Nanoparticles containing tacrolimus

Abstract

The present invention relates to nanoparticles comprising tacrolimus, a method for providing nanoparticles comprising tacrolimus, and nanoparticles comprising tacrolimus obtained by said method. The present invention also relates to nanoparticles comprising tacrolimus for use as a medicine. The present invention further relates to a mucoadhesive buccal film containing said nanoparticles comprising tacrolimus, and said mucoadhesive buccal film for use as a medicine, particularly in pediatric patients.

Description

[Technical field]

[0001] The present invention is directed to nanoparticles comprising tacrolimus, a method for providing nanoparticles comprising tacrolimus, and nanoparticles comprising tacrolimus obtained by said method.The present invention is further directed to nanoparticles comprising tacrolimus for use as a medicament, in particular in pediatrics, more particularly in the treatment of solid organ transplant rejection, in particular in pediatric patients.The present invention is further directed to a mucoadhesive buccal film containing said nanoparticles comprising tacrolimus, and said mucoadhesive buccal film for use as a medicament, in particular in pediatrics, more particularly in the treatment of solid organ transplant rejection, in particular in pediatric patients. [Background technology]

[0002] Tacrolimus, also known as fujimicin or FK506, is an immunosuppressant drug used primarily after allogeneic organ transplants to reduce the risk of organ rejection. Tacrolimus achieves this by suppressing the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, which are essential for the body's adaptive immune response.

[0003] Chemically, tacrolimus is a 23-membered macrolide lactone that was first discovered in the fermentation broth of soil samples containing the bacterium Streptomyces tsukubaensis. Despite the fact that oral formulations of tacrolimus have been on the market for over 20 years, an optimal pediatric formulation that allows for easy and convenient patient use is still not available.

[0004] Tacrolimus is a lipophilic compound with a molecular weight of approximately 822 Da, which is practically insoluble in water (0.004 mg / ml), resulting in low bioavailability.

[0005] Further factors that may lead to reduced and rather unpredictable bioavailability are the extensive first-pass metabolism of tacrolimus by CYP3A4 / 5 in the intestine and liver, P-glycoprotein-mediated drug efflux, genetic variations, food intake and the influence of concomitant medications.

[0006] This requires sophisticated formulations to achieve acceptable bioavailability of the drug. Summary of the Invention [Problem to be solved by the invention]

[0007] It was therefore an object of the present invention to provide tacrolimus in a form with increased water solubility, and a method for providing such a form. It was further an object of the present invention to provide a therapeutic system for delivering tacrolimus to a patient, which avoids or bypasses the first-pass metabolism of tacrolimus by buccal absorption, thus translating into higher and more predictable bioavailability. Furthermore, a therapeutic system for delivering tacrolimus should protect the drug from degradation due to the pH and digestive enzymes of the gastrointestinal tract, provide a rapid onset of action compared to the buccal route, and be an easy and convenient method of drug administration. It should also avoid the obstacles associated with drug administration via a nasogastric tube, and be versatile in physical shape, condition, size, and surface. Moreover, the therapeutic system should allow for accurate administration, and the possibility of masking the taste of tacrolimus. [Means for solving the problem]

[0008] These objects are solved by the nanoparticles according to claim 1, namely by nanoparticles comprising tacrolimus or a salt thereof, having a particle size of about 10 to about 400 nm. The inventors have surprisingly found that such nanoparticles in the nanometer range show a significant reduction in dissolution time and an increase in saturation solubility.

[0009] Such nanoparticles can be prepared using the method according to claim 5, namely a) providing a solution of tacrolimus or a salt thereof in an organic solvent; b) providing a liquid non-solvent for tacrolimus or a salt thereof, preferably water; c) precipitating nanoparticles containing tacrolimus or a salt thereof by colliding a stream of organic solvent from a) with a stream of non-solvent from b); d) isolating the nanoparticles having a size between 10 and 400 nm and preferably a polydispersity index of ≦about 0.4. The present invention can be provided by using a method for producing nanoparticles containing tacrolimus or a salt thereof, comprising:

[0010] Moreover, the inventors have revealed a mucoadhesive buccal film according to claim 15, in particular comprising at least one matrix layer containing the aforementioned nanoparticles comprising tacrolimus or a salt thereof, and at least one polymer as a therapeutic system for delivering tacrolimus to a patient. Such a mucoadhesive buccal film is particularly suitable for delivering tacrolimus to pediatric patients, i.e. children.

[0011] First, the present invention relates to nanoparticles containing tacrolimus or a salt thereof, having a particle size of about 10 to about 400 nm, preferably about 100 to about 200 nm.

[0012] Such nanoparticles have the advantage that they exhibit significantly reduced elution times and increased saturation solubility compared to single molecules.

[0013] The nanoparticles according to the invention are further preferably characterized in that the nanoparticles have a polydispersity index of about ≦0.4, preferably about ≦0.2.

[0014] The particle size of nanoparticles is defined as their diameter, determined by a suitable method, for example, using dynamic light scattering (DLS) (for example, using a Malvern Zetasizer ZS90 from Malvern Instruments Ltd.). DLS measures Brownian motion and relates this to the size of the particle. Brownian motion is the random movement of the particle due to the impact of the solvent molecules surrounding the particle. The larger the particle or molecule, the slower the Brownian motion will be. Smaller particles are "kicked" more by the solvent molecules and move faster. Since information about the viscosity is required (as the viscosity of a liquid is related to its temperature), a precisely known temperature is necessary for DLS. In this measurement, a temperature of 25° C. is used. This temperature is kept constant during the measurement. The speed of Brownian motion is defined by the translational diffusion coefficient (D). The size of the particle is calculated from the translational diffusion coefficient by using the Stokes-Einstein equation.

[0015]

number

[0016] [where d(H) is the hydrodynamic diameter, D is the translational diffusion coefficient, k is the Boltzmann constant, T is the absolute temperature, and η is the viscosity]. The diameter given by the Stokes-Einstein equation is the diameter of a sphere with the same translational diffusion coefficient as the particle. The translational diffusion coefficient of a particle will depend not only on the size of the particle "core" but also on any surface structures that affect the diffusion rate, as well as the concentration and type of ions in the medium. The Malvern Zetasizer series measures the rate at which particles diffuse due to Brownian motion by determining the rate at which the intensity of the scattered light fluctuates when detected using a suitable optical device. In the Zetasizer Nano ZS90 series, the detector position is 90°. The z-average diameter together with the polydispersity index (PDI) are calculated from the cumulant analysis of the DLS measured intensity autocorrelation function, as defined in ISO 22412:2008. The PDI is a dimensionless estimate of the width of the particle size distribution, scaled from 0 to 1. According to Malvern Instruments, samples with a PDI≦0.4 are considered monodisperse.

[0017] The polydispersity index (PDI) is a parameter that defines the particle size distribution of nanoparticles, obtained from dynamic light scattering (DSL) measurements. As mentioned above, the PDI can be measured using a Malvern Zetasizer according to the manufacturer's instructions. The smaller the PDI value, the narrower the width of the particle size distribution. In general, the polydispersity index PDI is used as a measure of the width of the particle size distribution. Thus, particles or particles in a suspension can generally be divided into monodisperse and polydisperse components. For monodisperse, i.e. homogeneous suspensions / particles, a narrow particle size distribution is given. For polydisperse suspensions / particles, the particle size varies considerably. Monodisperse particles are preferred.

[0018] Particle size and PDI are important factors that affect the dissolution rate of a particular substance, e.g., a pharmaceutical active ingredient. Thus, comparing the dissolution of two populations of nanoparticles of one pharmaceutical active ingredient with comparable mean particle size but significantly different PDIs, the nanoparticles with the higher PDI will have a slower dissolution and the nanoparticles with the lower PDI will have a faster dissolution, which can lead to significant changes in the dissolution behavior of the nanoparticles. Thus, in addition to particle size, PDI can affect the quality of the nanoparticles.

[0019] The nanoparticles according to the invention are preferably characterised in that they further comprise at least one stabilising agent.

[0020] The stabilizer has the function of stabilizing the nanoparticles according to the invention, especially in a pharmaceutical composition comprising the nanoparticles according to the invention.

[0021] The stabilizing agent is preferably adsorbed onto the surface of the nanoparticles, which in turn improves the stability of the nanoparticles.

[0022] The at least one stabilizer can include, but is not limited to, any suitable and pharma-ceutically acceptable polymer known to those skilled in the art for such purposes.The stabilizer can be added to the solvent or non-solvent.Preferably, the at least one stabilizer includes polyvinylpyrrolidone (PVP), vinylpyrrolidone- / vinyl acetate-copolymer, polyethylene glycol and / or cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose (HPC), and / or carboxymethylcellulose (CMC).

[0023] The nanoparticles according to the invention are further preferably characterized in that they further comprise at least one surfactant (amphiphilic agent), preferably comprising sodium dodecyl sulfate (SDS), polysorbates, amphiphilic triblock copolymers such as poloxamers, amphiphilic diblock copolymers with a hydrophilic block (e.g. PEG) and a hydrophobic block, e.g. polystyrene (PS), poly-ε-caprolactone (PCL), polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), deoxycholic acid or its salts, phosphatidylcholine and / or chitosan.

[0024] In a highly preferred embodiment, the nanoparticles comprise at least one stabilizing agent and at least one surfactant.

[0025] In a further aspect, the present invention is directed to a method for producing nanoparticles containing tacrolimus or a salt thereof, the method comprising: a) providing a solution of tacrolimus or a salt thereof in an organic solvent; b) providing a liquid non-solvent for tacrolimus or a salt thereof, preferably water; c) precipitating nanoparticles containing tacrolimus or a salt thereof by colliding a stream of organic solvent from a) with a stream of non-solvent from b); d) isolating the nanoparticles having a size between 10 and 400 nm and preferably a polydispersity index of ≦about 0.4; Includes.

[0026] The solvent is any type of fluid substance capable of dissolving tacrolimus.

[0027] The term "non-solvent" according to the present invention describes any fluid substance that can precipitate tacrolimus-containing nanoparticles by colliding a non-solvent fluid stream with a fluid mixture fluid stream.Therefore, "non-solvent" in the sense of the present invention should not be interpreted narrowly as, for example, a substance in which tacrolimus is insoluble.Preferably, the non-solvent cannot dissolve more than 1 mg / ml of tacrolimus.

[0028] The above-mentioned method for producing nanoparticles containing tacrolimus or a salt thereof is preferably carried out in a microjet reactor.

[0029] The term "microjet reactor" includes all geometric dimensions as defined in WO2017129177. The contents of this patent application are incorporated herein by reference. WO2017129177 provides a system for initiating a chemical or physical process, comprising at least two liquid media, each medium being injected through one nozzle, into a reactor chamber enclosed by a reactor housing and onto a shared impingement point, by a pump, preferably a high-pressure pump. Through the openings in the reactor chamber, gas, evaporated liquid, cooling liquid or cooling gas is introduced to maintain a gas atmosphere inside the reactor, especially at the impingement point of the liquid jets, and to cool the resulting product. The resulting product and excess gas are removed from the reactor housing through a further opening by a positive pressure on the gas input side or a negative pressure on the product and gas outlet side. Diffusion of the solvent into the non-solvent results in the formation of nanoparticles with a very defined particle size and particle size distribution.

[0030] Thus, the method of the present invention preferably involves controlled solvent / non-solvent precipitation, where the solvent and non-solvent streams collide as impinging jets having a high velocity of about 1 m / sec to about 100 m / sec, preferably about 50 m / sec, whereby the Reynolds number is preferably higher than about 500. It is noted that the velocities given above are the velocities of each impinging stream, i.e., both the fluid mixture fluid stream and the non-solvent fluid stream have this velocity.

[0031] The solvent and non-solvent are preferably sprayed through a nozzle, usually smaller than about 1000 μm (e.g., smaller than about 500 μm, or smaller than about 300 μm), at a pressure greater than about 1 bar. Pressures greater than about 10 bar and even greater than about 50 bar are suitable as well. The pressure can be regulated by a pressure regulator.

[0032] The two streams collide in the reactor, where very rapid mixing takes place. The mixing time is usually less than about 1 millisecond, preferably less than about 0.5 milliseconds, and even more preferably less than about 0.1 milliseconds. The flow rates of the solvent and non-solvent streams can reach more than about 600 l / h. Thus, the two impinging jets (or streams) collide in the reactor, where deposition takes place, forming disk-like structures depending on the geometry of the reactor.

[0033] The process according to the invention is further preferably carried out in a manner such that the solvent is ethanol, methanol, acetone, tetrahydrofuran, acetic acid, acetonitrile, anisole, 1-butanol, 2-butanol, butyl acetate, chloroform, cyclohexane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 1,2-dimethoxyethane, 1,4-dioxane, 2,2-dimethoxypropane, dichloromethane, diethyl ether, di-iso-propyl ether, dimethylsulfoxide, dimethylformamide, dimethylformamide, 2-ethoxyethanol, ethyl acetate, ethyl formate, ethylene glycol (1,2-ethanediol), formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate. , 2-methoxyethanol, 2-methyl-1-propanol, 3-methyl-1-butanol, 1-methyl-2-pyrrolidone, methyl acetate, methyl t-butyl ether, methyl butyl ketone, methylcyclohexane, methyl ethyl ketone (MEK), methyl isobutyl ketone, methyl isopropyl ketone, methyl tetrahydrofuran, n-methylpyrrolidone, 1-pentanol, 1-propanol, 2-propanol, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, t-butyl alcohol, 2,2,4-trimethylpentane (i-octane), toluol, trichloroacetic acid, trichloroethylene, trifluoroacetic acid and / or xylol.

[0034] Preferably, tacrolimus is dissolved in the solvent at a concentration of about 10 mg / ml to about 500 mg / ml.

[0035] The process according to the invention is further preferably characterized in that the solvent or non-solvent further comprises at least one stabilizer, preferably polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyethylene glycol and / or cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC) and / or carboxymethylcellulose (CMC).

[0036] The stabilizer may preferably be combined with at least one surfactant, such as sodium dodecyl sulfate (SDS), polysorbates, amphiphilic triblock copolymers such as poloxamers, amphiphilic diblock copolymers with a hydrophilic block (e.g., PEG) and a hydrophobic block, such as polystyrene (PS), poly-ε-caprolactone (PCL), polylactide (PLA), or poly(lactic-co-glycolic acid) (PLGA), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), deoxycholic acid or its salts, phosphatidylcholine, and / or chitosan. The surfactant may also be used without a stabilizer.

[0037] Preferably, the at least one stabilizing agent is present in the solvent at a concentration of from about 10 mg / ml to about 200 mg / ml of the solvent or non-solvent.

[0038] Preferably, the at least one surfactant is present in a concentration of from about 1 mg / ml to about 200 mg / ml of the solvent or non-solvent.

[0039] Preferably, the volume ratio of solvent to non-solvent is between about 1:1 and about 1:10, more preferably between about 1:2 and about 1:5, more preferably between about 1:2 and about 1:4.

[0040] Therefore, the nanoparticles formed as described above are preferably further processed into the final pharmaceutical formulation. If the final pharmaceutical formulation is aqueous, the first organic solvent must preferably be removed according to the set permitted limits. This can be achieved by using a diafiltration process or a lyophilization process. The pH and osmolarity can be easily adjusted during the diafiltration process as appropriate. If a solid dosage form is targeted, all nanoparticle suspensions are preferably further processed by a drying process (e.g., wet granulation or fluidized bed granulation, spray drying). The resulting powder can be further processed by common pharmaceutical processes.

[0041] The present invention also relates to nanoparticles containing tacrolimus, obtainable by the process described above.

[0042] The invention further relates to the nanoparticles described or obtainable by the described method for use as a medicament.

[0043] The present invention further relates to the nanoparticles as described or obtainable by the described method for use in the prevention and / or treatment of solid organ transplant rejection.

[0044] The invention further relates to the nanoparticles as described or obtainable by the method described, for use as a medicament for treating pediatric patients.

[0045] The invention further relates to the nanoparticles as described or obtainable by the described methods for use in the prevention and / or treatment of solid organ transplant rejection in paediatric patients.

[0046] By "pediatric patient" it is to be understood a child aged up to about 18 years, preferably between 28 days and 17 years.

[0047] The invention further relates to the buccal administration of the nanoparticles described or obtainable by the described methods.

[0048] The invention further relates to a mucoadhesive buccal film comprising at least one matrix layer containing nanoparticles containing tacrolimus as described or obtainable by the described method.

[0049] Mucoadhesive buccal films are thin films that contain at least one pharmaceutical active substance that is placed directly in the oral cavity or applied to the oral mucosa and dissolves there.In particular, they are thin polymer-based films that contain active ingredients, and when applied to the mucosa, especially the oral mucosa, they release the active ingredients directly into the mucosa.The active ingredients can be dissolved, emulsified or dispersed in the film.The very good blood circulation of the oral mucosa ensures the rapid transfer of the active substances into the blood circulation.

[0050] This delivery system has the advantage that the active ingredient is absorbed mostly through the mucosa, thus avoiding the "first-pass metabolism" that occurs in conventional delivery forms of active ingredients in tablet form. Moreover, such mucoadhesive buccal films have the advantage that the tacrolimus is protected from degradation due to the pH and digestive enzymes of the gastrointestinal tract. Mucoadhesive buccal films also provide a rapid onset of action compared to the oral route. Mucoadhesive buccal films are a particularly easy way of drug administration and are therefore particularly suitable for pediatric use. Moreover, such mucoadhesive buccal films avoid the obstacles associated with the administration of drugs via a nasogastric tube and are versatile in physical shape, condition, size and surface. Moreover, mucoadhesive buccal films allow for accurate dosing and the possibility of masking the taste of tacrolimus. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] In a preferred embodiment, the mucoadhesive buccal film according to the present invention is characterized in that the at least one polymer comprises a water-soluble and / or water-swellable polymer.

[0052] Water-soluble / water-swellable polymers include chemically very different natural or synthetic polymers whose common feature is their solubility / swellability in water or aqueous solvents. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for water solubility / swellability and are not crosslinked. The hydrophilic groups can be nonionic, anionic, cationic and / or zwitterionic.

[0053] Preferably, the at least one polymer of the mucoadhesive buccal film according to the invention is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, pea starch, pullulan, poly(meth)acrylates, e.g. known under the trade name Eudragit (Evonik), polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, e.g. known under the trade name Soluplus (BASF), chitosan, gum arabic, dextran, dextrin, alginates, polyvinyl alcohol, polyvinylpyrrolidone and / or vinylpyrrolidone-vinyl acetate-copolymers.

[0054] These polymers have the advantage of drying and forming a thin, stable film that dissolves or swells within a medicamentously acceptable time when applied to the mucosa, thus releasing tacrolimus into the mucosa, which has the advantage of relatively rapid availability of the active ingredient and preferably residue-free administration of tacrolimus.

[0055] In a preferred embodiment, the mucoadhesive buccal film according to the present invention is characterized in that at least one polymer is contained in the mucoadhesive buccal film in an amount of about 10 to about 99.9 wt %, based on the total weight of the mucoadhesive buccal film.

[0056] In another preferred embodiment, the mucoadhesive buccal film according to the present invention is characterized in that the nanoparticles comprising tacrolimus are contained in the mucoadhesive buccal film in an amount of about 0.1 to about 20% by weight, based on the total weight of the mucoadhesive buccal film.

[0057] The mucoadhesive buccal film according to the present invention is further preferably characterised in that it comprises at least one adjuvant selected from the group comprising dyes, fillers, disintegrants, flavours, sweeteners, taste masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0058] Each of these adjuvants is preferably contained in the mucoadhesive buccal film in an amount of about 0.01 to about 10% by weight, based on the total weight of the mucoadhesive buccal film.

[0059] The mucoadhesive buccal film according to the present invention is further preferably characterized in that the basis weight of the mucoadhesive buccal film is about 20 to about 300 g / m2, preferably about 50 to about 200 g / m2.

[0060] This preferably corresponds to a layer thickness of about 20 μm to about 500 μm, preferably about 50 μm to about 300 μm.

[0061] The mucoadhesive buccal film according to the present invention is preferably designed to achieve a daily dose of delivered tacrolimus ranging from about 0.2 mg to about 18 mg, preferably from about 0.3 mg to about 18 mg. Of course, the daily dose depends on the patient's body weight. Preferably, the daily dose is about 0.2 to about 0.4 mg per kg, more preferably about 0.3 mg per kg. To this end, the mucoadhesive buccal film is provided in a suitable size, for example, ranging from about 2 cm2 to about 6 cm2.

[0062] The mucoadhesive buccal film according to the present invention may contain, on one side of the matrix layer, at least one further layer comprising the same or a different polymer.

[0063] The at least one additional layer may also contribute to the stabilization of the mucoadhesive buccal film.

[0064] The at least one additional layer can be adhered onto the matrix layer using a medicamentously acceptable adhesive or by hot sealing.

[0065] Preferably, the further layer is a backing layer, which is preferably impermeable to tacrolimus.Thus, the mucoadhesive buccal film according to the invention preferably comprises one backing layer, preferably impermeable to tacrolimus, on one side of the at least one matrix layer.

[0066] In a further embodiment, the mucoadhesive buccal film according to the invention is disposed on a removable carrier foil, which may be made of polyethylene paper, polypropylene or polyethylene terephthalate foil, The carrier foil is removed prior to application of the mucoadhesive buccal film.

[0067] The present invention further relates to mucoadhesive buccal films which are described for medicinal use.

[0068] The present invention further relates to mucoadhesive buccal films which are indicated for use in the prevention and / or treatment of solid organ transplant rejection.

[0069] The present invention further relates to mucoadhesive buccal films which are described for use as medicaments for treating pediatric patients.

[0070] The present invention further relates to mucoadhesive buccal films which are indicated for use in the prevention and / or treatment of solid organ transplant rejection in pediatric patients.

Claims

1. 1. A mucoadhesive buccal film comprising at least one matrix layer containing at least one polymer and nanoparticles, said additional layer being a tacrolimus-impermeable backing layer on one side of said matrix layer, said nanoparticles comprising said tacrolimus or a salt thereof and having a particle size between 10 and 400 nm, said nanoparticles further comprising at least one stabilizer and / or surfactant, said at least one stabilizer comprising polyvinylpyrrolidone, vinylpyrrolidone- / vinyl acetate-copolymer and / or cellulose derivative.

2. The mucosally adhesive buccal film of claim 1, wherein the cellulose derivative is at least one selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), and carboxymethyl cellulose (CMC).

3. 3. The mucoadhesive buccal film of claim 1 or 2, wherein said nanoparticles have a polydispersity index of ≦0.

4.

4. 1. A method for producing nanoparticles containing tacrolimus or a salt thereof, comprising: a) providing a solution of tacrolimus or a salt thereof in an organic solvent; b) providing a liquid non-solvent for tacrolimus or a salt thereof; c) precipitating nanoparticles containing tacrolimus or a salt thereof by colliding a flow of organic solvent from a) with a flow of non-solvent from b); d) isolating the nanoparticles having a size between 10 and 400 nm and a polydispersity index of ≦0.4; Including, The process, wherein the solvent and / or non-solvent further comprises at least one stabilizer selected from polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, and / or cellulose derivatives.

5. The method described in claim 4, wherein the cellulose derivative is at least one selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), and carboxymethyl cellulose (CMC).

6. The method of claim 4 or 5, wherein the solvent comprises ethanol, methanol, acetone, and / or tetrahydrofuran.

7. 7. The method of claim 4, wherein the non-solvent comprises water.

8. 8. The method of claim 4, wherein the non-solvent further comprises a non-ionic surfactant and / or an ionic surfactant.

9. A method according to any one of claims 4 to 8, wherein the streams of fluid impinge at a velocity between 1 m / s and 100 m / s.

10. 9. A method according to any one of claims 4 to 8, wherein the streams of fluid impinge at a velocity of 50m / s.

11. 11. The method according to any one of claims 4 to 10, wherein the volume ratio of the solvent to the non-solvent is between 1:1 and 1:

5.

12. 4. The mucoadhesive buccal film according to any one of claims 1 to 3, wherein the at least one polymer comprises hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, pea starch, pullulan, poly(meth)acrylates, polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymers, chitosan, gum arabic, dextran, dextrin, alginates, polyvinyl alcohol, polyvinylpyrrolidone and / or vinylpyrrolidone-vinyl acetate-copolymers.

13. 4. The mucoadhesive buccal film according to any one of claims 1 to 3, wherein the at least one matrix layer further comprises at least one adjuvant selected from the group comprising colorants, flavorants, sweeteners, taste masking agents, emulsifiers, enhancers, pH adjusting agents, humectants, preservatives and / or antioxidants.

14. 14. The mucoadhesive buccal film of any one of claims 1, 2, 3, 12, or 13 for pharmaceutical use.

15. A mucoadhesive buccal film as described in any one of claims 1, 2, 3, 12, or 13 for use in the prevention and / or treatment of solid organ transplant rejection.

16. 16. The mucoadhesive buccal film of any one of claims 1, 2, 3, 12 to 15 for use as a medicament for treating a pediatric patient.

17. A mucoadhesive buccal film as defined in any one of claims 1, 2, 3, 12 to 15 for use in the prevention and / or treatment of solid organ transplant rejection in a pediatric patient.

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