Capsule device having an opening formed by the overlap of two semi-capsule shells

Abstract

This invention relates to pharmaceutical dosage forms for application to mucous membranes, particularly oral, intestinal, rectal, or vaginal mucosa. The pharmaceutical dosage form comprises at least one rope-like or strip-like formulation containing an active pharmaceutical ingredient, and the dosage form consists of first and second semi-capsule shells that together define the size of an orifice for dispensing the formulation. The invention also relates to a method for producing the pharmaceutical dosage form.

Description

Technical Field

[0001] This invention relates to a capsule device and a pharmaceutical dosage form for use on mucous membranes, particularly oral or gastrointestinal mucosa. The invention also relates to methods for manufacturing the capsule device and pharmaceutical dosage forms comprising the capsule device. Background Technology

[0002] Such capsule devices are known from WO 2020 / 183005 or WO 2016 / 102067 A1. The capsule device form of WO 2016 / 102067 A1 is designed such that it comprises at least one tablet (particularly film, foil, or sheet) formulation, which includes an active pharmaceutical ingredient, a release mechanism, and a triggering mechanism, wherein the triggering mechanism is adapted to trigger the release of the tablet formulation by the release mechanism at a predetermined site of action (particularly the gastrointestinal tract, rectum, or vagina). From WO 2016 / 102067 A1... Figure 8 a, Figure 8 b、 Figure 8 In an embodiment of c, a dosage form is known to have an elongated strip-shaped formulation containing an active pharmaceutical ingredient, the formulation being arrangeable in a compressed state and an expanded state, the dosage form having a capsule containing a hollow space for receiving the compressed formulation, the capsule device having an orifice and a first end of the formulation extending through the orifice in the compressed state to allow the formulation to be pulled out from the hollow space into the surrounding area of ​​the capsule, thereby changing the formulation from a compressed state to an expanded state.

[0003] It is also known in the art, particularly concerning the treatment of gastrointestinal membranes, especially esophageal membranes, to use catheters or stent-like devices for the local application of active ingredients. Another approach involves using liquid or gel-like media with relatively high viscosity. Summary of the Invention

[0004] The object of the present invention is to provide a capsule device that can be efficiently manufactured, and to provide a method for efficiently manufacturing capsule devices and pharmaceutical dosage forms, as well as a method for manufacturing pharmaceutical dosage forms, the method comprising a method for manufacturing capsule devices.

[0005] This problem is solved by the capsule device of claim 1 and the method for producing a capsule device for a pharmaceutical dosage form according to claim 10. Preferred embodiments of the invention are the subject of the dependent claims.

[0006] According to the present invention, the capsule device includes a first half-capsule shell and a second half-capsule shell, which are connected at a connection position by overlapping of the first half-capsule shell and the second half-capsule shell, wherein the first half-capsule shell has a hollow cylindrical wall including an opening, and the wall of the second half-capsule shell overlaps the cross-section of the opening, thereby forming an opening of the capsule device at the connection position.

[0007] Therefore, the connection position involves the location where the first and second capsule shells overlap or slide into each other, thereby forming a capsule device. By partially pushing them into each other, the two halves are mechanically connected and effectively stabilized.

[0008] The first half-capsule shell, having an opening, acts as a vessel through which the pharmaceutical preparation can be easily filled, either through the opening or alternatively through the open end of the first half-capsule shell. The second half-capsule shell, acting as a cover for the opening, can be easily placed over the opening to create an orifice of the desired size. The pharmaceutical dosage form according to the invention exhibits excellent mechanical stability, which is advantageous when the capsule is swallowed by a patient. Furthermore, it can be efficiently produced by the method according to the invention.

[0009] The term "semi-capsule shell" refers to a capsule device that is preferably composed of two parts, referred to as "half". The dimensions (e.g., the sizes of the two halves) may differ from each other; however, in a preferred embodiment, the two halves are substantially the same size. The first and / or second semi-capsule shells each have a hollow cylindrical wall, which is preferably covered by a cap portion, which is preferably circular in shape and, in particular, has a hollow hemispherical shape. In addition to the first and / or second semi-capsule shells, at least one third part may be used to form the capsule device; the third part may be, for example, a cylindrical or annular element. The first and / or second semi-capsule shells may be joined to each other at connection points by press-fit and / or positive-fit and / or adhesive or welding.

[0010] The first semi-capsule shell has a hollow cylindrical wall, which is preferably closed at a first end and open at a second end, wherein the opening is preferably completely surrounded by the material of the hollow cylindrical wall. In this way, the first semi-capsule shell, especially the wall surrounding the opening, maintains mechanical stability and provides strength to the capsule device.

[0011] As an alternative, and preferably, the hollow cylindrical wall of the first semi-capsule shell is closed at the first end and open at the second end, wherein the opening is formed as a recess starting from the second end and extending toward the first end. In this way, the opening size can be maximized, thereby facilitating the assembly of the drug dosage form.

[0012] Preferably, in the connected position, the first capsule shell is inserted into the second capsule shell. Preferably, in the connected position, the second capsule shell is inserted into the first capsule shell.

[0013] Preferably, before joining the first and second half-capsule shells, the dimensions of the cross-section of the opening are adapted to receive the formulation in its compacted state, wherein preferably, at the joining position, the dimensions of the cross-section of the orifice defined by the opening and the wall of the second half-capsule shell are adapted to prevent the formulation in its compacted state from passing through the orifice. The term "cross-section of the opening" refers to the area occupied by the opening within the wall of the first half-capsule shell. The term "cross-section of the orifice" refers to the area occupied by the orifice within the wall of the capsule device or, respectively, within the wall of the first half-capsule shell when the wall of the second half-capsule shell is superimposed or overlapped.

[0014] In particular, the second half-capsule shell may include a second opening or a second recess, which overlaps with the opening or recess of the first half-capsule shell at the joining position. In this way, greater flexibility is obtained in positioning the orifice along the length of the capsule device, which is measured along axis A (in particular, the cylindrical axis A passing through the capsule device).

[0015] Preferably, the dimension A_o of the cross-section of the orifice is a fraction f of the dimension A_a of the cross-section of the opening, where A_o = f * A_a, and wherein preferably 0.0010 < f < 0.7500, preferably 0.0100 < f < 0.5000, preferably 0.0100 < f < 0.2500, preferably 0.0500 < f < 0.15000. The area A_o is preferably adapted to allow a strip-shaped elongate formulation to be pulled out of the orifice.

[0016] Preferably, the orifice is a slit-shaped orifice configured to allow a strip-shaped formulation to pass through the orifice, and when the strip-shaped formulation extends through the orifice, the cross-section (CS) of the orifice is larger than the cross-section of the strip-shaped formulation.

[0017] Preferably, the capsule device is configured to be suitable for being swallowed by a patient.

[0018] Preferably, the capsule device includes a sedimentation device that occupies a part of the hollow space and provides additional weight to the pharmaceutical dosage form. In one embodiment, the sedimentation member is arranged in one of the half-capsule shells. Preferably, the sedimentation member is positioned in the second half-capsule. Thus, the second half-capsule includes a retaining device, such as a notch, to loosely position the sedimentation member in the hollow space of the second half-capsule, so that when the capsule is flipped, the sedimentation member remains in the hollow space of the second half-capsule and does not slide, for example, into the first half-capsule due to gravity, for example, to avoid the sedimentation member sliding onto the formulation. The notch can be formed by contracting and bending the outside of the capsule to the inside.

[0019] The shape of the orifice preferably corresponds to the outer profile of the elongated formulation in a plane perpendicular to its length axis. For example, a slit-shaped orifice is preferred in the case of a strip formulation, while a circular orifice may be provided in the case of a rope formulation. In this document, the orifice provides a substantially rectangular channel cross-section, and the cross-section of a strip formulation is also substantially rectangular. In the case of a rope formulation, the orifice may provide a circular channel cross-section, and the cross-section of a strip formulation may also be substantially circular. In this way, the movement of the elongated formulation relative to the capsule device is guided by the relative position of the orifice and the capsule device, and the formulation is stable when pulled out of the capsule device.

[0020] Preferably, the orifice is a slit-like orifice configured to allow the strip formulation to pass through it, wherein preferably, the cross-sectional area (CS) of the orifice is larger than the cross-sectional area of ​​the strip formulation as it moves through the orifice. In this document, the cross-sectional area of ​​the orifice defines a surface, and the cross-sectional area of ​​the strip formulation is preferably measured within said surface, with the strip formulation preferably centered within the orifice.

[0021] When the cross-section of the orifice and the cross-section of the elongated formulation are centered relative to the virtual axis A extending longitudinally through the capsule device, the distance S in the orifice cross-section between the elongated formulation and the surface of the capsule device defining the orifice is preferably measured. The size of the orifice that produces the distance S is preferably calculated by a dimension a, which is the diameter or width of the orifice, and t, which is the diameter of a rope-like formulation or the thickness of a strip-like formulation, where a = t + 2*S, see [reference needed]. Figure 1c S is preferably in the range of 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). S is greater than zero, and preferably greater than the value t, in particular S = f*t, where f is a numerical factor selected from 1 to 20, preferably from 2 to 15, more preferably from 3 to 12. The size of a is preferably selected to be in the range of 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).

[0022] In the case of strip formulations and slit-like orifices, when the strip formulation is pulled outward, the length c of the channel cross-section is greater than the width w of the strip formulation. The channel cross-section is larger than the cross-section of a slender formulation in the same plane.

[0023] Capsule devices are typically configured as containers for oral or gastrointestinal administration. In particular, capsule devices are swallowable objects, which specifically means that the size and shape of the capsule device are adapted for swallowing. This size is especially relevant to the geometry of the capsule.

[0024] The first semi-capsule shell may further include a sliding surface configured to guide the second semi-capsule when the first and second semi-capsules are stacked on top of each other to form a capsule device, wherein the opening of the first semi-capsule shell may further extend into the sliding surface such that the opening is partially covered by the second semi-capsule when the first and second semi-capsules are stacked on top of each other.

[0025] The capsule device can have an elongated shape, meaning that its length, measured along the virtual central axis A, is greater than its lateral external dimension. Without considering the orifice, the capsule device can be rotationally symmetrical relative to the central axis A.

[0026] The capsule device may have one or more openings, particularly two or more openings.

[0027] The present invention also relates to a method for producing a capsule device as described in any of the preceding claims, the method comprising at least the following steps:

[0028] a) Provide a first semi-capsule shell (11; 11') and a second semi-capsule shell (12; 12') having a hollow cylindrical wall (11c; 11c') including an opening (16; 16');

[0029] b) Slide the second half-capsule shell (12; 12′) and the first half-capsule shell (11; 11′) to the connection position, wherein the wall of the second half-capsule shell (12; 12′) overlaps with the cross-section of the opening (16; 16′) of the first half-capsule shell (12; 12′), thereby forming an opening (15) of the capsule device at the connection position.

[0030] The term "sliding" refers to joining or nesting the first half-capsule shell into the second half-capsule shell, and vice versa, such that the two halves reach an overlapping position to preferably form an opening in their final state, for example, without requiring further nesting or joining of the two halves to further reduce the opening. This can also include locking mechanisms, for example, meaning the mechanical friction of the sliding surfaces of one or two halves, which secures the two halves together so that no further manufacturing steps are required to join the two halves in a manner suitable for application in the dosage form. However, process steps preferably performed by machine may also be necessary to join the halves in a manner suitable for application, such as by means of heating or by welding, especially by material bonding.

[0031] Preferably, the method for producing the capsule device includes one or two of the following steps:

[0032] a) Provide materials for forming the capsule device (particularly the shells of the first and second half-capsules);

[0033] b) An opening, particularly a rectangular opening, is formed in the material of the first and / or second capsule shell.

[0034] For example, in the case of a circular opening, the first and second capsule halves can each have an arcuate opening, such that at the joining position, the halves are slid together to form a circle or ellipse. This is advantageous if a formulation with a circular cross-section is used.

[0035] The step of forming the capsule device using the material for forming the capsule device can be applied after the step of creating an opening in the material of the first half-capsule shell. Alternatively, the step of forming the capsule device using the material for forming the capsule device can be applied before the step of creating an opening in the material of the first half-capsule device.

[0036] Openings or recesses can be created using a workpiece of suitable shape (e.g., a stamping tool). The material used to form the capsule device can be the workpiece. In a corresponding preferred embodiment, the workpiece can be in the shape of a cube, foil, hollow cylinder, capsule, or half of a capsule.

[0037] Preferably, the method includes the step of creating an opening in the hollow cylindrical wall material of the first and / or second semi-capsule shell.

[0038] In other words, the opening can be created in the wall material of the first and / or second semi-capsule shell before the actual shell shape is formed; that is, the opening is created in a two-dimensional material shape, the shell shape of which is formed in a further step. Alternatively, the opening is created in the semi-capsule shell, i.e., the opening is created in the wall material of the first and / or second semi-capsule shell after the actual shell shape is formed; that is, the opening is created in a three-dimensional material shape, the shell shape of which is formed in the molding production step.

[0039] Openings can be created by cutting or ablating the capsule material using a laser. Alternatively, stamping can be used to create openings through the capsule material, producing rectangular holes via shearing. However, openings can also preferably be created by injection molding of a suitable material (e.g., plastic) forming the capsule device. The orifice preferably has the shape of a planar curved slit. The planar nature of the curved slit provides the advantage of facilitating the passage of the strip-shaped formulation through the slit in the pull-out direction P, thereby further improving the reliability of the mechanical process of expanding the formulation from a compressed state to an expanded state. If the opening in the capsule wall material is created by a stamping tool, the stamped material from the capsule wall can be conveyed away from the capsule by a suction device ideally integrated into the stamping tool, for example, by pressure suction.

[0040] The capsule device is preferably configured such that when a formulation having an elongated shape and containing an active pharmaceutical ingredient is inserted into the hollow space of the capsule device in a compressed state, with the end portion of the formulation extending through an orifice and the formulation being able to be pulled out from the orifice, a gap is provided in the orifice cross-section (CS) between the surfaces defining the orifice of the formulation and the capsule device. The capsule device is preferably configured to be swallowable by a patient.

[0041] The step of forming an opening may include at least one of the following features:

[0042] • Use a planar milling tool, such as a planar saw blade, or another tool that produces a plate-like cut volume, such as a cylindrical milling head that performs lateral movement;

[0043] • Use a laterally moving water jet during abrasive waterjet cutting;

[0044] • Use lasers to cut or ablate the material from the capsule material;

[0045] • Pierce the semi-capsule shell material to create a hole through shearing;

[0046] • Injection molding of appropriate materials, such as plastic, for use in forming the semi-capsule shell.

[0047] The steps of forming a capsule device may include applying an dip molding process to produce two half-capsule shells for the capsule device, which are joined together to form a capsule, for example, substantially as described in EP0102832A2. The steps of forming a capsule device may include applying an additive manufacturing process for forming capsules from suitable materials, particularly a 3D printing process for forming capsules from suitable materials. The steps of forming a capsule device may include injection molding a capsule from suitable materials.

[0048] The capsule device can be a capsule comprising a hollow cylinder covered on both sides by curved cap members. The cap members can be substantially hemispherical in shape. The cap members can be manufactured as a single piece with the cylindrical portion. The two portions of the capsule device can be joined to form the capsule device—this facilitates the assembly of the dosage form by first placing the formulation into one of the two portions and then securing the formulation by joining the two portions of the capsule device. The capsule can also be shaped to have an elliptical or oval cross-section, such that the capsule has, for example, an olive shape.

[0049] In a preferred embodiment, the capsule device is configured such that the orifice is offset from the central axis A, meaning that the central axis A does not pass through the cross-section of the orifice, or that the central axis A does not pass through the center point of the cross-section of the orifice. An advantage of this embodiment is that the force acting on the walls of the capsule device is reduced when the formulation is pulled out of the capsule device and administered to the patient, and thus the risk of damage to the capsule device is reduced. In the inventors' experiments, it should be found that, particularly for strip-shaped formulations, unwinding the formulation through an orifice arranged off-center from the central axis A is advantageous compared to a centrally located orifice, where the central axis A of the capsule device is extended through the center of the orifice.

[0050] In the case of a slit-shaped orifice, the orifice is preferably positioned offset from the central axis A of the capsule device. The slit is preferably formed by the opposing surfaces of the wall forming the capsule device.

[0051] For example, when the opening is initially prepared by milling the cylindrical wall that forms the first semi-capsule shell, a preferred shape of the slit is obtained such that the plate-shaped volume is subtracted from the wall when the first semi-capsule shell and the cut volume are considered as three-dimensional mathematical objects. The orientation of the plate-shaped volume subtracted from the capsule material is characterized by the orientation of the principal plane of the plate-shaped volume, particularly the direction relative to the virtual central axis A of the capsule device.

[0052] The hollow space inside the capsule device is defined by at least one inner wall of the capsule device, particularly by the first and second half-capsule shells.

[0053] In a preferred embodiment, the capsule device is defined by at least one wall having an outer side facing the periphery of the capsule device and an inner side facing the hollow space. Preferably, the inner side (inner surface) and the outer side (outer surface) extend parallel to each other, meaning 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 preferably, the inner surface of the capsule device is at least partially not parallel to the outer contour surface of the capsule device. This configuration allows for the definition of auxiliary structures within the capsule device, which facilitates the guidance of the movement of the formulation or other functions within the capsule device.

[0054] Preferably, the auxiliary structure is an internal guide wall of the capsule device, which is arranged to guide the unfolding and / or unwinding of the formulation inside the capsule device. The guide wall is arranged to guide the positioning of the formulation during unfolding and / or unwinding. The guide wall may be arranged parallel to the direction of movement P, through which the formulation moves towards the orifice inside the capsule device. Preferably, the guide wall is arranged to be aligned with the orifice; for example, the guide wall is preferably parallel to the longitudinal direction of the orifice, i.e., parallel to... Figure 1aThe Y direction is defined in the middle. The guide wall can also be achieved by a protrusion in the inner wall region of the capsule device, wherein the formulation is positioned to extend through the orifice. When viewed from the outside of the capsule device, such a protrusion or notch in the wall of the capsule device can be used to guide the formulation during extension, for example through the inner portion, i.e., the core of the rolled formulation mechanically supported by the protrusion, so that it can rotate, especially during the extension movement of the formulation.

[0055] Preferably, one or more inner walls of the capsule device are arranged to form guide compartments within the capsule device. The guide compartments are arranged to support the formulation in its compressed state and to assist in unwinding the formulation. Preferably, one or more inner walls of the capsule device are arranged to form sidewalls of a cubic hollow space that accommodates the formulation in its compressed state.

[0056] Preferably, the capsule device includes a guide member disposed within the internal space of the capsule device to guide the rope-like or tablet-like formulation toward the orifice of the capsule device. The guide member may be part of, or supported by, or connected to a part of, the internal wall of the capsule device, particularly a wall member. For example, the guide member may be a guide lip or guide nozzle located on one side of the edge of the orifice, or the guide member may always be mounted around the orifice or opening.

[0057] Preferably, the capsule device may include an auxiliary structure configured to guide the coiling and / or unwinding of a rope-like formulation or the winding and / or unwinding of a strip-like formulation, particularly by coiling or winding the formulation around one or more rods or pillars of the auxiliary structure. The rods or pillars may be rotatably disposed within the capsule device to facilitate unwinding or unwinding.

[0058] In another preferred embodiment, both the capsule device and the drug dosage form include a settling device. The settling device is configured to provide negative buoyancy to the capsule device. In experiments conducted by the inventors based on findings of this preferred embodiment, it was found that reducing buoyancy by increasing the mass of the capsule device, for example, leads to improved swallowability of the capsule device, i.e., improved reliability of the mechanical process of expanding the formulation from a compressed state to an expanded state. In the case of strip formulations, unwinding the formulation from a compressed state (where the strip formulation is wound around a winding shaft) to an expanded state is significantly facilitated and made more efficient. Such a settling device is described, for example, in WO 2020 / 183005 A1.

[0059] The present invention also relates to a pharmaceutical dosage form comprising a capsule device as defined herein, and further comprising a pharmaceutical preparation having an elongated shape, the pharmaceutical preparation comprising one or more active pharmaceutical ingredients, and the pharmaceutical preparation being capable of being arranged in a compressed state and an expanded state.

[0060] The present invention also relates to a method for producing a pharmaceutical dosage form, wherein the method includes the steps of a method for producing a corresponding capsule device, and the following further steps:

[0061] a) Provide a formulation having an elongated shape and containing one or more active pharmaceutical ingredients;

[0062] b) Provide a first half-capsule shell and a second half-capsule shell having a hollow cylindrical wall including an opening;

[0063] c) The formulation is preferably contained in a compressed state into the shell of the first semi-capsule through the opening, such that a portion or one end of the formulation extends through the opening;

[0064] d) Slide the second half-capsule shell onto the first half-capsule shell or slide the first half-capsule shell onto the second half-capsule shell to the joining position, thereby reducing the cross-section of the opening, while the end of the formulation extends through the opening until the opening forms the orifice of the capsule device in the joining position of the first and second half-capsule shells.

[0065] Preferably, the method includes the following steps:

[0066] Following step a) or b) of the method for producing the pharmaceutical dosage form, a rotating shaft (X) is provided, and preferably, this rotating shaft is positioned in front of or within the cross-section of the opening. The preparation is wound around the rotating shaft in its extended state, thereby preferably using the opening to guide and / or align the preparation until it has reached a wound and compressed state. In this way, any problems related to unwinding of the preparation before it reaches the interior of the capsule can be reduced or eliminated, since the compressed form of the preparation is formed within the opening and interior of the first semi-capsule device.

[0067] Preferably, the method for producing the drug dosage form includes the following steps:

[0068] Following step b) or c) of the method for producing the drug dosage form, a settling device is placed within at least a portion of the hollow space of the first and / or second semi-capsule shell, the settling device providing additional weight to the drug dosage form. This can be particularly beneficial for the swallowing of the drug dosage form.

[0069] Preferably, any methodological step (and in particular, loading the compressed formulation into the first half-capsule shell) is performed automatically by machine to preferably produce multiple drug dosage forms in parallel. This increases the yield of a large number of drug dosage forms produced per time period.

[0070] The step of placing or containing a formulation having an elongated shape and containing an active pharmaceutical ingredient in a compressed state within the hollow space of a capsule device and extending the end portion of the formulation through the orifice includes configuring the orifice and the formulation such that when the formulation is pulled out from the orifice, a gap is provided in the orifice cross-section (CS) of the orifice between the formulation and the surface of the capsule device defining the orifice.

[0071] The placement of the formulation is preferably performed by placing the formulation in the first portion or first half-capsule shell, preferably followed by extending the end portion of the formulation through an orifice, and attaching the second portion or second half-capsule shell to the first portion or first half-capsule shell. The first portion or first half-capsule shell or the second portion or second half-capsule shell may be a tubular element or a capped tubular element, or may be a cylindrical segment, particularly a semi-cylindrical element.

[0072] The present invention also relates to a kit comprising a pharmaceutical dosage form as claimed in claim 13, a drinking cup, and an applicator for administering the pharmaceutical dosage form to a patient, wherein the applicator is fluidly connected to the drinking cup and contains the pharmaceutical dosage form, and wherein the formulation of the pharmaceutical dosage form is connected to the applicator via a retainer for removing the formulation from the capsule device after administration to the patient.

[0073] Capsule devices and dosage forms containing pharmaceutical preparations according to the invention are particularly suitable for application to mucous membranes, especially oral or gastrointestinal mucosa, particularly the mucosa of the upper gastrointestinal tract, such as the pharynx, esophagus, cardia, and / or stomach. A pharmaceutical dosage form containing a pharmaceutical preparation and its application are described in WO2016 / 102067, which is incorporated herein by reference in its entirety, particularly concerning the shape, size, and (chemical) composition of the capsule device and pharmaceutical preparation, the active pharmaceutical ingredient, and the treatment and prevention of certain conditions and diseases disclosed therein. In other words, the chemical composition of the capsule device and pharmaceutical preparation has been described, at least to a large extent, in the aforementioned reference. This also applies to capsules.

[0074] The pharmaceutical dosage form of the present invention advantageously allows for increased bioavailability of the active pharmaceutical ingredient at the predetermined site of action.

[0075] The pharmaceutical dosage forms of the present invention are capable of and suitable for rapid release at a predetermined site of action with systemic effects, in the form of ropes or strips, particularly tablets, films, foils, or sheets, containing an active pharmaceutical ingredient. Furthermore, the pharmaceutical dosage forms according to the present invention enable the administration at a predetermined site of action of active pharmaceutical ingredients that cannot be administered orally due to poor bioavailability.

[0076] Rope-like or strip-like, especially film-like, foil-like, or sheet-like formulations containing active pharmaceutical ingredients can comprise a multilayer structure with a single layer or multiple layers. In the case of a multilayer structure, the first layer may contain a first active pharmaceutical ingredient, and a second / another layer may contain at least another active pharmaceutical ingredient. This allows for the application of, for example, two pharmaceutical ingredients that are incompatible with each other.

[0077] Preferably, the formulation is made mucoadhesive to allow targeted release of the active ingredient. This can be achieved by providing a monolayer that, in addition to containing the active pharmaceutical ingredient, is also made mucoadhesive, or by providing a multilayer formulation in which at least one layer (preferably the outermost layer) is made mucoadhesive.

[0078] According to a preferred embodiment, the pharmaceutical dosage form according to the invention is suitable for oral administration.

[0079] The capsule device is composed of or is primarily composed of a material that is substantially insoluble in fluids, with the fluid present along the path that will deliver the capsule device to the site of administration (particularly the gastrointestinal tract). Such materials are known in the art and are described in WO2016 / 102067. Of particular note are known gastric juice-resistant polymers, such as polymethyl methacrylate (Eudragit), HPMCAS, shellac, gelatin, etc., which can be formulated with known additives for improving processing properties (e.g., plasticizers; flavoring compounds and seasonings).

[0080] This formulation contains at least one active pharmaceutical ingredient selected from the following group (the drug name also includes any pharmaceutically acceptable salt thereof):

[0081] Diagnostic substances, such as dyes or staining agents, analgesics, preferably NSAIDs, such as ibuprofen or flurbiprofen;

[0082] Local anesthetics, such as benzocaine, butambine, debucaine, lidocaine, oxybucaine, or novocaine;

[0083] Antibiotics, such as penicillin, amoxicillin, or vancomycin; preservatives, such as 2,4-dichlorobenzyl alcohol, pentylmethylcresol, or hexadecylpyridine chloride;

[0084] Steroids, such as corticosteroids, glucocorticoids, fluticasone, budesonide, clotropone, perdesonide, hydrocortisone, clobetasol butyrate, flumethasone, fluprednisolone, hydrocortisone acetate propionate, hydrocortisone butyrate, hydrocortisone-17-butyrate, triamcinolone, ansilonide, betamethasone-17,21-dipropionate, betamethasone-17-valerate, deshydroxymethasone, difluoroacetone-21-valerate, fluorochloroacetone, fluconazole, fluticasone-17-propionate, methylprednisolone propionate, mometasone furoate, prednisolone, or clobetasol 17-propionate;

[0085] Parasitic agents, also known as antiparasitic drugs, include mebendazole, albendazole, thiabendazole, diethylaminomazine, diaminodiphenyl sulfone, benznidazole, ivermectin, pyrantel pamoate, and praziquantel.

[0086] Fungicides, such as nystatin, imidazole, triazole, thiazole, clotrimazole, ketoconazole, or undecenoic acid;

[0087] Hexamethyl pararosaniline chloride, amphotericin B, botulinum toxin, sucralfate, nitric oxide or nitric oxide forming agents such as isosorbide dinitrate or nitroglycerin, furanocoumarin, benzoic acid, citric acid, lactic acid, pH buffers, antacids, calcium carbonate, magnesium carbonate or aluminum carbonate.

[0088] Additionally or alternatively, the formulation may contain, in particular, an anti-inflammatory agent such as montelukast, interleukin receptor, or interleukin antibody. Additionally or alternatively, the tablet formulation may contain, in particular, beclomethasone dipropionate, budesonide, or cyclosporine, which are particularly beneficial for the treatment of asthma. Additionally or alternatively, the tablet formulation may contain, in particular, mesalazine, sulfasalazine, or olsalazine, which are particularly beneficial for the treatment of inflammatory bowel disease.

[0089] The active pharmaceutical ingredient contained in the tablet formulation according to the invention can be selected in particular from proteins and peptides, especially insulin, busherin, desmopressin, calcitonin, and estrogens, as well as biotechnologically manufactured drugs, such as antibodies, for example rituximab. It should be understood that proteins and peptides, especially insulin, busherin, desmopressin, calcitonin, and estrogens, may exhibit poor bioavailability in certain circumstances (particularly poor oral bioavailability), and are therefore good candidates for application by means of the formulation according to the invention.

[0090] Substances from the following groups may also be used as active pharmaceutical ingredients: drugs acting on bones and muscles, drugs acting on the nervous system, hormones and drugs acting on the hormonal system, gynecological drugs, drugs acting on the cardiovascular system, drugs acting on the respiratory system, drugs acting on the gastrointestinal tract, diuretics, drugs acting on sensory organs and the dermatic skin, vitamins and micronutrients, peptide-based drugs and proteins, analgesics, anti-infectives, and antiparasitics.

[0091] In one embodiment, the active ingredient is selected from corticosteroids. Exemplary examples include budesonide, mometasone, fluticasone, and cyclosone, and pharmaceutically acceptable salts thereof.

[0092] As for the conditions to be treated, such as those related to the gastrointestinal mucosa, preferably the esophagus, such as GERD, NERD and eosinophilic esophagitis, they are very well treated with the above-mentioned steroid group and the above-mentioned nitric oxide or nitric oxide forming agent.

[0093] This pharmaceutical formulation contains an amount of active pharmaceutical ingredient known to be effective for the condition being treated; this amount depends on the site of administration and the active ingredient. For example, the concentration / amount of budesonide in the formulation is significantly higher than in formulations containing mometasone.

[0094] Additionally or alternatively, in some embodiments of the capsule device according to the invention, the rope-like or strip-like formulation is adapted to dissolve, for example, through biodegradation, preferably in a time-controlled manner, such as within one hour, or within one to two hours, or within one to five hours, or within one to twelve hours, or within one to twenty-four hours. This improves user convenience because the tablet-like formulation does not need to be removed.

[0095] There are no particular limitations on the methods for preparing formulations containing these active ingredients, and these methods are known to those skilled in the art. Similarly, reference is made to WO2016 / 102067 regarding the pharmaceutical dosage forms of this invention.

[0096] The formulation (particularly rope- or strip-shaped formulations) can be prepared by those skilled in the art using substantially known methods, such as coating an inert carrier with a liquid composition comprising a polymer, an active pharmaceutical ingredient, and optional additives and solvents, by means of, for example, methods involving a doctor blade, a spray processor, or an extrusion processor. The film layer obtained in this manner is dried. For multilayer sheet formulations, one or more coatings can be applied to an existing film layer in the same manner, or they can be manufactured separately and subsequently laminated.

[0097] The shape of the orifice preferably corresponds to the outer profile of the elongated formulation in a plane perpendicular to its length axis. For example, a slit-shaped orifice is preferred in the case of a strip formulation, while a circular orifice may be provided in the case of a rope formulation. In this document, the orifice provides a substantially rectangular channel cross-section, and the cross-section of a strip formulation is also substantially rectangular. In the case of a rope formulation, the orifice may provide a circular channel cross-section, and the cross-section of a strip formulation may also be substantially circular. In this way, the movement of the elongated formulation relative to the capsule device is guided by the relative position of the orifice and the capsule device, and the formulation is stable when pulled out of the capsule device.

[0098] Preferably, the rope or strip formulation is flexible, allowing it to be transformed from a compressed form to an expanded form, particularly sheet formulations that are folded, collapsed, coiled, rolled up, or coiled, and which may preferably have a rope, thread, strip, or tubular shape. Such a sheet formulation is exemplarily described, for example, in the following application WO 2020 / 183005.

[0099] In a preferred embodiment of the capsule device, the formulation contained within the capsule can be expanded from a compressed form to an expanded form in order to remove the formulation from the hollow space of the capsule into the surrounding area of ​​the capsule device. Therefore, the formulation preferably includes a retaining device. When the retaining device is secured, the formulation can be removed from the capsule device by a pulling motion and / or pulling force. The securing of the retaining device is preferably achieved by connecting the retaining device to a retaining member. This retaining member can be a cord component, such as a line, rope, or tie. The retaining member then generates a pulling force, for example, by holding the retaining device in place, preventing it from moving with the capsule device. For example, this is achieved by attaching the retaining device to one end of a line, the other end of which is secured to the applicator. Thus, when the retaining member line is tightened by moving the capsule away from the applicator, the retaining device generates a pulling force, thereby pulling the formulation out of the capsule device. Since the retaining device is preferably part of or attached to the formulation, it can be a handle, strap, or adhesive tape, or may include an adhesive area. The retaining device is adapted to establish and maintain a connection that can transmit force between the retaining device and the area to which it is attached. Furthermore, such a connection can be established or maintained when the dosage form and / or tablet formulation is in its compressed form and / or expanded form. Preferably, the retaining device can hold itself, and possibly other parts thereof, in a defined position or area by pressure fitting (particularly by frictional engagement), form fitting, or by material bonding (particularly by mucosal adhesion, preferably by adhesive bonding). Such a retaining device is described, for example, in WO 2016 / 102067 A1.

[0100] As used herein, the term "compressed form" preferably refers to a folded form, a coiled form, a rolled-up form, a coiled form, or a collapsed form. In particular, compared to non-compressed forms (especially expanded forms), rope or strip formulations in a compressed form have a smaller spatial extent and / or expose a smaller amount of their surface area. Preferably, the compressed form of a rope or strip formulation is folded, collapsed, coiled, rolled up, coiled, compressed, aggregated, or otherwise transformed into a smaller form. In particular, when in a compressed form, the rope or strip formulation may have a predetermined size or spatial extent.

[0101] As used herein, the term "expanded form" preferably refers to an folded form, a spread-out form, an open form, an elongated form, a stretched form, or a rounded rectangular form. In particular, rope or strip formulations in their expanded form have a larger spatial extent and / or expose a greater amount of their surface area than their non-expanded form (especially their compressed form). Preferably, rope or strip formulations in their expanded form are opened, spread out, opened, stretched, unfolded, extended, stretched, expanded, or otherwise transformed into a larger form. In particular, when in their expanded form, rope or strip formulations can have a predetermined size or spatial extent. Alternatively, the size or spatial extent of a rope or strip formulation can depend on the conditions present and the site of action or application, and therefore may not be predetermined.

[0102] In a particularly preferred embodiment, the formulation is wound around the outside of the capsule device. In this case, for example, the formulation in its compressed form is positioned inside the first half-capsule shell, and then only the second half-capsule shell is attached to the first half-capsule shell to form the capsule device.

[0103] However, alternatively, the formulation is wound inside the capsule device. If wound inside the capsule device, it is advantageous to provide the expanded formulation from the outside, and to supply it into the capsule device, for example, during winding, through an opening and / or orifice. In this case, the capsule device preferably has a first half-capsule shell having a hollow cylindrical wall including the opening, and the wall of a second half-capsule shell overlapping the cross-section of the opening. However, the two halves do not necessarily overlap to ultimately form the orifice. Alternatively, the wall portion used to cover the opening to form the orifice is preferably not provided during winding, but after winding is complete.

[0104] Preferably, the winding of the formulation is performed by a machine (e.g., a winding device or unit). Alternatively, the formulation may be wound manually. During both manual and machine winding of the formulation, the end segments of the formulation are clamped, for example, between two retaining jaws, or, if a substantially continuous formulation is used, the segments of the formulation are clamped and the portion outside the clamped segments is cut off, thereby forming the end segments of the formulation to be wound. Further exemplarily, the clamped segments of the formulation are woven into the forked or U-shaped ends of a winding pin, thereby winding the formulation around the end of the pin by rotating the pin. Subsequently, for example, the pin with the formulation wound around it is placed through an opening in the capsule device, and the pin is pulled out from the wound formulation. In a particularly preferred embodiment, the coiled formulation is positioned in a first semi-capsule shell through an opening.

[0105] Alternatively, the formulation, in its expanded state, is fed into the compression chamber via a conveyor (e.g., a conveyor belt). Preferably, multiple surfaces rotating in a common direction are arranged inside the compression chamber, causing the drawn-in but not yet folded formulation to rotate. Furthermore, the rotational motion of the formulation can be supported by rollers. The principle is similar to that of a packaging machine. The rotational motion of the rotating surfaces within the compression chamber is transmitted to the formulation, causing the formulation itself to be set into rotational motion and thus begin to coil. Once the formulation has reached a predetermined size and / or weight, the rotational motion stops and the coiled formulation is discharged from the compression chamber and, for example, directly into the opening of a capsule device.

[0106] Machines used for winding formulations into compressed form have a balance, thereby determining the amount of active ingredient contained in the formulation by measuring its weight during winding or by measuring the weight of a portion of the formulation intended for winding. Alternatively, a device can be used to measure the length, width, or thickness of the portion of the formulation to be wound, or any combination of these quantities (e.g., volume). In a further alternative, it must be able to determine the concentration of the active ingredient in the formulation in compressed form.

[0107] The present invention also relates to a production machine for producing pharmaceutical dosage forms according to the invention, particularly by performing the method according to the invention, the production machine including a positioning device for positioning a first semi-capsule shell in an installation position.

[0108] The connecting device has a movable element configured to connect the second half-capsule shell and the first half-capsule shell to a connecting position by moving the first half-capsule shell and the second half-capsule shell toward each other, such that the wall of the second half-capsule shell overlaps with the cross-section of the opening by an amount controlled by the movement of the movable element, thereby forming an orifice of the capsule device at the connecting position.

[0109] The positioning device preferably includes one or more retaining members for holding one or more first and / or second capsule shells in place. The retaining members preferably include retaining spaces shaped to hold the first and / or second capsule shells by a positive-fit connection. The positioning device (especially the retaining members) can be configured to hold multiple first and / or second capsule shells in place in parallel. In this way, the throughput of the production process can be increased. The positioning device can provide more than one mounting position for positioning one or more first and / or second capsule shells. Therefore, multiple steps of the pharmaceutical dosage form production can be performed in parallel using multiple mounting positions (especially workstations).

[0110] The positioning device preferably includes a movable platform carrying one or more workstations. Each workstation preferably includes at least one or more retaining members. The movable platform may be rotatably arranged at the base member for rotation about an axis, configured to rotate each workstation to a working position on the production machine. At a first working position, a feeding device may be arranged for feeding at least one first half-capsule shell to at least one mounting position provided by at least one retaining member. At a second working position, a feeding device may be arranged for feeding at least one second half-capsule shell to at least one mounting position provided by at least one retaining member. At a third working position, a dispensing device may be arranged for dispensing the formulation into the first half-capsule shell, preferably in its compressed state. This dispensing device may include a conveying device for delivering at least a portion or all of the formulation to the mounting position, and / or a clamping device, particularly a winding device, for changing the formulation from an elongated state to a compressed state, particularly a folded or wound state. At a fourth working position, a receiving station may be provided for receiving the produced pharmaceutical dosage form and for transporting it to a storage or conveying system.

[0111] Preferably, the production machine includes a conveying device for conveying the end of a formulation having an elongated shape and containing an active pharmaceutical ingredient from a formulation storage location to an installation location, where the formulation is positioned to be inserted into the hollow space of a first semi-capsule shell in the installation location, particularly through an opening. In a preferred embodiment, the conveying device has a rotatable conveying member configured to receive at least a portion or the entire formulation at a first location, particularly from a formulation storage device, and to convey said at least a portion of the formulation to the installation location by rotation. The rotatable conveying member may be a rotatable rod member or a disc member. The movement or rotation of the conveying device may be controlled by an electronic control unit of the production machine. The production machine and / or the rotatable conveying member includes a winding device for winding the formulation from its elongated state to its compressed position. The rotatable conveying member may include a winding device for winding the formulation in its elongated state to form a wound state. The winding device may include one or two or more rotatable shafts configured to be electrically driven and controlled by an electronic control unit of the production machine. One, two, or more rotatable shafts may be arranged at positions offset from the axis of rotation of the rotatable conveying member. The rotatable conveying member and / or winding device may be configured to wind up the formulation in its elongated state in the mounting position, particularly if the rotatable shaft is located in front of or within an opening, such that the formation of the formulation in its compressed state occurs in the compressed position. The rotatable shaft is preferably located in front of or even within an opening, and therefore preferably, when the first semi-capsule shell is in the mounting position, the formulation is at least partially directly located within the hollow space of the first semi-capsule shell. This significantly facilitates the transfer of the formulation into the capsule. The winding of the formulation is preferably performed using winding pins. Therefore, the winding device preferably includes winding pins.

[0112] Preferably, the production machine and / or conveying device includes a clamping device, particularly a winding device for winding the formulation from its elongated state to its clamping position, or a folding device for folding the formulation from its elongated state to its clamping position. This clamping preferably occurs in the clamping position of the production machine.

[0113] Preferably, the production machine includes a cutting device for cutting the formulation to form the formulation to be inserted into the hollow space of the first semi-capsule shell.

[0114] Preferably, the production machine includes an actuation device for moving the formulation, which is in its compressed state, from the compressed position to its final position within the hollow space of the first semi-capsule shell.

[0115] Preferably, the production machine further includes a pressing device for pressing the settling material, such as powder, to obtain a settling device. Preferably, the pressing device is configured to feed the obtained settling device to a further processing device for producing a pharmaceutical dosage form.

[0116] In one embodiment, an applicator for assisting swallowing the capsule device, combined with a drinking cup, can be used for drug delivery. Such an applicator is described, for example, in WO2020 / 183003A1. This is particularly advantageous if the dosage form is for periodic administration, especially daily administration, because drug delivery of the capsule device does not require professional assistance.

[0117] The applicator includes a housing and a capsule holder configured to receive a capsule device. The applicator preferably further includes a spacer. In one embodiment of the applicator, the applicator is not directly attached to the opening of the drinking cup. Instead, a spacer is positioned between the drinking cup and the applicator. Therefore, the spacer reduces the risk of moisture from the drinking cup before use rendering the dosage form unusable. For example, residual moisture from the drinking cup may enter the applicator. This spacer preferably has a tubular or annular shape and is preferably screwed onto the openings of the applicator and drinking cup, respectively, after the corresponding caps have been removed. The length of the spacer is preferably 1 to 10 mm, preferably 2 to 8 mm, and most preferably 5 mm.

[0118] The present invention also relates to a retainer. The retainer is part of an applicator, which further includes the retainer. In a preferred embodiment, the retainer consists of or includes a cord element. The retainer is wound around a capsule retainer. Thus, the capsule retainer includes a wall structure. The retainer is preferably attached to or secured to the capsule retainer such that it can transmit forces (e.g., mechanical traction) to the capsule retainer and thus to the applicator. The retainer is preferably made of or includes yarn, fiber, cord, or filament having a first end and a second end. The first end of the retainer is connected to one end of the formulation, for example, to a retaining device connected to the formulation, extending through the orifice of the capsule device. The second end of the retainer is connected to the capsule retainer of the applicator, for example, the wall structure of the capsule retainer. Because the retainer is connected to the formulation, when the capsule moves away from the applicator and the retainer is tensioned, the retainer unwinds from the capsule retainer. When the patient swallows the capsule, the capsule moves away from the capsule retainer, thereby unwinding the retainer from the capsule retainer. When a patient swallows the capsule, the retainer will at some point completely unwind from the capsule holder, creating a tensile stress that pulls the formulation out of the capsule. Therefore, the retainer (e.g., a cord component) advantageously allows for the release of the active pharmaceutical ingredient, particularly into the mucosa surrounding relatively small lumens or cavities (such as the esophagus or nasal cavity).

[0119] Before using the applicator, the retainer is wound around the wall structure of the retainer. A knot is prevented from forming on the retainer by winding the retainer around the retainer. When the patient swallows the dosage form, the retainer is unwound from the retainer.

[0120] The winding of the retainer around the structure of the retainer and / or the binding of the retainer to the formulation, such as binding to a cord comprising the formulation, or binding to a retaining device of the formulation, is preferably performed by a machine (e.g., by a winding and / or binding machine, especially in the binding area of ​​the machine).

[0121] In the first step of winding the retainer around the retainer, the retainer is mechanically secured in the machine, for example, by being clamped by support jaws. In the second step, the retainer is taut. In the third step, the retainer is positioned along the taut retainer, meaning that the mechanical clutch and the retainer are clamped in grooves in the wall structure of the retainer. In the fourth step, the support jaws for clamping the retainer are opened. In the fifth step, the retainer is rotated by rotating the clutch that holds and supports the retainer, thereby winding the retainer around the retainer. The rotational movement of the coupling is superimposed on the vertical translational movement, causing the retainer to be wound around the retainer in a juxtaposed position. In the sixth step, the support jaws secure the retainer again, and in the seventh step, a blade-like part of the machine cuts through one end of the retainer, which is connected to the formulation in a further step. In the eighth step, the retainer with the retainer wound around it is positioned, in particular, by the machine, over an opening in the applicator housing, and preferably its opening is pushed over a shaft, for example, an auxiliary tube that extends through the housing positioned in the machine. Furthermore, the cut end of the retainer is positioned on one end of the formulation, which is subsequently pulled out of the capsule. In the ninth step, the retainer is attached to one end of the formulation in the clamping engagement region. As described above, the retainer can be wound around a retainer by rotating the retainer about a winding axis, or alternatively, the retainer can be wound around a fixed retainer by rotating the retainer about a fixed retainer.

[0122] In a preferred embodiment of the applicator, the cap of the applicator, which covers the opening of the applicator and is removed before use to allow the dosage form to leave the body of the applicator, includes a cap and a plurality of springs configured to press a support element against the capsule, the support element preferably contacting the end of the capsule positioned inside a retainer, preferably facing the cap. For example, the cap is similar to the cap of an effervescent tablet. Thus, in a preferred embodiment, the capsule is vertically positioned within the retainer and the support element presses against the end of the capsule facing the cap. The cap preferably further includes a desiccant to prevent moisture from rendering the dosage form unusable, for example, during storage. The plurality of springs can be made of plastic or any elastic material, such that pressure is applied by the springs to the support element, and the capsule is then mechanically secured in the retainer by pushing the support element toward the surface of the capsule. The support element preferably has a shape complementary to the contour of the capsule, such that the capsule contour fits into the support element.

[0123] In a preferred embodiment, the pharmaceutical dosage form includes a capsule device containing a pharmaceutical preparation for application to a mucosa, preferably to an esophageal mucosa, and a settling element, wherein the preparation is connected to a retainer of the applicator configured to remove the preparation upon swallowing the dosage form, wherein the retainer dissolves in the oral cavity after a period of time, and wherein the preparation adheres to the mucosa, particularly the esophageal mucosa, and wherein the settling element and the capsule device dissolve in the stomach.

[0124] In a preferred embodiment, a pharmaceutical dosage form is produced according to the following process steps, which is then attached to a retainer and packaged into an applicator:

[0125] In the first step, the capsule device is inserted into the machine via an insertion box. The capsule device includes first and second half-capsule shells, which are connected by the overlap of the first and second half-capsule shells at a connection position.

[0126] In the second step, the second capsule shell is inserted into the cartridge and held in place, separating it from the first capsule shell. Additionally, the applicator housing is positioned on the machine.

[0127] In the third step, the first semi-capsule shell is moved by a piston in the direction of the stamping tool, causing the insertion pin of the stamping tool to enter the cavity of the first semi-capsule shell, particularly the cylindrical cavity. The insertion pin thus holds the first semi-capsule shell in place, causing a portion of the stamping tool, which moves laterally relative to the direction of movement of the insertion pin, to stamp openings and / or recesses into the wall of the first semi-capsule shell.

[0128] In the fourth step, the insertion pin is pulled out of the cavity of the first half-capsule shell. The first half-capsule shell is positioned such that the stamping opening preferably points towards the applicator housing. The stamping tool uses negative pressure to convey the material stamped from the capsule wall away from the first half-capsule shell.

[0129] In the fifth step, the formulation is clamped between two retaining jaws and slightly stretched by increasing the distance between the two clamping jaws. On one side of one of the retaining jaws, the portion of the formulation extending beyond that retaining jaw is cut flush with the retaining jaw, thus creating a cut end of the formulation while it remains stretched. This cut end of the formulation serves as the starting point for winding the formulation. Therefore, a winding mandrel is inserted onto the stretched formulation between the two jaws. Since the end portion of the formulation is now also held by the winding mandrel, one of the retaining jaws used for cutting is opened. After or during the opening of the jaw, the winding mandrel rotates, causing the cut end of the formulation previously clamped in the retaining jaw to be wound onto the winding mandrel, thus creating the first winding.

[0130] In the sixth step, the other of the two retaining jaws is opened, and the winding mandrel rotates. During this process, further formulation is wound onto the rotating winding mandrel. Once a predetermined length of formulation has been wound up, the rotational movement of the winding mandrel stops. The length is preferably determined such that the end portions of the formulation are not wound, i.e., the formulation is not completely coiled. These end portions of the formulation are used to connect the formulation to the retainer, i.e., to the end portions of the retainer.

[0131] In the seventh step, the formulation wound on the winding mandrel is positioned in front of the stamped opening of the first semi-capsule shell. The wound formulation may also partially protrude into the stamped opening or recess. The unwound end portion of the formulation remains outside the first semi-capsule shell.

[0132] In the eighth step, the winding mandrel is pulled out from the coiled formulation, and the coiled formulation is mechanically pushed into the first semi-capsule shell through the opening, thereby positioning the coiled formulation inside the first semi-capsule shell.

[0133] In the ninth step, the insertion pin moves into the hollow cylindrical opening of the first semi-capsule shell, thereby positioning the coiled formulation, which was positioned inside the first semi-capsule shell in the eighth step, more deeply within the first semi-capsule shell. The end portion of the formulation (uncoiled) is positioned on the engagement area of ​​the machine.

[0134] In step ten, the retainer is configured to be wound around the holder of the applicator. Step ten can also be performed simultaneously with, earlier than, or later than other production steps. To wind the retainer around the holder, the retainer is mechanically secured in the machine by a clamping and cutting unit. The clamping and cutting unit includes clamping jaws between which the retainer can be clamped to tension it. The clamping and cutting unit further includes a cutter for cutting the retainer and guide blocks to ensure a smooth cut of the retainer. In step ten, the retainer is tightened by moving the clamping jaws.

[0135] In step eleven, the cage is positioned on the winding unit and placed along the taut retainer, and the retainer is attached to the wall structure of the cage. Because the retainer is attached to the cage, it is wound onto the cage as the cage rotates.

[0136] In the twelfth step, one of the clamping jaws of the clamping and cutting unit is opened, allowing the retainer to slide in a guided manner through the clamping jaws for winding. The other clamping jaw of the unit, which further includes the cutter, remains closed.

[0137] In step thirteen, the winding unit begins to rotate, for example by rotating a clutch that secures and supports the cage, thereby winding the retainer around the cage. Ideally, the rotational motion is superimposed with the vertical translational motion, causing the retainer to be wound around the cage in a juxtaposed position.

[0138] In the fourteenth step, after the retainer of a predetermined length is wound around the retainer, the clamping jaws of the winding unit further clamp the retainer such that the retainer remains clamped by the clamping jaws of the winding unit when the cutter cuts the retainer with the still closed clamping jaws of the clamping and cutting unit. The cutter then cuts the retainer. However, the retainer is not cut directly at the clamping jaws of the winding unit, but rather away from the unit. Therefore, a shorter section of the retainer remains outside the clamping jaws of the winding unit after cutting. This shorter section of the retainer is used to attach the retainer to the formulation in a further processing step. The winding unit further includes a robotic gripper.

[0139] In step fifteen, the robotic gripper of the winding unit delivers the retainer to the machine section, where the retainer is wound around the retainer and clamped at one end by the clamping jaws of the winding unit. The first semi-capsule shell is positioned in the machine section, and the applicator housing is placed in the machine section. The robotic gripper positions the retainer on the shaft by pushing it into a shaft located inside the housing. In doing so, the retainer is only pushed onto the shaft to such an extent that the shorter segment of the retainer used to attach the retainer to the formulation can be positioned on the engagement area located outside the housing. The engagement area further includes an end segment of the formulation that extends through an opening in the first semi-capsule shell, i.e., when the two semi-shells are engaged in the engagement position, the end segment extends through an orifice of the capsule device, and this end segment is unwound.

[0140] In the sixteenth step, the retaining element and / or formulation are preferably wetted through the atomizer nozzle. Humidification occurs in the bonding area.

[0141] In step seventeen, the retainer is pressed onto the formulation using an impression mold to attach the formulation to the retainer. This connection allows tension to be transferred between the retainer and the formulation.

[0142] In step eighteen, a settling element is produced and inserted into the second capsule shell. Step eighteen can also be performed simultaneously with, earlier than, or later than other production steps. The settling element is preferably formed by pressing powder using a pressing pin. A robotic rotary arm can move into the powder, draw in a predetermined amount of powder, and press the powder. Then, the robotic rotary arm removes the powder and rotates on the second capsule shell, where the pressed powder is preferably inserted directly into the second capsule shell as a settling element. The step of producing the settling element can be performed independently of other processing steps. That is, the settling element can be produced in advance or in parallel with further processing steps, and the robotic arm can simply hold the settling element that has already been pressed or otherwise manufactured. The capsule device may also be devoid of a settling element, thus omitting step eighteen.

[0143] In the nineteenth step, a second capsule shell, having and / or not having a settling element, is positioned above the first capsule shell using an insert box. After the capsule halves are positioned on top of each other, the second capsule shell is pressed onto or into the first capsule shell by the insert box, thereby obtaining a pharmaceutical dosage form, wherein the second capsule shell has a wall that overlaps with the cross-section of the opening, thus forming an orifice of the capsule device at the connection position. The unfolded end portion of the formulation then extends out of the orifice and reaches the bonding area, connecting to the end portion of the retainer.

[0144] In the twentieth step, the capsule device of the drug dosage form is held with a clamping tool and positioned above the holder, and then placed in the holder.

[0145] In step twenty-one, the shell is pushed toward and over the retainer. An end cap is positioned on the shell. This closes the shell, which now contains a retainer wound around the retainer and a drug dosage form placed in the retainer, with the end portion of the retainer connected to the end portion of the dosage form such that when the retainer is fully unwound, for example if the patient swallows the dosage form, the retainer pulls the dosage form out of the capsule device.

[0146] Further preferred embodiments of the method for producing a pharmaceutical dosage form according to the invention and further preferred embodiments of the method for producing a capsule device for a pharmaceutical dosage form according to the invention can be obtained from the description of the invention and its embodiments, as well as the description of the embodiments according to the accompanying drawings. Attached Figure Description

[0147] Exemplary embodiments of the invention will now be described in more detail with reference to the accompanying drawings and examples, from which further details of the features, advantages, and embodiments can be obtained.

[0148] Figure 1a A schematic side view of a dosage form according to a first embodiment of the present invention is shown.

[0149] Figure 1b It shows Figure 1a Details of the area marked with an "X".

[0150] Figure 1c It shows Figure 1a Alternative configuration for the area marked with "X" in the text.

[0151] Figure 2a A top view of the first and second half-capsule shells according to another preferred embodiment of the invention is shown, the first and second half-capsule shells being aligned with each other to form a capsule device for a pharmaceutical dosage form.

[0152] Figure 2b A top view of the first and second half-capsule shells according to another preferred embodiment of the invention is shown, the first and second half-capsule shells being aligned with each other to form a capsule device for a pharmaceutical dosage form.

[0153] Figure 2c It shows Figure 2a A top view of the first and second capsule shells, which are glued together along the direction of motion M.

[0154] Figure 2d It shows the result of Figure 2a A top view of the capsule device formed by the connection position of the first and second half capsule shells.

[0155] Figure 2e Corresponding to Figure 2d The second capsule shell is shown as transparent to mark the area where the wall of the second capsule shell overlaps with the opening to form an orifice.

[0156] Figure 3a yes Figure 2a A side view of the situation.

[0157] Figure 3b Exemplary steps of a method for producing a pharmaceutical dosage form according to the invention are shown, in which a pharmaceutical preparation is inserted in its compressed form through an opening of a first semi-capsule device.

[0158] Figure 3c Another exemplary step of a method for producing a pharmaceutical dosage form according to the invention is shown, in which a pharmaceutical preparation is inserted in its compressed form into the hollow space of a first semi-capsule device.

[0159] Figure 3d The use according to an embodiment of the present invention is shown. Figure 2d A capsule-shaped drug dosage form.

[0160] Figure 3e It shows Figure 3d The drug dosage form in which the second half-capsule shell is shown as transparent.

[0161] Figure 4a Exemplary steps of a method for producing a pharmaceutical dosage form according to the invention are shown, including first and second half-capsule shells for a pharmaceutical formulation, a rotating shaft X located within an opening, and a strip of formulation connected to the shaft.

[0162] Figure 4b It shows that according to Figure 3d The first and second semi-capsule shells for pharmaceutical formulations include a rotating shaft X located within an opening, and have exemplary steps of forming a strip of formulation partially wound around the shaft by rotation (R) to form a pharmaceutical dosage form according to the invention.

[0163] Figure 4c It shows that according to Figure 3d The first and second semi-capsule shells for pharmaceutical formulations include a rotating shaft X located within an opening, and have an exemplary step of forming a strip of formulation completely wound around the shaft by rotation (R) to form a pharmaceutical dosage form according to the invention.

[0164] Figure 4d It shows that according to Figure 3d A second capsule shell for a pharmaceutical formulation, the second capsule shell including a settling element inserted into a hollow space of the second capsule shell, thereby forming an exemplary step of a method for producing a pharmaceutical dosage form according to the present invention.

[0165] Figure 5a This describes the first step in facilitating drug delivery by using a kit before the patient swallows the dosage form.

[0166] Figure 5b This describes the second step of using a kit to facilitate drug delivery after the patient swallows the dosage form.

[0167] Figure 6a The kit is described and the steps for attaching the retainer to the wall structure of the cage are explained.

[0168] Figure 6b The kit is described and the steps of a method for winding the retainer around the retainer of the applicator after the retainer has been attached to the wall structure of the retainer are explained.

[0169] Figure 6c The kit is described, and the steps for attaching the retainer to the container of the formulation are explained.

[0170] Figure 6d The kit is described and the steps of a method for connecting the first half-capsule shell to the second half-capsule shell when the retainer is attached to the formulation are explained.

[0171] Figure 6e The kit is described and the steps of assembling the capsule device with the applicator are explained.

[0172] Figure 7 This describes how the end portion of the formulation is connected to the retainer of the applicator.

[0173] Figure 8 An exemplary production machine according to the invention for producing pharmaceutical dosage forms according to the invention is shown, particularly by performing the method according to the invention.

[0174] Figure 9a An exemplary apparatus is shown for assembling a production machine for assembling a first semi-capsule shell with a formulation in a first step, wherein an elongated formulation is rolled up in an mounting position.

[0175] Figure 9b An example is shown in the second step Figure 9a The equipment includes a device in which slender formulations are easily rolled up and now cut by a cutting device.

[0176] Figure 9c An example is shown in the third step. Figure 9b The device is equipped with an actuation mechanism in which an elongated formulation is easily rolled up, cut from a storage roll, and inserted through an opening into the hollow space of a first semi-capsule shell by actuation of the actuating device.

[0177] Figure 10a A schematic cross-section of an applicator with a drug dosage form is shown, which is arranged within the bottom portion of the applicator holder and covered by an applicator cap.

[0178] Figure 10b A schematic cross-section of an applicator is shown, in which a drug dosage form is internally arranged and an improved applicator cap is provided.

[0179] Figure 11 A schematic side view of a pharmaceutical dosage form according to another embodiment of the present invention is shown. Detailed Implementation

[0180] Figure 1aA capsule device 1 for application to mucous membranes is shown, comprising a formulation 2 having an elongated shape and including an active pharmaceutical ingredient. Formulation 2 is shown in a compressed state: assuming the formulation has a strip-like shape, then... Figure 1a A side view shows the strip formulation wound into a spiral shape around a virtual axis perpendicular to the drawing. In the expanded state, when the formulation is pulled out from the slit-like opening 5 of the capsule 3, the strip formulation will have an elongated shape as a substantially straight strip.

[0181] The capsule device 3 has the shape of a capsule and includes a hollow space 4 that contains the formulation 2 in a compressed state. The capsule consists of a thin wall with a thickness of approximately 50 μm to 200 μm, which is made of a biodegradable or non-biodegradable material.

[0182] The capsule device has an opening 5 formed as a planar curved slit.

[0183] The width 'a' of the orifice 5, formed as a curved slit, is defined by measuring the distance 'a' between the opposing surfaces 5a of the capsule walls of the first and second semi-capsule shells 3a and 3b in a direction parallel to the length axis A. The distance 'a' can be a constant value, for example, between 200 μm and 600 μm. The thickness t of the formulation can be a constant value, for example, between 20 μm and 150 μm.

[0184] Regarding the external dimensions of the capsule device, for example, the height H of capsule 3 could be 8 mm, and the width W of capsule could be 4 mm. However, other dimensions of the capsule device are often possible, taking into account the patient's desired administration site.

[0185] In the compressed state of the formulation, the first end 2a of the formulation 2 extends through the orifice 5 to allow the formulation to be grasped from the hollow space and pulled out into the surrounding area of ​​the capsule device, thereby changing the formulation 2 from the compressed state to the expanded state. Pulling out the formulation, i.e., the pull-out motion P (see...) Figure 1b This could be the result of fixing the end 2a of the formulation 2 and pulling the capsule device in the direction M opposite to P. This is, for example, the case of administering the capsule device by swallowing the capsule device and connecting the end 2a of the formulation to a holder of an applicator including a drinking cup, as... Figure 5a , Figure 5b As shown.

[0186] The first end 2a may have an end portion (see...) Figure 1c The end portion has a shape different from that of strip 2. For example, the end portion can form a sealing member adapted to be disposed at orifice 5 for sealing orifice 5 before the end portion is pulled out of orifice. The end portion can be further configured to connect to the retainer of the applicator by providing a bonding area.

[0187] Figure 1b An enlarged view of orifice region 5 is shown. (As shown) Figure 1b , Figure 1c As shown, the orifice 5 is created by a second semi-capsule shell 3b nested on the first semi-capsule shell 3a, thereby overlapping with the opening 6 of the first semi-capsule shell to form a slit-like orifice 5. The slit-like orifice 5 and the strip-shaped formulation 2 are sized such that when the formulation is pulled out of the orifice, a spacing (S1; S2) is provided, which is measured in the orifice cross-section CS of the orifice 5 between the formulation 2 and the surface 5a of the capsule device defining the orifice 5. In this text, the central length axis A of the capsule extends parallel to the orifice cross-section CS. Figure 1a The capsule device 3 shown includes a first semi-capsule shell 3a and a second semi-capsule shell 3b, wherein when the first semi-capsule shell 3a and the second semi-capsule shell 3b are stacked on top of each other to form the capsule device 3, the opening 6 of the first semi-capsule shell 3a is partially covered by the second semi-shell 3b to form a slit-like opening 5. This opening 6 can be created by milling capsule material using a plate milling tool (e.g., a plate saw blade). The overlapping position (i.e., the connection position between the two semi-capsule shells 3a, 3b) is determined by... Figure 1a The dashed line marked B in the middle represents this.

[0188] like Figure 1b As shown, the thickness t of band 2 is significantly smaller than the width a of the planar curved slit 5. For example, the thickness t can be a constant value between 20 μm and 150 μm. The spacing S = S1 = S2 is measured by positioning the formulation 2 at the center of the orifice 5 and positioning the strip surface parallel to and facing the capsule surface 5a in a centered and aligned position. The spacing S is present and can be substantially constant on average as the formulation 2 is pulled out of the orifice (meaning substantially along the entire length of the elongated formulation). However, the scope of the invention can also cover this embodiment of the dosage form in which the spacing between the formulation and the surface 5a defining the orifice varies (due to variations in the thickness t of the formulation 2), or in which the spacing is partially interrupted (due to partial variations in dimensions a and t, including partial variations in the dimension a = t).

[0189] When a formulation has a rope-like shape, its size can be measured by analogy, and when the formulation has an irregular shape, its size can be determined by taking the average value.

[0190] like Figure 1cAs shown, the first end portion 2a may have an end portion forming an enlarged portion, which may be configured to prevent the formulation from being lost within the capsule 3, making it difficult for the patient or applicant to recover the end portion 2a to pull out the band and apply the dosage form in the intended manner. The end portion 2a may also be configured to be positioned at the orifice 5 before the end portion 2a is pulled out of the orifice for sealing the orifice 5. A portion 7 may be provided at the end portion, configured to connect a thread (e.g., a retainer from the applicator) to the end portion 2a. The width a′ of the orifice 5, extending in a direction perpendicular to the axis A representing the elongated shape of the capsule 3, is measured between the opposing surfaces 5a′ of the second half-capsule shell. The dimension of the width a′ may be similar to the width of the formulation end portion 2a.

[0191] Figure 2a A top view of a first semi-capsule shell 11 and a second semi-capsule shell 12 according to another preferred embodiment of the invention is shown, the first and second semi-capsule shells being aligned with each other to form a capsule device 13 for a pharmaceutical dosage form 10. The first semi-capsule shell 11 has a first end closed by a spherical cap 11a and a second end, the second end being a hollow cylindrical wall 11b providing an opening for the first semi-capsule shell 11. The second semi-capsule shell 12 has a first end closed by a spherical cap 12a and a second end, the second end being a hollow cylindrical wall 12b providing an opening for the second semi-capsule shell 12. The first semi-capsule shell 11 has a hollow cylindrical wall 11c that completely surrounds an opening 16, the opening being essentially a hole in the wall 11c. Stability is provided by a wall frame 11c surrounding the opening 16.

[0192] Figure 2b A top view of a first semi-capsule shell 11′ and a second semi-capsule shell 12′ according to another preferred embodiment of the invention is shown, the first and second semi-capsule shells being aligned with each other to form a capsule device for a pharmaceutical dosage form. The first semi-capsule shell 11′ has a first end closed by a spherical cap 11a′ and a second end, which is a hollow cylindrical wall 11b′ providing an opening for the first semi-capsule shell 11′. The second semi-capsule shell 12′ has a first end closed by a spherical cap 12a′ and a second end, which is a hollow cylindrical wall 12b′ providing an opening for the second semi-capsule shell 12′. A hollow cylindrical wall segment 11c′ does not completely surround the opening 16, particularly a recess 16′ extending from the wall boundary of the second end 11b′ toward the first end 11a′. This recess provides sufficient space for processing the formulation, particularly for inserting the formulation 2 in its compressed shape into the hollow space of the first semi-capsule shell 11′ along a direction perpendicular to the plane of the drawing and / or along direction M.

[0193] Figure 2c It shows Figure 2aA top view of the first and second capsule shells, which are glued together by sliding motion along the direction of motion M. The cylindrical portion of the second capsule shell 12 may have a slightly larger diameter than the cylindrical portion of the first capsule shell 11 to facilitate the engagement of the first capsule shell 11 and the second capsule shell 12.

[0194] Figure 2d It shows the result of Figure 2a A top view of the capsule device 13 formed at the junction of the first half-capsule shell 11 and the second half-capsule shell 12. The orifice 15 is a slit extending circumferentially and tangentially within the capsule wall around axis a. The cross-section A_o of the orifice is significantly smaller than the cross-section A_a of the opening 16, for example, by a factor f = 0.05-0.2: A_o = f * A_a. In this way, a formulation easily inserted through the opening 16 at the separated position of the first half-capsule shell 11 and the second half-capsule shell 12 will not fall out through the orifice 15 in its compressed state, but can be easily pulled out through the orifice 15 in its extended position when unwound from the coiled state during swallowing (see...). Figure 9b ).

[0195] Figure 2e Corresponding to Figure 2d The second capsule shell is shown as transparent to mark the area 12c where the wall 12b of the second capsule shell overlaps with the opening 16, thereby forming an aperture 15.

[0196] Figure 3a yes Figure 2a A side view of the situation. Opening 16 has a rectangular shape when projected onto the plane, but conforms to the cylindrical shape of wall 11b in the circumferential direction. The opening essentially opens the column along almost its entire width W (see...). Figure 1b This allows the formulation, in its compressed state, to move along a direction N perpendicular to axis A (see...). Figure 3b It is inserted into the hollow space 14 of the capsule device or the shell of the first half capsule through the opening 16.

[0197] Figure 3b A compressed form of a pharmaceutical preparation is shown, inserted through the opening 16 of the first semi-capsule shell 11.

[0198] Figure 3c A compressed form of pharmaceutical preparation is shown, fully inserted into the hollow space 14 of the first semi-capsule shell 11, with the compressed end 2a extending through the opening 16. Even as the second semi-capsule shell 12 moves to engage with the first semi-capsule shell 11, the free cross-section of the opening 16 continuously decreases until it reaches... Figure 3d The diagram shows the connection points of the completed drug dosage form 10.

[0199] Figure 3d It shows the use of Figure 2d Drug dosage form 10 with capsule device. Figure 3e A pharmaceutical dosage form 10 is shown, wherein the second half-capsule shell 12 is shown as transparent to show the position of the formulation within the hollow space 14 in its compressed state.

[0200] Figure 4a A first half-capsule shell 11 and a second half-capsule shell 12 for a pharmaceutical formulation are shown, and a rotating shaft X located within an opening 16 is shown, with a strip-shaped formulation 2 connected to the shaft X, thereby forming exemplary steps of a method for producing a capsule and assembling a pharmaceutical dosage form according to the present invention.

[0201] Figure 4b It shows that according to Figure 3d The first and second half-capsule shells 11 and 12 for pharmaceutical formulations include an axis X for rotation R located within or in front of an opening, and have a strip of formulation 2 partially wound around the axis by rotation (R), thereby forming an exemplary step of the method of producing capsules and assembling pharmaceutical dosage forms according to the invention. Figure 4b The rotation direction (R) in the example is chosen, and therefore could also be the opposite direction to the rotation direction (R) shown.

[0202] Figure 4c It shows that according to Figure 3d The first and second half-capsule shells 11 and 12 for pharmaceutical formulations include a rotating shaft X located within an opening and have a strip of formulation that is completely wound around the shaft by rotation (R), thereby forming an exemplary step of the method of producing a capsule device and assembling a pharmaceutical dosage form according to the invention.

[0203] Figure 4d It shows that according to Figure 3d The second half-capsule shell for a pharmaceutical preparation includes a settling element 60 inserted into the hollow space of the second half-capsule shell 12, thereby forming an exemplary step of the method of producing a capsule and assembling a pharmaceutical dosage form according to the present invention.

[0204] Figure 5a A pharmaceutical dosage form comprising a capsule device as described herein, to be administered to a patient, is shown. A drinking cup 901 is filled with liquid, and an applicator 902 is attached to the cup 901. The applicator 902 includes a pharmaceutical dosage form comprising a capsule device 903 and a retainer 904 connected to the formulation contained in the capsule device 903.

[0205] Figure 5bThe process is illustrated when a patient swallows the capsule device 903 and the capsule device is transported through the esophagus toward the stomach. A retainer 904 pulls the formulation 905 out of the capsule device 903. The formulation 905 then diffuses along the esophagus, such that the active ingredient of the formulation 905 is delivered to the esophageal mucosa.

[0206] Figure 6a This relates to a method of winding the retainer 101 around the retainer 102 of the applicator 103 using a machine 100. Therefore, as... Figure 6a As shown, in the first step of winding the retainer 101 around the retainer 102, the retainer 101 is mechanically secured in the machine 100, which includes a clamping and cutting unit 110. The cutting unit 110 includes clamping jaws 106, a cutter 108, and a guide device 107. In the second step, the retainer 101 is tightened by moving the clamping jaws 106. In the third step, the retainer 102 is positioned along the tightened retainer 101, which means that the mechanical clutch 109 and the retainer 101 are clamped in a groove in the wall structure of the retainer 102.

[0207] Figure 6b This relates to a method of winding the retainer around the retainer of the applicator after the retainer has been attached to the wall structure of the retainer. In the first step, as... Figure 6b As shown, the jaws 106 for clamping the retainer 101 are opened. In the second step, the retainer 102 rotates in the winding unit, for example by rotating the clutch 109 that fixes and supports the retainer 102, thereby winding the retainer 101 around the retainer 102. The rotational motion is superimposed with the vertical translational motion, causing the retainer 101 to be wound around the retainer 102 in a juxtaposed position, and after the retainer is fully wound around the retainer 102, the clamping jaws fix the retainer 101 again in the sixth step.

[0208] In the third step, the blade-shaped part 108 of the machine 100 cuts through one end of the retainer 101, which is connected to the formulation 104 in a further subsequent step.

[0209] Figure 6cThe method relates to attaching a retainer to a carrier of a formulation, meaning that the retainer 101 is coupled to the formulation 104, while further assembling the kit by machine. In a first step, positioning the retainer 101 around a carrier 102 wound around it above an opening 110 of an applicator housing 111 is specifically accomplished by machine. Thus, the carrier 102 is pushed through its opening 110 on a shaft 112, such as an auxiliary tube. The shaft 112 thus extends through the housing 111 already positioned in the machine 100. A first half-capsule shell 105a of the capsule device 105 is further positioned in the machine 100 and arranged adjacent to the applicator housing 111, such that the formulation 104 extends at least partially from the first half 105a onto a bonding region 113 of the machine 100. A cut end 101a of the retainer 101 is further arranged within the bonding region 113 of the machine 100. The cut end 101a then pulls the formulation 104 out of the capsule device 103.

[0210] Figure 6d This invention relates to a method of connecting a first half-capsule shell to a second half-capsule shell while simultaneously connecting a retainer to the formulation. As shown in the first step, the retainer end portion 101a is engaged to one end of the formulation 104 in a clamping engagement region 113. Consequently, a support 114 moves downward toward the engagement region 113 and presses against the overlapping formulation 104 and retainer end portion 101a. The engagement is further illustrated in Figure 10. In the second step, the second half-capsule shell 105b is positioned above the first half 105a together with a settling element 115. In the third processing step, the two halves 105a, 105b are nested, connected, or slid into each other such that the opening is partially closed to form an orifice of the capsule device 105 through which the end portion of the formulation 104 can be pulled out through the orifice by the now finally connected or engaged retainer 101.

[0211] Figure 6e This relates to a method for assembling the capsule device and the applicator, in which a retainer is connected to the formulation. Therefore, Figure 6e The steps for assembling a drug dosage form (i.e., capsule device 105) using an applicator 103 are shown. The capsule device includes a formulation 104 and, in the case shown, a settling element 115. Thus, in a first step, a clamping element 116, for example, is positioned above the capsule device 103 by negative pressure to hold the device 103 and deliver it over the housing 111 of the applicator 105. In a second step, the capsule device 103 is placed inside the housing 111. The housing 111 further includes a retainer 101 wound around a retainer 102 and positioned within an opening 110 of the housing 111, as previously described. Figure 6c and Figure 6d As described in the steps. In the third step, the housing 111 of the applicator 105 is closed by the end cap 117.

[0212] Figure 7 The diagram shows an end portion of formulation 701 connected to a retainer 702 of the applicator, such as the end portion of the retainer. To connect the retainer 702 to the end portion of formulation 701, in a first step, the retainer is immersed in a pure aqueous solution. In this embodiment, water acts as an adhesive. However, other embodiments are contemplated in which substances other than water can be used as adhesives.

[0213] Preferably, the retainer is immersed in the solution for a period of 1 to 10 seconds, or 1 to 5 seconds, or approximately 1 second. In the second step, the immersed retainer 702 is positioned on the water-wetted end portion 701. Thus, the retainer 702 overlaps the end portion of the formulation 701 at an overlap distance d, which ranges from 0.5 to 2 cm, or 0.5 to 1.5 cm, or 0.5 to 1 cm, or preferably 1 cm. After positioning the retainer 702, the retainer 702 is pressed onto the end portion of the formulation 701, while the end portion 701 remains water-wetted. The pressing time is preferably 1 to 10 seconds, or 1 to 5 seconds, or 2 to 3 seconds. Pressing is performed using a contact pressure mold. In a further third step, prior to the further processing of the connector, the connected retainer 702-formulation 701 is dried for a period of 1 to 10 minutes, or 2 to 8 minutes, or preferably 5 minutes. Alternatively, the retainer 702 is not submerged but is positioned dry on the end portion 701 such that the retainer 702 overlaps with the end portion of the formulation 701 at an overlap distance d, and the retainer, together with the end portion 701, is sprayed with pure water before pressing. The spraying can be achieved by means of a nozzle (e.g., a spray nozzle or atomizer nozzle) to atomize the liquid onto the surface to be sprayed. Using a nozzle helps disperse the liquid into a spray. Therefore, the nozzle distributes the liquid over an area that includes at least the overlap distance d, which increases the liquid surface area and generates an impact force on the solid surface.

[0214] Figure 8An exemplary manufacturing machine according to the invention for producing pharmaceutical dosage forms according to the invention is shown, particularly by performing the method according to the invention. The manufacturing machine 200 is configured to produce pharmaceutical dosage forms according to the invention, particularly by performing the method according to the invention. The manufacturing machine includes a positioning device 240 for positioning a first semi-capsule shell in an installation position. A connecting device 260 has a movable element 261 configured to connect the second semi-capsule shell and the first semi-capsule shell to a connecting position by moving the first semi-capsule shell 11; 11′ and the second semi-capsule shell 12; 12′ toward each other, such that the wall 12c of the second semi-capsule shell overlaps with the cross-section of the opening 16; 16′ by an amount controlled by the movement of the movable element 261, thereby forming the orifice 5; 15 of the capsule device 3; 13 in the connecting position.

[0215] The positioning device 240 includes four retaining members 243.1; 243.2; 243.3; 243.4 for holding one or more first and / or second capsule shells in place. The retaining members provide retaining spaces shaped to hold the first and / or second capsule shells by a positive-fit connection. The positioning device 240 (retaining members) can be configured to hold multiple first and / or second capsule shells in place in parallel, with only one capsule produced at each mounting position. In this way, the throughput of the production process can be increased. The positioning device 240 is used to position four first and four second capsule shells in four mounting positions, each provided by the retaining members 243.1; 243.2; 243.3; 243.4. Therefore, by using multiple mounting positions, particularly workstations defined by the retaining members, multiple steps of the pharmaceutical dosage form production can be performed in parallel.

[0216] The positioning device 240 includes a rotatable platform 241 that carries workstations. Each workstation includes a retaining member positioned along a radially outer region of the rotatable platform. The movable platform 241 is rotatably arranged at a base member (not shown) for rotation about an axis 242, configured to rotate each workstation to a working position on the production machine. In a first working position (where the retaining member 243.1 is in...) Figure 11 (As shown in the diagram), a feeding device 251 is arranged for feeding at least one first semi-capsule shell 11; 11′ to the mounting position provided by the retaining member 243.1. In the second working position (wherein the retaining member 243.2 is in...) Figure 11 As shown in the figure, a feeding device 252 is arranged for feeding the second half-capsule shell 12; 12′ to the mounting position provided by the retaining member 243.2.

[0217] In the third working position (where retaining member 243.3 is in) Figure 8 As shown in the figure, the equipping device 201 can be arranged to equip the formulation 2, preferably in its compressed state, for the first semi-capsule shell 11; 11′. The equipping device 201 includes a conveying device 220 for conveying the ends 212a; 2a of the formulation to the mounting position, and includes a clamping device 223.1; 223.2, in particular a winding device, for changing the formulation 212; 2 from an extended state to a compressed state, in particular a folded or wound state.

[0218] In the fourth working position (where retaining member 243.4 is in) Figure 8 (as shown in the figure) A receiving station 270 may be provided for receiving the readily produced drug dosage form 10 and may transport the drug dosage form to a storage or transport system (not shown).

[0219] In each case, the production machine preferably includes an electronic control unit 280 for controlling each action, which is automatically performed by the production machine, particularly by controlling the activity and parameters of at least one drive that controls the rotation of the positioning device about axis 242, feeding capsule portions through devices 252 and 251, conveying the formulation through the conveying device, the movement of the pressing device, especially the rotation of the winding device, the cutting movement of the cutting device, the actuating movement of the actuating device, the connecting movement of the connecting device 260, and any other device. The electronic control unit 280 may include a user interface for allowing the user to control the production machine, and / or control software for controlling the production machine, particularly a computer program programmed to implement each step of the method according to the invention, which includes all possible and preferred steps described herein.

[0220] The production machine includes a formulation storage device 210 that provides a storage roll 212 of formulation, which can be released from the roll by rotation of the roll 212 about a shaft 211, thereby moving the elongated formulation in a direction toward the cutting device 230 and toward the holding member 243.3, which provides a working position. The movement of the elongated formulation 212 is guided by a guide unit 213, which also includes a roller 214. The position 212a of the formulation 212 (which subsequently forms the first end 2a of the elongated formulation 2) is held by a rotating shaft 223.1, which is moved to a mounting position at the holding member 243.3 by rotation of a rotating disk 222 about an axis R1. See also Figure 9a .

[0221] Figure 9a An exemplary device 201 for equipping a production machine 200 with a first semicapsule shell 11; 11′ of formulation 2 is shown for use in a first step, wherein the elongated formulation 212 is rolled up in a mounting position at the retaining member 243.3.

[0222] The production machine 200 includes a conveying device 220 for conveying one end of a formulation 212a, having an elongated shape and containing an active pharmaceutical ingredient, from a formulation storage location to an installation location, where the formulation is positioned to be inserted into the hollow space 14 of a first semi-capsule shell 11; 11′ at installation location 243.3, particularly through an opening 16. Herein, the conveying device has a rotatable conveying member 222 configured to receive at least a portion 212a of the formulation 212a at a first location 223.2, particularly after release from the formulation storage device 210, and to convey at least a portion of the formulation 212a to the installation location 243.3 by rotation R1. Movement or rotation of the conveying device 222 can be controlled by an electronic control unit 280 of the production machine 200.

[0223] The rotatable conveyor 222 may include winding devices 223.1 and 223.2 for winding up the formulation in its elongated state to form a wound state. The winding device has two rotatable shafts 223.1 and 223.2, which are configured to be electrically driven and controlled by an electronic control unit 280 of the production machine. The two rotatable shafts are arranged at a position offset from the rotation axis R1 of the rotatable conveyor 222. The rotatable conveyor 222 and / or the winding device are configured to wind up the formulation 212 in its elongated state in the mounting position at 243.3, particularly if the rotatable shaft 223.1 is positioned in front of and within the opening 16, such that the formation of the formulation 2 in its compressed state occurs... Figure 9a and Figure 9b The compression position shown indicates that the formulation is located in front of the opening and even within the opening 16, and therefore, when the first semi-capsule shell is in the mounting position at 243.3, it is at least partially directly within the hollow space 14 of the first semi-capsule shell 11; 11′. This significantly facilitates the transfer of the formulation into the capsule.

[0224] Figure 9b An example is shown in the second step Figure 9a The equipment 201, in which the elongated formulation 212 is easily rolled up and now cut by the cutting device 230.

[0225] The production machine includes a cutting device 230 for cutting the formulation to form a hollow space to be inserted into the shell of a first semi-capsule. The cutting device includes a first portion 231 having a first cutting edge and a second portion 232 having a second cutting edge.

[0226] Figure 9c An example is shown in the third step. Figure 9bThe equipment 201 includes an elongated formulation 2 that is easily rolled up by an actuation from an actuation device 233, cut from a storage roll 212, and inserted through an opening 16 into the hollow space 14 of the first half-capsule shell 11, in this example, the actuation device being part of a second part 232. The production machine includes an actuation device 233 for moving the formulation 2, which is in its compressed state, from a compressed position to its final position within the hollow space 14 of the first half-capsule shell 11.

[0227] Figure 10a A schematic cross-section of an applicator 1000 having a drug dosage form 1002 has a formulation 1013 disposed within a bottom portion 1005 of an applicator holder 1007, and is covered by an applicator cap 1003 including a closure 1004. The bottom portion 1005 is indicated by dashed lines to separate the bottom portion from the top (i.e., the cap 1003), and these two portions form a housing 1006 of the applicator 1000. The dosage form 1002 is positioned within the housing 1006, and more specifically, within the holder 1007. Thus, the dosage form 1002 is arranged vertically (i.e., along an axis indicating its elongated shape) within the holder 1007. The holder 1007 includes rods 1007a. These rods extend along the dosage form 1002 and serve to support the dosage form 1002, i.e., the capsule device, in an vertical position within the holder structure 1007. A retainer 1008 is wound around the rods 1007a. Dosage form 1002 also includes a settling element 1009. The rod structure of the retainer 1007 allows dosage form 1002 to move in the vertical direction indicated by the arrow.

[0228] Figure 10b As shown Figure 10a The diagram shows a schematic cross-section of the applicator. For vertical movement of the inhibitor type 1002, a curved retainer 1010 is positioned on the spherical cap of dosage form 1002 when the applicator 1000 is inverted or shaken. Therefore, the retainer 1010 preferably has an external profile similar to the end cap of dosage form 1002. Furthermore, the retainer 1010 is secured by a spring 1011, which also presses the retainer 1010 against the cap of dosage form 1002. Therefore, dosage form 1002 cannot move vertically. Additionally, the cap 1004 of the applicator 1000 includes a desiccant 1012 to prevent dosage form 1002 from becoming unusable.

[0229] Figure 11A translucent view of a pharmaceutical dosage form 1100 is shown. Dosage form 1100 includes a first half-capsule shell 1102 and a second half-capsule shell 1101 nested together. An orifice 1106 is obtained by sliding the first half 1102 and the second half 1101 onto each other, such that the opening 1104 of the first half 1102 is partially covered to form the orifice 1106. Formulation 1105 is shown in a compressed form, while the end of formulation 1107 extends from the orifice 1106 to the outside of dosage form 1100. Dosage form 1100 further includes a settling element 1103 drawn on the top of formulation 1105. The settling element 1103 is secured by notches 1108 to prevent vertical movement of the element 1103 along the length axis of dosage form 1100. Preferably, a plurality of notches 1108 are distributed within the walls of dosage form 1100.

[0230] List of reference numerals

[0231] Figures 1a-1c 1. Drug dosage form 2. Formulation

[0232] 2a. End portion of the formulation; 3. Capsule device.

[0233] 3a First capsule shell 3b Second capsule shell

[0234] 4. Hollow space; 5. Orifice

[0235] 5a, 5a′ Surface of capsule wall 6 Opening of the first semi-capsule shell

[0236] 7. The end portion of the formulation

[0237] Figures 2a-2e , Figures 3a-3e , Figures 4a-4d ,

[0238] 10. Drug dosage form 11. First half-capsule shell

[0239] 11a Spherical cap 11b Hollow cylindrical wall

[0240] 11c capsule wall

[0241] 12 Second capsule shell 12a Spherical cap

[0242] 12b Hollow cylindrical wall; 12c Region of the capsule wall.

[0243] 13 Capsule device 14 Hollow space

[0244] 15. Hole opening; 16. Opening

[0245] 17 Hollow cylindrical wall section 18 Strip

[0246] 60 Settling element

[0247] Figure 5a , Figure 5b

[0248] 901 Drinking cup; 902 Applicator

[0249] 903 Capsule device; 904 Retainer

[0250] 905 formulation

[0251] Figures 6a-6e

[0252] 100 Machine 101 Retainer

[0253] 101a Retainer end portion 102 Applicator retainer

[0254] 105a First capsule shell; 105b Second capsule shell

[0255] 106 Clamping jaws 107 Guiding device

[0256] 108 Cutter 109 Support Clutch

[0257] 110 Cutting unit 111 Applicator housing

[0258] 112 Axis 113 Joint Area

[0259] 114 Support component 115 Settlement element

[0260] 116 Clamping element 117 End cap

[0261] Figure 7

[0262] 701 Formulation 702 Retainer

[0263] Figure 8 , Figures 9a-9c

[0264] 200 Production machines 201 Equipped with devices

[0265] 210 Storage device 211 Shaft

[0266] 212 Storage of the Formulation 212a End Portion of the Formulation

[0267] 213 Guide unit 214 Roller

[0268] 220 Conveying device 222 Rotary disc

[0269] 223.1 Clamping device 223.2 Clamping device

[0270] 230 Cutting device 231 First part of the cutting device

[0271] 232 Second part of the cutting device with a cutting blade 233 Actuating device

[0272] 240 Positioning device 241 Rotatable platform

[0273] 242 Axis 243.1 Holding Member

[0274] 243.2 Retaining Member 243.3 Retaining Member

[0275] 243.4 Holding component 251 Feeding device

[0276] Device 251 Device 252

[0277] 260 Connecting device 261 Movable element

[0278] 270 Receiving Station 280 Control Device

[0279] Figure 10a , Figure 10b

[0280] 1000 Applicator 1002 Drug Dosage Form

[0281] 1003 Applicator cap 1004 Cover

[0282] 1005 Bottom part of the applicator 1006 Housing

[0283] 1007 Cage 1008 Retainer

[0284] 1009 Settling element; 1010 Bending cage

[0285] 1011 Spring; 1012 Desiccant

[0286] 1013 Formulation

[0287] Figure 11

[0288] 1100 Pharmaceutical dosage form 1101 Second half capsule shell

[0289] 1102 First semi-capsule shell 1103 Settling element

[0290] 1104 Opening 1105 Formulation

[0291] 1106 Orifice; 1107 End portion of the formulation.

[0292] 1108 Notch

Claims

1. A capsule device for use on a mucosa, said mucosa being oral or gastrointestinal mucosa, or esophageal mucosa, said capsule device being configured to contain a pharmaceutical preparation having an elongated shape and comprising an active pharmaceutical ingredient, and capable of being arranged in a compressed state and a distended state. The capsule device includes a hollow space for containing the formulation in a compressed state. The capsule device has an orifice configured to allow a first end of the formulation in a compressed state to extend through the orifice, enabling the formulation to transition from a compressed state in the hollow space to an expanded state in the surrounding area of ​​the capsule device. The capsule device includes a first half-capsule shell and a second half-capsule shell, which are joined together by overlapping the first half-capsule shell and the second half-capsule shell at a connection location. Its features The first semi-capsule shell has a hollow cylindrical wall including an opening, and The second half-capsule shell has a wall that overlaps with the cross-section of the opening, thereby forming an orifice of the capsule device at the connection position.

2. The capsule device according to claim 1, wherein, The hollow cylindrical wall of the first semi-capsule shell is closed at a first end and open at a second end, wherein the opening is completely surrounded by the material of the hollow cylindrical wall.

3. The capsule device according to claim 1, wherein, The hollow cylindrical wall of the first semi-capsule shell is closed at a first end and open at a second end, wherein the opening is formed as a recess that begins at the second end and extends toward the first end.

4. The capsule device according to any one of claims 1 to 3, wherein, The cross-section of the opening is sized to receive the formulation in its compressed state before the first and second half-capsule shells are joined, wherein, in the joined position, the orifice defined by the opening and the walls of the second half-capsule shells has a cross-sectional dimension that prevents the formulation in its compressed state from passing through the orifice.

5. The capsule device according to any one of claims 1 to 3, wherein, The cross-sectional dimension A_o of the orifice is a fraction f of the cross-sectional dimension A_a of the opening, where A_o = f * A_a, and where 0.0010 <f<0.7500。 6. The capsule device according to any one of claims 1 to 3, wherein, At the connection position, the first half-capsule shell is inserted into the second half-capsule shell.

7. The capsule device according to any one of claims 1 to 3, wherein, The orifice is a slit-like opening configured to allow the formulation to pass through it, wherein the cross-section of the orifice is larger than the cross-section of the strip formulation when the strip formulation extends through it.

8. The capsule device according to any one of claims 1 to 3, wherein, The capsule device is configured to be swallowed by a patient.

9. The capsule device according to any one of claims 1 to 3, the capsule device comprising a settling device that occupies a portion of the hollow space and provides additional weight to the capsule device.

10. A method for producing a capsule device as defined in any one of claims 1 to 9 for containing a pharmaceutical formulation, the method comprising the steps of: a) Provide a first and a second half-capsule shell having a hollow cylindrical wall including an opening; b) Slide the second half-capsule shell and the first half-capsule shell to the connection position, wherein the wall of the second half-capsule shell overlaps with the cross-section of the opening of the first half-capsule shell, thereby forming the orifice of the capsule device at the connection position.

11. The method according to claim 10, wherein, Step a) includes further steps: a) Providing a material for forming a capsule device, said material for forming the shells of the first and second half-capsules; b) Create openings in the material of the first and / or second capsule shell.

12. The method according to claim 11, wherein, The opening is formed in the shaped hollow cylindrical wall material of the first and / or second semi-capsule shell.

13. A pharmaceutical dosage form comprising a capsule device and a pharmaceutical preparation according to any one of claims 1 to 9, the pharmaceutical preparation having an elongated shape and comprising an active pharmaceutical ingredient, and being capable of being arranged in a compressed state and an expanded state.

14. A method for producing a pharmaceutical dosage form according to claim 13, comprising a method for producing a capsule device according to claims 10 to 12, the method comprising the following steps: a) Provide a formulation having an elongated shape and containing an active pharmaceutical ingredient; b) Provide a first and a second half-capsule shell having a hollow cylindrical wall including an opening; c) In the compressed state, the formulation is contained into the first semi-capsule shell through the opening, such that a portion or one end of the formulation extends through the opening; d) Slide the second half-capsule shell onto the first half-capsule shell or slide the first half-capsule shell onto the second half-capsule shell to the joining position, thereby reducing the cross-section of the opening, while the end of the formulation extends through the opening until the opening forms the orifice of the capsule device at the joining position of the first and second half-capsule shells.

15. The method of claim 14, further comprising the following steps: After step a) or b), a rotating shaft is provided and positioned in front of or within the cross-section of the opening, and the elongated formulation is wound around the rotating shaft to guide and / or align the formulation using the opening until the formulation reaches a compressed state.

16. The method according to any one of claims 14 to 15, comprising the following steps: After step b) or c), the settling device is placed in at least a portion of the hollow space of the first and / or second semi-capsule shell.

17. A kit comprising a pharmaceutical dosage form as claimed in claim 13, a drinking cup, and an applicator for administering the pharmaceutical dosage form to a patient, wherein, The applicator is fluidly connected to a drinking cup and contains a drug dosage form, wherein the formulation of the drug dosage form is connected to the applicator via a retainer for use in withdrawing the formulation from the capsule device after administration to the patient.

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