Nanoparticles comprising tacrolimus

Abstract

The present invention relates to a nanoparticle comprising tacrolimus, a method for providing a nanoparticle comprising tacrolimus, and a nanoparticle comprising tacrolimus obtainable by the method. The invention also relates to nanoparticles comprising tacrolimus for use as a medicament. The invention further relates to a mucoadhesive oral film containing said nanoparticles comprising tacrolimus and said mucoadhesive oral film for use as a medicament, in particular in pediatric patients.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of December 04, 2019, an application number of 201980080368.4, and an invention title of "Nanoparticles Containing Tacrolimus".

[0002] The present invention relates to nanoparticles containing tacrolimus, methods for providing nanoparticles containing tacrolimus, and nanoparticles containing tacrolimus obtainable by said methods. The present invention further relates to nanoparticles containing tacrolimus for use as a medicament, particularly as a medicament in paediatrics, more particularly for the treatment of solid organ transplant rejection, especially in paediatric patients. The present invention further relates to a mucoadhesive oral film containing said nanoparticles containing tacrolimus, and said mucoadhesive oral film for use as a medicament, particularly as a medicament in paediatrics, more particularly for the treatment of solid organ transplant rejection, especially in paediatric patients.

[0003] Tacrolimus, also known as FK506 or Fujimycin, is an immunosuppressive drug mainly used after allogeneic organ transplantation to reduce the risk of organ rejection. It achieves this by inhibiting the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, which are crucial for the learned (or adaptive) immune response of the human body.

[0004] Chemically, it is a 23-membered macrolide lactone that was first discovered in the fermentation broth of a soil sample containing the bacterium Streptomyces tsukubaensis. Although oral formulations of tacrolimus have been on the market for over two decades, there is no optimal paediatric formulation that is convenient for patient application.

[0005] Tacrolimus is a lipophilic compound with a molecular weight of approximately 822 Da and is poorly soluble in water (0.004 mg / ml), which results in low bioavailability.

[0006] Further factors contributing to the reduced and rather unpredictable bioavailability are the extensive first-pass metabolism of tacrolimus in the intestine and liver by CYP3A4 / 5, P-glycoprotein-mediated drug efflux, genetic variation, the effect of food intake, and concomitant medications.

[0007] This requires complex formulations in order to achieve acceptable drug bioavailability.

[0008] Accordingly, an object of the present invention is to provide tacrolimus in a form with increased water solubility and a method for providing such a form of tacrolimus. Another object of the present invention is to provide a therapeutic system for delivering tacrolimus to a patient, which avoids or bypasses first-pass metabolism by buccal absorption of tacrolimus, thereby resulting in higher and more predictable bioavailability. In addition, the therapeutic system for delivering tacrolimus should protect the drug from degradation due to the pH of the gastrointestinal tract and digestive enzymes, the therapeutic system should provide a rapid onset of action relative to the buccal route, and should be a convenient mode of drug administration. It should further avoid the obstacles associated with drug administration via a nasogastric tube and should be flexible in physical shape, state, size, and surface. In addition, the therapeutic system should allow for accurate dosing and provide the possibility of masking the taste of tacrolimus.

[0009] These objects have been solved by the nanoparticles according to claim 1, i.e., by nanoparticles comprising tacrolimus or a salt thereof, wherein the nanoparticles have a particle size of from about 10 to about 400 nm. The inventors have surprisingly found that such nanoparticles in the said nanoscale range exhibit a significant reduction in dissolution time and an increase in saturated solubility.

[0010] Such nanoparticles can be provided by the method according to claim 5, i.e., by using a method for producing nanoparticles containing tacrolimus or a salt thereof, which method comprises the following steps:

[0011] a) providing a solution of tacrolimus or a salt thereof in an organic solvent;

[0012] b) providing a liquid non-solvent for tacrolimus or a salt thereof, preferably water;

[0013] c) precipitating nanoparticles containing tacrolimus or a salt thereof by causing the organic solvent stream from a) to collide with the non-solvent stream from b); and

[0014] d) separating the nanoparticles, wherein the nanoparticles have a size of 10 to 400 nm and preferably a polydispersity index ≤ about 0.4.

[0015] In addition, the inventors have determined a mucoadhesive oral film according to claim 15, in particular a mucoadhesive oral film comprising at least one matrix layer, as a therapeutic system for delivering tacrolimus to a patient, the matrix layer containing the above-mentioned nanoparticles comprising tacrolimus or a salt thereof and at least one polymer. Such a mucoadhesive oral film is particularly suitable for delivering tacrolimus to pediatric patients, i.e., to children.

[0016] First, the present invention relates to nanoparticles comprising tacrolimus or a salt thereof, wherein the nanoparticles have a particle size of from about 10 to about 400 nm, preferably from about 100 to about 200 nm.

[0017] The advantage of such nanoparticles is that, compared to individual molecules, they show a significant reduction in dissolution time and an increase in saturation solubility.

[0018] A further preferred feature of the nanoparticles according to the invention is that the polydispersity index of the nanoparticles is about ≤ 0.4, preferably about ≤ 0.2.

[0019] Their particle size is defined as their diameter determined by a suitable method, such as using dynamic light scattering (DLS) (e.g., using a Malvern Zetasizer ZS90 from Malvern Instruments Ltd.). DLS measures Brownian motion and correlates it with the size of the particles. Brownian motion is the random movement of particles caused by the bombardment of solvent molecules surrounding the particles. The larger the particle or molecule, the slower the Brownian motion. Smaller particles are further "kicked" by the solvent molecules and move faster. DLS requires an accurately known temperature because the viscosity needs to be known (since the viscosity of a liquid is related to its temperature). In this measurement, the temperature used is 25 °C. During the measurement, this temperature is kept constant. The speed of Brownian motion is defined by the translational diffusion coefficient (D). The size of the particles is calculated from the translational diffusion coefficient using the Stokes-Einstein equation

[0020]

[0021] 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 obtained from the Stokes-Einstein equation is the diameter of a sphere having the same translational diffusion coefficient as the particle. The particle translational diffusion coefficient will depend not only on the size of the particle "core", but also on any surface structure that affects the diffusion rate, as well as the concentration and type of ions in the medium. The Malvern Zetasizer series measures the rate at which the particles diffuse due to Brownian motion by determining the rate of fluctuation of the scattered light intensity when detected using a suitable optical device. In the Zetasizer Nano ZS90 series, the detector position is 90°. The z-average diameter and the polydispersity index (PDI) are calculated from the cumulant analysis of the intensity autocorrelation function of the DLS measurement 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, a sample with a PDI ≤ 0.4 is considered monodisperse.

[0022] The polydispersity index (PDI) is a parameter that defines the particle size distribution of nanoparticles obtained from dynamic light scattering (DLS) measurements. As described above, the PDI can be measured using a Malvern Zetasizer according to the manufacturer's instructions. The smaller the PDI value, the smaller the width of the particle size distribution. Generally, the polydispersity index PDI is used as a measure of the width of the particle size distribution. Thus, particles or the particles in a suspension can generally be classified into monodisperse and polydisperse entities. For monodisperse, such as a homogeneous suspension / particles, a narrow particle size distribution is given. For polydisperse suspensions / particles, the particle size varies greatly. Monodisperse particles are preferred.

[0023] Particle size and PDI are important factors that affect the dissolution rate of a specific substance, such as a drug active ingredient. Thus, comparing the dissolution of two nanoparticle populations of an active pharmaceutical ingredient with comparable average particle sizes but significantly different PDIs may result in significant changes in the dissolution behavior of these nanoparticles, where the nanoparticles with a higher PDI dissolve more slowly, while the nanoparticles with a lower PDI dissolve more rapidly. Thus, in addition to affecting particle size, PDI may also affect the quality of the nanoparticles.

[0024] A further preferred feature of the nanoparticles according to the present invention is that the nanoparticles further comprise at least one stabilizer.

[0025] The stabilizer has the function of stabilizing the nanoparticles according to the present invention, especially in a pharmaceutical composition comprising the nanoparticles according to the present invention.

[0026] The stabilizer is preferably adsorbed on the surface of the nanoparticles, which in turn improves the stability of the nanoparticles.

[0027] The at least one stabilizer is not particularly limited, but may comprise any suitable and pharmaceutically acceptable polymer known to those skilled in the art for this purpose. The stabilizer can be added in a solvent or in a non-solvent. Preferably, the at least one stabilizer comprises polyvinylpyrrolidone (PVP), 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 carboxymethyl cellulose (CMC).

[0028] A further preferred feature of the nanoparticles according to the invention is that they further comprise at least a surfactant (which is an amphiphile). Preferably, the surfactant comprises sodium dodecyl sulfate (SDS), polysorbate, amphiphilic triblock copolymers such as polaxamer, amphiphilic diblock copolymers having a hydrophilic block (e.g., PEG) and a hydrophobic block consisting of, for example, polystyrene (PS), poly-ε-caprolactone (PCL), polylactide (PLA) or poly(lactic-co-glycolic acid) (PLGA), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), deoxycholic acid or its salts, phosphatidylcholine and / or chitosan.

[0029] In a very preferred embodiment, the nanoparticles comprise at least a stabilizer and at least a surfactant.

[0030] In another aspect, the invention relates to a method for producing nanoparticles containing tacrolimus or a salt thereof, wherein the method comprises the following steps:

[0031] a) providing a solution of tacrolimus or a salt thereof in an organic solvent;

[0032] b) providing a liquid non-solvent for tacrolimus or a salt thereof, preferably water;

[0033] c) precipitating nanoparticles containing tacrolimus or a salt thereof by causing the organic solvent stream from a) to collide with the non-solvent stream from b); and

[0034] d) separating the nanoparticles, wherein the nanoparticles have a size of 10 to 400 nm and preferably a polydispersity index ≤ about 0.4.

[0035] The solvent is any kind of fluid substance capable of dissolving tacrolimus.

[0036] The term "non-solvent" according to the invention describes any fluid substance capable of precipitating nanoparticles containing tacrolimus by causing its fluid stream to collide with the fluid stream of a fluid mixture. Thus, "non-solvent" in the context of the present invention should not be narrowly interpreted as, for example, a substance in which tacrolimus is insoluble. Preferably, the non-solvent cannot dissolve more than 1 mg / ml of tacrolimus.

[0037] The above method for producing nanoparticles containing tacrolimus or a salt thereof is preferably carried out in a microjet reactor.

[0038] The term "microjet reactor" encompasses all geometries defined in WO2017129177 A1. The content of this patent application is incorporated herein by reference. WO2017129177 A1 provides a system for initiating chemical or physical processes, which includes at least two liquid media that are injected into a reactor chamber enclosed by a reactor housing by means of pumps, preferably high-pressure pumps, and reach a common collision point, with each medium being injected through a nozzle. Gas, evaporated liquid, cooled liquid, or cooled gas is introduced through an opening in the reactor chamber to maintain the gas atmosphere inside the reactor, especially at the collision point of the liquid jets, and to cool the resulting product. The resulting product and excess gas are removed from the reactor housing via another opening by positive pressure on the gas input side or negative pressure on the product and gas discharge side. Nanoparticles with a very well-defined particle size and particle size distribution are formed by solvent diffusion into a non-solvent.

[0039] Thus, the method of the present invention preferably includes controlled solvent / non-solvent precipitation, where the solvent and non-solvent streams collide as impinging jets at a high speed of about 1 m / sec to about 100 m / sec, preferably about 50 m / sec. Accordingly, the Reynolds number is preferably higher than about 500. It should be noted that the speeds indicated above are the speeds of each colliding stream, i.e., both the fluid stream of the fluid mixture and the fluid stream of the non-solvent have this speed.

[0040] The solvent and non-solvent are preferably sprayed at a pressure greater than about 1 bar through nozzles that are typically less than about 1000 μm (e.g., less than about 500 μm or about 300 μm). Pressures greater than about 10 bar, and even greater than about 50 bar are also suitable. The pressure can be regulated by a pressure regulator.

[0041] The two streams collide in the reactor, and very rapid mixing occurs in the reactor. The mixing time is typically below about 1 millisecond, preferably below about 0.5 millisecond, and even more preferably below about 0.1 millisecond. The flow rates of the solvent stream and the non-solvent stream can reach above about 600 l / hour. Thus, the two impinging jets (or streams) collide in the reactor, and precipitation occurs in the reactor, forming a disk-like structure depending on the geometry of the reactor.

[0042] Further preferred features of the method according to the present invention are that the solvent comprises 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, diisopropyl ether, dimethyl sulfoxide, 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 tert-butyl ether, methyl butyl ketone, methylcyclohexane, methyl ethyl ketone (MEK), methyl isobutyl ketone, methyl isopropyl ketone, methyltetrahydrofuran, n-methylpyrrolidone, 1-pentanol, 1-propanol, 2-propanol, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butanol, 2,2,4-trimethylpentane (isooctane), toluene, trichloroacetic acid, trichloroethylene, trifluoroacetic acid and / or mixed xylenes.

[0043] Preferably, tacrolimus is dissolved in the solvent at a concentration of about 10 mg / ml to about 500 mg / ml.

[0044] Further preferred features of the method according to the present invention are that the solvent or the 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 carboxymethyl cellulose (CMC).

[0045] The stabilizer can preferably be combined with at least one surfactant, such as sodium dodecyl sulfate (SDS), polysorbate, amphiphilic triblock copolymers such as poloxamer, amphiphilic diblock copolymers having a hydrophilic block (e.g., PEG) and a hydrophobic block composed of, for example, polystyrene (PS), poly-ε-caprolactone (PCL), polylactide (PLA) or poly(lactic-co-glycolic acid) (PLGA), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), deoxycholic acid or its salts, phosphatidylcholine and / or chitosan. Surfactants can also be used without the stabilizer.

[0046] Preferably, based on the solvent or the non-solvent, at least one stabilizer is present in the solvent at a concentration of about 10 mg / ml to about 200 mg / ml.

[0047] Preferably, based on the solvent or the non-solvent, at least one surfactant is present at a concentration of from about 1 mg / ml to about 200 mg / ml.

[0048] Preferably, the volume ratio of the solvent to the non-solvent is between about 1:1 and about 1:10, more preferably between about 1:2 and about 1:5, and even more preferably between about 1:2 and about 1:4.

[0049] Then, preferably, the nanoparticles formed as described above are further processed into a final pharmaceutical formulation. In the case where the final pharmaceutical formulation is an aqueous formulation, it is preferred that the organic solvent must first be removed according to the specified official limits. This can be achieved by using a diafiltration or freeze-drying method. Accordingly, the pH and the osmolality can be easily adjusted during the diafiltration method. If the goal is a solid dosage form, the entire nanoparticle suspension is preferably further processed by a drying method (such as wet granulation or fluidized bed granulation, spray drying). The obtained powder can be further processed by conventional pharmaceutical methods.

[0050] The present invention also relates to nanoparticles containing tacrolimus obtainable by the above method.

[0051] The present invention further relates to nanoparticles as described or obtainable by the described method, which are used as a medicine.

[0052] The present invention further relates to nanoparticles as described or obtainable by the described method, which are used for preventing and / or treating solid organ transplant rejection.

[0053] The present invention further relates to nanoparticles as described or obtainable by the described method, which are used as a medicine for treating pediatric patients.

[0054] The present invention further relates to nanoparticles as described or obtainable by the described method, which are used for preventing and / or treating solid organ transplant rejection in pediatric patients.

[0055] Children up to about 18 years of age, preferably children from 28 days to 17 years of age, should be understood as "pediatric patients".

[0056] The present invention further relates to the buccal administration of nanoparticles as described or obtainable by the described method.

[0057] The present invention further relates to a mucoadhesive oral film comprising at least one matrix layer containing nanoparticles containing tacrolimus as described or obtained by the described method.

[0058] A mucoadhesive oral film is a thin film containing at least one pharmaceutically active substance, which is directly placed in the oral cavity or applied to the oral mucosa and dissolved therein. In particular, these are polymer-based thin films containing active ingredients, which directly release the active ingredients into the mucosa when applied to the mucosa, especially the oral mucosa. The active ingredient 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 substance into the blood circulation.

[0059] The advantages of this delivery system are that the active ingredient is mostly absorbed through the mucosa, thus avoiding the "first-pass metabolism" that occurs in the conventional delivery forms of active ingredients in tablet form. In addition, such mucoadhesive oral films have the advantage of protecting tacrolimus from degradation due to the pH and digestive enzymes of the gastrointestinal tract. Compared with the oral route, the mucoadhesive oral film further provides a rapid onset of action. The mucoadhesive oral film is a particularly easy way of drug administration and is therefore especially suitable for use in pediatrics. Moreover, such mucoadhesive oral films avoid the obstacles associated with drug administration via a nasogastric tube and are flexible in terms of physical shape, state, size and surface. Moreover, the mucoadhesive oral film allows accurate dosing and provides the possibility of masking the taste of tacrolimus.

[0060] In a preferred embodiment, the mucoadhesive oral film according to the invention is characterized in that the at least one polymer comprises a water-soluble and / or water-swellable polymer.

[0061] Water-soluble / water-swellable polymers include chemically very different natural or synthetic polymers, the common feature of which is their solubility / swellability in water or aqueous media. The prerequisite is that these polymers have a sufficient number of hydrophilic groups for water solubility / water swellability and are not crosslinked. The hydrophilic groups can be nonionic, anionic, cationic and / or zwitterionic.

[0062] Preferably, the at least one polymer in the mucoadhesive oral film according to the invention is selected from: hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, pea starch, amylopectin, poly(meth)acrylates (e.g., known under the trade name Eudragit (Evonik)), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., known under the trade name Soluplus (BASF)), chitosan, gum arabic, dextran, dextrin, alginate, polyvinyl alcohol, polyvinylpyrrolidone and / or vinylpyrrolidone-vinyl acetate-copolymer.

[0063] These polymers have the advantage that when dry, they form thin, stable films which, when applied to the mucosa within a pharmaceutically acceptable time, dissolve or swell and thus release tacrolimus in the mucosa. This has the advantages of relatively rapid utilization of the active ingredient and preferably residue-free administration of tacrolimus.

[0064] In a preferred embodiment, the mucoadhesive oral film according to the invention is characterized in that at least one polymer is comprised in the mucoadhesive oral film in an amount of from about 10 to about 99.9% by weight, based on the total weight of the mucoadhesive oral film.

[0065] In another preferred embodiment, the mucoadhesive oral film according to the invention is characterized in that nanoparticles comprising tacrolimus are comprised in the mucoadhesive oral film in an amount of from about 0.1 to about 20% by weight, based on the total weight of the mucoadhesive oral film.

[0066] A further preferred feature of the mucoadhesive oral film according to the invention is that the mucoadhesive oral film comprises at least one adjuvant selected from the group consisting of dyes, fillers, disintegrants, flavoring agents, sweeteners, taste-masking agents, emulsifiers, enhancers, pH regulators, humectants, preservatives and / or antioxidants.

[0067] Each of these adjuvants is preferably comprised in the mucoadhesive oral film in an amount of from about 0.01 to about 10% by weight, based on the total weight of the mucoadhesive oral film.

[0068] A further preferred feature of the mucoadhesive oral film according to the invention is that the basis weight of the mucoadhesive oral film is from about 20 to about 300 g / m 2 , preferably from about 50 to about 200 g / m 2 .

[0069] This preferably corresponds to a layer thickness of from about 20 μm to about 500 μm, preferably from about 50 μm to about 300 μm.

[0070] The mucoadhesive oral film according to the invention is preferably designed to achieve a daily dose of the delivered tacrolimus in the range of from about 0.2 mg to about 18 mg, and preferably in the range of from about 0.3 mg to about 18 mg. Of course, the daily dose depends on the weight of the patient. Preferably, the daily dose is from about 0.2 to about 0.4 mg / kg, more preferably about 0.3 mg / kg. For this purpose, the mucoadhesive oral film is provided in a suitable size, for example in the range of from about 2 cm 2 to about 6 cm 2 .

[0071] The mucoadhesive oral film according to the invention may comprise at least one additional layer on one side of the matrix layer, which comprises the same or different polymers.

[0072] Said at least one additional layer may also be used to stabilize the mucoadhesive oral film.

[0073] The at least one additional layer may be glued or heat-sealed to the matrix layer using a pharmaceutically acceptable adhesive.

[0074] Preferably, the additional layer is a backing layer which is preferably impermeable to tacrolimus. Thus, the mucoadhesive oral film according to the invention preferably comprises a backing layer which is preferably impermeable to tacrolimus on one side of the at least one matrix layer.

[0075] In a further embodiment, the mucoadhesive oral film according to the invention is arranged on a removable carrier foil which may be made of polyethylene paper, polypropylene or polyethylene terephthalate foil. The carrier foil is removed before application of the mucoadhesive oral film.

[0076] The invention further relates to the described mucoadhesive oral film for use as a medicament.

[0077] The invention further relates to the described mucoadhesive oral film for the prevention and / or treatment of solid organ transplant rejection.

[0078] The invention further relates to the described mucoadhesive oral film for use as a medicament for treating paediatric patients.

[0079] The invention further relates to the described mucoadhesive oral film for the prevention and / or treatment of solid organ transplant rejection in paediatric patients.

Claims

1. Nanoparticles comprising tacrolimus or a salt thereof, wherein the particle size of the nanoparticles is from about 10 to about 400 nm.

2. The nanoparticles according to claim 1, wherein the polydispersity index of the nanoparticles is ≤ about 0.

4.

3. The nanoparticles according to any one of claims 1 or 2, wherein the nanoparticles further comprise at least one stabilizer and / or surfactant.

4. The nanoparticles according to claim 3, wherein the at least one stabilizer comprises polyvinylpyrrolidone, 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).

5. A method for producing nanoparticles containing tacrolimus or a salt thereof, the method comprising the following steps: 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 the organic solvent stream from a) with the non-solvent stream from b); and d) separating the nanoparticles, wherein the size of the nanoparticles is 10 to 400 nm, and preferably the polydispersity index is ≤ about 0.

4.

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

7. The method according to any one of claims 5 or 6, wherein the non-solvent comprises water.

8. The method according to any one of claims 5 to 7, wherein the solvent and / or the non-solvent further comprise at least one stabilizer, preferably polyvinylpyrrolidone, 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).

9. The method according to any one of claims 5 to 8, wherein the non-solvent further comprises a nonionic surfactant and / or an ionic surfactant.

10. The method according to any one of claims 5 to 9, wherein the fluid streams collide at a speed of about 1 m / sec to about 100 m / sec, preferably about 50 m / sec.

11. The method according to any one of claims 5 to 10, wherein the volume ratio of the solvent to the non-solvent is between about 1:1 and about 1:

5.

12. Nanoparticles containing tacrolimus obtainable by the method according to any one of claims 5-11.

13. The nanoparticles according to any one of claims 1-4 or 12, which are used as a medicament, in particular for preventing and / or treating solid organ transplant rejection.

14. A nanoparticle according to any one of claims 1 - 4 or 12, which is used as a medicament for treating pediatric patients, in particular for preventing and / or treating solid organ transplant rejection in pediatric patients.

15. A mucoadhesive oral film, which comprises at least one matrix layer, and the matrix layer contains a nanoparticle according to any one of claims 1 to 4 or 12 and at least one polymer.

16. The mucoadhesive oral film according to claim 15, wherein the at least one polymer comprises hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, pea starch, amylopectin, poly(meth)acrylate, polyvinylcaprolactam - polyvinyl acetate - polyethylene glycol graft copolymer, chitosan, gum arabic, dextran, dextrin, alginate, polyvinyl alcohol, polyvinylpyrrolidone, and / or vinylpyrrolidone - vinyl acetate - copolymer.

17. The mucoadhesive oral film according to any one of claims 15 or 16, wherein the at least one matrix layer further comprises at least one adjuvant selected from the following: colorant, flavoring agent, sweetening agent, taste - masking agent, emulsifier, enhancer, pH regulator, wetting agent, preservative, and / or antioxidant.

18. The mucoadhesive oral film according to any one of claims 15 to 17, wherein the mucoadhesive oral film comprises a lining layer, and the lining layer is preferably impermeable to tacrolimus on one side of the at least one matrix layer.

19. The mucoadhesive oral film according to any one of claims 15 to 18, which is used as a medicament, in particular for preventing and / or treating solid organ transplant rejection.

20. The mucoadhesive oral film according to any one of claims 15 to 18, which is used as a medicament for treating pediatric patients, in particular for preventing and / or treating solid organ transplant rejection in pediatric patients.

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