Pharmaceutical dosage form for administration to mucous membranes and method for production thereof

Abstract

The present invention relates to a pharmaceutical dosage form for administration to mucous membranes, in particular buccal, intestinal, rectal or vaginal mucous membranes, comprising at least one string-or strip-shaped formulation comprising an active pharmaceutical ingredient, said dosage form being configured to be wettable during the step of administration to a patient. The invention also relates to a method for producing said pharmaceutical dosage form.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080020959.5 and application date of March 13, 2020. The patent application 202080020959.5 is an application for international patent application PCT / EP2020 / 056934 to enter the Chinese national phase.

[0002] The present invention relates to a pharmaceutical dosage form for administration to a mucosa, in particular to the buccal, gastrointestinal, rectal or vaginal mucosa. The present invention also relates to a method for producing a pharmaceutical dosage form and a method for producing a capsule device for a pharmaceutical dosage form.

[0003] Such a dosage form is known from WO 2016 / 102067 A1. The pharmaceutical dosage form of WO 2016 / 102067 A1 is designed so that it comprises: at least one sheet-shaped, in particular film-shaped, foil-shaped or sheet-shaped preparation comprising an active pharmaceutical ingredient, a release mechanism and a trigger mechanism, wherein the trigger mechanism is adapted to be triggered at a predetermined site of action, in particular the gastrointestinal tract, the rectum or the vagina, and the sheet-shaped preparation is released through the release mechanism.

[0004] From the invention according to WO 2016 / 102067 A1 Figure 8 The known dosage form has an elongated strip-shaped preparation comprising an active pharmaceutical ingredient, the preparation being capable of being arranged in a compact state and in an expanded state, the dosage form having a capsule comprising a hollow space for accommodating the compact preparation, the capsule device having an orifice, and a first end of the preparation in the compact state extending through the orifice for allowing the preparation to be pulled out of the hollow space into the surrounding area of ​​the capsule, thereby transferring the preparation from the compact state to the expanded state.

[0005] In the experiments of the inventors, it was unexpectedly found that the wetting of the compacted sheet preparation during the administration of the dosage form to the desired site of action is not a situation that is generally avoided, but is quite beneficial for improving the reliability of the mechanical process of the preparation expanding from the compact state to the expanded state. Pull-out tests show that the maximum pulling force for pulling the preparation out of the capsule under wet conditions is generally lower than that under dry conditions. Therefore, the dosage form can be easily administered to the site of action, and the risk of the sheet preparation breaking is reduced.

[0006] Based on experimental findings, the problem underlying the present invention is to improve the reliability of the mechanical process of the formulation expanding from a compact state to an expanded state.

[0007] This problem is solved by a pharmaceutical dosage form according to claim 1, a method for producing a capsule device for a pharmaceutical dosage form according to claim 15 and a method for producing a pharmaceutical dosage form according to claim 16. Preferred embodiments of the invention are subject matter of the dependent claims.

[0008] According to the present invention, the size of the opening and the preparation is arranged so that when the preparation is pulled out from the opening, the spacing is arranged in the opening cross section of the opening between the preparation and the surface of the capsule device defining the opening. Due to the spacing in the opening, when the preparation is pulled out through the opening, any friction between the preparation and the capsule surface defining the opening is minimized and the risk of the elongated preparation getting stuck is reduced. In addition, the wetting of the preparation inside the capsule device is possible, for example, by flushing the opening of the capsule device with water. Wetting can be achieved, for example, during the oral administration of the dosage form, wherein the patient swallows the dosage form with a mouthful of water. The resulting advantage of the configuration of the dosage form according to the present invention is to enhance the reliability of the mechanical process of the preparation expanding from a compact state to an expanded state.

[0009] The shape of the opening preferably corresponds to the outer contour of the elongated preparation in a plane perpendicular to the length axis of the elongated preparation. For example, in the case of a strip preparation, a slit-shaped opening is preferred, while a circular opening can be provided in the case of a string preparation. The opening here basically provides a rectangular channel cross section, while the cross section of the strip preparation is also basically rectangular. In the case of a string preparation, the opening can provide a circular channel cross section, while the cross section of the strip preparation can also be basically circular. In this way, the movement of the elongated preparation relative to the capsule device is guided by the opening and relative position of the capsule device, and the preparation is stabilized while being pulled out of the capsule device.

[0010] Preferably, the opening is a slit-shaped opening configured to allow the strip preparation to pass through the opening, wherein preferably, when the strip preparation moves through the opening, the cross-section (CS) of the opening is greater than the cross-section of the strip preparation. Herein, the cross-section of the opening defines a surface, and the cross-section of the strip preparation is preferably measured within the surface, and the strip preparation is preferably centered within the opening.

[0011] The spacing S in the opening cross section of the opening between the elongated preparation and the surface of the capsule device defining the opening is preferably measured when the cross section of the opening and the cross section of the elongated preparation are centered longitudinally on an imaginary axis A of the capsule device. The size of the opening resulting in the spacing S is preferably calculated by the dimension a, which is the diameter or width of the opening, and t, which is the diameter of a string-like preparation or the thickness of a strip of a strip-like preparation, where a=t+2*S, see Figure 1c. : S preferably ranges from 10 to 2000 or 20 to 1500 or 50 to 1000 or 100 to 750 or 200 to 500 or 300 to 400 micrometers (μm), respectively. S is greater than zero and is preferably greater than the value t, in particular S=f*t, f being a numerical factor selected from 1 to 20, preferably 2 to 15, more preferably 3 to 12. Dimension a is preferably selected such that it ranges from 100 to 4000, 100 to 2000 or 200 to 1500 or 300 to 1000 or 400 to 800 or 500 to 700 or 600 micrometers (μm), respectively.

[0012] In the case of a strip-shaped preparation and a slit-shaped opening, the length c of the passage section through which the strip-shaped preparation passes when it is pulled outward is greater than the width w of the strip of the strip-shaped preparation. The passage section is greater than the section of the elongated preparation in the same plane.

[0013] The capsule device is usually a container configured for buccal, gastrointestinal, rectal or vaginal administration, respectively. In particular, the capsule device is a swallowable object, which particularly means that the size and outer shape of the capsule device are suitable for swallowing the capsule device.

[0014] The capsule device may be a capsule comprising a hollow cylinder, both sides of which are capped by a curved cap member. The cap member may have substantially the shape of a hemisphere. The cap member may be manufactured as one piece with the cylindrical portion. The two parts of the capsule device may be joined to form the capsule device - this facilitates assembling the dosage form by first placing the formulation in one of the two parts and then securing the formulation by joining the two parts of the capsule device. The capsule may also be shaped to have an elliptical or oval cross-section, so that the capsule has the shape of, for example, an olive.

[0015] The capsule device may have an elongated shape, which means that the length measured along an imaginary central axis A of the capsule device is greater than one or more lateral outer dimensions thereof. The capsule device may be rotationally symmetric relative to the central axis A without taking the opening into account.

[0016] The capsule device may have more than one opening, in particular two openings, or more than two openings.

[0017] In a preferred embodiment, the capsule device is configured so that the opening is offset from the central axis A, which means that the central axis A does not intersect the opening cross section or that the central axis A does not intersect the center point of the opening cross section. Such an embodiment has the advantage that when the preparation is pulled out of the capsule device and the capsule device is administered to a patient, the force acting on the wall forming the capsule device is reduced and the risk of damaging the capsule device is thereby reduced. In experiments by the inventors, it was found that, in particular for a strip-shaped preparation, the unwinding of a rolled preparation is facilitated by an opening arranged offset from the central axis A compared to a central position of the opening (a central position such that the central axis A of the capsule device passes through the center of the opening).

[0018] In case of a slit-like opening, the opening is preferably arranged offset from the central axis A of the capsule device. The slit is formed by opposing surfaces forming the walls of the capsule device.

[0019] For example, when milling away the walls forming the capsule device, a preferred shape of the slit is achieved such that a plate-shaped volume is subtracted from the capsule wall - when considering the capsule device and the cut volume as three-dimensional mathematical objects. The orientation of the plate-shaped volume subtracted from the capsule material is characterized by the orientation of the main planes of the plate-shaped volume, in particular with respect to the direction of the virtual center axis A of the capsule device. Figure 7e In the drawing, the principal plane is defined by lines C and B, B being perpendicular to the drawing surface and perpendicular to A. The resulting shape of the slit is hereinafter referred to as a "planar curved slit", in which the slit follows the outer curved contour of the capsule device, but is straight when viewed perpendicular to the open cross section or in the principal plane, respectively. The length b of the slit (see Figure 1b ) parallel to the principal plane BC (see Figure 7e ). This can be achieved by using a flat milling tool, such as a flat saw blade, or other tools that produce a plate-shaped cutting volume, for example, a cylindrical milling head that performs lateral movement, or a water jet that uses a lateral movement in an abrasive water jet cutting process. In addition, a laser can be used to cut or ablate material from the capsule material to produce the slit. In addition, punching can be used to produce a slit through the capsule material to produce a slit-shaped hole via shearing. However, the opening can also be produced by injection molding a suitable material such as plastic to form the capsule device. The opening preferably has the shape of a flat curved slit. The planar characteristics of the curved slit provide the advantage of facilitating the passage of the strip preparation through the slit in the pull-out direction P, and thereby further improving the reliability of the mechanical process of the preparation expanding from a compact state to an expanded state.

[0020] The slit-shaped opening is preferably arranged such that the normal N to the main plane of the planar curved slit comprises an angle α with the central axis A of the capsule device, wherein preferably 0°<α<90° (see Figure 7e). In a preferred configuration of the slit-shaped opening, wherein the slit-shaped opening is offset from the central axis A of the capsule device, the angle α is zero. In another preferred configuration of the slit-shaped opening, the angle α is 45°, and in a more preferred embodiment, the angle α is 90°.

[0021] The slit-like openings are preferably arranged such that a main plane extending through the openings is parallel to an axis B which is perpendicular to a central axis A of the capsule device (see Figure 7e ). Such a configuration matches the winding of the strip preparation, which is wound around a winding axis parallel to the axis B, and facilitates the unwinding process.

[0022] Preferably, the capsule device comprises a guide member, which is arranged inside the inner space of the capsule device to guide the movement of the string-shaped or sheet-shaped preparation toward the opening of the capsule device. The guide member can be a part of the inner wall of the capsule device or a part supported by or connected to the inner wall of the capsule device, in particular a wall member.

[0023] The capsule device may include an auxiliary device configured to guide the winding and / or uncoiling of a string-like preparation or the winding and / or unwinding of a strip-like preparation, in particular by winding or winding the preparation around one or more rods or cylinders of the auxiliary device. The rod or cylinder may be rotatably arranged inside the capsule device to facilitate the unwinding or unwinding.

[0024] The hollow space inside the capsule device is defined by at least one inner wall of the capsule device. In a preferred embodiment, the capsule device is defined by a wall having an outer side facing the surrounding of the capsule device and having an inner side facing the hollow space. Preferably, the inner side (inner surface) and the outer side (outer surface) extend parallel to each other, which means that the outer contour surface of the hollow space is similar to the outer contour surface of the capsule device. However, it is also possible and preferred that the inner surface of the capsule device is at least partially not parallel to the outer contour surface of the capsule device. Such a configuration allows an auxiliary structure to be defined inside the capsule device, which helps to guide the movement or other effects of the preparation inside the capsule device. Preferably, the auxiliary structure is an internal guide wall of the capsule device, which is arranged to guide the unwinding and / or unwinding of the preparation inside the capsule device. The guide wall is arranged to guide the positioning of the preparation during the unwinding and / or unwinding of the preparation. Preferably, the guide wall is arranged to be parallel to the direction of movement P, through which the preparation moves toward the opening inside the capsule device. Preferably, the guide wall is arranged to align with the opening.

[0025] Preferably, one or more inner walls of the capsule device are arranged to form a guide compartment inside the capsule device. The guide compartment is arranged to support the preparation in its compact state and to help unwind the preparation. Preferably, one or more inner walls of the capsule device are arranged to form side walls of a rectangular hollow space containing the preparation in its compact state.

[0026] In another preferred embodiment, the pharmaceutical dosage form, particularly the capsule device, includes a sinker device. The sinker device is configured to provide negative buoyancy to the capsule device. In the experiments of the inventors based on the discovery of the preferred embodiment, it was found that, for example, the reliability of the mechanical process of the preparation extending from the compact state to the unfolded state is improved by reducing the buoyancy by increasing the mass of the capsule device. In the case of a strip preparation, the preparation is significantly promoted and more effective to be unwound from the compact state (wherein the strip preparation is wound around the winding axis). The fundamental problem of the preferred embodiment is that it is observed that the preparation is sometimes incomplete when it is transferred from the compact state to the unfolded state. Although the present invention has improved the efficiency of expansion or unwinding respectively by setting a spacing between the opening and the preparation, the sinker device additionally increases the expansion efficiency. Assuming that the capsule device is not completely filled with water if it is swallowed correctly by the patient in the presence of water or an aqueous solution, the bubble sometimes stays inside the capsule device. Air contributes to buoyancy, and the sinker device helps to resist the buoyancy effect by assisting air displacement or by using a material denser than water to utilize gravity.

[0027] The settler device can be realized by various preferred configurations. The settler device can be configured to include at least one settler element, preferably exactly one settler element, the settler element being an insert part or an attachment part, respectively, preferably having a density greater than air, the air density being about 1.2 kg / m 3 .

[0028] The settler element as the insertion part is preferably inserted, preferably loosely inserted or preferably attached inside the hollow space of the capsule device. The insertion part occupies a certain occupied volume inside the hollow space of the capsule device. Therefore, the occupied volume can no longer be occupied by air. As a result, the buoyancy is reduced. When the density of the insertion part is greater than the density of water (i.e. about 1 g / cm 3), the expansion of the compact formulation is also supported by the excess weight of the insert portion - the excess weight being the weight of the difference between the mass of the insert portion and the mass of water displaced by the insert portion. The insert portion may be attached to the inner wall of the capsule device, for example by a force fit connection or by an adhesive that is preferably soluble in water. Preferably, the insert portion is attached to the inner side of the capsule device by sizing the insert portion so that the insert portion is sandwiched between portions of the inner wall of the capsule device, for example inside the capsule device between opposing portions of the inner wall. For example, an insert portion having a circular cross section of radius R may be inserted into a capsule device having a circular cross section that is substantially the same as or slightly smaller than radius R.

[0029] The settler element may be attached to any part of the pharmaceutical dosage form, thereby forming an attachment portion of the pharmaceutical dosage form or the capsule device, respectively. The attachment portion may in particular be attached to the outer surface of the pharmaceutical dosage form or the capsule device, respectively. The density of the attachment portion or a part thereof is preferably greater than the density of water (i.e. about 1 g / cm3).

[0030] The density of the settler element or the material comprised by the settler element is preferably greater than 1.2 kg / m 3 , preferably greater than the density of water measured at 21°C, and preferably greater than 1.0 g / cm 3 . The density of the settler element or the material comprised by the settler element is preferably between 1.0 g / cm3 and 2.0 g / cm3. This range is achieved by many water-soluble materials, such as sucrose, dextrose, lactose, fructose, each of which is preferred. Preferred materials also include microcrystalline cellulose, sorbitol, xylitol, isomalt and gelatin. It is also preferred that the density of the settler element or the material comprised by the settler element is preferably between 1.0 g / cm3 and 20.0 g / cm3, between 1.0 g / cm3 and 5.0 g / cm3, between 1.0 g / cm3 and 10.0 g / cm3, thereby including even denser materials, such as metals, preferably tungsten. Such a settler element is also referred to as a "weight element".

[0031] In a preferred embodiment, the settler element comprises or consists of a compressed material, in particular a granular substance or a mixture, comprising or consisting of dicalcium phosphate, preferably anhydrous dicalcium phosphate, preferably in a concentration of preferably 93 mol% to 99 mol%, preferably 98 mol%. The material may also include crosslinked sodium carboxymethylcellulose, preferably in a concentration of preferably 0.25 mol% to 0.75 mol%, preferably 0.5 mol%, which is particularly used as a disintegrant. The material may also include magnesium stearate, preferably in a concentration of preferably 1.0 mol% to 2.0 mol%, preferably 1.5 mol%, which is particularly used as a glidant and / or lubricant. The material may also include colloidal silicon dioxide, preferably in a concentration of preferably 0.25 mol% to 0.75 mol%, preferably 0.5 mol%, which is particularly used as a flow regulator and / or disintegrant. The material consisting of one or more of the components or similar components is preferably substantially insoluble in water, and the material is disintegrated by the disintegrant component. The material may include additional suitable excipients. Calcium hydrogen phosphate dihydrate, preferably at a concentration of 93 to 98 mol% (93-98% m / m), is preferably used as filler material. Disintegrants: soybean polysaccharide 0.25-5%; polyvinyl pyrrolidone 0.25-5%; sodium starch 0.25-5%. Lubricants and form release agents: magnesium stearate 0.25-2.5%.

[0032] Glidant: highly dispersed silicon dioxide 0.25-1.5%. Possible additional excipients: fillers: starch (corn starch, potato, pea starch, wheat starch); lactose; barium sulfate; sodium chloride; urea; PEG. Lubricants: talc; calcium behenate; glyceryl monostearate; stearic acid; hydrogenated vegetable fat; PEG 4000.

[0033] The present invention also relates to a method for producing a settler element by tableting a granular material, in particular a powder mixture (the material being defined in the previous paragraph) into a shape, in particular a substantially cylindrical shape, which preferably fits inside a hollow space of a capsule device, in particular in a half of the capsule device. The present invention also relates to a method for producing a pharmaceutical dosage form, the method comprising the steps of: in particular by providing a granular material, in particular a powder mixture (the material being defined in the previous paragraph) and by tableting the material into a shape, in particular a substantially cylindrical shape, which preferably fits inside a hollow space of a capsule device, in particular in a half of the capsule device. Tabletting can utilize any eccentric press or rotary press. Alternatively, the method for producing the settler element can also utilize casting, injection molding or 3D printing of the settler element.

[0034] The settler device, the settler element of the settler device or the weight element, respectively, preferably consists of a water-soluble material or comprises a water-soluble material. It is also possible and preferred that the settler device or the weight element, respectively, consists of a water-insoluble material or comprises a water-insoluble material.

[0035] The settler device may also include a settler element, respectively an insert portion, which is configured to be filled with water once the pharmaceutical dosage form is administered to the patient in the presence of water or an aqueous solution. For this purpose, the insert portion preferably includes at least one opening or passage. Preferably, the insert portion or a portion thereof is porous by including an open-cell material, thereby allowing water to enter the internal volume of the hole and allowing water to discharge air. Suitable porous materials can be fibrous materials or granular materials, or mesh materials, woven materials or nonwoven materials. The porous material can be a cellulose material. The porous material can be a paper material or a textile material.

[0036] The settler device may further comprise at least one hole in the wall of the capsule device, which allows water to enter the hollow space and air to leave the hollow space. In addition to the opening for the formulation, the wall of the capsule device may comprise at least one hole in the wall of the capsule device, which allows water to enter the hollow space and air to leave the hollow space. Such at least one hole may be arranged in a curved (especially hemispherical) face wall of the capsule, or in two opposite curved face walls, and / or in other parts of the capsule, for example in a hollow cylindrical wall part of the capsule. It is possible and preferred that the wall of the capsule device only comprises an opening (5) used as a passage for the formulation, and in particular does not comprise any other holes or openings.

[0037] Preferably, the settler element is arranged, preferably attached, to one half of the capsule device, and in particular, is not arranged in the other half of the capsule device. Thus, a sufficient portion of the hollow space, in particular a sufficient portion of the hollow space inside the other half of the capsule interior, is available for the formulation in its compact form. In case the settler element is attached, e.g. clamped or adhered to the capsule device, it is ensured that expansion of the formulation from its compact form to its expanded form (e.g. by unwinding) is not hindered by the settler element.

[0038] The settler element may be an insert that fits inside the hollow space of the capsule device. The shape of the insert may be cylindrical.

[0039] The settler device can also be embodied such that the wall of the capsule device has a dense material, preferably with a density >1.0 g / cm 3 , so that the capsule wall acts as a settler element or weight element, respectively.

[0040] The settler device can also be implemented so that the settler element is attached to the outside of the capsule device, for example using a weight element connected to the outer wall of the capsule device, preferably a curved wall, the connection preferably being an adhesive connection, and / or using a deformable connector, such as a wire, for allowing the settler element to be arranged at a certain distance from the capsule wall.

[0041] In particular, the present invention relates to a pharmaceutical dosage form for preferably applying to the upper gastrointestinal tract such as the throat, esophagus, cardia and / or stomach, and in particular applying to the respective mucosa, which enables local drug treatment and / or diagnostic investigation. Local diseases, in particular esophageal diseases, can be treated with locally acting drugs. However, generally current pharmaceutical dosage forms or administration systems are usually not targeted at specific diseased locations; in particular, they are not targeted at the esophagus and / or its mucosa. Therefore, drugs, in particular active pharmaceutical ingredients, which are usually administered in large quantities are absorbed systemically, which can cause side effects, in particular adverse reactions. In particular, the purpose of the present invention is therefore to improve the local administration of drugs, in particular active pharmaceutical ingredients. Preferably, according to certain embodiments of the present invention, this purpose is particularly achieved and / or only for the present invention. In addition, according to certain embodiments of the present invention, another purpose of the present invention can be achieved. In addition, certain embodiments of the present invention may have the purpose of increasing the bioavailability of active pharmaceutical ingredients, locally delivering useful substances (preferably drugs such as active pharmaceutical ingredients), treating the esophagus with locally acting drugs and / or reducing side effects, in particular adverse reactions.

[0042] In particular, the inventors have exploited in an advantageous manner the different permeabilities of various mucosal membranes and in particular their suitability for absorbing various drugs, which differ inter alia in their molecular size and lipophilicity, in order to provide a dosage form which allows direct contact of the dosage form with the mucosa after release at the intended site of action.

[0043] In particular, the present invention is a pharmaceutical dosage form for administration to a mucosa, in particular the buccal, intestinal, rectal or vaginal mucosa.

[0044] Such a pharmaceutical dosage form according to the invention advantageously allows to improve the bioavailability of an active pharmaceutical ingredient, which is contained in particular in a medicament for oral, vaginal or rectal administration, at the intended site of action. Furthermore, the release of the active pharmaceutical ingredient at its intended site of action is achieved by the pharmaceutical dosage form according to the invention, whereby, in particular, the amount of active pharmaceutical ingredient available for reabsorption can be increased, and an increased bioavailability and an increased reabsorption rate can be achieved.

[0045] In particular, this is achieved with the dosage form according to the invention by the fact that the dosage form according to the invention rapidly releases the string- or strip-shaped, in particular sheet-shaped, film-shaped, foil-shaped or wafer-shaped preparation comprising the active pharmaceutical ingredient at the intended site of action with systemic action. Furthermore, the dosage form according to the invention makes it possible to administer at the intended site of action active pharmaceutical ingredients that cannot be administered orally due to poor bioavailability.

[0046] Preferably, the intended site of action is a mucosa, in particular the buccal, gastrointestinal, rectal or vaginal mucosa.

[0047] Therefore, the pharmaceutical dosage form according to the present invention advantageously allows contact (particularly direct contact) with a predetermined site of action, particularly a mucosa, preferably a tissue that absorbs the active pharmaceutical ingredient, and further advantageously absorbs the drug into the blood. The embodiment of the preparation comprising the active pharmaceutical ingredient is a string-like or strip-like, particularly a sheet-like, film-like, foil-like or thin sheet-like preparation, particularly a so-called thin sheet, which advantageously allows the sheet-like preparation to be released directly onto the mucosa and contacted at a predetermined release site or site of action, respectively, preferably with a larger surface area, so that the sheet-like preparation can dissolve and release the active pharmaceutical ingredient. Such contact with the predetermined site of action advantageously allows enhanced reabsorption of the active pharmaceutical ingredient, particularly reabsorption of the active pharmaceutical ingredient on the mucosa, and thereby increases the amount of the active pharmaceutical ingredient available for reabsorption. Thereby also achieved increased bioavailability and / or increased absorption rate.

[0048] Advantageously, the intestinal first-pass effect, i.e. the conversion (conversation) of the active pharmaceutical ingredient, especially the oral dosage form, during its first passage through the intestinal mucosa and possibly also through the liver can be reduced by the pharmaceutical dosage form according to the present invention. In addition, the destruction of the active pharmaceutical ingredient before reaching the predetermined site of action (e.g., by gastric acid and / or digestive enzymes) is advantageously reduced by the pharmaceutical dosage form according to the present invention. The bioavailability of the active pharmaceutical ingredient is also advantageously increased by the pharmaceutical dosage form according to the present invention. The pharmaceutical dosage form according to the present invention particularly advantageously allows a reduction in the dose that maintains a roughly equal therapeutic effect, especially when compared with the administration of comparable conventional preparations such as tablets, solutions, vaginal creams or suppositories. In addition, the pharmaceutical dosage form according to the present invention advantageously allows a more precise administration of the active pharmaceutical ingredient and, when necessary, reduces side effects, especially gastrointestinal side effects. The pharmaceutical dosage form according to the present invention further advantageously allows relatively simple and discrete handling and simple, particularly space-saving storage, wherein the active pharmaceutical ingredient included in the pharmaceutical dosage form according to the present invention can have improved stability, for example, under high heat and high humidity, especially compared with solutions and gels.

[0049] Thus, the pharmaceutical dosage form according to the invention allows targeting and complete adhesion to the intended site of action, respectively site of administration.

[0050] Furthermore, this particularly advantageously allows a prolongation of the residence time at the absorption window, a fluid displacement which may lead to an early detachment or dissolution of the preparation, in particular of the flakes.

[0051] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the pharmaceutical dosage form further comprises a shell, in particular a capsule, wherein the shell contains at least one string- or strip-shaped, in particular sheet-shaped, film-shaped, foil-shaped or flake-shaped formulation comprising an active pharmaceutical ingredient, and wherein preferably the shell comprises at least one opening through which a fluid surrounding the shell can come into contact with the inner space of the shell while the strip- or string-shaped formulation is pulled out of the capsule device. Preferably, the opening is formed as a slit and / or the opening is formed to have a circular or oval cross-section. The slit may have rounded corners and may be formed by a single surface 5a.

[0052] In particular, the capsule device of the dosage form makes it possible to protect the formulation from unwanted release by configuring the capsule device.

[0053] It will be appreciated that the pharmaceutical dosage form according to the present invention may comprise a capsule device containing at least one or more tablet-like formulations comprising the active pharmaceutical ingredient.

[0054] The release of the tablet-like dosage form by the release mechanism is preferably performed by at least partially removing the dosage form from at least a portion of the capsule device.

[0055] When the preparation is pulled out of the capsule device, this means that when the dosage form is administered to the respective site of action, the opening of the capsule device allows access and / or contact with the fluid surrounding the shell in a particularly advantageous manner. The wetting of the preparation inside the capsule device facilitates pulling the preparation out of the capsule device during (or shortly before) administration, and thereby facilitates administration and improves the reliability of the pulling-out process.

[0056] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the opening is formed as a slit. Such a slit can be embodied in different arrangements and configurations. For example, such a slit can be arranged completely or partially circumferentially at the capsule device. The slit arranged completely circumferentially at the capsule device can be arranged so that the slit divides the shell into a plurality of parts, in particular two parts, which can be connected by a connector part of the capsule device.

[0057] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the capsule device is formed of a material that is substantially insoluble in the fluid present at the intended administration site, in particular at the gastrointestinal tract. However, it should be understood that such a capsule device may be insoluble not only at the administration site, but also at other compartments that must be passed through to reach the administration site - in other words, on the complete path to the administration site.

[0058] In a preferred embodiment according to the present invention, the capsule device is composed of or mainly composed of a material that is substantially insoluble in a fluid that is present in a pathway for transporting the fluid to the administration site, particularly the rectum, vagina or gastrointestinal tract, preferably vaginal fluid, gastric fluid, respectively.

[0059] The material that is substantially insoluble in vaginal fluid, gastric fluid, respectively, is preferably selected from the group comprising: gastric juice-resistant polymers, including acidic polymethacrylates, such as methacrylic acid: methyl methacrylate copolymer 1: 1 (Eudragit L), methacrylic acid: methyl methacrylate copolymer 1: 2 (Eudragit L), methacrylic acid: ethyl acrylate copolymer 1: 1 (Eudragit L100-55), acidic cellulose derivatives, such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) -LF, -MF and / or -HF, acetate phthalate HPMC and cellulose acetate phthalate; vinyl alcohol-based acidic polymers, such as polyvinyl acetate and vinyl acetate: crotonic acid copolymer; zein, keratin, gluten, shellac, gelatin and alginic acid hardened with formaldehyde or glutaraldehyde.

[0060] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the capsule device is made of a material selected from the group comprising hard gelatin, polymers, thermoplastics (such as e.g. Eudragit), etc. In this respect, in particular materials which have been successfully tested, used and / or approved, e.g. for oral dosage forms, may be of advantage.

[0061] In a further preferred embodiment of the pharmaceutical dosage form according to the invention the capsule means consists of a material selected from the group consisting of hard gelatin or polymers.

[0062] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the capsular device is formed as a capsule, wherein the shape of the capsular device can generally be selected to allow a desired administration to a patient.

[0063] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the capsule device is made of a material that is substantially insoluble in the fluids present in the path to the administration site, in particular inside the gastrointestinal tract, preferably insoluble in gastric fluid, wherein preferably the shell consists of a material selected from the group comprising polymers and / or hard gelatin.

[0064] Preferably, such substantially insoluble materials, in particular materials substantially insoluble in vaginal fluid, gastric fluid, respectively, are selected from the group comprising: gastric fluid-resistant polymers, including acidic polymethacrylates, such as methacrylic acid:methyl methacrylate copolymer 1:1 (Eudragit L), methacrylic acid:methyl methacrylate copolymer 1:2 (Eudragit L), methacrylic acid:ethyl acrylate copolymer 1:1 (Eudragit L100-55), ammonium methacrylate copolymers (e.g. Eudragit RS), acidic cellulose derivatives, such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) -LF, -MF and / or -HF, acetate phthalate HPMC and cellulose acetate phthalate; acidic polymers based on vinyl alcohol, such as polyvinyl acetate and vinyl acetate:crotonic acid copolymer; zein, keratin, gluten, shellac, gelatin and alginic acid hardened with formaldehyde or glutaraldehyde. In particular, ammonium methacrylate copolymers are materials for the shell and / or for the trigger mechanism.

[0065] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the dosage form, in particular a capsule device, comprises a wick system, in particular a capillary system adapted to guide a fluid into the dosage form by capillary forces.

[0066] Such a core system advantageously allows a preferably predetermined and / or controlled entry (particularly by capillary forces) of fluid leaving the tissue into the dosage form, in particular into the inner space of the shell, via the capillary action of the core system.

[0067] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the dosage form, in particular a capsule device, comprises a core system.

[0068] Providing the formulation in a compact state advantageously allows relatively small dosage forms to be provided, in particular for rectal, oral or vaginal administration, wherein the surface area of ​​a sheet-like formulation can be particularly advantageously increased by expanding or sheet-like formulations, in particular for active ingredient release at the intended site of action.

[0069] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the capsule device comprises a first tube element and at least a second tube element, wherein the second tube element has a smaller tube diameter than the first tube element. Preferably, the capsule device is formed by at least one first tube element and / or at least one first and at least one further tube element.

[0070] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the capsule device comprises a first tube element and at least a second tube element, wherein the second tube element has a smaller tube diameter than the first tube element and wherein the second tube element is at least partially arranged to be inserted into the first tube element, respectively.

[0071] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the capsule means comprises a first semi-cylindrical element and at least a second semi-cylindrical element, wherein the second semi-cylindrical element has a smaller diameter than the first semi-cylindrical element. Preferably, the capsule means is formed by at least one first semi-cylindrical element and / or at least one first and at least one further semi-cylindrical element. A semi-cylindrical element is understood to be half of a hollow cylindrical portion, which is obtained by cutting the cylinder into two equal halves along its axis of symmetry (central length axis).

[0072] In any case, the tubular element or semi-cylindrical element may comprise a front face closing the tubular / semi-cylindrical portion.

[0073] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the preparation is a wafer.

[0074] In particular, the strip preparation of the dosage form according to the present invention can be formed as a so-called thin sheet. After absorbing moisture, such a thin sheet can be assembled to the predetermined site of action, in particular the irregular surface contour of the mucous membrane, such as the intestinal wall, rectal wall or vaginal wall. In addition, the strip preparation of the dosage form according to the present invention can be gelled or swellable.

[0075] In a preferred embodiment, the strip of the dosage form according to the present invention is already flexible and stretchable before it is released from the shell and can absorb fluid entering the shell, for example, fluid from the administration process or fluid inside the gastrointestinal tract.

[0076] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the thickness of the strip preparation is 0.01 mm to 2 mm, preferably 0.03 mm to 1 mm, preferably 0.05 mm to 0.75 mm, preferably 0.05 mm to 0.5 mm, preferably 0.05 mm to 0.2 mm, preferably 0.08 mm to 0.15 mm or 0.1 to 0.12 mm.

[0077] In particular, this is advantageous for providing a strip-shaped preparation having a relatively small thickness.

[0078] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the strip preparation has a width between 0.5 and 25 cm 2 Between, preferably between 1 and 10 cm 2 The area between.

[0079] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the rope- or strip-shaped, in particular film-, foil- or sheet-shaped, preparation comprising the active pharmaceutical ingredient contains the active pharmaceutical ingredient in an amount known to be effective for the condition to be treated and depending on the site of administration and the active ingredient. For example, for budesonide, the concentration / amount within the dosage form is significantly higher compared to dosage forms containing mometasone.

[0080] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the rope-shaped or strip-shaped, in particular film-shaped, foil-shaped or sheet-shaped preparation comprising the active pharmaceutical ingredient has a single-layer or multi-layer structure consisting of a single layer or multiple layers, wherein at least one (preferably the first) layer contains the active pharmaceutical ingredient.

[0081] It should be understood that such a first layer comprising an active pharmaceutical ingredient may be any layer of the multilayer formulation in terms of its arrangement, and in particular, it is not limited to an outer layer, an inner layer, a bottom layer or an upper layer.

[0082] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the rope- or strip-shaped, in particular film-, foil- or sheet-shaped, preparation comprising an active pharmaceutical ingredient comprises a multilayer structure of multiple layers, wherein at least a first layer comprises a first active pharmaceutical ingredient and wherein at least a further layer comprises at least a further active pharmaceutical ingredient.

[0083] It is also within the scope of the present invention that the active pharmaceutical ingredient contained in the first layer is identical to or different from the active pharmaceutical ingredient contained in the further layer. In particular, the strip preparation of the dosage form according to the present invention can be embodied as a so-called combination sheet and can contain a combination of active pharmaceutical ingredients of at least two active pharmaceutical ingredients individually or jointly in one or more layers.

[0084] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the rope-shaped or strip-shaped, in particular film-shaped, foil-shaped or sheet-shaped preparation comprising the active pharmaceutical ingredient comprises at least a first layer comprising the active substance and / or a further layer comprising the active substance, wherein the first layer comprising the active substance and / or the further layer comprising the active substance comprises a polymer, preferably a film-forming polymer.

[0085] Such a layer comprising a polymer, preferably a film-forming polymer, is advantageously used as an active ingredient reservoir, wherein such a layer can release the active pharmaceutical ingredient under the influence of a fluid.

[0086] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the rope- or strip-shaped, in particular film-, foil- or sheet-shaped preparation comprising the active pharmaceutical ingredient comprises at least one first layer comprising the active ingredient and / or further layers comprising the active ingredient.

[0087] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the string-shaped or strip-shaped, in particular film-shaped, foil-shaped or sheet-shaped preparation comprising the active pharmaceutical ingredient comprises at least a first layer comprising the active ingredient and / or an additional layer comprising the active ingredient, wherein at least one first layer comprising the active ingredient and / or an additional layer comprising the active ingredient is an adhesive layer.

[0088] In a preferred embodiment of the pharmaceutical dosage form according to the invention, at least one first layer comprising the active ingredient and / or the further layer comprising the active ingredient comprises a polymer, preferably a film-forming polymer, wherein the polymer is a water-dispersible and / or decomposable and / or water-disintegrable film-forming polymer.

[0089] The polymer for the first layer comprising the active substance and / or for the further layer comprising the active substance can in particular be selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, polyethylene glycol, polyethylene oxide polymers, polyurethanes, polyacrylic acid, polyacrylates, polymethacrylates, poly(methyl vinyl ether-maleic anhydride), starch, starch derivatives, natural gums, algin, pectin and gelatin, pullulan, gel-forming proteins, chitosan, agar-agar, agarose, carrageenan, xanthan gum, tragacanth, dextran and cellulose ethers (such as ethylcellulose, hydroxyethylcellulose, propylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, cellulose acetate), povidone and copovidone.

[0090] Polymers can be used alone or in combination with each other to make tablets according to the dosage form of the present invention with desired properties such as adhesion, release or disintegration properties. In particular, the string-like or strip-like preparations according to the present invention can be composed of a single polymer layer. In addition, when at least one of the layers contains an active pharmaceutical ingredient, the tablets according to the dosage form of the present invention can have a structure with two or more layers. If a plurality of layers contain one or more active pharmaceutical ingredients, they can differ from each other in their active ingredient content and their active ingredient combination, and can differ from each other in their polymer composition and therefore their adhesion and / or decomposition properties.

[0091] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the rope- or strip-shaped, in particular film-, foil- or sheet-shaped preparation comprising the active pharmaceutical ingredient comprises at least one first inactive ingredient-free layer which does not contain the active pharmaceutical ingredient.

[0092] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the rope- or strip-shaped, in particular film-, foil- or sheet-shaped preparation comprising the active pharmaceutical ingredient comprises at least one further inactive ingredient layer which does not contain the active pharmaceutical ingredient.

[0093] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the first layer of inactive ingredients and / or at least one further layer of inactive ingredients is a water-insoluble layer, which preferably comprises a water-insoluble substance selected from the following group: ethylcellulose and / or a combination of ethylcellulose with other water-insoluble substances, hydrophobic plasticizers (especially triethyl citrate) and / or molds and / or fragrances and / or seasonings.

[0094] In particular, the use of ethylcellulose may be beneficial due to its properties including good processability, biocompatibility, and water insolubility.

[0095] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the first inactive ingredient-free layer and / or the at least one further inactive ingredient-free layer is an adhesive layer which preferably comprises hydroxypropylmethylcellulose.

[0096] The adhesive layer may vary in its desired thickness. Additionally or alternatively, the adhesive layer may be a mucoadhesive polymer selected from the group consisting of cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylate derivatives, polyvinyl pyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan, and mixtures thereof.

[0097] The adhesive layer may vary in its desired thickness. Additionally or alternatively, the adhesive layer may include a solvent selected from the group comprising: water, ethanol, methanol, acetone, organic solvents and mixtures thereof.

[0098] Furthermore, the adhesive layer may additionally contain additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, transdermal absorption enhancers, solubilizers, disintegration enhancers, pore formers, lubricants, and mixtures thereof.

[0099] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the rope- or strip-shaped preparation has a multilayer structure, preferably has two or three layers, and comprises at least one layer containing an active substance and at least one layer without active ingredients.

[0100] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the rope-shaped or strip-shaped preparation comprises a multilayer structure, preferably having three layers, wherein a first layer containing an active ingredient and / or an additional layer containing an active ingredient is arranged between a first layer inactive ingredient and / or an additional layer inactive ingredient, wherein, preferably, the first layer inactive ingredient is a water-insoluble layer, which preferably comprises ethylcellulose, and at least one additional layer inactive ingredient is an adhesive layer, which preferably comprises hydroxypropyl methylcellulose.

[0101] The medicament according to the present invention, in particular the string-shaped or strip-shaped preparation, may additionally contain one or more additives. In particular, the following substances are qualified as additives: lubricants, lubricants, glidants, binders, additional active ingredients, disintegrants, antioxidants, chelating agents, coating agents, leveling agents, preservatives, fillers, surfactants, plasticizers and pigments. In addition, the additive can be selected from the following group: pore formers, transdermal absorption enhancers, solubilizers, emulsifiers, including polyethoxylated sorbitan fatty acid esters, ethoxylated fatty alcohols and lecithin; plasticizers, including polyethylene glycol, glycerol and other polyols, higher alcohols, such as dodecanol, undecanol or octanol, sorbitol, mannitol and other sugar alcohols, dexpanthenol and triglycerides; fillers, including highly dispersed silicon dioxide, titanium dioxide, zinc oxide, chalk and starch; colorants; sweeteners and flavoring agents; wetting agents; preservatives; pH adjusters and antioxidants; disintegration promoters; penetration enhancers that improve the reabsorption of estradiol into the mucosa, for example fatty acids and fatty acid esters, polyols such as propylene glycol, tocopherol or essential oils such as menthol.

[0102] The fraction of these additives can be up to 60% by weight relative to the total weight of the sheet-like preparation. Preferably, the fraction of the additives is between 5% and 40% by weight. By adding one or more of the additives, the person skilled in the art can particularly influence the chemical and physical properties of the film-shaped medicament containing the active ingredient, making it possible to adjust, for example, the desired flexibility, adhesion, swelling or decomposability and diffusion properties.

[0103] According to a preferred embodiment, the pharmaceutical dosage form according to the invention, in particular a string- or strip-shaped formulation, is intended to allow a time-delayed release of the active ingredient. The active pharmaceutical ingredient is preferably released within a 4-hour period, preferably within a 6-hour period and most preferably within an 8-hour period. In order to achieve a delayed release of the active ingredient in the case of a two- or multi-layer formulation, at least one of the layers comprising the active ingredient, in particular the polymer layer, has a delayed release of the active ingredient.

[0104] For delayed active ingredient release, film-shaped medicaments are preferably formulated as slowly dissolving or slowly disintegrating films, which completely disintegrate or dissolve only after a few hours. Preferably, they completely disintegrate or dissolve only after 4 hours, preferably only after 6 hours and even most preferably only after 8 hours or even only after more than 24 hours.

[0105] According to alternative preferred embodiments, the pharmaceutical dosage form according to the present invention, in particular the string-shaped or strip-shaped preparation, is a rapid release dosage form that releases the active pharmaceutical ingredient within 1 hour, preferably within 30 minutes, and even most preferably within 5 minutes. For rapid active ingredient release, the film-shaped preparation can preferably be formulated as a fast-dissolving or fast-disintegrating film. The sheet-shaped preparation is adapted to substantially completely disintegrate to be converted into a gel-like state or preferably dissolve within a few minutes after release. Preferably, the sheet-shaped preparation completely disintegrates, is converted into a gel-like state or is completely dissolved within 1 hour, preferably within 30 minutes, more preferably within 15 minutes, and most preferably within 5 minutes.

[0106] According to a preferred embodiment, the film-shaped medicament according to the invention is adhesive, in particular mucoadhesive. Particularly preferred is an embodiment comprising only an adhesive, in particular mucoadhesive surface. Thus, adhesion of the drug preparation to the intended site of action, in particular the mucosa, is achieved during the duration of administration, and one or more active pharmaceutical ingredients can be directly reabsorbed at the intended site of action, in particular through the mucosa.

[0107] Furthermore, the string- or strip-shaped preparation may comprise a layer on the side opposite to the adhesive (particularly at the mucoadhesive surface), wherein the layer is impermeable to the active pharmaceutical ingredient, so that upon application at the intended site of action, a targeted active ingredient release can be achieved.

[0108] Pharmaceutical dosage forms, in particular string-like or strip-like preparations, can be prepared by a person skilled in the art by essentially known methods, for example by coating an inert support with a liquid composition comprising one or more polymers, one or more active pharmaceutical ingredients and optionally one or more additives and one or more solvents, by means of a method involving, for example, a doctor blade, a spray processor or an extrusion processor. The film layer obtained in this way is dried. For multilayer sheet-like preparations, one or more coatings can be applied to an existing film layer in the same manner, or can be produced separately and then subsequently laminated.

[0109] Pharmaceutical dosage forms, particularly capsule devices and / or string-like or strip-like preparations, may further include at least one taste-masking additive. This advantageously allows masking of bitter or otherwise unpleasant active pharmaceutical ingredients, but may also be useful in accelerating the onset of active pharmaceutical ingredients. Taste-masking additives are known to those skilled in the art. Such taste-masking additives may particularly include sugar alcohols selected from: mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol, threitol and isomalt, and sodium bicarbonate.

[0110] The active pharmaceutical ingredient contained in the string- or strip-shaped preparation of the pharmaceutical dosage form according to the invention can be selected in particular from the group comprising proteins and peptides, in particular insulin, buserelin, desmopressin, calciotonin and estrogens, and biotechnologically produced drugs, such as the antibody rituximab. It should be understood here that proteins and peptides, in particular insulin, buserelin, desmopressin, calciotonin and estrogens, can in some cases exhibit a poor, in particular poor oral, bioavailability and are therefore good candidates for administration by means of the dosage form according to the invention.

[0111] Substances from the following groups are particularly suitable as active pharmaceutical ingredients: drugs acting on bones and muscles, drugs acting on the nervous system, hormones and drugs acting on the hormonal system, drugs acting on gynecological agents, drugs acting on the cardiovascular system, drugs acting on the respiratory system, drugs acting on the gastrointestinal tract, diuretics, drugs acting on the sense organs, dermatics, vitamins and micronutrients, peptide-based drugs and proteins, analgesics, anti-infectives and parasiticides.

[0112] In particular, the string-like or strip-like preparation may include at least a first region and at least a second region, wherein at least one first region includes an active pharmaceutical ingredient. Preferably, at least one second region includes an additional active pharmaceutical ingredient that is different from the active pharmaceutical ingredient of at least one first region of the sheet-like preparation. Also preferably, at least one second region does not include the active pharmaceutical ingredient of at least one first region of the sheet-like preparation. Alternatively and preferably, at least one second region includes the active pharmaceutical ingredient of at least one first region of the sheet-like preparation, the concentration of which by area, volume or mass is different from the concentration of the active pharmaceutical ingredient of the first region.

[0113] It should be understood that in this context, an active pharmaceutical ingredient may also refer to a mixture of active pharmaceutical ingredients and / or additives. Thus, at least one second region of the sheet-like preparation may include a mixture that is different from the mixture of at least one first region. In particular, the mixture of at least one first region and at least one second region may differ in the composition of the active pharmaceutical ingredients and / or additives and in the amount of the respective active pharmaceutical ingredients and / or additives.

[0114] In particular, this advantageously allows the release of different active pharmaceutical ingredients to different areas of the body, in particular to different mucosa or to different areas of mucosa, such as gastrointestinal, buccal, oral, esophageal, gastric, intestinal, rectal or vaginal mucosa, in a single pharmaceutical dosage form. Preferably, one active pharmaceutical ingredient or one mixture of active pharmaceutical ingredients can be applied to a first area of ​​the vaginal mucosa that is closer to the cervix than a second area of ​​the vaginal mucosa, and another active pharmaceutical ingredient or another mixture can be applied to the second area. In addition, the active pharmaceutical ingredient is not released to the first or second area of ​​the vaginal mucosa. Alternatively and preferably, the first area of ​​the sheet-like preparation can be in contact with the esophageal mucosa and the second area of ​​the sheet-like preparation can be in contact with the buccal mucosa. In this way, the esophageal mucosa can be treated with an active pharmaceutical ingredient, while the buccal mucosa is treated with another active pharmaceutical ingredient, and additives are not treated or released to the buccal mucosa. In particular, flavoring agents and / or local anesthetics can be released, in particular to increase or reduce the production of saliva and / or to make the administration of the pharmaceutical dosage form more pleasant and / or to suppress the urge to vomit.

[0115] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, wherein the string-like or strip-like preparation comprises at least a first region and at least a second region, the second region may comprise an additional active pharmaceutical ingredient that counteracts the active pharmaceutical ingredient of the first region. This may be beneficial in inhibiting the systemic effect of the active pharmaceutical ingredient of the first region. In particular, the fluid passing along the mucosa may first pass through the first region and then the second region, and thus may first absorb the active pharmaceutical ingredient of the first region, which is then counteracted, preferably neutralized, by the additional active pharmaceutical ingredient of the second region. In particular, such an active pharmaceutical ingredient that counteracts other pharmaceutical ingredients may be selected from the following list: enzymes such as esterases that decompose active pharmaceutical ingredients; ions that form complexes with other active pharmaceutical ingredients, such as calcium, iron or magnesium; sympathomimetic and antisympathetic drugs; parasympathomimetic and antiparasympathetic drugs; antibodies that bind drugs; drugs that treat the side effects of other active pharmaceutical ingredients without counteracting the effects of other active pharmaceutical ingredients. Additionally or alternatively, a sheet-like preparation may include a first layer with an active pharmaceutical ingredient and a second layer with an additional active pharmaceutical ingredient that counteracts the active pharmaceutical ingredient of the first layer in a similar manner. In this case, the above-mentioned advantages can be achieved, wherein the action of the active pharmaceutical ingredient of the first layer is directed in the direction of the mucosa or away from the mucosa.

[0116] Preferred embodiments of the pharmaceutical dosage form according to the invention are adapted for administration to the upper gastrointestinal tract such as the throat, esophagus, cardia and / or stomach, and in particular to the respective mucosa and / or preferably to the buccal and / or esophageal mucosa.

[0117] A preferred embodiment of the pharmaceutical dosage form according to the invention is adapted for administration to the nasopharyngeal mucosa.

[0118] In a preferred embodiment of the pharmaceutical dosage form according to the invention, in particular a dosage form for administration to the buccal and / or esophageal mucosa, the shape of the dosage form or a part of the dosage form, in particular the shell, is such that it can be swallowed.

[0119] In particular, the shell having the shape of the capsule device is swallowable. Preferably, the perimeter of the capsule device measured in a plane perpendicular to the longitudinal axis A is shorter than 6 cm, preferably shorter than 3 cm and preferably shorter than 2 cm and longer than 0.2 cm, preferably longer than 0.5 cm and preferably longer than 1 cm. Preferably, the length of the capsule device measured along the longitudinal axis A of the capsule device is shorter than 5 cm, preferably shorter than 3 cm and preferably shorter than 2 cm and longer than 0.5 cm, preferably longer than 1 cm and preferably longer than 1.5 cm. In particular, the capsule device can have a shape according to a standard capsule form (such as 00, 0, 1 or 3), having a length along the longitudinal axis A between 16.1 mm and 23.5 mm and a perimeter between 17.9 mm and 26.7 mm. The pharmaceutical dosage form or the portion of the pharmaceutical dosage form to be swallowed can be shaped in a similar manner. In addition, a smooth and / or glidable surface of the shell, dosage form or portion of the dosage form may be beneficial to promote swallowing.

[0120] This advantageously allows oral administration of the pharmaceutical dosage form according to the invention. In particular, only the dosage form or part of the dosage form, preferably the shell, having a suitable shape is swallowed. In this context, it is understood that parts of the dosage form may be adapted to be swallowed, while other parts of the dosage form may not be adapted to be swallowed.

[0121] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, in particular a dosage form for administration to the buccal and / or esophageal mucosa, nasopharyngeal mucosa, gastrointestinal mucosa, rectal mucosa or vaginal mucosa, the sheet preparation comprises at least one active pharmaceutical ingredient selected from the group consisting of a diagnostic substance, such as a dye or stain, an analgesic, preferably an NSAID, such as ibuprofen or flurbiprofen; a local anesthetic, such as benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine or novocaine; an antibiotic, such as penicillin, amoxicillin or vancomycin; a disinfectant, such as 2,4-dichlorobenzyl alcohol, amylmetacresol or cetylpyridinium chloride; a steroid, such as a corticosteroid, a glucocorticoid, fluticasone, budesonide, clocortolone, perdesonide, hydrocortisone, clobetasone butyrate, flumethasone, flupredniidine, hydrocortisone acepromazine, hydrocortisone buprofen, hydrocortisone butylate, hydrocortisone acepromazine, hydrocortisone butylate ... buteprate), hydrocortisone-17-butyrate, triamcinolone acetonide, amcinoid, betamethasone-17,21-dipropionate, betamethasone-17-valerate, desoximetasone, diflucortolone-21-valerate, fluocinolone acetonide, fluocinolone acetonide, fluticasone-17-propionate, methylprednisolone acetate, mometasone furoate, pednicarbat or clobetasol-17-propionate; parasiticides (which are also called parasiticides) such as mebendazole, albendazole, thiabendazole, diethylcarbamazine, diaminodiphenyl sulfone, benznidazole, ivermectin, pyrantel, praziquantel; fungicides such as nystatin, imidazole, triazole, thiazole, clotrimazole, ketoconazole or undecylenic acid; hexamethyl pararosaniline chloride (hexamethyl In some embodiments, the present invention relates to a pharmaceutical composition comprising the following: a pharmaceutical composition comprising ...

[0122] In one embodiment, the active ingredient is selected from corticosteroids. Exemplary budesonide, mometasone, fluticasone and ciclesonide, and pharmaceutically acceptable salts thereof are mentioned. As for the conditions to be treated, those exemplary conditions associated with the gastrointestinal mucosa, preferably the esophagus, such as GERD, NERD and eosinophilic esophagitis are mentioned.

[0123] In particular, a string-like or strip-like preparation comprising a specific active pharmaceutical ingredient advantageously allows, preferably locally, to treat a respective disease or infection. Thus, a specific active pharmaceutical ingredient can be applied to a respective site of application, particularly a mucosa, and compared to systemic administration, local concentrations and / or therapeutic effects can be increased and / or side effects, particularly adverse reactions can be reduced. In this context, it should be understood that, in addition to local effects, systemic effects may also be possible, preferably by taking in the active pharmaceutical ingredient via the mucosa to enter the body. In addition, in a preferred embodiment, a sheet-like preparation may include different active pharmaceutical ingredients, wherein at least one active pharmaceutical ingredient is selected so that it at least substantially remains confined to the mucosa and / or in the mucosa, and at least another active pharmaceutical ingredient is selected so that it enters the body through the mucosa, thereby particularly causing a systemic effect.

[0124] Preferred embodiments of the pharmaceutical dosage form according to the present invention are adapted for oral administration. Therefore, the dosage form or a portion of the dosage form, in particular the capsule device, is shaped in a swallowable manner. Preferably, the dosage form is formed as described above. In addition, the preferred embodiment may include drugs that are traditionally unsuitable for oral administration of one or more active pharmaceutical ingredients, in particular due to low bioavailability, highly variable intra-individual or inter-individual plasma levels, denaturation or inactivation of drugs by digestive secretions and enzymes, dilution effects of intestinal fluids, poor reabsorption, high first-pass effect and / or very short residence time at the absorption window. Among these, drugs are, for example: proteins and peptides, such as insulin, buserelin, calcitonin or desmopressin, also referred to as desmopressin (oesmopressin); hormones, such as estrogens; and drugs produced by biotechnology, such as antibodies, in particular rituximab.

[0125] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, in particular for a dosage form for application to the buccal, intestinal, rectal or vaginal mucosa, a string-like or strip-like preparation provides a relatively large surface area after it is released by a release mechanism. In particular, the sheet-like preparation is adapted to contact with a relatively large surface area of ​​a preferred mucosa, preferably at a predetermined release site or site of action, after it is released by a release mechanism. Therefore and preferably, the sheet-like preparation can cover a relatively large surface area of ​​the mucosa, in particular relatively large compared to the volume of the sheet-like preparation and / or the amount of the active pharmaceutical ingredient. Some specific advantages have been described above. In particular, the enhanced reabsorption of the active pharmaceutical ingredient contained in the sheet-like preparation can be achieved. In addition, in a preferred variant of this embodiment, in particular with respect to a sheet-like preparation with multiple layers, the release of the active pharmaceutical ingredient can be directed into the mucosa. Therefore, the local concentration and / or bioavailability and / or absorption rate and / or local action of the active pharmaceutical ingredient can be increased. In addition, the concentration of the active pharmaceutical ingredient in the fluid present near the mucosa can be reduced by directional release, and therefore side effects can be reduced and / or bioavailability and / or local action can be increased.

[0126] As used herein, the term "relatively large" preferably refers to one thing being larger than another thing and / or one thing being larger than such a thing or a corresponding amount that would be in a conventional embodiment of the thing, wherein preferably the degree, spatial extent, length, area, volume, surface area, cross-sectional area, enveloping cross-sectional area, contact area, coverage area, diameter, perimeter, path length, size, amount, quantity, range, capacity and / or average size or range is larger by a factor of preferably at least 125%, preferably at least 200%, preferably at least 500%, preferably at least 1000% and preferably at least 5000%. In particular, the relatively large surface area of ​​the sheet-like preparation according to the present invention is larger than the surface area of ​​a conventional dosage form or its preparation. In particular, the surface area of ​​the sheet-like preparation according to the present invention can be relatively large compared to the volume of the sheet-like preparation. In particular, the area, preferably the surface area, can be compared to the corresponding volume. Preferably, the area is relatively greater than the volume if the square root of the area is greater than the cube root of the volume, by a factor of preferably at least 125%, preferably at least 200%, preferably at least 500%, preferably at least 1000% and preferably at least 5000%. Additionally or alternatively, the relatively large surface area of ​​the sheet-like preparation preferably means that the surface area of ​​the sheet-like preparation is greater than the surface area of ​​a conventional dosage form or its preparation with the same amount of active pharmaceutical ingredient, preferably by the factor given above. It should be understood that the surface area of ​​a sheet-like preparation is an at least substantially uninterrupted surface area, while in particular powders can also comprise a large surface area, which, however, is not a substantially closed surface, but rather a huge number of small surface areas of individual particles of the powder. In particular, this also applies, mutatis mutans, to drugs or active pharmaceutical ingredients dissolved in a fluid. In particular, contact with a relatively large surface area, in particular of a mucosal membrane, means that the contact area and / or the area covered, in particular the area covered by the sheet-like preparation, is greater than the area contacted and / or the area covered by a conventional dosage form or its preparation. In particular, if a conventional dosage form is to be dissolved in a fluid, the fluid may have a large contact area with their respective mucosa, but the surface area will not be a substantially uninterrupted surface area as described above, and / or the concentration of the drug or active pharmaceutical ingredient in the fluid may be lower than that in the sheet and / or in the mucosa covered by the sheet and / or in the fluid-filled gaps between the sheet and the covered area of ​​the respective mucosa.

[0127] In particular, the esophagus can be treated with an active pharmaceutical ingredient that is topically applied to the esophageal mucosa. Therefore, in particular, the active pharmaceutical ingredient can be applied to the extended area of ​​the esophageal mucosa. In addition, the active pharmaceutical ingredient can act locally on the esophageal mucosa. Therefore, the side effects caused by the systemic effect of the active pharmaceutical ingredient can be reduced and / or the local effect on the esophageal mucosa can be enhanced, especially due to the local increased concentration of the active pharmaceutical ingredient. In addition, when the sheet preparation releases the active pharmaceutical ingredient locally and / or over an extended period of time, the therapeutic response can be improved, and the local effect of the active pharmaceutical ingredient can be especially increased. In addition, in particular, due to the extended area of ​​action of the space, the necessity of systemic administration can be reduced. Even more particularly, esophagitis, particularly eosinophilic esophagitis, can be treated by such a pharmaceutical dosage form. Here, the drug, in particular the active pharmaceutical ingredient, may target the esophageal mucosa and / or may preferably be selected from the group comprising: steroids, such as corticosteroids, glucocorticoids, fluticasone, budesonide, clocortolone, perdesonide, hydrocortisone, clobetasone butyrate, flumethasone, flupredniidine, hydrocortisone acepromazine, hydrocortisone buprofen, hydrocortisone-17-butyrate, triamcinolone acetonide, amcinoid, betamethasone- 17,21-dipropionate, betamethasone-17-valerate, desoximetasone, diflucortolone-21-valerate, fluocinolone, fluocinolone acetate, fluticasone-17-propionate, methylprednisolone acetate, mometasone furoate, bencarbate or clobetasol-17-propionate; nitric oxide or nitric oxide forming agents such as isosorbide dinitrate or nitroglycerin, beclomethasone dipropionate, ciclesonide, pH buffer, antacid, calcium carbonate, magnesium carbonate or aluminum carbonate. Additionally or alternatively, the sheet preparation may include, in particular, an inflammatory modulator such as montelukast, an interleukin receptor or an interleukin antibody.

[0128] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, in particular for a dosage form for application to the buccal and / or esophageal mucosa and / or nasopharyngeal mucosa, the release mechanism comprises a string member, wherein the string member can be extended from a compact form to an expanded form. In particular, when the release mechanism is activated, the string member can be extended or can be extended by a pulling motion and / or force. Preferably, the string member comprises a string-like or strip-like preparation or an end portion connected to a string-like or strip-like preparation. The string member can include a string-like or strip-like preparation in a compact form and / or an expanded form. Alternatively and preferably, the string-like or strip-like preparation can be adapted to form the string member. Therefore, the string member contains an active pharmaceutical ingredient. It should be understood that the string member can only partially include a string-like or strip-like preparation, or the string-like or strip-like preparation can only partially form the string member. In addition, only a portion of the string member can be converted from a compact form to an expanded form, while at least one other portion of the string member remains in a compact form or an expanded form.

[0129] As used herein, term " compact form " preferably refers to folded form, coiled form, curled form, coiled form or collapsed form.Especially, the string-like or strip-like preparation under compact form has a smaller spatial range and / or exposes a smaller amount of its surface than non-compact form, particularly the form of unfolded form.Preferably, the string-like or strip-like preparation under compact form is folded, collapsed, coiled, curled, coiled, compressed, gathered together or becomes less form in another way.Especially, when the string-like or strip-like preparation is in compact form, it can have a predetermined size or spatial range.

[0130] As used herein, the term "unfolded form" preferably refers to unfolded form, spread out form, open form, elongated form, stretched form or rectangular form. Especially, the string-like or strip-shaped preparation under the unfolded form has a larger spatial range and / or exposes a larger amount of its surface than in non-unfolded form, particularly in the form of compact form. Preferably, the string-like or strip-shaped preparation under the unfolded form is unfolded, spread out, opened, uncurled, unrolled, opened wide, stretched, stretched, expanded or becomes a larger form in another way. Especially, when the string-like or strip-shaped preparation is in the unfolded form, it can have a predetermined size or spatial range. Alternatively, the size or spatial range of the string-like or strip-shaped preparation can depend on the disease and the site of action or the site of application present, and therefore may not be predetermined.

[0131] The string member advantageously allows the release of the active pharmaceutical ingredient, particularly to the mucosa of a closed relatively small lumen or cavity such as the esophagus or nasal cavity. In addition, the compact form of the string member advantageously makes it possible to provide a relatively small pharmaceutical dosage form, particularly for oral administration, which promotes the swallowing of dosage forms. Additionally, the string member can be expanded, particularly unfolded, unrolled, uncurled, stretched or stretched to an expanded form, and thereby the active pharmaceutical ingredient can be released to the mucosa, particularly the elongated area of ​​the cheek and / or esophageal mucosa and / or nasopharyngeal mucosa. In particular, it is beneficial that when the string member is expanded (particularly stretched or stretched) to the expanded form from the compact form, the exposed surface area and / or length of the string member or sheet-like preparation exposed to the environment, particularly the mucosa, is increased. By this advantageous manner, the release of the active pharmaceutical ingredient is protected and / or the active pharmaceutical ingredient is enhanced by a relatively large and / or long contact area in the expanded form under the compact form. An advantage of a preferred variant of this embodiment is the use of a string member to support and / or transport the tablet and thus in particular allows the selection of different substances and compositions for the tablet. Another advantage of an alternative and preferred variant derives from the fact that the tablet forming the string member and thus in particular allows the number of components of the dosage form to be reduced and preferably simplifies the manufacture of the release mechanism and / or the tablet.

[0132] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the string-shaped preparation, in particular in an unfolded form, is string-shaped, rope-shaped or tube-shaped. Preferably or alternatively, the string-shaped or strip-shaped preparation is bendable.

[0133] In a further precise or alternative preferred embodiment of the pharmaceutical dosage form according to the invention, the strip-shaped preparation is adapted to form, in particular, a string, a rope, a strip or a tube in an unfolded form. Preferably, the string-shaped or strip-shaped preparation is bendable so that it can be transformed from a compact form, in particular a folded, collapsed, rolled, curled, coiled sheet-shaped preparation (which may preferably have a string-shaped, rope-shaped, strip-shaped or tube-shaped) to an unfolded form.

[0134] In particular, this advantageously allows the administration of dosage forms and the release of string-like or strip-like preparations to mucous membranes containing relatively small lumens (especially with small diameters) and / or, when its larger area is covered or its lumen or a part thereof is closed by string-like or strip-like preparations, the processing of mucous membranes showing adverse effects or organs with mucous membranes. In particular, such adverse effects can be the obstruction of gagging reflex, sneezing stimulation or fluids such as liquids, water, intestinal fluids or air. Another advantage is that it is possible to simplify manufacturing. Additionally and preferably, the spatial range of the unfolded form, particularly the length of the string-like or strip-like preparations in its unfolded form (especially along its longitudinal and / or elongation axis), can be significantly greater than the spatial range of the compact form, particularly the maximum diameter of the sheet-like preparations in its compact form. As used herein, the term "significantly larger" preferably refers to a ratio greater than or equal to 3:1, preferably 6:1, preferably 10:1, preferably 20:1, preferably 30:1, particularly with regard to aspect ratio, area ratio or volume ratio. It will be appreciated that it may also be beneficial to limit the maximum spatial extension and thus the ratio to preferably 200:1, preferably 100:1, preferably 60:1 and preferably 40:1. In this way, in particular in the case of a string-shaped or strip-shaped preparation whose volume remains constant, a minimum diameter along a cross section (which is at least substantially orthogonal to the longitudinal axis of the string-shaped or strip-shaped preparation in its expanded form) may be ensured. On the other hand, in the case of a preparation which, at least in its expanded form, is shaped as a tube with a relatively large diameter (preferably with a diameter corresponding to the diameter of the respective lumen closed by the respective mucosa), the mucosa may be covered in a greater amount than with a preparation having a smaller diameter, such as a string-shaped preparation.

[0135] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the string-like or strip-like preparation, at least in the unfolded form, is longer than 5 cm, preferably longer than 10 cm, preferably longer than 30 cm and preferably longer than 40 cm, and preferably shorter than 95 cm, preferably shorter than 70 cm and preferably shorter than 50 cm. In this context, it should be understood that the dosage form comprising at least one end adapted to be held during swallowing, and in particular the string-like or strip-like preparation requires a correspondingly longer length of the sheet-like preparation compared to the numbers given above, preferably at least 5 cm longer, preferably at least 10 cm longer and preferably at least 20 cm longer. Thus, such a sheet-like preparation may preferably have a length of at least substantially 60 cm.

[0136] In this context and / or in the present invention, the term "length" or terms related to length such as "longer" or "shorter" preferably refers to the length measured along the longitudinal and / or expansion and / or elongation axis of the respective object, particularly the string-like or strip-shaped preparation. In particular, the length of the string-like or strip-shaped preparation in its unfolded form, preferably in an elongated form, can be measured with a tape measure. More particularly, the string-like or strip-shaped preparation may include a first end and a second end, and in order to measure the length of the string-like or strip-shaped preparation, the tape measure may be guided from the first end to the second end along the string-like or strip-shaped preparation. In particular, when the respective object, such as the string-like or strip-shaped preparation at least substantially follows a straight line, the length of the respective object is the length along this line. In particular, if the length is the longest spatial extent, the direction of the straight line corresponds to the longitudinal axis.

[0137] In a preferred embodiment of the pharmaceutical dosage form according to the invention, the rope-shaped or strip-shaped preparation has an area and / or surface area between 0.5 and 25 cm 2 Between, preferably between 2 and 25 cm 2 Between, preferably between 5 and 25 cm 2 Between 5 and 15 cm 2 Between, preferably greater than 0.5cm 2 and preferably less than 40 cm 2 Preferably, the ratio of the length of the sheet to the width of the sheet is between 40:1 and 400:1 or preferably between 60:1 and 300:1 or preferably between 80:1 and 200:1. The width can be the average width of the sheet, for example measured perpendicularly to the length of the sheet. The ratio can be the ratio of the length of the sheet to the circumference of the sheet, in particular the average value, wherein in the case of a strip-shaped sheet, the circumference can be, for example, twice the width of the sheet.

[0138] In particular, this is beneficial for application to mucosa. In particular, the mucosa of the esophagus can be covered and / or locally treated by such a strip preparation including an active pharmaceutical ingredient. It should be understood that, depending on the specific embodiment of the dosage form, the string-like or strip-like preparation can at least partially and preferably cover the esophageal mucosa to a significant extent and / or can extend to a significantly large length along the longitudinal axis of the esophagus at least partially and preferably. Therefore, in a preferred variant, the active pharmaceutical ingredient can be released on the extended area of ​​the esophageal mucosa, and therefore the extended area can be treated. In addition, in an alternative or precise preferred variant with a sheet-like preparation that does not dissolve immediately but preferably dissolves and / or adheres to the mucosa in a time-controlled manner, the active pharmaceutical ingredient can be released over an extended period of time, and therefore, the therapeutic effect can be particularly improved.

[0139] In particular, in the case where the orally administered dosage form is preferably used for administration to the esophagus, the dosage form will be transported by external movement, which can be the movement of the dosage form when the dosage form is swallowed. Therefore, the esophageal muscles generate a force acting on the dosage form or a part thereof. In particular, the esophageal mucosa can act directly on the dosage form and / or can act indirectly on the dosage form, preferably via a fluid, particularly a liquid, such as a beverage, water or saliva, which is preferably swallowed together with the dosage form. In these movements, force or pressure can be generated. From another point of view, the force and / or pressure of the esophagus, its mucosa and muscles can cause the movement.

[0140] In certain embodiments, securing the end portion of the formulation in the oral cavity may increase user convenience. Furthermore, the end portion adapted to be secured in the oral cavity may be manufactured in a simple and therefore cost-effective manner, and / or may be particularly reliable, particularly because the user may notice whether the end portion is properly secured before continuing to administer the dosage form (e.g., swallowing the dosage form or a portion thereof). Similar advantages may arise for a holding device adapted to be held in the hand when administering the dosage form.

[0141] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, at least during the release of the string-like or strip-like preparation, the release portion of the string-like or strip-like preparation and the pharmaceutical dosage form move relative to each other, and thereby define the movement path of the dosage form. In addition, when observed in the direction of the movement path, the envelope cross-sectional area of ​​the dosage form is greater than the envelope cross-sectional area of ​​the string-like or strip-like preparation. In particular, the envelope cross-sectional area of ​​the dosage form can refer to the envelope cross-sectional area of ​​the swallowable portion of the dosage form, preferably the capsule device. In particular, the envelope cross-sectional area of ​​the string-like or strip-like preparation can refer to the envelope cross-sectional area of ​​the release portion of the string-like or strip-like preparation. It should be understood that these relationships are particularly applicable during the release of the string-like or strip-like preparation. In particular, the string-like or strip-like preparation can be extended and therefore has a larger envelope cross-sectional area than the subsequent dosage form. It should be understood that the above relationship is particularly important for the portion of the string-like or strip-like preparation that has just been released by the dosage form. Preferably, the length of the portion measured along the movement path is at least substantially as long, preferably twice as long, preferably five times as long and preferably twenty times as long as the length of the dosage form measured along the movement path. In particular, the relationship of the envelope cross-sectional areas may reflect and / or correspond to the relationship of the respective maximum diameters or minimum diameters, which follow the respective transverse axis or are at least substantially orthogonal to the respective longitudinal axis or movement direction.

[0142] This can advantageously allow the movement of the dosage form to be promoted by swallowing the dosage form or by peristaltic movement. Certain variants of this embodiment can improve user convenience and / or reduce the risk of injury. In particular, since the string-like or strip-like preparation released near at least one section of the dosage form has a smaller cross-sectional area, such a dosage form is better swallowable. In particular, this gradual taper behind the dosage form helps the esophageal muscles to swallow the dosage form. Preferably, the dosage form, in particular a capsule device, such as a capsule, also tapers at least in the direction of the expected movement path and / or in the direction opposite to the expected movement path, and thereby further promotes the swallowing of the dosage form. In addition, the dosage form can be adapted so that its longitudinal axis is at least substantially parallel to the expected movement path. In addition, the dosage form can release the sheet-like preparation in the direction opposite to the expected movement path, for example relative to the expected movement path of the dosage form or moving at the rear side of the dosage form.

[0143] In a preferred embodiment of the pharmaceutical dosage form according to the present invention, the string-like or strip-like preparation has at least a first part and a second part with different envelope cross-sectional areas, in particular when viewed in the direction of the moving path, wherein the part released before the other part can have a smaller cross-sectional area. In an alternative and preferred embodiment, the sheet-like preparation tapers from the second end of the string-like or strip-like preparation to the first end of the string-like or strip-like preparation, wherein the first end of the string-like or strip-like preparation is on one side of the string-like or strip-like preparation released first. In particular, for application to the esophagus, both embodiments produce a string-like or strip-like preparation that is smaller in the upper region of the esophagus and oral cavity and larger in the lower region of the esophagus after its release. This can beneficially promote swallowing of the dosage form and / or increase user convenience, in particular suppress or avoid gagging reflexes. In a preferred variant, the first part is a string member.

[0144] It should be understood that, as used herein, the terms "pharmaceutical dosage form" and "dosage form" are preferably interchangeable. Preferably, the dosage form may have non-pharmaceutical applications. In particular, the dosage form may be used to treat and / or diagnose a disease.

[0145] It should be understood that certain embodiments of the pharmaceutical dosage forms according to the present invention differ from catheters in that they are at least substantially completely enclosed by the user's body after administration. Additionally or alternatively, administration is performed without additional tools and / or without applying force or movement outside the user's body. However, an applicator for assisting swallowing of the dosage form may be used for administration (see Figures 9a to 9d ). Preferably, the pharmaceutical dosage form according to the present invention can be administered by the user without professional assistance. This is particularly beneficial if the dosage form is to be administered regularly, in particular daily. In addition, user convenience can be improved, safety can be increased and / or the risk of injury can be reduced. In particular, convenient administration is also beneficial to the handling of animals. Similarly, it should be understood that the pharmaceutical dosage form according to the present invention is different from a stent. In particular, the stent generally does not include a trigger mechanism in the sense of the present invention. In addition, the universal purpose of the stent is to keep the hollow organ open. Certain embodiments of the pharmaceutical dosage form according to the present invention can also keep the hollow organ open, but in addition to the purpose of keeping the hollow organ open, their purpose is to at least improve the local application of the drug, in particular the active pharmaceutical ingredient. Some other embodiments of the pharmaceutical dosage form according to the present invention have the purpose of improving the local application of the drug, in particular the active pharmaceutical ingredient, and closing the hollow organ, in particular even during the administration of the dosage form. In particular, this can be achieved by a pharmaceutical dosage form comprising a string member or a sheet-like preparation, in particular in an unfolded form, in a string-shaped, rope-shaped, strip-shaped or tubular shape. In particular, this is particularly conducive to the handling of the esophagus.

[0146] In some embodiments of the pharmaceutical dosage form according to the present invention, the string-like or strip-like preparation is solid, particularly when it is in its compact form and / or immediately after its release. This can beneficially enhance, enable or promote some of the advantages mentioned above. In particular, when it is in a solid state before release, this can enhance storability. In particular, when the active pharmaceutical ingredient is in a solid state after its release, this can enhance and / or enable the targeting and / or sustained release of the active pharmaceutical ingredient. Additionally or alternatively, in some embodiments of the pharmaceutical dosage form according to the present invention, the string-like or strip-like preparation is adapted to dissolve in a time-controlled manner, immediately, after a delay, or after its release under stimulation, such as biological degradation. This can beneficially enhance, enable or promote some of the advantages mentioned above. In particular, this can improve user convenience because there is no need to remove the sheet-like preparation.

[0147] All embodiments of the pharmaceutical dosage form according to the invention show the following advantages: a pharmaceutical dosage form is provided in which the bioavailability of the active pharmaceutical ingredient contained in the administration dosage form is improved or in which, in particular additionally or alternatively, the local action of the active pharmaceutical ingredient is improved. In addition, with the aid of the pharmaceutical dosage form according to the invention, a dosage form is provided in which the release of the active pharmaceutical ingredient at its intended site of action is improved. Further advantages of the pharmaceutical dosage form according to the invention are:

[0148] - May produce equivalent effects at lower doses

[0149] - Reduce side effects caused by low doses

[0150] - Faster onset of action through direct contact with the application site.

[0151] The present invention also relates to a method for producing a pharmaceutical dosage form according to the invention, comprising the following steps:

[0152] - providing a capsule device comprising an opening;

[0153] - A preparation having an elongated shape and comprising an active pharmaceutical ingredient is placed in a compact state of the preparation within the hollow space of the capsule device, with the end portion of the preparation extending through the opening, the opening and the preparation being configured such that when the preparation is pulled out of the opening, a spacing (S1; S2) is provided in an opening cross section (CS) of the opening (5) between the preparation (2) and a surface (5a) of the capsule device defining the opening (5).

[0154] The step of providing the capsule device may also include the steps of providing at least a first part, in particular a first half, of the capsule device and providing at least a second part, in particular a second half, of the capsule device. The step of placing the formulation is performed by preferably placing the formulation in the first part or first half of the capsule device, preferably subsequently extending the end portion of the formulation through the opening, and connecting the second part or second half to the first part or first half of the capsule device. The first part or first half or the second part or second half may be a tube element or a capped tube element, respectively, or may be a cylindrical segment, in particular a semi-cylindrical element.

[0155] The present invention also relates to a method for producing a capsule device for a pharmaceutical dosage form according to the present invention, comprising the following steps:

[0156] - providing materials for forming a capsule device;

[0157] - producing openings, in particular slits, in the material of the capsule device;

[0158] - Forming capsule device.

[0159] The step of forming the capsule device using the material for forming the capsule device may be applied after the step of producing the opening in the material of the capsule device. The step of forming the capsule device using the material for forming the capsule device may also be applied before the step of producing the opening in the material of the capsule device.

[0160] The opening can be produced by using a workpiece with a suitable shape. The material used to form the capsule device can be the workpiece. In a respective preferred embodiment, the workpiece can have the shape of a foil, a hollow cylinder, a capsule or half of a capsule.

[0161] The capsule device is preferably formed so that - when a preparation having an elongated shape and including an active pharmaceutical ingredient (in a compact state of the preparation) is inserted into the hollow space of the capsule device and an end portion of the preparation extends through the opening and the preparation can be pulled out of the opening - a spacing (S1; S2) is provided in an opening cross section (CS) of the opening (5) between the preparation (2) and a surface (5a) of the capsule device defining the opening (5). The capsule device is preferably formed to be swallowable by a patient.

[0162] The step of forming the opening may include at least one of the following features:

[0163] Using a flat milling tool, such as a flat saw blade, or by other tools that produce a plate-shaped cutting volume, such as a cylindrical milling head with a lateral movement;

[0164] A sideways moving water jet used in abrasive water jet cutting processes;

[0165] Using lasers to cut or ablate material from capsule material;

[0166] Punching through the capsule material to create holes via shearing;

[0167] • Injection moulding of a suitable material, such as plastic, for forming the capsule device.

[0168] The step of forming the capsule means may comprise the step of applying a dip molding process for producing two halves of the capsule, which are connected to form the capsule, as described, for example, in EP 0 102 832 A2. The step of forming the capsule means may comprise the step of applying an additive manufacturing process for forming the capsule from a suitable material, in particular a 3D printing process for forming the capsule from a suitable material. The step of forming the capsule means may comprise the step of injection molding the capsule from a suitable material.

[0169] Further preferred embodiments of a method for producing a pharmaceutical dosage form according to the invention and of a method for producing a capsule device for a pharmaceutical dosage form according to the invention can be gathered from the description of the pharmaceutical dosage form according to the invention and its embodiments and from the description of the embodiments with the aid of the drawings.

[0170] Exemplary embodiments of the invention will be described in more detail below with reference to the accompanying drawings and examples, from which further features, advantages and embodiments will emerge.

[0171] Figure 1a A schematic side view of a dosage form according to a first embodiment of the present invention is shown.

[0172] Figure 1b Shows Figure 1a The dosage form is rotated 90° around the central length axis A.

[0173] Figure 1c Shows Figure 1a Details of the area marked by an "X".

[0174] Figure 1d Shows Figure 1a Alternative configurations for the areas marked by an "X" in .

[0175] Figure 2a An isometric oblique view of a capsule device as part of a dosage form according to a second embodiment of the invention is shown.

[0176] Figure 2b The two-part capsule device is shown before assembly. Figure 2a Capsule device.

[0177] Figure 2c Shows Figure 2b Side view of the layout.

[0178] Figure 2d Shows Figure 2b Front view of the layout.

[0179] Figure 2e Shows Figure 2a Front view of the capsule device in FIG.

[0180] Figure 3a An isometric oblique view of a dosage form according to a third embodiment of the invention is shown.

[0181] Figure 3b The apparatus is shown consisting of two parts of the capsule device and the strip preparation before assembling the capsule device. Figure 3a dosage form.

[0182] Figure 3c Shows Figure 3a Front view of the medium dosage form.

[0183] Figure 3d Shows Figure 3b Front view of the layout.

[0184] Figure 3e Shows Figure 3a Oblique bottom view of the medium dosage form.

[0185] Figure 3f Shows Figure 3b Side view of the medium layout.

[0186] Figure 4a Shown is a perspective side view of a rope-like formulation in its compacted state, which is suitable for use in a dosage form according to the invention.

[0187] Figure 4b Another rope-shaped formulation is shown in a side view in its compacted state, which is suitable for use in a dosage form according to the present invention.

[0188] Figure 4c A side view of a stick-shaped formulation in its compacted state is shown, which is suitable for use in a dosage form according to the invention.

[0189] Figure 4d Another strip-shaped preparation, which is suitable for use in a dosage form according to the invention, is shown in a side view in its compacted state.

[0190] Figure 4e Shows Figure 4a or Figure 4b A side view of a string-like preparation in its unfolded state.

[0191] Figure 4f Shows Figure 4c or Figure 4d A side view of a strip preparation in its unfolded state.

[0192] Figure 5a An oblique isometric view of a capsule portion of a capsule device as part of a dosage form according to a fourth embodiment of the invention is shown.

[0193] Figure 5b An oblique isometric view of a capsule portion of a capsule device as part of a dosage form according to a fifth embodiment of the invention is shown.

[0194] Figure 5c An oblique isometric view of a capsule portion of a capsule device as part of a dosage form according to a sixth embodiment of the invention is shown.

[0195] Figure 6a Shown in top view Figure 5a The capsule part.

[0196] Figure 6b Shown in top view Figure 5b The capsule part.

[0197] Figure 6c Shown in top view Figure 5c The capsule part.

[0198] Figure 7a Shown in side view Figure 5a A schematic cross section of a capsule part and a stick preparation in its compacted state, the stick preparation being placed inside the capsule part and extending through the opening of the capsule device.

[0199] Figure 7b Shown in side view Figure 5b A schematic cross section of a capsule part and a stick preparation in its compacted state, the stick preparation being placed inside the capsule part and extending through the opening of the capsule device.

[0200] Figure 7c Shown in side view Figure 5c A schematic cross section of a capsule part and a stick preparation in its compacted state, the stick preparation being placed inside the capsule part and extending through the opening of the capsule device.

[0201] Figure 7d Shows Figure 7c A modified version of the embodiment of the present invention, wherein the width of the slit-shaped opening is greater than Figure 7c In.

[0202] Figure 7e yes Figure 5b Schematic side view of an embodiment of a capsule portion in , depicting the location of the opening as a planar curved slit.

[0203] Figure 8The results for dry and wet conditions are shown. Figures 7a to 7d FIG. 4 is a graph showing the results of a tensile test performed on a dosage form according to an embodiment.

[0204] Figure 9a A diagram is shown explaining the first step of a procedure involving administration of a swallowable dosage form configured in accordance with the present invention.

[0205] Figure 9b Shows the explanation from Figure 9a Illustration of the second step of the procedure starting.

[0206] Fig.9c Shows the explanation from Figure 9a Illustration of the third step of the procedure to start.

[0207] Figure 9d Shows the explanation from Figure 9a Illustration of the fourth step of the procedure to start.

[0208] Fig.10 A schematic side view of a dosage form according to a further embodiment of the invention is shown.

[0209] Figure 1a A pharmaceutical dosage form 1 for administration to a mucosa, in particular to the buccal, gastrointestinal, rectal or vaginal mucosa, is shown, which comprises a preparation 2 having an elongated shape and comprising an active pharmaceutical ingredient. The preparation 2 is shown in a compact state: the preparation is assumed to have a strip-like shape, Figure 1a The side view of the strip preparation is shown as being wound into a spiral shape around an imaginary axis, which is perpendicular to the drawing. In the unfolded state, when the preparation is pulled out from the slit-shaped opening 5 of the capsule 3, the strip preparation will have an elongated shape of a substantially straight strip, such as Figure 4f shown.

[0210] The capsule device 3 has a capsule shape and comprises a hollow space 4 which contains the formulation 2 in a compacted state. The capsule consists of a thin wall having a thickness of about 50 μm to 200 μm, which is made of a biodegradable or non-biodegradable material.

[0211] The capsule device has an opening 5 which is a planar curved slit centered on the central length axis A of the capsule 3. Such a slit can be produced by milling out the capsule material using a plate-shaped milling tool, such as a plate-shaped saw blade. The width a of the planar curved slit is defined by measuring the distance of the opposite surfaces 5a of the capsule wall in a direction perpendicular to the length axis A. The distance 'a' can be a constant value, for example, between 200 μm and 600 μm. For example, the thickness t of the preparation can be a constant value between 20 μm and 150 μm.

[0212] like Figure 1b, where the dosage form is rotated 90° about the axis A, the length of the outer edge of the surface 5a is indicated as 'b'. Due to the convex shape of the upper cap of the capsule 3 with the slit, the distance b is greater than the distance 'c', c representing the direct connection between two opposite end points 5b of a single outer edge of the surface 5a. The rectangular area (not directly shown) defined by the four edge points 5b of the slit-like opening and having the dimensions a*c is also called the passage cross section, because it limits the area available for the strip 2 when passing through the slit 5, the strip 2 having a sufficiently small rectangular cross section to pass through the surface 5a at a certain distance (= spacing).

[0213] Regarding the outer dimensions of the capsule device, for example, the height H of the capsule 3 may be 8 mm, and the width W of the capsule may be 4 mm. However, other dimensions of the capsule device are generally possible, taking into account the desired administration site of the patient.

[0214] The first end 2a of the preparation 2 extends through the opening 5 in the compact state of the preparation to allow the preparation to be grasped and pulled out from the hollow space into the surrounding area of ​​the capsule device, thereby transferring the preparation 2 from the compact state to the expanded state. Pulling out the preparation, i.e., the pulling movement P (see Figure 1c ), may be the result of fixing the end 2a of the preparation 2 and pulling the capsule device in the direction M opposite to P. This is the case, for example, with a process of administering a capsule device by swallowing the capsule device and fixing the end 2a of the preparation on the patient's teeth (see Figures 9a to 9d ).

[0215] The first end 2a may have an end portion (see Figure 1d ), which has a shape different from the strip 2. For example, the end portion may form a sealing portion adapted to be arranged at the opening 5 for sealing the opening 5 before the end portion is pulled out of the opening.

[0216] The dimensions of the slit-shaped opening 5 and the strip-shaped preparation 2 are set so that when the preparation is pulled out from the opening, the spacing (S1; S2; see Figure 1c ) is arranged to be measured in an opening cross section CS of the opening 5 between the formulation 2 and a surface 5a of the capsule means defining the opening 5. Here, the central length axis A of the capsule extends perpendicularly to the opening cross section CS.

[0217] like Figure 1c As shown, the thickness t of the strip 2 is significantly less than the width a of the planar curved slit 5. For example, the thickness t may be a constant value between 20 μm and 150 μm. The spacing S=S1=S2 is measured by positioning the preparation 2 in the center of the opening 5 and the centered and aligned position of the strip surface parallel to and facing the surface 5a of the capsule. When the preparation 2 is pulled out of the opening, the spacing S exists and may be substantially constant on average, which means that it is substantially constant along the entire length of the elongated preparation (see Figure 4e ,4f ). However, the scope of the present invention may also cover embodiments of dosage forms in which the spacing between the dosage form and the surface 5a defining the opening varies due to different thicknesses t of the dosage form 2, or in which the spacing is partially interrupted - due to partial variations in dimensions a and t (including partial dimensions set to a=t).

[0218] In cases where the preparation has a string-like shape, the size can be measured analogously, and in the case of irregularly shaped preparations, the size can be determined by taking an average value.

[0219] like Figure 1d As shown, the first end 2a can have an end portion forming an enlarged portion, which can be configured to avoid loss of the preparation in the capsule 3, which will make the patient or the administrator withdraw the end 2a to pull out the strip and apply the dosage form in a predetermined manner. The end portion 2a can also be configured to be arranged at the opening 5 to seal the opening 5 before the end portion is pulled out from the opening. Part 7 can be provided at the end part, configured to connect a line to the end part, which the patient or the administrator can use to grab the preparation or manipulate the preparation. In Figures 9a to 9d In the case of the oral dosage form shown, the wire can be secured to the patient's teeth rather than having the end 2a secured directly to the patient.

[0220] Figures 2a to 2e Different arrangements of the capsule device 23 and the two semi-cylindrical elements 23a and 23b forming the capsule device are shown. The two semi-cylindrical elements can be manufactured using a type of molding process. The arrangement of the capsule 23 and Figures 5a to 5cCompared with the capsules in the present invention, these capsules can be produced by the Colton method traditionally, including connecting two tube elements, followed by the step of setting an opening for the capsule. The lower part includes a rectangular parallelepiped recess 25c on one of its circular end faces. Such a configuration allows the dosage form to be easily assembled by the following: the lower part 23a of the capsule 23 is horizontally arranged, wherein the hollow space is upward, and the compact preparation is placed inside the hollow space of the lower part 23a, and then the end part 2a of the preparation is simply dropped on the surface 25a.1 defining the opening 25, followed by the step of placing the upper half 23b on the lower half 23a. The parts can be connected by adhesion, force matching and / or using an adhesive. The positioning of the two half parts 23a, 23b makes the surfaces 25a.1 and 25a.2 aligned relative to each other, thereby defining the opening 25. The opening 25 is arranged to deviate from the length axis A, which means that the axis A does not intersect with the center point 25x of the opening 25. Surface 25a.2 is defined by the outer surface of the half part 23b. The lower half 23a of the capsule device has a (male) connector portion 23d.1, here configured as a protrusion 23d.1 on the connection side of the half 23a, which extends circumferentially around the interior space of the capsule device and thereby forms an annular protrusion. The upper half has a corresponding connector portion 23d.2, here configured as a recess 23d.2 on the connection side of the half 23b, which extends circumferentially around the interior space of the capsule device and thereby forms an annular recess configured to receive the protrusion 23d.1 by a form-fit connection, which ensures an accurate relative positioning of the two semi-cylindrical elements 23a, 23b.

[0221] Figures 2a to 2e Each semi-cylindrical element 23a, 23b of the capsule device 23 in the embodiment is made of a wall 23c having an inner side 23c.1 and an outer side 23c.2, which extend parallel to each other. The shape of the resulting hollow space of the capsule device 23 is substantially similar to the outer contour of the capsule 23, which means that the hollow space is capsule-shaped, comprising a hollow cylindrical portion capped by a hollow hemispherical portion at each end of the cylinder, wherein one (hollow) cap portion is connected to the opening 25. Alternatively, any edge of the opening 25 may be trimmed to avoid sharp edges.

[0222] Figures 3a to 3f The arrangement of a dosage form 31 with a capsule device 33 is shown. The capsule device 33 has Figures 2a to 2e The capsule device 23 shown has the same features, except for the shape of the hollow space or the inner side of the capsule wall, respectively. In addition, a strip of preparation 32 is shown here, which is placed in the hollow space of the capsule device 33 and extends through the opening 35. The same preparation 32 can be used for Figures 2a to 2e The capsule device 23 forms a dosage form.

[0223] The inner side 33c.1, 33c.3 of the capsule wall 33c is shaped to provide a substantially rectangular hollow space. Each side acts as a guide member 33c.1, 33c.3. Such a rectangular hollow space provides the function of a guide compartment for guiding the winding position of the strip preparation 2, which may be particularly advantageous during the process of unwinding the compact preparation 2 during the preparation is pulled out. It is found that the rectangular hollow space (which provides a form-fitting shell (in the shape / state of a cylindrical coil) of the preparation 2) provides a guiding structure, which stabilizes the preparation to prevent rotation around the central length axis A. Therefore, the torsion of the preparation around the axis A is avoided and the unwinding process becomes more reliable, particularly when the preparation is quite deformable.

[0224] Figures 5a to 5c A capsule part 43a is shown, respectively, having the shape of a cylindrical part capped by a hemispherical shaped part with a slit-shaped opening 45.1, 45.2, 45.3, respectively. Such a capsule part can be produced by the known Colton method and after placing the compact formulation inside the hollow space of the capsule part 43a, a corresponding cylindrical counterpart part (not shown) can be used to close the capsule part 43a and thereby form the dosage form according to the invention. The slit-shaped openings 45.1, 45.2, 45.3 can be provided by milling a plate-shaped recess from the capsule material using a plate-shaped milling tool, such as a saw blade or any tool with a comparable effect.

[0225] Figures 7a to 7c Corresponding to Figures 5a to 5c 6a to 6c show embodiments of the capsule part 43a, in which the positioning of the slit-like openings is varied. In each case, the positions of the openings 45.1, 45.2, 45.3, 45.3' are offset from the longitudinal axis A of the capsule part 43. The opening 45.3 is identical to the opening 45.3', but the width a.2 of the opening 45.3' is approximately 50% greater than the width a.1 of the opening 45.3, so that a.2=1.5*a.1. Figures 7a to 7d The image is copied to Figure 8 .

[0226] The slit-shaped opening 45.2 is arranged such that the normal N to the main plane of the planar curved slit 45.2 comprises an angle α=45° with the central axis A of the capsule part 43a (see Figure 7e ). For the slit-shaped opening 45.1, wherein the slit-shaped opening is offset from the central axis A of the capsule part, the angle α is zero. In another preferred configuration of the slit-shaped openings 45.3, 45.3', the angle α is 90° respectively. The slit-shaped openings 45.1, 45.2, 45.3, 45.3' are respectively arranged such that the main plane extending through the opening is parallel to the axis B, which is perpendicular to the central axis A of the capsule device (see Figure 7e). Such a configuration matches the winding of the strip preparation, which is wound around a winding axis parallel to the axis B, and facilitates the unwinding process.

[0227] Figure 8 The figure shows the maximum pulling force that occurs when pulling out a strip preparation 2 from a dosage form having a capsule part 43a and one of openings 45.1, 45.2, 45.3, 45.3' of different types due to the selection of opening type and dry or wet conditions. In order to conduct the experiment, a standard setting for measuring tension was used. The dosage form is arranged and fixed in a vertical position, wherein the central length axis of the capsule part 43a is arranged vertically. The end portion of the strip preparation 2 extending through the opening in each case is connected to a force sensor. Then the force sensor with the end portion of the preparation is vertically raised at a constant speed (e.g., 0.02m / s) somewhere between 0.01 and 0.05, and the maximum force is determined by continuously monitoring the occurring force (occurringforce). In the case of dry conditions, the preparation stored at room temperature 21°C and standard humidity is directly transferred to a force measuring device and measured. In the case of wet conditions, the dosage form is rinsed with distilled water for 10 seconds, and then transferred to a force measuring device and measured. Surprisingly, the maximum tension was generally lower in wet conditions compared to dry conditions, and no rupture of the formulation was observed during the experiments, either in wet or dry conditions. Increasing the width of the slit (comparing the results for openings 45.3 and 45.3') resulted in lower maximum tension.

[0228] Fig.10A pharmaceutical dosage form 51 for application to a mucosa, particularly an esophageal membrane, is shown, comprising a preparation 52 and a capsule device 53, the preparation having an elongated shape with an end portion 52a and comprising an active pharmaceutical ingredient, the at least one preparation being able to be arranged in a compact state and in an expanded state, the capsule device comprising a hollow space 54a, 54b for accommodating the preparation 52 in a compact state. More particularly, the preparation is located inside the upper half 54a of the hollow space, and the "upper half" means that when the patient swallows the dosage form with a water flow, the half is oriented toward the upstream direction. Inside the lower half 54b of the hollow space, a settler element is sandwiched between opposite sides 53a, 53b of the capsule inside. The settler element 60 is a substantially cylindrical portion and is arranged coaxially with the capsule device along its axis A. The settler device 60 occupies a larger portion of the lower half 54b of the hollow space. The "lower half" means that when the patient swallows the dosage form with a water flow, the half is oriented toward the downstream direction. The upper and lower parts are also illustrated by virtual line C, which divides the hollow space into two substantially equal-sized volumes 54a, 54b. The presence of a settler element 60 avoids the lower part 54b of the hollow space from being filled with air. The settler element is made of glucose, for example, with a density of about 1.5g / cm3, thereby being heavier than water. When the patient is administering dosage form in the presence of a current, the weight element 60 will improve the deployment efficiency of the compact strip preparation 52 by the gravity-driven displacement in the downstream direction. Placing the settler element 60 in the lower part 54b of the hollow space of the capsule will help align the capsule with the current direction, which can be the gravity direction substantially.

[0229] The sedimentation element 60 and the dosage form 51 are respectively produced by the method according to the present invention, using a process for tableting a granular material mixture, the granular material mixture exemplarily comprising the following excipients: cross-linked carboxymethylcellulose-Na 0.25; anhydrous calcium hydrogen phosphate 97.75; magnesium stearate 1.5; highly dispersed silicon dioxide 0.5, all figures are in mol%.

[0230] The physical properties of the settler element 60 as a tablet, which fits in the lower half of the capsule and has a diameter of 7.0 mm, are as follows: density: approximately 1.65 g / cm3; mass: 366 mg±5%; height: 5.3-5.7 mm; diameter: 6.95 mm.

[0231] The total density of dosage form 51 without sinker element 60 is 0.4 g / cm3, and the total density of dosage form 51 with sinker element 60 is 1.05 g / cm3.

[0232] Alternatively, the settler element may also be porous by containing open pores that allow water to enter the pores. The porous material may be any absorbent material. In this case, water entering the pores and displacing the air will contribute to the negative buoyancy provided by the settler device.

[0233] The capsule device has an opening 55, and the first end 52a of the preparation in the compact state extends through the opening 55 for allowing the preparation to be pulled out from the hollow space into the surrounding area of ​​the capsule device, thereby transferring the preparation from the compact state to the expanded state. During administration, the end 52a of the preparation can be fixed to the patient's teeth. Also here, the size of the opening 55 and the preparation 52 is set so that when the preparation is pulled out from the opening 55, the spacing is set in the opening cross section of the opening between the preparation and the surface of the capsule device defining the opening. This spacing and the optional hole 53c that additionally extends through the wall of the capsule device in this embodiment allow water to enter the hollow space and air to leave the hollow space. In this case, water enters the hole and the opening, thereby displacing the air, contributing to the negative buoyancy provided by the settler device.

[0234] The dosage forms according to the invention are further illustrated by the following examples.

[0235] Example 1

[0236] The monolayer or multilayer preparation according to the invention preferably has a paper-like form.

[0237] The preparation according to the present invention dissolves preferably within 1 h, more preferably within 30 min, most preferably within 15 min and most preferably within 5 min after contact with the site of action, in particular the mucosa.

[0238] They basically comprise a mucoadhesive layer containing the active substance, which preferably comprises: a mucoadhesive polymer such as cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylic acid (polyacryl) derivatives, polyvinyl pyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan and mixtures thereof, plasticizers such as polyethylene glycol, glycerol, sorbitol and mixtures thereof, and solvents such as water, ethanol, methanol, acetone, organic solvents and mixtures thereof. In addition, additives such as colorants, fragrances, flavorings, preservatives, antioxidants, transdermal absorption enhancers, solubilizers, disintegration promoters, lubricants and mixtures thereof may be included.

[0239] In particular, substances from the following groups are suitable as active pharmaceutical ingredients: drugs acting on bones and muscles, drugs acting on the nervous system, hormones and drugs acting on the hormonal system, drugs acting on gynecological agents, drugs acting on the cardiovascular system, drugs acting on the respiratory system, drugs acting on the gastrointestinal tract, diuretics, drugs acting on the sense organs, dermatological drugs, vitamins and micronutrients, peptide-based drugs and proteins, analgesics, anti-infectives and parasiticides.

[0240] Development and testing

[0241] In order to develop and test formulations suitable for the sheet form of the present invention, a testing method based on the following test and selection scheme 1 has been performed.

[0242] In this way, preparations are obtained which meet the requirements arising in particular in connection with the use of the dosage form.

[0243] In particular, the flakes according to the invention differ from previously known flakes by the fact that they do not dissolve even on only slight contact with fluids and that they have a relatively high stretchability and resistance to breakage.

[0244] Testing and selecting option 1

[0245] Developing membrane preparations

[0246] Optical evaluation:

[0247]

[0248]

[0249] Particularly for vaginal, rectal or intestinal mucosa, a tensile strength of less than 3.5 MPa may be beneficial for increasing safety, user convenience and / or enabling a tight but flexible fitting of the sheet-like preparation to the corresponding mucosa.

[0250] Especially for esophageal mucosa and / or administration to the esophagus, a tensile strength of more than 15 MPa may be beneficial, especially for avoiding breakage of the sheet-like formulation during its administration, especially during swallowing of the dosage form.

[0251] Example 2 - Single layer formulation

[0252] Monolayer preparations suitable for use according to the invention, in particular sheets, may in particular comprise the following preparations:

[0253] A 10% PVA

[0254] 20% PEG 400

[0255] 5% HPMC

[0256] x% active pharmaceutical ingredient

[0257] Add to 100% desalinated water

[0258] B 5% PVA

[0259] 15% IR

[0260] x% active pharmaceutical ingredient

[0261] Add to 100% desalinated water

[0262] or

[0263] C 5% PVA

[0264] 15% IR

[0265] 8% Glycerin 85%

[0266] x% active pharmaceutical ingredient

[0267] Add to 100% desalinated water

[0268] Example 3 - Two-layer formulation

[0269] The two-layer preparation according to the invention, in particular the sheet, comprises a mucoadhesive layer containing the active substance and a water-impermeable layer called a backing layer. The mucoadhesive layer containing the active substance is preferably composed of a mucoadhesive polymer such as cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylate derivatives, polyvinyl pyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan and mixtures thereof, plasticizers such as polyethylene glycol, glycerol, sorbitol and mixtures thereof, and solvents such as water, ethanol, methanol, acetone, organic solvents and mixtures thereof. In addition, additives such as colorants, fragrances, flavorings, preservatives, antioxidants, transdermal absorption promoters, solubilizers, disintegration promoters, lubricants and mixtures thereof may be included. Substances from the following groups are suitable as active pharmaceutical ingredients: drugs acting on bones and muscles, drugs acting on the nervous system, hormones and drugs acting on the hormonal system, drugs with gynecological effects, drugs acting on the cardiovascular system, drugs acting on the respiratory system, drugs acting on the gastrointestinal tract, diuretics, drugs acting on the sense organs, drugs for dermatological use, vitamins and micronutrients, peptide-based drugs and proteins, analgesics, anti-infectives and parasiticides.

[0270] The backing layer preferably comprises ethylcellulose layers of different thicknesses, wherein ethylcellulose of different viscosities can be used.In addition, other additives such as coloring agents, spices, flavoring agents, preservatives, antioxidants, solubilizers, pore formers, lubricants and mixtures thereof can be incorporated.

[0271] Table 1 below shows various exemplary compositions of the layers of the two-layer sheet 3 according to the present invention.

[0272] Table 1:

[0273]

[0274]

[0275] The strip-shaped, in particular film-shaped, foil-shaped, sheet-shaped preparation 2 comprising an active pharmaceutical ingredient comprises at least one first layer containing the active substance. The layer containing the active substance preferably comprises a polymer, more preferably a film-forming polymer, wherein the polymer fraction in the layer containing polymer and active substance is 10 to 90% by weight, preferably 20 to 70% by weight and more preferably 30 to 60% by weight, and wherein, in particular in a two-layer sheet, the layer containing the active substance is an adhesive layer, and wherein the polymer is a water-dispersible and / or water-decomposable and / or water-disintegrable film-forming polymer.

[0276] In addition, the strip-shaped, in particular film-shaped or sheet-shaped preparation 2 comprising an active pharmaceutical ingredient comprises at least one layer of inactive substances that does not contain an active pharmaceutical ingredient. In a three-layer sheet 2, the sheet 2 comprises a layer of an additional inactive substance that also does not contain an active pharmaceutical ingredient. Such a first layer of inactive substances and / or such an additional layer of inactive substances is preferably a water-insoluble layer, for example, made of ethylcellulose or including ethylcellulose. The layer of inactive substances and / or the additional layer of inactive substances can be formed as an adhesive layer, in particular in a two-layer sheet 2, wherein the layer consists of, for example, hydroxypropylmethylcellulose or includes, for example, hydroxypropylmethylcellulose. In a multi-layer, in particular three-layer sheet 2, the layer containing the active substance is preferably arranged between two layers without active substances, wherein the layer containing the active substance can be arranged between a first layer without active substances and a further layer without active substances, and wherein preferably, the first layer without active substances is a water-insoluble layer, which more preferably comprises ethylcellulose, and wherein at least one further layer without active substances 9d is an adhesive layer, which more preferably comprises hydroxypropyl methylcellulose.

[0277] Example 4 - Three-layer formulation

[0278] The three-layer preparation according to the invention, in particular the sheet, preferably comprises a mucoadhesive layer containing the active substance, a water-impermeable layer called a backing layer, and an adhesive protective layer. The mucoadhesive layer containing the active substance can be composed of mucoadhesive polymers such as cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylic acid derivatives, polyvinyl pyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan and mixtures thereof, plasticizers such as polyethylene glycol, glycerol, sorbitol and mixtures thereof, and solvents such as water, ethanol, methanol, acetone, organic solvents and mixtures thereof. In addition, additives such as colorants, fragrances, flavorings, preservatives, antioxidants, transdermal absorption promoters, solubilizers, disintegration promoters, lubricants and mixtures thereof may be included. In particular, the material in the following group is suitable as active pharmaceutical ingredient: medicines acting on bones and muscles, medicines acting on the nervous system, hormones and medicines acting on the hormonal system, gynecological medicines, medicines acting on the cardiovascular system, medicines acting on the respiratory system, medicines acting on the gastrointestinal tract, diuretics, medicines acting on sense organs, dermatological medicines, vitamins and micronutrients, medicines and proteins based on peptides, analgesics, anti-infectives and parasiticides. The backing layer is made of ethylcellulose layers of different thicknesses, wherein ethylcellulose with various viscosities can be used. In addition, other additives can be mixed, such as coloring agents, spices, flavoring agents, preservatives, antioxidants, solubilizers, pore-forming agents, lubricants and mixtures thereof. The adhesive protective layer may vary in thickness and be made of mucoadhesive polymers such as cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylic acid derivatives, polyvinyl pyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan and mixtures thereof, and solvents such as water, ethanol, methanol, acetone, organic solvents and mixtures thereof. In addition, additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, transdermal absorption enhancers, solubilizers, disintegration enhancers, pore formers, lubricants and mixtures thereof may be included.

[0279] Table 2 below shows various exemplary compositions of the layers of such a three-layer sheet 3 .

[0280] Table 2:

[0281]

[0282]

[0283] The sheet-like preparation 3 of the pharmaceutical dosage form 1 according to the invention can also be formed from one layer or from multiple layers, in particular from two layers.

[0284] Example 5

[0285] Calculation of the amount of active ingredient per sheet:

[0286] In particular, the amount of active ingredient based on the layer thickness of the wet polymer film can be calculated according to the following formula:

[0287]

[0288] in

[0289] mMass [g]

[0290] pDensity [g / cm 3 ]

[0291] A area [cm 2 ]

[0292] hHeight [μm]

[0293] In this context, it is important to remember that the height of the doctor blade is not equal to the layer thickness of the wet sheet. Reasons for this are, for example, shearing of the polymer film as it is rolled out, flow separation or co-flow of the polymer composition after rolling out and the formation of thicker areas at the edges of the polymer film. The extent of these processes depends, inter alia, on the viscosity of the polymer solution and on the active pharmaceutical ingredient used. Therefore, for each active pharmaceutical ingredient, a specific individual fraction can be added to the calculated amount of active ingredient. This additional fraction is

[0294] -35% for luciferin sodium

[0295] -40% for quinine

[0296] -35% for diclofenac sodium

[0297] In addition, the calculated amount can be adjusted using a drug specific factor, where, in particular, the drug specific factor is 100% + additional fraction, and thus the formula reads:

[0298]

[0299] Example 6 - Fabrication of a single layer sheet:

[0300] The production of a single-layer sheet is carried out by a solvent casting method, wherein all ingredients are first dissolved in a solvent, homogenized, and then spread to the desired thickness on a suitable release liner using a doctor blade. The resulting film is then dried under defined conditions and then cut into pieces of suitable size.

[0301] The preparation method of the preparation mentioned in the above embodiment 2 is described in detail below:

[0302] AFirst, polyvinyl alcohol (PVA) was dissolved in deionized water in a beaker at a temperature of 90°C and at a stirring speed of 400rpm. Then, polyethylene glycol 400 (PEG 400) and a medicinal substance or a medicinal substance solution were added respectively and the solution was homogenized. Finally, hydroxypropyl methylcellulose (HPMC) was added under stirring, homogenized, and evaporation losses were compensated with deionized water. The polymer solution was covered and placed overnight, and centrifuged at 4400rpm for 50min to remove bubbles on the second day. Then, the solution was evenly spread on the release liner by means of a scraper, and the polymer film was dried in a drying oven at 40°C for 6h. Before testing and further use, the film was cut into pieces of appropriate size and separated from the release liner. The single-layer sheet was stored on the release liner and wrapped in aluminum foil.

[0303] First, polyvinyl alcohol (PVA) and IR is dissolved in deionized water in a beaker. Then, the medicinal substance or medicinal substance solution is added, homogenized and the evaporation loss is compensated with deionized water. The polymer solution is covered and left overnight and centrifuged at 4400rpm for 15min on the second day to remove bubbles. Then, the polymer solution is evenly spread on the release liner with the help of a spatula, and the polymer film is dried in a drying oven at 40°C for 5h. Before testing and further use, the film is cut into pieces of appropriate size and separated from the release liner. The single-layer sheet is stored on the release liner and wrapped in aluminum foil.

[0304] First, polyvinyl alcohol (PVA) and IR is dissolved in deionized water in a beaker. Then, glycerol 85% and the medicinal substance or medicinal substance solution are added, homogenized and the evaporation loss is compensated with deionized water. The polymer solution is covered and left overnight, and centrifuged at 4400rpm for 15min on the second day to remove bubbles. Then, the polymer solution is evenly spread on the release liner with the help of a spatula, and the polymer film is dried in a drying oven at 40°C for 5h. Before testing and further use, the film is cut into pieces of appropriate size and separated from the release liner. The single-layer sheet is stored on the release liner and wrapped in aluminum foil.

[0305] Example 7 - Making a Multilayer Sheet

[0306] For the manufacture of multilayer sheets, such as those mentioned in Examples 3 and 4, each layer is initially manufactured by a solvent casting process. Thus, all the ingredients of the layer are dissolved in a solvent, homogenized and then spread to the desired thickness using a doctor blade. The individual layers are then spread on top of each other or connected together in various ways (such as pressure or "gluing"). Thereafter, the resulting film is cut into pieces of appropriate size.

[0307] The following is a detailed description of the preparation method of the above-mentioned two-layer and three-layer sheets:

[0308] Make two layers of sheet:

[0309] 1. First, a polymer solution for a mucoadhesive layer containing an active substance was prepared according to "Manufacturing a single-layer sheet A", and a 4% (w / v) ethylcellulose solution EC solution in acetone was prepared. Then, the EC solution was sprayed uniformly onto the release liner at the desired layer thickness and dried at room temperature for 15 min. Then, the polymer solution was spread uniformly thereon with the aid of a doctor blade, and the resulting two-layer film was dried in a drying oven at 40° C. for 6 h. Before testing and further use, the film was cut into pieces of appropriate size and separated from the release liner. The two-layer sheet was stored on the release liner and wrapped in aluminum foil.

[0310] 2. First, prepare a polymer solution for the mucoadhesive layer containing the active substance according to "Manufacturing a single-layer sheet A" and prepare a 4% (w / v) EC solution in acetone. Then, spread the polymer solution evenly onto the release liner with the help of a doctor blade, and dry the polymer film in a drying oven at 40°C for 4 h. Then, spray the EC solution evenly onto the partially dried, still sticky polymer film with the desired layer thickness. Finally, the resulting two-layer film is dried again in a drying oven at 40°C for 2 h so that the two layers are firmly connected to each other. Before testing and further use, cut the film into pieces of appropriate size and pull them out of the release liner. The two-layer sheet is stored on the release liner and wrapped in aluminum foil.

[0311] 3. First, prepare the polymer solution for the mucoadhesive layer containing the active substance according to "Manufacturing a single-layer sheet A" and prepare a 4% (w / v) EC solution in acetone. Then, spread the polymer solution evenly onto the release liner with the help of a doctor blade, and dry the polymer film in a drying oven at 40°C for 4 h. In parallel, spray the EC solution evenly onto the second release liner with the desired layer thickness and dry it at room temperature for 15 min. Then, carefully separate the resulting EC film from the release liner and press it onto the partially dried, still sticky polymer film with the help of a roller. Finally, dry the now two-layer film at 40°C in a drying oven for 2 h so that the two layers are firmly connected to each other. Before testing and further use, cut the film into pieces of appropriate size and separate them from the release liner. The two-layer sheet is stored on the release liner and wrapped in aluminum foil.

[0312] Make three-layer sheets:

[0313] 1. First, a polymer solution for a mucoadhesive layer containing an active substance was prepared according to "Manufacturing a single-layer sheet A", and a 4% (w / v) EC solution in acetone and a 0.5% (w / v) HPMC solution in cold deionized water were prepared. Then, the EC solution was sprayed uniformly onto the release liner at the desired layer thickness and dried at room temperature for 15 min. Then, the polymer solution was spread evenly thereon with the aid of a doctor blade, and the resulting two-layer film was dried in a drying oven at 40° C. for 6 h. Finally, the HPMC solution was spread thereon as the third layer with the aid of a doctor blade, and then the resulting three-layer film was dried again in a drying oven at 40° C. for 2 h, so that all layers were firmly connected to each other. Before testing and further use, the film was cut into pieces of appropriate size and separated from the release liner. The three-layer sheet was stored on the release liner and wrapped in aluminum foil.

[0314] 2. First, prepare the polymer solution for the mucoadhesive layer containing the active ingredient according to "Making a single-layer sheet", prepare a 4% (w / v) EC solution in acetone, and prepare a 0.5% (w / v) HPMC solution in cold deionized water. Then, spray the EC solution evenly onto the release liner at the desired layer thickness and dry at room temperature for 15 min. Then, spread the polymer solution evenly onto it with the help of a doctor blade, and dry the resulting two-layer film in a drying oven at 40°C for 6 h. In parallel, spread the HPMC solution onto the second release liner at their desired layer thickness and dry it in a drying oven at 40°C for 2 h. Then, carefully pull the HPMC film off the release liner and glue it to the two-layer film with water as an adhesive. Finally, dry the resulting two-layer film in a drying oven at 40°C for 1 h so that all layers are firmly connected to each other. Before testing and further use, cut the film into pieces of appropriate size and pull it out of the release liner. The three-layer sheet is stored on a release liner and wrapped in aluminum foil.

[0315] 3. First, a polymer solution for the mucoadhesive layer containing the active substance was prepared according to "Manufacturing a monolayer sheet A", a 4% (w / v) EC solution in acetone and a 0.5% (w / v) HPMC solution in cold deionized water. The polymer solution was then spread evenly onto the release liner with the aid of a doctor blade, and the polymer film was dried in a drying oven at 40° C. for 6 h. In parallel, the HPMC solution was spread onto the second release liner in the desired layer thickness and dried in a drying oven at 40° C. for 1 h. The resulting polymer film was then carefully pulled off the release liner and pressed onto the partially dried, still tacky HPMC film with the aid of a roller. The now two-layer film was then dried in a drying oven at 40° C. for 1 h, so that the two layers were firmly connected to each other. Finally, the EC solution was sprayed evenly onto the two-layer film in the desired layer thickness, and the resulting three-layer film was dried at room temperature for 30 min. Prior to testing and further use, the film was cut into pieces of appropriate size and pulled from the release liner. The three-layer sheet was stored on a release liner and wrapped in aluminum foil.

[0316] 4. First, a polymer solution for the mucoadhesive layer containing the active substance was prepared according to "Manufacturing a monolayer sheet A", a 4% (w / v) EC solution in acetone was prepared, and a 0.5% (w / v) HPMC solution in cold deionized water was prepared. The HPMC solution was then spread onto the release liner in the desired layer thickness and dried in a drying oven at 40°C for 2 h. The polymer solution was then spread onto it with the aid of a doctor blade, and the resulting two-layer film was dried in a drying oven at 40°C for 4 h. In parallel, the EC solution was sprayed uniformly onto the second release liner in the desired thickness and dried at room temperature for 15 min. Subsequently, the resulting EC film was carefully pulled off the release liner and pressed onto the partially dried, still sticky two-layer film with the aid of a roller. Finally, the now three-layer film was dried in a drying oven at 40°C for 2 h so that all layers were firmly connected to each other. Before testing and further use, the film was cut into pieces of appropriate size and pulled out of the release liner. The three-layer sheet is stored on a release liner and wrapped in aluminum foil.

[0317] The features of the invention disclosed in the above description, the claims and the drawings may be essential individually and also in any combination to implement the invention in its various embodiments.

[0318] In particular, exemplary embodiments of the present invention relate to orally administrable dosage forms for treating esophageal mucosa. Figures 9a to 9dAn exemplary process of administering a formulation by swallowing a dosage form is shown in FIG. An applicator 100 is used, which contains a pharmaceutical dosage form according to the present invention. A curled string member 2b is connected to the end portion 2a of the formulation 2 of the dosage form (1 or 31). The applicator is connected to a container 101 with water. Drinking from the applicator involves flushing the applicator with the water in the container and thereby transporting the dosage form to the patient's mouth while the string member 2b remains connected to the applicator. After the dosage form is completely swallowed and reaches the patient's stomach ( Fig.9c ), the patient removes the end portion of the string member 2b and attaches it to the teeth to fix the string member and the preparation in its unfolded state located in the esophagus. In this case, the preparation 2 can deliver useful substances such as active pharmaceutical ingredients to the esophageal mucosa by unwinding the sheet-like preparation 2 while moving along the esophagus when swallowing the preparation ( Figure 9b , c). Therefore, the active pharmaceutical ingredient contained in the sheet preparation 2 can be locally released to the mucosa of the esophagus. The current treatment of local diseases of the esophagus usually adopts the contents of the swallowing administration system (these administration systems are designed for pulmonary inhalation treatment), or swallowing a gel containing a specific drug. However, the swallowed contents of the administration system or gel generally have a short contact time with the esophageal mucosa. Therefore, in particular, compared with the application form with extended contact time, the local effect is reduced and the systemic effect is increased. By applying the sheet preparation 2 of the pharmaceutical dosage form according to an embodiment of the present invention to the esophageal mucosa, the treatment of local diseases of the esophagus can be improved, and in particular, the contact time can be extended, and the reliability of the process of pulling the preparation out of the capsule and thus the reliability of the entire administration process can be improved. When applied to the esophageal mucosa, the sheet preparation 2 remains in contact with the mucosa while providing controlled release of the active pharmaceutical ingredient to achieve local treatment or diagnosis. Preferably, the controlled release may not be immediate, continuous or extended, and it is also preferred that the sheet preparation 2 dissolves and is preferably swallowed during or after the release of one or more active pharmaceutical ingredients. Furthermore, the shell (=capsule) 3 can be separated from the sheet-like preparation 2 immediately after the release of the sheet-like preparation 2 ( Fig.9c , d) or can be dissolved while still attached to the sheet preparation 2. Preferably, the shell 3 is made of a soluble and / or digestible material. In particular, the end portion 2a can be adapted to be fixed in the oral cavity. Therefore, the end portion 2 can include a mucoadhesive surface, preferably including: cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylate derivatives, polyvinyl pyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan, and mixtures thereof. Therefore, preferably, the retaining device 5 can be attached to the oral mucosa, in particular the buccal mucosa, i.e. the inside of the cheek.

[0319] Even more particularly, embodiments of the present invention may relate to pharmaceutical dosage forms for the treatment of eosinophilic esophagitis. Eosinophilic esophagitis is an inflammatory, immune-mediated disease with increased relevance to gastrointestinal disorders. This disease can be treated with topical steroids. Preferably, shell 3 is a capsule made of hard gelatin. In the initial state of the dosage form, sheet preparation 2 is in a compact form, particularly in coil form, and is connected to an applicator containing the dosage form and water in the initial stage. When administering, end portion 2a is attached in the oral cavity, preferably to the buccal mucosa, particularly by gluing it to the mucosa. Then, preferably with a drink or water, the dosage form is swallowed, and therefore, the dosage form moves along the esophagus and forces are applied to the end portion 2a by delivering the capsule to the stomach. When the dosage form moves downward along the esophagus, sheet preparation 1 is uncurled, and thereby released. Preferably, the sheet preparation is mucoadhesive, and therefore can adhere to the mucosa of the esophagus. In this case, the contact and / or position of the sheet preparation does not depend on or only depends on the position of the end portion 2a in the oral cavity. The rectangular area of ​​the esophageal mucosa is then covered by or at least adjacent to the sheet 2. It can thus be treated with an active pharmaceutical ingredient, in particular a topical steroid, released by the sheet 2. Preferably, the sheet 2 may comprise and release fluticasone or budesonide.

[0320] Preferably, the sheet preparation 2 according to an embodiment of the present invention is manufactured by a solvent casting method, in which all ingredients are first dissolved in a solvent, homogenized, and then spread to a desired thickness on a suitable release liner using a doctor blade. The resulting film is then dried under defined conditions and then cut into pieces of a suitable size.

[0321] In a preferred variant, the ingredients, in particular the polymer matrix, consist of 10% m / m polyvinyl alcohol (PVA) (Mowiol 40-88) suspended in a 20% m / m aqueous solution of Kollicoat IR. In addition, an active pharmaceutical ingredient such as fluticasone or budesonide and an additive such as methylene blue are added as a visual control.

[0322] The sheet preparation 2 manufactured according to this preferred variant has been experimentally analyzed. For this purpose, the film thickness and mass uniformity of the sheet preparation 2 were tested. In addition, the disintegration time was tested for both purified water and moistened alginate gel (3% m / m) to simulate mucous membranes. Complete disintegration is defined as the absence of any solid matrix particles. Tensile strength, elongation and pull-out force have been measured using a texture analyzer. All tests were performed in triplicate and the mean value plus / minus standard deviation was reported. The resulting sheet preparation 3 has a thickness of 114 ± 5 ​​μm and a mass of 9.39 ± 0.03 mg / cm 2The average mass of the cellulose ester was 2.3477 g / cm2. The disintegration time in water was 760 ± 35 s, and the disintegration time on alginate gel was greater than 1200 s. The tensile strength was 31.35 MPa. The elongation at break was 7.41 ± 0.90%.

[0323] Preferably, in particular the pharmaceutical dosage form according to an embodiment of the present invention can be manufactured as described below:

[0324] - Cut the film obtained from the solvent casting technique into strips of 400 mm x 4 mm;

[0325] - folding or rolling the obtained sheet preparation 2;

[0326] - providing a hard gelatin capsule of size 1 is shell 3;

[0327] - milling an opening 5 into a portion of the hard gelatin capsule 3, in particular the upper portion, as shown;

[0328] - threading one end of the sheet preparation 2 through the opening 5; and

[0329] - Closed capsule.

[0330] The dosage forms manufactured as described above, including the preferred variants of the tablet preparation 2 particularly for the embodiments of the present invention, have been experimentally analyzed as described above. The extraction force of the tablet preparation 2 from the capsule was recorded at Figure 8 .

[0331] In addition, if Figure 4f As shown, the sheet preparation 2 may optionally include two regions, a first region of the sheet preparation 2c and a second region of the sheet preparation 2c. The first region 2c is pulled out from the opening, and the second region 2c follows the first region 2c to be pulled out. The first region 2c and the second region 2d may include different active pharmaceutical ingredients. Preferably, the first region 2c may include a local anesthetic, such as benzocaine, butanben, dibucaine, lidocaine, oxybuprocaine or novocaine, and the second region 2d may include a steroid, such as a corticosteroid, a glucocorticoid, fluticasone, budesonide or clocortolone. In particular, in this way, when treating the esophagus, the gag reflex may be suppressed by a local anesthetic, and the esophageal mucosa may be treated with steroids. In addition, the first region 2c has a cross-sectional area that is smaller than the second region 2d. In particular, this beneficially promotes swallowing of the dosage form.

[0332] Furthermore, the end portion 2a is connected to the sheet-like preparation 2 or is a widened portion of the sheet-like preparation 2 having a mucoadhesive layer, the mucoadhesive layer preferably comprising: a mucoadhesive polymer such as cellulose derivatives, starch and starch derivatives, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectin, dextran, lectin and mixtures thereof.

[0333] Preferably, the preparation 2 is manufactured according to one of the manufacturing methods described herein. In particular, a sheet-like preparation having a plurality of regions, in particular at least one first region 2c and at least one second region 2d, can be manufactured similarly to a multilayer preparation, wherein at least some layers are offset from each other but still partially overlap. Also in this way, the end portion 2a can be manufactured and / or connected to the sheet-like preparation 2.

Claims

1. A pharmaceutical dosage form (1; 51) for administration to a mucosa, in particular to the buccal, gastrointestinal, rectal or vaginal mucosa, preferably to the gastrointestinal mucosa, more preferably to the esophageal mucosa, the pharmaceutical dosage form comprising at least one preparation (2; 52), the at least one preparation having an elongated shape and comprising an active pharmaceutical ingredient, the at least one preparation being arrangable in a compact state and in an expanded state, a capsule device (3; 53), the capsule device comprising a hollow space (4; 54a, 54b) for accommodating the at least one preparation in a compact state, The capsule device has an opening (5; 25; 35; 45.1; 45.2; 45.3; 55), and the first end (2a; 52a) of the preparation in the compact state extends through the opening (5; 25; 35; 45.1; 45.2; 45.3; 55) for allowing the preparation to be pulled out of the hollow space into the surrounding area (6) of the capsule device, thereby transferring the preparation from the compact state to the expanded state, It is characterized in that The dimensions of the opening (5; 55) and the preparation (2; 52) are arranged so that when the preparation is pulled out of the opening (5; 25; 35; 45.1; 45.2; 45.3; 55), a spacing (S1; S2) is arranged in an opening cross section (CS) of the opening (5; 55) between the preparation (2; 52) and a surface (5a) of the capsule device defining the opening (5; 55).

2. The pharmaceutical dosage form (1) according to claim 1, wherein: The capsule device (3) extends along a central length axis (A) of the capsule device (3), and wherein the opening (5; 25; 35; 45.1; 45.2; 45.3) is arranged so that the center point of the opening (5; 25; 35; 45.1; 45.2; 45.3) deviates from the central length axis (A).

3. The pharmaceutical dosage form (1) according to claim 1 or 2, wherein: The opening (5; 25; 35; 45.1; 45.2; 45.3) is a slit-shaped opening (5; 25; 35; 45.1; 45.2; 45.3) configured to allow a strip preparation (2) to pass through the opening (5; 25; 35; 45.1; 45.2; 45.3), and when the strip preparation moves through the opening, a cross-section (CS) of the opening (5; 25; 35; 45.1; 45.2; 45.3) is larger than a cross-section of the strip preparation (2).

4. The pharmaceutical dosage form (1) according to claim 3, wherein: The slit-shaped opening (5; 25; 35; 45.1; 45.2; 45.3) has two opposite edges of length (b), and the edges extend along a main plane (BC) of the slit-shaped opening (45.2), and the main plane includes a first line (B) and a second line (C) perpendicular to the first line (B), and the first line (B) is perpendicular to the central length axis (A) of the capsule device (3), and the normal (N) of the main plane includes an angle α with the central length axis (A), wherein 0<=α<=90°.

5. The pharmaceutical dosage form (1) according to claim 4, wherein: 1°<α<＝90°。 6. The pharmaceutical dosage form (1) according to claim 4, wherein: α＝45°。 7. The pharmaceutical dosage form (1) according to claim 4, wherein: α＝90°。 8. The pharmaceutical dosage form (1) according to claim 3, wherein: The width (a) of the slit-shaped opening (5; 25; 35; 45.1; 45.2; 45.3) is greater than the thickness (t) of the strip preparation (2), and the strip preparation is moved out of the capsule device (3) through the slit-shaped opening (5; 25; 35; 45.1; 45.2; 45.3).

9. The pharmaceutical dosage form (1) according to any one of the preceding claims, wherein The spacing S is 100 μm to 2000 μm.

10. The pharmaceutical dosage form (1) according to any one of the preceding claims, wherein The capsule device (3) comprises at least one guide member (33c.1; 33c.3), which is arranged in the internal space of the capsule device (3) to guide the movement of the string-shaped or sheet-shaped preparation (2) toward the opening (5; 25; 35; 45.1; 45.2; 45.3) of the capsule device (3).

11. The pharmaceutical dosage form (1) according to claim 4, wherein: The at least one guiding member (33c.1; 33c.3) forms a guiding compartment for containing and guiding the preparation (2).

12. The pharmaceutical dosage form (1) according to any one of the preceding claims, wherein The capsule device (3) is configured to be swallowed by a patient.

13. The pharmaceutical dosage form (1) according to any one of the preceding claims, wherein The capsule device (3) comprises a first tube element (43a), and preferably the capsule device (3) comprises an additional second Tube elements, wherein preferably the second tube element has a tube diameter which is at least partially smaller than the first tube element (43a), and wherein preferably the second tube element is arranged at least partially in the first tube element (43a) and thereby connected to the first tube element (43a).

14. The pharmaceutical dosage form (31) according to any one of the preceding claims 1 to 12, wherein The capsule device (23; 33) comprises at least a first semi-cylindrical element (23a; 33a), and preferably the capsule device (23; 33) comprises a second semi-cylindrical element (23b; 33b), which is connected to the first semi-cylindrical element (23a; 33a) to form the capsule device (23; 33).

15. The pharmaceutical dosage form (51) according to any one of the preceding claims 1 to 13, wherein The pharmaceutical dosage form comprises sinker means (60) which occupies a portion of the hollow space and provides additional weight to the pharmaceutical dosage form.

16. A method for producing a capsule device (3; 23; 33) for a pharmaceutical dosage form (1; 31) as defined in any one of the preceding claims, the method comprising the steps of: - providing a device for forming a capsule (3; 23; 33) Materials; - producing an opening (5), in particular a slit-shaped opening (5; 25; 35; 45.1; 45.2; 45.3), in the material of the capsule means (3; 23; 33); - forming said capsule means (3; 23; 33).

17. A method for producing a pharmaceutical dosage form according to any one of claims 1 to 15, comprising the following steps: - providing an opening (5; 25; 35; 45.1; 45.2; 45.3) capsule device (3; 23; 33); - placing a preparation (2) having an elongated shape and comprising the active pharmaceutical ingredient in a compact state of the preparation (2) in the hollow space (4) of the capsule device (3; 23; 33) with the end portion of the preparation (2) extending through the opening, the opening (5; 25; 35; 45.1; 45.2; 45.3) and the preparation (2) are configured so that when the preparation (2) is introduced from the opening (5; 25; 35; 45.1; 45.2; 45.3), the spacing (S1; S2) is set between the preparation (2) and the opening (5; 25; 35; 45.1; 45.2; 45.3) in the opening cross section (CS) of the opening (5) between the surfaces (5a) of the capsule device (3; 23; 33).

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