ORODISPERSIBLE FILM

FIELD OF THE INVENTION

[001] The present invention relates to pharmaceutical compositions, in particular, it relates to orodispersible films. The present invention further relates to film forming suspensions and to processes for preparing the orodispersible films and the film forming suspensions.

BACKGROUND OF THE INVENTION

[002] The oral administration of drugs still represents the most widely used method of administration. Traditional forms of administration are, for example, tablets or capsules, which are generally swallowed. However, this requires that the patient has access to a liquid and is capable of holding e.g. a glass of water, with which he can take the dosage form. To some extent, however, particularly in elderly persons and children who have a narrower esophagus, there is discomfort in swallowing, such that these patients refuse the intake of tablets or capsules, or the intake only happens reluctantly. This, not infrequently, results in poor medication compliance, which has adverse effects for the healing progress and the success of the therapy.

[003] Even in groups of patients with mental illnesses, for which monitoring of the actual medication intake is essential, the administration of conventional dosage forms such as tablets or capsules is not unproblematic. Due to delayed disintegration, such carriers of active ingredients can easily be removed from the mouth, without being noticed by the supervising medical personnel.

[004] To overcome these problems, pharmaceutical dosage forms have been developed, such as for example granules or oral films which can be taken without fluids and which disintegrate rapidly in the oral cavity.

[005] Oral films are characterized for example by the fact that they have a low thickness and a large surface and are able to disintegrate in short time in the oral cavity. Depending on the patient's needs, they can be taken anytime and anywhere and also discretely. Furthermore, a simultaneous intake of liquid is not necessary, because the salivary fluid in the oral cavity is sufficient to dissolve the film and release the drug. [006] Oral films containing pharmaceutical and non-pharmaceutical active ingredients, and processes for their preparation are described, for example, in WO 2007/009800, WO 2007/009801 and WO 03/01 1259.

[007] A homogeneous distribution of the active pharmaceutical ingredient (API) in the oral film is essential to achieve an excellent product complying with regulatory requirements. If the API is well soluble, a solution can be prepared by dissolving and re-stabilizing it by means of a solid solution with a polymer. However, if the API is poorly soluble a suspension has to be prepared. In such case, suspensions are frequently affected by the problems of sedimentation and aggregation (self- aggregation). The latter may also occur during the film-forming process.

[008] Films suffering from the aggregation or conglomeration of particles, i.e., self- aggregation, are inherently non-uniform.

[009] The formation of agglomerates randomly distributes the film components and any active pharmaceutical ingredient present as well. When large dosages are involved, a small change in the dimensions of the film would lead to a large difference in the amount of API in the film. If such films were to include low dosages of API, it is possible that portions of the film may be substantially devoid of any API. Sheets of film are usually cut into unit doses; certain doses may, therefore, be devoid of or contain an insufficient amount of API for the recommended treatment. Failure to achieve a high degree of accuracy with respect to the amount of API in the cut film can be harmful to the patient.

[0010] It is an object of the present invention to provide an orodispersible film which is subject to less aggregation in its components, in particular API containing film components should not aggregate. Hence, it is an object of the present invention to provide an orodispersible film with a uniform distribution of all the components or constituents thereof, in particular a uniform distribution of the API in the film. It is an object of the present invention to provide a film forming suspension that is not affected by sedimentation problems or aggregation problems and that allows preparing non-aggregated films with a uniform (homogeneous) distribution of the API. It is a further object of the present invention to provide a process for preparing uniform orodispersible films with an even API distribution and a process for preparing stable non-self-aggregating film forming suspensions. SUMMARY OF THE INVENTION

[0011] The above mentioned problems are solved by the orodispersible films of the invention. The orodispersible films of the invention comprise a low soluble API and a surfactant having specific solubility characteristics. The orodispersible films of the invention are uniform films free from aggregates, in particular API aggregates.

[0012] Hence, in a first aspect the present invention relates to an orodispersible film comprising:

a) an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP; and

b) at least one surfactant

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

[0013] In a second aspect, the present invention provides a film forming suspension comprising:

a) an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP;

b) at least one surfactant

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and c) water or a mixture of water and at least a solvent selected from a (d.

C ₅ )-alcohol, acetone and mixtures thereof; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

[0014] In a third aspect, the present invention is directed to a method for preparing an orodispersible film comprising:

1 ) preparing a film forming suspension according to the invention; and 2) drying the suspension of step 1 ) to form the orodispersible film.

[0015] In a fourth aspect, the present invention is directed to a method for preparing the film forming suspension of the invention. The method comprises mixing the API having a solubility of less than 10 mg/ml in water at RTP with a surfactant and water or a mixture of water and at least a solvent selected from a (Ci-C ₅ )-alcohol, acetone and mixtures thereof, wherein the surfactant has a solubility greater than 30 mg/ml in water at RTP, greater than 5 mg/ml in ethanol at RTP; and a solubility in water at RTP at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

[0016] In a fifth aspect, the present invention relates to an orodispersible film obtainable according to a method of the invention.

[0017] In a sixth aspect, the present invention is directed to an orodispersible film according to the present invention, for use as a medicament.

[0018] In a seventh aspect, the present invention is directed to a packaging comprising the orodispersible film according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention relates to an orodispersible film comprising a low soluble API, which is, nevertheless, uniform and free from aggregates. Uniform/uniformity in the present context means that the API is homogenously distributed in the film. Uniformity is determined in accordance with Ph. Eur. 7.4 chapter 2.9.40 (content uniformity).

[0020] In addition, the orodispersible film of the invention has the desired dissolution time and excellent mechanical properties. Indeed, during its production the film is required to adhere to the support liner, but at the same time needs to be easily removable from the support liner (pull-off ability) without being damaged. Generally, it is difficult to achieve this balance as it mainly depends on the composition of the film and its viscosity. Advantageously, it has been found that the orodispersible film of the invention meets this balance.

[0021] The orodispersible film of the invention is prepared by film forming suspensions. The present inventors have surprisingly found that by selecting a specific class of surfactants to be added to the suspension, the problem of the sedimentation of the suspension is solved, the suspension is stable and the API is homogeneously distributed in the suspension. Additionally, the problem of the aggregation of the API particles during the film-forming process is avoided. The selected surfactant preferably has a good solubility not only in the solvent system of the suspension, but also in the solvent system formed during the drying step. For example, if a solvent system such as a water/ethanol system is used, the composition of the solvent system may change during the drying step, because the more volatile solvent (ethanol) evaporates first. The evaporation causes the solvent system to become enriched in the solvent having the highest boiling point (i.e., water). Additionally, since the solvent(s) evaporate, the viscosity of the suspension during the drying step changes: the suspension tends to become more viscous.

[0022] The present inventors have found that a surfactant

• having a solubility greater than 30 mg/ml in water at RTP,

• a solubility greater than 5 mg/ml in ethanol at RTP and

• a solubility in water at RTP of at least 15 times greater than the solubility of the API in water at RTP

solves the problem of the sedimentation in suspensions comprising a low soluble API and the problem of aggregate formation during the film forming process.

[0023] Hence, a non-aggregated orodispersible film and a stable suspension are provided by the present invention. Additionally, the orodispersible film has the desired dissolution properties and excellent pull-off properties.

First aspect: Orodispersible films

[0024] In a first aspect, the present invention provides an orodispersible film comprising:

a) an active pharmaceutical ingredient having a solubility of less than 10 mg/ml at RTP in water; and

b) at least one surfactant:

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP. [0025] In a preferred embodiment, the orodispersible film of the present invention comprises

a) an active pharmaceutical ingredient having a solubility of from 0.01 to less than 10 mg/ml in water at RTP; and

b) at least one surfactant:

1 ) having a solubility greater than 30 to 10000 mg/ml in water at RTP; preferably greater than 30 to 1000mg/ml, more preferably greater than 30 to 100mg/ml

2) having a solubility greater than 5 to 10000 mg/ml in ethanol at RTP; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

[0026] In another preferred embodiment, the orodispersible film of the present invention comprises:

a) an active pharmaceutical ingredient having a solubility of less than 10 mg/ml at RTP in water; and

b) at least one surfactant:

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and wherein the solubility of the surfactant in water at RTP is at least 100 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

Surfactants

[0027] As explained above, the problem of avoiding APIs sedimentation in the film forming suspension and the aggregation problem during the film-forming process is solved by the selection of surfactants having a solubility greater than 30 mg/ml in water at RTP and a solubility greater than 5 mg/ml in ethanol at RTP. In addition, the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the API in water at RTP. Surfactants that meet these features solve the above mentioned problems. [0028] Poorly soluble APIs are difficult to suspend. They tend to float on the surface of water or other polar liquids due to the entrapped air and poor wetting. Poor wetting reflects the high surface tension between the API and the solvent. Preferably, the surfactants of the invention decrease the interfacial tension between API particles and water or the solvent system. Thus, water or the solvent system penetrates in the pores of the API particles, displaces air from them and ensures wettability, leading then to a stable suspension. As already mentioned, in the film forming preparation variations in the solvent system composition may alter the wetting properties of the surfactant. The surfactants of the invention are able to maintain excellent wettability throughout the entire film forming process.

[0029] Preferably, the surfactants of the present invention have a solubility in water at RTP that is greater than 40 mg/ml, more preferably is greater than 80 mg/ml, even more preferably is greater than 100 mg/ml in (all the solubility values refer to water at RTP).

[0030] The surfactants of the invention have a solubility in water at RTP that is at least 15 times greater than the solubility of the selected API in water at RTP. By way of a non-limiting example: if an API has a solubility of 5 mg/ml water at RTP, then the selected surfactant has a solubility of at least 75 mg/ml in water and a solubility in ethanol of greater than 5 mg/ml (solubility measured at RTP).

[0031] For a practically insoluble API, it is assumed that the solubility of the API is less than 0.1 mg/ml in water at RTP. The European Pharmacopoeia describes solubility using seven groups each with different expressions (see "Definitions" section below). The lowest class is described as "practically insoluble". The compounds with a solubility of less than 0.1 mg/ml are considered "practically insoluble". By way of a non-limiting example: olanzapine is considered to be practically insoluble in water. The surfactant Polysorbate 80 (Tween 80) has a solubility in water at RTP above 50 mg/ml. Hence, the solubility of Tween 80 is at least 500 times greater than the solubility of olanzapine. At the same time, Tween 80 has a solubility in ethanol greater than 5 mg/ml and hence meets the requirements of a surfactant according to the present invention. The solubility values are in water at RTP.

[0032] Surprisingly, it has been found by the present inventors that even with

"practically insoluble" APIs, by means of the selected surfactant a uniform

(homogenous) film forming suspension can be prepared. Uniformity is maintained during the film-forming process despite the increased viscosity of the suspension and the change in solvent composition.

[0033] Surfactants having the required solubility are preferably selected from anionic or non-ionic surfactants. Anionic and non-ionic surfactants have a high water solubility and good wettability property that allow the API to be uniformly suspended in the film forming suspension and through all the variations of solvent compositions occurring during the film-forming process. Non-ionic surfactants offer the additional advantages of no change in pH and reduced or no foam formation. Foam formation is generally caused by the incorporation of air bubbles during the initial stirring of the film forming suspension. However, even for an ionic surfactant, with the undesirable characteristic of foam formation in the orodispersible film, it was found that the problem of foam formation may still be overcome by degasing the film forming suspension before the drying step to achieve an excellent product. Ionic surfactants may also cause a change in the pH of the suspension. The correct pH can be obtained by addition of a pharmaceutically acceptable buffer system.

[0034] Preferably, the surfactant is selected from

polyoxyalkylene sorbitan esters;

alkoxylated fatty alcohols of formula RO(Ci-C ₄ alkyl-0) _n H wherein R is a (C ₆ -Ci ₈ )alkyl and n is 10 to 50, preferably R is (Ci ₂ -Ci ₈ )alkyl, C C ₄ alkyl-0 is ethoxy (EO) and n is 20,

polyoxyethylene glycols and polyoxyethylene glycolethers (macrogols); block polymer surfactants; and

alkyl sulfates.

[0035] Polyoxyalkylene sorbitan esters are, for example, polyethylene 20 sorbitan monolaurate (polysorbate 20), polyethylene 20 sorbitan monopalmitate (polysorbate 40), polyethylene 20 sorbitan monostearate (polysorbate 60) and polyethylene 20 sorbitan monooleate (polysorbate 80). Commercially these surfactant are known as TWEENS®.

[0036] Alkoxylated fatty alcohols are commercially known as Brij®, for example polyoxyethylene 10 stearyl ether is commercially available as Brij 98 and is preferably used. [0037] Polyoxyethylene glycols and polyoxyethylene glycol ethers are commercially known as "macrogol". A suitable and good macrogol according to the invention is Cetomacrogol 1000 (macrogol cetostearyl ether).

[0038] Block copolymer surfactants are also known as polyoxyalkylene block copolymers. They are prepared by block copolymerization of ethylene oxide (EO), propylene oxide (PO) or butylene oxide (BO). Polyoxyalkylene block copolymers of the invention are polaxamers (synthetic polyoxyethylene-polyoxypropylene block copolymers) which are commercially known as Pluronics®. Pluronic F68 is the preferred Pluronics of the invention.

[0039] The (Ci ₀ -Ci ₈ )alkyl sulfates are a known class of ionic surfactants. Sodium lauryl (d ₂ ) sulfate is an example of a pharmaceutically acceptable surfactant of this family of surfactants.

[0040] Preferably, the surfactant of the invention is selected from polysorbates and (C-io-C-i ₈ )-alkyl sulfates. More preferably, the polysorbate is selected from polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) and polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate). More preferably, the (Ci ₀ -Ci ₈ )-alkyl sulfate is sodium lauryl sulfate. Even more preferably, the surfactant is Polysorbate 80 (also known as TWEEN® 80).

[0041] Surfactants of the invention have a hydrophilic-lipophilic balance (HLB) greater than 10. It is known that the hydrophilic-lipophilic balance of a surfactant is a measure of the degree to which it is hydrophilic or lipophilic and hence it is a measure of the solubility of the surfactant in oil/water. The HLB according to the present invention is calculated according to the Davies' method. As mentioned above, the surfactants according to the present invention have a solubility in water that allows keeping the API uniformly distributed in the film forming suspension and the viscosity variations that occur during the drying step. It was found that surfactants having a HLB greater than 7 meet this need. Preferably, the surfactant of the invention has an HLB greater than 14, more preferably greater than 15. Surfactants such as alkyl sulfates having a high HLB can have effects on foaming. However, this problem may be overcome by employing a lower concentration of the surfactant, preferably less than 0.10 mg/ml, provided that the chosen concentration does not affect the purpose of preparing stable suspension and avoiding aggregation. [0042] The amount of surfactant present in the film of the invention is preferably from 0.01 % wt. to 0.5% wt., more preferably from 0.1 % wt. to 0.2% wt. The weight value refers to the dry weight of the orodispersible film. The concentration of the surfactant varies and depends on the solid content intended for the suspension. However, it is not suggested using a surfactant at a concentration less than 0.01 % wt. as it can result in an incomplete wetting, loss in stability of the suspension and formation of aggregates in the film. On the other hand, concentrations above 0.5% wt. may increasingly solubilize or dissolve the API particles or lead to a change in the API particle size distribution, once again, causing instability and aggregation.

Active Pharmaceutical Ingredients (APIs)

[0043] The APIs of the present invention are "slightly soluble" "very slightly soluble" or "practically insoluble" APIs. The three classes are defined in the European Pharmacopoeia. The solubility in the present context, unless otherwise specified, refers to the solubility measured at RTP:

[0044] The APIs of the present invention have a solubility of less than 10 mg/ml in water at RTP.

[0045] Preferably, the solubility of the API is less than 5 mg/ml, more preferably the solubility is less than 1 mg/ml, even more preferably the solubility is less than 0.1 mg/ml. The solubility of a "practically insoluble" API is less than 0.1 mg/ml according to the European Pharmacopoeia. Hence, also practically insoluble APIs are contemplated by the present invention. By way of a non-limiting example, olanzapine which is considered "practically insoluble" in water at RTP is an API according to the present invention.

[0046] Low water soluble APIs are generally difficult to formulate. It has been seen that by means of the formulation of the present invention, even APIs having a very low solubility or being practically insoluble can be satisfactory formulated.

[0047] Mixtures of APIs are also contemplated according to the invention. Each API has a solubility of less than 10 mg/ml in water at RTP, preferably has a solubility of less than 5 mg/ml, more preferably has a solubility of less than 1 mg/ml, even more preferably of less than 0.1 mg/ml. All the solubility values are "in water at RTP".

[0048] APIs suitable according to the present invention are for example olanzapine, sildenafil, ambroxol, citalopram, losartan, mirtazapine, verapamil, buprenorphine, risperidone, fentanyl, loperamide, loratadine and/or pharmaceutically acceptable salts thereof, provided that the salts have a solubility of less than 10 mg/ml in water at RTP.

[0049] A particularly preferred API is olanzapine, more preferably olanzapine free base, even more preferably olanzapine polymorphic form I or olanzapine polymorphic form II.

[0050] Olanzapine polymorphic forms I and II are disclosed in patent application WO1996/030375. In particular, form II, obtainable by the process disclosed in WO1996/030375, is characterized by an X-ray powder diffraction pattern as represented by the following interplanar spacings: d (A) 10.2689, 8.577, 7.4721 , 7.125, 6.1459, 6.071 , 5.4849, 5.2181 , 5.1251 , 4.9874, 4.7665, 4.7158, 4.4787, 4.3307, 4.2294, 4.141 , 3.9873, 3.7206, 3.5645, 3.5366, 3.3828, 3.2516, 3.134, 3.0848, 3.0638, 3.01 1 1 , 2.8739, 2.8102, 2.7217, 2.6432, 2.6007. The polymorph of olanzapine designated as form I is obtainable by the process taught in the U.S. Patent No. 5,229,382. Form I has a typical x-ray powder diffraction pattern substantially represented by the following interplanar spacings: d (A) 9.9463, 8.5579, 8.2445, 6.8862, 6.3787, 6.2439, 5.5895, 5.3055, 4.9815, 4.8333, 4.7255, 4.6286, 4.533, 4.4624, 4.2915, 4.2346, 4.0855, 3.8254, 3.7489, 3.6983, 3.5817, 3.5064, 3.3392, 3.2806, 3.2138, 3.1 1 18, 3.0507, 2.948, 2.8172, 2.7589, 2.6597, 2.6336, 2.5956. The spectra have been obtained using a Siemens D5000 x-ray powder diffractometer.

[0051] The amount of API per single dosage form is from 2.5 mg to 70 mg, preferably from 2.5 mg to 50 mg. Olanzapine is preferably present in the film in an amount of from 2.5 mg to 20 mg per oral dosage form.

[0052] The content of the API in the film of the invention is from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the film.

[0053] The API is preferably micronized in the form of nano- or microparticles. The micronized form is especially preferred, because nano- or microparticles of the API are stabilized against agglomeration by the surfactant surface adsorption. The particles provide a higher surface and hence a greater surfactant surface adsorption. This improves wettability of the API particles. In addition, due to the high surface area of the particles a quicker absorption of the API by the patient is conferred. Preferably, the mean particle size of the micronized API is from 1 μηπ to 20 μηπ, preferably from 1 μηπ to 15 μηπ, even more preferably from 5 μηπ to 10 μηπ. It has been noted that this is the optimal particle size in order to achieve an optimal balance between the requirement of high surface area for a quicker patient absorption and avoiding the aggregation problem. It has been seen that a particle size lower than 1 μηπ does not assure a sufficient surface area for surfactant absorption and consequent stabilization. Additionally, smaller particles may be solubilized by the surfactant, which is undesirable in the present context. The mean particle size as defined herein is measured using the standard method of the light diffraction measurement of particle size as indicated in the US Pharmacopoeia (USP 36 <429>).

Disintegration time

[0054] The orodispersible film of the invention rapidly disintegrates in the oral cavity of a patient. The disintegration time is preferably less than 100 seconds, more preferably less than 60 seconds, even more preferably less than 20 seconds. The disintegration time is determined as described below in the context of the Examples.

[0055] It has been surprisingly found by the present inventors that the presence of a surfactant in the film formulation improves the disintegration of the film in the oral cavity by reducing the disintegration time. It is believed that the reduction of the surface tension due to the presence of the surfactant enhances the wettability of the API particles in the oral cavity causing an increase in solubility of the particles and a reduced disintegration time.

Thickness

[0056] The orodispersible film of the invention has a dry film thicknesses ranging from 50 μηπ to 500 μηπ, preferably from 100 μηπ to 200 μηπ, more preferably from 140 μηπ to 180 μηπ. A dry film thickness within and including the mentioned limits ensures rapid disintegration of the film within the oral cavity. This ensures that the API is completely absorbed by the patient. Also films with lower or higher layer thicknesses can be provided, which are encompassed by the invention as well.

[0057] It has been observed that the use of a surfactant of the invention, in particular, polyoxyalkylene sobitan esters, and preferably polyoxyethylene (20) sorbitan monooleate (polysorbate 80), advantageously allows having a thinner orodispersible film. One problem in film production is the tendency of the film to be damaged during the pull-off step. Thicker films are less affected by this problem. However, thick films have a longer disintegration time and are generally less favorable in relation to patient compliance. The above surfactants solve this problem by sticking a balance between film thickness requirements and pull-off integrity.

Additional excipients

[0058] The orodispersible film of the invention may further comprise one or more excipients selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler. These are disclosed in details in the section below: "Additional pharmaceutical acceptable excipients".

[0059] In a preferred specific embodiment of the invention, the orodispersible film comprises

a) 20 to 40% wt. of active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP; and

b) 0.01 to 0.5% wt. of at least one surfactant

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

The above embodiment further comprises, preferably: c) 15 to 60% wt. of film forming polymer(s); and

d) 5 to 35% wt. of plasticizer.

The percentages refer to the dry weight of the orodispersible film.

[0060] In a further preferred specific embodiment, the orodispersible film comprises a) 20 to 40% wt., preferably 25 to 35% wt. of active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is selected from olanzapine, olanzapine free base, olanzapine free base polymorphic form I and olanzapine free base polymorphic form II ;

b) 0.01 to 0.5% wt., preferably 0.10 to 0.20% wt. of surfactant, wherein the surfactant is selected from a polyethylene sorbitan mono-oleate or sodium alkyl sulfate, more preferably is Polysorbate 80;

c) 15 to 60% wt. preferably 30 to 55% wt. of film forming polymer, wherein the film forming polymer is selected from cellulose derivatives, preferably cellulose ethers, more preferably hydroxy propyl cellulose, hydroxy propyl methyl cellulose and mixtures thereof, even more preferably the film forming polymer is hydroxy propyl methyl cellulose (such as Methocel E5LV); an additional film forming polymer may be present; the additional film forming polymer is preferably polyvinylpyrrolidone (PVP). When present in combination, the cellulose derivative is in an amount ranging from 20% wt. to 40% wt., preferably 25 to 35% wt. and PVP is present in an amount ranging from 15 to 35% wt., preferably 15 to 20% wt. The sum of the weight percentages of the cellulose derivative and of PVP preferably does not exceed 60% wt.

d) 5 to 35% wt. of plasticizer, wherein the plasticizer is selected from propylene glycol or glycerol, preferably propylene glycol.

The weight percentages refer to the dry weight of the orodispersible film.

[0061] In general for all of the aspects of this invention and in particular for the two specific embodiments described above, preferably, the surfactant is selected from polysorbate 80 and sodium lauryl sulfate. More preferably, the active pharmaceutical ingredient is olanzapine, the surfactant is polysorbate 80 or sodium lauryl sulfate, the film forming agent is hydroxy propyl methyl cellulose and/or povidone, and the plasticizer is glycerol and/or propylene glycol; even more preferably, the active pharmaceutical ingredient is olanzapine, the surfactant is polysorbate 80, the film forming agent is hydroxy propyl methyl cellulose and/or povidone, and the plasticizer is glycerol and/or propylene glycol. Second aspect: Film forming suspension

[0062] In a second aspect, the present invention is directed to a film forming suspension comprising:

a) an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP;

b) at least one surfactant

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in the ethanol at RTP; and c) water or a mixture of water and one or more solvents selected from a (Ci-C ₅ )-alcohol, acetone and mixtures thereof; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

Surfactants

[0063] The surfactants of the film forming suspension are as disclosed in the first aspect of the invention and its embodiments.

[0064] The amount of surfactant present in the film forming suspension of the invention is from 0.01 % wt. to 0.5% wt. of the suspension, preferably 0.1 % wt. to 0.2% wt. of the suspension. The percentage amounts refer to the dry weight of the suspension and solvent(s) are not considered in this calculation.

Active pharmaceutical ingredients (APIs)

[0065] The APIs are as disclosed above in the first aspect of the invention and its embodiments.

[0066] The content of the API in the film forming suspension of the invention is preferably from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the suspension.

Solvents

Solvents suitable according to the invention are water, (CrC ₅ )-alcohol or acetone. Water may be present as sole solvent or may be present in a mixture with one or more solvents selected from a (Ci-C ₅ )-alcohol and acetone. The mixture of solvents in the present context may be referred to as "solvent system".

[0067] Preferably, a solvent system is used to prepare the film forming suspension of the invention. Preferred solvents (in addition to water) of the solvent system are ethanol or isopropanol; hence, the solvent system is preferably a mixture of 1 ) water and ethanol or 2) water and isopropanol. Even more preferably, the solvent system is a mixture of water and ethanol.

[0068] The amount of solvent other than water in the solvent system is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. of the solvent system. Hence, in the preferred solvent system of water/ethanol, the amount of ethanol is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt.

[0069] Acetone can also be present in the solvent system. In this case, acetone preferably does not exceed the 5% wt. of the solvent system.

[0070] The quantity of solvent or the solvent system is such that a suspension is formed. Typically, the ratio dry/solid component to solvent/solvent system is from 1 :3 to 1 :1 , preferably 1 :2.5 to 1 :1 .5, more preferably 1 :2.2 to 1 :2. The ratio refers to the weight: for example 100g of the total solid component of the suspension is mixed with 200g of the solvent system i.e. with a ratio of 1 :2.

Viscosity

[0071] The film forming suspension of the invention has a viscosity (dynamic viscosity) at RTP from 1000 mPa ^* s to 5000 mPa ^* s, preferably 2000 mPa ^* s to 4000 mPa ^* s, even more preferably 2000 mPa ^* s to 2500 mPa ^* s (measured with a cone- plate viscometer at a shear rate of 1 /100 sec according to Ph. Eur. 7.0 chapter 2.2.10). A high viscosity of the film forming suspension is preferable in general to obtain a stable suspension free from sedimentation problems. On the other hand, a highly viscous suspension will result in a non-homogeneous film with aggregate formation observed during the film-forming process and in the final film. The use of the surfactant of the invention allows suspensions with a lower viscosity and yet stable suspensions free from sedimentation problems. Since suspensions with lower viscosity can be advantageously used due to the presence of the surfactant of the invention, the above mentioned problems connected with a high viscosity are avoided by the film forming suspension of the invention.

Additional excipients

[0072] The film forming suspension of the invention, may further comprise one or more components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler. These are disclosed in details in the below section "Additional pharmaceutical acceptable excipients".

[0073] In a preferred embodiment of the invention, the film forming suspension comprises

a) 20 to 40% wt. of active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP; and

b) 0.01 to 0.5% wt. of at least one surfactant

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP. The above embodiment further comprises, preferably: c) 15 to 60% wt. of film forming polymer(s); and

d) 5 to 35% wt. of plasticizer.

[0074] The percentage amounts refer to the dry weight of the film forming suspension. Additionally, the suspension comprises water or a solvent system. Preferred solvent systems are a water/ethanol solvent system and a water/isopropanol solvent system; even more preferred is the water/ethanol solvent system. Preferably, the amount of solvent other than water in the solvent system is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. of the solvent system. Hence in the preferred solvent system of water/ethanol, the amount of ethanol is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. The percentage amounts refer to the solvent system. [0075] In a further preferred embodiment, the film forming suspension comprises a) 20 to 40% wt., preferably 25 to 35% wt. of active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is selected from olanzapine, olanzapine free base, olanzapine free base polymorph form I and olanzapine free base polymorph form II ;

b) 0.01 to 0.5% wt., preferably 0.10 to 0.20% wt. of surfactant, wherein the surfactant is selected from a polyethylene sorbitan mono-oleate or sodium alkyl sulfate, more preferably Polysorbate 80;

c) 15 to 60% wt. preferably 30 to 55% wt. of film forming polymer wherein the film forming polymer is selected from cellulose derivatives, preferably cellulose ethers, more preferably hydroxy propyl cellulose, hydroxy propyl methyl cellulose and mixtures thereof, even more preferably the film forming polymer is hydroxy propyl methyl cellulose (such as Methocel E5LV); an additional film forming polymer may be present; the additional film forming polymer is polyvinylpyrrolidone (PVP). When present in combination, the cellulose derivative is in amount ranging from 20 to 40% wt., preferably 25 to 35% wt and PVP is present in an amount ranging from 15 to 35% wt., preferably 15 to 20% wt. The sum of the weight percentages of the cellulose derivative and of PVP preferably does not exceed the 60% wt.

d) 5 to 35% wt. of plasticizer, wherein the plasticizer is selected from propylene glycol or glycerol, preferably propylene glycol.

The weight percentages refer to the dry weight of the film forming suspension.

[0076] Additionally, the suspension comprises water or a solvent system. Preferred solvent systems are a water/ethanol solvent system and a water/isopropanol solvent system; even more preferred is the water/ethanol solvent system. Preferably, the amount of solvent other than water in the solvent system is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. of the solvent system. Hence in the preferred solvent system of water/ethanol, the amount of ethanol is from 0% wt. to 65% wt., preferably from 20% wt. to 40% wt., even more preferably from 25% wt. to 35% wt. The percentage amounts refer to the solvent system. Third Aspect: Method for preparing an orodispersible film

[0077] In a third aspect, the present invention provides a method for preparing an orodispersible film comprising:

a) preparing a film forming suspension as defined above in the second aspect of the invention and in its embodiments; and

b) drying the suspension to form the orodispersible film.

[0078] In general, the suspension is homogeneously spread out on a foil (carrier liner) and dried. A second foil (backing foil) can be laminated on top to protect the film, if desired. The foil or foils are removed afterwards.

[0079] Preferably, the drying of the film is done by application of heat. The application of heat can for example be done by a hot air blower. There is of course also the possibility that the film is dried in an oven or a comparable drying device. The film is preferably dried for 15 to 30 minutes, more preferably for 15 to 20 minutes. The drying temperature may preferably range from 40 to 70°C.

[0080] After drying the thus formed film can be cut into the final form representing the single dosage unit, for example into a round, any rounded, oval, elliptical, triangular, rectangular, square or polygonal shape.

Fourth Aspect: Method for preparing the film forming suspension

[0081] In a fourth aspect, the present invention is directed to a method for preparing the film forming suspension as defined in the second aspect of the invention and its embodiments.

[0082] The method comprises mixing the API having a solubility of less than 10 mg/ml in water at RTP, with the surfactant and water or the mixture of water and a solvent selected from a (Ci-C ₅ )-alcohol, acetone and mixtures thereof, wherein the surfactant has a solubility greater than 30 mg/ml in water at RTP and greater than 5 mg/ml in ethanol at RTP; and a solubility in water at RTP at least 15 times greater than the solubility of the API in water at RTP. The API can be added to the water or the solvent system already containing the surfactant. Alternatively, the surfactant can be added after the API was added to the water or the solvent system. In a further alternative, the API and the surfactant can be added to the water or the solvent system simultaneously. [0083] Further substance(s) can be added before, after or simultaneously with the API to the solvent or solvent mixture of the suspension. Film forming agents, flavorings, sweeteners and/or plasticizers can be dissolved or dispersed, for example prior to the addition of the API, in the solvent or solvent mixture. The mixture thus obtained can then be used as solvent for the suspension. Of course, further substances may be added to the suspension later, i.e. for example, after the addition of the API.

Fifth Aspect: Film obtainable according to a method of the invention

[0084] In a fifth aspect, the present invention is directed to an orodispersible film obtainable according to a method as defined in the third aspect of the invention and its embodiments. Hence, the orodispersible films of the invention are obtainable from film forming suspensions according to the second aspect of the invention and its embodiments in a process that comprises drying the film forming suspension.

Sixth Aspect: Medicaments

[0085] In a sixth aspect, the present invention is directed to the orodispersible film of the invention as defined in the first aspect and its embodiments and in the fifth aspect and its embodiments, for use as a medicament.

Seventh Aspect: Packages

[0086] In a seventh aspect, the present invention is directed to a package comprising the orodispersible film of the invention as defined in the first aspect and its embodiments and in the fifth aspect and its embodiments. The packaging materials used for oral films are, for example, sachets made from flexible multilayer foils which preferably may have an aluminum barrier layer and a heat sealer layer.

Additional pharmaceutical acceptable excipients

[0087] The orodispersible film of the invention and the film forming suspension of the invention may further comprise one or more additional components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler. a) Film forming polymer

[0088] Preferred film forming polymers are selected from cellulose, cellulose derivatives, starch, starch derivatives (preferably semisynthetic derivatives), pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, sodium alginate, and mixtures thereof.

[0089] Suitable cellulose derivatives include carboxy methylcellulose, hydroxy ethylcellulose, hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), methyl cellulose (MC) and ethyl cellulose (EC). HMPC is preferred as the film forming polymer of the invention. HMPCs are, for example, commercially available as Methocel® and Pharmacoat®. Examples of Methocels are Methocel E5LV and Methocel E15LV. Examples of Pharmacoats are Pharmacoat 603 and Pharmacoat 606. Methocel E5LV and E15LV are particularly preferred film forming polymers of the present invention. HPC is commercially available as Klucel®. A preferred Klucel® is Klucel® EF. Mixtures of MC/HPMC are commercially known as Metolose®. Preferred Metolose® polymers are Metolose SM-100, SM-15 and SM4.

[0090] Advantageously, mixtures of film forming polymers can be used to prepare the orodispersible film of the invention. It has been seen that preferably mixtures of cellulose derivatives and polyvinyl pyrrolidone (PVP) together with the surfactant of the invention provide a film forming dispersion that has excellent stability and leads to a non-aggregating orodispersible film with excellent pull-off properties and the desired disintegration time. PVPs are commercially known as Kollidon®. Preferred Kollidons are Kollidon 25 and Kollidon CL.

[0091] The preferred percentage amount of the film forming polymer in the orodispersible film or in the film forming suspension of the invention is from 15 to 60% wt., preferably 30 to 55% wt., even more preferably 30 to 40% wt. of the dry weight of the film or suspension. When more than one film forming polymer is present in combination, the sum of the weight percentages of each film forming component preferably does not exceed the 60% wt. of the dry weight of the orodispersible film and is more preferably in the range of from 45 to 60% wt. of the dry weight of the film or suspension.

[0092] Preferably, when two film forming polymers are present, the first film forming polymer is in amount ranging from 20 to 40% wt., preferably 25 to 35% and the second film forming polymer is present in an amount ranging from 15 to 35% wt., preferably 15 to 20% wt. of the dry weight of the film or suspension. b) Wetting agents

[0093] A wetting agent may be present in the film and in the film forming suspension of the invention. The wetting agents are useful to retain water in the dosage form. A certain amount of water remaining in the film (0.5 to 10% wt., preferably 1 to 8% wt.) is preferable in view of the elasticity, which facilitates the processing of the product and the handling by the patient. Any wetting agent suitable for the purpose of retaining water in the film is contemplated by the present invention. Preferred wetting agents include sorbitols, xylitols and malto-dextrine. The percentage amount of the wetting agent, when present, ranges from 0.5 to 10% wt., preferably 5 to 10% wt. The weight both of the film and the suspension refers to the dry weight of the film or of the suspension. c) Plasticizer

[0094] A plasticizer is optionally comprised in the film and suspension of the invention. The plasticizer may serve to reduce the brittleness of the composition provided in the form of a film and to increase its flexibility. In a preferred embodiment, the plasticizers may be selected from glycerol, propylene glycol, dibutyl sebacate, triacetin, triethyl citrate and isopropyl myristate. The use of propylene glycol and glycerol is particularly preferred.

[0095] When a plasticizer is used, the percentage amount in the orodispersible film or film forming suspension of the invention is from 5 to 35% wt., preferably 10 to 20% wt. The weight both of the film and the suspension refers to the dry weight of the film or of the suspension. d) Taste masking agents, flavoring agents and sweeteners

[0096] Taste masking may be advantageous for APIs with a bitter or otherwise unpleasant taste. A flavoring agent may be optionally a further component of the orodispersible film and of the suspension of the invention. Normally, liquid flavors are used, although amounts of flavors may be lost during drying. When a flavor is employed, the proportion in the orodispersible film or in the film forming suspension of the invention is from 0.1 to 10% wt., preferably 0.1 to 5% wt., more preferably 0.2 to 2% wt. related to the dry weight of the composition. Peppermint oil, peppermint flavor, menthol, and/or levomenthol are flavors according to the invention. Alternatively or additionally, flavors with sour fresh taste, especially grapefruit flavor, lemon and/or orange flavor can be present. The taste of the orodispersible film and the taste sensation occurring after ingestion can thus be made more comfortable for the patient. Further to the aforementioned flavoring agents or combinations of these, the flavoring agent can also be selected from flavoring agents with sweet, nutty taste, in particular from those flavoring agents that produce a nut flavor, a chocolate flavor, a cinnamon or spice flavor or the like. Naturally, there is also the possibility to use a mixture of the aforesaid with the flavoring agents as previously described. Besides the mentioned flavoring agents, any other suitable flavoring agents can be used to determine or define the flavor of respective compositions to thereby increase patient's compliance.

[0097] Further systems may be used as taste receptor competitors (e.g. sodium chloride) or bitter masking substances. Ion exchange resins (e.g. Amberlite types) may be also used.

[0098] Additionally or alternatively, a sweetener can be used. The sweetener may support taste masking and enhance acceptability of the film. Sweeteners can be selected from monosaccharides, disaccharides, polysaccharides, in particular maltodextrin, sucralose, neotame, alitame, cyclamate, sorbitol, xylitol, saccharin, aspartame, and mixtures of the aforesaid. Synthetic sweeteners that can typically be used are sucralose, aspartame and saccharin. When a sweetener is used, its proportion is desirably from 0.1 % to 5% by weight, preferably 0.5 to 4% wt., more preferably 1 to 2 % wt. related to the dry weight of the film or suspension. e) Fillers

[0099] Additionally, a filler may be present. Preferably a filler is used when a low dose API (an API to be administered in a low dose, such as 2.5 to 20 mg API per single dosage form) is present in the film or suspension. Microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium carbonate and mixtures thereof may be used as filler according to the present invention. f) Dye

[00100] Additionally, a dye may be present in the film and in the suspension of the invention. Titanium oxide may be used preferably.

EXAMPLES

Example 1

[00101] The film forming suspension was prepared by stirring 227.6 g of a water/ethanol solvent system (30% wt. ethanol) with 0.15 g of Polysorbat 80 (Tween® 80) for 5 minutes. 30 g of olanzapine (olanzapine free base polymorphic form II) was added and stirred for another 5 minutes at 200 rotations per minute (rpm). 35 g of hydroxy propyl methyl cellulose (Methocel E5LV) were added and stirred for another 2 minutes. Whilst stirring, 17.85 g of Kollidon 25, 13.0 g of propylene glycol, 1 g sucralose, 0.5 g levomenthol, 0.5 g peppermint flavor and 2 g titanium dioxide were slowly added. The stirring of the suspension was continued for 2 hours. The viscosity of the suspension was measured to be 2318 mPa ^* s at RTP. The suspension was cast on a polyethylene terephthalate (PET) foil. The resulting laminate was dried at 50°C for 15 minutes. After drying, the film was cut into squares of 2 cm ² , the foil was removed and the film packaged into sachets. Aggregation was measured according to the procedure disclosed below. No aggregation was observed. The film met the content uniformity requirement according to Ph. Eur. 7.4 chapter 2.9.40. In addition, the pull-off properties of the obtained film were excellent and the film was readily removed from the foil without any damages. The flexibility was tested and was found to be good. No foam formation was observed during the production process. Ethanol and water are removed during the drying process. The results are summarized in Table 2.

[00102] Table 1

Examples 2-12

[00103] The suspension and the film of examples 2-12 were prepared according to the procedure of example 1 . An amount of 0.15 g of Sodium Lauryl Sulfate was used in place of Polysorbate 80. Further components can be identified in Table 1 .

[00104] No aggregation was observed according to the method disclosed below. The pull-off properties of the obtained film were excellent and the film was readily removed from the foil without any damages. The flexibility was tested with good results. The results are summarized in Table 2.

Examples 13 and 14

[00105] The suspension and the film of examples 13 and 14 were prepared according to the procedure of example 1 . The surfactant was omitted. Olanzapine and PVP were stirred for 30 minutes to improve the wettability of olanzapine. The components and quantities thereof are reported in Table 1 .

[00106] The formation of agglomerates as measured according to the method disclosed below was observed. Further, the formation of stripes in the film was observed and the film did not meet the content uniformity requirement according to the European Pharmacopoeia. The pull-off test failed.

Agglomerates formation measurement

[00107] The agglomerates formation in the orodispersible film made according to examples 1 to 12 was compared to the agglomerate formation of the standard orodispersible films comprising olanzapine of examples 13 and 14. The agglomeration test was performed using an optical microscope. A 6 cm ² sample of each orodispersible film was analyzed. The sample was divided into a 10x10 (100) squares matrix. The expression "presence of agglomerates" means in the present context that more than 10% of the squares (e.g. at least 10 squares) show agglomerate formation. The expression "free from agglomerates" means in the present context that 10% or less of the squares show agglomerate formation. Content uniformity

[00108] Content uniformity was determined according to Ph. Eur. 7.4, chapter 2.9.40.

Pull-off adhesion test

[00109] The pull-off-adhesion properties of orodispersible films made according to examples 1 to 12 were compared to the pull-off-adhesion properties of the standard orodispersible films comprising olanzapine of examples 13 and 14. The test was performed by manually pulling off the orodispersible film from the support foil (as it is done by the health care personnel or the patient). Provided that the orodispersible film can be removed from the support foil without breaking into pieces and the weight of the orodispersible film removed from the support foil is within the range of +/- 5% wt. compared to the calculated weight of the orodispersible film, the test is passed.

Disintegration time measurement

[00110] The disintegration time of the orodispersible films made according to examples 1 to 12 were compared to the disintegration time of the standard orodispersible films comprising olanzapine of examples 13 and 14. The disintegration test was performed using the following test procedure: A Petri dish was filled with 4 ml of demineralized water having a temperature of 25°C and was placed on a dark surface. The orodispersible film was taken out of the sachet with a pair of tweezers and was placed centered and horizontally onto the water surface. Time measurement starts when the film gets into contact with the water. The disintegration of the film was observed visually. The disintegration time is the time at which the film starts disrupting in its central parts. .

[00111] Table 2 is a summary table of the properties of the films of the invention.

[00112] Table 2

DEFINITIONS

[00113] The terms "slightly soluble", "very slightly soluble" and "practically insoluble" as used herein are taken from the European Pharmacopoeia (Ph. Eur. 7.6, chapter "General Notices" 1 .4). The solubility of an API may be expressed in a number of ways. The European Pharmacopoeia describes the solubility of drugs as volume of solvent in millilitres per gram of solute. The Ph. Eur. 7.6 describes solubility using the seven groups listed in following Table 3:

[00114] Table 3

[00115] The APIs of the present invention have a solubility of less than 10 mg/ml and hence are "slightly soluble", "very slightly soluble" or "practically insoluble" APIs according to the above Table 3. Sometimes, APIs are generally indicated as "low soluble" or "insoluble" (the latter where appropriate) in the present context.

[00116] The term "RTP" means in the present context "room temperature and pressure". Room temperature in this context is 25 °C and room pressure is 1 atm. Further preferred variants of the invention

[00117] In a first aspect the present invention is directed to an orodispersible film comprising:

a) an active pharmaceutical ingredient having a solubility of less than

10mg/ml in water at RTP, and

b) at least one surfactant:

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

[00118] In a first embodiment of the first aspect: The orodispersible film is a orodispersible film wherein the amount of surfactant is from 0.01 % wt. to 0.5% wt., preferably from 0.1 % wt. to 0.2% wt. related to the dry weight of the film.

[00119] In a second embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the amount of the active pharmaceutical ingredient is from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the film.

[00120] In a third embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the surfactant is Tween 80 and the active pharmaceutical ingredient is olanzapine, preferably olanzapine free base or olanzapine polymorph forms I and II.

[00121] In a fourth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the solubility of the active ingredient is less than 5 mg/ml, preferably less than 1 mg/ml, more preferably less than 0.1 mg/ml in water at RTP. [00122] In a fifth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the surfactant is an anionic or a non-ionic surfactant.

[00123] In a sixth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the fifth embodiment of the first aspect, wherein the surfactant is selected from

• polyoxyalkylsorbitan esters;

• alkoxylated fatty alcohols of formula RO(Ci-C ₄ alkyl-0) _n H wherein R is a (C ₆ -Ci ₈ )alkyl and n is 10 to 50, preferably R is (Ci ₂ -Ci ₈ )alkyl, Ci-C ₄ alkyl-0 is ethoxy (EO) and n is 20;

• polyoxyethylene glycols and polyoxyethylene glycolethers (macrogols);

• block polymer surfactants; and

• alkyl sulfates.

[00124] In a seventh embodiment of the first aspect: The orodispersible film is the orodispersible film according to the sixth aspect, wherein the surfactant is selected from a (Ci ₀ -Ci ₄ )-alkyl sulfate or a polyoxyethylene sorbitan monooleat, preferably sodium lauryl sulfate and polysorbate 80, more preferably polysorbate 80.

[00125] In an eight embodiment of the first aspect: The orodispersible film is the orodispersible film of the first aspect and any embodiments thereof, wherein the active pharmaceutical ingredient is a micronized active pharmaceutical ingredient.

[00126] In a ninth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the eight embodiment wherein the mean particle size of the micronized active pharmaceutical ingredient is between 1 and 20 μηπ, preferably between 1 and 10 μηπ.

[00127] In a tenth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof, wherein the active pharmaceutical ingredient is olanzapine, preferably olanzapine free base, olanzapine polymorph form I and olanzapine polymorph form II. [00128] In a eleventh embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof further comprising one of more components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler.

[00129] In a twelfth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof comprising:

a) 20 to 40% wt. of active pharmaceutical ingredient;

b) 0.01 to 0.5% wt. of surfactant;

c) 15 to 60% wt. of film forming agent; and

d) 5 to 35% wt. of plasticizer related to the dry weight of the film.

[00130] In a thirteenth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof comprising:

a) 20 to 40% wt. of active pharmaceutical ingredient;

b) 0.01 to 0.5% wt. of surfactant;

c) 15 to 60% wt. of film forming agent; and

d) 5 to 35% wt. of plasticizer;

related to the dry weight of the film, wherein the surfactant is selected from polysorbate 80 and sodium lauryl sulfate.

[00131] In a fourteenth embodiment of the first aspect: The orodispersible film is the orodispersible film according to the first aspect and any of the embodiments thereof comprising:

a) 20 to 40% wt. of active pharmaceutical ingredient;

b) 0.01 to 0.5% wt. of surfactant;

c) 15 to 60% wt. of film forming agent; and d) 5 to 35% wt. of plasticizer;

related to the dry weight of the film, wherein the active pharmaceutical ingredient is olanzapine, the surfactant is polysorbate 80, the film forming agent is hydroxy propyl methyl cellulose and/or povidone, and the plasticizer is glycerol and/or propylene glycol.

[00132] In a fifteenth embodiment of the first aspect: The orodispersible film is the orodispersible film according the first aspect and any of the above embodiments thereof comprising:

a) 20 to 40% wt. of active pharmaceutical ingredient;

b) 0.01 to 0.5% wt. of surfactant;

c) 15 to 60% wt. of film forming agent; and

d) 5 to 35% wt. of plasticizer;

related to the dry weight of the film, wherein the active pharmaceutical ingredient is olanzapine, the surfactant is sodium lauryl sulfate, the film forming agent is hydroxy propyl methyl cellulose and/or povidone, and the plasticizer is glycerol and/or propylene glycol.

[00133] In a second aspect the present invention is directed to a film forming suspension comprising:

a) an active pharmaceutical ingredient having a solubility of less than 10 mg/ml in water at RTP;

b) at least one surfactant:

1 ) having a solubility greater than 30 mg/ml in water at RTP;

2) having a solubility greater than 5 mg/ml in ethanol at RTP; and c) water or a mixture of water and a solvent selected from a (Ci.C ₅ )- alcohol, acetone and mixtures thereof; and wherein the solubility of the surfactant in water at RTP is at least 15 times greater than the solubility of the active pharmaceutical ingredient in water at RTP.

[00134] In a first embodiment of the second aspect, the film forming suspension is the film forming suspension according to the second aspect, wherein the amount of the solvent is from 0% wt. to 65% wt. of the water/solvent mixture, preferably from 20% wt. to 40% wt. of the water/solvent mixture, more preferably from 25% wt. to 35% wt. of the water/solvent mixture.

[00135] In a second embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the solvent is ethanol or isopropanol, preferably ethanol.

[00136] In a third embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the amount of surfactant is from 0.01 % wt. to 0.5% wt., preferably from 0.1 % wt. to 0.2% wt., related to the dry weight of the suspension.

[00137] In a fourth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the amount of the active pharmaceutical ingredient is from 20 to 70% wt., preferably from 20 to 50% wt., even more preferably from 20 to 40% wt. related to the dry weight of the film or suspension.

[00138] In a fifth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any embodiments thereof, wherein the suspension has a viscosity at RTP of from 1000 to 5000 mPa ^* s, preferably 2000 to 4000 mPa ^* s, more preferably 2000 to 2500 mPa ^* s.

[00139] In a sixth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any of the first to fifth embodiments thereof, wherein the solubility of the active ingredient is less than 5 mg/ml, preferably less than 1 mg/ml, more preferably less than 0.1 mg/ml in water at RTP.

[00140] In a seventh embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any of the first to sixth embodiments thereof, wherein the surfactant is an anionic or a non-ionic surfactant.

[00141] In an eighth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the seventh embodiment, wherein the surfactant is selected from

• polyoxyalkylsorbitan esters;

• alkoxylated fatty alcohols of formula RO(CrC ₄ alkyl-0) _n H wherein R is a (C ₆ -Ci ₈ )alkyl and n is 10 to 50, preferably R is (Ci ₂ -Ci ₈ )alkyl, Ci-C ₄ alkyl-0 is ethoxy (EO) and n is 20;

• polyoxyethylene glycols and polyoxyethylene glycolethers (macrogols);

• block polymer surfactants; and

• alkyl sulfates.

[00142] In a ninth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the eighth embodiment, wherein the surfactant is selected from a (Ci ₀ -Ci ₄ )-alkyl sulfate or a polyoxyethylene sorbitan monooleat, preferably sodium lauryl sulfate and polysorbate 80, more preferably polysorbate 80.

[00143] In a tenth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and to any of the embodiments thereof, wherein the active pharmaceutical ingredient is a micronized active pharmaceutical ingredient.

[00144] In an eleventh embodiment of the second aspect: The film forming suspension is the film forming suspension according to the tenth embodiment, wherein the mean particle size of the micronized active pharmaceutical ingredient is between 1 and 20 μηπ, preferably between 1 and 10 μηπ.

[00145] In an twelfth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, wherein the active pharmaceutical ingredient is olanzapine, preferably olanzapine free base, olanzapine polymorph form I and olanzapine polymorph form II.

[00146] In an thirteenth embodiment of the second aspect: The film forming suspension is the film forming suspension according to the second aspect and any of the embodiments thereof, further comprising one of more components selected from a film forming polymer/agent, a plasticizer, a wetting agent, a flavoring, a taste masker, a preservative, a sweetener, a coloring agent and a filler.