Perforated Film Delivery System

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 perforated.

Description

[Technical Field]

[0001] The present invention relates to a film delivery system comprising a perforated mucoadhesive layer, and to its manufacture, processing and use. [Background technology]

[0002] Drug delivery via traditional oral dosage forms, such as tablets, pills, caplets, and capsules, is the standard route of drug administration. However, swallowing tablets can be difficult for elderly people and infants. In addition, oral administration is associated with presystemic elimination of the active drug, which may involve gastrointestinal (GI) degradation, metabolism, or first-pass clearance via the liver, and often suffers from limitations such as low systemic bioavailability, food effect, slow onset of action, and / or the formation of inactive and sometimes toxic metabolites.

[0003] Considering such limitations, dosage forms, which may be in the form of thin films, such as transmucosal therapeutic systems, have been gaining in applicability in recent years. Transmucosal drug delivery offers the combined advantages of bypassing the digestive tract and the ease and convenience of oral administration, as drugs are absorbed directly into the systemic circulation through mucosal tissues. Compared with mucosal dosage forms, such as orodispersible tablets, oral film delivery systems have the advantage of being applied to the mucosa and ideally being completely or barely noticeable to the patient thereafter, resulting in less discomfort for the patient.

[0004] A transmucosal therapeutic system, or a transmucosal delivery system in the form of a film, consists of one or more thin layers that are applied to and adhere to the mucous membranes of, for example, the oral cavity, to deliver a drug over a period of time. In such a transmucosal therapeutic system, the active agent is contained in a dissolvable layer, and active delivery 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 for application to the oral cavity (including transmucosal therapeutic systems) are sometimes called "oral films" or OTFs, although OTFs are not necessarily intended to adhere to the mucosa. Such OTFs may be intended to disintegrate quickly in saliva (e.g., called "flash wafers"), thus providing benefits such as aiding the patient in taking the medication.

[0006] In summary, as outlined above, film-based dosage forms, i.e., film delivery systems, offer a variety of alternative drug delivery forms and administration routes, which may be advantageous in terms of patient convenience, ease, and comfort, and / or by providing improved pharmacokinetic behavior, such as higher bioavailability and faster onset of action. More specifically, due to their thin and flexible nature, films are less noticeable and more readily accepted by patients, compared to, for example, tablets. For example, when formulated as a (trans)mucosal dosage form, film delivery systems offer a promising non-invasive alternative to traditional oral dosage forms, as they can deliver active agents directly into the systemic circulation, avoiding the gastrointestinal (GI) tract and potentially improving efficacy, and eliminating side effects due to first-pass metabolism.

[0007] However, because film delivery systems are a relatively new form of drug delivery, knowledge about formulation techniques is limited. Formulating a suitable film delivery system, for example for transmucosal administration, is difficult due to the many aspects to be considered and problems to be solved. The main requirements for such a film delivery system are good adhesion and active penetration, as well as appropriate behavior and disintegration time. Since the application of the thin film must not cause discomfort to the patient, the tactile feel of the film must be considered as a basic physical property.

[0008] Thin film design requires unique consideration of film dimensions and thickness, as well as drug-to-polymer ratio, because the film must be thin enough to be imperceptible to the patient. This requirement limits film thickness and, consequently, drug loading. Higher doses increase film thickness, resulting in longer dissolution times and / or increased foreign body sensation, making the delivery system less convenient for the patient. Furthermore, film-forming materials that form relatively stiff films may be desirable from the standpoint of dissolution characteristics and / or drug release behavior, but their tendency to cause foreign body sensation limits their use. Other film-forming agents may be desirable in terms of providing a desirable active agent release behavior, but may dissolve or disintegrate too slowly.

[0009] Micro-perforated or perforated thin films have been proposed in the past, for example, there have been reports of using perforated films in dental treatments, where the perforations are intended to allow for correct positioning of the film, for example, within the oral cavity.

[0010] However, to date, little attention appears to have been paid to improving the tactile feel of film delivery systems, particularly by incorporating perforations. Improved tactile feel would not only make application of the film more convenient for patients and allow for administration of thicker and / or less flexible films, enabling higher drug loadings, but also broadening the range of materials used in such films. On the other hand, faster dissolving films without changing the polymeric material would also offer the possibility of using materials such as polymers that dissolve too slowly to be useful as matrices for drug-containing films.

[0011] In summary, film delivery systems are promising new drug delivery systems that address the shortcomings of traditional oral dosage forms; however, they face certain limitations regarding the materials that may be used, as well as the size, thickness, and drug loading that can be achieved taking into account patient compliance and dissolution behavior.

[0012] Therefore, there is a need in the art for improved film delivery systems that simultaneously combine controllable dissolution behavior with high drug loading capacity and improved tactile sensation. Summary of the Invention

[0013] SUMMARY OF THE INVENTION It is an object of the present invention to provide a film delivery system that overcomes the above-mentioned drawbacks.

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

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

[0016] It is therefore also an object of the present invention to provide such a film delivery system that simultaneously has improved tactile feel and controlled dissolution / disintegration behavior.

[0017] It is also an object of the present invention to provide a film delivery system that has suitable tactile feel and / or dissolution / disintegration kinetics despite the film being thick and / or stiff.

[0018] It is also an object of the present invention to provide a film delivery system for administration of an active ingredient, in particular for transmucosal administration of an active ingredient, which has suitable tactile sensation and / or dissolution / disintegration kinetics despite a drug load high enough to achieve, for example, an effective amount, in particular a therapeutically effective amount.

[0019] Another object of the present invention is to provide a film delivery system that provides adequate adhesion to, for example, mucosa, not only initially but also over time.

[0020] These and other objects are achieved by the present invention. The present invention, according to one aspect, relates to a film delivery system comprising a mucoadhesive layer, wherein the mucoadhesive layer comprises a film-forming agent, and 2 Each piece has 5 to 100 perforations.

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

[0022] According to another embodiment, the present invention relates to a method of treatment in which a film delivery system according to the present invention is administered to a human patient.

[0023] According to yet another embodiment, the present invention relates to the use of the film delivery system of the present invention for the manufacture of a medicament for treating a human patient.

[0024] According to yet another aspect, the present invention provides a method for making a film delivery system comprising a mucoadhesive layer, the method comprising: i) preparing a mucoadhesive layer, and ii) Using a drilling tool, 2 5 to 100 perforations are made in the mucoadhesive layer per unit area. The method includes the steps of:

[0025] According to a particular aspect, the present invention also relates to a film delivery system obtainable by such a manufacturing method.

[0026] According to another aspect, the present invention also provides a film delivery system comprising a mucoadhesive layer, The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 10 to 20 perforations per unit, The perforations are at least 10% and not more than 30% of the surface area per unit area of ​​the mucoadhesive layer; Perforation must be at least 4cm / cm per unit area of ​​mucoadhesive layer. 2 , and 15cm / cm 2 It has a circumference of: All perforations have a circular shape and are uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 400 g / m 2 having an areal weight of: Regarding the above system.

[0027] According to yet another aspect, the present invention also provides a film delivery system comprising a mucoadhesive layer, The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 50 to 60 perforations per unit, The perforations are at least 5% and not more than 30% of the surface area per unit area of ​​the mucoadhesive layer; Perforation must be at least 8cm / cm per unit area of ​​mucoadhesive layer. 2 , 15cm / cm 2 It has a circumference of: All perforations have a circular shape and are uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 400 g / m 2 having an areal weight of: Regarding the above system.

[0028] Within the meaning of the present invention, the term "film delivery system", which may also be called a "film dosage form" or "film therapeutic system", refers to an administration system for an active ingredient, composed of one or more layers. The film delivery system comprises a mucoadhesive layer and is applied to mucous membranes, such as the oral mucosa (e.g., buccal mucosa, sublingual mucosa, gingival mucosa, palatal mucosa), vaginal mucosa, rectal mucosa, nasal mucosa, or ocular mucosa. This term refers to the entire individual dosage unit applied to the mucosa of a patient, and particularly contains an effective amount, particularly a therapeutically effective amount, of an active ingredient in the mucoadhesive layer or one of the additional layers. The mucoadhesive layer may be located on a release liner (peelable protective layer), and therefore the film delivery system may further comprise a release liner.

[0029] Within the meaning of the present invention, the term "film delivery system" includes dosage forms intended to provide active delivery, also or primarily via the oral route. In this case, the film may serve as a convenient oral dosage form, allowing for easy swallowing without the need for water or any other beverage to assist in the ingestion of the drug, and therefore the film can be easily taken "on the go." On the other hand, a "film delivery system" is a system specifically intended for transmucosal administration, providing passive transmucosal administration, excluding active transport, such as methods involving microporation. When the film is applied to the patient's oral cavity, enteral administration of the active ingredient by swallowing is also possible and is not necessarily undesirable in a film delivery system. Using a film delivery system, the active ingredient can be administered not only transmucosally to the systemic circulation, but also locally (to the mucosa at the administration site and / or tissue adjacent to the administration site).

[0030] Within the meaning of the present invention, the term "transmucosal" refers to a route of delivery of an active ingredient via mucosal tissue. Accordingly, the term "transmucosal therapeutic system" or "transmucosal delivery system" refers to a system intended for administration of an active ingredient to the systemic circulation primarily via transmucosal delivery, i.e., through the mucosa, by application to the mucosa, in particular the oral mucosa. This term refers to an entire individual dosage unit, as outlined above for the general film delivery system, which is applied to the mucosa of a patient and contains an effective amount, in particular a therapeutically effective amount, of the active ingredient in one of the mucoadhesive or further layers.

[0031] A transmucosal therapeutic system can be considered a type of "oral thin film," but within the meaning of the present invention, "oral thin film" also includes film delivery systems that emphasize rapid dissolution / disintegration in saliva rather than mucoadhesive properties (sometimes called "flash wafers"). The intended delivery route of such rapidly disintegrating oral thin films or flash wafers may be transmucosal as well as oral / enteral, and patients may be instructed to prioritize one or the other delivery route, for example, by placing the film sublingually or buccally and not swallowing until it dissolves, or by placing the film on their tongue and swallowing.

[0032] Within the meaning of the present invention, the term "mucoadhesive layer" refers to one of the layers constituting a film delivery system, which contains a film-forming agent that provides the necessary cohesion and stability to the film and has at least one uncovered surface intended for application to the patient's mucosa. In other words, the mucoadhesive layer within the meaning of the present invention is a mucosal contact layer. The release site is provided by the location of the active ingredient-containing layer. The mucoadhesive layer does not necessarily have to be the active ingredient-containing layer at the same time, but may be used additionally to enhance adhesion. The size of the mucoadhesive layer and the active ingredient-containing layer is usually comparable (i.e., they have the same size / dimensions and shape) and corresponds to the release site. The simplest form of a film delivery system comprises an active ingredient-containing mucoadhesive layer and no additional layers. The mucoadhesive layer is the final solidified layer obtained after coating and drying a solvent-containing coating composition, for example by a film casting process, or after extrusion of a film-forming agent or a mixture containing a film-forming agent.

[0033] The terms "dissolve," "dissolvable," "dissolving," and the like, with respect to the film delivery system, any layer of the film delivery system, such as the mucoadhesive layer, and the film-forming agent when cast into a film, should be understood very broadly and not in the strict scientific sense of chemically dissolving molecules in a solvent. Any change from a solid state to a liquid state of the layer, such as dispersing, forming a suspension, gelling a film, breaking up a gel into small parts, etc., should be considered "dissolving" within the meaning of the present invention, as long as the "dissolved" substance can move freely in a liquid (e.g., saliva). In preferred embodiments, the meaning is limited to the ordinary chemical meaning of dissolving molecules in a solvent. It should be noted that the term "dissolve" with respect to the substance itself, such as any excipient, continues to be used in the ordinary chemical sense of dissolving molecules in a solvent. For example, the film-forming agent itself may be present in the coating composition during the manufacture of a film delivery system in a dissolved form in the general chemical sense (e.g., not dispersed, in the form of small pieces of gel, etc.), but when the film-forming agent is cast into a film, "dissolving" such a film also includes the gelling of the film and its disintegration into small pieces of gel, i.e., a "dissolvable" film-forming layer must also be understood in a very broad sense.

[0034] The mucoadhesive layer may also be produced by laminating two or more such solidified layers (e.g., dry layers) of the same composition to provide the desired areal weight. The mucoadhesive layer shown above is intended to be applied to the mucosa where it should provide adequate adhesion. That is, within the meaning of the present invention, the term "mucoadhesive" refers in particular to a material that adheres to the mucosa when in contact with it, but is preferably not tacky in its dry state, and can be touched with, for example, a finger and manipulated for application in the oral cavity without unintentionally adhering to the skin of the finger. When in contact with the mucosa, the mucoadhesive layer is "self-adhesive," i.e., typically provides adhesion to the mucosa such that no further assistance is required for fixation. The adhesive strength is preferably so strong that typical movements in the oral cavity are not sufficient to move the mucoadhesive layer adhered to the mucosa.

[0035] As used herein, the term "active ingredient" refers to any substance of interest delivered by a film delivery system that provides a beneficial or desired effect on a subject's condition systemically or locally at the delivery site. Specifically, active ingredients include biologically or pharmacologically active compounds and may also be referred to as active agents, drugs, medicaments, active ingredients, active pharmaceutical ingredients (APIs), etc. Within the meaning of the present invention, the term "effective amount" or "therapeutically effective amount" refers to the amount of active ingredient in a film delivery system that, when administered to a patient via the film delivery system, is sufficient to provide a desired (therapeutic) effect, as determined, for example, by a blood concentration in a similar range (e.g., about 10% to about 1000%, as measured as AUC) compared to the blood concentration obtained after a single dose of an approved drug product of the same active ingredient, or by an amount of active agent similar to the amount of active agent contained in another locally-acting approved drug product of the same active ingredient (e.g., about 10% to about 1000%).

[0036] Within the meaning of the present invention, the term "administration" refers to the application of the dosage form, i.e., the film delivery system, to the oral mucosa (e.g., buccal, sublingual, gingival, palatal), vaginal, rectal, nasal or ocular mucosa, in particular the oral mucosa, of a patient, after which the dosage form remains on the mucosa for a specified period of administration time or until the active ingredient-containing layer dissolves, erodes or substantially disintegrates.

[0037] Within the meaning of the present invention, the term "area weight" refers to the dry weight of a particular layer, for example an active ingredient-containing layer, and is expressed in g / m 2 The area weight values ​​are subject to ±10%, preferably ±5% of the nominal value due to manufacturing variations.

[0038] The unit "%" may refer to a percentage given as weight per volume (w / v), volume per volume (v / v), or weight %, and unless otherwise specified, "%" preferably refers to weight %.

[0039] Within the meaning of the present invention, the term "polymer" refers to a substance or material containing so-called repeating units obtained by polymerizing one or more monomers, including homopolymers composed of one type of monomer and copolymers composed of two or more types of monomers. Polymers can be of any structure, such as linear polymers, star polymers, comb polymers, or brush polymers, and in the case of copolymers, they can be of any monomer arrangement, such as alternating, statistical, block, or graft copolymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can have molecular weights of, for example, more than 2,000 daltons, preferably more than 5,000 daltons, and more preferably more than 10,000 daltons. Correspondingly, compounds with molecular weights less than 2,000 daltons, preferably less than 5,000 daltons, or more preferably less than 10,000 daltons are commonly called oligomers.

[0040] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory room where the experiment is performed, which is usually in the range of 15-35°C, preferably about 18-25°C.

[0041] Within the meaning of the present invention, the term "patient" refers to a subject who presents with clinical evidence of a particular condition or symptoms indicating the need for treatment, who is being treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.

[0042] Within the meaning of the present invention, the term "coating composition" refers to a composition comprising all the ingredients of one of the layers, such as a mucoadhesive layer, in a solvent, which may be coated to form the corresponding layer, such as a mucoadhesive layer, upon drying.

[0043] Within the meaning of the present invention, the term "solvent" refers to any liquid substance, preferably a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride, hexane, n-heptane, heptane, toluene and mixtures thereof.

[0044] Within the meaning of the present invention, unless otherwise specified, the term "about" refers to an amount that is ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±2% of the disclosed amount.

[0045] Within the meaning of the present invention, the terms "substantial" or "substantially" are used to refer to the majority of the corresponding entity or component; for example, a composition "consisting essentially of" a component contains a major amount of that component, such as at least 95% by weight, preferably at least 98% by weight, or even at least 99% by weight.

[0046] Within the meaning of the present invention, the term "surface area" means the maximum area of ​​the perforation when viewed from above, i.e. in the case of a conical perforation the surface area is calculated based on the shape at the pierced surface.

[0047] Within the meaning of the present invention, "triangular", "rectangular", "staggered" or "diagonal" pitch refers to the shape formed with respect to the pitch of the nearest perforations in an arrangement in which the perforations are evenly distributed (see Figures 10a to 10d).

[0048] Within the meaning of the present invention, "margin" refers to the non-perforated peripheral edge of the mucoadhesive layer.

[0049] The figures are for illustrative purposes only, are not intended to limit the scope of the claims, and are not to scale. [Brief explanation of the drawings]

[0050] [Figure 1] FIG. 1 is a schematic top view of a film delivery system of the present invention, comprising a mucoadhesive layer with circular perforations in an 8x8 checkerboard grid pattern (i.e., arranged with a rectangular pitch) with white space (Pattern A). [Figure 2] 1 shows a film delivery system comprising a mucoadhesive layer perforated according to perforation pattern A. [Figure 3] FIG. 1 is a schematic top view of a film delivery system of the present invention, comprising a mucoadhesive layer with circular perforations in a 10x10 checkerboard grid pattern (i.e., arranged with a rectangular pitch) with white space (Pattern B). [Figure 4] 1 shows a film delivery system comprising a mucoadhesive layer perforated according to perforation pattern B. [Figure 5] FIG. 1 is a schematic top view of a film delivery system of the present invention, comprising a mucoadhesive layer with circular perforations in a 19x19 checkerboard grid pattern (i.e., arranged with a rectangular pitch) with white space (Pattern C). [Figure 6]1 shows a film delivery system comprising a mucoadhesive layer perforated according to perforation pattern C. [Figure 7a] 1 shows a perspective view of a single perforation in the sense of the invention, which is a circular cylindrical through-hole. [Figure 7b] 1 shows a perspective view of a single perforation in the sense of the invention, which is a perfect cylindrical slit. [Figure 7c] 1 shows a side view of a single perforation in the sense of the present invention, which is a complete cylindrical slit or cylindrical through-hole. [Figure 7d] FIG. 1 is a side view of a single perforation in the sense of the present invention, which is a complete cylindrical slit or cylindrical through-hole, showing a slightly widened opening on the pierced side and a frayed edge on the opposite side, with an edge formed by the perforation tool extruding material as it penetrates the layer. [Figure 8a] 1 shows a perspective view of a single perforation in the sense of the invention, which is a circular conical through-hole. [Figure 8b] 1 shows a top view of a single perforation in the sense of the invention, which is a circular conical through-hole, and also shows the larger circular shape that is the basis for calculating the surface area. [Figure 8c] 1 shows a side view of a single perforation in the sense of the invention, which is a perfect conical slit or conical through-hole. [Figure 9a] 1 shows a perspective view of a single drilling hole in the sense of the invention, which is a circular cylindrical pocket hole. [Figure 9b] 1 shows a side view of a single drilling hole in the sense of the present invention, which is a circular cylindrical pocket hole. [Figure 9c] 1 shows a perspective view of a single perforation in the sense of the invention, which is a conical incomplete slit. [Figure 9d] 1 shows a side view of a single perforation in the sense of the invention, which is a conical incomplete slit. [Figure 10a] A top view of perforations evenly spaced with a triangular pitch is shown. [Figure 10b] A top view of perforations evenly spaced with a rectangular pitch is shown. [Figure 10c]A top view of perforations evenly spaced at a staggered pitch is shown. [Figure 10d] The figure shows a top view of perforations evenly spaced at an oblique pitch. DETAILED DESCRIPTION OF THE INVENTION

[0051] Film Delivery System The present invention relates to a film delivery system comprising a mucoadhesive layer.

[0052] The film delivery system is intended for use in administering active ingredients useful in the treatment and / or prevention of diseases and medical conditions and is applied to the mucosa of a patient. The mucoadhesive layer comprises a film-forming agent and is 1 cm thick. 2 Each piece has 5 to 100 perforations.

[0053] Thus, in accordance with the present invention, a film delivery system may be provided that includes a film-forming agent and is 1 cm 2 It contains a mucoadhesive layer with 5 to 100 perforations per layer.

[0054] The film delivery systems of the present invention comprise one or more thin layers, and the active ingredient may be contained in the mucoadhesive layer and / or one or more additional layers, which then form a separate active ingredient-containing layer. In other words, the mucoadhesive layer does not necessarily also serve as the active ingredient-containing layer, but may be used additionally to enhance adhesion. On the other hand, if the mucoadhesive layer is the only active ingredient-containing layer, the film delivery system is simpler and easier to manufacture; in its simplest form, the film delivery system comprises an active ingredient-containing mucoadhesive layer and no additional layers. In certain embodiments, the film delivery system may comprise additional layers, such as a backing layer, which may prevent the active ingredient from being released from the therapeutic system into saliva at its non-mucoadhesive surface, thereby preventing or reducing unintended delivery via the gastrointestinal route; an adhesive layer, which may serve to hold layers such as the backing layer and the active ingredient-containing layer together; or a cosmetic layer, which may provide decorative means, such as coloring or marking, and / or prevent the patient from touching the other layers.

[0055] 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 is understood that such additional layers may also have perforations, which are advantageously formed simultaneously with the perforations in the mucoadhesive layer and thus become part of the same perforations extending through two or more, and preferably all, layers of the film delivery system. Furthermore, when the film delivery system includes such additional layers, particularly when 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 a means may include one-sided coloring or marking, or the presence of a releasable release liner. As further outlined below, when the film delivery system does not have additional layers but does include a mucoadhesive layer, for example, if the perforations do not extend through the entire thickness of the layer or if one of the sides exhibits frayed edges of the perforations, one of the two sides may still be preferred for application to the mucosa over the other. In such situations, the film delivery system may include a means for indicating which side must be applied to the mucosa, which may be as mentioned above.

[0056] In yet other embodiments, the film delivery system is a mucoadhesive delivery system.

[0057] In terms of limiting the size of the entire system for ease of manufacture and surface area, preferably, all layers of the film delivery system are coextensive, i.e., have the same shape and size, so that the release area in such cases corresponds to the area defined by the film layer. The film is preferably large enough that the patient can conveniently manipulate it with their fingers without the aid of any special instrument such as tweezers, and also requires a certain minimum size to prevent the film from prematurely peeling off from the mucosa and to allow the inclusion of a sufficient amount of active ingredient without using a very thick film. On the other hand, if the film is too large, it will be uncomfortable to apply and wear, and patient compliance will decrease. With this in mind, in certain embodiments of the present invention, the film delivery system should be at least 0.2 cm 2 , preferably at least 0.5 cm 2 , 1 or 2 cm 2 or 10cm 2 Less than 7cm, preferably 2 , 6 or 5 cm 2 or have a release area of ​​0.2 to 10 cm 2 , and more preferably 0.5 to 7 cm 2 , 1~6cm 2 or 2-5cm 2 In certain further embodiments, the film delivery system has a total weight of at least 5 mg or 10 mg, up to 175 mg or 150 mg, or from 5 to 175 mg, or from 10 to 150 mg.

[0058] As outlined above, the film delivery systems of the present invention are in the form of a film that includes one or more thin layers and may have a circular, rectangular, or square shape.

[0059] The film preferably has a certain thickness, as it would otherwise be difficult to incorporate the required amount of active ingredient, and very thin films are not easy to manufacture, especially with regard to providing a uniform thickness. Without wishing to be bound by theory, as will be explained in more detail below in the section on mucoadhesive layers, the presence of perforations in the mucoadhesive layer may improve the tactile feel of the film delivery system as well as facilitate the dissolution / disintegration of the film, which means that the film delivery system may be thicker without causing discomfort to the patient, compared to conventional film delivery systems without perforations. Thus, in certain embodiments, the film delivery system has a thickness of at least 80 g / m 2 , preferably at least 120 g / m 2 , or more preferably at least 250 g / m 2 In particular embodiments, the film delivery system is in the form of a thin film having a total area weight (disregarding any release liner) of 900 g / m. In terms of its thickness, the mucoadhesive layer structure is in the form of a thin film having a total thickness of at least 50 μm, preferably at least 100 μm, and more preferably at least 200 μm. On the other hand, very thick films are still perceived by patients as a nuisance 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 (disregarding any release liner) of at least 900 g / m. 2 Less than 700 g / m 2 or less, or more preferably 500 g / m 2 or less, or most preferably 300 g / m 2 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 a preferred embodiment, the film delivery system is in the form of a thin film having a total area weight of 80-900 g / m 2 , preferably 120 to 700 g / m 2 , or more preferably 250 to 500 g / m 2 , or most preferably 250 to 300 g / m 2It has a total surface area weight or is in the form of a thin film having a total thickness of 50 to 700 μm, preferably 100 to 500 μm, and more preferably 200 to 400 μm.

[0060] The film delivery system according to the present invention can be stored without further protective means in any conventional packaging material known to those skilled in the art, such as a pouch with sealed seams. Also, the film delivery system may or may not be located on a peelable protective layer (peel liner) that is peeled off immediately before application to the patient's oral mucosa. The packaging material may have safety measures for children and / or may be easy for the elderly to handle.

[0061] Mucosal adhesive layer As outlined in more detail above, the film delivery system according to the present invention includes a mucosal adhesive layer containing a film-forming agent. Also, as explained in the previous section, past film delivery systems have been limited in their application mainly due to thickness limitations, dissolution behavior, and limitations of the film-forming materials imposed by patient compliance, which may be due to the discomfort associated with thick films and / or non-flexible films that are necessary to actually make such film delivery systems practicable. The film delivery system of the present invention addresses these concerns by perforating the mucosal adhesive layer at 5 to 100 per cm <00000,37>to improve the tactile and / or dissolution / disintegration behavior of the film.

[0062] Thus, the mucosal adhesive layer i) a film-forming agent, and ii) 5 to 100 perforations per cm2, and includes.

[0063] Similar to what is shown for the overall film delivery system, the mucoadhesive layer is preferably an active ingredient-containing layer. In such cases, the mucoadhesive layer preferably has a certain thickness that allows the necessary amount of active ingredient to be incorporated and avoids very thin films that are not easy to manufacture, especially with regard to providing a uniform thickness. Due to the improved tactile sensation and the potential for perforations to facilitate film dissolution / disintegration, the mucoadhesive layer may be thicker without causing discomfort to the patient compared to conventional film delivery systems without perforations. Thus, in certain embodiments, the mucoadhesive layer has a thickness of at least 70 g / m 2 , at least 100g / m 2 , or at least 200 g / m 2 In a particular embodiment, the mucoadhesive layer has an area weight of 700 g / m 2 Below 500g / m 2 Below 400g / m 2 or less, or 300 g / m 2 In a particular embodiment, the mucoadhesive layer has an area weight of 70 g / m 2 ~700g / m 2 , 100g / m 2 ~500g / m 2 , 200g / m 2 ~400g / m 2 , or 200 g / m 2 ~300g / m 2 It has an area weight of

[0064] The manufacturing process for the film delivery system, as described in more detail below, involves preparing the mucoadhesive layer, for example, by a hot melt process or a film casting process. Thus, in certain embodiments, the mucoadhesive layer is obtained by a hot melt process, while in other particular embodiments of the invention, the mucoadhesive layer is obtained by a film casting process.

[0065] perforation In accordance with the present invention, the mucoadhesive layer included in the film delivery system is 1 cm 2The perforations are 5 to 100 perforations per film. Experiments, the details of which are described further below, have surprisingly shown that film delivery systems having such perforated mucoadhesive layers are not only improved in terms of tactility, i.e., more comfortable for the patient to wear, but also in terms of dissolution / disintegration kinetics, in that they dissolve / disintegrate faster compared to film delivery systems without perforations. While these advantageous properties were unexpected and without wishing to be bound by theory, it is believed that the perforations not only increase the surface area but also provide a mucoadhesive layer that is composed, if anything, of a network of residual "bridges." In this way, faster dissolution / disintegration is achieved upon contact with moist mucosa, which in turn leads to faster softening of the dry, and therefore somewhat stiff, film; the softened film is more comfortable for the patient, especially considering that only the remaining "bridges" of the network need to be softened.

[0066] As mentioned above, the mucoadhesive layer is 1 cm 2 In certain embodiments, the mucoadhesive layer has 5 to 100 perforations per cm. 2 At least 7, at least 10, at least 20, or at least 50 perforations per cm 2 There are fewer than 90, 80, or 60 perforations per cm or the mucoadhesive layer is 2 There are 7 to 90 perforations per piece, 10 to 80 perforations per piece, 20 to 60 perforations per piece, or 50 to 60 perforations per piece.

[0067] The perforations may have any size and configuration, both in terms of the shape of the perforations at the surface of the mucoadhesive layer and in terms of their cross-sectional shape through the mucoadhesive layer, although certain configurations are preferred, particularly from the standpoint of ease of manufacture. That is, holes can be easily made by employing a perforation tool selected from a needle or a punching device, and slits can be easily made by using a cutting device as the perforation tool. Exemplary configurations and shapes of perforations according to the present invention are shown in Figures 7a-7d, 8a-8c, and 9a-9d, and are described below.

[0068] Depending on the depth to which the mucoadhesive layer is penetrated by the perforation tool, the perforation may span the entire thickness of the mucoadhesive layer (through-holes or complete slits) as shown in Figures 7a-7d and 8a-8c, with no residual thickness, or may span only a portion of the thickness of the mucoadhesive layer (pocket holes as shown in Figures 9a-9b, or incomplete slits as shown in Figures 9c-9d), with the perforation having residual thickness, as shown in Figures 9a-9c. Specifically, the cutting device may cut perforations in the form of complete slits by a full-depth cut as shown in Figure 7b, or perforations in the form of incomplete slits by a depth-controlled cut as shown in Figures 9c-9d. A needle-like device may create perforations in the form of through-holes by penetrating the mucoadhesive layer as shown in Figures 7a-8c, or create pocket-hole-like perforations by penetrating the mucoadhesive layer in a controlled depth direction as shown in Figures 9a-9b. Alternatively, the punching device may punch a perforation, thereby removing the punched portion from the mucoadhesive layer.

[0069] Thus, in certain embodiments, the perforations are in the form of holes, particularly through holes or pocket holes, or in the form of slits, particularly complete or incomplete slits, and / or in which the perforations have a circular, elliptical, triangular, rectangular, or hexagonal shape. The perforations may all have the same shape, or they may have two or more different shapes. A substantial portion of the perforations, for example, more than 50%, more than 70%, more than 90%, or even all of the perforations, may have a shape selected from circular, elliptical, triangular, rectangular, and hexagonal shapes, and in particular may have a circular shape. The shape of the perforations viewed from above may be the same throughout the layer thickness, such as cylindrical perforations (Figures 7a, 7b, 9a, and 9b), or tapered and conical perforations (Figures 8a, 8b, 9c, and 9d), or may have any other shape variation within the layer thickness. If the perforations extend only partially through the layer thickness, one side is closed and the perforation opening is on the pierced side. In certain embodiments, the film delivery system is intended to be applied with the pierced side as the mucosa-contacting side, while the closed side faces away from the mucosa. In certain embodiments, the perforations have a frayed edge on one side. Such a frayed edge may be the result of perforations being introduced by piercing with a needle-like device, which pushes material from the pierced layer to the other side, forming a frayed edge (FIG. 7d). The frayed edge may protrude from the surface of the mucoadhesive layer; therefore, while both sides of the mucoadhesive layer can be applied to the mucosa, it is the pierced side, not the frayed side, that is preferably applied to the mucosa, given improved tactility. In such situations, the film delivery system may comprise a means for indicating which side should be applied to the mucosa, which may be as mentioned above.

[0070] In terms of dimensions, the perforations are 1cm in number. 2 The only limitations are that the perforations should be no more than 5-100 per hole and that film delivery systems have practical limitations on their size. Thus, in certain embodiments of the present invention, the perforations are at least 0.0005 cm per hole. 2, at least 0.001 cm 2 , or at least 0.002 cm 2 or perforations have a surface area of ​​0.15 cm per perforation 2 Less than 0.05cm 2 Less than or equal to 0.03cm 2 In certain embodiments, the perforations have a surface area of ​​at least 2%, at least 5%, or at least 10% of the surface area of ​​the mucoadhesive layer, or the surface area of ​​the mucoadhesive layer is 70% or less, 50% or less, or 30% or less. For example, in the case of a film delivery system in which each perforation has the same shape, the surface area of ​​the mucoadhesive layer can be calculated by multiplying the surface area of ​​one perforation by the total number of perforations and dividing the resulting value by the total area of ​​the mucoadhesive layer. If the surface area of ​​the mucoadhesive layer is too small, the beneficial effects of improving tactile sensation and dissolution / disintegration properties may not be significant. On the other hand, if the surface area of ​​the mucoadhesive layer is too large, the integrity and stability of the film may be affected and the amount of film material may be reduced to the extent that a sufficient amount of active ingredient cannot be incorporated.

[0071] In certain embodiments of the invention, the perforations have a circumference of at least 0.1 cm, at least 0.2 cm, or at least 0.3 cm per perforation, or the perforations have a circumference of no more than 2 cm, no more than 1 cm, or no more than 0.8 cm per perforation. In certain embodiments, the circumference per area of ​​the mucoadhesive layer is at least 2 cm / cm 2 , at least 4cm / cm 2 , or at least 8cm / cm 2 or the circumference per area of ​​the mucoadhesive layer is 30 cm / cm 2 Below, 20cm / cm 2 or less, or 15cm / cm 2The circumference per area of ​​the mucoadhesive layer can be calculated, for example, in the case of a film delivery system in which each perforation has one identical configuration, by multiplying the circumference of one perforation by the total number of perforations and dividing the resulting value by the total area of ​​the mucoadhesive layer. Increasing the circumference can be beneficial in promoting dissolution behavior by increasing the sidewall area of ​​the holes or slits, but on the other hand, too long a circumference can also have a negative effect on the stability of the film.

[0072] In certain embodiments of the present invention, the perforations are evenly or non-evenly distributed. If the perforations are evenly distributed, they may be arranged in a triangular, rectangular, staggered, or diagonal pitch. Such even distributions are exemplarily depicted in Figure 10a (triangular pitch), Figure 10b (rectangular pitch), Figure 10c (staggered pitch), or Figure 10d (diagonal pitch).

[0073] In certain embodiments of the present invention, the mucoadhesive layer has non-perforated or no margins, which may have the advantage of providing a more stable edge that can be manipulated with the fingers, for example to remove it from a packaging pouch, without the risk of tearing or breaking the film.

[0074] As outlined above, the perforations may be created by employing a suitable perforation processing tool. Thus, in certain embodiments of the present invention, the perforations are incorporated by using a perforation tool, which may be selected from a cutting device, a needle device, and a punching device.

[0075] Needle-like devices in the sense of the present invention may be selected from the group consisting of needles, needle elements, and pin rollers. They may also comprise needles or pins with 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. Furthermore, needle-like devices may have a blunt tip or a sharp needle head. Needle-like devices incorporate perforations in the form of through-holes by penetrating the mucoadhesive layer, or perforations in the form of pocket holes by penetrating the mucoadhesive layer to a controlled depth.

[0076] Active ingredient As outlined above, the film delivery system according to the present invention comprises an active ingredient, which may be contained in the mucoadhesive layer and / or one or more additional layers. The active ingredient may be any substance of interest that is delivered by the film delivery system to provide a beneficial or desired effect on a subject's condition, either systemically or locally at the delivery site. The active ingredient may be selected in particular from any known active pharmaceutical ingredient, food, supplements such as dietary and / or nutritional supplements (including vitamins, minerals, enzymes, probiotics, etc.), substances for oral care and / or oral hygiene, such as substances acting against bad breath, and lifestyle agents, such as stimulants, natural extracts, and substances for better sleep or against snoring.

[0077] Film-forming agents As outlined above, the film delivery system according to the present invention comprises a mucoadhesive layer that includes a film-forming agent.

[0078] The film-forming polymer that can be used in the present invention is not particularly limited, and any known polymer having film-forming properties, preferably a pharmaceutically acceptable (e.g., approved for pharmaceutical use) polymer, can be used. The film-forming agent may particularly be a dissolvable film-forming agent.

[0079] The film-forming agent forms a matrix that provides sufficient cohesion of the mucoadhesive layer as long as it is kept dry. According to certain embodiments, the film-forming agent may provide sufficient adhesion to the mucosa once wetted, i.e., brought into contact with the mucosa. In such embodiments, but also in general, the film-forming agent may be selected from mucoadhesive polymers.

[0080] The film-forming agent is the primary control of the dissolution / disintegration behavior of the mucoadhesive layer. By selecting an appropriate film-forming agent, the adhesion to the mucosa and disintegration behavior can be appropriately adjusted, for example, in terms of disintegration time as well as the integrity of the film delivery system. In such embodiments, but also in general, the film-forming agent may be selected from dissolvable mucoadhesive polymers.

[0081] In certain embodiments, the film-forming agent may be a polymer, a natural film-forming agent, or a mixture thereof.

[0082] Suitable film formers according to the present invention are, for example, 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® 250L from Ashland Industries), hydroxypropylcellulose (commercially available as Klucel® from Ashland Industries), hydroxypropylmethylcellulose (also known as hypromellose, available from Shin-Etsu as Pharmacoat®), sodium carboxymethylcellulose (the uncrosslinked sodium salt of carboxymethylcellulose, also known as CMC or carmellose, Ashland Industries), and the like. Industries as Blanose®), graft copolymers based on polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam (available commercially as Soluplus® from BASF), polyvinyl alcohol (available commercially as Mowiol® from Kuraray or, for example, as Parteck® MXP from Merck), polyvinyl alcohol-polyethylene glycol copolyesters (available commercially as Kollicoat® IR from BASF), polyvinylpyrrolidone-polyvinyl acetate copolymers (also known as copovidone, available commercially, for example, as Kollidon® VA64 from BASF), polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymers (available commercially as Eudragit® L100, Eudragit® L12, 5, Eudragit® S100, and Eudragit® S12 from Evonik,5), and methacrylic acid-ethyl methacrylate copolymers (available from Evonik as Eudragit® L100-55 and Eudragit® L30D55), and natural film-forming agents such as shellac, pectin, gelatin, alginates, pullulan, and starch derivatives, and mixtures of any thereof.

[0083] In certain embodiments, the film-forming agent is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene oxide, polyvinyl alcohol, and any mixture thereof.

[0084] In a particular embodiment of the present invention, the film-forming agent is hydroxypropyl cellulose.

[0085] Hydroxypropyl cellulose is commercially available from Ashland under the trade name Klucel™ and is available in several grades.

[0086] The grades differ from each other by molecular weight MW (measured by GPC size exclusion chromatography) and Brookfield viscosity (25° C., LVF, free of moisture) and are as follows: The HF grade has a MW of 1,150,000 and a Brookfield viscosity of 1500-3000 (1% aqueous solution). The MF grade has a MW of 850,000 and a Brookfield viscosity of 4000-6500 (2% aqueous solution). The GF grade has a MW of 370,000 and a Brookfield viscosity of 150-400 (2% aqueous solution). The JF grade has a MW of 140,000 and a Brookfield viscosity of 150-400 (5% aqueous solution). The LF grade has a MW of 95,000 and a Brookfield viscosity of 75-150 (5% aqueous solution). The EF grade has a MW of 80,000 and a Brookfield viscosity of 300-600 (10% aqueous solution). The ELF grade has a MW of 40,000 and a Brookfield viscosity of 150-300 (10% aqueous solution).

[0087] In certain embodiments, the film-forming agent is hydroxypropyl cellulose having a molecular weight of 30,000 to 1,500,000, 30,000 to 500,000 (as measured by GPC size exclusion chromatography), or any mixture thereof, and in particular, the hydroxypropyl cellulose is Between 35,000 and 45,000, especially 40,000, Between 75,000 and 85,000, especially 80,000, Between 90,000 and 100,000, especially 95,000, Between 130,000 and 150,000, especially 140,000, Between 350,000 and 400,000, especially 370,000, Between 800,000 and 900,000, especially 850,000, Between 1,100,000 and 1,200,000, especially 1,150,000, or any mixture thereof, having a molecular weight (as measured by GPC size exclusion chromatography) selected from:

[0088] In certain embodiments, the film-forming agent is hydroxypropyl cellulose having a molecular weight of 80,000, 95,000, or 370,000, or any mixture thereof.

[0089] In a particular embodiment of the present invention, the film-forming agent is hydroxypropyl methylcellulose.

[0090] Hydroxypropyl methylcellulose is commercially available from DuPont under the trade name AFFINISOL™ HPMC HME and is offered in several grades.

[0091] The grades differ from each other by molecular weight MW, as follows: The MW of a 15LV grade is 85,000. The MW of a 100LV class is 180,000. The MW of the 4M grade is 550,000.

[0092] Thus, in certain embodiments, the film-forming agent is hydroxypropyl methylcellulose having a MW of 85,000, 190,000, or 550,000, or any mixture thereof.

[0093] In a particular embodiment of the present invention, the film-forming agent is polyethylene oxide.

[0094] Polyethylene oxide is commercially available from Dupont under the trade name POLYOX™ and is offered in several grades.

[0095] The grades differ from each other by molecular weight MW, as follows: The MW of the N-10 grade is 100,000. The MW of the N-80 grade is 200,000. The MW of the N-750 grade is 300,000. The MW of the 205 grade is 600,000. The MW of the 1105 grade is 900,000. The MW of the N-12K grade is 1,000,000. The MW of N-60K is 2,000,000. The MW of the 301 grade is 4,000,000. The MW of the coagulant grade is 5,000,000. The MW of the 303 grade is 7,000,000.

[0096] Thus, in certain embodiments, the film-forming agent is polyethylene oxide having a molecular weight in the range of 100,000 to 7,000,000, or any mixture thereof, and in particular 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.

[0097] More preferably, the film former is polyethylene oxide having a molecular weight of 100,000 or 200,000, or a mixture thereof.

[0098] In a particular embodiment of the invention, the film-forming agent is polyvinyl alcohol.

[0099] Polyvinyl alcohol is commercially available from Kuraray under the trade name Mowiol and from Merck under the trade name Parteck® MXP, for example, and is offered in different grades. In certain embodiments, the film former is polyvinyl alcohol having a molecular weight in the range of 20,000 to 150,000, or any mixture thereof.

[0100] Mowiol partially hydrolyzed grades differ from each other by molecular weight MW and are as follows: The MW of PVA3-83 is 14,000. The MW of PVA4-88 is 31,000. The MW of PVA5-88 is 37,000. The MW of PVA3-82 is 47,000. The MW of PVA8-88 is 67,000. The MW of PVA18-88 is 130,000. The MW of PVA23-88 is 150,000. The MW of PVA26-88 is 160,000. The MW of PVA40-88 is 205,000. Meanwhile, Mowiol fully hydrolyzed grades differ from each other according to molecular weight MW as follows: The MW of PVA3-98 is 16,000. The MW of PVA4-98 is 27,000. The MW of PVA6-98 is 47,000. The MW of PVA10-98 is 67,000. The MW of PVA20-98 is 125,000. The MW of PVA56-98 is 195,000. The MW of PVA28-99 is 145,000. Parteck® MXP4-88 grade PVA has a MW of 32,000, while Parteck® MXP3-82 grade PVA has a MW of 47,000. In these grade names, the first number indicates the apparent viscosity of a 4% aqueous solution at 20°C in mPa·s, and the second number indicates the hydrolysis grade in percent. Thus, Parteck® MXP3-82 indicates a viscosity of 3 mPa·s and an 82% hydrolysis grade, while Parteck® MXP4-88 indicates a viscosity of 4 mPa·s and an 88% hydrolysis grade. Merck similarly offers polyvinyl alcohol grades 5-88, 8-88, 18-88, 26-88, 28-99, and 40-88.

[0101] In a particular embodiment, the film former is polyvinyl alcohol having a molecular weight of 32,000.

[0102] In certain embodiments, the amount of film-forming agent in the mucoadhesive layer is: at least 40 wt%, at least 70 wt%, or at least 80 wt%, 100 wt% or less, or 95 wt% or less, or 100wt% or 90wt% is.

[0103] Further excipients The layers of the film delivery system according to the present invention, in particular the mucoadhesive layer, may each comprise further excipients. Such excipients that can be used in the present invention are not particularly limited, and any known excipients for pharmaceutical preparations, in particular pharmaceutically acceptable (and, for example, approved for pharmaceutical use) excipients, can be employed.

[0104] Thus, in certain embodiments, any one of the layers of the film delivery system, particularly the mucoadhesive layer, further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavoring agents, colorants, penetration enhancers, solubilizers, plasticizers, humectants, disintegrants, wetting enhancers, dissolution enhancers, emulsifiers, antioxidants, stabilizers, buffering agents, and additional film-forming agents.

[0105] In certain embodiments, the plasticizer is selected from the group consisting of mono-, di-, oligo- and polysaccharides and derivatives such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol and medium chain triglycerides.

[0106] In particular embodiments, the fatty acid is selected from the group consisting of saturated or unsaturated, straight-chain or branched carboxylic acids containing from 4 to 24 carbon atoms, in particular caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, and docosahexaenoic acid.

[0107] In certain embodiments, the disintegrant is selected from cross-linked polyvinylpyrrolidones.

[0108] In certain embodiments, any one of the layers of the film delivery system, particularly 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 sodium saccharin.

[0109] In certain embodiments, any one of the layers of the film delivery system, particularly the mucoadhesive layer, comprises one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin, and eucalyptol, and flavoring compositions such as peppermint flavoring.

[0110] Treatment methods / medical uses / applications According to a particular aspect of the present invention, the film delivery system according to the present invention is for use in a method for the treatment and / or prevention of diseases and medical conditions, preferably in a human patient. According to another aspect, the present invention relates to a method of treatment, in which a 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 film delivery system of the present invention for the manufacture of a medicament for treatment, preferably a medicament for the treatment of a human patient.

[0111] In certain embodiments, the film delivery system is for application to a mucosa, particularly a mucosa of the oral cavity of a human patient. In other words, the film delivery system is administered by applying the film to a mucosa, particularly a mucosa of the oral cavity of a human patient, and remaining on the mucosa for a period of time (the administration period), after which the film delivery system dissolves, erodes, substantially disintegrates, or is removed from the application site. In certain embodiments, the present invention also relates to methods of administering a film delivery system according to the present invention to a mucosa, particularly a mucosa of the oral cavity of a human patient. In certain embodiments, the present invention relates to the use of a film delivery system according to the present invention for the manufacture of a medicament for application to a mucosa, particularly a mucosa of the oral cavity of a human patient.

[0112] In the above embodiments, the film delivery system may be applied to the buccal, sublingual, gingival, or palatal mucosa of the oral cavity of a human patient, preferably the buccal mucosa. The administration time may be as short as less than 1 minute, or as long as a few minutes, e.g., 1-10 minutes, 2-10 minutes, or slightly longer, e.g., 10-30 minutes, or even longer, e.g., 30-60 minutes and even longer. If the film delivery system is left in the oral cavity and not removed, the administration time is the time until the film delivery system dissolves, erodes, or substantially disintegrates. The dissolution behavior of the film delivery system can be determined in vitro, e.g., by dissolution experiments. Thus, in certain embodiments, at least 5 wt%, 25 wt%, or 40 wt%, or less than 90 wt%, 70 wt%, or 60 wt%, or 5-90 wt%, 25-70 wt%, or 40-60 wt% of the film delivery system dissolves after 5 minutes when measured using USP Apparatus 1 (basket) in 900 mL of 0.01 N HCl at 37±0.5° C. In certain embodiments, at least 5 wt%, 25 wt%, or 40 wt%, or less than 90 wt%, 70 wt%, or 60 wt%, or 5-90 wt%, 25-70 wt%, or 40-60 wt% of the film delivery system dissolves after 30 minutes when measured using USP Apparatus 1 (basket) in 900 mL of 0.01 N HCl at 37±0.5° C.

[0113] In certain embodiments, the film delivery system according to the present invention is for administration of an active ingredient. In certain further embodiments, the film delivery system is for oral and / or transmucosal administration of an active ingredient. In certain embodiments, the present invention also relates to methods of administration, particularly methods of oral and / or transmucosal administration of 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 a film delivery system according to the present invention for the manufacture of a medicament for administration, particularly oral and / or transmucosal administration of an active ingredient.

[0114] Manufacturing Process The present invention further relates to a process for manufacturing a film delivery system, and in particular to the inventive film delivery system as described above.

[0115] In such a manufacturing process, the mucoadhesive layer is prepared in a first step i) and then perforated in a second step ii). Thus, the inventive manufacturing process of a film delivery system includes a mucoadhesive layer, which is i) preparing a mucoadhesive layer, and ii) Using a drilling tool, 2 5 to 100 perforations per mucoadhesive layer Includes steps.

[0116] The mucoadhesive layer can be prepared by any known conventional method, particularly by a hot melt process or a film casting process. Polymers for hot melt manufacturing processes can be more rigid and often require a certain film thickness (which also results in a more rigid film), for example, to allow for the incorporation of a sufficient amount of active ingredient and / or to ensure the necessary processability. However, thicker and / or harder films can be disadvantageous in terms of tactile sensation and may cause discomfort to the patient. The film delivery system of the present invention, as further described above, provides an improved mouthfeel that compensates for the potentially stiff and thick films of hot melt processable polymers, thus broadening the selection of potential hot melt materials.

[0117] Any conventional hot melt process can be used, such as a vacuum compression molding process commonly used on a laboratory scale, as well as a hot melt extrusion process that is advantageous for large-scale production. Thus, in a particular embodiment, in step i) of the manufacturing process, the mucoadhesive layer is prepared by a hot melt process, which comprises: a) introducing a film-forming agent or a mixture containing a film-forming agent into an extruder; b) heating the film-forming agent or the mixture to at least the softening temperature of the film-forming agent or the mixture; and c) extruding a heated film-forming agent or a heated mixture containing a film-forming agent into a film to obtain a mucoadhesive layer. or a hot melt extrusion process comprising the steps of: a) introducing a film-forming agent or a mixture containing a film-forming agent into the sample chamber; and b) compressing the film-forming agent or the mixture by lowering a piston 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; It is a vacuum compression molding process including steps.

[0118] Of course, the mucoadhesive layer can also be prepared by a conventional film casting process suitable for most polymers. Thus, in a particular embodiment, in step i) of the manufacturing process, the mucoadhesive layer is prepared by a film casting process, which film casting process comprises: a) combining a film-forming agent and a solvent to obtain a coating composition; b) coating the coating composition; and c) drying the coated coating composition to form a mucoadhesive layer Includes steps.

[0119] In step ii), perforations are applied using a perforation tool. As outlined above, in its simplest form, the film delivery system comprises a mucoadhesive layer, and only the mucoadhesive layer needs to be perforated. If the film delivery system is comprised of more layers, perforations may be applied throughout the entire film through all layers, or through at least some of the layers, and more than just the mucoadhesive layer.

[0120] On the other hand, in certain embodiments, the mucoadhesive layer may be perforated and then laminated or otherwise adhered to the remaining layers, thereby resulting in a film delivery system in which only the mucoadhesive layer is perforated. Such a film delivery system may also be made by puncturing to a controlled depth only the mucoadhesive film of the multi-layer film delivery system.

[0121] In any case, the perforations provide the mucoadhesive layer with at least one side covered with openings (the pierced or pierced side), and it is this pierced or orifice-covered side that is intended to be placed on the mucosa (i.e., the mucosa-contacting side).

[0122] Exemplary perforation tools are cutting devices, needle-like devices and punching devices, i.e. in certain embodiments, in step ii) perforations are applied to the mucoadhesive layer by using a perforation tool selected from cutting devices, needle-like devices and punching devices.

[0123] In step ii), when the perforations are made in the mucoadhesive layer by piercing it with a perforation tool selected from needle-like devices, these may be selected from simple needles, needle assemblies, i.e., multiple needles assembled in one device so that multiple perforations can be made simultaneously, and pin rollers, i.e., rollers with multiple pins for piercing that can be installed on a production line for large-scale production processes. Such needle-like devices may comprise needles or pins with a diameter of at least 0.1, 0.2, 0.3, or 0.5 mm, or not more than 3 mm, not more than 2 mm, not more than 1 mm, and may have blunt or sharp needle heads.

[0124] When such needle-like devices are used to create perforations (e.g., through-holes or complete slits) through the entire thickness of the mucoadhesive layer, the penetration with the tip or needle head can push material from the pierced layer to the opposite side, creating a frayed edge (Figure 7d). In such cases, it is the pierced side without the edge that is preferably applied to the mucosa in order to improve tactile sensation.

[0125] When a punching device is used as the perforation device, in step ii) the mucoadhesive layer is perforated by punching it with such a perforation device selected from the punching devices, thereby removing the punched portion from the mucoadhesive layer. By using such a punching device, the formation of edges, which is thought to be advantageous for improved tactile sensation, is avoided. On the other hand, punching removes a portion from the mucoadhesive layer, thereby reducing the amount of active ingredient contained, so from that point of view, piercing or cutting may be more preferable. [Example]

[0126] 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 merely illustrative and should not be construed as limiting the present invention in any way. The numerical values ​​provided in the examples regarding the amount or area weight of components in the composition may vary slightly due to manufacturing variations, but this does not affect the advantages provided by the present invention.

[0127] Example 1 Preparation of mucoadhesive layer samples The formulations and perforation patterns of the mucoadhesive layers used in Comparative Experiments 1a-1e, as well as the area weights, are summarized in Table 1.1 below.

[0128] [Table 1]

[0129] Hydroxypropyl cellulose polymer (Klucel EF, molecular weight: 80,000) was loaded into the sample holder of a MeltPrep® vacuum compression molding (VCM) device from MeltPrep GmbH, which included a sample holder, piston, and lid connected to a vacuum source. The sample was heated to 160°C using a hotplate heater, a vacuum was applied, and the piston was lowered to compress the sample and prevent air bubbles. The resulting homogeneous disk was cooled by convection air cooling and cut into a disk with a diameter of 2.5 cm and an area of ​​4.91 cm. 2 A mucoadhesive layer sample of 1000 mg / ml was obtained.

[0130] Perforation Pattern (for all examples) The mucoadhesive layers were perforated using needles according to one of three perforation patterns (A, B, C), varying the needle diameter and number of perforations. For each perforation pattern, a template with an alternating pattern was prepared (see Figure 1) and attached to a black foam plastic board (pattern A) or a bifold cellulose sheet (patterns B and C). The mucoadhesive samples were attached to the template and manually pierced to the maximum possible penetration depth at each intersection, resulting in uniformly shaped circular perforations. Tables 1.2 and 1.3 below outline the patterns (Table 1.2) and perforation specifications (Table 1.3).

[0131] [Table 2]

[0132] [Table 3]

[0133] Preparation of Film Delivery Systems (for all examples) In this example, the mucoadhesive discs correspond to individual (placebo) film delivery systems. In specific embodiments, such film delivery systems may comprise additional layers, such as cosmetic and / or backing layers. The film delivery systems are then enclosed in pouches of primary packaging material, as is conventional in the art.

[0134] Sample evaluation: Comparative experiments 1a to 1e Each film delivery system was evaluated in terms of initial mouthfeel, fast adhesion to mucosa / low foreign body sensation, and dissolution behavior by applying one film delivery system to each of the left and right buccal mucosa, and the performance of the two delivery systems was compared as shown in Table 1.4. A preliminary experiment was performed to demonstrate that the results were independent of application side; that is, whether one of the two compared systems was applied to the left or right administration site was not critical to the evaluation.

[0135] [Table 4]

[0136] Comparisons 1a-1c show that perforated systems exhibit faster mucosal adhesion, less foreign body sensation, and faster dissolution (as observed by less material remaining on the mucosa) compared to non-perforated systems of the same formulation. Systems with perforation patterns B and C also exhibit favorable initial mouthfeel compared to non-perforated systems. Comparative experiments 1d and 1e show that a higher number of perforations is beneficial to mouthfeel performance, both in terms of initial mouthfeel, as well as mucosal adhesion and foreign body sensation.

[0137] Example 2 Preparation of mucoadhesive layer samples The formulations and perforation patterns of the mucoadhesive layers used in Comparative Experiments 2a-2c, as well as the area weights, are summarized in Table 2.1 below.

[0138] [Table 5]

[0139] The polymer hydroxypropyl cellulose (Klucel EF, molecular weight: 80,000) was mixed with sorbitol and ground using a mortar and pestle. The resulting mixture was loaded into the sample holder of a MeltPrep® VCM device, and mucoadhesive layer samples were prepared in the same manner as described in Example 1.

[0140] Perforation Pattern Perforation of the mucoadhesive layer was performed using needles 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 patterns and perforation specifications).

[0141] Sample evaluation: Comparative experiments 2a-2c Each (placebo) film delivery system (see Example 1 for system preparation) was evaluated in a manner similar to that described in Example 1, resulting in a comparison of the performance of the two administration systems, as shown in Table 2.2 below.

[0142] [Table 6]

[0143] Comparisons 2a and 2b show that perforated systems exhibit faster mucosal adhesion, less foreign body sensation, and faster dissolution (as observed by less material remaining on the mucosa) compared to non-perforated systems of the same formulation. Systems with perforation patterns B and C also exhibit favorable initial mouthfeel compared to non-perforated systems. Comparative experiment 2c shows that a higher number of perforations is beneficial for mouthfeel performance, not only in terms of initial mouthfeel, but also in terms of mucosal adhesion and foreign body sensation. This is particularly beneficial for any relatively stiff film.

[0144] Example 3 Preparation of mucoadhesive layer samples The formulation and perforation pattern of the mucoadhesive layer used in Comparative Experiment 3, as well as the area weight, are summarized in Table 3.1 below.

[0145] [Table 7]

[0146] Mucoadhesive layer samples were prepared as described in Example 1, except that the polymer hydroxypropyl methylcellulose (Affinisol HME 15LV, molecular weight: 85,000) was loaded into the sample holder of the MeltPrep® VCM device and the sample material was heated to 250°C.

[0147] Perforation Pattern Perforation of the mucoadhesive layer was performed using needles according to perforation pattern B described in Example 1 (see Tables 1.2 and 1.3 above for a summary of the pattern and perforation specifications).

[0148] Sample evaluation: Comparative experiment 3 Each (placebo) film delivery system (see Example 1 for system preparation) was evaluated in a manner similar to that described in Example 1, and the performance of the two administration systems was compared, as shown in Table 3.2 below.

[0149] [Table 8]

[0150] Comparative experiment 3 shows that the perforated system performs better in all mouthfeel and dissolution evaluations compared to the non-perforated system of the same formulation.

[0151] Example 4 Preparation of mucoadhesive layer samples The formulation and perforation pattern used in Comparative Experiment 4, as well as the area weight of the mucoadhesive layer, are summarized in Table 4.1 below.

[0152] [Table 9]

[0153] Mucoadhesive layer samples were prepared in a similar manner as described in Example 1, except that the polymer polyethylene oxide (Polyox N10, molecular weight: 100,000) was loaded into the sample holder of the MeltPrep® VCM device and the sample material was heated to 130°C.

[0154] Perforation Pattern Perforation of the mucoadhesive layer was performed using needles according to perforation pattern B described in Example 1 (see Tables 1.2 and 1.3 above for a summary of the pattern and perforation specifications).

[0155] Sample evaluation: Comparative experiment 4 Each (placebo) film delivery system (see Example 1 for system preparation) was evaluated in a manner similar to that described in Example 1, and the performance of the two administration systems was compared, as shown in Table 4.2 below.

[0156] [Table 10]

[0157] Comparative experiment 4 shows that the perforated system performs better in all mouthfeel and dissolution evaluations compared to the non-perforated system of the same formulation.

[0158] Example 5 Preparation of mucoadhesive layer samples The formulations and perforation patterns used in Comparative Experiments 5a-5e, as well as the area weight of the mucoadhesive layer, are summarized in Table 5.1 below.

[0159] [Table 11]

[0160] Mucoadhesive layer samples were prepared in a similar manner as described in Example 1, except that the polymer polyethylene oxide (Polyox N80, molecular weight: 200,000) was loaded into the sample holder of the MeltPrep® VCM device and the sample material was heated to 130°C.

[0161] Perforation Pattern Perforation of the mucoadhesive layer was performed using needles following 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 patterns and perforation specifications).

[0162] Sample evaluation: Comparative experiments 5a to 5e Each (placebo) film delivery system (see Example 1 for system preparation) was evaluated in a manner similar to that described in Example 1, resulting in a comparison of the performance of the two administration systems, as shown in Table 5.2 below.

[0163] [Table 12]

[0164] Comparisons 5a-5c show that perforated systems exhibit faster mucosal adhesion, less foreign body sensation, and faster dissolution (as observed by less material remaining on the mucosa) compared to non-perforated systems of the same formulation. Systems with perforation patterns B and C also exhibit favorable initial mouthfeel compared to non-perforated systems. Comparisons 5d and 5e show that a higher number of perforations is beneficial to mouthfeel performance, both in terms of initial mouthfeel, as well as mucosal adhesion and foreign body sensation.

[0165] Example 6 Preparation of mucoadhesive layer samples The formulation and perforation pattern of the mucoadhesive layer used in Comparative Experiment 6, as well as the area weight, are summarized in Table 6.1 below.

[0166] [Table 13]

[0167] The polymer polyvinyl alcohol (Parteck® MXP4-88, molecular weight: 32,000) was mixed with sorbitol and ground using a mortar and pestle. The resulting mixture was loaded into the sample holder of a MeltPrep® VCM device, and mucoadhesive layer samples were prepared in the same manner as described in Example 1, except that the sample material was heated to 230°C.

[0168] Perforation Pattern Perforation of the mucoadhesive layer was performed using needles according to perforation pattern B described in Example 1 (see Tables 1.2 and 1.3 above for a summary of the pattern and perforation specifications).

[0169] Sample evaluation: Comparative experiment 6 Each (placebo) film delivery system (see Example 1 for system preparation) was evaluated in a manner similar to that described in Example 1, resulting in a comparison of the performance of the two administration systems, as shown in Table 6.2 below.

[0170] [Table 14]

[0171] Comparative experiment 6 shows that the perforated system performs better in all mouthfeel and dissolution evaluations compared to the non-perforated system of the same formulation.

[0172] The present invention particularly relates to the following further items: 1. A film delivery system comprising a mucoadhesive layer, wherein: The mucoadhesive layer comprises a film-forming agent and is 1 cm 2 Each piece has 5 to 100 perforations. The film delivery system. 2. The film delivery system of item 1, wherein the film delivery system has a total weight of at least 5 mg or 10 mg, a total weight of no more than 175 mg or no more than 150 mg, or a total weight of 5 to 175 mg or 10 to 150 mg. 3. The mucoadhesive layer is 1 cm 2 At least 7, at least 10, at least 20, or at least 50 perforations per cm 2 3. The film delivery system of claim 2, wherein the film delivery system has fewer than 90, fewer than 80, or fewer than 60 perforations per film. 4. the perforations are in the form of holes, in particular through holes or pocket holes, or in the form of slits, in particular complete or incomplete slits; and / or 4. The film delivery system of any one of items 1 to 3, wherein the perforations have a circular, oval, triangular, rectangular, or hexagonal shape. 5. The perforations are at least 0.0005 cm per perforation. 2 , at least 0.001 cm 2 , or at least 0.002 cm 2 or at least 2%, at least 5%, or at least 10% of the surface area of ​​the mucoadhesive layer. 6. The perforations are 0.15cm per perforation 2 Less than 0.05cm 2 Less than or equal to 0.03cm 2 6. The film delivery system of any one of items 1 to 5, having a surface area of ​​70% or less, 50% or less, or 30% or less per area of ​​the mucoadhesive layer. 7. The perforations have a circumference of at least 0.1 cm, at least 0.2 cm, or at least 0.3 cm per perforation, or the circumference per area of ​​the mucoadhesive layer is at least 2 cm / cm 2 , at least 4cm / cm 2 , or at least 8cm / cm 2 7. The film delivery system of any one of items 1 to 6, wherein 8. The perforations have a circumference of 2 cm or less, 1 cm or less, or 0.8 cm or less per perforation, or the circumference per area of ​​the mucoadhesive layer is 30 cm / cm 2 Below, 20cm / cm 2 or less, or 15cm / cm 2 8. The film delivery system of any one of items 1 to 7, wherein: 9. The film delivery system of any one of items 1 to 8, wherein the perforations all have the same configuration or have two or more different configurations. 10. The film delivery system of any one of items 1-9, wherein the perforations are evenly or non-uniformly spaced. 11. The film delivery system of item 10, wherein the perforations are uniformly spaced at a triangular, rectangular, staggered, or diagonal pitch. 12. The film delivery system of any one of items 1 to 11, wherein the mucoadhesive layer has non-perforated margins or no margins. 13. The film delivery system of any one of items 1-12, wherein the perforations are incorporated by using a perforation tool. 14. The film delivery system of claim 13, wherein the perforation tool is selected from a cutting device, a needle-like device, and a punching device. 15. The film delivery system of item 14, wherein the needle-like device is selected from the group consisting of a needle, a needle assembly, and a pin roller. 16. The film delivery system of item 14 or 15, wherein the needle-like device comprises a needle or pin having a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm, or 0.5 mm. 17. The film delivery system of any one of items 14-16, wherein the needle-like device comprises a needle or pin having a diameter of 3 mm or less, 2 mm or less, or 1 mm or less. 18. The film delivery system of any one of items 14 to 17, wherein the needle-like device comprises a blunt tip or a sharp needle head. 19. The film delivery system according to item 14, wherein the cutting device cuts perforations in the form of complete slits by full depth cutting or cuts perforations in the form of incomplete slits by depth controlled cutting, the needle device penetrates the mucoadhesive layer to incorporate perforations in the form of through-holes or penetrates the mucoadhesive layer to a controlled depth to incorporate pocket-hole-like perforations; and the punching device punches a perforation, thereby removing the punched portion from the mucoadhesive layer; The film delivery system. 20. The film delivery system according to any one of items 1 to 19, wherein the mucoadhesive layer is obtainable by a hot melt process or a film casting process. 21. The film delivery system of any one of items 1 to 20, wherein the film former is a dissolvable film former. 22. The film delivery system of any one of items 1 to 21, wherein the film former is a polymer, a natural film former, or any mixture thereof. 23. The film delivery system according to any one of items 1 to 22, wherein the film-forming agent is: a polymer selected from the group consisting of polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyethylene glycol, polyvinyl acetate, and polyvinyl caprolactam-based graft copolymers, 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-forming agent selected from the group consisting of shellac, pectin, gelatin, alginate, pullulan, and starch derivatives; or It is a mixture of them, The film delivery system. 24. The film delivery system of item 23, wherein the film-forming agent is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyvinyl alcohol, and any mixture thereof. 25. The film delivery system of item 24, wherein the film-forming agent is hydroxypropyl cellulose. 26. The film delivery system according to item 25, wherein 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. 27. The film delivery system of item 26, wherein the film former is hydroxypropyl cellulose having a molecular weight of 80,000, 95,000, or 370,000, or any mixture thereof. 28. The film delivery system of item 24, wherein the film former is hydroxypropyl methylcellulose. 29. The film delivery system of item 24, wherein the film former is hydroxypropyl methylcellulose having a molecular weight of 85,000, 180,000, or 550,000, or any mixture thereof. 30. The film delivery system of item 24, wherein the film former is polyethylene oxide. 31. The film delivery system of item 30, wherein the film former is polyethylene oxide having a molecular weight in the range of 100,000 to 7,000,000, or any mixture thereof. 32. The film delivery system of item 31, 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. 33. The film delivery system of item 32, wherein the film former is polyethylene oxide having a molecular weight of 100,000 or 200,000, or a mixture thereof. 34. The film delivery system of item 24, wherein the film former is polyvinyl alcohol. 35. The film delivery system of item 34, wherein the film former is polyvinyl alcohol having a molecular weight in the range of 20,000 to 150,000, or any mixture thereof. 36. The film delivery system of item 35, wherein the film former is polyvinyl alcohol having a molecular weight of 32,000. 37. The film delivery system according to any one of items 1 to 36, wherein the amount of the film-forming agent is: at least 40 wt%, at least 70 wt%, or at least 80 wt%, 100 wt% or less, or 95 wt% or less, or 100wt% or 90wt%, The film delivery system. 38. The film delivery system of any one of items 1 to 37, wherein the mucoadhesive layer further comprises one or more excipients selected from the group consisting of fatty acids, sweeteners, flavoring agents, coloring agents, penetration enhancers, solubilizers, plasticizers, humectants, disintegrants, wetting enhancers, dissolution enhancers, emulsifiers, antioxidants, stabilizers, buffering agents, and additional film-forming agents. 39. The film delivery system of item 38, wherein the adhesive layer further comprises a plasticizer selected from the group consisting of mono-, di-, oligo-, and polysaccharides and derivatives such as sorbitol, polyethylene glycol, triacetin, triethyl citrate, propylene glycol, glycerol, and medium chain triglycerides. 40. The film delivery system according to item 39, wherein the mucoadhesive layer is fatty acids selected from the group consisting of saturated or unsaturated, linear or branched carboxylic acids containing from 4 to 24 carbon atoms, in particular caprylic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexaenoic acid, and / or 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 sodium saccharin; and / or one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin, and eucalyptol, and flavoring compositions such as peppermint flavoring; The film delivery system further comprises: 41. The mucoadhesive layer has a thickness of at least 70 g / m 2 , at least 100g / m 2 , or at least 200 g / m 2 41. The film delivery system of any one of items 1 to 40, having an areal weight of 42. The mucoadhesive layer has a thickness of 700 g / m 2 Below 500g / m 2 Below 400g / m 2 or less, or 300 g / m 2 42. The film delivery system of any one of items 1 to 41, having an areal weight of: 43. The film delivery system according to any one of items 1 to 42, wherein: the film delivery system may or may not include a cosmetic layer; and / or the film delivery system may or may not include a backing layer; and / or the film delivery system is provided with a means for indicating which side must be applied to the mucosa, in particular, the means being one-sided coloring or marking, or the presence of a removable release liner; The film delivery system. 44. The film delivery system of any one of items 1 to 43, which is a tacky adhesive delivery system. 45. A film delivery system according to any one of items 1 to 44, for application to mucous membranes, in particular the oral mucosa of a human patient. 46. ​​A film delivery system according to item 45 for application to the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient, preferably the buccal mucosa. 47. A film delivery system according to any one of items 1 to 46 for administration of an active ingredient, in particular for oral and / or transmucosal administration of an active ingredient. 48. The film delivery system according to any one of items 45 to 47, wherein: The film delivery system is administered by applying and maintaining the film on the mucosa for an administration period, after which the film delivery system dissolves, erodes, or substantially disintegrates or is removed from the application site; and / or At least 5 wt%, 25 wt%, or 40 wt%, or less than 90 wt%, 70 wt%, or 60 wt%, or 5-90 wt%, 25-70 wt%, or 40-60 wt% of the film delivery system dissolves after 5 minutes when measured in 900 mL of 0.01 N HCl at 37±0.5°C using USP Apparatus 1 (basket). The film delivery system. 49. The film delivery system of any one of items 1 to 48 for use in a method of treating a human patient. 50. A method of treatment comprising administering the film delivery system described in any one of items 1 to 49 to a human patient. 51. Use of a film delivery system according to any one of items 1 to 49 for the manufacture of a medicament for treating a human patient. 52. A process for manufacturing a film delivery system comprising a mucoadhesive layer, comprising: i) preparing a mucoadhesive layer, and ii) Using a drilling tool, 25 to 100 perforations per mucoadhesive layer The manufacturing process includes the steps of: 53. The process according to item 52, wherein in step i) the mucoadhesive layer is prepared by a hot melt process or a film casting process. 54. The process according to item 53, wherein in step i) the mucoadhesive layer is prepared by a hot melt process, which comprises: a) introducing a film-forming agent or a mixture containing a film-forming agent into an extruder; b) heating the film-forming agent or the mixture to at least the softening temperature of the film-forming agent or the mixture; and c) extruding a heated film-forming agent or a heated mixture containing a film-forming agent into a film to obtain a mucoadhesive layer. or a hot melt extrusion process comprising the steps of: a) introducing a film-forming agent or a mixture containing a film-forming agent into the sample chamber; and b) compressing the film-forming agent or the mixture by lowering a piston 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; A vacuum compression molding process including the steps of: The process in question. 55. The process according to item 53, wherein: In step i), the mucoadhesive layer is prepared by a film casting process, the film casting process comprising: a) combining a film-forming agent and a solvent to obtain a coating composition; b) coating the coating composition; and c) drying the coated coating composition to form a mucoadhesive layer The process, including steps. 56. The process according to any one of items 52 to 55, wherein in step ii) perforations are made in the mucoadhesive layer by using a perforation tool selected from a cutting device, a needle-like device and a punching device. 57. The process according to item 56, In step ii), perforating the mucoadhesive layer by piercing the mucoadhesive layer with a perforation tool selected from a needle-like device; and The needle-like device is selected from the group consisting of a needle, a needle assembly, and a pin roller. The process in question. 58. The process according to item 57, wherein the needle-like device comprises a needle or pin having a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm, or 0.5 mm. 59. The process according to item 57 or 58, wherein the needle-like device comprises a needle or pin having a diameter of 3 mm or less, 2 mm or less, or 1 mm or less. 60. The process according to any one of items 57 to 59, wherein the needle-like device has a blunt tip or a sharp needle head. 61. The process according to item 56, wherein in step ii), perforations are provided in the mucoadhesive layer by punching the mucoadhesive layer with a perforation device selected from the punching devices, thereby removing the punched portions from the mucoadhesive layer. 62. A film delivery system comprising a mucoadhesive layer, wherein: The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 10 to 20 perforations per unit, the perforations occupy at least 10% and no more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 4 cm / cm per unit area of ​​the mucoadhesive layer. 2 , and 15cm / cm 2 It has a circumference of: The perforations are all circular in shape and uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 400 g / m2 having an areal weight of: The film delivery system. 63. A film delivery system comprising a mucoadhesive layer, wherein: The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 50 to 60 perforations per unit, the perforations occupy at least 5% and not more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 8 cm / cm per unit area of ​​the mucoadhesive layer. 2 , 15cm / cm 2 It has a circumference of: The perforations are all circular in shape and uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 400 g / m 2 having an areal weight of: The film delivery system. 64. A film delivery system comprising a mucoadhesive layer, wherein: the film delivery system has a total weight of 5 to 175 mg; The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 10 to 20 perforations per unit, the perforations occupy at least 10% and no more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 4 cm / cm per unit area of ​​the mucoadhesive layer. 2 , and 15cm / cm 2 It has a circumference of: The perforations are all circular in shape and uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 400 g / m 2 having an areal weight of: The film delivery system. 65. A film delivery system comprising a mucoadhesive layer, wherein: the film delivery system has a total weight of 5 to 175 mg; The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 50 to 60 perforations per unit, the perforations occupy at least 5% and not more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 8 cm / cm per unit area of ​​the mucoadhesive layer. 2 , 15cm / cm 2 It has a circumference of: The perforations are all circular in shape and uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 400 g / m 2 having an areal weight of: The film delivery system. 66. A film delivery system comprising a mucoadhesive layer, wherein: The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 10 to 20 perforations per unit, the perforations occupy at least 10% and no more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 4 cm / cm per unit area of ​​the mucoadhesive layer. 2 , and 15cm / cm 2 It has a circumference of: The perforations are all circular in shape and uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 300 g / m 2 The film delivery system has an areal weight of: 67. A film delivery system comprising a mucoadhesive layer, wherein: The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm 2 At least 50 to 60 perforations per unit, the perforations occupy at least 5% and not more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 8 cm / cm per unit area of ​​the mucoadhesive layer. 2 , 15cm / cm 2 It has a circumference of: The perforations are all circular in shape and uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m 2 , and 300 g / m 2 having an areal weight of: The film delivery system.

Claims

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

2. 10. The film delivery system of claim 1, wherein the film delivery system has a total weight of at least 5 mg or 10 mg, a total weight of no more than 175 mg or no more than 150 mg, or a total weight of 5 to 175 mg or 10 to 150 mg.

3. The mucoadhesive layer is 1 cm ２ at least 7, at least 10, at least 20, or at least 50 perforations per cm ２ and / or the perforations are in the form of holes, in particular in the form of through holes or pocket holes, or in the form of slits, in particular in the form of complete or incomplete slits; and / or The perforations have a circular, oval, triangular, rectangular or hexagonal shape; 3. The film delivery system of claim 1 or 2.

4. The perforations have a thickness of at least 0.0005 cm per perforation ２ , at least 0.001 cm ２ , or at least 0.002 cm ２ surface area of ​​0.15 cm ２ Below, 0.05cm ２ Less than or equal to 0.03 cm ２ 4. The film delivery system of claim 1, wherein the film has a surface area of ​​at least 2%, at least 5%, or at least 10% of the surface area per area of ​​the mucoadhesive layer, or at most 70%, at most 50%, or at most 30% of the surface area per area of ​​the mucoadhesive layer.

5. The perforations have a circumference of at least 0.1 cm, at least 0.2 cm, or at least 0.3 cm per perforation, a circumference of no more than 2 cm, no more than 1 cm, or no more than 0.8 cm per perforation, and at least 2 cm / cm per area of ​​the mucoadhesive layer. ２ , at least 4 cm / cm ２ , or at least 8 cm / cm ２ or 30 cm / cm per area of ​​the mucoadhesive layer ２ Below, 20cm / cm ２ or less, or 15cm / cm ２ 5. The film delivery system of any one of claims 1 to 4, having a perimeter of:

6. 6. The film delivery system of any one of claims 1 to 5, wherein the perforations all have the same configuration or have two or more different configurations, or are evenly or non-evenly spaced.

7. The film delivery system of any one of claims 1 to 6, wherein the film former is a dissolvable film former.

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

9. The mucoadhesive layer has a thickness of at least 70 g / m ２ , at least 100 g / m ２ , or at least 200 g / m ２ or 700 g / m ２ Below, 500g / m ２ Below, 400g / m ２ or less, or 300 g / m ２ 9. The film delivery system of any one of claims 1 to 8, having an areal weight of:

10. 10. A film delivery system according to any one of claims 1 to 9 for application to a mucosa, in particular the oral mucosa of a human patient, preferably the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient.

11. A film delivery system according to any one of claims 1 to 10 for administration of an active ingredient, preferably for oral and / or transmucosal administration of an active ingredient.

12. 1. A method of making a film delivery system comprising a mucoadhesive layer, comprising: i) preparing a mucoadhesive layer, and ii) Using a drilling tool, ２ 5-100 perforations per mucoadhesive layer The manufacturing method includes the steps of:

13. 13. The process according to claim 12, wherein in step ii) perforations are made in the mucoadhesive layer by using a perforation tool selected from a cutting device, a needle-like device and a punching device, wherein preferably: the perforation tool is selected from a needle-like device selected from the group consisting of a needle, a needle assembly, and a pin roller, and more preferably has a diameter of at least 0.1 mm, 0.2 mm, 0.3 mm, or 0.5 mm, or comprises a needle or pin having a diameter of 3 mm or less, 2 mm or less, or 1 mm or less; or the perforation tool is selected from a punching device, whereby the punched portion is removed from the mucoadhesive layer; 13. The process of claim 12.

14. 1. A film delivery system comprising a mucoadhesive layer, wherein: The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm ２ At least 10 to less than 20 perforations are provided per unit area; the perforations occupy at least 10% and no more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 4 cm / cm per unit area of ​​the mucoadhesive layer. ２ , and 15 cm / cm ２ It has a circumference of: the perforations all have a circular shape and are uniformly distributed; and The mucoadhesive layer has a thickness of at least 200 g / m ２ , and 400 g / m ２ having an areal weight of: The film delivery system.

15. 1. A film delivery system comprising a mucoadhesive layer, wherein: The mucoadhesive layer comprises a dissolvable film-forming agent and is 1 cm ２ At least 50 to less than 60 perforations are provided per unit area; the perforations occupy at least 5% and no more than 30% of the surface area per unit area of ​​the mucoadhesive layer; The perforations are at least 8 cm / cm per unit area of ​​the mucoadhesive layer. ２ , 15cm / cm ２ It has a circumference of: the perforations all have a circular shape and are uniformly distributed; and the mucoadhesive layer has an area weight of at least 200 g / sq. m and no more than 400 g / sq. m; The film delivery system.

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