Transmucosal therapeutic system containing a macrolide immunosuppressant

Abstract

The present invention relates to a transmucosal therapeutic system for the transmucosal administration of an active agent comprising a mucoadhesive layer structure comprising a macrolide immunosuppressant as an active agent, such a transmucosal therapeutic system for use in methods of treatment and / or prevention, and a process for the manufacture of such a transmucosal therapeutic system.

Description

[Technical field]

[0001] The present invention relates to a transmucosal therapeutic system for the transmucosal administration of macrolide immunosuppressants into the systemic circulation, as well as processes for their manufacture, methods of treatment and use. [Background technology]

[0002] Macrolides are natural or partially synthetic macrocyclic compounds that contain a macrocyclic lactone ring. Some macrolides exhibit antibacterial or antifungal properties, while others act as immunomodulators, i.e., they can modulate, e.g., activate or suppress, the immune system. Immunosuppressants are generally used primarily as medicines in cases of organ transplantation and autoimmune diseases to promote immune tolerance and prevent the immune system from attacking itself or a transplanted foreign organ.

[0003] Tacrolimus, everolimus, sirolimus, and pimecrolimus, for example, are non-antibiotic macrolide immunosuppressants. The first three are used in organ transplant medicine to prevent organ rejection, while pimecrolimus as well as tacrolimus are used to treat inflammatory skin diseases. Macrolides share a high molecular weight and low solubility in aqueous media. [ka]

[0004] Tacrolimus is sold, for example, by Astellas Pharma under the brand name Prograf® in the form of oral capsules containing 0.5, 1, or 5 mg of tacrolimus, and is indicated for the prevention of organ rejection in patients receiving allogeneic liver, kidney, or heart transplants.

[0005] Oral dosage forms such as capsules are easy and convenient to take, and allow self-administration.However, these types of dosage forms have the disadvantage that the drug is absorbed through the gastrointestinal (GI) tract and metabolized before reaching the systemic circulation, so that the bioavailability is often greatly reduced (so-called first-pass effect).The bioavailability of tacrolimus in Prograf® has been reported to be indeed low, and drug release appears to vary to some extent due to food effect when taken orally.

[0006] The oral mucosa is an administration site that is less commonly used than traditional oral dosage forms, but which offers the advantage of combining ease and convenience of use with avoidance of the Gl tract, as the drug is absorbed directly into the systemic circulation through the mucosal tissue.

[0007] A transmucosal therapeutic system or transmucosal delivery system (sometimes referred to as buccal patch, oral film, etc.) consists of one or more thin layers that are applied to and adhere to the mucous membrane of the oral cavity to deliver the drug over a period of time. Dosage forms in the form of thin films for application to the oral cavity may also be referred to as "oral thin films" or OTFs, although many OTFs are not intended to adhere to the mucosa. In a transmucosal therapeutic system, the active substance is typically contained in a dissolving or disintegrating layer, which often has mucoadhesive properties. Once the film adheres to the mucosa, delivery of the active substance can be achieved by a combination of direct release of the active substance from the transmucosal therapeutic system to the mucosa, and in the absence of a backing layer, indirect delivery of the active substance via dissolution in saliva, often followed by swallowing of the saliva and absorption of the active substance from the gastrointestinal tract. Ideally, an OTF does not cause any negative sensation of an intrusive object in the mouth, because the film adhered to the mucosa does not move freely around in the oral cavity, and because the film is thin enough that it is usually not perceptible to the patient once applied.

[0008] However, transmucosal therapeutic systems are a relatively new form of drug delivery, which means that knowledge about formulation techniques is limited. Formulating a suitable dosage form for transmucosal delivery by OTF is difficult due to the many aspects that must be considered and problems that must be solved.

[0009] One such aspect is the aqueous environment of the oral cavity, where most of the film-forming polymers used in transmucosal therapeutic systems are water-soluble, and it is often difficult to find a formulation for hydrophobic drugs and / or relatively high molecular weight formulations, such as macrolide immunosuppressants, that are suitable for delivering a therapeutically effective amount of drug and still provide sufficient mucoadhesion. Low solubility in aqueous media not only means that the saturation concentration of the drug in the drug layer will be lower than the required amount of drug and the drug may be at risk of precipitation, but also that the drug release will be slow due to limited solubility in the oral aqueous environment. Low solubility affects both the drug release from the matrix and the erosion of the matrix layer and needs to be matched to the hydrophobicity of the drug. Otherwise the matrix will erode too quickly and release the drug into the saliva before it can be absorbed through the mucosa. Indirect delivery via saliva is undesirable, especially for slow-releasing drugs, due to the risk of unintended swallowing and loss to the GI system.

[0010] Mucoadhesive buccal films containing nanoparticles of tacrolimus have been proposed recently. However, the use of nanoparticles to increase the solubility of tacrolimus is complicated and expensive, since the nanoparticles must be manufactured in a separate step and process controls must be implemented to characterize the nanoparticles. Another known tacrolimus buccal film is based on chitosan and hydroxypropylmethylcellulose HPMC, but contains only a small amount of tacrolimus (about 2% by weight of tacrolimus in 15 mg of film, i.e., about 0.3 mg of tacrolimus per film).

[0011] In summary, there is a great need for a mucosal therapeutic system for macrolide immunosuppressants such as tacrolimus that overcomes the shortcomings of known systems. As outlined above, a mucosal therapeutic system could address the shortcomings of the oral route of administration, namely low bioavailability, but finding a suitable formulation for drugs with low solubility is difficult.

[0012] Therefore, there is a need for a transmucosal therapeutic system for macrolide immunosuppressants such as tacrolimus that has an improved yet simple formulation and ensures sufficient and adequate delivery of the drug. Summary of the Invention

[0013] It is an object of the present invention to provide a transmucosal therapeutic system for the transmucosal administration of macrolide immunosuppressants which overcomes the above-mentioned drawbacks of the current systems.

[0014] It is therefore an object of the present invention to provide a transmucosal therapeutic system for the transmucosal administration of a macrolide immunosuppressant that incorporates a sufficient, eg, therapeutically effective, amount of the drug.

[0015] It is therefore an object of the present invention to provide a transmucosal therapeutic system for the transmucosal administration of a macrolide immunosuppressant that incorporates a sufficient, eg, therapeutically effective, amount of the drug.

[0016] It is a further object of the present invention to provide a transmucosal therapeutic system for the transmucosal administration of macrolide immunosuppressants that is also capable of delivering a therapeutically effective amount of the drug to the systemic circulation.

[0017] It is another object of the present invention to provide a transmucosal therapeutic system for transmucosal administration of macrolide immunosuppressants that provides sufficient mucoadhesion and unidirectional delivery of the drug across the mucosa.

[0018] It is yet another object of the present invention to provide a transmucosal therapeutic system for transmucosal administration of macrolide immunosuppressants which is simple to manufacture and cost effective.

[0019] These and other objects are provided, according to one aspect, a transmucosal therapeutic system for transmucosal administration of an active agent, comprising: A mucoadhesive layer structure comprising: A) a backing layer comprising a first film-forming polymer; B) an adhesive layer, Laminating adhesives, and an adhesive layer comprising a first plasticizer; C) an active agent-containing layer, Macrolide immunosuppressants, and and an active agent-containing layer comprising a second film-forming polymer, the first film-forming polymer is ethyl cellulose; the macrolide immunosuppressant is selected from the group consisting of tacrolimus, sirolimus, everolimus, and pimecrolimus; This is accomplished by the present invention with respect to a transmucosal therapeutic system, wherein the second film-forming polymer is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof.

[0020] According to another aspect, the present invention provides an active agent-containing layer for a transmucosal therapeutic system, the active agent-containing layer comprising: i) tacrolimus in amorphous form; and ii) a film forming polymer selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof.

[0021] According to a further aspect, the present invention provides a mucoadhesive layer structure for a transmucosal therapeutic system, comprising: A) an active agent-containing layer, i) tacrolimus in amorphous form, and ii) an active agent-containing layer comprising a film-forming polymer selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof; B) an adhesive layer, Laminating adhesives, and and an adhesive layer comprising a plasticizer.

[0022] According to yet another particular aspect, the present invention provides a process for producing a transmucosal therapeutic system, comprising: (a) At least a first film-forming polymer; and Combining the solvents, Obtaining a backing layer coating composition; coating a backing layer coating composition onto a release liner; drying the coated backing layer coating composition to form a backing layer; (b) At least Activator, a second film-forming polymer, and Combining the solvents, Obtaining an active agent layer coating composition; coating an active agent layer coating composition onto a release liner; drying the coated active agent layer coating composition to form a single layer active agent-containing layer; and optionally repeating the coating step by coating an active agent layer coating composition onto the coated active agent layer coating composition before drying or onto the dried active agent-containing layer to obtain a dual layer active agent-containing layer; (c) At least Laminating adhesives, and A first plasticizer, and Combining the solvents, Obtaining an adhesion layer coating composition; Coating an adhesive layer coating composition onto the backing layer obtained in step (a); drying the coated adhesive layer coating composition to form a two-layer laminate consisting of the adhesive layer and the backing layer on the release liner; (d) laminating the bilayer laminate obtained in step (c) with the single or bilayer active agent-containing layer obtained in step (b), the first film-forming polymer is ethyl cellulose; the macrolide immunosuppressant is selected from the group consisting of tacrolimus, sirolimus, everolimus, and pimecrolimus; The process wherein the second film-forming polymer is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof.

[0023] According to yet a further aspect of the invention, the transmucosal therapeutic system according to the invention is for use in a method of treatment, preferably for the treatment and / or prevention of organ rejection after organ transplantation in a human patient, more preferably for the prevention of organ rejection after allogeneic liver, kidney or heart transplantation in a human patient.

[0024] According to another aspect, the present invention provides a transmucosal therapeutic system for transmucosal administration of an active agent, comprising: A mucoadhesive layer structure comprising: A) a backing layer, 55-95% and preferably about 60% by weight ethylcellulose having a viscosity of 30-60 mPa·s, more preferably 40-52 mPa·s, when measured as a 5% solution at 25° C. in 80:20 toluene:ethanol by weight according to ASTM D914, and an ethoxyl substitution of 48.0-49.5% when measured according to ASTM D914; 5-20% by weight and preferably about 10% by weight of triacetin, and 10 to 35% by weight and preferably about 30% by weight, about 19% by weight of polyvinylpyrrolidone, Approximately 80% by weight of polyvinyl acetate, About 0.8% by weight of sodium lauryl sulfate, and a backing layer comprising a mixture of about 0.2% by weight silica; B) an adhesive layer adjacent on one side to the active agent-containing layer and adjacent on its other side to the backing layer, 70-90% by weight and preferably about 80% by weight, about 19% by weight of polyvinylpyrrolidone, Approximately 80% by weight of polyvinyl acetate, About 0.8% by weight of sodium lauryl sulfate, and A mixture consisting of about 0.2% by weight silica; 10-30% by weight, preferably about 15% glycerin, and an adhesive layer comprising 0-10% by weight, preferably about 5% by weight, ethyl cellulose having a viscosity of 30-60 mPa·s, more preferably 40-52 mPa·s, as measured as a 5% solution at 25° C. in 80:20 toluene:ethanol by weight according to ASTM D914, and an ethoxyl substitution of 48.0-49.5% as measured according to ASTM D914; C) an active agent-containing layer, At least 0.8 mg / cm of amorphous form 2 Tacrolimus, ethylcellulose in an amount of 25 to 35% by weight of the active agent-containing layer having a viscosity of 30 to 60 mPa·s, more preferably 40 to 52 mPa·s, when measured as a 5% solution at 25° C. in 80:20 toluene:ethanol by weight according to ASTM D914, and an ethoxyl substitution of 48.0 to 49.5% when measured according to ASTM D914; Hydroxypropylcellulose in an amount of 7 to 15% by weight of the active agent-containing layer, having a molecular weight of about 370,000 (as measured by GPC size exclusion chromatography) and a Brookfield viscosity of 150 to 400 mPa·s when measured as a 2% aqueous solution; Hydroxypropylcellulose in an amount of 30-45% by weight of the active agent-containing layer, having a molecular weight of about 80,000 (as measured by GPC size exclusion chromatography) and a Brookfield viscosity of 300-600 mPa·s when measured as a 10% aqueous solution; a mixed calcium / sodium salt of methyl vinyl ether and maleic anhydride copolymer as a further film-forming polymer in an amount of 2-5% by weight of the active agent-containing layer; Optionally, a vinylpyrrolidone-vinyl acetate copolymer in an amount of 1-4% by weight of the active agent-containing layer, and The present invention relates to a transmucosal therapeutic system comprising a mucoadhesive layer structure and an active agent-containing layer, the active agent-containing layer containing glycerin in an amount of 3 to 6% by weight of the active agent-containing layer.

[0025] Within the meaning of the present invention, the term "mucosal therapeutic system" or "mucosal delivery system" refers to a system in which an active agent (e.g., tacrolimus) is administered to the systemic circulation via transmucosal delivery by application to the mucous membrane of the oral cavity, and refers to an entire individual dosage unit that is applied to the mucous membrane of a patient and contains a therapeutically effective amount of the active agent in a mucoadhesive layer structure. The mucoadhesive layer structure may be located on a release liner (a removable protective layer), and thus the transmucosal therapeutic system may further include a release liner. In contrast to certain oral thin films (sometimes referred to as "flash wafers") that are not necessarily mucoadhesive and are intended to disintegrate very quickly in saliva, enteral delivery is not intended or desired with a transmucosal therapeutic system.

[0026] Within the meaning of the present invention, the term "mucoadhesive layer structure" refers to an active agent-containing multi-layer laminate structure that provides a release area for the active agent during administration.

[0027] As used herein, the term "active agent" refers to a biologically or pharmacologically active compound, which may also be referred to as an active substance, drug substance, drug, active ingredient, active pharmaceutical ingredient (API), etc. Within the meaning of the present invention, the term "therapeutically effective amount" refers to an amount of an active agent in a transmucosal therapeutic system sufficient to provide a desired therapeutic effect when administered to a patient by the transmucosal therapeutic system, e.g., as determined by a similar range of blood levels (e.g., about 10% to about 1000% when measured as AUC), when compared to the blood levels obtained after a single administration of an approved drug product of the same active agent.

[0028] There are two main types of transmucosal therapeutic systems: those with and without a backing layer. The delivery of active ingredients by open-system transmucosal therapeutic systems without a backing layer is always a combination of direct delivery from the transmucosal therapeutic system through the mucosa at the site of attachment and indirect delivery via dissolution of the active substance from the transmucosal therapeutic system into saliva and from saliva through the mucosa of the oral cavity (and also the stomach or intestine if the saliva is swallowed). The ratio of the different delivery routes depends mainly on the effect of permeability through the mucosa, although it depends on factors such as the solubility of the active substance and the disintegration time of the transmucosal therapeutic system. The higher the solubility and the faster the disintegration of the transmucosal therapeutic system, the more dissolution in saliva will be preferred over direct delivery to the mucosa at the site of attachment. Such indirect delivery may have the advantage of providing a practical increase in the mucosal surface area from which the active substance is released systemically. However, dissolution in saliva means that it is difficult to control the concentration of the active substance and therefore the final amount delivered, and the risk of enteral delivery due to unintentional swallowing of saliva is serious. Accordingly, the present invention is directed to a transmucosal therapeutic system that includes a backing layer.

[0029] A transmucosal therapeutic system using a backing layer has a completely different approach. In such a system, the use of a backing layer would substantially limit the delivery route to direct transmucosal delivery, which can be controlled much better, reducing the risk of intestinal delivery, and even more advantageously, it would be possible to substantially reduce any irritating sensation or unpleasant taste potentially caused by the active agent by limiting its dissolution in saliva. The challenge of a transmucosal therapeutic system using a backing layer is still to provide sufficient transmucosal penetration and delivery of the active agent. Thus, in the sense of the present invention, a "backing layer" is any layer in a transmucosal therapeutic system that can prevent the dissolution in saliva of (at least a substantial amount of) the active agent contained in the transmucosal therapeutic system. Such a backing layer may be insoluble or poorly soluble for a long time. In the latter case, the time it takes for the backing layer to dissolve is at least as long as the time it takes for (a substantial amount of) the active agent to be delivered through the mucosa.

[0030] The active agent-containing layer may be, for example, the final solidified layer obtained after coating and drying a solvent-containing coating composition. The active agent-containing layer may also be produced by laminating two or more such solidified layers (e.g., dried layers) of the same composition to provide the desired areal weight. The active agent-containing layer may be mucoadhesive (in the form of a mucoadhesive layer) or the transmucosal therapeutic system may include an additional mucocontact layer that is mucoadhesive to provide sufficient adhesion. Advantageously, the active agent-containing layer is a mucoadhesive layer.

[0031] Within the meaning of the present invention, the term "mucoadhesive" refers in particular to a material that adheres to and adheres to the mucosa when in contact with the mucosa, but is preferably non-tacky when in the dry state and can be touched, for example, with a finger and manipulated for application to the oral cavity, without unintentionally adhering to the skin of the finger. The mucoadhesive layer is "self-adhesive" when in contact with the mucosa, i.e. typically provides adhesion to the mucosa such that no further auxiliaries are required for fixation. The adhesive strength is preferably so strong that typical movements in the oral cavity are not sufficient to displace the mucoadhesive layer adhered to the mucosa. The "mucoadhesive" layer structure comprises a mucoadhesive layer for mucosal contact, which can be provided in the form of a mucoadhesive active agent-containing layer or in the form of an additional layer, i.e. a mucoadhesive mucocontact layer.

[0032] Within the meaning of the present invention, the term "mucosal contact layer" refers to a layer included in the transmucosal therapeutic system that directly contacts the mucosa of the patient during administration. When the transmucosal therapeutic system includes a mucosal contact layer and one or more other layers, the other layers do not necessarily contact the mucosa and do not necessarily have mucoadhesive properties. The release area is provided by the area of ​​the active agent-containing layer. At the same time, a mucosal contact layer that is not an active agent-containing layer may be used to enhance adhesion. The size of the additional mucosal contact layer and the active agent-containing layer is usually coextensive and corresponds to the release area.

[0033] Within the meaning of the present invention, the term "areal weight" means g / m 2 Refers to the dry weight of a particular layer, e.g., an active agent-containing layer, given in units. Due to manufacturing variations, areal weight values ​​require a tolerance of ±10% of the nominal value, preferably ±7.5%.

[0034] The unit "%" may refer to a percentage given in weight per volume (w / v), volume per volume (v / v), or weight %, and unless otherwise indicated, "%" preferably refers to weight %.

[0035] Within the meaning of the present invention, the term "polymer" refers to any substance or material consisting of so-called repeating units obtained by polymerizing one or more monomers, including homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. Polymers can be of any structure, such as linear polymers, star polymers, comb polymers, brush polymers, and in the case of copolymers, of any monomer sequence, for example, alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can have a molecular weight of, for example, more than 2,000 Daltons, preferably more than 5,000 Daltons, and more preferably more than 10,000 Daltons. Correspondingly, compounds with a molecular weight of less than 2,000 Daltons, preferably less than 5,000 Daltons, or more preferably less than 10,000 Daltons are usually referred to as oligomers.

[0036] Within the meaning of the present invention, the term "administration" refers to the application of a dosage form, i.e., a transmucosal therapeutic system, to the oral mucosa of a patient, which is then maintained on the mucosa for a specific period of administration or until the active agent-containing layer dissolves, erodes, or substantially disintegrates.

[0037] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory where the experiments are performed, which is usually within the range of 15-35°C, preferably about 18-25°C.

[0038] Within the meaning of the present invention, the term "patient" refers to a subject presenting clinical signs of a particular symptom or symptoms indicating the need for treatment, a subject being treated preventatively or prophylactically against a condition, or a subject who has been diagnosed with a condition to be treated.

[0039] Within the meaning of the present invention, the term "coating composition" refers to a composition comprising all the components of one of the layers of the mucoadhesive layer structure in a solvent, which can be coated to form a corresponding layer upon drying.

[0040] Within the meaning of the present invention, the term "solvent" refers to any liquid substance, preferably a volatile organic liquid, such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, heptane, toluene, and mixtures thereof.

[0041] Within the meaning of the present invention, unless otherwise specified, the term "about" refers to an amount that is ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±2% of the disclosed amount.

[0042] Within the meaning of the present invention, the terms "substantial" or "substantially" are used to refer to the majority of the associated corresponding object or component, e.g., a composition "consisting essentially of" a component contains a major amount of such component, e.g., at least 95% by weight, preferably at least 98% by weight, or even at least 99% by weight. [Brief description of the drawings]

[0043] [Figure 1] 1 depicts a schematic diagram of a manufacturing process for a transmucosal therapeutic system according to one embodiment. [Diagram 2] A comparison of the XRD diffractograms obtained for Layer E and placebo Layer E with the XRPD diffractogram obtained for pure crystalline tacrolimus is plotted. [Diagram 3] A comparison of the XRD diffractograms obtained for Layer J and placebo Layer J with the XRPD diffractogram obtained for pure crystalline tacrolimus is plotted. [Figure 4] A comparison of the XRD diffractograms obtained for Layer K and Placebo Layer K with the XRPD diffractogram obtained for pure crystalline tacrolimus is plotted. [Diagram 5] A comparison of the XRD diffractograms obtained for reference layer I and placebo layer I with the XRPD diffractogram obtained for pure crystalline tacrolimus is plotted. [Figure 6]1 depicts the cumulative release of tacrolimus over time obtained in the in vitro release experiment of Example 4 for the transmucosal therapeutic systems prepared according to Examples 2E, 2H, and 2I. [Figure 7] 1 depicts the release rate of tacrolimus over time obtained in the in vitro release experiment of Example 4 for transmucosal therapeutic systems prepared according to Examples 2E, 2H, and 2I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] Structure of the transmucosal therapeutic system The present invention relates to a transmucosal therapeutic system comprising a mucoadhesive layer structure comprising a backing layer, an adhesive layer, and an active agent-containing layer.

[0045] The transmucosal therapeutic system is intended to be used for transmucosal administration of active agents useful in the treatment and / or prevention of diseases and medical conditions. The backing layer comprises a film-forming polymer, the adhesive layer comprises a laminating adhesive and a plasticizer, and the active agent-containing layer comprises a macrolide immunosuppressant and a film-forming polymer as well.

[0046] Thus, according to the present invention, a transmucosal therapeutic system for transmucosal administration of an active agent comprises a mucoadhesive layer structure comprising: A) a backing layer comprising a first film-forming polymer; B) an adhesive layer, Laminating adhesives, and an adhesive layer comprising a first plasticizer; C) an active agent-containing layer, Macrolide immunosuppressants, and and an active agent-containing layer comprising a second film-forming polymer.

[0047] As outlined above, it is believed that the backing layer prevents the active substance from being released from the therapeutic system on its non-mucoadhesive side into the saliva, and thus prevents or reduces unintended delivery via the gastrointestinal route, as well as any irritating sensation or discomfort, as well as unpleasant taste, that the macrolide immunosuppressant may cause when present in dissolved form in the oral cavity. Further details regarding the backing layer will be discussed below in a separate chapter.

[0048] The adhesive layer serves to keep the backing layer and the active agent-containing layer adhered to one another. Thus, in certain embodiments, the adhesive layer is adjacent to the active agent-containing layer on one side and to the backing layer on the other side, i.e., the adhesive layer is "sandwiched" between the backing layer and the active agent-containing layer. The active agent-containing layer, which may be mucoadhesive, may represent the layer that is applied directly to the mucosa.

[0049] In a particular preferred embodiment, the mucoadhesive layer structure of the transmucosal therapeutic system according to the present invention does not include any additional layers and consists of the above three layers from the viewpoint of ease of manufacture and from the viewpoint of keeping the total thickness of the laminate low to prevent any patient discomfort. In such a structure, the active agent-containing layer is mucoadhesive and directly contacts the oral mucosa upon administration, i.e., the active agent-containing layer is the mucosal contact layer.

[0050] In certain other embodiments, the mucoadhesive layer structure may further comprise additional layers, such as a separate mucocontact layer or a cosmetic layer.

[0051] Whether provided as an additional layer or not, the mucosal contact layer is mucoadhesive and preferably ensures sufficient adhesion to the oral mucosa over the intended administration period and even longer. In contrast to the mucosal contact layer, any optional cosmetic layer may provide decorative means such as coloring or imprinting or may simply prevent the patient from touching the backing layer, and is located on top of the mucoadhesive layer structure and is not intended to contact the mucosa.

[0052] From the viewpoint of manufacturing convenience and limiting the overall patch size in terms of surface area, preferably the active agent-containing layer and the adhesive layer, and even more preferably all layers of the mucoadhesive layer structure are coextensive, i.e., identical in shape and size, so that the release area in such a case corresponds to the area defined by the mucoadhesive layer structure. The mucoadhesive layer structure is preferably large enough to allow the patient to conveniently manipulate it with his fingers without resorting to any specific device such as tweezers, and also requires a certain minimum size to ensure that the laminate does not peel off from the mucosa prematurely and to be able to contain a sufficient amount of active substance without using a very thick film. On the other hand, if the laminate is too large, it becomes difficult to apply and wear, and patient compliance decreases. With this in mind, in certain embodiments of the present invention, the transmucosal therapeutic system is at least 0.2 cm 2 , preferably at least 0.5 cm 2 or 10 cm 2 Less than or equal to 7cm, preferably 2 or less than 0.2 to 10 cm 2 , and more preferably 0.5 to 7 cm 2 The discharge area is .

[0053] As also outlined above, the mucoadhesive layer structure of the transmucosal therapeutic system consists of one or more thin layers and thus, in certain embodiments, is in the form of a film. Such films may have a circular, rectangular, or square shape.

[0054] The film preferably has a certain thickness, otherwise it is difficult to incorporate the required amount of active agent, and very thin films are not easy to manufacture, especially with respect to providing a uniform thickness. Thus, in certain embodiments, the mucoadhesive layer structure has a thickness of at least 100 g / m 2 , preferably at least 150 g / m 2 , or more preferably at least 200 g / m 2With respect to its thickness, the mucoadhesive layer structure is in the form of a thin film having a layer thickness of at least 100 μm, preferably at least 150 μm, and more preferably at least 200 μm. On the other hand, a very thick film is perceived by the patient as a nuisance object in the oral cavity and is therefore disadvantageous in terms of patient compliance. Thus, in one particular embodiment, the mucoadhesive layer structure has a layer thickness of at least 450 g / m 2 Less than 350 g / m 2 Less than or equal to 300 g / m 2 Alternatively, in terms of thickness, the mucoadhesive layer structure is in the form of a thin film having a total area weight of less than 500 μm, preferably less than 400 μm, and more preferably less than 300 μm. In a preferred embodiment, the mucoadhesive layer structure is in the form of a thin film having a total area weight of less than 100 to 450 g / m 2 , preferably 150 to 350 g / m 2 , or more preferably 200 to 300 g / m 2 or in the form of a thin film having a total area weight of 100 to 500 μm, preferably 150 to 400 μm, and more preferably 200 to 300 μm.

[0055] The transmucosal therapeutic system according to the present invention is usually stored in a seam-sealed pouch without any additional protective measures. However, the mucoadhesive layer structure may be located on a removable protective layer (release liner), which is removed immediately before application to the mucosa of the patient's oral cavity. Thus, the transmucosal therapeutic system may or may not further include a release liner. The transmucosal therapeutic system protected by a release liner is also usually stored in a seam-sealed pouch. This packaging may be child-resistant and / or elderly-friendly.

[0056] Backing Layer As outlined in more detail above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising a backing layer, the backing layer comprising a film-forming polymer which is ethyl cellulose.

[0057] Since the backing layer is used to prevent (at least a substantial amount of) the active substance from dissolving in saliva, the backing layer is preferably water-insoluble or can be poorly water-soluble, and the time it takes for the backing layer to dissolve is at least the same as the time it takes for the active substance to be delivered through mucous membrane, for example, the same as the time it takes for the active agent-containing layer to dissolve. Here, water-insoluble means that the backing layer does not dissolve in any aqueous environment, especially in human saliva. In certain embodiments, the backing layer also does not swell by absorbing water. The backing layer is preferably free of active agents, i.e., in preferred embodiments, the backing layer does not contain any substantial amount of any active agent, preferably also contained in the active agent layer.

[0058] In terms of surface area size, the backing layer can be the same size as or larger than the active agent-containing layer. Thus, in certain embodiments, the backing layer and the active agent-containing layer are coextensive in shape and size, while in other embodiments, the backing layer is larger than and extends beyond the surface area of ​​the active agent-containing layer. A mucoadhesive layer structure having a backing layer and an active agent-containing layer of the same size is easier to manufacture because a multi-layer laminate can be die-cut to provide the mucoadhesive layer structure, while a mucoadhesive layer structure in which the backing layer is larger than the active agent-containing layer is more difficult to manufacture, but also offers the advantage of less risk of active substance leakage, since the edge of the active substance-containing layer will also be covered by the backing layer.

[0059] Regarding the area weight of the backing layer, a certain thickness is necessary to provide sufficient protection for the active substance, and in addition, it is difficult to coat a very thin layer with sufficient accuracy. On the other hand, a thick layer may not only cause discomfort in the oral cavity, but also be difficult to manufacture. Taking into account the balance, the backing layer should have a weight of at least 20 g / m 2 , preferably at least 40 g / m 2 , and more preferably about 50 g / m 2 or 100g / m 2 Less than 70 g / m 2 It is preferred that the area weight is less than 100 mm.

[0060] As outlined above, the backing layer comprises ethylcellulose as a film-forming polymer, which serves as a matrix to provide sufficient cohesive properties of the layer. This film-forming polymer is also referred to herein as the "first" film-forming polymer, to distinguish it from the film-forming polymers used in other layers of the mucoadhesive layer structure, e.g., the film-forming polymer contained in the active agent-containing layer is referred to as the "second" film-forming polymer. The amount of film-forming polymer in the backing layer should be appropriate to provide a layer with sufficient mechanical stability and low water solubility. Thus, in certain embodiments, the backing layer comprises 55-95% by weight, and preferably about 60% by weight, of the first film-forming polymer. In other embodiments, when the backing layer does not comprise a substantial amount of additional excipients, particularly polymers such as laminating adhesive aids, which are further discussed below, the backing layer may comprise 70-90% by weight, and preferably about 80% by weight, of ethylcellulose as the first film-forming polymer. As discussed further below, ethylcellulose is commercially available, for example, from Ashland under the brand name Aqualon™ ethylcellulose, and in certain embodiments, the ethylcellulose is and / or a viscosity of 30 to 60 mPa·s, more preferably 40 to 52 mPa·s, when measured as a 5% solution in 80:20 toluene:ethanol by weight at 25°C according to ASTM D914; and / or 48.0 to 49.5% ethoxyl substitution as measured in accordance with ASTM D914, and / or having a moisture content of 3% by weight or less according to ASTM D914; This corresponds to a commercial grade of ethyl cellulose of N50NF.

[0061] The backing layer may contain, in addition to the (first) film-forming polymer, a plasticizer (then referred to as a "second" plasticizer) and / or a lamination adhesion aid. As will be seen from the examples, the proper use of such a second plasticizer and / or lamination adhesion aid results in improved adhesion of the laminate.

[0062] Thus, in certain embodiments, the backing layer preferably comprises a plasticizer in an amount of 5-20% by weight of the backing layer, and even more preferably in an amount of about 10% by weight. Such plasticizers, when present in the backing layer, are preferably selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides, and derivatives thereof, polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, propylene glycol, glycerin, medium chain triglycerides, and any mixtures thereof. In terms of improved adhesion, the plasticizer, when present in the backing layer, is more preferably glycerin, triacetin, or any mixtures thereof, and most preferably triacetin.

[0063] As indicated above, in certain embodiments, the backing layer comprises a laminating adhesive co-agent, preferably in an amount of up to 60% by weight of the backing layer, or more preferably 10-35% by weight. Such laminating adhesive co-agent, when present in the backing layer, is preferably selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, and any mixture thereof, more preferably a mixture consisting essentially of polyvinylpyrrolidone and polyvinyl acetate or vinylpyrrolidone-vinyl acetate copolymer, and most preferably is the same as the laminating adhesive present in the adhesive layer. As used herein, in certain preferred embodiments, the mixture consisting essentially of polyvinylpyrrolidone and polyvinyl acetate is 10-30% by weight, preferably 15-25% by weight, and more preferably about 19% by weight of polyvinylpyrrolidone; 70-90% by weight, preferably 75-85% by weight, and more preferably about 80% by weight of polyvinyl acetate; It comprises, and more preferably consists of, about 1% by weight of one or more stabilizers, and preferably comprises, about 0.8% by weight of sodium lauryl sulfate and about 0.2% by weight of silica as stabilizers.

[0064] Further preferred embodiments relating to such mixtures consisting essentially of polyvinylpyrrolidone and polyvinyl acetate are described in more detail below and are likewise preferred for the mixtures used herein as laminating adhesion aids to further enhance adhesive properties.

[0065] Considering the stability of the backing layer with respect to its composition, it is preferred that the backing layer does not contain any volatile constituents that run the risk of evaporating and altering the composition upon storage, or that run the risk of being digested and potentially resulting in health concerns for the patient.Thus, in certain embodiments, the backing layer is substantially free of (volatile) solvents such as methanol, ethanol, acetone, 1-propanol, 2-propanol, ethyl acetate, hexane, n-heptane, and any mixtures thereof, in particular the backing layer comprises 5% by weight or less, preferably 3% by weight or less, and more preferably 1% by weight or less of each such solvent.

[0066] Adhesive Layers and Laminating Adhesives As outlined in more detail above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising an adhesive layer. As outlined above, adhesive layers previously proposed for use in multi-layer laminates for application to mucosa dissolved too quickly in saliva, making them unsuitable for longer administration periods and for use in systems comprising hydrophobic layers, such as water-insoluble backing layers.

[0067] The adhesive layer used in the present invention solves this problem by combining low solubility in aqueous media with excellent adhesive properties, especially towards adjacent (non-adhesive) layers, and it can also be hydrophobic and does not have to comprise, for example, a hydrophilic polymer.

[0068] As used herein, low solubility means that the adhesive layer resists dissolution in an aqueous medium such as saliva for a sufficient period of time, e.g., in a preferred embodiment, an adhesive layer according to the invention is provided between a backing layer and an active agent-containing layer in a mucoadhesive layer structure and retains integrity when placed in natural or artificial saliva for at least 30 minutes, preferably at least 60 minutes.

[0069] By excellent adhesive properties, it is meant that the mucoadhesive layer structure obtained by laminating the adhesive layer between the backing layer and the active agent-containing layer does not show any layer separation.In certain further preferred embodiments, the adhesive layer provides excellent adhesive properties, but is still non-tacky to the touch, which is advantageous for handling, for example, during the manufacture of the mucoadhesive layer structure, because the operator does not have to worry about the adhesive layer being unintentionally stuck to fingers, hands, or other surfaces when manipulating the adhesive layer.

[0070] In terms of size (i.e., surface area) and with respect to the particular transmucosal therapeutic system, the adhesive layer may be the same size as the remaining layers of the mucoadhesive layer structure, in particular the backing layer and the active agent-containing layer, and preferably at least one of the layers adjacent to the adhesive layer. Thus, in certain embodiments, the adhesive layer and the backing layer and / or the active agent-containing layer are coextensive in shape and size.

[0071] With respect to the area weight of the adhesive layer, a certain thickness is necessary to provide sufficient adhesive properties. On the other hand, the adhesive layer is preferably thin enough so that the total thickness of the transmucosal therapeutic system is not uncomfortable when administered in the oral cavity. Thus, in certain embodiments, the adhesive layer has a thickness of at least 30 g / m 2 , preferably at least 50 g / m 2 , and more preferably about 60 g / m 2 or 100g / m 2 and preferably less than 80 g / m 2 has an areal weight of less than

[0072] As also indicated above, the adhesive layer includes a laminating adhesive. The laminating adhesive is the main component of the adhesive layer and provides the adhesive properties. Thus, the laminating adhesive is included in the adhesive layer in an amount appropriate to provide sufficient adhesion, and in certain embodiments, the adhesive layer includes 50-90% by weight, and preferably 60-85% by weight, of the laminating adhesive.

[0073] In certain embodiments, the laminating adhesive is selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, and any mixture thereof, preferably vinylpyrrolidone-vinyl acetate copolymer, or a mixture comprising polyvinylpyrrolidone and polyvinyl acetate, and even more preferably the mixture consists essentially of polyvinylpyrrolidone and polyvinyl acetate.

[0074] In certain such embodiments, the vinylpyrrolidone-vinyl acetate copolymer may have a molar ratio of the monomers vinylpyrrolidone and vinyl acetate of about 6:4, a K value of 25-31, and / or a molecular weight of 45,000-70,000, also referred to as Copovidone Ph. Eur. and is available from BASF under the brand name Kollidon® VA64.

[0075] In mixtures comprising (or consisting of) polyvinylpyrrolidone and polyvinyl acetate, the hydrophobic polyvinyl acetate is the predominant component ensuring that sufficient adhesion is achieved even when the adhesive layer is used to laminate relatively hydrophobic layers. Thus, in certain preferred embodiments, the mixture comprises 70-90% by weight, preferably 75-85% by weight, and more preferably about 80% by weight of polyvinyl acetate. The amount of polyvinylpyrrolidone is correspondingly lower, thus, in certain preferred embodiments, the mixture comprises 10-30% by weight, preferably 15-25% by weight, and more preferably about 19% by weight of polyvinylpyrrolidone.

[0076] In certain embodiments, the polyvinylpyrrolidone is selected from soluble polyvinylpyrrolidones, preferably polyvinylpyrrolidones having a K value of 28 to 32 and / or a molecular weight of 44,000 to 54,000, and preferably about 50,000, as measured by SEC using a detection system that does not require a reference standard. Such polyvinylpyrrolidones are commercially available, for example, under the brand name Kollidon® 30 from BASF.

[0077] In one particular embodiment, the polyvinyl acetate has an average molecular weight Mw of 400,000 to 500,000, and preferably about 450,000.

[0078] In certain embodiments, the mixture may include additional conventional excipients, in particular one or more stabilizers. In certain preferred embodiments, the mixture includes about 1% by weight of one or more stabilizers, preferably about 0.8% by weight of sodium lauryl sulfate and about 0.2% by weight of silica as stabilizers.

[0079] Thus, in an even more preferred embodiment, the mixture comprises: 10-30% by weight, preferably 15-25% by weight, and more preferably about 19% by weight of polyvinylpyrrolidone; 70-90% by weight, preferably 75-85% by weight, and more preferably about 80% by weight of polyvinyl acetate; It contains about 1% by weight of one or more stabilizers, and preferably contains about 0.8% by weight of sodium lauryl sulfate and about 0.2% by weight of silica as stabilizers.

[0080] The average molecular weight of the mixture is expressed as a K value according to the method described in the monograph "Povidone" and may be measured in a 1% solution in tetrahydrofuran. In a preferred embodiment, the mixture also has such a K value of 60 to 68 and / or a glass transition temperature Tg of about 35°C. Such mixtures are commercially available, for example under the brand name Kollidon® SR from BASF, and have the additional advantage that the mixtures are readily available and do not require the additional time-consuming step of preparing the mixture by combining the individual components.

[0081] As also indicated above, the adhesive layer also contains a plasticizer. The plasticizer serves to increase the flexibility and plasticity of the laminating adhesive and is required to achieve adequate adhesive properties. Thus, a plasticizer is also included in the adhesive layer in an amount appropriate to provide sufficient adhesion with the laminating adhesive. This plasticizer is also referred to herein as a "first" plasticizer to distinguish it from the plasticizers used in the different layers of the mucoadhesive layer structure, for example, the plasticizer contained in the backing layer is referred to as a "second" plasticizer. In certain embodiments, the adhesive layer contains 10-45% by weight and preferably about 15% by weight of the first plasticizer.

[0082] According to the present invention, the first plasticizer is selected from the group consisting of mono-, di-, oligo- and polysaccharides and their derivatives, polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, propylene glycol, glycerin, medium chain triglycerides, and any mixtures thereof.

[0083] As will become clear from the examples, the inventors have found that the adhesive properties can be further enhanced by including a film-forming polymer, but the amount is preferably limited, since a large amount of (e.g. hydrophobic) film-forming polymer may lead to brittleness of the film. Thus, in certain embodiments, the adhesive layer preferably includes a film-forming polymer in an amount of 0-10% by weight of the adhesive layer, and even more preferably in an amount of about 5% by weight. The film-forming polymer is not particularly limited and may in particular be selected from any of the film-forming polymers listed further below in another chapter. In a preferred embodiment, the film-forming polymer contained in the adhesive layer is ethyl cellulose, in particular having the characteristics further defined below. It is further preferred that the film-forming polymer in the adhesive layer is the same as that contained in the layer adjacent to the adhesive layer, i.e. the first film-forming polymer of the backing layer and / or the second film-forming polymer of the active agent-containing layer.

[0084] Thus, in certain particularly preferred embodiments, the adhesive layer comprises: 50 to 90% by weight, preferably 60 to 85% by weight, of a laminating adhesive; 10-45% by weight, preferably about 15% by weight, of a first plasticizer; and 0-10% by weight, preferably about 5% by weight each, of the first film-forming polymer and / or the second film-forming polymer.

[0085] Activator In accordance with the present invention, the transmucosal therapeutic system comprises a therapeutically effective amount of a macrolide immunosuppressant as an active agent in a mucoadhesive layer structure, in a preferred embodiment, substantially all of the active agent is contained in the active agent-containing layer, which is further described below.

[0086] The macrolide immunosuppressant used in the present invention is not particularly limited, as long as it is suitable for transmucosal delivery, since the adhesive layer of the present invention allows the use of a backing layer that protects the active agent-containing layer from dissolution and the unpleasant taste or irritating sensation in the oral cavity caused by the active substance from presenting an obstacle in principle. The transmucosal therapeutic system is particularly suitable for macrolide immunosuppressants that have a relatively high molecular weight, are generally poorly soluble in saliva, and therefore require a long time for delivery, since it can be designed and adapted for long-term administration.

[0087] The macrolide immunosuppressant may be selected, for example, from the group consisting of tacrolimus, sirolimus, everolimus, and pimecrolimus, more preferably tacrolimus.

[0088] As shown in the examples, the active agent may be incorporated in large and particularly therapeutically effective amounts into the active agent-containing layer by using a film-forming polymer, which in a particularly preferred embodiment includes a mixture of relatively hydrophobic polymers such as ethyl cellulose and hydroxypropyl cellulose, as outlined above. In certain preferred embodiments, the transmucosal therapeutic system includes a therapeutically effective amount of tacrolimus. In yet further preferred embodiments, the active agent-containing layer includes a concentration of at least 0.5 mg / cm. 2of tacrolimus, more preferably at least 0.8 mg / cm 2 of tacrolimus, and most preferably at least 2.0 mg / cm 2 and / or 6.0 mg / cm 2 Less than 4.0 mg / cm 2 Less than 2.5 mg / cm 2 As shown in the examples, such a content of tacrolimus in the active agent-containing layer allows the transmucosal therapeutic system to contain an amount of tacrolimus equivalent to that of a commercially available oral capsule. That is, in certain embodiments, the transmucosal therapeutic system contains at least 0.1 mg, at least 0.5 mg, at least 1.0 mg, or even at least 5.0 mg of tacrolimus.

[0089] The active agent is preferably incorporated into the film-forming polymer by using an organic solvent such as ethanol, which can dissolve both the (second) film-forming polymer and the active agent, as further shown in the manufacturing process section below. Upon removal of the solvent, the active agent remains in the matrix formed by the film-forming polymer in amorphous form (some will refer to such a state as a substance in solution in the polymer matrix, which may also be named "solid solution"), which is advantageously characterized by the absence of any crystallinity, although it is understood that a small amount of crystalline active agent may also remain without affecting the performance of the active agent system form. The absence of crystalline form can be confirmed, for example, by X-ray diffraction analysis (XRD), which reveals a typical 2-theta (2θ) peak in the diffractogram when the investigated layer contains the active agent in crystalline form. This is exemplarily shown in the example of a tacrolimus transmucosal therapeutic system.

[0090] Therefore, in a preferred embodiment of the present invention, the active agent is in amorphous form.In other words, the X-ray diffraction pattern of the active agent-containing layer is characterized by the absence of crystalline active agent reflections, as can be determined by comparing with a reference layer that does not contain active agent or that contains the same active agent but in crystalline form.In certain embodiments, the active agent is present in homogeneously distributed form, as can be determined by methods known to those skilled in the art.

[0091] In a further preferred embodiment, the active agent is tacrolimus in amorphous form, i.e., in other words, the X-ray diffraction pattern of the active agent-containing layer is characterized by the absence of reflections of crystalline tacrolimus. The 2-theta peaks characteristic of tacrolimus are, for example, 6.45°, 8.55°, 10.35°, 11.25°, 11.75°, 13.75°, 14.15°, and 15.30°. Thus, in a further preferred embodiment, the active agent is tacrolimus, and the X-ray diffraction pattern of the active agent-containing layer does not include reflections at 2-theta angles of 6.45°, 8.55°, 10.35°, 11.25°, 11.75°, 13.75°, 14.15°, and 15.30°±0.2° degrees. In certain embodiments, the active agent is tacrolimus, and is present in a homogeneously dispersed form, as can be determined by methods known to those skilled in the art.

[0092] Active Agent-Containing Layer As outlined in more detail above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising an active agent-containing layer, the active agent-containing layer comprising a macrolide immunosuppressant as an active agent and a film-forming polymer.

[0093] As outlined above, the active agent-containing layer is preferably a mucosal contact layer, and in certain such embodiments, it is necessary to provide sufficient mucoadhesion during the administration period. As discussed, macrolide immunosuppressants are hydrophobic drugs that require a relatively long time to be delivered transmucosally due to low solubility. Thus, the mucoadhesive properties need to be retained for a sufficiently long period, such as 30 minutes, 60 minutes, or even longer. The film-forming polymer of the active agent-containing layer is selected accordingly to ensure adequate mucoadhesive properties and in view of potential dissolution or disintegration in saliva. In certain embodiments, the active agent-containing layer disintegrates over time to release the active substance, but maintains its integrity for the administration period, e.g., at least 30 minutes, 60 minutes, or even longer.

[0094] As discussed above in the sections regarding the adhesive layer and the backing layer, these layers can be the same shape and size as the active agent-containing layer, but in other embodiments, the backing layer is sized larger than and extends the surface area of ​​the active agent-containing layer. In the simplest manner, and according to a preferred embodiment, all three layers are coextensive in shape and size.

[0095] Regarding the areal weight of the active agent-containing layer, a certain minimum thickness is usually required for the transmucosal therapeutic system to contain a therapeutically effective amount of the macrolide immunosuppressant without being too large. Considering that the total thickness of the system should be such that it does not cause any discomfort to the patient, the active agent-containing layer should be at least 100 g / m 2 , preferably at least 130 g / m 2 , and more preferably about 150 g / m 2 or 250g / m 2 Less than or 200g / m 2 Such relatively thick layers can be prepared by repeated coating and drying of the active agent layer coating composition, e.g., as shown in the examples, up to 150 g / m2. 2 The layer of the coating composition is 75 g / m 2In other words, such double (or multiple) layers prepared by repeated coating and drying of the active agent layer coating composition are considered as active agent-containing layers in the sense of the present invention.

[0096] As outlined above, the active agent-containing layer includes a film-forming polymer, referred to as the "second" film-forming polymer, which serves as a matrix to provide sufficient cohesive properties of the layer. Polymers that can be used as film-forming polymers, particularly as the "second" film-forming polymer, are further described below. The amount and type of film-forming polymer in the active agent-containing layer should be appropriate to provide the layer with adequate mucoadhesive properties, but also in view of potential dissolution or disintegration in saliva. Thus, in certain embodiments, the second film-forming polymer is included in the active agent-containing layer in a total amount of 70-90% by weight of the active agent-containing layer, and even more preferably about 80% by weight, particularly in the case of a mixture of polymers, in an amount per polymer of 5-50% by weight of the active agent-containing layer, and preferably 10-40% by weight. The selection of a particular film-forming polymer as the second film-forming polymer is further outlined below.

[0097] In addition to the second film-forming polymer and the active agent, the active agent-containing layer may contain additional excipients as known to those skilled in the art and as further listed below. In certain embodiments, the active agent-containing layer contains one or more additional excipients selected from the group consisting of additional film-forming polymers, additional plasticizers, colorants, antioxidants, taste masking agents, and stabilizers. In certain preferred embodiments, the active agent-containing layer contains one or more additional excipients selected from the group consisting of additional film-forming polymers, additional plasticizers, colorants, antioxidants, taste masking agents, and stabilizers. at least one further film-forming polymer, preferably in an amount of 1 to 6% by weight of the active agent-containing layer, and even more preferably in an amount of 2 to 5% by weight; an additional plasticizer, preferably in an amount of 2-10% by weight of the active-agent-containing layer, and even more preferably in an amount of 3-6% by weight, and / or Preferably, the colorant is present in an amount of 1 to 6% by weight of the active agent-containing layer, and even more preferably in an amount of 2 to 5% by weight.

[0098] Additional preferred specific film-forming polymers, plasticizers, colorants, and other excipients are listed below in separate sections and may be suitably used in the active agent-containing layer.

[0099] In certain embodiments, the present invention is also directed to the active agent-containing layer itself. As outlined above, the active agent-containing layer of the present invention is advantageous in that it allows the incorporation of sufficient amounts of active agent, particularly therapeutically effective amounts of active agent. This is particularly true for tacrolimus. The inventors have been surprisingly successful in showing that substantial and therapeutically effective amounts can be incorporated into the active agent-containing layer amorphously, as a solid solution, while achieving the mechanical and mucoadhesive properties required for its use for transmucosal administration and drug delivery. Furthermore, such active agent-containing layer of the present invention provides chemical and physical product stability in that it is chemically compatible with the amorphous drug to an extent that it can achieve a commercially attractive shelf life with low chemical degradation of the active ingredient, which is generally a substantial technical risk associated with the amorphous form of the active ingredient. Also, in terms of physical stability, solid solutions of amorphous active ingredients are associated with some increased risks in that many initially promising formulations fail over time, as they exhibit recrystallization of the active ingredient induced by factors such as temperature fluctuations on storage, mechanical stress, and / or humidity. As demonstrated in the examples, when the active agent is in amorphous form, the release of the active substance is suitable for transmucosal delivery, there is substantially no active agent in crystalline form, and no recrystallization behavior was observed for the formulation over time. Thus, according to one of such aspects, the present invention also provides an active agent-containing layer for a transmucosal therapeutic system, the active agent-containing layer comprising: i) tacrolimus in amorphous form; and ii) a film forming polymer selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof. In certain embodiments of such aspects, the X-ray diffraction pattern of the active agent-containing layer is characterized by the absence of crystalline tacrolimus reflections, and preferably does not include reflections at 2-theta angles of 6.45°, 8.55°, 10.35°, 11.25°, 11.75°, 13.75°, 14.15°, and 15.30°±0.2° degrees.

[0100] In certain further aspects, the present invention also covers the use of such active agent-containing layers in transmucosal therapeutic systems. That is, the active agent-containing layers disclosed herein can also be used as transmucosal therapeutic systems by themselves, for example in therapeutic applications where the functionality of the backing layer is not considered essential, particularly in consideration of the administration site that limits dissolution in saliva and therefore reduces the risk of unintended enteral delivery, such as between the gums and the buccal surface (confined to the buccal / gingival site) or sublingual administration (confined under the tongue). Alternatively, the active agent-containing layers disclosed herein can be used as part of a transmucosal therapeutic system in combination with alternative backing layers that may or may not have the same properties and functionality as described for the backing layers of the transmucosal therapeutic systems provided herein, but may use different compositions.

[0101] In some of the preferred embodiments of the active agent-containing layer of the present invention and its uses, further optional and preferred features of the active agent-containing layer and its components, such as the active agent, the (second) film-forming polymer, the further film-forming polymer, the plasticizer, the colorant, and other excipients, are the same as those further described above for the active agent-containing layer as part of the transmucosal therapeutic system of the present invention.

[0102] In certain yet further aspects, the present invention is also directed to a mucoadhesive layer structure for a transmucosal therapeutic system comprising such an active agent-containing layer. According to such aspects, the present invention provides a mucoadhesive layer structure for a transmucosal therapeutic system, comprising: A) an active agent-containing layer, i) tacrolimus in amorphous form, and ii) an active agent-containing layer comprising a film-forming polymer selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof; B) an adhesive layer, Laminating adhesives, and The present invention is directed to a mucoadhesive layer structure comprising an adhesive layer that includes a plasticizer.

[0103] In certain additional aspects, the present invention is also directed to the use of such mucoadhesive layer structures in transmucosal therapeutic systems. The surprising and beneficial effects to be achieved by such inventive mucoadhesive layer structures and the associated uses have already been discussed and the reader is referred to the sections above, in particular the sections relating to active agents and active agent-containing layers.

[0104] In all the above aspects relating to the mucoadhesive layer structure and its uses for a transmucosal therapeutic system, further preferred features regarding the mucoadhesive layer structure, the active agent-containing layer and its constituents, such as the active agent, the (second) film-forming polymer, the further film-forming polymer, the plasticizers, the colorants and other excipients, are the same as those further described above or below for the mucoadhesive layer structure, in particular the active agent-containing layer as part of the transmucosal therapeutic system of the present invention.

[0105] Film-forming polymers As outlined in more detail above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising a backing layer, an adhesive layer, and an active agent-containing layer, both of which comprise a film-forming polymer.

[0106] The film-forming polymer that can be used in the present invention is not particularly limited, and any known polymer having film-forming properties, preferably a polymer that is pharma- ceutically acceptable (and, e.g., approved for pharmaceutical use), can be used.

[0107] Exemplary film-forming polymers that can be used in the present invention are, for example, ethylcellulose (available, for example, under the brand name Aqualon™ ethylcellulose from Ashland), copolymers based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (available, for example, under the brand name Eudragit™ E100 from Evonik), hydroxypropylcellulose (available, for example, under the brand name Klucel™ from Ashland), neutralized forms of hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, hydroxyethylcellulose, methacrylic acid-methyl methacrylate copolymer (1:1) (available, for example, under the brand name Eudragit™ L100 from Evonik), mixed calcium / sodium salts of methyl vinyl ether and maleic anhydride copolymers (available, for example, under the brand name Gantrez™ from Ashland), vinylpyrrolidone-vinyl acetate copolymers (available, for example, under the brand name Kollidon™ from BASF), and any mixtures thereof.

[0108] In certain preferred embodiments, the ethyl cellulose is and / or a viscosity of 30 to 60 mPa·s, more preferably 40 to 52 mPa·s, when measured as a 5% solution in 80:20 toluene:ethanol by weight at 25°C according to ASTM D914; and / or 48.0 to 49.5% ethoxyl substitution as measured in accordance with ASTM D914, and / or Has a moisture content of 3% by weight or less according to ASTM D914.

[0109] Such ethylcellulose is commercially available, for example, from Ashland Specialty Ingredients and corresponds to the grade ethylcellulose N50NF.

[0110] Hydroxypropyl cellulose is commercially available, for example, from Ashland under the brand name Klucel™ and is offered in several grades.

[0111] The grades differ from one another by molecular weight Mw (measured by GPC size exclusion chromatography) and Brookfield viscosity (25° C., LVF, water free) and are as follows: The HF grade has a Mw of 1,150,000 and a Brookfield viscosity of 1500-3000 mPa·s (1% in water). The MF grade has a Mw of 850,000 and a Brookfield viscosity of 4000-6500 mPa·s (2% in water). The GF grade has a Mw of 370,000 and a Brookfield viscosity of 150-400 mPa·s (2% in water). The JF grade has a Mw of 140,000 and a Brookfield viscosity of 150-400 mPa·s (5% in water). The LF grade has a Mw of 95,000 and a Brookfield viscosity of 75-150 mPa·s (5% in water). The EF grade has a Mw of 80,000 and a Brookfield viscosity of 300-600 mPa·s (10% in water). The ELF grade has a Mw of 40,000 and a Brookfield viscosity of 150-300 mPa·s (10% in water).

[0112] Thus, in certain embodiments, the hydroxypropyl cellulose has a molecular weight of 30,000 to 1,500,000 (as measured by GPC size exclusion chromatography), and in particular, the hydroxypropyl cellulose is 35,000-45,000, especially 40,000 75,000-85,000, especially 80,000 90,000-100,000, especially 95,000 130,000-150,000, especially 140,000 350,000-400,000, especially 370,000, 800,000 to 900,000, especially 850,000, and It has a molecular weight (measured by GPC size exclusion chromatography) selected from 1,100,000 to 1,200,000, in particular 1,150,000.

[0113] In a preferred embodiment, the hydroxypropyl cellulose is Mw of approximately 370,000 and a Brookfield viscosity of 150-400 mPa·s (2% in water), or It has a Mw of approximately 80,000 and a Brookfield viscosity of 300-600 mPa·s (10% in water).

[0114] In one particular embodiment, the mixed calcium / sodium salt of methyl vinyl ether and maleic anhydride copolymer has a number average molecular weight Mn of about 600,000 to 700,000 and a weight average molecular weight Mw of about 790,000. Such mixed calcium / sodium salt of methyl vinyl ether and maleic anhydride copolymer is commercially available, for example, under the brand name Gantrez™ MS-955 from Ashland.

[0115] In certain embodiments, the vinylpyrrolidone-vinyl acetate copolymer may have a molar ratio of the monomers vinylpyrrolidone and vinyl acetate of about 6:4, a K value of 25-31, and / or a molecular weight of 45,000-70,000. Such vinylpyrrolidone-vinyl acetate copolymers, as described for the laminating adhesives above, are also synonymously referred to as Copovidone Ph. Eur. and are available from BASF under the brand name Kollidon® VA64.

[0116] When used as the first film-forming polymer, i.e., the film-forming polymer included in the backing layer, the film-forming polymer should be practically water-insoluble so that it can protect the underlying active agent-containing layer. The first film-forming polymer is ethyl cellulose, preferably N50NF grade ethyl cellulose as described above, more preferably used in an amount of 55-95% by weight of the backing layer, and even more preferably in an amount of about 60% by weight.

[0117] As outlined above, the second film-forming polymer, i.e., the film-forming polymer included in the active agent-containing layer, must be carefully selected to provide the layer with adequate mucoadhesive properties as well as relatively slow dissolution, erosion, or disintegration in saliva so that the administration period may be long enough to ensure the delivery of a therapeutically effective amount of the active agent. The polymer must also allow for the incorporation of a sufficient amount of the active agent. In view of such considerations, the second film-forming polymer is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixtures thereof. Such polymers and mixtures encompassed by the expression "film-forming polymer" in this context, particularly mixtures of two or more polymers with different degrees of hydrophilicity (or hydrophobicity, respectively), may provide balanced film properties. Ethyl cellulose, hydroxypropyl cellulose, and any mixtures thereof, although relatively hydrophobic, are still able to absorb water and adhere to the mucosa, and are capable of incorporating large amounts of hydrophobic active agents, such as macrolide immunosuppressants.

[0118] In certain preferred embodiments, when used in the second film-forming polymer, ethylcellulose has grade N50NF as described above, and is preferably used in an amount of 20-40% by weight and more preferably 25-35% by weight of the active agent-containing layer, especially when a mixture of film-forming polymers is used as the second film-forming polymer. In certain preferred embodiments, when used in the second film-forming polymer, hydroxypropylcellulose preferably has grade GF as described above, and is more preferably used in an amount of 5-20% by weight and more preferably 7-15% by weight of the active agent-containing layer, especially when a mixture of film-forming polymers is used as the second film-forming polymer, or (ii) has grade EF as described above, and is more preferably used in an amount of 25-50% by weight and more preferably 30-45% by weight of the active agent-containing layer, especially when a mixture of film-forming polymers is used as the second film-forming polymer. In yet a further embodiment, the second film-forming polymer is Ethyl cellulose, and / or a viscosity of 30 to 60 mPa·s, more preferably 40 to 52 mPa·s, when measured as a 5% solution in 80:20 toluene:ethanol by weight at 25°C according to ASTM D914; and / or 48.0 to 49.5% ethoxyl substitution as measured in accordance with ASTM D914, and / or having a moisture content of 3% by weight or less; ethyl cellulose, preferably in an amount of 20-40% by weight of the active agent-containing layer and more preferably 25-35% by weight; Hydroxypropyl cellulose, a molecular weight of 350,000 to 400,000, in particular about 370,000 (measured by GPC size exclusion chromatography); and / or It has a Brookfield viscosity of 150-400 mPa·s when measured as a 2% aqueous solution. Hydroxypropyl cellulose, preferably in an amount of 5 to 20% by weight of the active agent-containing layer and more preferably 7 to 15% by weight of the active agent-containing layer; Hydroxypropyl cellulose, and / or a molecular weight of 75,000 to 85,000, in particular about 80,000 (measured by GPC size exclusion chromatography); and / or It has a Brookfield viscosity of 300-600 mPa·s when measured as a 10% aqueous solution. Preferably it is a mixture with hydroxypropyl cellulose in an amount of 25-50% by weight of the active agent-containing layer, and more preferably 30-45% by weight.

[0119] In certain embodiments, the active agent-containing layer comprises an additional film-forming polymer, in such case the additional film-forming polymer is more preferably selected from the group consisting of a mixed calcium / sodium salt of methyl vinyl ether and maleic anhydride copolymer having a number average molecular weight Mn of about 600,000-700,000 and a weight average molecular weight Mw of about 790,000, and more preferably a vinylpyrrolidone-vinyl acetate copolymer having a molar ratio of the monomers vinylpyrrolidone-vinyl acetate copolymer of about 6:4, a K value of 25-31, and / or a molecular weight of 45,000-70,000, and any mixtures thereof.

[0120] In certain embodiments, the adhesive layer also comprises a film-forming polymer, which is preferably the same as the first film-forming polymer and / or the second film-forming polymer.In other words, in certain embodiments, the adhesive layer comprises a film-forming polymer selected from the group consisting of ethyl cellulose and hydroxypropyl cellulose.When used as a film-forming polymer in the adhesive layer, hydroxypropyl cellulose preferably has grade EF as described above, and ethyl cellulose has grade N50NF as described above.

[0121] Plasticizer As outlined in more detail above, the transmucosal therapeutic system according to the present invention comprises a mucoadhesive layer structure comprising a backing layer, an adhesive layer, and an active agent-containing layer, the adhesive layer comprising a plasticizer, and the backing layer and the active agent-containing layer may also comprise a plasticizer.

[0122] The plasticizer that can be used in the present invention is not particularly limited, and any plasticizer known to those of skill in the art, preferably a pharma- ceutically acceptable (and, e.g., approved for pharmaceutical use) plasticizer can be used.

[0123] Exemplary plasticizers that can be used in the present invention are, for example, selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides and their derivatives, polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, propylene glycol, glycerin, medium chain triglycerides, and any mixtures thereof.

[0124] When used in the backing layer, the plasticizer is referred to as a second plasticizer and may be selected, for example, from the plasticizers listed above. In certain preferred embodiments, the second plasticizer is glycerin, triacetin, or any mixture thereof, preferably triacetin. The second plasticizer is preferably used in an amount of 5-20% by weight of the backing layer, and even more preferably in an amount of about 10% by weight.

[0125] When used in the adhesive layer, the plasticizer is referred to as the first plasticizer and may be selected, for example, from the plasticizers listed above. In certain preferred embodiments, the second plasticizer is glycerin, triacetin, or any mixture thereof, preferably glycerin. The first plasticizer is preferably used in an amount of 10-45% by weight of the adhesive layer, and more preferably about 15% by weight.

[0126] When used in the active agent-containing layer, the plasticizer may be selected, for example, from the plasticizers listed above. In certain preferred embodiments, the plasticizer used in the active agent-containing layer is glycerin, triacetin, or any mixture thereof, more preferably glycerin, preferably used in an amount of 2-10% by weight of the active agent-containing layer, and even more preferably 3-6% by weight.

[0127] Further excipients Each layer of the transmucosal therapeutic system according to the present invention may comprise additional excipients selected from the group consisting of fatty acids, taste masking agents, sweeteners, flavoring agents, colorants, permeation enhancers, solubilizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents, and additional film-forming polymers.

[0128] Such excipients may be present in the relevant layer in an amount per additive of 0.001-15% by weight of the layer, hi certain embodiments, the total amount of all additives is 0.001-25% by weight of the layer.

[0129] In certain embodiments, the colorant is titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorubine, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotin, chlorophyll, chlorophyllin, copper complexes of chlorophyll and chlorophyllin , Green S, Plain Caramel, Caustic Sulfite Caramel, Ammonia Caramel, Sulfite Ammonia Caramel, Brilliant Black BN, Black PN, Vegetable Carbon, Brown HT, Carotene, Annatto, Bixin, Norbixin, Paprika Extract, Capsanthione, Capsorubin, Lycopene, Beta-Apo-8'-Carotenal, Lutein, Canthaxanthin, Beetroot Red, Betanin, Anthocyanin, Calcium Carbonate, Iron Oxide and Hydroxide, Aluminum, Silver, Gold, and Lysol Rubin BK.

[0130] In certain embodiments, the antioxidant may be selected from BHT and vitamin E (α-tocopherol).

[0131] In certain embodiments, the stabilizer may be selected from organic acids selected from mono-, di-, oligo-, and polycarboxylic acids, such as chelating agents such as succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, oxalic acid, sorbic acid, and mixtures thereof.

[0132] Treatment Methods / Medical Use According to a particular aspect of the invention, the transmucosal therapeutic system according to the invention is for use in a method for the treatment and / or prevention of diseases and medical conditions, preferably in a human patient.

[0133] According to a particular embodiment, the present invention is also directed to a method for the treatment and / or prevention of diseases and medical conditions, in which a transmucosal therapeutic system according to the present invention is administered to a patient, and preferably a human patient.

[0134] According to a particular aspect, the present invention is also directed to the use of the transmucosal therapeutic system of the present invention for the manufacture of a medicament for the treatment and / or prevention of diseases and medical conditions, preferably in a human patient.

[0135] The macrolide immunosuppressants used as active agents in the present invention are indicated for managing the risk of organ rejection after organ transplantation. Thus, in certain embodiments, the treatment and / or prevention of the above-mentioned diseases and medical conditions is the treatment and / or prevention of organ rejection after organ transplantation in a human patient, more preferably the prevention of organ rejection after allogeneic liver, kidney or heart transplantation in a human patient.

[0136] The transmucosal therapeutic system is preferably administered by applying the mucoadhesive layer structure to the mucosa of the oral cavity of a human patient and remaining on the mucosa for a certain period (administration period) and / or until dissolved. In the case of insoluble backing or adhesive layers, or layers with low solubility such that they do not completely dissolve during the administration period (preferred), these layers must be removed from the administration site or swallowed after the administration period. In a preferred embodiment, the transmucosal therapeutic system is administered by applying the mucoadhesive layer structure to the buccal, sublingual, gingival, or palatal mucosa of the oral cavity of a human patient. The administration period is long enough to ensure adequate delivery of the active agent, at least a few minutes, e.g., 1-10 minutes, slightly longer, e.g., 10-30 minutes, or even longer, e.g., 30-60 minutes, and even longer.

[0137] Manufacturing Process The present invention further relates to a transmucosal therapeutic system, and in particular to a process for the manufacture of the inventive transmucosal therapeutic system as outlined above. According to one aspect, the present invention also relates to a process for the manufacture of the active agent-containing layer as described above.

[0138] In such a manufacturing process, a coating composition is prepared for each of the backing layer, the active agent-containing layer, and the adhesive layer by combining all of the components of the layer with a solvent.The backing layer and the active agent-containing layer are then prepared by coating and drying the backing layer coating composition and the active agent layer coating composition on a release liner (which may be an intermediate release liner that is subsequently removed), and a two-layer laminate is obtained by coating and drying the adhesive layer on the backing layer.The two-layer laminate thus prepared can then be laminated with the active agent-containing layer, for example, using a conventional lamination station.The lamination preferably does not require the use of a solvent, and is therefore referred to as a "dry-bonded laminate".In yet another preferred embodiment, the lamination can also be carried out without the application of heat, which is advantageous in that the active agent is therefore not exposed to thermal stress.

[0139] In summary, the inventive process for the manufacture of a transmucosal therapeutic system comprises: (a) combining at least the backing layer components as described above and a solvent to obtain a backing layer coating composition; coating a backing layer coating composition onto a release liner; drying the coated backing layer coating composition to form a backing layer; (b) combining at least the active agent layer components as described above and a solvent to obtain an active agent layer coating composition; coating an active agent layer coating composition onto a release liner; drying the coated active agent layer coating composition to form an active agent-containing layer; (c) combining at least the adhesive layer components and a solvent as described above to obtain an adhesive layer coating composition; Coating an adhesive layer coating composition onto the backing layer obtained in step (a); drying the coated adhesive layer coating composition to form a two-layer laminate consisting of the adhesive layer and the backing layer on the release liner; (d) laminating the bilayer laminate obtained in step (c) with the active agent-containing layer obtained in step (b).

[0140] In step (b), the coating step is optionally repeated by coating an active agent layer coating composition onto the coated active agent layer coating composition before drying, or onto the dried active agent-containing layer, to obtain a bilayer active agent-containing layer.

[0141] In steps (a) and (b), the release liner is in a preferred embodiment an intermediate release liner that can be removed later. In all steps, the drying time is adapted in view of the solvent and matrix polymer used. In step (c), the drying step is preferably carried out as long as necessary to obtain a surface that is dry to the touch. Without wishing to be bound by theory, in such a case, the adhesive layer may still contain some residual amount of solvent, which may be beneficial for the subsequent dry bonding lamination step in that good adhesion can be achieved.

[0142] The active agent-containing layer of the present invention for a transmucosal therapeutic system, however, may be prepared by a similar process which essentially includes only step (b). In certain preferred embodiments, in such a process, the active agent is tacrolimus.

[0143] In such an inventive process as outlined above, the characteristics of the components used, and of the resulting layer, are preferably as outlined above in the corresponding chapters.

[0144] The solvent used in each step is not particularly limited, but from the viewpoint of ease of coating, the solvent is preferably capable of dissolving substantially all layer components except optional inorganic components such as titanium dioxide, and is therefore selected from organic solvents selected from, for example, ethanol, ethyl acetate, acetone, and any mixture thereof. In a preferred embodiment, the solvent used in step (a) for the backing layer is selected from organic solvents, preferably ethanol or a solution of ethanol and acetone. In a preferred embodiment, the solvent used in step (b) for the active agent-containing layer is ethanol, which allows dissolution of the active substance and the film-forming polymer (see examples). From the viewpoint of the need to be able to completely dissolve the active agent, the solvent used in step (b) preferably does not contain a large amount of water, more preferably does not contain any substantial amount of water. In a further preferred embodiment, the solvent used in step (c) for the adhesive layer is an organic solvent, preferably selected from the group consisting of ethanol, ethyl acetate, acetone, and any mixture thereof, preferably a solution of ethyl acetate, acetone, or acetone and ethanol.

[0145] Finally, according to one aspect, the present invention is also directed to a transmucosal therapeutic system, an active agent-containing layer, or a mucoadhesive layer structure obtainable by the process as described above. EXAMPLES

[0146] The present invention will now be described more completely with reference to the accompanying examples.However, it should be understood that the following description is merely illustrative and should not be construed as limiting the present invention in any way.The numerical values ​​provided in the examples with respect to the amount or area weight of components in the composition may vary slightly due to manufacturing variations.

[0147] Example 1: Coating Composition Backing Layer Coating Composition formulation The formulations of the backing layer coating compositions A and B are summarized below in Table 1. As also shown in Table 1, the formulations are based on weight percent.

[0148] [Table 1]

[0149] Preparation of the Coating Composition (Backing Layer) Backing layer coating compositions A and B were prepared by combining all of the components of the formulation listed above in Table 1 using standard equipment, such as a laboratory stirrer and a glass beaker, and standard procedures known to those skilled in the art.

[0150] Adhesive Layer Coating Composition formulation The formulations of adhesive layer coating compositions C and D are summarized below in Table 2. As also shown in Table 2, the formulations are based on weight percent.

[0151] [Table 2]

[0152] Preparation of the coating composition (adhesive layer) Adhesive layer coating compositions C and D were prepared by combining all the components of the formulation listed above in Table 2 using standard equipment, such as a laboratory stirrer and a glass beaker, and standard procedures known to those skilled in the art.

[0153] Active Agent Layer Coating Composition formulation The formulations of active agent layer coating compositions EH, J, and K, as well as reference composition I, are summarized below in Table 3. As also shown in Table 3, the formulations are based on weight percent.

[0154] [Table 3]

[0155] Preparation of Coating Composition (Active Agent-Containing Layer) Active agent layer coating compositions EK were prepared by combining all the components of the formulations listed above in Table 3 using standard equipment, e.g., a laboratory stirrer and glass beaker, and standard procedures known to those skilled in the art. The active agent tacrolimus was dissolved in coating compositions EH, J, and K, whereas in reference composition I, tacrolimus was unable to dissolve due to its low solubility in water and therefore exists in a suspended state.

[0156] Example 2: Preparation of a transmucosal therapeutic system The transmucosal therapeutic systems were prepared as described below. Coating and drying of the coating composition and lamination were performed by standard procedures known to those skilled in the art using standard equipment such as a coating box or coating knife for casting, a drying cabinet for drying, and a conventional laminating station for lamination. The composition and area weight of each layer, as well as the amount of active agent of each transmucosal therapeutic system 2E to 2K, are further shown in Table 4 below.

[0157] Preparation of two-layer laminates The two-layer laminate was prepared by coating and drying the backing layer coating composition B obtained in Example 1 on a release liner to form a backing layer, and coating and drying the adhesive layer coating composition D obtained in Example 1 on the dried backing layer to obtain an adhesive layer / backing layer two-layer laminate on a release liner. The coating thickness was adjusted to 50 g / m for the backing layer. 2 , 60g / m for adhesive layer 2 The area weight was obtained.

[0158] Preparation of Single and Double Layer Active Agent-Containing Layers A single layer active agent-containing layer was prepared by coating and drying the reference coating composition I obtained in Example 1 on a release liner to obtain Reference Layer I. The coating thickness was adjusted to 100 g / m 2 The area weight was obtained.

[0159] The dual-layer active-containing layers were prepared by coating and drying the active-layer coating compositions E-H, J, and K obtained in Example 1 onto a release liner to form a single-layer active-containing layer, and by repeatedly coating and drying using the same active-layer coating compositions onto the single-layer active-containing layer to obtain dual-layer active-containing layers E-H, J, and K. The coating thickness was adjusted to a total area weight of 150 g / m 2 (75g / m 2 As mentioned above, such a bilayer is also encompassed by the expression "active agent-containing layer".

[0160] Preparation of transmucosal therapeutic systems 2E-2K Transmucosal therapeutic systems 2E-2K can be prepared by laminating the resulting adhesive / backing layer bilayer laminate with each of the bilayer active agent-containing layers E-K (with the laminate and layers E-K positioned so that the adhesive layer faces the active agent-containing layer), removing the release liner covering the backing layer, and forming a 6 cm 2 Individual transmucosal therapeutic systems of size were prepared by punching.

[0161] The transmucosal therapeutic system was shown to provide sufficient mucoadhesion in preliminary in vivo studies using a placebo layer containing no active agent.

[0162] [Table 4-1] [Table 4-2]

[0163] Example 3: Presence of crystalline tacrolimus The active agent-containing layers E and J, as well as the reference layer I, were examined for the presence of crystalline tacrolimus immediately after preparation. In addition, the active agent-containing layer K was also examined after 2.5 months at 25°C. The examination was carried out using XRD, using the crystalline tacrolimus and placebo layers as references. The placebo layer was prepared similarly to the active agent-containing layers E, J, and K, as well as the reference layer I, as outlined in Examples 1 and 2, except that the formulations of coating compositions E, J, and K, as well as the formulation of reference composition I, were modified by omitting the active agent tacrolimus and linearly extrapolating the amounts of the remaining components to be equal to approximately 100%.

[0164] The films to be measured were fixed on conventional zero background films for reflectance measurements. For active agent-containing layers E, I, J, and K and placebo layers E, I, J, K, X-ray diffractograms XRD were recorded in the 2θ range of 2° to 40°, and for pure crystalline tacrolimus, X-ray powder diffractograms XRPD were obtained in the same 2θ range of 2° to 40°. To improve the detection limit, the integration time (time per step) was varied. The measurement parameters are summarized in Table 5 below.

[0165] [Table 5]

[0166] The recorded diffraction patterns are shown in Figure 2 (layer E, placebo layer E, and pure tacrolimus), Figure 3 (layer J, placebo layer J, and pure tacrolimus), Figure 4 (layer K, placebo layer K, and pure tacrolimus), and Figure 5 (reference layer I, placebo layer I, and pure tacrolimus).

[0167] As can be seen in Figure 5, the diffractogram of the reference layer I shows peaks that are also present in the diffractogram of pure crystalline tacrolimus, whereas the peaks are absent in the placebo layer I. This confirms that tacrolimus is present in crystalline form in the reference layer I and in suspended form in the coating composition I, and that the X-ray measurements used are suitable to investigate the presence of crystalline tacrolimus in the active agent-containing layers.

[0168] On the other hand, as is evident from Figures 2-4, peaks characteristic of tacrolimus that are present in the diffraction pattern of pure crystalline tacrolimus are absent in the diffraction patterns of active agent-containing layers E, J, and K as well as the corresponding placebo layers, confirming that these layers do not contain crystalline tacrolimus, and that tacrolimus is present only in amorphous form.

[0169] In addition, in contrast to layers E and J, which were measured immediately after manufacture, layer K as well as placebo layer K were stored for 2.5 months under controlled conditions of 25° C. and 60% relative humidity, indicating that the active agent-containing layers are also stable against recrystallization upon storage.

[0170] Example 4: In vitro release experiments The released amount of tacrolimus and the corresponding release rate were determined for transmucosal therapeutic systems E, H, and I. The release rate determination was performed using a standard Franz cell (volume 24 mL). The donor and acceptor compartments were separated using a membrane (Spectra Por® 7 dialysis membrane 25 kD). The 0.525 cm 2 A die cut with an area of ​​100 mm was punched from each of the transmucosal therapeutic systems and applied to the membrane of the donor compartment filled with 600 μl acetate buffer pH 4.0. The acceptor compartment was filled with 24 mL acetate buffer pH 4.0. The experiment was carried out for 180 min. During the experiment, the temperature of the Franz cell was kept constant at 32° C.±0.5° C. using a water bath and the acceptor medium was continuously stirred at 350 rpm. Complete exchange of the acceptor medium was carried out at 15, 30, 60, 90, 120, 150, and 180 min. The released amount of tacrolimus in the exchanged acceptor medium was measured by HPLC and the corresponding release rate was calculated. No solubilizing agent such as SDS was used to prevent the occurrence of false positive results. The results are shown in Tables 6 and 7 and Figures 6 and 7, respectively.

[0171] [Table 6]

[0172] [Table 7]

[0173] In the transmucosal therapeutic system of Reference Example 2I, in which tacrolimus exists in crystalline (and dispersed) form, tacrolimus could not be detected in the acceptor medium at any time point, which was assumed to be due to the low water solubility of tacrolimus, which resulted in tacrolimus not being released from the transmucosal therapeutic system of Reference Example 2I (due to the absence of a solubilizer) and tacrolimus not being able to permeate the membrane.

[0174] On the other hand, as is clear from the above Tables 5 and 6, and Figures 5 and 6, it is shown that tacrolimus is actually present in the acceptor medium of the transmucosal therapeutic systems of Examples 2E and 2H, and it is confirmed that tacrolimus was able to pass through the membrane. These results support that the transmucosal therapeutic system of the present invention can transmucosally release tacrolimus under in vivo conditions.

Claims

1. 1. A transmucosal therapeutic system for transmucosal administration of an active agent, comprising: A mucoadhesive layer structure comprising: A) a backing layer comprising a first film-forming polymer; B) an adhesive layer, Laminating adhesives, and the adhesive layer comprising a first plasticizer; C) an active agent-containing layer, Macrolide immunosuppressants, and and said active agent-containing layer comprising a second film-forming polymer; the first film-forming polymer is ethyl cellulose; the macrolide immunosuppressant is selected from the group consisting of tacrolimus, sirolimus, everolimus, and pimecrolimus; The transmucosal therapeutic system, wherein the second film-forming polymer is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof.

2. The transmucosal therapeutic system according to claim 1, wherein the macrolide immunosuppressant is tacrolimus, preferably in an amorphous form.

3. The transmucosal therapeutic system comprises a therapeutically effective amount of tacrolimus, The active agent-containing layer preferably has a surface area of ​​at least 0.5 mg / cm ２ of tacrolimus, more preferably at least 0.8 mg / cm ２ of tacrolimus, and most preferably at least 2.0 mg / cm ２ and / or 6.0 mg / cm ２ Less than 4.0 mg / cm ２ or less than 2.5 mg / cm ２ The transmucosal therapeutic system according to claim 1 or 2, comprising less than about 100 mg of tacrolimus.

4. said second film-forming polymer comprising: Ethyl cellulose, and / or a viscosity of 30 to 60 mPa·s, more preferably 40 to 52 mPa·s, measured as a 5% solution in 80:20 toluene:ethanol by weight at 25° C. according to ASTM D914; and / or 48.0 to 49.5% ethoxyl substitution as measured in accordance with ASTM D914; and / or having a moisture content of 3% by weight or less; said ethylcellulose preferably in an amount of 20-40% by weight of said active agent-containing layer and more preferably 25-35% by weight; Hydroxypropyl cellulose, and / or a molecular weight of 350,000 to 400,000, in particular about 370,000 (as measured by GPC size exclusion chromatography); and / or having a Brookfield viscosity of 150 to 400 mPa·s when measured as a 2% aqueous solution; said hydroxypropyl cellulose preferably in an amount of 5-20% by weight of said active agent-containing layer and more preferably 7-15% by weight; Hydroxypropyl cellulose, and / or a molecular weight of 75,000 to 85,000, in particular about 80,000 (as measured by GPC size exclusion chromatography); and / or having a Brookfield viscosity of 300 to 600 mPa·s when measured as a 10% aqueous solution; The transmucosal therapeutic system according to any one of claims 1 to 3, preferably in a mixture with said hydroxypropyl cellulose in an amount of 25 to 50% by weight and more preferably 30 to 45% by weight of said active agent-containing layer.

5. the first film-forming polymer is ethyl cellulose; and / or a viscosity of 30 to 60 mPa·s, more preferably 40 to 52 mPa·s, measured as a 5% solution in 80:20 toluene:ethanol by weight at 25° C. according to ASTM D914; and / or 48.0-49.5% ethoxyl substitution; and / or having a moisture content of 3% by weight or less; The transmucosal therapeutic system according to any one of claims 1 to 4, wherein the ethylcellulose is preferably in an amount of 55 to 95% by weight of the backing layer, and even more preferably in an amount of about 60% by weight.

6. The backing layer is water insoluble, preferably a second plasticizer, preferably in an amount of 5-20% by weight of said backing layer and even more preferably in an amount of about 10% by weight, said second plasticizer being preferably selected from the group consisting of mono-, di-, oligo- and polysaccharides and derivatives thereof, polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, propylene glycol, glycerin, medium chain triglycerides and any mixtures thereof, more preferably triacetin; and / or The transmucosal therapeutic system according to any one of claims 1 to 5, further comprising a laminate adhesive aid, preferably in an amount of up to 60% by weight of the backing layer, or more preferably 10 to 35% by weight, preferably selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, and any mixture thereof, more preferably a mixture consisting essentially of polyvinylpyrrolidone and polyvinyl acetate or vinylpyrrolidone-vinyl acetate copolymer, and most preferably the same as the laminate adhesive.

7. The transmucosal therapeutic system according to any one of claims 1 to 6, wherein the adhesive layer is adjacent on one side to the active agent-containing layer and on the other side to the backing layer.

8. The transmucosal therapeutic system according to any one of claims 1 to 7, wherein the first plasticizer is selected from the group consisting of monosaccharides, disaccharides, oligosaccharides, and polysaccharides, and derivatives thereof, polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, propylene glycol, glycerin, medium chain triglycerides, and any mixture thereof, preferably glycerin or triacetin, and more preferably glycerin.

9. The laminating adhesive is selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, and any mixture thereof, preferably a mixture consisting essentially of polyvinylpyrrolidone and polyvinyl acetate or vinylpyrrolidone-vinyl acetate copolymer, more preferably The mixture is 10-30% by weight, preferably 15-25% by weight, and more preferably about 19% by weight of polyvinylpyrrolidone; 70-90% by weight, preferably 75-85% by weight, and more preferably about 80% by weight of polyvinyl acetate; and / or comprising about 1% by weight of one or more stabilizers, preferably about 0.8% by weight of sodium lauryl sulfate and about 0.2% by weight of silica as stabilizers; the mixture has a K value of 60 to 68 and / or a glass transition temperature Tg of about 35° C.; and / or the polyvinylpyrrolidone is selected from soluble polyvinylpyrrolidones, preferably having a K value of 28 to 32 and / or a molecular weight of 44,000 to 54,000; and / or the polyvinyl acetate has a molecular weight of 400,000 to 500,000 and preferably about 450,000; and / or The transmucosal therapeutic system according to any one of claims 1 to 8, wherein the vinylpyrrolidone-vinyl acetate copolymer has a molar ratio of the monomers vinylpyrrolidone and vinyl acetate of about 6:4, a K value of 25 to 31, and / or a molecular weight of 45,000 to 70,000.

10. The adhesive layer further comprises a film-forming polymer, preferably the same as the first film-forming polymer and / or the second film-forming polymer, more preferably The adhesive layer is 50-90% by weight, preferably 60-85% by weight, of said laminating adhesive; 10-45% by weight, preferably about 15% by weight, of said first plasticizer; The transmucosal therapeutic system according to any one of claims 1 to 9, comprising 0 to 10% by weight, preferably about 5% by weight each, of the first film-forming polymer and / or the second film-forming polymer.

11. The active agent-containing layer is a mucosal contact layer and preferably further comprises one or more further excipients selected from the group consisting of further film forming polymers, further plasticizers, colorants, antioxidants, taste masking agents, and stabilizers, more preferably at least one further film-forming polymer, preferably in an amount of 1-6% by weight of said active agent-containing layer each, and even more preferably in an amount of 2-5% by weight, said further film-forming polymer being selected from the group consisting of mixed calcium / sodium salts of methyl vinyl ether and maleic anhydride copolymers, and vinylpyrrolidone-vinyl acetate copolymers and any mixtures thereof; an additional plasticizer, preferably in an amount of 2-10% by weight of said active agent-containing layer, and even more preferably in an amount of 3-6% by weight, said additional plasticizer being selected from the group consisting of mono-, di-, oligo- and polysaccharides and derivatives thereof, polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, propylene glycol, glycerin, medium chain triglycerides and any mixtures thereof, preferably glycerin; and / or Preferably a colouring agent in an amount of 1-6% by weight of said active agent containing layer, and even more preferably in an amount of 2-5% by weight, said colouring agent being selected from the group consisting of titanium dioxide, brilliant blue FCF, indigo carmine, fast green FCF, erythrosine, allura red AC, tartrazine and sunset yellow FCF, curcumin, riboflavin, riboflavin-5'-phosphate, quinoline yellow, orange yellow S, cochineal, carminic acid, azorubin, carmoisine, amaranth, ponceau 4R, cochineal red A, patent blue V, indigotine, chlorophyll, chlorophyllin, chlorophyll and chlorophyllin. The transmucosal therapeutic system according to any one of claims 1 to 10, comprising the colorant selected from the group consisting of copper complex, Green S, plain caramel, caustic sulfite caramel, ammonia caramel, sulfite ammonia caramel, brilliant black BN, black PN, vegetable carbon, brown HT, carotene, annatto, bixin, norbixin, paprika extract, capsanthan, capsorubin, lycopene, beta-apo-8'-carotenal, lutein, canthaxanthin, beetroot red, betanin, anthocyanin, calcium carbonate, iron oxide and iron hydroxide, aluminum, silver, gold, and lysolubin BK.

12. The backing layer has a thickness of at least 20 g / m ２ , preferably at least 40 g / m ２ , and more preferably about 50 g / m ２ or 100 g / m ２ less than 70 g / m ２ and / or The adhesive layer has a thickness of at least 30 g / m ２ , preferably at least 50 g / m ２ , and more preferably about 60 g / m ２ or 100 g / m ２ less than 80 g / m ２ and / or The active agent-containing layer has a thickness of at least 100 g / m ２ , preferably at least 130 g / m ２ , and more preferably about 150 g / m ２ or 250 g / m ２ Less than or equal to 200 g / m ２ The transmucosal therapeutic system according to any one of claims 1 to 11, having an area weight of less than 100 g / m2.

13. A process for manufacturing a transmucosal therapeutic system, comprising: (a) At least a first film-forming polymer; and Combining the solvents, Obtaining a backing layer coating composition; coating the backing layer coating composition onto a release liner; drying the coated backing layer coating composition to form a backing layer; (b) At least Activator, a second film-forming polymer, and Combining the solvents, Obtaining an active agent layer coating composition; coating the active agent layer coating composition onto a release liner; drying the coated active agent layer coating composition to form a single layer active agent-containing layer; and optionally repeating the coating step by coating the active agent layer coating composition onto the coated active agent layer coating composition before drying or onto the dried active agent-containing layer to obtain a dual layer active agent-containing layer; (c) At least Laminating adhesives, and A first plasticizer, and Combining the solvents, Obtaining an adhesion layer coating composition; coating the adhesive layer coating composition onto the backing layer obtained in step (a); drying the coated adhesive layer coating composition to form a two-layer laminate consisting of an adhesive layer and a backing layer on the release liner; (d) laminating the bilayer laminate obtained in step (c) with the single layer or bilayer active agent-containing layer obtained in step (b), the first film-forming polymer is ethyl cellulose; the macrolide immunosuppressant is selected from the group consisting of tacrolimus, sirolimus, everolimus, and pimecrolimus; The process wherein the second film-forming polymer is selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof.

14. The transmucosal therapeutic system according to any one of claims 1 to 12, for use in a method of treatment, preferably for the treatment and / or prevention of organ rejection after organ transplantation in a human patient, more preferably for said prevention of organ rejection after allogeneic liver, kidney or heart transplantation in a human patient.

15. 1. An active agent-containing layer for a transmucosal therapeutic system, comprising: i) tacrolimus in amorphous form; and ii) a film forming polymer selected from the group consisting of ethyl cellulose, hydroxypropyl cellulose, and any mixture thereof.

16. 16. The active agent-containing layer of claim 15, wherein the X-ray diffraction pattern of the active agent-containing layer is characterized by the absence of crystalline tacrolimus reflections, preferably does not include reflections at 2-theta angles of 6.45°, 8.55°, 10.35°, 11.25°, 11.75°, 13.75°, 14.15°, and 15.30°±0.2° degrees.

17. A mucoadhesive layer structure for a transmucosal therapeutic system, comprising: A) an active agent-containing layer according to claim 16; B) an adhesive layer, Laminating adhesives, and the adhesive layer comprising a plasticizer.

18. 1. A transmucosal therapeutic system for transmucosal administration of an active agent, comprising: A mucoadhesive layer structure comprising: A) a backing layer, 55-95% and preferably about 60% by weight ethylcellulose having a viscosity of 30-60 mPa·s, more preferably 40-52 mPa·s, as measured as a 5% solution at 25° C. in 80:20 toluene:ethanol by weight according to ASTM D914, and an ethoxyl substitution of 48.0-49.5% as measured according to ASTM D914; 5-20% by weight and preferably about 10% by weight of triacetin, and 10 to 35% by weight and preferably about 30% by weight, about 19% by weight of polyvinylpyrrolidone, about 80% by weight polyvinyl acetate, About 0.8% by weight of sodium lauryl sulfate, and the backing layer comprising a mixture of about 0.2% by weight silica; B) an adhesive layer adjacent on one side to the active agent-containing layer and adjacent on its other side to the backing layer, 70-90% by weight and preferably about 80% by weight, about 19% by weight of polyvinylpyrrolidone, about 80% by weight polyvinyl acetate, About 0.8% by weight of sodium lauryl sulfate, and A mixture consisting of about 0.2% by weight silica; 10-30% by weight, preferably about 15% glycerin, and the adhesive layer comprising 0-10% by weight, preferably about 5% by weight, ethylcellulose having a viscosity of 30-60 mPa·s, more preferably 40-52 mPa·s, as measured as a 5% solution at 25° C. in 80:20 toluene:ethanol by weight according to ASTM D914, and an ethoxyl substitution of 48.0-49.5% as measured according to ASTM D914; C) an active agent-containing layer, At least 0.8 mg / cm of amorphous form ２ Tacrolimus, ethylcellulose in an amount of 25-35% by weight of said active agent-containing layer, having a viscosity of 30-60 mPa·s, more preferably 40-52 mPa·s, as measured as a 5% solution at 25° C. in 80:20 toluene:ethanol by weight according to ASTM D914, and an ethoxyl substitution of 48.0-49.5% as measured according to ASTM D914; Hydroxypropylcellulose in an amount of 7 to 15% by weight of said active agent-containing layer, having a molecular weight of about 370,000 (as measured by GPC size exclusion chromatography) and a Brookfield viscosity of 150 to 400 mPa·s when measured as a 2% aqueous solution; Hydroxypropylcellulose in an amount of 30-45% by weight of said active agent-containing layer, having a molecular weight of about 80,000 (as measured by GPC size exclusion chromatography) and a Brookfield viscosity of 300-600 mPa·s when measured as a 10% aqueous solution; a mixed calcium / sodium salt of methyl vinyl ether and maleic anhydride copolymer as a further film forming polymer in an amount of 2-5% by weight of said active agent containing layer; Optionally, a vinylpyrrolidone-vinyl acetate copolymer in an amount of 1-4% by weight of said active agent-containing layer; and the active agent-containing layer comprising glycerin in an amount of 3-6% by weight of the active agent-containing layer;

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