutes after immersion in an aqueous solution having a pH of 3.8 at a temperature of 37±0.5 ℃.

74. The oral film of any one of items 50 and 54-73, the use of any one of items 51 and 54-73 in the manufacture of a medicament, or the method of treatment of any one of items 52-73, wherein at least 70% or at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after being immersed in an aqueous solution at a pH of 3.8.

75. The oral film for use of any one of items 50 and 54 to 74, the use of any one of items 51 and 54 to 74 in the manufacture of a medicament or the method of treatment of any one of items 52 to 74, wherein the oral film comprises:

40 to 45wt.% lurasidone hydrochloride,

10 To 25wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

10 To 25wt.% of a polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol,

4 To 10wt.% of a plasticizer, in particular glyceryl triacetate,

5 To 15wt.% of a sweetener, preferably a mixture of sucralose, sorbitol, and neotame,

2.5 To 7.5wt.% of a first flavoring agent, in particular cherry flavoring agent,

0 To 2.5wt.% of a second flavoring agent, in particular peppermint oil,

0 To 2wt.% of a colorant, in particular erythrosine,

0.5 To 2wt.% of an emulsifier, in particular polyoxyethylene- (20) -sorbitan monooleate, and optionally a residual process solvent, in particular water.

76. The oral film for use of any one of items 50 and 54 to 75, the use of any one of items 51 and 54 to 75 in the manufacture of a medicament, or the method of treatment of any one of items 52 to 75, wherein the oral film is obtainable by drying a coated coating composition comprising lurasidone, polyvinyl alcohol, a polyvinyl alcohol-polyethylene glycol graft copolymer, and water.

Claims (27)

1. An oral film comprising a matrix layer, wherein the matrix layer comprises lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000 g/mol.

2. The oral film of claim 1, wherein lurasidone or a pharmaceutically acceptable salt thereof is provided in the matrix layer in an amount of 35 to 55wt.%, preferably 35 to 53wt.%, more preferably 40 to 45wt.%, relative to the total weight of the matrix layer.

3. The oral film of claim 1 or 2, wherein at least one polyvinyl alcohol-polyethylene glycol graft copolymer has a polyethylene glycol backbone with grafted polyvinyl alcohol units thereon.

4. The oral film of any of the preceding claims, wherein the molar ratio of polyethylene glycol monomer units to polyvinyl alcohol monomer units is 1:3.

5. The oral film of any of the preceding claims, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer has an average molecular weight in the range of 40000 to 50000g/mol, preferably about 45000g/mol.

6. The oral film according to any of the preceding claims, wherein at least one polyvinyl alcohol is provided in the matrix layer in an amount of 5 to 30wt.%, preferably 10 to 25wt.%, relative to the total weight of the matrix layer.

7. The oral film according to any of the preceding claims, wherein at least one polyvinyl alcohol-polyethylene glycol graft copolymer is provided in the matrix layer in an amount of 5 to 35wt.%, preferably 10 to 30wt.%, relative to the total weight of the matrix layer.

8. The oral film of any preceding claim, wherein the at least one polyvinyl alcohol-polyethylene glycol graft copolymer and the at least one polyvinyl alcohol are present in a combined amount of 25 to 65wt.%, preferably 30 to 60wt.%, more preferably 30 to 45wt.%, relative to the total weight of the matrix layer.

9. The oral film of any preceding claim, wherein the matrix layer comprises at least one plasticizer, preferably selected from polyethylene glycol, glycerol and glyceryl triacetate, preferably wherein at least one plasticizer is glyceryl triacetate.

10. The oral film of claim 9, wherein the plasticizer is present in an amount of 1 to 15wt.%, preferably 4 to 10wt.%, most preferably 5 to 10 wt.%.

11. The oral film of any preceding claim, wherein the matrix layer comprises at least one emulsifier, preferably selected from polyoxyethylene- (20) -sorbitan monooleate, polyoxyethylene- (20) -sorbitan monostearate, monoglycerides and diacetyl esters of diglycerides, most preferably wherein the emulsifier is polyoxyethylene- (20) -sorbitan monooleate.

12. The oral film of any preceding claim, wherein the matrix layer comprises at least one emulsifier in an amount of 0.1 to 2wt.%, preferably 0.5 to 1.5wt.%, based on the total weight of the matrix layer.

13. The oral film of any of the preceding claims, wherein the matrix layer further comprises at least one auxiliary substance selected from colorants, flavors, sweeteners, taste masking agents, enhancers, pH adjusters, humectants, preservatives, and/or antioxidants.

14. The oral film according to any of the preceding claims, wherein lurasidone or a pharmaceutically acceptable salt thereof is present in particulate form, preferably with

-D ₉₀ is 1 to 20 μm, preferably 1 to 10 μm, and/or

-D ₅₀ is 0.1 to 25 μm, preferably 0.5 to 5 μm.

15. The oral film of any one of the preceding claims, wherein lurasidone, or a pharmaceutically acceptable salt thereof, is substantially insoluble in the matrix layer.

16. The oral film of any one of the preceding claims, wherein the oral film has an areal density of 50 to 300g/m ², preferably 150 to 250g/m ².

17. The oral film of any one of the preceding claims, wherein the lurasidone or pharmaceutically acceptable salt thereof is provided in the matrix layer in an amount of from 35 to 55wt.%, preferably from 35 to 53wt.%, relative to the total weight of the matrix layer, and wherein the oral film has an areal density of from 50 to 300g/m ², preferably from 150 to 250g/m ².

18. The oral film of any of the preceding claims, wherein the lurasidone or a pharmaceutically acceptable salt thereof comprises lurasidone hydrochloride in a total amount of 15 to 55mg, preferably 25 to 55mg, and most preferably about 40 mg.

19. The oral film according to any of the preceding claims, having an in vitro disintegration time of from 10 to 120 seconds, preferably from 15 to 60 seconds.

20. The oral film of any preceding claim, having a tensile strength of 3 to 15N, preferably 5 to 15N.

21. The oral film of any of the preceding claims, wherein at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after immersion in an aqueous solution having a pH of 1.2 at a temperature of 37±0.5 ℃, and/or at least 90% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes after immersion in an aqueous solution having a pH of 3.8 at a temperature of 37±0.5 ℃.

22. The oral film of any of the preceding claims, wherein at least 70% or at least 80% of the lurasidone, or a pharmaceutically acceptable salt thereof, is released within the first 15 minutes of being immersed in an aqueous solution having a pH of 3.8.

23. The oral film of any one of the preceding claims, wherein the oral film comprises:

40 to 45wt.% lurasidone hydrochloride,

10 To 25wt.% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

10 To 25wt.% of a polyvinyl alcohol having an average molecular weight of 20000 to 40000g/mol,

4 To 10wt.% of a plasticizer, in particular glyceryl triacetate,

5 To 15wt.% of a sweetener, preferably a mixture of sucralose, sorbitol, and neotame,

2.5 To 7.5wt.% of a first flavoring agent, in particular cherry flavoring agent,

0 To 2.5wt.% of a second flavoring agent, in particular peppermint oil,

0 To 2wt.% of a colorant, in particular erythrosine,

From 0.5 to 2wt.% of an emulsifier, in particular polyoxyethylene- (20) -sorbitan monooleate,

And optionally residual process solvents, in particular water.

24. The oral film of any one of the preceding claims, wherein the oral film is obtainable by drying a coated coating composition comprising lurasidone, polyvinyl alcohol-polyethylene glycol graft copolymer, and water.

25. A method for preparing an oral film:

a) Preparing a dispersion comprising lurasidone or a pharmaceutically acceptable salt thereof, at least one polyvinyl alcohol-polyethylene glycol graft copolymer, and at least one polyvinyl alcohol having an average molecular weight of 20000 to 40000 g/mol;

b) Spreading the dispersion from step a),

C) Drying the spread dispersion from step b) to obtain a matrix layer of the oral film.

26. Use of an oral film according to any one of claims 1 to 24 or obtainable by a method according to claim 25 in the manufacture of a medicament.

27. Use of an oral film according to any one of claims 1 to 24 or obtainable by a method according to claim 25 in the manufacture of a medicament for the treatment of psychotic disorders, in particular schizophrenia, depression and/or bipolar disorders.