Film delivery system with perforations

Abstract

The present invention relates to a film delivery system comprising a mucoadhesive layer, wherein the mucoadhesive layer comprises a film-forming agent and is provided with perforations.

Description

Technical Field

[0001] The present invention relates to a film delivery system comprising a mucoadhesive layer provided with perforations, and a method for manufacturing the same, a method for treating the same and a use thereof. Background Art

[0002] Drug delivery by conventional oral dosage forms (such as tablets, pills, caplets and capsules) is a standard route of drug administration. However, tablets and the like may be difficult to swallow for the elderly and infants. In addition, oral administration is associated with pre-systemic elimination of the active agent, which may include gastrointestinal (GI) degradation, metabolism or first-pass clearance via the liver, and often has limitations such as low systemic bioavailability, food effects, slow onset and / or formation of inactive and sometimes toxic metabolites.

[0003] In view of such limitations, dosage forms that can be in the form of thin films (such as transmucosal therapeutic systems) have become increasingly important in the past few years. Oral mucosal drug delivery has the advantages of being simple to use, convenient and bypassing the GI tract for oral administration because the drug is directly absorbed into the systemic circulation via the mucosal tissue. When compared with oral mucosal dosage forms (such as orally dispersible tablets), the advantage of the oral mucosal film delivery system is that it can cause a reduction in discomfort to the patient because they can be applied to the mucosa, and then, ideally, the patient will no longer or almost not notice them.

[0004] Transmucosal therapeutic systems or transmucosal delivery systems in the form of thin films consist of one or more thin layers that are applied to, for example, the mucous membranes of the oral cavity and adhere to the mucous membranes of the oral cavity to deliver the drug over a period of time. In such transmucosal therapeutic systems, the active substance is contained in a dissolvable layer, and delivery of the active substance is intended to be achieved at least in part through the mucous membrane to which the film adheres.

[0005] Dosage forms in the form of thin films applied to the oral cavity (including transmucosal therapeutic systems) are sometimes also referred to as "oral thin films" or OTFs, however, OTFs are not necessarily intended to adhere to the mucosa. Such OTFs may also be intended to disintegrate rapidly in saliva (e.g., so-called "flash wafers") and thus offer the advantage of, for example, assisting patients in taking the medication.

[0006] In summary, as outlined above, the dosage form in the form of a film, i.e., a film delivery system, provides a variety of alternative drug delivery forms and administration routes, which may have advantages in terms of convenience, ease, and comfort for the patient, and / or by providing improved pharmacokinetic behavior (such as higher bioavailability and faster onset). In more detail, due to the thin and flexible nature of the film, for example, compared to tablets, the film has a smaller sense of protrusion and is more easily accepted by patients. When formulated into, for example, (through) mucosal administration forms, the film delivery system can deliver the active substance directly to the systemic circulation, avoiding the gastrointestinal (GI) tract, which can improve drug efficacy, and also eliminate the side effects caused by first-pass metabolism, and therefore present a non-invasive administration form, which is a promising alternative dosage form for conventional oral dosage forms.

[0007] However, film delivery system is a relatively new form of drug delivery, which means that the knowledge of relevant formulation technology is limited. Due to the need to consider many aspects and solve many problems, it is challenging to prepare a suitable film delivery system (for example, for transmucosal delivery). The main requirement of this type of film delivery system is a combination of good adhesion and active substance permeability with suitable disintegration behavior and time. Since the application of thin films should not cause patient discomfort, the sense of touch of the film needs to be considered as basic physical quality.

[0008] The design of thin films requires special consideration of the size and thickness of the film and the ratio of drug to polymer, because the film needs to be thin enough that the patient cannot detect it. This requirement limits the thickness of the film and therefore limits the drug loading capacity of the film. Higher doses will increase the thickness of the film, which will lead to an increase in dissolution time and / or an increase in foreign body sensation, making the delivery system less convenient for the patient. In addition, film-forming materials that form relatively hard films may be desirable in terms of solubility characteristics and / or drug release behavior, but because they will more easily cause foreign body sensation, their use is limited. Other film-forming agents may be desirable in providing the desired active agent release behavior, but may dissolve or disintegrate too slowly.

[0009] Microperforated or perforated thin films have been proposed in the past. For example, there are reports that perforated films can be used for dental care, where the perforations are intended, for example, to enable the film to be positioned correctly in the oral cavity.

[0010] However, to date, there appears to be little attention paid to improving the tactile feel of thin film delivery systems, and in particular by incorporating perforations. An improved tactile feel could make the application of the film more convenient for the patient and could even make thick and / or inflexible films acceptable for application, thereby allowing for higher drug loadings and a wider selection of materials for use in such films. On the other hand, making the film dissolve faster without changing the polymer material would also offer the possibility of using materials (such as polymers) that would otherwise dissolve too slowly to be useful as a matrix for a drug-containing film.

[0011] In summary, thin film delivery systems are a promising new drug delivery system that addresses the shortcomings of conventional oral dosage forms. However, considering patient compliance and dissolution behavior, the thin film delivery system faces certain limitations in terms of the materials that can be used and the achievable size, thickness, and drug loading.

[0012] Therefore, there is a need in the art for improved thin film delivery systems that combine controlled dissolution behavior with high drug loading capacity while having improved tactile feel. Summary of the Invention

[0013] It is an object of the present invention to provide a film delivery system that overcomes the above mentioned disadvantages.

[0014] It is therefore an object of the present invention to provide a thin film delivery system that provides an improved tactile sensation, such as a reduced foreign body sensation and a less obtrusive, smoother and / or more comfortable feel at the application site.

[0015] It is an object of the present invention to provide a dissolvable and / or disintegrable film delivery system with controlled dissolution / disintegration behavior.

[0016] Therefore, it was also an object of the present invention to provide such a film delivery system having both improved tactile sensation and controlled dissolution / disintegration behavior.

[0017] It is also an object of the present invention to provide a film delivery system that has appropriate tactile feel and / or dissolution / disintegration kinetics despite the film's greater thickness and / or stiffness.

[0018] It is also an object of the present invention to provide a thin film delivery system for active ingredient administration, and in particular for transmucosal administration of active ingredients, which despite a high drug load has appropriate tactile and / or dissolution / disintegration kinetics, e.g. sufficient to achieve an effective dose, and in particular a therapeutically effective dose.

[0019] Another object of the present invention is to provide a thin film delivery system that provides adequate adhesion to the mucosa, eg, initially, but also over time.

[0020] These and other objects are achieved by the present invention, which, according to one aspect, relates to a film delivery system comprising a mucoadhesive layer, wherein the mucoadhesive layer comprises a film forming agent and has a thickness of 1 cm 2 There are 5 to 100 perforations.

[0021] According to certain embodiments of the present invention, the thin film delivery system according to the present invention is used in a method of treatment.

[0022] According to other embodiments, the present invention relates to a method of treatment, wherein the thin film delivery system according to the present invention is administered to a human patient.

[0023] According to yet a further aspect, the present invention relates to the use of the thin film delivery system of the present invention for the manufacture of a medicament for the treatment of a human patient.

[0024] According to yet another aspect, the present invention relates to a method for manufacturing a thin film delivery system comprising a mucoadhesive layer, the method comprising the steps of:

[0025] i) preparing a mucoadhesive layer; and

[0026] ii) By using a perforating tool, per cm 2 There are 5 to 100 perforations.

[0027] According to certain aspects, the present invention also relates to a thin film delivery system obtainable by such a manufacturing method.

[0028] According to another aspect, the present invention also relates to a film delivery system comprising a mucoadhesive layer, wherein

[0029] The mucoadhesive layer contains a soluble film-forming agent and contains 2 There are at least 10 and less than 20 perforations,

[0030] The surface area per unit area of ​​the perforated mucoadhesive layer is at least 10% and 30% or less,

[0031] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 4 cm / cm 2 and 15 cm / cm 2 or smaller,

[0032] The perforations are all circular and evenly distributed, and

[0033] The area weight of the mucoadhesive layer is at least 200 g / m² and 400 g / m² or less.

[0034] According to yet another aspect, the present invention also relates to a film delivery system comprising a mucoadhesive layer, wherein

[0035] The mucoadhesive layer contains a soluble film-forming agent and contains 2 There are at least 50 to less than 60 perforations,

[0036] The surface area per unit area of ​​the perforated mucoadhesive layer is at least 5% and 30% or less,

[0037] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 8 cm / cm 2 and 15 cm / cm 2 or smaller,

[0038] The perforations are all circular and evenly distributed, and

[0039] The area weight of the mucoadhesive layer is at least 200 g / m² and 400 g / m² or less.

[0040] Within the meaning of the present invention, the term "thin film delivery system", sometimes also referred to as "thin film dosage form" or "thin film therapeutic system", refers to a system consisting of one or more layers for administering an active ingredient. The thin film delivery system comprises a mucoadhesive layer and is applied to a mucosa, such as the oral mucosa (e.g., buccal mucosa, sublingual mucosa, gingival mucosa, palatal mucosa), vaginal mucosa, rectal mucosa, nasal mucosa or ocular mucosa. It refers to the entire individual dosing unit applied to the patient's mucosa and particularly comprises an effective amount, and in particular a therapeutically effective amount, of the active ingredient in one of the mucoadhesive layer or other layers. The mucoadhesive layer may be located on a release liner (a removable protective layer), and thus the thin film delivery system may further comprise a release liner.

[0041] Within the meaning of the present invention, the term "thin film delivery system" includes dosage forms that are intended to provide active delivery by the oral route or primarily by the oral route, in which case the film can serve as a convenient oral administration form, allowing easy swallowing and also without the need for water or any beverage to assist in taking the drug, so that the film can be easily taken "anytime, anywhere". On the other hand, "thin film delivery system" refers specifically to a system that is intended for transmucosal administration, in particular providing passive transmucosal delivery, excluding active transport in methods including microporation. In the case where the film is applied to the patient's mouth, enteral delivery by swallowing the active ingredient is also possible and is not necessarily undesirable in a thin film delivery system. With a thin film delivery system, the active ingredient can be administered not only transmucosally to the systemic circulation, but can also be limited only locally (to the mucosa at the site of administration and / or tissues near the site of administration).

[0042] Within the meaning of the present invention, the term "transmucosal" refers to a route of delivery of an active ingredient through mucosal tissue. Thus, the term "transmucosal therapeutic system" or "transmucosal delivery system" refers to a system intended to administer an active ingredient to the systemic circulation primarily via transmucosal delivery (i.e., through the mucosa, by application to the mucosa, and in particular the oral mucosa). It refers to the entire individual dosage unit applied to the patient's mucosa and includes an effective amount, and in particular a therapeutically effective amount, of the active ingredient in one of the mucoadhesive or other layers, as generally described above for thin film delivery systems.

[0043] While transmucosal therapeutic systems can be considered a type of "oral thin film," within the meaning of the present invention, "oral thin film" also includes film delivery systems that focus less on mucosal adhesion and more on rapid dissolution / disintegration in saliva (sometimes referred to as "flash-release films"). The intended delivery routes for such rapidly disintegrating orally thin or flash-release films can be transmucosal as well as oral / enteral, and the patient can be instructed, for example, to place the film under the tongue or cheek and not swallow until dissolved, or to place the film on the tongue and swallow, to facilitate one or the other delivery route.

[0044] Within the meaning of the present invention, the term "mucoadhesive layer" refers to one of the layers that constitute a thin film delivery system, which contains a film-forming agent that provides the necessary adhesion and stability to the film and has at least one uncovered side, intended for application to the patient's mucosa. In other words, the mucoadhesive layer in the sense of the present invention is a mucosal contact layer. The release area is provided by the area of ​​the layer containing the active ingredient. The mucoadhesive layer does not need to be the layer containing the active ingredient at the same time, but can be used in addition to enhance adhesion. The size of the mucoadhesive layer and the layer containing the active ingredient are generally coextensive (i.e., they have the same size / dimensions and form) and correspond to the release area. In its simplest form, a thin film delivery system consists of a mucoadhesive layer containing the active ingredient and does not include any other layers. The mucoadhesive layer is the final solidified layer, obtained, for example, after applying and drying a coating composition containing a solvent by a film casting process, or after extruding a film-forming agent or a mixture containing a film-forming agent.

[0045] Terms such as "dissolution," "dissolvable," and "dissolve" with respect to the thin film delivery system, any layer of the thin film delivery system (such as a mucoadhesive layer), and with respect to the film-forming agent when cast into a thin film should be understood very broadly and not in the strict scientific sense of chemically dissolving a molecule in a solvent. Any transformation of the solid to liquid state of the layer involved, such as dispersion, formation of a suspension, gelation of the film, and disintegration into smaller gel portions, should be considered "dissolved" within the meaning of the present invention, as long as the "dissolved" material is able to move freely in the liquid (e.g., saliva). In preferred embodiments, the meaning is limited to the usual chemical sense of dissolving a molecule in a solvent. It should be noted that the term "dissolve" with respect to the substance itself (such as any excipient) will continue to be used in the usual chemical sense of dissolving a molecule in a solvent. For example, the film-forming agent itself may be present in the coating composition during the manufacture of the thin film delivery system in a dissolved form in the usual chemical sense (e.g., not dispersed, in the form of small gel portions, etc.), but when the film-forming agent is cast into a film, "dissolving" such a film also includes the gelation and disintegration of the film into smaller gel portions, that is, a "soluble" film-forming layer must also be understood in a very broad sense.

[0046] Mucoadhesive layers can also be made by laminating two or more such cured layers (e.g., dried layers) of the same composition to provide the desired areal weight. As indicated above, mucoadhesive layers are intended to be applied to mucous membranes, where they should provide sufficient adhesion. Within the meaning of the present invention, the term "mucoadhesive" refers to a material that adheres specifically to and comes into contact with the mucous membranes, but which is preferably non-sticky and can be touched (e.g., with a finger) and manipulated, e.g., for application to the oral cavity, without inadvertently adhering to the skin of the finger in a dry state. When in contact with the mucous membrane, the mucoadhesive layer is "self-adhesive," i.e., provides adhesion to the mucous membrane such that no further aid is typically required for fixation. The adhesive strength is preferably strong enough so that typical movements within the oral cavity are insufficient to dislodge the mucoadhesive layer adhered to the mucous membrane.

[0047] As used herein, the expression "active ingredient" refers to any substance of interest delivered by a thin film delivery system to provide a beneficial or desired effect on the physical condition of a subject systemically or locally at the delivery site. Active ingredients particularly include biologically or pharmacologically active compounds, which may also be referred to as active substances, drug substances, drugs, active ingredients, active pharmaceutical ingredients (API), etc. Within the meaning of the present invention, the term "effective amount" or "therapeutically effective amount" refers to the amount of the active ingredient in a thin film delivery system that, if administered to a patient via a thin film delivery system, is sufficient to provide a desired (therapeutic) effect (e.g., as determined by a blood level in a similar range (e.g., as measured as about 10% to about 1000% of AUC) when compared to a blood level obtained after a single administration of an approved drug product of the same active ingredient, or an amount of an active substance similar to the amount of the active ingredient contained in other locally acting approved drug products of the same active ingredient (e.g., about 10% to about 1000%).

[0048] Within the meaning of the present invention, the term "administering" refers to applying a dosage form (i.e., a thin film delivery system) to the oral mucosa (e.g., buccal mucosa, sublingual mucosa, gingival mucosa, palatal mucosa), vaginal mucosa, rectal mucosa, nasal mucosa or ocular mucosa, and in particular the oral mucosa of a patient, and then maintaining the dosage form on the mucosa for a specific administration duration period, or until the layer containing the active ingredient dissolves, erodes or substantially disintegrates.

[0049] Within the meaning of the present invention, the term "areal weight" refers to the dry weight of a specific layer (the layer containing the active ingredient) expressed in g / m 2 Due to manufacturing variability, the tolerance for areal weight values ​​is ± 10%, preferably ± 5%, of the nominal value.

[0050] The unit "%" may refer to a percentage given as weight / volume (w / v), volume / volume (v / v) or weight %, and if not otherwise specified, "%" preferably refers to weight %.

[0051] Within the meaning of the present invention, the term "polymer" refers to any substance or material comprising so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers comprising one type of monomer and copolymers comprising two or more types of monomers. The polymer may have any architecture such as linear polymers, star polymers, comb polymers, brush polymers and, in the case of copolymers, any monomer arrangement, such as alternating copolymers, statistical copolymers, block copolymers or grafted polymers. The minimum molecular weight varies depending on the polymer type and is known to the skilled person. The polymer may, for example, have a molecular weight higher than 2,000, preferably higher than 5,000 and more preferably higher than 10,000 daltons. Correspondingly, compounds having a molecular weight lower than 2,000, preferably lower than 5,000 or more preferably lower than 10,000 daltons are generally referred to as oligomers.

[0052] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature in a laboratory room where the experiments are performed and is typically within the range of 15 to 35°C, preferably about 18 to 25°C.

[0053] Within the meaning of the present invention, the term "patient" refers to a subject who has clinical manifestations indicating a specific symptom or symptoms indicating a need for treatment, who is receiving preventive or disease-preventive treatment for a condition, or who has been diagnosed with a condition to be treated.

[0054] Within the meaning of the present invention, the term "coating composition" refers to a composition comprising all components of one of the layers, such as the mucoadhesive layer, in a solvent, which can be applied after drying to form the corresponding layer, such as the mucoadhesive layer.

[0055] Within the meaning of the present invention, the term "solvent" refers to any liquid substance, which is preferably a volatile organic liquid, such as methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, hexane, n-heptane, heptane, toluene and mixtures thereof.

[0056] Within the meaning of the present invention, unless otherwise indicated, the term "about" refers to an amount of ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount of ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount of ±2% of the disclosed amount.

[0057] Within the meaning of the present invention, the terms "substantially" or "essentially" are used to refer to the majority of the corresponding object or component involved, for example, a composition "consisting essentially of a certain component" contains a large amount of this component, such as at least 95% by weight, preferably at least 98% by weight or even at least 99% by weight.

[0058] Within the meaning of the present invention, the term "surface area" refers to the maximum area of ​​a perforation when viewed from a top view, ie for a tapered perforation the surface area should be calculated based on the surface shape of the piercing side.

[0059] Within the meaning of the present invention, "triangular," "rectangular," "staggered," or "diagonal" spacing refers to the shape formed when considering the closest spacing of perforations in an arrangement where the perforations are uniformly distributed (see Figures 10a to 10d ).

[0060] "Margin" within the meaning of the present invention refers to the non-perforated circumferential edge of the mucoadhesive layer. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 is a schematic diagram of a film delivery system of the present invention as viewed from above, wherein the mucoadhesive layer is provided with circular perforations in an 8*8 checkerboard grid pattern (ie, arranged at rectangular intervals) and provided with edges (pattern A).

[0062] Figure 2 A thin film delivery system consisting of a mucoadhesive layer perforated according to perforation pattern A is depicted.

[0063] Figure 3 is a schematic diagram of a film delivery system of the present invention from a top view, wherein the mucoadhesive layer is provided with circular perforations in a 10*10 checkerboard grid pattern (ie, arranged at rectangular intervals) and provided with edges (pattern B).

[0064] Figure 4 A thin film delivery system consisting of a mucoadhesive layer perforated according to perforation pattern B is depicted.

[0065] Figure 5 is a schematic diagram of a film delivery system of the present invention as viewed from above, wherein the mucoadhesive layer is provided with circular perforations in a 19*19 checkerboard grid pattern (ie, arranged at rectangular intervals) and provided with an edge (pattern C).

[0066] Figure 6 A thin film delivery system consisting of a mucoadhesive layer perforated according to a perforation pattern C is depicted.

[0067] Figure 7a A single through-hole in the sense of the invention, which is a through-hole in circular form and cylindrical, is depicted in a bird's-eye view.

[0068] Figure 7b A single perforation in the sense of the invention, which is a complete cylindrical slit, is depicted in a bird's-eye view.

[0069] Figure 7cA single through-hole in the sense of the present invention, which is a complete cylindrical slit or cylindrical through-hole, is depicted from a side view.

[0070] Figure 7d A single perforation in the sense of the present invention is depicted from a side view, which is a complete cylindrical slit or cylindrical through-hole showing a slightly widened opening on the piercing side and a worn edge on the opposite side with striations formed due to the perforating tool pushing out the material when piercing the layer.

[0071] Figure 8a A single perforation in the sense of the invention, which is a through-hole in the form of a circle and a cone, is depicted in a bird's-eye view.

[0072] Figure 8b A single perforation in the sense of the invention, which is a through-hole in the form of a circle and a cone, is depicted from a top view, also showing a larger circular shape which forms the basis for the calculation of the surface area.

[0073] Figure 8c A single through-hole in the sense of the invention, which is a complete conical slit or conical through-hole, is depicted from a side view.

[0074] Figure 9a A single perforation in the sense of the invention is depicted in a bird's eye view, said perforation being a cylindrical pocket hole in the form of a circle.

[0075] Figure 9b A single perforation in the sense of the invention is depicted from a side view, said perforation being a cylindrical pocket hole in the form of a circle.

[0076] Figure 9c A single perforation in the sense of the invention is depicted in a bird's eye view, said perforation being a conical incomplete slit.

[0077] Figure 9d A single perforation in the sense of the present invention is depicted from a side view, said perforation being a conical incomplete slit.

[0078] Figure 10a The top view shows the evenly spaced perforations with triangular spacing.

[0079] Figure 10b The top view shows the evenly spaced perforations with rectangular spacing.

[0080] Figure 10c The top view shows the evenly spaced perforations at staggered intervals.

[0081] Figure 10d The top view shows the evenly spaced diagonal perforations.

[0082] These drawings are for illustration purposes only and are not intended to limit the scope of the claimed invention and are not drawn to scale. DETAILED DESCRIPTION

[0083] Film delivery system

[0084] The present invention relates to a thin film delivery system comprising a mucoadhesive layer.

[0085] Thin film delivery systems are intended for the administration of active ingredients useful in the treatment and / or prevention of diseases and medical conditions and are applied to the patient's mucosal membranes. The mucoadhesive layer contains a film-forming agent and is provided with 5 to 100 perforations per cm².

[0086] Thus, according to the present invention, a thin film delivery system comprises a mucoadhesive layer comprising a film-forming agent and is provided with 5 to 100 perforations per cm².

[0087] The film delivery system of the present invention is composed of one or more thin layers, and the active ingredient can be contained in the mucoadhesive layer and / or in one or more other layers, which then form a separate layer containing the active ingredient. In other words, the mucoadhesive layer does not need to be a layer containing the active ingredient at the same time, but can be used in addition to enhance adhesion. On the other hand, if the mucoadhesive layer is the only layer containing the active ingredient, the film delivery system is simpler and easier to manufacture, and in its simplest form, the film delivery system consists of the mucoadhesive layer containing the active ingredient and does not include any other layers. In certain embodiments, the film delivery system may include other layers, such as a backing layer, which prevents the active ingredient from being released from the therapeutic system into the saliva at its non-mucoadhesive surface and is therefore believed to be able to prevent or reduce accidental delivery via the gastrointestinal route; an adhesive layer, which can be used to keep layers (such as the backing layer and the layer containing the active ingredient) adhered to each other; or a cosmetic layer, which can provide decorative means such as coloring or imprinting and / or prevent the patient from contacting the other layers.

[0088] Thus, in some embodiments, the film delivery system may or may not include a cosmetic layer. In some embodiments, the film delivery system may or may not include a backing layer. It should be understood that such an additional layer may also have perforations, which will advantageously be formed simultaneously with those of the mucoadhesive layer and thus form part of a single perforation extending through two or more layers of the film delivery system (and preferably through all layers of the film delivery system). Furthermore, where the film delivery system includes such an additional layer, and particularly where a backing layer is present, the film delivery system may be provided with a means for indicating which side must be applied to the mucosa. Such means may be single-sided coloring or embossing, or the presence of a removable release liner. As will be further described below, similarly, where the film delivery system does not include an additional layer and consists solely of a mucoadhesive layer, for example, where the perforations do not extend through the entire layer thickness, or where one side exhibits a frayed edge of the perforations, one of the two sides may be more preferably applied to the mucosa than the other. In such cases, the film delivery system may be provided with a means for indicating which side must be applied to the mucosa, such means being as described above.

[0089] In yet other embodiments, the thin film delivery system is a mucoadhesive delivery system.

[0090] In view of the convenience of manufacture and limiting the overall system size in terms of surface area, preferably, all layers of the film delivery system are coextensive (that is, have the same shape and size) so that the area released in this case corresponds to the area limited by the film layer. The film is preferably large enough to allow the patient to operate with fingers conveniently without the assistance of any specific device (such as tweezers), and also requires a certain minimum size to ensure that the film does not break away from the mucosa prematurely, and can also contain a sufficient amount of active ingredients without the need to use a very thick film. On the other hand, if the film is too large, applying and wearing will be uncomfortable, thereby causing the patient's compliance to be low. In view of this, in certain embodiments of the present invention, the release area of ​​the film delivery system is at least 0.2 cm², preferably at least 0.5 cm², 1 cm² or 2 cm², or the release area is less than or equal to 10 cm², preferably less than or equal to 7 cm², 6 cm² or 5 cm², or the release area is 0.2 cm² to 10 cm², and more preferably 0.5 cm² to 7 cm², 1 cm² to 6 cm² or 2 cm² to 5 cm². In certain other embodiments, the thin film delivery system has a total weight of at least 5 mg or 10 mg, less than or equal to 175 mg or 150 mg, or a total weight of 5 mg to 175 mg or 10 mg to 150 mg.

[0091] As also outlined above, the film delivery system of the present invention consists of one or more thin layers and is in the form of a film that can have a circular, rectangular or square shape.

[0092] The film preferably has a certain degree of thickness, otherwise it will be difficult to incorporate the required amount of active ingredient, and because very thin films are not easy to manufacture, particularly with respect to providing uniform thickness. Without wishing to be bound by theory, and as will be further elaborated below in the chapters and sections about the mucoadhesive layer, the presence of perforations in the mucoadhesive layer leads to an improved sense of touch of the film delivery system, and may accelerate the dissolution / disintegration of the film, which means that when compared with conventional film delivery systems without perforations, the film delivery system can be thicker and will not cause discomfort to the patient. Therefore, in certain embodiments, the film delivery system is in the form of a thin film, and its gross area weight (ignoring any release liner) is at least 80 g / m², preferably at least 120 g / m² or more preferably at least 250 g / m². In terms of its thickness, the mucoadhesive layer structure is in the form of a thin film, and its total thickness is at least 50 μm, preferably at least 100 μm and more preferably at least 200 μm. On the other hand, very thick films will still be perceived by the patient as an interfering object in the oral cavity, and are therefore disadvantageous in terms of patient compliance. Thus, in certain embodiments, the film delivery system is in the form of a thin film having a total area weight of less than or equal to 900 g / m², preferably less than or equal to 700 g / m², more preferably less than or equal to 500 g / m², or most preferably less than or equal to 300 g / m². Alternatively, in terms of thickness, the mucoadhesive layer structure is in the form of a thin film having a total thickness of less than 700 μm, preferably less than 500 μm, and more preferably less than 400 μm. In preferred embodiments, the film delivery system is in the form of a thin film having a total area weight of 80 to 900 g / m², preferably 120 to 700 g / m², more preferably 250 to 500 g / m², or most preferably 250 to 300 g / m², or a total thickness of 50 to 700 μm, preferably 100 to 500 μm, and more preferably 200 to 400 μm.

[0093] The film delivery system according to the present invention can be stored in any conventional packaging known to those skilled in the art, such as a seam-sealed bag without any further means of protection. In addition, the film delivery system may or may not be located on a removable protective layer (release liner) from which the film delivery system is removed immediately prior to application to the patient's oral mucosa. The packaging can be child-resistant and / or elderly-friendly.

[0094] mucoadhesive layer

[0095] As outlined in more detail above, the thin film delivery system according to the present invention comprises a mucoadhesive layer comprising a film-forming agent. As also explained in the previous section, previous thin film delivery systems have been limited in their application primarily due to limitations on dissolution behavior, thickness, and film-forming materials, as well as patient compliance limitations due to discomfort caused by the thick and / or inflexible films required to make such thin film delivery systems practical. The thin film delivery system of the present invention addresses these issues by providing the mucoadhesive layer with 5 to 100 perforations per cm², thereby improving the film's tactile feel and / or dissolution / disintegration behavior.

[0096] Thus, the mucoadhesive layer contains:

[0097] i) film formers, and

[0098] ii) 5 to 100 perforations per cm².

[0099] Similar to the description of the entire film delivery system, the mucoadhesive layer is preferably the layer containing the active ingredient. In this case, the mucoadhesive layer preferably has a certain thickness to allow for the incorporation of the desired amount of active ingredient and to avoid very thin films that are difficult to manufacture, particularly with respect to providing a uniform thickness. Because the tactile feel is improved and the perforations may accelerate the dissolution / disintegration of the film, the mucoadhesive layer can be thicker without causing discomfort to the patient when compared to conventional film delivery systems without perforations. Thus, in certain embodiments, the mucoadhesive layer has an area weight of at least 70 g / m², at least 100 g / m², or at least 200 g / m². In certain embodiments, the mucoadhesive layer has an area weight of 700 g / m² or less, 500 g / m² or less, 400 g / m² or less, or 300 g / m² or less. In certain embodiments, the mucoadhesive layer has an area weight of 70 g / m² to 700 g / m², 100 g / m² to 500 g / m², 200 g / m² to 400 g / m², or 200 g / m² to 300 g / m².

[0100] Methods for manufacturing the thin film delivery system are explained in further detail below, but include preparing the mucoadhesive layer, for example, by a hot melt process or a film casting process. Thus, in certain embodiments, the mucoadhesive layer can be obtained by a hot melt process, while in certain other embodiments of the present invention, the mucoadhesive layer can be obtained by a film casting process.

[0101] perforation

[0102] According to the present invention, the mucoadhesive layer contained in the film delivery system has a thickness of 1 / cm 2The film delivery system is provided with 5 to 100 perforations. Through experiments, details of which can be found below, we surprisingly discovered that film delivery systems having a mucoadhesive layer provided with such perforations exhibit an improvement in tactile feel, i.e., they are more comfortable for the patient to wear, and also exhibit improved dissolution / disintegration kinetics, as they dissolve / disintegrate faster than film delivery systems without perforations. While these advantageous properties are unexpected, without wishing to be bound by theory, it is believed that the perforations not only provide an expanded surface area but also result in the mucoadhesive layer being composed of a network of residual "bridges." This results in faster dissolution / disintegration upon contact with moist mucosa, which in turn leads to faster softening of the dry and therefore somewhat stiff film, and the softened film is more comfortable for the patient, particularly considering that only the residual "bridges" in the network need to be softened.

[0103] As shown above, the mucoadhesive layer is 2 There are 5 to 100 perforations provided. In a particular embodiment, the mucoadhesive layer has 5 to 100 perforations per cm. 2 There are at least 7, at least 10, at least 20 or at least 50 perforations, or per cm 2 The mucoadhesive layer may have fewer than 90, fewer than 80 or fewer than 60 perforations, or the mucoadhesive layer may have 7 to fewer than 90, 10 to fewer than 80, 20 to fewer than 60 or 50 to fewer than 60 perforations per cm².

[0104] Although the perforations may be of any size and form, and with respect to the shape of the perforations on the surface of the mucoadhesive layer and the shape of the cross-section through the mucoadhesive layer, certain shapes are preferred, particularly in view of ease of manufacture. Specifically, holes can be easily prepared by using a perforating tool selected from a needle or a perforating device, while slits can be easily prepared by using a cutting device as the perforating tool. Figures 7a to 7d 、 Figures 8a to 8c as well as Figures 9a to 9d Exemplary forms and shapes of the perforations according to the invention are shown in FIG and will be explained below.

[0105] Depending on the depth to which the mucoadhesive layer is pierced with the piercing instrument, the perforation may span the entire thickness of the mucoadhesive layer, e.g. Figures 7a to 7d as well as Figures 8a to 8c as shown (through hole or complete slit), so that there is no residual thickness, or as Figures 9a to 9c As shown, only a portion of it is spanned ( Figure 9a and Figure 9b Pocket holes or Figure 9c and Figure 9d In particular, the cutting device can be as follows Figure 7bThe perforations are cut as complete slits by full depth cutting as shown, or as Figure 9c and Figure 9d As shown, a perforation is cut in the form of an incomplete slit by controlled depth cutting; the needle device can be as shown Figure 7a and Figures 8a to 8c By piercing the mucoadhesive layer and incorporating perforations in the form of through-holes as shown, or as Figure 9a and Figure 9b The mucoadhesive layer is shown to be penetrated to a controlled depth by incorporating perforations in the form of pocket holes, while the opening device can open the hole and thereby remove the opened portion from the mucoadhesive layer.

[0106] Thus, in certain embodiments, the perforations are in the form of holes, and in particular through holes or pocket holes, or in the form of slits, and in particular complete slits or incomplete slits, and / or wherein the perforations have a circular, oval, triangular, rectangular or hexagonal form. The perforations may all have the same form, or two or more different forms. The majority of the perforations, for example more than 50%, 70%, 90%, may also have a circular, oval, triangular, rectangular or hexagonal form, or all the perforations may have a form selected from the group consisting of circular, oval, triangular, rectangular and hexagonal forms, and in particular may have a circular form. From a top view, the shape of the perforations may be the same throughout the layer thickness, so that the perforations are cylindrical ( Figure 7a 、 Figure 7b 、 Figure 9a and Figure 9b ), or the perforation tapers and becomes conical ( Figure 8a 、 Figure 8b 、 Figure 9c and Figure 9d ), or may have any other shape variation within the layer thickness. In the case where the perforation spans only a portion of the layer thickness, one side is closed and the perforation opening is on the punctured side. In certain embodiments, the film delivery system is intended to be applied with the punctured side as the mucosal contacting side, while the closed side is intended to face away from the mucosa. In certain embodiments, one side of the perforation has a frayed edge. Such a frayed edge may be caused by puncturing the perforation with a needle device, thereby pushing out the material of the punctured layer on the opposite side and forming stripes, thereby producing such a frayed edge ( Figure 7d ). The frayed edge may protrude from the surface of the mucoadhesive layer, and therefore, although both sides of the mucoadhesive layer can be applied to the mucosa, it is preferred to apply the pierced side rather than the frayed side to the mucosa in view of improved tactile sensation. In such cases, the film delivery system may be provided with a means for indicating which side must be applied to the mucosa, which means may be as mentioned above.

[0107] In terms of size, the perforations are limited only by the following: 2The number of perforations should be between 5 and 100, and thin film delivery systems have practical limitations on size. Therefore, in certain embodiments of the invention, the surface area of ​​each perforation is at least 0.0005 cm 2 , at least 0.001 cm 2 or at least 0.002 cm 2 , or the surface area of ​​each perforation is 0.15 cm 2 or smaller, 0.05 cm 2 or smaller, or 0.03 cm 2 or less. In certain embodiments, the surface area per unit area of ​​the perforated mucoadhesive layer is at least 2%, at least 5%, or at least 10%, or the surface area per unit area of ​​the mucoadhesive layer is 70% or less, 50% or less, or 30% or less. The surface area per unit area of ​​the mucoadhesive layer can be calculated, for example, for a film delivery system in which each perforation has the same form, by multiplying the surface area of ​​one perforation by the total number of perforations and then dividing the resulting value by the total area of ​​the mucoadhesive layer. If the surface area per unit area of ​​the mucoadhesive layer is too low, the beneficial effects of the improved tactile sensation and dissolution / disintegration characteristics may be less pronounced. On the other hand, if the surface area per unit area of ​​the mucoadhesive layer is too high, the integrity and stability of the film may be affected, and the amount of film material may be reduced to the point where a sufficient amount of the active ingredient cannot be incorporated.

[0108] In certain embodiments of the invention, the perimeter of each perforation is at least 0.1 cm, at least 0.2 cm, or at least 0.3 cm, or the perimeter of each perforation is 2 cm or less, 1 cm or less, or 0.8 cm or less. In certain embodiments, the perimeter per unit area of ​​the mucoadhesive layer is at least 2 cm / cm 2 , at least 4 cm / cm 2 or at least 8cm / cm 2 , or the perimeter per unit area of ​​the mucoadhesive layer is 30 cm / cm 2 or smaller, 20 cm / cm 2 or smaller, or 15 cm / cm 2 or less. The perimeter per unit area of ​​the mucoadhesive layer can be calculated, for example, for a thin film delivery system in which each perforation has the same form, by multiplying the perimeter of one perforation by the total number of perforations and then dividing the resulting value by the total area of ​​the mucoadhesive layer. It is believed that a longer perimeter is beneficial for accelerating dissolution behavior by increasing the sidewall area of ​​the pores or slits, but on the other hand, if the perimeter is too long, the stability of the film may again be adversely affected.

[0109] In certain embodiments of the present invention, the perforations are uniformly distributed or non-uniformly distributed. If the perforations are uniformly distributed, the perforations may be arranged in a triangular, rectangular, staggered, or diagonal spacing. This uniform distribution is Figure 10a (Triangle spacing), Figure 10b (rectangular spacing), Figure 10c (interleaved) or Figure 10d (diagonal spacing) are exemplarily shown.

[0110] In certain embodiments of the invention, the mucoadhesive layer has or does not have an edge, and the edge does not contain perforations. The edge may have the advantage of providing a more stable edge that can be manipulated with the fingers, such as by peeling from a package, without the risk of tearing or damaging the film.

[0111] As outlined above, the perforations may be prepared by employing an appropriate perforation tool.Thus, in certain embodiments of the present invention, the perforations are incorporated by employing a perforation tool, and such perforation tool may be selected from a cutting device, a needle device, and a puncturing device.

[0112] Needle devices within the meaning of the present invention can be selected from the group consisting of needles, needle assemblies, and pin rollers. They can also be provided with needles or pins having a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm, or 0.5 mm, or having a diameter of less than 3 mm, 2 mm, or 1 mm. Furthermore, needle devices can have blunt or sharp needles. Needle devices incorporate perforations in the form of through-holes that penetrate the mucoadhesive layer or in the form of pocket holes that penetrate the mucoadhesive layer to a controlled depth.

[0113] Active ingredient

[0114] As outlined above, the thin film delivery system according to the present invention comprises an active ingredient, and the active ingredient may be contained in the mucoadhesive layer and / or in one or more other layers.

[0115] The active ingredient can be any substance of interest that is delivered by the thin film delivery system to provide a beneficial or desired effect on the subject's physical condition systemically or locally at the site of delivery. The active ingredient is particularly selected from any known active pharmaceutical ingredient, supplements (such as foods, dietary and / or nutritional supplements, including vitamins, minerals, enzymes, probiotics, etc.), substances for oral care and / or oral hygiene (such as substances to combat bad breath), and lifestyle medications (such as stimulants, natural extracts, and substances for better sleep or prevention of snoring).

[0116] film-forming agent

[0117] As outlined above, the thin film delivery system according to the present invention comprises a mucoadhesive layer comprising a film-forming agent.

[0118] The film-forming polymers that can be used in the present invention are not particularly limited and any known polymers having film-forming properties may be used, preferably those that are pharmaceutically acceptable (and for example approved for pharmaceutical applications). The film-forming agent may in particular be a soluble film-forming agent.

[0119] Such film-forming agents form a matrix and provide sufficient adhesion to the mucoadhesive layer as long as they remain in a dry state. According to certain embodiments, the film-forming agent may also provide sufficient adhesion to the mucosa once wetted, i.e., when in contact with the mucosa. In such embodiments, and in general, the film-forming agent may be selected from mucoadhesive polymers.

[0120] The film-forming agent is the primary control over the dissolution / disintegration behavior of the mucoadhesive layer. By selecting an appropriate film-forming agent, the adhesion to the mucosa and the disintegration behavior, for example in terms of disintegration time, as well as the integrity of the film delivery system, can be appropriately adjusted. In such embodiments, and in general, the film-forming agent can be selected from soluble mucoadhesive polymers.

[0121] In certain embodiments, the film former may be a polymer, a natural film former, or any mixture thereof.

[0122] Film formers suitable according to the invention are, for example, selected from the group consisting of polymers such as polyvinylpyrrolidone (commercially available as Kollidon® 30F from BASF), methylcellulose (commercially available as Methocel® from Colorcon), ethylcellulose (commercially available as Ethocel® from Colorcon), hydroxyethylcellulose (commercially available as Natrosol® 250 L from Ashland Industries), hydroxypropylcellulose (commercially available as Klucel® from Ashland Industries), hydroxypropylmethylcellulose (also known as hypromellose, commercially available as Pharmacoat® from Shin-Etsu), sodium carboxymethylcellulose (the sodium salt of uncrosslinked carboxymethylcellulose, also known as CMC or carboxymethylcellulose, commercially available as Blanose® from Ashland Industries), graft copolymers based on polyethylene glycol-polyvinyl acetate and polyvinylcaprolactam (commercially available as Soluplus® from BASF), polyvinyl alcohol (commercially available as Mowiol® from Kuraray or, for example, as Parteck ®MXP from Merck), polyvinyl alcohol-polyethylene glycol copolymer (commercially available as Kollicoat® IR from BASF), polyvinyl pyrrolidone-polyvinyl acetate copolymer (also known as copovidone and commercially available, for example, as Kollidon® VA64 from BASF), polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer (commercially available as Eudragit® L100, Eudragit® L12,5, Eudragit® S100 and Eudragit® S12,5 from Evonik) and methacrylic acid-ethyl methacrylate copolymer (commercially available as Eudragit® L100-55 and Eudragit® L30D55 ​​from Evonik), as well as natural film-forming agents such as shellac, pectin, gelatin, alginates, pullulan and starch derivatives, and any mixtures thereof.

[0123] In certain embodiments, the film former is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyvinyl alcohol, and any mixture thereof.

[0124] In certain embodiments of the present invention, the film former is hydroxypropyl cellulose.

[0125] Hydroxypropyl cellulose is available under the trade name Klucel TM Commercially available from Ashland, and available in several grades.

[0126] These grades differ from each other in terms of molecular weight MW (as measured by GPC size exclusion chromatography) and Brookfield viscosity (25°C, LVF, moisture free) and are as follows:

[0127] HF grades have a MW of 1,150,000 and a Brookfield viscosity of 1500-3000 (1% in water),

[0128] MF grade has a MW of 850,000 and a Brookfield viscosity of 4000-6500 (2% in water),

[0129] GF grade has a MW of 370,000 and a Brookfield viscosity of 150-400 (2% in water),

[0130] JF grade has a MW of 140,000 and a Brookfield viscosity of 150-400 (5% in water),

[0131] LF grades have a MW of 95,000 and a Brookfield viscosity of 75-150 (5% in water),

[0132] EF grade has a MW of 80,000 and a Brookfield viscosity of 300-600 (10% in water),

[0133] The ELF grade has a MW of 40,000 and a Brookfield viscosity of 150-300 (10% in water).

[0134] In certain embodiments, the film-forming agent is hydroxypropyl cellulose having a molecular weight (as measured by GPC size exclusion chromatography) of 30,000 to 1,500,000, 30,000 to 500,000, or any mixture thereof, and in particular, the hydroxypropyl cellulose has a molecular weight (as measured by GPC size exclusion chromatography) selected from:

[0135] Between 35,000 and 45,000, especially 40,000,

[0136] Between 75,000 and 85,000, especially 80,000,

[0137] Between 90,000 and 100,000, especially 95,000,

[0138] Between 130,000 and 150,000, especially 140,000,

[0139] Between 350,000 and 400,000, especially 370,000,

[0140] Between 800,000 and 900,000, especially 850,000,

[0141] Between 1,100,000 and 1,200,000, especially 1,150,000,

[0142] or any mixture thereof.

[0143] In certain embodiments, the film former is hydroxypropyl cellulose having a molecular weight of 80,000, 95,000, or 370,000, or any mixture thereof.

[0144] In certain embodiments of the present invention, the film former is hydroxypropyl methylcellulose.

[0145] Hydroxypropyl methylcellulose is available under the trade name AFFINISOL TM HPMC HME is commercially available from Dupont and is provided in several grades.

[0146] These grades differ from each other in terms of molecular weight MW and are as follows:

[0147] The MW of 15LV is 85,000,

[0148] The MW of the 100LV level is 180,000, and

[0149] The MW of the 4M grade is 550,000.

[0150] Thus, in certain embodiments, the film former is hydroxypropyl methylcellulose having a MW of 85,000, 190,000, or 550,000, or any mixture thereof.

[0151] In certain embodiments of the present invention, the film former is polyethylene oxide.

[0152] Polyethylene oxide is sold under the trade name POLYOX TM Commercially available from Dupont, and available in several grades.

[0153] These grades differ from each other in terms of molecular weight MW and are as follows:

[0154] N-10 grade has a MW of 100,000,

[0155] N-80 grade has a MW of 200,000,

[0156] N-750 grade has a MW of 300,000,

[0157] The MW of 205 grade is 600,000,

[0158] The MW of 1105 grade is 900,000,

[0159] N-12K grade has a MW of 1,000,000,

[0160] N-60K grade has a MW of 2,000,000,

[0161] The MW of 301 grade is 4,000,000,

[0162] Coagulant grade has a MW of 5,000,000,

[0163] The MW of 303 grade is 7,000,000,

[0164] Thus, in certain embodiments, the film former is a polyethylene oxide having a molecular weight in the range of 100,000 to 7,000,000, or any mixture thereof, and in particular a polyethylene oxide having a molecular weight selected from the group consisting of 100,000, 200,000, 300,000, 600,000, 900,000, 1,000,000, 2,000,000, 4,000,000, 5,000,000, and 7,000,000, or any mixture thereof.

[0165] More preferably, the film former is polyethylene oxide having a molecular weight of 100,000 or 200,000, or any mixture thereof.

[0166] In certain embodiments of the present invention, the film former is polyvinyl alcohol.

[0167] Polyvinyl alcohol is commercially available under the trade name Mowiol from Kuraray and, for example, under the trade name Parteck ® MXP is commercially available from Merck and is provided in several grades.In certain embodiments, the film former is a polyvinyl alcohol having a molecular weight in the range of 20,000 to 150,000, or any mixture thereof.

[0168] Mowiol partially hydrolyzed grades differ from each other in terms of molecular weight MW and are as follows:

[0169] PVA 3-83 has a MW of 14,000

[0170] PVA 4-88 has a MW of 31,000

[0171] PVA 5-88 has a MW of 37,000

[0172] PVA 3-82 has a MW of 47,000

[0173] PVA 8-88 has a MW of 67,000

[0174] PVA 18-88 has a MW of 130,000

[0175] PVA 23-88 has a MW of 150,000

[0176] PVA 26-88 has a MW of 160,000

[0177] The MW of PVA 40-88 is 205,000.

[0178] Whereas Mowiol fully hydrolyzed grades differ from each other in terms of molecular weight MW and are as follows:

[0179] PVA 3-98 has a MW of 16,000

[0180] PVA 4-98 has a MW of 27,000

[0181] PVA 6-98 has a MW of 47,000

[0182] PVA 10-98 has a MW of 67,000

[0183] PVA 20-98 has a MW of 125,000

[0184] PVA 56-98 has a MW of 195,000

[0185] PVA 28-99 has a MW of 145,000

[0186] Parteck ® MXP 4-88 grade PVA has a MW of 32,000 and Parteck ® MXP 3-82 grade PVA has a MW of 47,000. In these grade names, the first digit provides the apparent viscosity of a 4% aqueous solution at 20°C (mPa·s), and the second digit provides the hydrolysis level (%). ® MXP 3-82 showed a viscosity of 3 mPa•s and a hydrolysis level of 82%, while Parteck ® MXP 4-88 exhibits a viscosity of 4 mPa·s and is an 88% hydrolysis grade. Merck also offers polyvinyl alcohol grades 5-88, 8-88, 18-88, 26-88, 28-99, and 40-88.

[0187] In certain embodiments, the film former is polyvinyl alcohol having a molecular weight of 32,000.

[0188] In certain embodiments, the amount of film forming agent is

[0189] At least 40 wt%, at least 70 wt%, or at least 80 wt%,

[0190] 100 wt% or less or 95 wt% or less, or

[0191] 100 wt% or 90 wt%.

[0192] Other excipients

[0193] The layers of the film delivery system according to the present invention, and in particular the mucoadhesive layer, may each contain other excipients. There are no particular limitations on the excipients that can be used in the present invention, and any known excipients for pharmaceutical formulations, and in particular those that are pharmaceutically acceptable (and, for example, approved for pharmaceutical use), may be employed.

[0194] Thus, in certain embodiments, any of the layers of the thin film delivery system, and in particular the mucoadhesive layer, further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavorings, colorants, penetration enhancers, solubilizers, plasticizers, humectants, disintegrants, wetting promoters, dissolution promoters, emulsifiers, antioxidants, stabilizers, buffering agents, and other film-forming agents.

[0195] In certain embodiments, the plasticizer is selected from the group consisting of mono-, disaccharides, oligo-, and polysaccharides and derivatives, such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol, and medium chain triglycerides.

[0196] In certain embodiments, the fatty acid is selected from the group consisting of saturated or unsaturated, linear or branched carboxylic acids comprising 4 to 24 carbon atoms, and in particular selected from the group consisting of caprylic acid, myristic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, trans-linolenic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid.

[0197] In certain embodiments, the disintegrant is selected from cross-linked polyvinyl pyrrolidone.

[0198] In certain embodiments, any of the layers of the thin film delivery system, and in particular the mucoadhesive layer, further comprises one or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin, and saccharin sodium.

[0199] In certain embodiments, any of the layers of the thin film delivery system, and in particular the mucoadhesive layer, further comprises one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl esters, levulinyl esters, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithialane, ethyl vanillin and eucalyptol, and flavoring compositions such as mint flavor.

[0200] Treatment methods / medical uses / applications

[0201] According to a specific aspect of the present invention, the thin film delivery system according to the present invention is used in a method for treating and / or preventing diseases and medical conditions, preferably in human patients. According to another aspect, the present invention relates to a method of treatment, wherein the thin film delivery system according to the present invention is administered to a human patient. In yet another aspect, the present invention relates to the use of the thin film delivery system according to the present invention for the manufacture of a medicament for treatment, preferably for the treatment of human patients.

[0202] In certain embodiments, the film delivery system is used to be applied to mucosa, and is particularly applied to the mucosa of a human patient's oral cavity. In other words, the film delivery system is applied by applying the film to the mucosa, and is particularly applied to the mucosa of a human patient's oral cavity and maintains a certain time period (application period) on the mucosa, after which the film delivery system dissolves, erodes or substantially disintegrates, or is removed from the application site. In certain embodiments, the present invention further relates to a film delivery system according to the present invention that is applied to mucosa, and is particularly applied to the mucosa of a human patient's oral cavity. In certain embodiments, the present invention relates to the purposes of the film delivery system of the present invention, which is used to manufacture a medicine that is applied to mucosa, and is particularly applied to the mucosa of a human patient's oral cavity.

[0203] In the above-mentioned embodiment, the film delivery system can be applied to buccal mucosa, sublingual mucosa, gingival mucosa or palatal mucosa, is preferably applied to the buccal mucosa of people's patient's oral cavity.The application period can be as short as less than one minute or several minutes, such as 1 minute to 10 minutes, 2 minutes to 10 minutes, slightly longer time, such as 10 minutes to 30 minutes, or even the time of prolongation such as 30 minutes to 60 minutes and even longer time.When the film delivery system stays in the oral cavity and is not removed, the application period is the time until the film delivery system dissolves, erodes or disintegrates substantially.The dissolution behavior of the film delivery system can for example be determined in vitro by dissolution experiment. Thus, in certain embodiments, at least 5%, 25%, or 40%, or less than 90%, 70%, or 60%, or between 5% and 90%, between 25% and 70%, or between 40% and 60%, of the thin film delivery system is dissolved after 5 minutes as measured in 900 mL of 0.01 N HCl using USP Apparatus 1 (Basket) at 37°C ± 0.5°C. In certain embodiments, at least 5%, 25%, or 40%, or less than 90%, 70%, or 60%, or between 5% and 90%, between 25% and 70%, or between 40% and 60%, of the thin film delivery system is dissolved after 30 minutes as measured in 900 mL of 0.01 N HCl using USP Apparatus 1 (Basket).

[0204] In certain embodiments, the film delivery system according to the present invention is used to administer an active ingredient. In certain other embodiments, the film delivery system is used for oral administration and / or transmucosal administration of an active ingredient. In certain embodiments, the present invention further relates to a method of administration, and in particular to a method of orally administering and / or transmucosally administering an active ingredient by administering a film delivery system according to the present invention to a human patient. In certain embodiments, the present invention relates to the use of the film delivery system of the present invention for the manufacture of a medicine for administration, and in particular for oral administration and / or transmucosal administration of an active ingredient.

[0205] Manufacturing method

[0206] The present invention further relates to a method of manufacturing a thin film delivery system, and in particular to a method of manufacturing a thin film delivery system of the present invention as outlined above.

[0207] In this manufacturing method, the mucoadhesive layer is prepared in a first step i) and then provided with perforations in a second step ii). Thus, the manufacturing method of the film delivery system of the present invention comprises a mucoadhesive layer, said manufacturing method comprising the following steps:

[0208] i) preparing a mucoadhesive layer; and

[0209] ii) By using a perforating tool, per cm 2 There are 5 to 100 perforations.

[0210] The mucoadhesive layer can be prepared in any known conventional manner, and in particular by hot melt process or by film casting process. The polymer used for the hot melt manufacturing process may be harder, and generally requires a film of a certain thickness (thereby also causing the film to be harder), for example, in order to be able to incorporate a sufficient amount of active ingredient, and / or to ensure necessary processability. However, thicker and / or harder films are disadvantageous in terms of tactile sensation and may cause discomfort in the patient. As further explained above, the film delivery system of the present invention provides an improved mouthfeel, which makes up for the potential rigidity and thicker defects of the hot melt processable polymer film, and therefore has a larger possible hot melt material selection.

[0211] Any conventional hot melt process can be used, such as vacuum compression molding processes commonly used on a laboratory scale and hot melt extrusion processes that are advantageous for large-scale production. Thus, in certain embodiments, in step i) of the manufacturing method, the mucoadhesive layer is prepared by a hot melt process, and the hot melt process is

[0212] The hot melt extrusion process comprises the following steps:

[0213] a) introducing a film-forming agent or a mixture comprising a film-forming agent into an extruder;

[0214] b) heating the film-forming agent or the mixture to at least the softening temperature of the film-forming agent or the mixture; and

[0215] c) Extruding the heated film-forming agent or the heated mixture containing the film-forming agent in the form of a film to obtain a mucoadhesive layer

[0216] Or a vacuum compression molding process, the process comprising the following steps:

[0217] a) introducing a film-forming agent or a mixture comprising a film-forming agent into the sample chamber; and

[0218] b) compressing the film-forming agent or the mixture by moving a piston downwards while applying a vacuum and heating the film-forming agent or the mixture to at least the softening temperature of the film-forming agent or the mixture to obtain a mucoadhesive layer.

[0219] Of course, the mucoadhesive layer can also be prepared by conventional film casting processes applicable to most polymers. Therefore, in certain embodiments, in step i) of the manufacturing method, the mucoadhesive layer is prepared by a film casting process, and the film casting process comprises the following steps:

[0220] a) combining a film former with a solvent to obtain a coating composition;

[0221] b) applying the coating composition; and

[0222] c) drying the applied coating composition to form a mucoadhesive layer.

[0223] In step ii), perforations are provided using a perforation tool. As outlined above, in its simplest form, the film delivery system consists of a mucoadhesive layer, and then only the mucoadhesive layer needs to be provided with perforations. In the case of a film delivery system consisting of multiple layers, the perforations can be provided throughout the film, through all layers, or in at least some of the layers and beyond the mucoadhesive layer alone.

[0224] On the other hand, in certain embodiments, the mucoadhesive layer can be provided with perforations and then laminated or otherwise adhered to the remaining layers to thereby obtain a film delivery system in which only the mucoadhesive layer is provided with perforations. Such film delivery systems can also be prepared by puncturing only the mucoadhesive film of a multilayer film delivery system at a controlled depth.

[0225] In any case, the perforation provides the mucoadhesive layer with at least one side covered by an opening (the pierced side or the piercing side). The pierced side or the side covered by the opening is intended to be placed on the mucosa (ie, it is the mucosa contacting side).

[0226] Exemplary perforation tools are cutting devices, needle devices and puncture devices, ie in certain embodiments, in step ii), a perforation is provided in the mucoadhesive layer by using a perforation tool selected from the group consisting of a cutting device, a needle device and a puncture device.

[0227] In the case of step ii), the mucoadhesive layer is perforated by piercing the mucoadhesive layer with a perforation tool selected from a needle device, wherein the perforation tool can be selected from a simple needle, a needle assembly (i.e., a plurality of needles assembled in one device so that a plurality of perforations can be made simultaneously) and a pin roller (i.e., a roller equipped with a plurality of pins for piercing, which can be installed on a production line for large-scale production processes. Such a needle device can be provided with needles or pins having a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm or 0.5 mm, or a diameter of 3 mm or less, 2 mm or less, or 1 mm or less, and can have a blunt or sharp tip.

[0228] When perforations (e.g., through-holes or complete slits) are provided across the entire thickness of the mucoadhesive layer using such needle devices, it is possible that by piercing with the needle tip or needle, material of the pierced layer is pushed out and streaked on the opposite side, thereby creating a frayed edge ( Figure 7d). In this case, the piercing side without stripes is preferably applied to the mucosa in view of improved tactile sensation.

[0229] When a perforating device is used as the perforating tool, in step ii), the mucoadhesive layer is perforated with a perforating tool selected from the perforating device, thereby removing the perforated portion from the mucoadhesive layer and providing perforations in the mucoadhesive layer. Using such a perforating device avoids the formation of streaks, which are believed to improve tactile sensation. On the other hand, perforation can remove a portion of the mucoadhesive layer and thus reduce the amount of active ingredient contained therein. Therefore, from this perspective, puncturing or cutting may be more preferable.

[0230] Example

[0231] The present invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should not be construed as limiting the present invention in any way. The numerical values ​​provided in the examples regarding the amounts or areal weights of the components in the compositions may vary slightly due to manufacturing variability, however, this does not affect the advantages provided by the present invention.

[0232] Example 1

[0233] Preparation of mucoadhesive layer samples

[0234] Table 1.1 below summarizes the formulations and perforation patterns used in Comparative Experiments 1a to 1e, as well as the area weight of the mucoadhesive layer.

[0235] Table 1.1

[0236]

[0237] The polymer hydroxypropylcellulose (Klucel EF, molecular weight: 80,000) was filled into a MeltPrep from MeltPrep GmbH. ® The sample container of a vacuum compression molding (VCM) device, which consists of a sample container connected to a vacuum source, a piston, and a lid. The sample material is heated to 160°C using a hot plate heating unit, a vacuum is applied, and the piston moves downward to compact the sample and prevent the formation of bubbles. The resulting homogenous disk is cooled by convection air cooling to provide a mucoadhesive layer sample with a diameter of 2.5 cm and an area of ​​4.91 cm².

[0238] Perforation Pattern (applicable to all embodiments)

[0239] The mucoadhesive layer was perforated using a needle according to one of three perforation patterns (A, B, C), wherein the needle diameter and the number of perforations varied. For each perforation pattern, a template provided with a checkerboard grid pattern was prepared (see Figure 1 ) and mounted on a black foam board (Pattern A) or on a bifolded cellulose sheet (Pattern B and Pattern C). The mucoadhesive layer sample was fixed to the template and manually punctured at each intersection to achieve the maximum possible puncture depth, thereby forming perforations with a uniform geometric circular form. Tables 1.2 and 1.3 below provide a summary of the patterns (Table 1.2) and perforation details (Table 1.3).

[0240] Table 1.2

[0241]

[0242] Table 1.3

[0243]

[0244] *Maximum needle diameter

[0245] **Calculate the circumference / area of ​​a circle based on the maximum needle diameter

[0246] Preparation of thin film delivery system (applicable to all examples)

[0247] In the present case, the mucoadhesive layer disc corresponds to a single (placebo) thin film delivery system. In certain embodiments, this thin film delivery system may be provided with other layers, such as a cosmetic layer and / or a backing layer. The thin film delivery system is then sealed into a bag of primary packaging material according to conventional methods in the art.

[0248] Evaluation of samples: Comparative experiments 1a to 1e

[0249] By applying one thin film delivery system to each of the left and right buccal mucosa, the initial mouthfeel, rapid adhesion / low foreign body sensation on the mucosa, and dissolution behavior of the individual thin film delivery systems were evaluated, thereby comparing the performance of the two application systems, as shown in Table 1.4. Preliminary experiments were conducted to demonstrate that the results were independent of the application side, i.e., it was not important whether the two comparative systems were applied to the left or right application site.

[0250] Table 1.4

[0251]

[0252] *In the above table, ">" indicates superior performance, that is, when B > non-perforated, the system with pattern B performs better than the non-perforated system

[0253] Comparisons of experiments 1a to 1c show that, compared to non-perforated systems of the same formulation, systems provided with perforations adhered to the mucosa more quickly, exhibited less foreign body sensation, and dissolved more quickly (as observed by less residual material remaining on the mucosa). Systems with perforation patterns B and C also exhibited a favorable initial mouthfeel compared to non-perforated systems. Comparisons of experiments 1d and 1e show that a higher number of perforations favored mouthfeel performance in terms of both initial mouthfeel and adhesion to the mucosa and foreign body sensation.

[0254] Example 2

[0255] Preparation of mucoadhesive layer samples

[0256] Table 2.1 below summarizes the formulations and perforation patterns used in Comparative Experiments 2a to 2c, as well as the area weight of the mucoadhesive layer.

[0257] Table 2.1

[0258]

[0259] The polymer hydroxypropylcellulose (Klucel EF, molecular weight: 80,000) was mixed with sorbitol and crushed using a mortar and pestle. The resulting mixture was filled into the MeltPrep ® The samples were placed in the sample container of the VCM device and mucoadhesive layer samples were produced in the same manner as described in Example 1.

[0260] Perforation pattern

[0261] The mucoadhesive layer was perforated using a needle according to one of two perforation patterns (B, C), as described in Example 1 (see Tables 1.2 and 1.3 above for a summary of the patterns and perforation details).

[0262] Evaluation of samples: Comparative experiments 2a to 2c

[0263] The (placebo) thin film delivery system alone was evaluated in the same manner as described in Example 1 (see Example 1 for preparation of the system) and the performance of the two administration systems was thus compared as shown in Table 2.2 below.

[0264] Table 2.2

[0265]

[0266] *In the above table, ">" indicates superior performance, that is, when B > non-perforated, the system with pattern B performs better than the non-perforated system

[0267] Comparison of 2a and 2b shows that, compared to a non-perforated system of the same formulation, the system provided with perforations adheres to the mucosa more quickly, exhibits less foreign body sensation, and dissolves more quickly (as observed by less residual material remaining on the mucosa). Systems with perforation patterns B and C also exhibit a favorable initial mouthfeel compared to the non-perforated system. Comparison of experiment 2c shows that a higher number of perforations improves mouthfeel performance in terms of both initial mouthfeel and adhesion to the mucosa and foreign body sensation. This is particularly beneficial for any relatively hard film.

[0268] Example 3

[0269] Preparation of mucoadhesive layer samples

[0270] Table 3.1 below summarizes the formulations and perforation patterns used in Comparative Experiment 3, as well as the area weight of the mucoadhesive layer.

[0271] Table 3.1

[0272]

[0273] The polymer hydroxypropyl methylcellulose (Affinisol HME 15 LV, molecular weight: 85,000) was filled into the MeltPrep ® The sample was placed in a sample container of a VCM apparatus and a mucoadhesive layer sample was produced in the same manner as described in Example 1, except that the sample material was heated to 250°C.

[0274] Perforation pattern

[0275] The mucoadhesive layer was perforated using a needle according to perforation pattern B, as described in Example 1 (see Tables 1.2 and 1.3 above for a summary of pattern and perforation details).

[0276] Evaluation of samples: Comparative experiment 3

[0277] The (placebo) thin film delivery system alone was evaluated in the same manner as described in Example 1 (see Example 1 for preparation of the system) and the performance of the two administration systems was thus compared as shown in Table 3.2 below.

[0278] Table 3.2

[0279]

[0280] *In the above table, ">" indicates superior performance, that is, when B > non-perforated, the system with pattern B performs better than the non-perforated system

[0281] Comparative Experiment 3 shows that the system provided with perforations performed superior to the non-perforated system of the same formulation in all mouthfeel and dissolution evaluations.

[0282] Example 4

[0283] Preparation of mucoadhesive layer samples

[0284] Table 4.1 below summarizes the formulations and perforation patterns used in Comparative Experiment 4, as well as the area weight of the mucoadhesive layer.

[0285] Table 4.1

[0286]

[0287] Fill the MeltPrep with polyethylene oxide (Polyox N10, molecular weight: 100,000) ® The sample was placed in a sample container of a VCM apparatus and a mucoadhesive layer sample was produced in the same manner as described in Example 1, except that the sample material was heated to 130°C.

[0288] Perforation pattern

[0289] The mucoadhesive layer was perforated using a needle according to perforation pattern B, as described in Example 1 (see Tables 1.2 and 1.3 above for a summary of pattern and perforation details).

[0290] Evaluation of samples: Comparative experiment 4

[0291] The (placebo) thin film delivery system alone was evaluated in the same manner as described in Example 1 (see Example 1 for preparation of the system) and the performance of the two administration systems was therefore compared as shown in Table 4.2 below.

[0292] Table 4.2

[0293]

[0294] *In the above table, ">" indicates superior performance, that is, when B > non-perforated, the system with pattern B performs better than the non-perforated system

[0295] Comparative Experiment 4 shows that the system provided with perforations performed superior to the non-perforated system of the same formulation in all mouthfeel and dissolution evaluations.

[0296] Example 5

[0297] Preparation of mucoadhesive layer samples

[0298] Table 5.1 below summarizes the formulations and perforation patterns used in Comparative Experiments 5a to 5e, as well as the area weight of the mucoadhesive layer.

[0299] Table 5.1

[0300]

[0301] Fill the MeltPrep with polyethylene oxide (Polyox N80, molecular weight: 200,000) ® The sample was placed in a sample container of a VCM apparatus and a mucoadhesive layer sample was produced in the same manner as described in Example 1, except that the sample material was heated to 130°C.

[0302] Perforation pattern

[0303] The mucoadhesive layer was perforated using a needle according to one of three perforation patterns (A, B, C), as described in Example 1 (see Tables 1.2 and 1.3 above for a summary of the patterns and perforation details).

[0304] Evaluation of samples: Comparative experiments 5a to 5e

[0305] The (placebo) thin film delivery system alone was evaluated in the same manner as described in Example 1 (see Example 1 for preparation of the system) and the performance of the two administration systems was therefore compared as shown in Table 5.2 below.

[0306] Table 5.2

[0307]

[0308] *In the above table, ">" indicates superior performance, that is, when B > non-perforated, the system with pattern B performs better than the non-perforated system

[0309] Comparisons of 5a to 5c show that, compared to non-perforated systems of the same formulation, systems provided with perforations adhered to the mucosa more quickly, exhibited less foreign body sensation, and dissolved more quickly (as observed by less residual material remaining on the mucosa). Systems with perforation patterns B and C also exhibited a favorable initial mouthfeel compared to non-perforated systems. Comparisons of experiments 5d and 5e show that a higher number of perforations favored mouthfeel performance in terms of both initial mouthfeel and adhesion to the mucosa and foreign body sensation.

[0310] Example 6

[0311] Preparation of mucoadhesive layer samples

[0312] Table 6.1 below summarizes the formulations and perforation patterns used in Comparative Experiment 6, as well as the area weight of the mucoadhesive layer.

[0313] Table 6.1

[0314]

[0315] Polyvinyl alcohol (Parteck ®MXP 4-88, molecular weight: 32,000) was mixed with sorbitol and crushed using a mortar and pestle. The resulting mixture was filled into a MeltPrep ® The sample was placed in a sample container of a VCM apparatus and a mucoadhesive layer sample was produced in the same manner as described in Example 1, except that the sample material was heated to 230°C.

[0316] Perforation pattern

[0317] The mucoadhesive layer was perforated using a needle according to perforation pattern B, as described in Example 1 (see Tables 1.2 and 1.3 above for a summary of pattern and perforation details).

[0318] Evaluation of samples: Comparative experiment 6

[0319] The (placebo) thin film delivery system alone was evaluated in the same manner as described in Example 1 (see Example 1 for preparation of the system) and the performance of the two administration systems was therefore compared as shown in Table 6.2 below.

[0320] Table 6.2

[0321]

[0322] *In the above table, ">" indicates superior performance, that is, when B > non-perforated, the system with pattern B performs better than the non-perforated system

[0323] Comparative Experiment 6 shows that the system provided with perforations performed superior to the non-perforated system of the same formulation in all mouthfeel and dissolution evaluations.

[0324] The present invention particularly relates to the following other items:

[0325] 1. A film delivery system comprising a mucoadhesive layer, wherein

[0326] The mucoadhesive layer comprises a film-forming agent and has a 2 There are 5 to 100 perforations.

[0327] 2. The film delivery system according to item 1,

[0328] The total weight of the thin film delivery system is at least 5 mg or 10 mg, less than or equal to 175 mg or 150 mg, or a total weight of 5 mg to 175 mg or 10 mg to 150 mg.

[0329] 3. The film delivery system according to item 2,

[0330] wherein the mucoadhesive layer is per cm 2There are at least 7, at least 10, at least 20 or at least 50 perforations, or per cm 2 Fewer than 90, fewer than 80, or fewer than 60 perforations are provided.

[0331] 4. The thin film delivery system according to any one of items 1 to 3,

[0332] wherein the perforations are in the form of holes, and in particular through holes or pocket holes, or in the form of slits, and in particular complete slits or incomplete slits, and / or

[0333] The perforations are circular, oval, triangular, rectangular or hexagonal in shape.

[0334] 5. The thin film delivery system according to any one of items 1 to 4,

[0335] wherein each of the perforations has a surface area of ​​at least 0.0005 cm 2 , at least 0.001 cm 2 or at least 0.002 cm 2 , or the surface area per unit area of ​​the mucoadhesive layer is at least 2%, at least 5% or at least 10%.

[0336] 6. The thin film delivery system according to any one of items 1 to 5,

[0337] The surface area of ​​each perforation is 0.15 cm 2 or smaller, 0.05 cm 2 or smaller, or 0.03cm 2 or less, or the surface area per unit area of ​​the mucoadhesive layer is 70% or less, 50% or less, or 30% or less.

[0338] 7. The thin film delivery system according to any one of items 1 to 6,

[0339] wherein the perimeter of each perforation is at least 0.1 cm, at least 0.2 cm or at least 0.3 cm, or the perimeter per unit area of ​​the mucoadhesive layer is at least 2 cm / cm 2 , at least 4 cm / cm 2 or at least 8 cm / cm 2 .

[0340] 8. The thin film delivery system according to any one of items 1 to 7,

[0341] wherein the perimeter of each of the perforations is 2 cm or less, 1 cm or less, or 0.8 cm or less, or the perimeter per unit area of ​​the mucoadhesive layer is 30 cm / cm 2 or smaller, 20 cm / cm 2 or smaller or 15 cm / cm 2 or smaller.

[0342] 9. The thin film delivery system according to any one of items 1 to 8,

[0343] The perforations may all have the same form, or two or more different forms.

[0344] 10. The thin film delivery system according to any one of items 1 to 9,

[0345] The perforations are evenly distributed or non-evenly distributed.

[0346] 11. The film delivery system according to item 10,

[0347] The perforations are uniformly distributed in a triangular, rectangular, staggered or diagonal pattern.

[0348] 12. The thin film delivery system according to any one of items 1 to 11,

[0349] The mucoadhesive layer may have a border or may not have a border, wherein the border does not contain perforations.

[0350] 13. The thin film delivery system according to any one of items 1 to 12,

[0351] wherein the perforations are incorporated by using a perforation tool.

[0352] 14. The film delivery system according to item 13,

[0353] The perforation tool is selected from a cutting device, a needle device and a hole opening device.

[0354] 15. The film delivery system according to item 14,

[0355] wherein the needle device is selected from the group consisting of a needle, a needle assembly and a pin roller.

[0356] 16. The thin film delivery system according to item 14 or 15,

[0357] The needle device is provided with a needle or pin having a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm or 0.5 mm.

[0358] 17. The thin film delivery system according to any one of items 14 to 16,

[0359] The needle device is provided with a needle or pin having a diameter of 3 mm or less, 2 mm or less or 1 mm or less.

[0360] 18. The thin film delivery system according to any one of items 14 to 17,

[0361] The needle device may have a blunt or sharp needle.

[0362] 19. The film delivery system according to item 14,

[0363] The cutting device cuts the perforations in the form of complete slits by full-depth cutting or in the form of incomplete slits by controlled-depth cutting.

[0364] wherein the needle device incorporates perforations in the form of through holes through the mucoadhesive layer or in the form of pocket holes through the mucoadhesive layer with controlled depth, and

[0365] The perforating device creates a perforation and thereby removes the perforated portion from the mucoadhesive layer.

[0366] 20. The thin film delivery system according to any one of items 1 to 19,

[0367] The mucoadhesive layer can be obtained by a hot melt process or a film casting process.

[0368] 21. The thin film delivery system according to any one of items 1 to 20,

[0369] The film-forming agent is a soluble film-forming agent.

[0370] 22. The thin film delivery system according to any one of items 1 to 21,

[0371] The film former is a polymer, a natural film former or any mixture thereof.

[0372] 23. The thin film delivery system according to any one of items 1 to 22,

[0373] The film-forming agent is

[0374] a polymer selected from the group consisting of polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, a graft copolymer based on polyethylene glycol-polyvinyl acetate and polyethylene caprolactam, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl methacrylate copolymer, or

[0375] a natural film former selected from the group consisting of shellac, pectin, gelatin, alginates, pullulan and starch derivatives, or

[0376] any mixture thereof.

[0377] 24. The film delivery system according to claim 23,

[0378] The film-forming agent is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene oxide, polyvinyl alcohol and any mixture thereof.

[0379] 25. The film delivery system according to claim 24,

[0380] The film-forming agent is hydroxypropyl cellulose.

[0381] 26. The film delivery system according to claim 25,

[0382] The film-forming agent is hydroxypropyl cellulose having a molecular weight of 30,000 to 1,500,000, or 30,000 to 500,000, or any mixture thereof.

[0383] 27. The film delivery system according to item 26,

[0384] The film-forming agent is hydroxypropyl cellulose having a molecular weight of 80,000, 95,000 or 370,000, or any mixture thereof.

[0385] 28. The film delivery system according to claim 24,

[0386] The film-forming agent is hydroxypropyl methylcellulose.

[0387] 29. The film delivery system according to claim 24,

[0388] The film-forming agent is hydroxypropyl methylcellulose with a molecular weight of 85,000, 180,000 or 550,000, or any mixture thereof.

[0389] 30. The film delivery system according to claim 24,

[0390] The film-forming agent is polyethylene oxide.

[0391] 31. The film delivery system according to claim 30,

[0392] The film former is polyethylene oxide having a molecular weight ranging from 100,000 to 7,000,000, or any mixture thereof.

[0393] 32. The film delivery system according to claim 31,

[0394] wherein the film former is polyethylene oxide having a molecular weight selected from the group consisting of 100,000, 200,000, 300,000, 600,000, 900,000, 1,000,000, 2,000,000, 4,000,000, 5,000,000 and 7,000,000, or any mixture thereof.

[0395] 33. The film delivery system according to claim 32,

[0396] The film-forming agent is polyethylene oxide with a molecular weight of 100,000 or 200,000, or any mixture thereof.

[0397] 34. The film delivery system according to claim 24,

[0398] The film-forming agent is polyvinyl alcohol.

[0399] 35. The film delivery system according to claim 34,

[0400] The film former is polyvinyl alcohol having a molecular weight ranging from 20,000 to 150,000, or any mixture thereof.

[0401] 36. The film delivery system according to claim 35,

[0402] The film-forming agent is polyvinyl alcohol with a molecular weight of 32,000.

[0403] 37. The thin film delivery system according to any one of items 1 to 36,

[0404] wherein the amount of the film-forming agent is

[0405] At least 40 wt%, at least 70 wt%, or at least 80 wt%,

[0406] 100 wt% or less or 95 wt% or less, or

[0407] 100 wt% or 90 wt%.

[0408] 38. The thin film delivery system according to any one of items 1 to 37,

[0409] wherein the mucoadhesive layer further comprises one or more excipients selected from the group consisting of: fatty acids, sweeteners, flavorings, colorants, penetration enhancers, solubilizers, plasticizers, humectants, disintegrants, wetting promoters, dissolution promoters, emulsifiers, antioxidants, stabilizers, buffering agents and other film-forming agents.

[0410] 39. The film delivery system according to claim 38,

[0411] wherein the mucoadhesive layer further comprises a plasticizer selected from the group consisting of mono-, disaccharides, oligo- and polysaccharides and derivatives such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium chain triglycerides.

[0412] 40. The film delivery system according to claim 39,

[0413] wherein the mucoadhesive layer further comprises

[0414] fatty acids chosen from the group consisting of saturated or unsaturated, linear or branched carboxylic acids containing from 4 to 24 carbon atoms, and in particular chosen from the group consisting of caprylic acid, myristic acid, palmitoleic acid, hexadecenoic acid, oleic acid, elaidic acid, octadecenoic acid, linoleic acid, trans-linolenic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid, and / or

[0415] One or more natural or artificial sweeteners selected from the group consisting of sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatin and saccharin sodium, and / or

[0416] One or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, chamomile, diacetyl esters, levulinyl esters, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiazolane, ethyl vanillin and eucalyptol, and flavoring compositions such as mint flavor.

[0417] 41. The thin film delivery system according to any one of items 1 to 40,

[0418] The mucoadhesive layer may have an area weight of at least 70 g / m², at least 100 g / m², or at least 200 g / m².

[0419] 42. The thin film delivery system according to any one of items 1 to 41,

[0420] wherein the mucoadhesive layer has an area weight of 700 g / m² or less, 500 g / m² or less, 400 g / m² or less, or 300 g / m² or less.

[0421] 43. The thin film delivery system according to any one of items 1 to 42,

[0422] wherein the film delivery system includes or does not include a cosmetic layer, and / or

[0423] wherein the film delivery system includes or does not include a backing layer, and / or

[0424] The film delivery system is provided with means for indicating which side has to be applied to the mucosa, wherein in particular said means is colouring or embossing on one side, or the presence of a removable release liner.

[0425] 44. The thin film delivery system according to any one of items 1 to 43, which is a mucoadhesive delivery system.

[0426] 45. The thin film delivery system according to any one of items 1 to 44, for application to the mucosa, and in particular to the mucosa of the oral cavity of the human patient.

[0427] 46. ​​The thin film delivery system according to item 45, which is used for application to the buccal mucosa, sublingual mucosa, gingival mucosa or palatal mucosa, preferably to the buccal mucosa of the oral cavity of the human patient.

[0428] 47. The thin film delivery system according to any one of items 1 to 46, which is used for administering an active ingredient, and in particular for oral and / or transmucosal administration of an active ingredient.

[0429] 48. The thin film delivery system according to any one of items 45 to 47,

[0430] wherein the thin film delivery system is administered by applying the thin film to the mucosa and maintaining it on the mucosa for an administration period, after which the thin film delivery system dissolves, erodes or substantially disintegrates, or is removed from the application site, and / or

[0431] wherein at least 5%, 25%, or 40%, or less than 90%, 70%, or 60%, or between 5% and 90%, between 25% and 70%, or between 40% and 60% by weight of the thin film delivery system is dissolved after 5 minutes as measured in 900 mL of 0.01 N HCl using USP Apparatus 1 (Basket) at 37°C ± 0.5°C.

[0432] 49. The film delivery system according to any one of items 1 to 48

[0433] It is used in a method of treating a human patient.

[0434] 50. A method of treatment,

[0435] wherein the thin film delivery system according to any one of items 1 to 49 is

[0436] administration to human patients.

[0437] 51. Use of the thin film delivery system according to any one of items 1 to 49,

[0438] It is used in the manufacture of medicaments for treating human patients.

[0439] 52. A method of making a thin film delivery system comprising a mucoadhesive layer, the method comprising the steps of:

[0440] i) preparing a mucoadhesive layer; and

[0441] ii) by using a perforation tool to perforate the mucoadhesive layer every cm 2 There are 5 to 100 perforations.

[0442] 53. The method according to item 52, wherein in step i), the mucoadhesive layer is prepared by a hot melt process or by a film casting process.

[0443] 54. The method according to item 53, wherein

[0444] In step i), the mucoadhesive layer is prepared by a hot melt process, and the hot melt process is

[0445] The hot melt extrusion process comprises the following steps:

[0446] a) introducing a film-forming agent or a mixture comprising a film-forming agent into an extruder;

[0447] b) heating the film-forming agent or the mixture to at least the softening temperature of the film-forming agent or the mixture; and

[0448] c) extruding the heated film-forming agent or the heated mixture containing the film-forming agent in the form of a film to obtain the mucoadhesive layer

[0449] Or a vacuum compression molding process, the process comprising the following steps:

[0450] a) introducing a film-forming agent or a mixture comprising a film-forming agent into the sample chamber; and

[0451] b) compressing the film-forming agent or the mixture by moving a piston downwards while applying a vacuum, and heating the film-forming agent or the mixture to at least the softening temperature of the film-forming agent or the mixture to obtain the mucoadhesive layer.

[0452] 55. The method according to item 53, wherein

[0453] In step i), the mucoadhesive layer is prepared by a film casting process, and

[0454] The thin film casting process comprises the following steps:

[0455] a) combining a film former with a solvent to obtain a coating composition;

[0456] b) applying the coating composition; and

[0457] c) drying the applied coating composition to form the mucoadhesive layer.

[0458] 56. The method according to any one of items 52 to 55, wherein

[0459] In step ii), perforations are provided in the mucoadhesive layer by using a perforation tool selected from a cutting device, a needle device and a perforating device.

[0460] 57. The method according to item 56, wherein

[0461] In step ii), the mucoadhesive layer is perforated by piercing the mucoadhesive layer with a perforating tool selected from a needle device and

[0462] The needle arrangement is selected from the group consisting of a needle, a needle assembly, and a pin roller.

[0463] 58. The method according to item 57, wherein

[0464] The needle device is provided with a needle or pin having a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm or 0.5 mm.

[0465] 59. The method according to item 57 or 58, wherein

[0466] The needle device is provided with a needle or pin having a diameter of 3 mm or less, 2 mm or less, or 1 mm or less.

[0467] 60. The method according to any one of items 57 to 59, wherein

[0468] The needle device may have a blunt or sharp needle.

[0469] 61. The method according to item 56, wherein

[0470] In step ii), the mucoadhesive layer is perforated by perforating the mucoadhesive layer with a perforating tool selected from a perforating device, thereby removing the perforated portion from the mucoadhesive layer, thereby providing perforations in the mucoadhesive layer.

[0471] 62. A film delivery system comprising a mucoadhesive layer, wherein

[0472] The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 10 and less than 20 perforations,

[0473] The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 10% and 30% or less,

[0474] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 4 cm / cm 2 and 15 cm / cm 2 or smaller,

[0475] The perforations are all circular and evenly distributed, and

[0476] The mucoadhesive layer has an area weight of at least 200 g / m² and 400 g / m² or less.

[0477] 63. A film delivery system comprising a mucoadhesive layer, wherein

[0478] The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 50 to less than 60 perforations,

[0479] The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 5% and 30% or less,

[0480] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 8 cm / cm 2 and 15 cm / cm 2 or smaller,

[0481] The perforations are all circular and evenly distributed, and

[0482] The mucoadhesive layer has an area weight of at least 200 g / m² and 400 g / m² or less.

[0483] 64. A film delivery system comprising a mucoadhesive layer, wherein

[0484] The total weight of the thin film delivery system is 5 mg to 175 mg,

[0485] The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 10 and less than 20 perforations,

[0486] The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 10% and 30% or less,

[0487] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 4 cm / cm 2 and 15 cm / cm 2 or smaller,

[0488] The perforations are all circular and evenly distributed, and

[0489] The mucoadhesive layer has an area weight of at least 200 g / m² and 400 g / m² or less.

[0490] 65. A film delivery system comprising a mucoadhesive layer, wherein

[0491] The total weight of the thin film delivery system is 5 mg to 175 mg,

[0492] The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 50 to less than 60 perforations,

[0493] The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 5% and 30% or less,

[0494] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 8 cm / cm 2 and 15 cm / cm 2 or smaller,

[0495] The perforations are all circular and evenly distributed, and

[0496] The mucoadhesive layer has an area weight of at least 200 g / m² and 400 g / m² or less.

[0497] 66. A film delivery system comprising a mucoadhesive layer, wherein

[0498] The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 10 and less than 20 perforations,

[0499] The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 10% and 30% or less,

[0500] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 4 cm / cm 2 and 15 cm / cm 2 or smaller,

[0501] The perforations are all circular and evenly distributed, and

[0502] The mucoadhesive layer has an area weight of at least 200 g / m² and 300 g / m² or less.

[0503] 67. A film delivery system comprising a mucoadhesive layer, wherein

[0504] The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 50 to less than 60 perforations,

[0505] The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 5% and 30% or less,

[0506] The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 8 cm / cm 2 and 15 cm / cm 2 or smaller,

[0507] The perforations are all circular and evenly distributed, and

[0508] The mucoadhesive layer has an area weight of at least 200 g / m² and 300 g / m² or less.

Claims

1. A film delivery system comprising a mucoadhesive layer, wherein The mucoadhesive layer comprises a film-forming agent and has a 2 There are 5 to 100 perforations.

2. The film delivery system according to claim 1, The total weight of the thin film delivery system is at least 5 mg or 10 mg, less than or equal to 175 mg or 150 mg, or a total weight of 5 mg to 175 mg or 10 mg to 150 mg.

3. The thin film delivery system according to claim 1 or 2, wherein the mucoadhesive layer is per cm 2 There are at least 7, at least 10, at least 20 or at least 50 perforations, or per cm 2 is provided with fewer than 90, fewer than 80 or fewer than 60 perforations, and / or wherein the perforations are in the form of holes, and in particular through holes or pocket holes, or in the form of slits, and in particular complete slits or incomplete slits, and / or The perforations are circular, oval, triangular, rectangular or hexagonal in shape.

4. The thin film delivery system according to any one of claims 1 to 3, wherein each of the perforations has a surface area of ​​at least 0.0005 cm 2 , at least 0.001 cm 2 or at least 0.002cm 2 , the surface area of ​​each perforation is 0.15 cm 2 or smaller, 0.05 cm 2 or smaller or 0.03 cm 2 or less, the surface area per unit area of ​​the mucoadhesive layer is at least 2%, at least 5%, or at least 10%, or the surface area per unit area of ​​the mucoadhesive layer is 70% or less, 50% or less, or 30% or less.

5. The thin film delivery system according to any one of claims 1 to 4, wherein the perimeter of each of the perforations is at least 0.1 cm, at least 0.2 cm, or at least 0.3 cm, the perimeter of each perforation is 2 cm or less, 1 cm or less, or 0.8 cm or less, and the perimeter per unit area of ​​the mucoadhesive layer is at least 2 cm / cm 2 , at least 4 cm / cm 2 or at least 8 cm / cm 2 Alternatively, the perimeter per unit area of ​​the mucoadhesive layer is 30 cm / cm 2 or smaller, 20 cm / cm 2 or smaller or 15 cm / cm 2 or smaller.

6. The thin film delivery system according to any one of claims 1 to 5, The perforations all have the same form, or two or more different forms, or are evenly distributed or non-evenly distributed.

7. The thin film delivery system according to any one of claims 1 to 6, The film-forming agent is a soluble film-forming agent.

8. The thin film delivery system according to any one of claims 1 to 7, wherein the film former is a polymer, a natural film former or any mixture thereof, and is preferably a polymer selected from the group consisting of polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, a graft copolymer based on polyethylene glycol-polyvinyl acetate and polyethylene caprolactam, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymer and methacrylic acid-ethyl methacrylate copolymer, or a natural film former selected from the group consisting of shellac, pectin, gelatin, alginates, pullulan and starch derivatives, or any mixture thereof.

9. The thin film delivery system according to any one of claims 1 to 8, wherein the mucoadhesive layer has an area weight of at least 70 g / m², at least 100 g / m², or at least 200 g / m², or an area weight of 700 g / m² or less, 500 g / m² or less, 400 g / m² or less, or 300 g / m² or less.

10. The thin film delivery system according to any one of claims 1 to 9, which is applied to a mucosa, in particular to the mucosa of the oral cavity of a human patient, and preferably to the buccal mucosa, sublingual mucosa, gingival mucosa or palatal mucosa, preferably to the buccal mucosa of the oral cavity of a human patient.

11. The thin film delivery system according to any one of claims 1 to 10, which is used for administering an active ingredient, and preferably for oral and / or transmucosal administration of an active ingredient.

12. A method of making a thin film delivery system comprising a mucoadhesive layer, the method comprising the steps of: i) preparing a mucoadhesive layer; as well as ii) by using a perforation tool to perforate the mucoadhesive layer every cm 2 There are 5 to 100 perforations.

13. The method according to claim 12, wherein In step ii), perforations are provided in the mucoadhesive layer by using a perforation tool selected from a cutting device, a needle device and a perforation device, wherein preferably The perforating means is selected from a needle device selected from the group consisting of a needle, a needle assembly and a pin roller, and more preferably is provided with a needle or pin having a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm or 0.5 mm, or a diameter of 3 mm or less, 2 mm or less or 1 mm or less, or The perforating tool is selected from a perforating device to remove the perforated portion from the mucoadhesive layer.

14. A film delivery system comprising a mucoadhesive layer, wherein The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 10 and less than 20 perforations, The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 10% and 30% or less, The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 4 cm / cm 2 and 15 cm / cm 2 or smaller, The perforations are all circular and evenly distributed, and The mucoadhesive layer has an area weight of at least 200 g / m² and 400 g / m² or less.

15. A film delivery system comprising a mucoadhesive layer, wherein The mucoadhesive layer comprises a soluble film-forming agent and has a 2 There are at least 50 to less than 60 perforations, The surface area per unit area of ​​the mucoadhesive layer of the perforations is at least 5% and 30% or less, The perimeter per unit area of ​​the perforated mucoadhesive layer is at least 8 cm / cm 2 and 15 cm / cm 2 or smaller, The perforations are all circular and evenly distributed, and The mucoadhesive layer has an area weight of at least 200 g / m² and 400 g / m² or less.

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