Non-nanoparticulate forms of macrolides

Abstract

The present invention relates to a mucoadhesive layer, preferably a mucoadhesive buccal layer, comprising a non-nanoparticulate macrolide. Furthermore, the present invention relates to a mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer comprising a non-nanoparticulate macrolide and further comprising a backing layer. The present invention also relates to a mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer, a backing layer, and an intermediate layer. The present invention further relates to a mucoadhesive layer or a mucoadhesive film for use as a medicament and for use in the prevention and / or treatment of transplant rejection. Furthermore, the present invention relates to a method for preparing the mucoadhesive film.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a mucoadhesive layer, preferably a mucoadhesive buccal layer, comprising a non-nanoparticulate macrolide. Furthermore, the present invention relates to a mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer comprising a non-nanoparticulate macrolide and further comprising a backing layer. The present invention also relates to a mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer, a backing layer, and an intermediate layer. The present invention further relates to a mucoadhesive layer or a mucoadhesive film for use as a medicament and for use in the prevention and / or treatment of transplant rejection. Furthermore, the present invention relates to a method for preparing the mucoadhesive film. [Background technology]

[0002] 2. Background of the Invention Poor water solubility of active agents is a challenge in the development of pharmaceutical formulations. In fact, the majority of active drug ingredients exhibit low water solubility. To elicit a therapeutic effect, the active agent must dissolve and reach the bloodstream in sufficient concentration. Thus, active agents with low water solubility, such as macrolides, typically have poor bioavailability, i.e., only a small percentage of an administered active agent reaches the bloodstream after ingestion. Low bioavailability of a drug reflects incomplete absorption in the gastrointestinal tract and / or incomplete metabolism in the gastrointestinal tract. The rate and extent of absorption of macrolides, such as tacrolimus, can be reduced even in the presence of food.

[0003] Macrolides such as tacrolimus, which have a narrow therapeutic index, exhibit poor oral bioavailability due to such poor solubility, and furthermore, show high inter- and intra-individual variability of pharmacokinetic parameters. Therefore, the dose administered to the patient must be carefully monitored. Due to the patient-specific dosing (mg / kg body weight / day) of the macrolide tacrolimus, the available capsule formulations are often opened, the active ingredient is put into solution, and then applied to the patient; such a process is called "compounding". Compounding does not meet the high quality requirements of pharmaceutical products, and may even jeopardize drug safety by increasing the risk of incorrect dosing. Furthermore, drug compounding may result in decreased stability of the drug or microbial contamination of the prepared solution.

[0004] Drug delivery via the buccal mucosa represents a route of administration that provides direct access to the systemic circulation and bypasses the first-pass metabolism of the liver. Buccal drug delivery applications require drugs with adequate water solubility due to the permeation requirements through the buccal mucosa and the systemic drug absorption. Mucoadhesive buccal films have been proposed as a therapeutic system for delivering the macrolide tacrolimus. Tacrolimus is classified as a BCS Class II drug with low solubility and high permeability, and exhibits a high melting point of 126°C. Due to the fact that tacrolimus is a drug with a narrow therapeutic index, stricter bioequivalence standards are required for generic tacrolimus products, since small changes in dose or exposure may result in therapeutic failure or toxicity. EP 3 662 894 A1 relates to nanoparticles containing tacrolimus and mucoadhesive buccal films containing such nanoparticles. The manufacture of such buccal films requires the preparation of tacrolimus nanoparticles. There remains a need for mucoadhesive buccal films that allow for effective delivery of macrolides to patients. In particular, there remains a need for improved formulations of macrolides that allow for achieving sufficient blood levels of the macrolide.Furthermore, there remains a need for an efficient method of preparing buccal films containing tacrolimus.

[0005] Thus, there remains a need to provide formulations of macrolides with increased efficacy and / or enhanced bioavailability. In particular, formulations are needed that allow efficient administration of sufficient doses of macrolides to patients. Furthermore, there is a need for improved means, such as dosage forms, for administering macrolides, e.g., therapeutic systems that allow efficient administration of active agents such as macrolides. Summary of the Invention [Means for solving the problem]

[0006] Summary of the Invention Below, the components of the present invention are described. These components are listed with specific embodiments, but it should be understood that they can be combined in any manner and in any number to create further embodiments. The various described examples and preferred embodiments should not be interpreted as limiting the present invention to only the specifically described embodiments. This description should be understood to support and encompass embodiments that combine two or more specifically described embodiments, or combine one or more specifically described embodiments with any number of disclosed and / or preferred components. Furthermore, any variation and combination of all components described in this application should be considered to be disclosed by the description of this application, unless the context dictates otherwise.

[0007] In a first aspect, the present invention relates to a mucoadhesive layer, preferably a mucoadhesive buccal layer, comprising a non-nanoparticulate macrolide.

[0008] In one embodiment, the non-nanoparticulate macrolide is selected from a macrolide immunosuppressant, a macrolide antibiotic, and a macrolide antifungal; Here, preferably, - the macrolide immunosuppressant is selected from tacrolimus, sirolimus, everolimus, and pimecrolimus; - the macrolide antibiotic is selected from erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fidaxomicin; and / or - the macrolide antifungal agent is selected from polyenes, in particular nystatin, natamycin, and amphotericin B; Wherein, more preferably, said non-nanoparticulate macrolide is non-nanoparticulate tacrolimus or sirolimus, even more preferably non-nanoparticulate tacrolimus.

[0009] In one embodiment, the non-nanoparticulate macrolide is present in the layer in the form of a micronized macrolide, preferably a micronized crystalline macrolide, and / or in a molecularly dissolved non-nanoparticulate form.

[0010] In one embodiment, the micronised macrolide has an average particle size of 1-100 μm, preferably 1.5-50 μm, more preferably 2-25 μm.

[0011] In one embodiment, the mucoadhesive layer comprises mucoadhesive polymers, preferably selected from a) amphiphilic and hydrophilic polymers, b) poly(methacrylates), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers containing polyvinyl acetate and / or polyvinylpyrrolidone, and combinations thereof; Including, Here, preferably, the amphiphilic polymer is selected from polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, polyoxyl castor oil and D-α-tocopherol-polyethyleneglycol-succinate (TPGS); and / or The poly(methacrylates) are selected from neutral protonatable poly(methacrylates) and cationic poly(methacrylates), preferably copolymers of dialkylaminoethyl methacrylate and methacrylic acid esters, and copolymers of trialkylammonioethyl methacrylate and methacrylic acid esters, in particular copolymers of dimethylaminoethyl methacrylate and methacrylic acid esters, and copolymers of trimethylammonioethyl methacrylate and methacrylic acid esters; and wherein the mucoadhesive layer comprises: - cellulose derivatives, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof; a plasticizer; preferably selected from glycerol, polyethylene glycol, such as low molecular weight polyethylene glycols, such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate; more preferably glycerol; - optional colorant, preferably TiO2; - and non-nanoparticulate macrolides Further includes:

[0012] In one embodiment, the non-nanoparticulate macrolide is present in the layer in a molecularly dissolved, non-nanoparticulate form; and said mucoadhesive polymer and / or said cellulose derivative is a polymer that is soluble in an organic solvent.

[0013] In one embodiment, the mucoadhesive layer comprises a) a mucoadhesive polymer, preferably an amphiphilic polymer; hydroxypropylcellulose (HPC); carboxymethylcellulose (CMC); a plasticizer, preferably glycerol; and optionally a colorant, preferably TiO2; Preferably 10 wt% - 30 wt% of a mucoadhesive polymer; 25 wt% - 35 wt% of hydroxypropylcellulose (HPC); 10 wt% - 25 wt% of carboxymethylcellulose (CMC); 10 wt% - 16 wt% of said plasticizer; and optionally 1 wt% - 4 wt% of said colorant; or b) a mucoadhesive polymer, preferably selected from crosslinked polyacrylic acid polymers and copolymers of methyl vinyl ether and maleic anhydride; hydroxypropyl cellulose (HPC); ethyl cellulose (EC); a plasticizer, preferably glycerol; and optionally a colorant, preferably TiO2; Preferably, 2 wt% to 17 wt% of the mucoadhesive polymer; 30 wt% to 70 wt% of hydroxypropylcellulose (HPC); 5 wt% to 40 wt% of the ethylcellulose (EC); 3 wt% to 20 wt% of the plasticizer; and optionally 1 wt% to 5 wt% of the colorant. Includes.

[0014] In one embodiment, the macrolide is present at a concentration of at least 2 wt%, preferably at least 3 wt%, for example 3.2 wt%; and / or 2 In the case of the mucoadhesive layer, the amount is in the range of about 0.01 mg to about 10 mg, preferably in the range of 1 cm 2 The mucoadhesive layer is preferably in the range of about 0.1 mg to about 5 mg, more preferably 1 cm 2 is present in the mucoadhesive layer in an amount ranging from about 1.5 mg to about 3.5 mg with respect to the mucoadhesive layer.

[0015] In a further aspect, the present invention relates to a mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer, preferably as defined above, which comprises a non-nanoparticulate macrolide; and further comprising a backing layer, preferably a backing layer which is impermeable to the macrolide and / or impermeable to water.

[0016] In one embodiment, the backing layer comprises a plasticizer, preferably selected from glycerol, polyethylene glycol, low molecular weight polyethylene glycol such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol; and / or a water-insoluble polymer and / or a cellulose derivative, such as hydroxyethylcellulose, preferably a water-insoluble cellulose derivative, more preferably ethylcellulose.

[0017] In one embodiment, the mucoadhesive film further comprises an intermediate layer disposed between the mucoadhesive layer and the backing layer; wherein preferably the intermediate layer facilitates adhesion between the mucoadhesive layer and the backing layer; Wherein, if desired, the intermediate layer comprises a plasticizer, preferably selected from glycerol, polyethylene glycol, e.g. low molecular weight polyethylene glycol such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol; and a polymer, preferably a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, more preferably a vinylpyrrolidone-vinyl acetate copolymer.

[0018] In one embodiment, the mucoadhesive layer has a thickness of 70 g / m 2 ~180 g / m 2 in the range of 100 g / m 2 ~150 g / m 2 and / or The backing layer is 40 g / m 2 ~100 g / m 2 in the range of 40 g / m 2 ~60 g / m 2 range, e.g. 50 g / m 2 and / or The intermediate layer, if present, is 40 g / m 2 ~100 g / m2 in the range of 40 g / m 2 ~70 g / m 2 range, e.g. 60 g / m 2 It has an areal weight of

[0019] In one embodiment, the mucoadhesive layer and / or the backing layer comprises a colorant; Preferably, the mucoadhesive layer and the backing layer each comprise a colorant, wherein the mucoadhesive layer comprises a first colorant, e.g., TiO2, and the backing layer comprises a second colorant, e.g., brilliant blue, and wherein the first colorant and the second colorant are different from each other.

[0020] In one embodiment, the mucoadhesive layer has a water content of <5 wt%, preferably <3 wt%, more preferably <2 wt%.

[0021] In one embodiment, the non-nanoparticulate macrolide and / or the mucoadhesive layer are as defined above.

[0022] In a further aspect, the present invention relates to a mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer, a backing layer, and an intermediate layer, wherein said intermediate layer is disposed between a mucoadhesive layer and a backing layer, and wherein said mucoadhesive layer comprises a macrolide, preferably tacrolimus; wherein preferably the intermediate layer facilitates adhesion between the mucoadhesive layer and the backing layer; wherein, optionally, said intermediate layer comprises a plasticizer, preferably selected from glycerol, polyethylene glycol, e.g. low molecular weight polyethylene glycol such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol; Where appropriate, the intermediate layer comprises a polymer, preferably a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, more preferably a vinylpyrrolidone-vinyl acetate copolymer.

[0023] In one embodiment, the mucoadhesive layer, the backing layer, and / or the intermediate layer are as defined above.

[0024] In a further aspect, the present invention relates to a mucoadhesive layer as defined above, or a mucoadhesive film as defined above, for medical use.

[0025] In a further aspect, the present invention relates to a mucoadhesive layer as defined above, or a mucoadhesive film as defined above, for use in the prevention and / or treatment of transplant rejection, preferably solid organ transplant rejection, such as liver, kidney or heart allograft rejection; Where appropriate, the use includes placement of the film or layer in a body cavity of a patient, preferably in the buccal cavity of a patient.

[0026] In a further aspect, the present invention provides i) providing a micronized macrolide, preferably a non-nanoparticulate micronized macrolide; and a polymer mixture, wherein the polymer mixture mucoadhesive polymers, preferably selected from a) amphiphilic and hydrophilic polymers, b) poly(methacrylates), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers containing polyvinyl acetate and / or polyvinylpyrrolidone, and combinations thereof; - cellulose derivatives, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof; - optionally a plasticizer; preferably selected from glycerol, polyethylene glycol, for example low molecular weight polyethylene glycols such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate; more preferably glycerol; - optional colorant, preferably TiO2; Including, ii) optionally dispersing the micronized macrolide in a liquid medium to obtain a micronized macrolide dispersion and / or dissolving said micronized macrolide in an organic solvent to obtain a micronized macrolide solution; iii) mixing the micronized macrolide, optionally a micronized macrolide dispersion or a micronized macrolide solution, with the polymer mixture to obtain the mucoadhesive layer composition; iv) preparing a mucoadhesive layer with a mucoadhesive layer composition; optionally by coating the mucoadhesive layer composition onto a surface, preferably onto a process liner, e.g., by coating, hot melt extrusion, and / or casting; v) optionally drying the mucoadhesive layer, thereby obtaining a mucoadhesive film comprising the mucoadhesive layer. The present invention relates to a method for preparing a mucoadhesive film comprising:

[0027] In one embodiment, the method further comprises preparing a backing layer: a) providing a backing layer polymer mixture; optionally comprising a plasticizer, preferably glycerol, and a water insoluble polymer, preferably a water insoluble cellulose derivative, more preferably ethyl cellulose; b) preparing a backing layer with a backing layer polymer mixture, optionally on the surface of the mucoadhesive layer, e.g. by coating the polymer mixture on the surface of the mucoadhesive layer; c) Drying the backing layer, if necessary. Includes.

[0028] In one embodiment, the method further comprises preparing an intermediate layer: 1) providing an intermediate layer polymer mixture; optionally comprising a plasticizer, preferably glycerol, and a polymer, preferably a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, more preferably a vinylpyrrolidone-vinyl acetate copolymer; 2) preparing an intermediate layer with a polymer mixture, optionally on the surface of the mucoadhesive layer, e.g., by coating the polymer mixture on the surface of the mucoadhesive layer; 3) If necessary, dry the intermediate layer. Includes.

[0029] In one embodiment, the method further comprises the step of joining the mucoadhesive layer and the backing layer, optionally by compression and / or lamination, eg, heat lamination.

[0030] In one embodiment, the method further comprises the step of joining the mucoadhesive layer, the intermediate layer, and the backing layer, optionally by compression and / or lamination, eg, heat lamination.

[0031] In one embodiment, the macrolide, the non-nanoparticulate micronized macrolide, the mucoadhesive polymer, the plasticizer, the mucoadhesive layer, the backing layer, and / or the intermediate layer are as defined above.

[0032] In a further aspect, the present invention relates to a method for preventing and / or treating a disease or disorder, comprising administering a mucoadhesive layer as defined above, or a mucoadhesive film as defined above, to a patient in need thereof.

[0033] In one embodiment, the administering comprises placement of the film or layer in a body cavity of a patient, preferably in the buccal cavity of a patient.

[0034] In one embodiment, the mucoadhesive layer or film comprises a therapeutically effective amount of a non-nanoparticulate macrolide.

[0035] In one embodiment, the mucoadhesive layer, the mucoadhesive film, and the non-nanoparticulate macrolide are as defined above.

[0036] In a further aspect, the present invention relates to a method for preventing and / or treating transplant rejection, preferably solid organ transplant rejection, such as liver, kidney or heart allograft rejection, comprising administering to a patient in need thereof a mucoadhesive layer as defined above, or a mucoadhesive film as defined above.

[0037] In one embodiment, the administering comprises placement of the film or layer in a body cavity of a patient, preferably in the buccal cavity of a patient.

[0038] In one embodiment, the mucoadhesive layer or film comprises a therapeutically effective amount of a non-nanoparticulate macrolide.

[0039] In one embodiment, the mucoadhesive layer, the mucoadhesive film, and the non-nanoparticulate macrolide are as defined above.

[0040] In a further aspect, the present invention relates to the use of a non-nanoparticulate macrolide for the preparation of a mucoadhesive layer and / or a mucoadhesive film, preferably for the prevention and / or treatment of transplant rejection.

[0041] In one embodiment, the mucoadhesive layer, the mucoadhesive film, the non-nanoparticulate macrolide, and / or the prevention and / or treatment of transplant rejection are as defined above. [Brief description of the drawings]

[0042] BRIEF DESCRIPTION OF THE DRAWINGS The invention will now be further described by reference to the following drawings. All methods mentioned in the following figure descriptions were performed as detailed in the Examples. [Figure 1] FIG. 1 shows a schematic diagram of a method for producing the mucoadhesive layer and / or the mucoadhesive film of the present invention. [Diagram 2] FIG. 2 shows the release and directional release of a film containing a micronized crystalline macrolide (MFK10) and a film of the same composition but without Soluplus®. [Diagram 3] FIG. 3 shows the overlay of the XRPD spectra of MFK10 (3), TiO2 (2) and pure crystalline tacrolimus (1). [Figure 4] FIG. 4 shows in vivo macrolide blood levels following administration of the mucoadhesive films. [Diagram 5] FIG. 5 shows a schematic diagram of a method for producing a mucoadhesive film of the present invention comprising a mucoadhesive layer, an intermediate layer (adhesive layer), and a backing layer. [Figure 6] Figure 6 shows photographs of a film containing a micronized crystalline macrolide (MFK10) adhered onto the buccal mucosa during 30 minutes of treatment (the particular experiment shown is designated "T2_No.3_xx min", where xx designates the number of minutes of treatment that the film adhered to the buccal mucosa). Successful adherence and treatment was also observed with a film containing a molecularly dissolved non-nanoparticulate macrolide (FK1). [Figure 7] Figure 7 shows the mucosa of the animal from Figure 6 after treatment and removal of the film MFK10. No inflammation of the mucosa is visible. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Detailed Description The present invention aims to provide a mucoadhesive film for the application of macrolides, e.g. for the prevention and / or treatment of transplant rejection after organ transplantation, particularly solid organ transplantation. Furthermore, the present invention aims to provide a unidirectional mucoadhesive film, i.e. a film that releases macrolides directly to the mucosa and with negligible release into the body cavity, e.g. the buccal cavity. The present invention further aims to provide an efficient method for preparing the mucoadhesive film. The present invention further aims to provide a mucoadhesive film that can be efficiently prepared. Furthermore, it is an object of the present invention to prepare a mucoadhesive film that prevents the swallowing of the macrolide. It is also an object of the present invention to provide a therapeutic system, particularly a mucoadhesive film, that allows to achieve a therapeutic blood level of the macrolide. Furthermore, it is an object of the present invention to provide a therapeutic system, particularly a mucoadhesive film, that allows for an early onset of the therapeutic effect.

[0044] Although macrolides such as tacrolimus have very low water solubility, the layers and films of the present invention surprisingly achieve therapeutic macrolide blood concentrations. Unexpectedly, clinically relevant blood levels of macrolides are achieved using the layers and films of the present invention. Moreover, surprisingly, the layers and films of the present invention, which include crystalline or molecularly dissolved non-nanoparticulate macrolides, are highly stable against degradation.

[0045] The term "mucoadhesive layer" as used herein refers to a layer configured to adhere to mucosa and / or to adhere to mucosa, e.g. oral and / or buccal mucosa. In one embodiment, the mucoadhesive layer comprises a mucoadhesive polymer and / or cellulose derivative and further comprises a non-nanoparticulate macrolide. In one embodiment, the mucoadhesive layer comprises a non-nanoparticulate macrolide, preferably a micronized crystalline non-nanoparticulate macrolide and / or a molecularly dissolved non-nanoparticulate macrolide. In one embodiment, the mucoadhesive layer optionally comprises a surfactant, e.g. a polysorbate. In one embodiment, the mucoadhesive layer is swellable in aqueous liquids but insoluble in aqueous liquids and / or has negligible solubility in aqueous liquids. Insolubility or low solubility increases the adhesion time on the mucosa and thus allows the active ingredient to be released over an extended period of time, e.g. at least 60 minutes. The term "mucoadhesive buccal layer" or "MBF" as used herein refers to a mucoadhesive layer configured for buccal application.

[0046] The term "macrolide" as used herein refers to a class of natural products consisting of a large macrocyclic lactone ring, such as a 14-, 15-, or 16-membered lactone ring, to which one or more deoxy sugars, usually cladinose and desosamine, may be attached; such as tacrolimus, sirolimus, everolimus, pimecrolimus, erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fidaxomicin, nystatin, natamycin, and amphotericin B. In one embodiment, the macrolide is selected from a macrolide immunosuppressant, a macrolide antibiotic, and a macrolide antifungal. In one embodiment, the macrolide immunosuppressant is selected from tacrolimus, sirolimus, everolimus, and pimecrolimus. In one embodiment, the macrolide antibiotic is selected from erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fidaxomicin. In one embodiment, the macrolide antifungal agent is selected from polyenes, particularly nystatin, natamycin, and amphotericin B. In a preferred embodiment, the macrolide is selected from tacrolimus, sirolimus, everolimus, and pimecrolimus, preferably tacrolimus and sirolimus, more preferably tacrolimus. In one embodiment, the terms "active agent", "active ingredient", and "API" refer to a macrolide.

[0047] The term "non-nanoparticulate macrolide" as used herein relates to a macrolide that is not in the form of nanoparticles. In one embodiment, non-nanoparticulate macrolide relates to a macrolide that is not formulated as a nanoparticle, in particular not formulated as a nanoparticle having a size in the range of 1 nm to 1000 nanometers. In one embodiment, non-nanoparticulate macrolide is a macrolide that is formulated as a molecularly dissolved macrolide and / or a micronized crystalline macrolide. In one embodiment, the molecularly dissolved macrolide is not a molecularly dissolved macrolide in the form of a nanoparticle, e.g. not a molecularly dissolved macrolide present in a micelle or liposome. In one embodiment, the molecularly dissolved macrolide does not relate to a nanoparticle comprising a molecularly dissolved macrolide. In one embodiment, the molecularly dissolved macrolide is formulated in the form of a solid solution, e.g. embedded and / or dissolved in a polymer matrix. In one embodiment, the micronized crystalline macrolide is not in the form of a nanoparticle, e.g. not in the form of a nanoparticle comprising a micronized crystalline macrolide. In one embodiment, the micronized crystalline macrolide has an average particle size of >1000 nm. In one embodiment, the micronized crystalline macrolide is in the form of microparticles, preferably with an average particle size in the range of 1 μm to 1000 μm, preferably >1000 nm. In one embodiment, the non-nanoparticle macrolide contained in the mucoadhesive layer and / or mucoadhesive film of the present invention is not in the form of nanoparticles and / or is not contained in nanoparticles. In one embodiment, the non-nanoparticle macrolide is present in the layer in the form of micronized macrolide, preferably in the form of micronized crystalline macrolide, in the form of molecularly dissolved non-nanoparticles and / or in the form of crystalline macrolide; preferably, the non-nanoparticle macrolide is present in the layer in the form of micronized macrolide, preferably in the form of micronized crystalline macrolide and / or in the form of molecularly dissolved non-nanoparticles. In one embodiment, the mucoadhesive layer comprising the micronized macrolide, preferably in the form of micronized crystalline macrolide and / or in the form of molecularly dissolved non-nanoparticles further comprises the macrolide in crystalline form.

[0048] The term "average particle size" as used herein relates to the average diameter of an analyzed batch of particles, e.g. (micro)particles of a micronized macrolide. For example, the average particle size may be the average diameter of a batch of particles, where the longest extension of each particle is taken as the diameter if the particles are not spherical. In one embodiment, the average particle size is in the range of 1-100 μm, preferably 1.5-50 μm, more preferably 2-25 μm. In one embodiment, the average particle size of, e.g., a micronized macrolide is measured using any technique known to the skilled artisan, e.g., laser diffraction analysis or dynamic light scattering, preferably laser diffraction analysis. The average particle size is defined as the average diameter of the analyzed particles, determined by a suitable process, e.g., using dynamic light scattering. In one embodiment, the average particle size of the micronized macrolide is in the range of 2 μm to 25 μm. In one embodiment, the micronized macrolide has a particle size distribution D 10 2 μm; D 50 10 μm; and D 90 25 μm. In one embodiment, 10% of all particles have a particle size <2 μm, 50% of all particles have a particle size <10 μm, and 90% of all particles have a particle size <10 μm. In one embodiment, all particles have a particle size >1 μm. In one embodiment, the micronized macrolide is not in the form of nanoparticles. In one embodiment, the average particle size is D 50 In one embodiment, the average particle size of the micronized macrolide is >1 μm, preferably it being understood that none of the particles are nanoparticles. In one embodiment, the particle size of the micronized macrolide is >1 μm. In one embodiment, the particle size of each micronized macrolide particle is >1 μm. The term "micronized" as used herein refers to an average particle diameter reduced to the micrometer range and / or to the micrometer range, preferably by micronization. In one embodiment, "micronized crystalline macrolide" refers to a crystalline macrolide having an average particle diameter in the micrometer range.

[0049] In one embodiment, the term "mucoadhesive film" as used herein refers to a film configured to adhere to a mucosa and / or to adhere to a mucosa, e.g., oral and / or buccal mucosa. In one embodiment, the terms "film", "mucoadhesive film", "mucoadhesive buccal film" and "MBF" are used interchangeably. In one embodiment, when referring to "mucoadhesive buccal film" or "MBF", such abbreviation does not only refer to a mucoadhesive buccal film, but also to a mucoadhesive film for other applications than buccal application. In one embodiment, the mucoadhesive film is a solid formulation comprising one or more layers of a suitable material intended to be applied to a body cavity, preferably the buccal oral cavity, to obtain a systemic or local effect, preferably a systemic effect; and / or the mucoadhesive film is a flexible single-dose formulation configured to be applied to a body cavity, preferably the oral cavity, to obtain either a systemic or local effect by delivering a macrolide over a period of time, after which it is then removed. In one embodiment, the mucoadhesive film is an oral mucosal patch.

[0050] In one embodiment, the mucoadhesive film comprises a mucoadhesive layer and optionally a backing layer. In a preferred embodiment, the mucoadhesive film comprises a mucoadhesive layer and a backing layer. In one embodiment, the mucoadhesive film comprises a mucoadhesive layer; a backing layer, preferably an impermeable backing layer; and optionally an intermediate layer. In one embodiment, the mucoadhesive layer comprises a macrolide in a polymer matrix and provides prolonged contact of the macrolide with the buccal mucosa. In one embodiment, the film comprises at least two layers, such as two layers laminated together; preferably a mucoadhesive layer comprising an active ingredient and a backing layer. In one embodiment, the back side of the mucoadhesive layer is sealed with a backing layer, preferably a water-insoluble and / or macrolide-impermeable backing layer, to prevent release of the macrolide into the oral cavity. In one embodiment, the back side of the mucoadhesive layer is the side configured to face the oral cavity. In one embodiment, the two layers are attached to each other via an intermediate layer, preferably an adhesive layer. In one embodiment, the mucoadhesive layer is adapted to be administered to a patient, for example, by incorporating the mucoadhesive layer into a mucoadhesive film, an oral mucosal patch, or any other application system.

[0051] In one embodiment, the adhesive properties of the mucoadhesive layer and / or film are sufficient for application for at least 30 minutes, e.g., at least 60 minutes, i.e., the layer and / or film adheres to the mucosa for at least 30 minutes, e.g., at least 60 minutes. In one embodiment, ethylcellulose is included in the mucoadhesive layer and / or film, and its low water solubility allows for an application time of at least 30 minutes, e.g., at least 60 minutes. In one embodiment, the backing layer comprises ethylcellulose. In one embodiment, the mucoadhesive film is an insoluble film that must be removed from the mucosa, e.g., the buccal mucosa, after drug release. In one embodiment, the mucoadhesive film is applied to the patient for a period of at least 30 minutes, preferably 30 to 75 minutes.

[0052] In one embodiment, the mucoadhesive layer and / or the mucoadhesive film is 0.5 cm 2 ~10 cm 2 , preferably 2 cm 2 ~8 cm 2 In one embodiment, the mucoadhesive film has an areal weight of about 20 g / m 2 ~about 300 g / m 2 , preferably about 50 g / m 2 ~about 260 g / m 2 In one embodiment, the mucoadhesive film has a film thickness of about 20 μm to about 1000 μm, preferably about 50 μm to about 500 μm, more preferably about 50 μm to about 300 μm, for example, about 150 μm to about 260 μm.

[0053] In one embodiment, at least one of the layers comprises a coloring agent, for example, a white pigment is included in the mucoadhesive layer and a blue pigment is included in the backing layer, so as to be able to distinguish the adhesive layer from the backing layer. In one embodiment, the mucoadhesive film further comprises a flavoring agent and / or a sweetening agent, such as an agent selected from citric acid, peppermint oil, sodium saccharin, and citrus flavorings. In one embodiment, such flavoring agent and / or sweetening agent masks the unpleasant taste of the macrolide or other MBF components. In one embodiment, at least one layer further comprises at least one auxiliary agent selected from the group including a stabilizer, for example, a chelating agent, a coloring agent, a flavoring agent, a sweetening agent, a taste masking agent, an emulsifier, an enhancer, a pH adjuster, a humectant, a preservative, and / or an antioxidant. In one embodiment, at least one layer comprises a chelating agent, preferably EDTA. In one embodiment, when referring to a "layer", it means the mucoadhesive layer, the intermediate layer, and / or the backing layer.

[0054] In one embodiment, the dose strength of the film is determined by the size and / or area of ​​the film, where the quantitative composition per film area is constant, if desired. In one embodiment, the film contains a dose of macrolide up to 10 mg. In one embodiment, the amount of macrolide is measured using HPLC. In one embodiment, the macrolide is quantified using HPLC. In one embodiment, the mucoadhesive film is administered and / or configured to be administered to adult or pediatric patients, such as children up to about 18 years of age.

[0055] In one embodiment, the mucoadhesive layer and / or the backing layer comprise a coloring agent.In one embodiment, the mucoadhesive layer and the backing layer each comprise a coloring agent, wherein the mucoadhesive layer comprises a first coloring agent, such as TiO2, and the backing layer comprises a second coloring agent, such as brilliant blue, wherein the first coloring agent and the second coloring agent are different from each other.In one embodiment, the mucoadhesive layer and / or the mucoadhesive film has a water content of <5 wt%, preferably <3 wt%, more preferably <2 wt%.

[0056] The term "plasticizer" as used herein refers to any plasticizer known to those skilled in the art, preferably suitable for in vivo application. In one embodiment, the plasticizer, for example the plasticizer included in the mucoadhesive layer, intermediate layer, and / or backing layer, is selected from glycerol, poly(ethylene glycol), preferably low molecular weight poly(ethylene glycol) such as PEG 200 or PEG 400, propylene glycol sorbitol, triacetin, and tributyl citrate. In one embodiment, the low molecular weight poly(ethylene glycol) has a molecular weight of ≦600 Daltons, preferably ≦450 Daltons, for example 420 Daltons.

[0057] The term "backing layer" as used herein relates to a layer of a mucoadhesive film. In one embodiment, the backing layer covers the back side of the mucoadhesive layer in the mucoadhesive film. The back side is preferably the side of the mucoadhesive layer or film that is configured to face the body cavity, preferably the oral cavity, i.e. the side facing away from the mucosa. In one embodiment, the backing layer is impermeable to the macrolide and / or impermeable to water. In one embodiment, the backing layer prevents the release of the macrolide from the mucoadhesive layer into the body cavity, e.g. the oral cavity. In one embodiment, the backing layer covers the back side of the mucoadhesive layer and optionally further covers the lateral regions of the mucoadhesive layer. In one embodiment, the backing layer is a sealing layer. In one embodiment, the backing layer, preferably an impermeable backing layer, prevents the undesired release of the macrolide into the body cavity, preferably the oral cavity. In one embodiment, the backing layer is configured to ensure a unidirectional release of the macrolide into the mucosa, preferably the buccal mucosa. In one embodiment, the backing layer prevents the release of the macrolide into the buccal cavity. In one embodiment, the backing layer is insoluble in aqueous liquids such as water and / or saliva. In one embodiment, the backing layer does not dissolve in aqueous liquids such as water and / or saliva for a period of 30 minutes to 75 minutes, preferably at least 60 minutes. In one embodiment, the backing layer and / or the backing layer polymer mixture comprises a water-insoluble polymer and / or a cellulose derivative, such as hydroxyethylcellulose, preferably a water-insoluble cellulose derivative, more preferably ethylcellulose, and thus dissolution of the backing layer in the oral cavity is prevented. In one embodiment, the backing layer and / or the backing layer polymer mixture comprises a water-insoluble polymer and / or a polymer with low water solubility, preferably a water-insoluble polymer such as ethylcellulose. In one embodiment, the backing layer polymer mixture comprises at least one component, preferably all components of the backing layer. In one embodiment, the backing layer is organic solvent based, such as ethanol based, and / or the mucoadhesive layer is water based.In one embodiment, the backing layer comprises a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, preferably a polymer comprising polyvinyl acetate. In one embodiment, the backing layer comprises a colorant, such as brilliant blue. In one embodiment, the backing layer comprises a plasticizer, such as triacetin.

[0058] The term "water-insoluble polymer" as used herein refers to a polymer that is insoluble in water, such as ethyl cellulose and poly(methyl methacrylate). The term "polymer with low water solubility" as used herein refers to a polymer with negligible and / or low water solubility, such as hydroxyethyl cellulose. In one embodiment, the "water-insoluble polymer" and the "polymer with low water solubility" are polymers that prevent dissolution of the mucoadhesive film for at least 30 minutes during application in the body cavity, preferably in the buccal cavity. In one embodiment, the water-insoluble polymer and / or the polymer with low water solubility are preferably selected to provide a film application time of at least 15 minutes, preferably in the range of about 30 minutes to about 75 minutes, without dissolution of the film. In one embodiment, the water-insoluble polymer is ethyl cellulose and / or poly(methyl methacrylate). In one embodiment, the cellulose derivative included in the backing layer is hydroxyethyl cellulose and / or ethyl cellulose. In one embodiment, the backing layer is configured to be insoluble in aqueous liquids for at least 30 minutes, preferably at least 60 minutes. In one embodiment, the backing layer is configured to be impermeable to macrolides for at least 30 minutes, preferably at least 60 minutes; preferably configured to be impermeable to macrolides in aqueous liquids, such as saliva, for at least 30 minutes, preferably at least 60 minutes. In one embodiment, the backing layer and / or backing layer polymer blend comprises a polymer that is insoluble in aqueous liquids for at least 30 minutes. In one embodiment, the backing layer comprises ethyl cellulose, hydroxyethyl cellulose, and / or poly(methyl methacrylate), and optionally further comprises a plasticizer. In one embodiment, the backing layer comprises ethyl cellulose and / or poly(methyl methacrylate), and optionally further comprises a plasticizer.

[0059] The term "intermediate layer" as used herein refers to a layer of a mucoadhesive film, preferably a layer disposed between the mucoadhesive layer and the backing layer. In one embodiment, the intermediate layer is an adhesive layer. In one embodiment, the intermediate layer facilitates adhesion between the mucoadhesive layer and the backing layer. In one embodiment, the intermediate layer prevents migration of the macrolide into the backing layer. In one embodiment, the film comprises an intermediate layer between the mucoadhesive layer and the backing layer, which prevents migration of the macrolide into the backing layer. In one embodiment, the terms "adhesive intermediate layer" and "intermediate layer" are used interchangeably. In one embodiment, the mucoadhesive layer and the backing layer are bonded via an intermediate layer. In one embodiment, in the method of the invention, the film comprising the backing layer and the intermediate layer is combined with the mucoadhesive layer after drying of the layers, which prevents migration of the macrolide into the adhesive intermediate layer and / or the backing layer. In one embodiment, the incorporation of an intermediate layer into the film of the invention makes it possible to prevent dissolution of the macrolide into the backing layer during the method of preparing the film. In one embodiment, the intermediate layer prevents the amount of the macrolide in the mucoadhesive layer from decreasing and / or the macrolide from decomposing during the process of preparing the backing layer on the mucoadhesive layer. In one embodiment, the intermediate layer prevents the macrolide from dissolving in the ethanol contained in the backing layer. In one embodiment, the mucoadhesive film comprising a micronized macrolide, preferably a micronized crystalline macrolide, and / or a non-nanoparticulate macrolide in molecularly dissolved non-nanoparticulate form comprises an intermediate layer. In one embodiment, the intermediate layer comprises a polymer, optionally an adhesive polymer. In one embodiment, the intermediate layer comprises a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone; for example, selected from poly(vinylpyrrolidone), poly[(vinylpyrrolidone)-co-(vinyl acetate)], for example, a copolymer of 6 parts polyvinylpyrrolidone and 4 parts polyvinyl acetate, and a mixture of poly(vinyl acetate) and poly(vinylpyrrolidone), for example, an 8:2 mixture of poly(vinyl acetate) and poly(vinylpyrrolidone).In one embodiment, the intermediate layer includes a plasticizer, such as glycerol.

[0060] The term "solid solution" as used herein refers to a macrolide molecularly dissolved in a solid state diluent or matrix, preferably in a polymer matrix. In one embodiment, the term "solid solution" refers to a macrolide dissolved and optionally embedded in a polymer matrix. In one embodiment, the molecularly dissolved non-nanoparticulate form of the macrolide refers to a solid solution of the macrolide. In one embodiment, the terms "solid solution" and "molecularly dissolved non-nanoparticulate form" are used interchangeably. In one embodiment, the solid solution is a molecularly dissolved non-nanoparticulate macrolide provided in a polymer matrix, preferably comprising at least one polymer soluble in an organic solvent. In one embodiment, the molecularly dissolved non-nanoparticulate macrolide is provided in a polymer matrix, preferably comprising at least one polymer soluble in an organic solvent. In one embodiment, a polymer soluble in an organic solvent, such as a copolymer of methyl vinyl ether and maleic anhydride, is used to achieve proper mucoadhesion of the water-free mucoadhesive film formulation, e.g., for the solid solution. In one embodiment, the molecularly dissolved non-nanoparticulate macrolide is in the form of a solid solution of the macrolide. In one embodiment, the polymer soluble in an organic solvent is any polymer soluble in an organic solvent selected from a) amphiphilic and hydrophilic polymers, b) poly(methacrylates), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers containing polyvinyl acetate and / or polyvinylpyrrolidone, f) cellulose derivatives, and combinations thereof. In one embodiment, the polymer soluble in an organic solvent is an amphiphilic or hydrophilic polymer, such as Soluplus®; poly(methacrylates), such as methacrylic acid copolymers; cellulose derivatives, preferably hydroxypropyl cellulose (HPC) or ethyl cellulose (EC), more preferably HPC; crosslinked polyacrylic acid polymers, such as Carbopol®; copolymers of methyl vinyl ether and maleic anhydride, such as Gantrez®. TMand / or a polymer containing polyvinyl acetate and / or polyvinylpyrrolidone, such as Kollidon®. In one embodiment, the solid solution of macrolide is HPC; a crosslinked polyacrylic acid polymer, such as Carbopol®; a copolymer of methyl vinyl ether and maleic anhydride, such as Gantrez®. TM and / or a polymer comprising polyvinyl acetate and / or polyvinylpyrrolidone, such as Kollidon®. In one embodiment, the solid solution comprises HPC; and a crosslinked polyacrylic acid polymer, such as Carbopol®, and / or a copolymer of methyl vinyl ether and maleic anhydride, such as Gantrez®. TM In one embodiment, the non-nanoparticulate macrolide is present in the mucoadhesive layer in the form of a micronized macrolide, preferably a micronized crystalline macrolide, and / or in a molecularly dissolved non-nanoparticulate form, preferably a solid solution of the molecularly dissolved macrolide. As used herein, the term "molecularly dissolved non-nanoparticulate form" relates to a macrolide that is molecularly dissolved, e.g. in a polymer matrix. In one embodiment, the mucoadhesive layer comprises at least one component, preferably a polymer selected from a) amphiphilic polymers and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers containing polyvinyl acetate and / or polyvinylpyrrolidone, f) cellulose derivatives, and combinations thereof; preferably comprises at least one component selected from a)-e) and further comprises a cellulose derivative; wherein, preferably, when the layer comprises a molecularly dissolved non-nanoparticulate macrolide, the at least one component is a polymer soluble in an organic solvent, preferably ethanol, acetone, and / or isopropanol. In one embodiment, the mucoadhesive layer comprises a plasticizer. In one embodiment, the mucoadhesive layer comprises a non-nanoparticulate micronized crystalline macrolide, and / or a molecularly dissolved non-nanoparticulate macrolide.

[0061] In one embodiment, when the non-nanoparticle macrolide is present in the layer in a molecularly dissolved, non-nanoparticle form, the mucoadhesive polymer and / or cellulose derivative is a film-forming polymer, preferably a film-forming polymer that is soluble in an organic solvent, such as ethanol. In one embodiment, when the non-nanoparticle macrolide is present in the layer in a molecularly dissolved, non-nanoparticle form, the molecularly dissolved, non-nanoparticle form is solubilized in an organic solvent. In one embodiment, when the non-nanoparticle macrolide is present in the layer in a molecularly dissolved, non-nanoparticle form, the cellulose derivative is selected from HPC, EC, and combinations thereof. In one embodiment, when the non-nanoparticle macrolide is present in the layer in a molecularly dissolved, non-nanoparticle form, the mucoadhesive polymer is an amphiphilic or hydrophilic polymer, such as Soluplus®; cross-linked polyacrylic acid polymers, such as Carbopol®; copolymers of methyl vinyl ether and maleic anhydride, such as Gantrez®. TM polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, preferably polymers comprising polyvinyl acetate and / or polyvinylpyrrolidone, such as Kollidon®; and cellulose derivatives, such as HPC, EC, and combinations thereof.

[0062] In one embodiment, the macrolide is dissolved in an organic solvent at a concentration of about 10 mg / ml to about 500 mg / ml to molecularly dissolve the macrolide. The term "organic solvent" as used herein refers to any organic solvent known to those skilled in the art. In one embodiment, the organic solvent is an ICH class 3 or ICH class 2 solvent. In one embodiment, the organic solvent is non-toxic and / or volatile.In one embodiment, the organic 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, diisopropyl ether, dimethylsulfoxide, 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-pyrrolidine, methyl acetate, methyl t-butyl ether, methyl buylketone, methylcyclohexane, methyl ethyl ketone (MEK), methyl isobutyl ketone, methyl isopropyl ketone, The solvent is selected from acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, DMSO, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 2-methyltetrahydrofuran, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, trimethylamine, and combinations thereof; preferably selected from acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, DMSO, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, 2-methyltetrahydrofuran, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, trimethylamine; more preferably selected from ethanol, acetone, and isopropanol. In one embodiment, the term "micronized macrolide solution" as used herein relates to a solution of a micronized macrolide, particularly a solution of a micronized macrolide dissolved in an organic solvent.In one embodiment, the terms "micronized macrolide solution" and "macrolide solution" are used interchangeably.

[0063] The term "mucoadhesive polymer" as used herein refers to a polymer that facilitates and / or mediates mucoadhesion. In one embodiment, the mucoadhesive polymer is selected from a) amphiphilic and hydrophilic polymers, b) poly(methacrylates), c) cross-linked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising poly(vinyl acetate) and / or poly(vinylpyrrolidone), and mucoadhesive cellulose derivatives. In one embodiment, the mucoadhesive polymer is selected from poly(acrylic acid), such as Carbopol® 934 or Carbopol® 971 NF; cross-linked poly(acrylic acid), such as polycarbophil; amylopectin, such as Proloc® 100; TM 15; poly(methacrylic acid), such as Eudragit® L100 or Eudragit® S100; poly(methacrylate), such as Eudragit® E100, Eudragit® RL, or Eudragit® RS; poly[(maleic anhydride)-co-(vinyl methyl ether)] or a salt thereof, such as Gantrez TM AN 119, Gantrez TM AN 139, Gantrez TM AN 149, Gantrez TM AN 169, or Gantrez TMMS-955; gelatin; polysaccharides such as alginate, chitosan, xanthan gum, hyaluronic acid, pectin, or pullulan; cellulose derivatives such as sodium carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl methylcellulose (HEMC), hydroxyethyl cellulose (HEC), or methylcellulose (MC); poly(vinylpyrrolidone), such as Kollidon® 30LP or Kollidon® 90F; poly[(vinylpyrrolidone)-co-(vinyl acetate)], such as Kollidon® VA64; a mixture of poly(vinyl acetate) and poly(vinylpyrrolidone), such as Kollidon® SR; poly(vinyl alcohol); and poly(vinyl acetate).

[0064] The term "amphiphilic polymer" as used herein refers to any amphiphilic polymer known to those skilled in the art, preferably a mucoadhesive amphiphilic polymer. Typically, an amphiphilic polymer has a hydrophilic (polar) portion and a hydrophobic (non-polar) portion. In one embodiment, the amphiphilic polymer is selected from polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol graft copolymer, such as Soluplus®, polyoxyl castor oil, and D-α-tocopherol-polyethyleneglycol-succinate (TPGS).

[0065] In one embodiment, hydrophilic polymer is a polymer that contains polar or charged groups.In one embodiment, these groups are nonionic, anionic, or cationic and / or zwitterionic.In one embodiment, hydrophilic polymer is soluble in water.For example, hydrophilic polymer can be selected from starch and starch derivatives, dextran, cellulose and cellulose derivatives, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, sodium carboxymethylcellulose, ethyl or propylcellulose, polyacrylic acid, polyacrylate, polyvinylpyrrolidone, polyethylene glycol / polyvinyl alcohol copolymer, polyvinyl alcohol, polyethylene oxide polymer, polyethylene oxide / polyethylene glycol copolymer, polyacrylamide, polyethylene glycol, gelatin, collagen, alginate, pectin, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan, shellac, natural gum and / or copolymers thereof.

[0066] In one embodiment, the poly(methacrylate) is selected from neutral protonatable poly(methacrylate)s and cationic poly(methacrylate), preferably copolymers of dialkylaminoethyl methacrylate and methacrylic acid esters, and copolymers of trialkylaminoethyl methacrylate and methacrylic acid esters, in particular copolymers of dimethylaminoethyl methacrylate and methacrylic acid esters, and copolymers of trimethylammonioethyl methacrylate and methacrylic acid esters. For example, the poly(methacrylate) can be Eudragit® L100, Eudragit® S100, Eudragit® E100, Eudragit® RL, or Eudragit® RS.

[0067] As used herein, the term "crosslinked polyacrylic acid polymer" refers to polyacrylic acid polymers and crosslinked polyacrylic acid polymers known to those skilled in the art, preferably crosslinked polyacrylic acid polymers, homopolymers, copolymers, and interpolymers, such as acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, acrylic acid crosslinked with allyl pentaerythritol, and acrylic acid C 10 -C 30 It concerns copolymers including alkyl and carbomer homopolymers or block copolymers of polyethylene glycol and long chain alkyl acid esters. For example, the crosslinked polyacrylic acid polymer can be Carbopol® 934 or Carbopol® 971 NF.

[0068] The term "copolymer of methyl vinyl ether and maleic anhydride" as used herein refers to any copolymer of methyl vinyl ether and maleic anhydride / maleic acid known to those skilled in the art, such as copolymers of monoalkyl esters of poly(methyl vinyl ether / maleic acid) with various ester groups. In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride is prepared in the anhydride form or in hydrolyzed form, such as mixed sodium and calcium salts of methyl vinyl ether and maleic anhydride, e.g., Gantrez TM MS-955 polymer. In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride is selected from poly(methyl vinyl ether-co-maleic anhydride), poly(methyl vinyl ether-co-maleic acid), monoethyl ester of poly(methyl vinyl ether / maleic acid), a mixture of monoethyl ester of poly(methyl vinyl ether / maleic acid) and monobutyl ester of poly(methyl vinyl ether / maleic acid), and mixed sodium / calcium salt of poly(methyl vinyl ether / maleic anhydride). In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride is selected from poly(methyl vinyl ether-co-maleic anhydride), such as Gantrez®. TMis a mixed sodium and calcium salt of a copolymer of methyl vinyl ether and (hydrolyzed) maleic anhydride. In one embodiment, the copolymer of methyl vinyl ether and maleic anhydride is the complexing agent. For example, the copolymer of methyl vinyl ether and maleic anhydride is available from Gantrez, Inc. TM AN 119, Gantrez TM AN 139, Gantrez TM AN 149, Gantrez TM AN 169, Gantrez TM AN-903, Gantrez TM S-96, Gantrez TM S-97, Gantrez TM ES-225, Gantrez TM ES-425, or Gantrez TM It could be MS-955.

[0069] The terms "polymers containing polyvinyl acetate and / or polyvinylpyrrolidone" and "polymers containing polyvinyl acetate and polyvinylpyrrolidone" as used herein refer to any polyvinyl acetate and / or polyvinylpyrrolidone containing polymer known to those skilled in the art, such as poly(vinylpyrrolidone), poly(vinyl acetate), poly[(vinylpyrrolidone)-co-(vinyl acetate)], and mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone). In one embodiment, the polymers containing polyvinyl acetate and / or polyvinylpyrrolidone are selected from poly(vinylpyrrolidone), poly(vinyl acetate), poly[(vinylpyrrolidone)-co-(vinyl acetate)], such as a copolymer of 6 parts polyvinylpyrrolidone and 4 parts polyvinyl acetate, and mixtures of poly(vinyl acetate) and poly(vinylpyrrolidone), such as an 8:2 mixture of poly(vinyl acetate) and poly(vinylpyrrolidone). In one embodiment, the polymers containing polyvinyl acetate and / or polyvinylpyrrolidone comprise or consist of poly(vinylpyrrolidone). In one embodiment, the polymer containing polyvinyl acetate and / or polyvinylpyrrolidone comprises or consists of vinylpyrrolidone-vinyl acetate copolymer, particularly poly[(vinylpyrrolidone)-co-(vinyl acetate)]. In one embodiment, the polymer containing polyvinyl acetate and / or polyvinylpyrrolidone comprises or consists of a mixture of poly(vinyl acetate) and poly(vinylpyrrolidone). In one embodiment, the polymer containing polyvinyl acetate and / or polyvinylpyrrolidone comprises one or more, preferably a plurality of vinyl acetate monomers and / or one or more, preferably a plurality of vinylpyrrolidone monomers. For example, the polymer containing polyvinyl acetate and / or polyvinylpyrrolidone can be Kollidon® 30LP, Kollidon® 90F, Kollidon® VA64, or Kollidon® SR.

[0070] The term "cellulose derivative" as used herein refers to cellulose and its derivatives. In one embodiment, the cellulose derivative is preferably a cellulose derivative that swells rather than dissolves when in contact with water and / or saliva. In one embodiment, the cellulose derivative is selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), such as sodium carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof. In one embodiment, the mucoadhesive layer comprises a cellulose derivative that is a mucoadhesive cellulose derivative, such as a cellulose derivative selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), and combinations thereof. In one embodiment, the cellulose derivative that is soluble in organic solvents is HPC and / or EC. In one embodiment, CMC is soluble in water but not in organic solvents.

[0071] In the method of preparing a mucoadhesive film, the layers of the film can be prepared individually and then bonded, for example, via an intermediate layer and / or via an adhesive, and / or can be prepared on top of each other, for example, by first preparing a mucoadhesive layer, and then subsequently coating the mucoadhesive layer with a backing layer, optionally coating the mucoadhesive layer with an intermediate layer and a backing layer.For example, the method of preparing a mucoadhesive film can include preparing a mucoadhesive layer, a backing layer, and optionally an intermediate layer individually, and then bonding the layers by laminating, for example, by heat lamination, or by compression.For example, the mucoadhesive layer is molded, and then after drying the layer, a second layer, for example an intermediate layer or a backing layer, is molded on top of the mucoadhesive layer.In one embodiment, the first and second layers, for example a mucoadhesive layer and an intermediate layer or a backing layer, are attached on top of each other.In one embodiment, the mucoadhesive layer is not completely dried before applying the intermediate layer and / or the backing layer. In one embodiment, the layers can be compressed onto each other using a roll.In one embodiment, the method for preparing a mucoadhesive film includes preparing a mucoadhesive layer and a backing layer, and then joining the mucoadhesive layer and the backing layer, for example, by compression or gluing.In one embodiment, the method for preparing a mucoadhesive film includes preparing a mucoadhesive layer, an intermediate layer, and a backing layer, and then joining the layers, for example, by compression or gluing.

[0072] In one embodiment, the step of preparing a mucoadhesive layer and the step of preparing a backing layer are followed by a step of bonding the mucoadhesive layer and the backing layer by compression and / or lamination, for example, heat lamination.Optionally, the mucoadhesive layer and / or the backing layer are dried or partially dried before the step of bonding the mucoadhesive layer and the backing layer.In one embodiment, the step of preparing a mucoadhesive layer, the step of preparing an intermediate layer, and the step of preparing a backing layer are followed by a step of bonding the mucoadhesive layer, the intermediate layer, and the backing layer by compression and / or lamination, for example, heat lamination.Optionally, the mucoadhesive layer, the intermediate layer, and / or the backing layer are dried or partially dried before the step of bonding the mucoadhesive layer, the intermediate layer, and the backing layer.In one embodiment, the bonding is performed by compression and / or lamination, for example, heat lamination.

[0073] In one embodiment, the backing layer is prepared on the surface of the mucoadhesive layer, for example by coating the polymer mixture on the surface of the mucoadhesive layer, or prepared separately and then joined to the mucoadhesive layer, optionally via an intermediate layer.In one embodiment, when the mucoadhesive layer and the backing layer, optionally the intermediate layer, are prepared separately, the layer is prepared on a process liner.In one embodiment, when the mucoadhesive layer comprises a micronized macrolide, preferably a micronized crystalline macrolide, the backing layer is prepared on the surface of the mucoadhesive layer, for example by coating the polymer mixture on the surface of the mucoadhesive layer.In one embodiment, when the mucoadhesive layer comprises a molecularly dissolved macrolide, the backing layer is prepared separately from the mucoadhesive layer, and the mucoadhesive layer and the backing layer are subsequently joined after their preparation, optionally via an intermediate layer. In one embodiment, the mucoadhesive layer, the backing layer, and optionally the intermediate layer are each prepared on a process liner and subsequently bonded after their preparation.

[0074] In one embodiment, the method for preparing the mucoadhesive film comprises joining the mucoadhesive layer, the backing layer, and optionally the intermediate layer, for example by compression and / or lamination, for example by heat lamination.In one embodiment, the mucoadhesive layer, the backing layer, and optionally the intermediate layer are dried or partially dried before joining the layers.In one embodiment, the mucoadhesive layer, the backing layer, and optionally the intermediate layer are prepared separately and, after their preparation, are subsequently joined and / or prepared on top of each other.

[0075] In one embodiment, the mucoadhesive layer and / or film is for use in medicine.In one embodiment, the use comprises the film being attached to the body cavity of a patient, preferably in the buccal cavity, and the attachment is such that the mucoadhesive film contacts the site of attachment in the body cavity, preferably in the buccal cavity, through the side of the polymer matrix layer that is not attached to the backing layer.

[0076] Mucoadhesive films are advantageous in that the rich blood circulation of the oral and / or buccal mucosa ensures rapid transfer of the active substance into the blood circulation. Furthermore, the films and / or layers of the present invention are advantageous in that the active ingredient is largely absorbed through the mucosa and thus avoids the "first pass metabolism" that occurs in conventional delivery forms of active ingredients in tablet form. Furthermore, such mucoadhesive films of the present invention have the advantage that the macrolide is protected from degradation by the pH and digestive enzymes of the gastrointestinal tract. The mucoadhesive layer and / or film further provides a rapid onset of effect compared to, for example, the oral route. Mucoadhesive films are a simple method of drug administration and therefore particularly suitable for use in pediatrics. Furthermore, mucoadhesive films avoid the obstacles associated with drug administration via a nasogastric tube and are adaptable in physical shape, condition, size, and surface. Mucoadhesive films are further advantageous in that they allow for accurate dosing.

[0077] As used herein, the terms "of the present invention," "according to the present invention," "in accordance with the present invention," and the like are intended to refer to all aspects and embodiments of the invention described and / or claimed herein.

[0078] The term "comprising" as used herein should be interpreted as embracing both "including" and "consisting of," both meanings being specifically intended, and thus including the separately disclosed embodiments according to the present invention. As used herein, "and / or" should be interpreted as a specific disclosure of each of the two specified features or components, with or without the other. For example, "A and / or B" should be interpreted as a specific disclosure of each of (i) A, (ii) B, and (iii) A and B, as if each were individually described herein. In the context of the present invention, the terms "about" and "approximately" indicate a range of precision that a person skilled in the art can understand to ensure the technical effect of the feature. This term typically indicates a deviation of ±20%, ±15%, ±10%, and for example ±5% from the indicated numerical value. As will be understood by a person skilled in the art, the specific such deviation from the numerical value of a given technical effect will depend on the nature of the technical effect. For example, natural or biological technological effects are generally capable of greater deviations than man-made or engineered technological effects. When an indefinite or definite article is used when referring to a singular noun, such as "a", "an", or "the", this includes the plural of that noun unless otherwise specified.

[0079] Reference is now made to the following examples which are offered by way of illustration and not by way of limitation of the invention.

[0080] Working Example Example 1: Preparation of mucoadhesive films with micronized crystalline macrolides The polymer mixture was prepared by mixing water with acetone and dispersing titanium dioxide in the mixture with stirring. Glycerol and Soluplus® were added. Hydroxypropyl cellulose (HPC) powder was then slowly added and, after HPC was completely dissolved, sodium carboxymethyl cellulose (CMC) powder was added. The viscosity of the mixture increased with the dissolution of CMC. The stirring speed was reduced to avoid air bubbles in the polymer mixture.

[0081] The micronized macrolide was predispersed in 50 mM pH 4 sodium acetate buffer and then added to the polymer mixture. 10 2 μm; D 50 10 μm; D 90 The diameter of the 25 μm diameter fiber was 25 μm.

[0082] 300 g of the mixture was prepared. The concentration of solids in the mixture was 15% by weight.

[0083] [Table 1]

[0084] The resulting mixture was coated with a thickness of 850 μm (thickness in wet form) onto a process liner FL2000 using a twin screw coating knife at a speed of 5 mm / s and then dried at 60 °C for 40 min (Figure 1). Several sheets were produced. The targeted areal weight of the film was about 104 g / m 2 It was 6 cm 2 Die cuts of size were prepared and the area weights of the die cuts were determined:

[0085] [Table 2]

[0086] Example 2: Sealing of the mucoadhesive layer with the backing layer MFK12 A polymer mixture for the seal was prepared. Ethanol was mixed with glycerol (as a plasticizer) under stirring. Ethyl cellulose powder was then slowly added and the mixture was stirred until homogenous.

[0087] 300 g of the mixture was prepared. The concentration of solids in the mixture was 17.5% by weight.

[0088] [Table 3]

[0089] After drying of the mucoadhesive layer, the mucoadhesive layer sheet was coated with an ethanolic solution of ethylcellulose to a thickness of 425 μm using a twin screw coating knife at a speed of 5 mm / s, and then dried at 40° C. for 10 min (FIG. 1). The targeted areal weight of the film was approximately 50 g / m 2 It was 6 cm 2 Die cuts of size were prepared and the area weights of the die cuts were determined:

[0090] [Table 4]

[0091] 6 cm 2 Square films with rounded corners and an edge length of 2.48 cm were die cut from the two-layer laminate including the mucoadhesive layer and the backing layer. The process liner was removed and the films were packaged into individual air- and moisture-protected pouches measuring 8 cm x 9.6 cm. Approximately 70 laminates were produced.

[0092] Example 3: Preparation of mucoadhesive films with solid solutions of macrolides Solubility of tacrolimus Tacrolimus was dissolved in organic solvents. In particular, the saturation solubility of tacrolimus in different organic solvents was tested. The crystalline active ingredient was added to a specified amount of solvent at room temperature with stirring until an insoluble precipitate formed. After filtration, the concentration of the active ingredient in the supernatant was quantified by HPLC.

[0093] Tacrolimus was soluble in all tested organic solvents. For further experiments on solvent-based mucoadhesive films, ethanol was chosen as the organic solvent. Non-toxicity and low boiling point - and therefore possibility of complete removal by drying at low temperature - characterize the solvent ethanol.

[0094] [Table 5]

[0095] Polymer matrices for solid solutions To develop mucoadhesive films containing macrolides as solid solutions, polymers were chosen that are soluble in organic solvents, thus allowing the study of water-free systems. 2 Sample films having an area of ​​were prepared from each matrix and tested for water solubility and adhesion.

[0096] For example, polymers with film-forming and mucoadhesive properties that are soluble in ethanol include crosslinked polyacrylic acid polymers, such as Carbopol®; copolymers of methyl vinyl ether and maleic anhydride, such as Gantrez®; TM poly(methacrylates), such as Eudragit®; polymers containing polyvinyl acetate and / or polyvinylpyrrolidone, such as Kollidon® SR (an 8:2 mixture of poly(vinyl acetate) and poly(vinylpyrrolidone)).

[0097] Various combinations of polymers were tested:

[0098] [Table 6]

[0099] The combinations tested were successful in demonstrating mucoadhesion. Additionally, the polymer combinations tested provided low water solubility.

[0100] Preparation of mucoadhesive layer FK1 An ethanol-based polymer mixture was prepared. Titanium dioxide was dispersed in ethanol under stirring. Glycerol was added. Powdered polymer was slowly added and stirring was continued until completely dissolved. An active ingredient was dissolved in ethanol and added to the prepared polymer mixture with stirring to obtain the layer composition.

[0101] The layer composition was coated onto a process liner (FO Scotchpak 9755) and subsequently dried. The targeted areal weight of the film was approximately 150 g / m 2 500 g of the mixture was prepared. The concentration of solids in the mixture was 20% by weight.

[0102] Preparation of the Backing Layer The polymer mixture for the seal was prepared as described above. 1000 g of the mixture was prepared. The concentration of solids in the mixture was 15% by weight.

[0103] The mixture was coated onto a process liner and subsequently dried. The target area weight of the film was approximately 50 g / m 2 It was.

[0104] [Table 7]

[0105] The backing layer and the mucoadhesive layer were joined via an adhesive intermediate layer.

[0106] Example 4: Preparation of intermediate layer FK9 The mixture was prepared and coated onto a process liner (FO Scotchpak 9755) and subsequently dried. The target area weight of the film was approximately 60 g / m 2 1000 g of the mixture was prepared. The concentration of solids in the mixture was 55% by weight.

[0107] [Table 8]

[0108] Alternatively, the middle layer contained a blend of polyvinyl acetate and povidone (K 30) in a ratio of 8:2, ie, the vinylpyrrolidone-vinyl acetate copolymer Kollidon® SR instead of Kollidon® VA64.

[0109] The three layers, the mucoadhesive layer, the intermediate layer, and the backing layer, were laminated on top of each other by pressing. Rectangular films with edge lengths of 2x3 cm were punched out of the finished three-layer laminate, and the films were packaged in individual pouches (Hutamaki COC) to protect them from air and moisture. Approximately 150 laminates were produced.

[0110] Example 5: Layer Composition The layer composition is as follows:

[0111] [Table 9]

[0112] Example 6: Film characterization The films prepared were analyzed for content, release, unidirectional release, water content and solvent content. The analytical methods used are given in Table 10 and the results of the investigations are given in Table 11.

[0113] To determine the macrolide release, the films were placed with the backing layer on a rotating cylinder (mucoadhesive layer facing the medium) and the amount of drug released into the medium at the indicated time points was quantified by HPLC. The medium used was 500 ml of phosphate buffer with pH 7 containing 0.1% sodium dodecyl sulfate. Values ​​are given as mean values; minimum and maximum values ​​of n individual measurements are given in brackets.

[0114] To determine unidirectional release, the films were placed with the mucoadhesive layer on a rotating cylinder (with the backing layer facing the medium) and the amount of drug released into the medium was quantified as above after 10, 20 and 30 minutes. The medium was the same as above.

[0115] [Table 10]

[0116] Both films, the one containing the micronized crystalline macrolide and the one containing the molecularly dissolved macrolide (MFK10 and FK1, respectively), were successful in almost completely releasing the macrolide. The macrolide release of MFK10 (Figure 2) was not triggered by the presence of Soluplus® (3-fold excess over the active ingredient).

[0117] Only small amounts of tacrolimus (up to 5%) were released through the edges of the film. The backing layer effectively prevented the release of tacrolimus. Thus, the release of the active ingredient into the oral cavity - and therefore the possible swallowing of the active ingredient - can be effectively prevented by the backing layer.

[0118] Small amounts of ethanol were detected in both films. The determined values ​​are below the allowable limits defined by the ICH for ethanol and are therefore suitable for in vivo applications. Acetone was not detected in any of the films.

[0119] Films containing micronized crystalline macrolides, such as MFK10, had a water content of less than 3%; films containing molecularly dissolved macrolides, such as FK1, were prepared without the use of water and therefore water content was not analyzed.

[0120] The low moisture content and low residual solvent content of both films attests to efficient drying of the laminate.

[0121] [Table 11]

[0122] Example 7: Laminate stability Both laminates, the films containing micronized crystalline macrolide and the films containing molecularly dissolved macrolide (MFK10 and FK1, respectively), were stored under controlled temperature and humidity and analytically characterized after the indicated time points. The results are reported in Tables 12 and 13.

[0123] [Table 12]

[0124] The macrolide content of laminate MFK10 decreased by only 4.2% within 6 weeks when stored at room temperature due to degradation of the active ingredient.

[0125] [Table 13]

[0126] After 2 weeks of storage at 40°C of a film containing molecularly dissolved macrolide (Laminate FK1), 1.5% decomposition products were detected. After production, this batch contained 0.4% decomposition products. Thus, 1.1% decomposition products were formed by 2 weeks of storage at 40°C and 3.4% decomposition products were formed after 4 weeks of storage at 40°C.

[0127] [Table 14]

[0128] Thus, the water-free formulation of the film (Laminate FK1) containing the molecularly dissolved macrolide increases the chemical stability of the film even further. TM Due to its complexing and stabilizing properties, it improves the chemical stability of the film even further.

[0129] Example 8: Surfactant morphology Film MFK10 was characterized radiographically. A sample of the active ingredient, micronized tacrolimus, and a sample of the colorant titanium dioxide served as controls.

[0130] The XRPD image (Figure 3) of a film containing micronized crystalline tacrolimus (MFK10; red, 3) shows characteristic reflections of the crystalline tacrolimus (blue, 1) and the excipient TiO2 (orange, 2). The reflection detected at approximately 28° can be assigned to silicon, which was used as the substrate for the XRPD measurements.

[0131] As shown in FIG. 3, the morphology of the micronized crystalline macrolide was not altered by the incorporation of the micronized crystalline macrolide into the film (MFK10).

[0132] Example 9: In vivo application (first study) Pigs were chosen as the animal model because they closely resemble the functional anatomical relationships of humans. All animals were 6-8 months old with body weights between 14 and 16 kg at the time of treatment. The animals were fasted (overnight) for at least 16 hours before treatment and were anesthetized during the procedure. The film was placed with the mucoadhesive layer side on the animal's oral mucosa and pressed gently until the film adhered. The film remained on the buccal mucosa for 30 minutes and then removed.

[0133] Blood samples were collected via an intravenous catheter. For the determination of blood levels of tacrolimus, 2 ml of blood was collected from all animals into K2EDTA-coated tubes. Samples were collected at the following time points: immediately before administration (0 min), then 15, 30, 60, 90, 120, 180, and 240 min, and 6, 8, 12, 18, and 24 h after administration of the film. After blood collection, blood tubes were cooled on ice and stored in a freezer (temperatures ranging from -30°C to -15°C) until analysis. The concentrations of tacrolimus were determined by a reliable LC-MS / MS method.

[0134] After application to the animals, the tacrolimus content of the applied film was determined (drug content after treatment). The active dose corresponds to the tacrolimus content of the film minus the residual content after application. The biologically active dose was calculated in relation to the weight of the individual animals (active dose / body weight).

[0135] Pharmacokinetic parameters were calculated from the time course of blood concentrations. The calculated AUC was normalized to the active dose and related to the individual weight of the animals (AUC_all / dose).

[0136] [Table 15]

[0137] Residual macrolide levels in the films were between 54.3% and 58.4%. Tacrolimus was successfully detected in the blood of both pigs after buccal administration; maximum concentrations were reached after 1.5 and 2 hours, respectively (t_max). The films did not cause local irritation of the buccal mucosa.

[0138] These results demonstrate that buccal absorption of micronized crystalline macrolides is effective.

[0139] There were no treatment-related deaths, clinical signs, or changes in body weight. There was no inflammation at the application site of the micronized tacrolimus-loaded MBF.

[0140] Mean blood concentration-time profiles from three animals following buccal application of micronized tacrolimus-loaded MBF and oral administration of a 5 mg Prograf capsule. It successfully demonstrated that micronized tacrolimus can cross the buccal mucosa following application as MBF.

[0141] Example 10: In vivo application (second study) The first study was repeated in five additional animals using a film containing a molecularly dissolved macrolide (FK1). The animals were not the same animals tested in the first study. The film was left on the buccal mucosa for 60 minutes and then removed. Further procedures were similar to the first study.

[0142] [Table 16]

[0143] Analysis of the drug content of the films after treatment indicates that approximately 55% of the macrolide is biologically active and 45% remains in the film.

[0144] Tacrolimus was detected in the blood of all five pigs after buccal application (Figure 4). Maximum concentrations were reached after 2-3 hours (t_max). The films did not cause local irritation of the buccal mucosa.

[0145] The achieved blood concentrations were within the range of those obtained with oral administration of the commercial product Prograf. The time required to reach the maximum blood level, i.e. 2-3 hours, was comparable to the commercial product. Thus, both the films containing micronized crystalline macrolide and the films containing molecularly dissolved macrolide allowed for efficient administration of the macrolide. Moreover, unexpectedly, the films allowed for achieving blood level concentrations of the macrolide suitable for in vivo application in patients.

[0146] Example 11: Further optimization of MBF to prevent migration of macrolides into the backing layer The backing layer was based on ethylcellulose dissolved in ethanol and was cast onto the dried mucoadhesive layer containing tacrolimus. Due to the good solubility of tacrolimus in ethanol, some of the active substance was extracted into the backing layer during manufacture.

[0147] The composition and manufacturing process of the MBF was optimized by including an intermediate layer, specifically an adhesive intermediate layer, between the mucoadhesive layer and the backing layer. The combined backing layer and adhesive intermediate layer were dried before lamination onto the dried mucoadhesive layer (Figure 5). Experiments with this modified manufacturing process and MBF composition showed that tacrolimus was not detectable in the backing layer / adhesive intermediate layer, as tested using dissolution tests and HPLC. Thus, the adhesive intermediate layer prevents dissipation of the macrolide from the adhesive layer into the backing layer.

[0148] Example 12: In vivo application (third study) Further variations of MBF were developed, and in all cases tacrolimus was incorporated molecularly dissolved into the film matrix.

[0149] The layer composition is as follows:

[0150] [Table 17]

[0151] The study was carried out on 5 pigs that were the same individuals as in the second study (Example 10). The film remained on the buccal mucosa for 60 minutes and was then removed. Further procedures were similar to the previous study. In session 1, two films were placed on the same side of the oral cavity at the same time. In sessions 2, 3 and 4, one film was placed on one side of the oral cavity in the morning hours, and about 4 hours later, a second one was placed on the same side. Thus, session 1 analyzed the treatment once a day, and sessions 2, 3 and 4 analyzed the treatment twice a day.

[0152] [Table 18]

[0153] [Table 19]

[0154] [Table 20]

[0155] [Table 21]

[0156] [Table 22]

[0157] Interestingly, the twice-daily treatment achieved higher blood levels than the once-daily treatment, although the same dose was applied in both treatments. Notably, as seen in the above table, a higher AUC was achieved with the twice-daily treatment than with the once-daily treatment. Furthermore, the blood levels achieved after the second application (4 hours after the first application) were much higher than after the first application, although the same MBF was applied. Such pharmacokinetic properties of the mucoadhesive film are highly advantageous for fine-tuning the dosing scheme to the patient's requirements. For example, the mucoadhesive film can be administered twice a day for patients who require higher blood levels, whereas the mucoadhesive film can be administered once a day for patients who require lower levels. Furthermore, the time between the two applications can be adapted to the individual requirements of the patient. For example, the appropriate macrolide blood level of the patient can be fine-tuned and controlled by adjusting the time window between two subsequent applications of the mucoadhesive film.

[0158] Moreover, it was interestingly observed that higher blood concentrations were achieved with mucoadhesive films having a higher areal concentration. The pharmacokinetic properties of mucoadhesive films are highly advantageous for fine-tuning the dosing scheme to the patient's needs. The inventors observed that mucoadhesive films containing non-nanoparticulate macrolides, particularly in the form of micronized macrolides or in the form of molecularly dissolved non-nanoparticulate macrolides, allow to achieve higher blood concentrations than mucoadhesive films containing nanoparticulate macrolides.

[0159] The features of the invention disclosed in the specification, the claims and / or the accompanying drawings may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.

Claims

1. A mucoadhesive layer, preferably a mucoadhesive buccal layer, containing a non-nanoparticle macrolide.

2. The non-nanoparticle macrolide is selected from macrolide immunosuppressants, macrolide antibiotics, and macrolide antifungals; where preferably, - the macrolide immunosuppressant is selected from tacrolimus, sirolimus, everolimus, and pimecrolimus; - the macrolide antibiotic is selected from erythromycin, clarithromycin, azithromycin, roxithromycin, josamycin, spiramycin, telithromycin, tylosin, and fidaxomicin; and / or - the macrolide antifungal is selected from polyenes, particularly nystatin, natamycin, and amphotericin B, where more preferably, the non-nanoparticle macrolide is non-nanoparticle tacrolimus or sirolimus, and even more preferably non-nanoparticle tacrolimus, the mucoadhesive layer according to claim 1.

3. The non-nanoparticle macrolide is present in the layer in the form of micronized macrolide, preferably micronized crystalline macrolide, and / or in a molecularly dissolved non-nanoparticle form, the mucoadhesive layer according to claim 1 or 2.

4. The micronized macrolide has an average particle size of 1 to 100 μm, preferably 1.5 to 50 μm, more preferably 2 to 25 μm, the mucoadhesive layer according to claim 3.

5. The mucoadhesive layer is - a mucoadhesive polymer, preferably a polymer selected from a) amphiphilic polymers and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers containing polyvinyl acetate and / or polyvinyl pyrrolidone, and combinations thereof; includes Here, preferably, the amphiphilic polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyoxyl castor oil, and D-α-tocopherol-polyethylene glycol-succinate (TPGS), and / or the poly(methacrylate) is selected from neutral protonable poly(methacrylate) and cationic poly(methacrylate), preferably a copolymer of dialkylaminoethyl methacrylate and methacrylic acid ester, and a copolymer of trialkylammonioethyl methacrylate and methacrylic acid ester, particularly a copolymer of dimethylaminoethyl methacrylate and methacrylic acid ester, and a copolymer of trimethylammonioethyl methacrylate and methacrylic acid ester; and here the mucoadhesive layer is: - a cellulose derivative, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof; - a plasticizer; preferably selected from glycerol, polyethylene glycol, low molecular weight polyethylene glycol such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate; more preferably glycerol; - a colorant, preferably TiO 2 ; - and a non-nanoparticle macrolide The mucoadhesive layer according to claim 1 or 2, further comprising.

6. The non-nanoparticle macrolide is present in the layer in a non-nanoparticle form in which it is molecularly dissolved; and the mucoadhesive polymer and / or the cellulose derivative is a polymer soluble in an organic solvent. The mucoadhesive layer according to claim 3.

7. The mucoadhesive layer is a) a mucoadhesive polymer, preferably an amphiphilic polymer; hydroxypropyl cellulose (HPC); carboxymethyl cellulose (CMC); a plasticizer, preferably glycerol; and optionally a colorant, preferably TiO 2 ; preferably 10 wt% - 30 wt% of the mucoadhesive polymer; 25 wt% - 35 wt% of hydroxypropyl cellulose (HPC); 10 wt% - 25 wt% of carboxymethyl cellulose (CMC); 10 wt% - 16 wt% of the plasticizer; and optionally 1 wt% - 4 wt% of the colorant; or b) a mucoadhesive polymer, preferably selected from crosslinked polyacrylic acid polymers and copolymers of methyl vinyl ether and maleic anhydride; hydroxypropyl cellulose (HPC); ethyl cellulose (EC); a plasticizer, preferably glycerol; and optionally a colorant, preferably TiO 2 ; preferably 2 wt% - 17 wt% of the mucoadhesive polymer; 30 wt% - 70 wt% of hydroxypropyl cellulose (HPC); 5 wt% - 40 wt% of the ethyl cellulose (EC); 3 wt% - 20 wt% of the plasticizer; and optionally 1 wt% - 5 wt% of the colorant The mucoadhesive layer according to claim 1 or 2, comprising

8. The macrolide is present in the mucoadhesive layer at a concentration of at least 2 wt%, preferably at least 3 wt%, for example 3.2 wt%; and / or in an amount in the range of about 0.01 mg to about 10 mg, preferably in the range of about 0.1 mg to about 5 mg, more preferably in the range of about 1.5 mg to about 3.5 mg, per 1 cm 2 of the mucoadhesive layer; preferably per 1 cm 2 of the mucoadhesive layer; more preferably per 1 cm 2 of the mucoadhesive layer. The mucoadhesive layer according to claim 1 or 2.

9. A mucoadhesive film, preferably a mucoadhesive buccal film, comprising a mucoadhesive layer containing non-nano particle macrolide, preferably the mucoadhesive layer defined in claim 1 or 2; and further comprising a backing layer, preferably a backing layer impermeable to macrolide and / or impermeable to water.

10. The mucoadhesive film according to claim 9, wherein the backing layer contains a plasticizer selected from glycerol, polyethylene glycol, such as low molecular weight polyethylene glycols like PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol; and / or contains a water-insoluble polymer and / or a cellulose derivative, such as hydroxyethyl cellulose, preferably a water-insoluble cellulose derivative, more preferably ethyl cellulose (EC).

11. The mucoadhesive film further comprises an intermediate layer disposed between the mucoadhesive layer and the backing layer; wherein, preferably, the intermediate layer facilitates the adhesion between the mucoadhesive layer and the backing layer; wherein, optionally, the intermediate layer contains a plasticizer selected from glycerol, polyethylene glycol, such as low molecular weight polyethylene glycols like PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol; and a polymer, preferably a polymer containing polyvinyl acetate and / or polyvinyl pyrrolidone, more preferably a vinyl pyrrolidone-vinyl acetate copolymer, of the mucoadhesive film according to claim 9.

12. The mucoadhesive layer has an area weight in the range of 70 g / m 2 to 180 g / m 2 preferably in the range of 100 g / m 2 to 150 g / m 2 ; and / or The backing layer has a basis weight of 40 g / m 2 to 100 g / m 2 in the range of, preferably 40 g / m 2 to 60 g / m 2 in the range of, for example 50 g / m 2 ; and / or The intermediate layer, if present, has a basis weight of 40 g / m 2 to 100 g / m 2 in the range of, preferably 40 g / m 2 to 70 g / m 2 in the range of, for example 60 g / m 2 The mucoadhesive film according to claim 9.

13. A mucoadhesive film comprising a mucoadhesive layer, a backing layer, and an intermediate layer, wherein the intermediate layer is disposed between the mucoadhesive layer and the backing layer, and wherein the mucoadhesive layer contains a macrolide, preferably tacrolimus; wherein, preferably, the intermediate layer facilitates adhesion between the mucoadhesive layer and the backing layer; wherein, optionally, the intermediate layer contains a plasticizer selected from glycerol, polyethylene glycol, such as low molecular weight polyethylene glycols like PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate, more preferably glycerol; wherein, optionally, the intermediate layer contains a polymer, preferably a polymer containing polyvinyl acetate and / or polyvinylpyrrolidone, more preferably a vinylpyrrolidone-vinyl acetate copolymer, A mucoadhesive film, preferably a mucoadhesive buccal film.

14. The mucoadhesive layer according to claim 1 or 2 for use as a medicament.

15. The mucoadhesive film according to claim 9 for use as a medicament.

16. For use in the prevention and / or treatment of transplant rejection, preferably solid organ transplant rejection such as liver, kidney or heart allograft rejection, wherein, optionally, the use comprises attachment of the film or layer in a body cavity of the patient, preferably in the buccal cavity of the patient. The mucoadhesive layer according to claim 1 or 2 for use.

17. For use in the prevention and / or treatment of transplant rejection, preferably solid organ transplant rejection such as liver, kidney or heart allograft rejection, wherein, optionally, the use comprises attachment of the film or layer in a body cavity of the patient, preferably in the buccal cavity of the patient. The mucoadhesive film according to claim 9 for use.

18. i) providing a micronized macrolide, preferably a non-nanoparticle micronized macrolide; and a polymer mixture, wherein the polymer mixture - a mucoadhesive polymer, preferably a polymer selected from a) amphiphilic polymers and hydrophilic polymers, b) poly(methacrylate), c) crosslinked polyacrylic acid polymers, d) copolymers of methyl vinyl ether and maleic anhydride, e) polymers comprising polyvinyl acetate and / or polyvinyl pyrrolidone, and combinations thereof; - a cellulose derivative, preferably selected from hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), and combinations thereof; - optionally, a plasticizer; preferably selected from glycerol, polyethylene glycol, low molecular weight polyethylene glycols such as PEG 200 or PEG 400, propylene glycol, sorbitol, triacetin, and tributyl citrate; more preferably glycerol; - Optionally, a colorant, preferably TiO 2 ; including ii) Optionally, dispersing the micronized macrolide in a liquid medium to obtain a micronized macrolide dispersion and / or dissolving the micronized macrolide in an organic solvent to obtain a micronized macrolide solution; iii) Mixing the micronized macrolide, optionally the micronized macrolide dispersion or the micronized macrolide solution, with the polymer mixture to obtain a mucoadhesive layer composition; iv) Preparing a mucoadhesive layer using the mucoadhesive layer composition; optionally by coating the mucoadhesive layer composition on a surface, preferably on a process liner, for example by coating, heat melt extrusion, and / or molding; v) Optionally, drying the mucoadhesive layer to thereby obtain a mucoadhesive film containing the mucoadhesive layer A method for preparing a mucoadhesive film, including

19. Further including preparing a backing layer, a) Providing a backing layer polymer mixture; optionally containing a plasticizer, preferably glycerol; optionally containing a water-insoluble polymer and / or a cellulose derivative, for example hydroxyethyl cellulose, preferably a water-insoluble cellulose derivative, more preferably ethyl cellulose; b) Preparing a backing layer using the backing layer polymer mixture, optionally by coating the polymer mixture on the surface of the mucoadhesive layer, for example; c) Optionally, drying the backing layer The method according to claim 18, including

20. Further including preparing an intermediate layer, 1) An intermediate layer polymer mixture; optionally containing a plasticizer, preferably glycerol, and a polymer, preferably a polymer containing polyvinyl acetate and / or polyvinyl pyrrolidone, more preferably a vinyl pyrrolidone-vinyl acetate copolymer; providing the same; 2) Preparing an intermediate layer by using the polymer mixture, optionally on the surface of the mucoadhesive layer, for example by coating the polymer mixture on the surface of the mucoadhesive layer; 3) Optionally drying the intermediate layer The method according to claim 18 or 19, comprising the above.

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