Capsule device having a gap formed by overlapping two half capsule shells

Abstract

The present invention relates to a pharmaceutical dosage form for application to mucous membranes, in particular the buccal, intestinal, rectal or vaginal mucosa, comprising at least one string- or strip-shaped preparation containing an active pharmaceutical ingredient, the dosage form consisting of first and second half capsule shells which together define the size of the gap through which the preparation is released. The present invention also relates to a method for producing the pharmaceutical dosage form.

Description

[Technical field]

[0001] The present invention relates to a capsule device and a pharmaceutical dosage form for application to a mucous membrane, in particular the buccal or gastrointestinal mucosa. The present invention also relates to a method for producing the capsule device and a pharmaceutical dosage form comprising the capsule device. [Background technology]

[0002] Such capsule devices are known from Patent Document 1 or Patent Document 2. The capsule device of Patent Document 2 is designed to include at least one sheet-shaped, specifically film-shaped, foil-shaped or wafer-shaped preparation containing an active pharmaceutical ingredient, a release mechanism and a triggering mechanism, the triggering mechanism being adapted to trigger the release of the sheet-shaped preparation by the release mechanism at a predetermined action site, specifically the gastrointestinal tract, the rectum or the vagina. From the embodiment according to Figs. 8a, 8b and 8c of Patent Document 2, a dosage form is known that includes an elongated strip-shaped preparation and contains an active pharmaceutical ingredient, the preparation being capable of being placed in a compressed state and an expanded state, the dosage form having a capsule with a hollow space that contains the compressed preparation, the capsule device having an aperture and a first end of the preparation extending through the aperture in the compressed state that allows the preparation to be pulled from the hollow space to the surrounding area of ​​the capsule, thereby transitioning the preparation from the compressed state to the expanded state.

[0003] Additionally, it is known in the art to use catheter or stent-like devices for the local application of active ingredients with particular reference to the treatment of the gastrointestinal mucosa, particularly the esophageal mucosa. Another approach uses a liquid or gel-like medium having a relatively high viscosity. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2020 / 183005 [Patent Document 2] International Publication No. 2016 / 102067 Summary of the Invention [Problem to be solved by the invention]

[0005] The objectives underlying the present invention are to provide a capsule device that can be efficiently produced and to provide methods for efficiently manufacturing capsule devices and pharmaceutical dosage forms, as well as methods for manufacturing pharmaceutical dosage forms, including methods for manufacturing capsule devices. [Means for solving the problem]

[0006] The problem is solved by a capsule device according to claim 1 and a method for producing a capsule device of a pharmaceutical dosage form according to claim 10. Preferred embodiments of the invention are the subject matter of the dependent claims.

[0007] According to the present invention, a capsule device includes a first half capsule shell and a second half capsule shell, the first half capsule shell and the second half capsule shell being joined by overlapping the first half capsule shell and the second half capsule shell at a joining position, the first half capsule shell having a hollow cylindrical wall including an opening, and the wall of the second half capsule shell overlapping a cross-section of the opening, thereby forming a gap in the capsule device at the joining position.

[0008] The joining position thus refers to the position where the first and second half capsule shells are fitted or slid relative to one another to form the capsule device. By partially forcing the first and second half capsule shells relative to one another, the two halves are mechanically connected and effectively stabilized.

[0009] The first half capsule shell with an opening serves as a container that can be easily filled with a pharmaceutical preparation through the opening or, alternatively, the open end of the first half capsule shell. The second half capsule shell serves as a cover for the opening and can be easily placed over the opening, providing the desired gap size. The pharmaceutical dosage form according to the invention has excellent mechanical stability, which is advantageous for the patient when swallowing the capsule. Moreover, the pharmaceutical dosage form can be efficiently manufactured by the method according to the invention.

[0010] The term "half capsule shell" refers to the fact that the capsule device is preferably composed of two parts called "halves". The dimensions, e.g. size, of the two halves may differ from each other, but in a preferred embodiment, the two halves are dimensioned to have substantially the same dimensions, i.e. the same size. Each of the first and second half capsule shells has a hollow cylindrical wall. The hollow cylindrical wall preferably has a round shape, and is preferably capped by a cap part, in particular having a hollow hemispherical shape. In addition to the first and / or second half capsule shell, there may be at least one third part used to form the capsule device. The third part is, for example, a cylindrical or annular element. The first and / or second half capsule shell may be connected to each other at the joining location by a press-fit connection and / or a form connection and / or by gluing or welding.

[0011] The first half capsule shell preferably has a hollow cylindrical wall that is closed at a first end and open at a second end, and the opening is preferably completely surrounded by the material of the hollow cylindrical wall. In this way, the first half capsule shell, and in particular the wall around the opening, remains mechanically stable and provides strength to the capsule device.

[0012] Alternatively and preferably, the hollow cylindrical wall of the first half capsule shell is closed at the first end and open at the second end, the opening being formed as a recess starting at the second end and extending towards the first end, in this manner the size of the opening can be maximized allowing for easy assembly of the pharmaceutical dosage form.

[0013] Preferably, the first half-capsule shell is inserted into the second half-capsule shell at the joining position. Preferably, the second half-capsule shell is inserted into the first half-capsule shell at the joining position.

[0014] Preferably, the cross-section of the opening is dimensioned to accommodate the preparation in the compressed state before joining the first and second half-capsule shells. Preferably, at the joining position, the gap defined by the opening and the wall of the second half-capsule shell has a cross-section dimensioned to prevent the preparation in the compressed state from passing through the gap. The term "cross-section of the opening" refers to the area occupied by the opening in the wall of the first half-capsule shell. The term "cross-section of the gap" refers to the area occupied by the gap within the wall of the capsule device or within the wall of the first half-capsule shell when the walls of the second half-capsule shell intersect or overlap.

[0015] Specifically, the second half-capsule shell may include a second opening or a second indentation that overlaps the opening or indentation of the first half-capsule shell at the joining position. In this way, higher flexibility is obtained for positioning the gap along the length of the capsule device (the length is measured along the axis A passing through the capsule device, specifically the cylindrical axis A).

[0016] Preferably, the size A_o of the cross-section of the gap is a fraction f of the size A_a of the cross-section of the opening, A_o = f * A_a, 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 enable a strip-shaped preparation to be pulled out of the gap.

[0017] Preferably, the gap is a slit-shaped gap configured to allow a strip-shaped preparation to pass through the gap, and the cross-section (CS) of the gap is larger than the cross-section of the strip-shaped preparation when the strip-shaped preparation extends through the corners.

[0018] Preferably, the capsule device is adapted to be suitable for being swallowed by a patient.

[0019] Preferably, the capsule device comprises a weight device that occupies a portion of the hollow space and provides additional weight to the pharmaceutical dosage form. In one embodiment, the weight is located in one of the half capsule shells. Preferably, the weight is located in the second half capsule. Thus, the second half capsule comprises a retaining means, e.g. a notch, for roughly locating the weight in the hollow space of the second half capsule, so that when the capsule is turned upside down, the weight stays in the hollow space of the second half capsule and does not slide into the first half capsule, e.g. due to gravity, e.g. avoiding the weight sliding into the preparation. The notch can be created by pinching the outside of the capsule and curving it inwards.

[0020] The shape of the gap preferably corresponds to the outer contour of the elongated preparation in a plane perpendicular to the longitudinal axis of the elongated preparation. For example, in the case of a strip-shaped preparation, a slit-shaped gap is preferred, and in the case of a string-shaped preparation, a circular gap may be provided, where the gap provides an essentially rectangular passage cross-section and the cross-section of the strip-shaped preparation is also essentially rectangular. In the case of a string-shaped preparation, the gap may provide a circular passage cross-section and the cross-section of the strip-shaped preparation may also be essentially circular. In this way, the movement of the elongated preparation relative to the capsule device is guided by the gap, and the relative positions of the preparation and the capsule device are stable during the extraction of the preparation from the capsule device.

[0021] Preferably, the gap is a slit-like gap configured to allow the strip-like preparation to pass through the gap, and preferably the cross section (CS) of the gap is larger than the cross section of the strip-like preparation when it moves through the corner. Herein, the cross section of the gap defines a surface, the cross section of the strip-like preparation is preferably measured within said surface, and the strip-like preparation is preferably located centrally within the gap.

[0022] The gap distance S of the gap cross section between the elongated preparation and the surface of the capsule device defining the gap is preferably measured when the cross section of the gap and the cross section of the elongated preparation are centered and an imaginary axis A extends lengthwise through the capsule device. The dimension of the gap resulting in the distance S is preferably calculated by the dimension a, which is the diameter or width of the gap, and t, which is the diameter of the string-like preparation or the thickness of the strip of the strip-like preparation, a=t+2*S. See FIG. 1c. S is preferably in the range of 10-2000, or 20-1500, or 50-1000, or 100-750, or 200-500, or 300-400 micrometers (μm), respectively. S is greater than zero, preferably greater than the value t, in particular S=f*t, where f is a numerical coefficient selected from 1-20, preferably 2-15, more preferably 3-12. The dimension 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), respectively.

[0023] In the case of strip-like preparations and slit-like gaps, the length c of the passage cross-section through which the strip-like preparation passes when pulled outwards is greater than the width w of the strip of the strip-like preparation. The passage cross-section is greater than the cross-section of a coplanar elongated preparation.

[0024] Generally, a capsule device is a container configured for buccal or gastrointestinal administration, respectively. In particular, a capsule device is a swallowable object. This in particular means that the dimensions and the outer shape of the capsule device are suitable for swallowing the capsule device. In particular, the dimensions relate to the geometric size of the capsule.

[0025] The first half capsule shell may further comprise a sliding surface configured to guide the second half shell when the first and second half shells are fitted together to form the capsule device, and further, the opening of the first half capsule shell may extend into the sliding surface such that the opening is partially covered by the second half shell when the first and second half shells are fitted together.

[0026] The capsule device may have an elongated shape, meaning that the length measured along an imaginary central axis A of the capsule device is greater than its lateral outer dimension. Without considering clearances, the capsule device may be rotationally symmetric about the central axis A.

[0027] The capsule device may have more than one gap, specifically two gaps or three or more gaps.

[0028] The present invention also relates to a method for manufacturing a capsule device as defined in any of the preceding claims, comprising at least a) providing a first half capsule shell (11, 11') having a hollow cylindrical wall (11c, 11c') with an opening (16, 16') and a second half capsule shell (12, 12'); b) sliding the second half capsule shell (12, 12') and the first half capsule shell (11, 11') into a joining position, where the walls (12b, 12c) of the second half capsule shell (12, 12') overlap a cross-section of the opening (16, 16') of the first half capsule shell (12, 12'), thereby forming a gap (15) of the capsule device at the joining position.

[0029] The term sliding refers to joining or fitting the first half capsule shell to the second half capsule shell, or vice versa, so that both halves reach an overlapping position and preferably form a final gap without the need to further reduce the opening, for example by further fitting or joining the two halves. This may include a locking mechanism, for example meaning mechanical friction of the sliding surfaces constituted by one or both of the two halves. This fixes both halves together and thus does not require any further manufacturing steps to join the two halves together in a manner suitable for application in the dosage form. However, process steps, preferably performed by a machine, may also be required to join the halves in a manner suitable for application, for example by heating or welding, in particular by material bonding.

[0030] Preferably, the method of manufacturing a capsule device comprises: a) providing materials for forming a capsule device, specifically a first half capsule shell and a second half capsule shell; b) creating an opening, particularly a rectangular opening, in the material of the first and / or second half capsule shells.

[0031] For example, in the case of a circular opening, the first and second capsule halves may each have an arc-shaped opening, such that a circle or ellipse is formed by the halves sliding together into a mating position, which is advantageous when preparations having a circular cross-sectional area are used.

[0032] The step of forming the capsule device with a material for forming the capsule device may be applied after the step of creating an opening in the material of the first half capsule shell, or the step of forming the capsule device with a material for forming the capsule device may be applied before the step of creating an opening in the material of the first half capsule device.

[0033] The opening or recess may be created using a workpiece having a suitable shape, for example by a punch tool. The workpiece may be a material for forming the capsule device. In each preferred embodiment, the workpiece may have the shape of a cube, a foil, a hollow cylinder, a capsule, or a capsule half.

[0034] Preferably, the method includes the step of creating an opening in the material of the hollow cylindrical wall of the first half capsule shell and / or the second half capsule shell.

[0035] The openings can be created in the wall material of the first and / or second half capsule shells before forming the actual shell shape, i.e. the openings are created in a two-dimensional material shape and then the shell shape is formed in a further step. Alternatively, the openings are created in the half capsule shells, i.e. the openings are created in the wall material of the first and / or second half capsule shells after forming the actual shell shape, i.e. the openings are created in the three-dimensional material shape that forms the shell in a shape-making step.

[0036] The opening may be created using a laser to cut or peel the material from the capsule material. Furthermore, a punch may be used to create an opening through the capsule material and create a rectangular hole by shearing. However, it may be preferable for the opening to be created by injection molding of a material suitable for forming the capsule device, for example a plastic. The gap preferably has the shape of a planar curved slit. The planar nature of the curved slit provides the advantage that it facilitates the passage of the strip-shaped preparation through the slit in the pulling direction P, thereby further improving the reliability of the mechanical process of unfolding the preparation from the compressed state to the unfolded state. If the opening in the capsule wall material is created by a punch tool, the punched material of the capsule wall can be conveyed from the capsule by a suction device, ideally integrated in the punch tool, for example by pressure suction.

[0037] The capsule device is preferably formed to have an elongated shape and such that a gap cross section (CS) of a gap between the preparation containing the active pharmaceutical ingredient and a surface of the capsule device defining the gap is spaced when the preparation is inserted into a hollow space of the capsule device in a compressed state of the preparation such that an end portion of the preparation extends through the gap and the preparation can be pulled out of the gap. The capsule device is preferably formed to be swallowable by a patient.

[0038] The step of forming the opening may include at least one of the following features. Use of a plane milling tool, e.g. a plane saw blade, or another tool that results in a plate-shaped cut block, e.g. a cylindrical milling head that performs a transverse movement Use of a lateral moving water jet in abrasive water jet cutting processes Use of a laser to cut or peel material from the encapsulant Punching of half capsule shell material to create holes by shearing Injection moulding of suitable material, e.g. plastic, to form the semi-capsule shells

[0039] Forming the capsule device may comprise applying a dip-molding process to manufacture two half capsule shells of the capsule device that are joined to form a capsule, for example essentially as described in EP 0102832. Forming the capsule device may comprise applying an additive manufacturing process to form a capsule from a suitable material, in particular a three-dimensional printing process to form a capsule from a suitable material. Forming the capsule device may comprise injection molding the capsule from a suitable material.

[0040] The capsule device may be a capsule comprising a hollow cylinder capped on both sides by curved cap members. The cap members may have an essentially hemispherical shape. The cap members may be manufactured with a cylindrical portion as one piece. Two parts of the capsule device may be joined to form the capsule device. This facilitates assembling the dosage form by first placing the preparation inside one of the two parts and then joining the two parts of the capsule device to fix the preparation. The capsule may also be shaped with an elliptical or oval cross section, so that the capsule has, for example, an olive shape.

[0041] In a preferred embodiment, the capsule device is configured such that the gap is offset from the central axis A. This means that the central axis A does not intersect the cross section of the gap or that the central axis A does not intersect the center point of the cross section of the gap. The advantage of such an embodiment is that when the preparation is pulled out of the capsule device and the capsule device is administered to a patient, the force acting on the wall of the capsule device is reduced, thereby reducing the risk of damaging the capsule device. In the inventors' experiments, it was found that it is easier to unwind a wound preparation from a gap that is offset from the central axis A than from a central position of the gap (where the central axis A of the capsule device runs through the center of the gap), especially for a strip-shaped preparation.

[0042] In the case of a slit-shaped gap, the gap is preferably positioned offset from the central axis A of the capsule device. The slit is preferably formed by opposing surfaces of the walls forming the capsule device.

[0043] For example, if one considers the first half capsule shell and the cut mass as three-dimensional mathematical objects, the preferred shape of the slit is achieved by first preparing the opening by milling the cylindrical wall forming the first half capsule shell, thereby removing a plate-shaped mass from the wall. The orientation of the plate-shaped mass removed from the capsule material is specifically characterized by the orientation of the major plane of the plate-shaped mass relative to the direction of an imaginary central axis A of the capsule device.

[0044] The hollow space within the capsule device is defined by at least one interior wall of the capsule device, specifically the first and second half capsule shells.

[0045] 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) run parallel to each other. This means that the outer contour surface of the hollow space is similar to the outer contour surface of the capsule device. However, it is also possible and preferred that the inner surface of the capsule device is not at least partially parallel to the outer contour surface of the capsule device. Such a configuration allows for the definition of ancillary structures within the capsule device, which serve to guide the movement of the preparation within the capsule device or other functions.

[0046] Preferably, the accessory structure is an inner guide wall of the capsule device arranged to guide the unrolling and / or unwinding of the preparation in the capsule device. The guide wall is arranged to guide the positioning of the preparation during unrolling and / or unrolling of the preparation. The guide wall may be arranged parallel to the movement direction P in which the preparation moves in the capsule device towards the gap. Preferably, the guide wall is arranged to be aligned with the gap. For example, the guide wall is preferably parallel to the longitudinal orientation of the gap, i.e. parallel to the Y direction as defined in FIG. 1a. The guide wall may also be realised by a protrusion in the region of the inner wall of the capsule device. In this case, the preparation is arranged to unroll through the gap. Such a protrusion of the wall of the capsule device, or a cutout as seen from the outside of the capsule device, can serve to guide the preparation during unrolling, for example by the inner part of the rolled preparation, i.e. the core, being mechanically supported by the protrusion, in particular being able to rotate during the unrolling operation of the preparation.

[0047] Preferably, one or more inner walls of the capsule device are arranged to form a guide compartment within the capsule device, the guide compartment being arranged to support the compressed preparation and aid in unrolling the preparation. Preferably, one or more inner walls of the capsule device are arranged to form side walls of a cubic hollow space that contains the compressed preparation.

[0048] Preferably, the capsule device includes a guide member. The guide member is disposed in the inner space of the capsule device and guides the movement of the string-like or sheet-like preparation toward the gap of the capsule device. The guide member may be a part of the inner wall of the capsule device, or a part supported by or connected to the inner wall of the capsule device, specifically a wall member. For example, the guide member may be a guide lip or a guide spout disposed on one side of the edge of the gap, or may be attached to the entire periphery of the gap or opening.

[0049] Preferably, the capsule device may include an attachment structure configured to guide the rolling and / or unrolling of a string of preparation or the rolling and / or unrolling of a strip of preparation, particularly by rolling or winding the preparation around one or more rods or cylinders of the attachment structure. The rods or cylinders may be rotatably disposed within the capsule device to facilitate rolling or unwinding.

[0050] In another preferred embodiment, the capsule device and the pharmaceutical dosage form each comprise a weight device. The weight device is configured to provide a negative buoyancy to the capsule device. In the inventors' experiments, which are the basis of the findings of this preferred embodiment, it was found that reducing the buoyancy, for example by increasing the mass of the capsule device, leads to an improvement in the swallowability of the capsule device, i.e., an improvement in the reliability of the mechanical process of unrolling the preparation from a compressed state to an unrolled state. In the case of a strip-shaped preparation, it becomes considerably easier and more efficient to unroll the preparation from a compressed state to an unrolled state, in which the strip-shaped preparation is wound around a winding axis. For example, such weights are described in WO2020 / 183005.

[0051] The present invention also relates to a pharmaceutical dosage form comprising a capsule device as defined herein, the pharmaceutical preparation having an elongated shape, containing one or more active pharmaceutical ingredients, and capable of being placed in a compressed and expanded state.

[0052] The present invention also relates to a method for producing a pharmaceutical dosage form, the method comprising the steps of a method for producing a capsule device according to the invention, further comprising: a) providing a preparation having an elongated shape and comprising one or more active pharmaceutical ingredients; b) providing a first half capsule shell and a second half capsule shell having a hollow cylindrical wall including an opening; c) placing the preparation, preferably in a compressed state, in the first half capsule shell through the opening such that a portion or end of the preparation extends through the opening; d) sliding the second capsule half shell over the first capsule half shell into joining position, or sliding the first capsule half shell over the second capsule half shell into joining position, until an opening forms a gap in the capsule device at the joining position of the first and second capsule half shells, thereby reducing the cross-section of the opening while an end of the preparation extends through the opening.

[0053] Preferably, the method comprises the steps of: After step a) or step b) of the method for producing a pharmaceutical dosage form, the method comprises the steps of providing a rotating shaft (X), preferably positioning the rotating shaft (X) in front of the opening or within the cross section of the opening, and rotating the rotating shaft until the preparation reaches a rolled and compressed state, thereby preferably rolling the preparation in an elongated state using the opening to guide and / or align the preparation. In this way, any problems with unrolling the preparation before reaching the inside of the capsule can be reduced or eliminated, since the compressed form of the preparation is formed in the opening and inside the first half capsule device.

[0054] Preferably, the method for producing a pharmaceutical dosage form comprises: After step b) or c) of the method of producing the pharmaceutical dosage form, the method may include disposing a weighting device in at least a portion of the hollow space of the first and / or second half capsule shell, the weighting device providing additional weight to the pharmaceutical dosage form, which may in particular facilitate swallowing of the pharmaceutical dosage form.

[0055] Preferably, any of the method steps, particularly the loading of the compressed form preparation into the first half capsule shell, are preferably performed automatically by machine to produce multiple pharmaceutical dosage forms in parallel, thereby increasing the throughput of producing a large number of pharmaceutical dosage forms per hour.

[0056] The step of placing or housing a preparation having an elongated shape and containing an active pharmaceutical ingredient in a compressed state of the preparation in a hollow space of the capsule device and extending an end portion of the preparation through the gap includes a gap and the preparation configured such that when the preparation is pulled out of the gap, a gap cross section (CS) of the gap between the preparation and a surface of the capsule device defining the gap is spaced.

[0057] The step of placing the preparation is preferably performed by placing the preparation in the first part or first half capsule shell and preferably thereafter extending an end portion of the preparation through the gap and connecting the second part or second half capsule shell to the first part or first half capsule shell. The first part or first half capsule shell and the second part or second half capsule shell may be a pipe element or a capped pipe element, respectively, or a cylindrical section, in particular a half-cylindrical element.

[0058] 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, the applicator being in fluid connection with the drinking cup and containing the pharmaceutical dosage form, the pharmaceutical dosage form preparation being connected to said applicator by a retainer for withdrawing the preparation from the capsule device after administration to the patient.

[0059] The capsule device and pharmaceutical dosage form comprising the pharmaceutical preparation according to the present invention are particularly suitable for application to mucous membranes, particularly buccal or gastrointestinal mucosa, in particular mucous membranes in the upper gastrointestinal tract, such as the throat, esophagus, cardia, and / or stomach. Pharmaceutical dosage forms comprising the pharmaceutical preparation and their application are described in WO 2016 / 102067, which is incorporated herein by reference in its entirety. In particular, in relation to the shape, size, and (chemical) composition of the capsule device and pharmaceutical preparation, active pharmaceutical ingredients, and treatment and prevention methods of certain conditions and diseases already disclosed therein. Thus, in other words, the chemical components of the capsule device and pharmaceutical preparation are described at least to a considerable extent in the above references. This also applies to capsules.

[0060] Advantageously, the pharmaceutical dosage form of the present invention allows for increased bioavailability of the active pharmaceutical ingredient at a given site of action.

[0061] The pharmaceutical dosage form of the present invention is capable and adapted to rapidly release pharmaceutical preparations in the form of strings or strips, in particular in the form of sheets, films, foils or wafers, containing active pharmaceutical ingredients having a systemic effect at a desired site of action.Furthermore, the pharmaceutical dosage form according to the present invention allows the application to a desired site of action of active pharmaceutical ingredients that cannot be administered orally due to their low bioavailability.

[0062] The preparations in the form of strings or strips, in particular in the form of films, foils or wafers, containing an active pharmaceutical ingredient may comprise a monolayer structure or a multilayer structure with several layers. In the case of a multilayer structure, a first layer may contain a first active pharmaceutical ingredient and a second / further layer may contain at least a further active pharmaceutical ingredient. This allows, for example, the application of two pharmaceutical ingredients that are not compatible with each other as such.

[0063] Preferably, the preparation is made mucoadhesive to allow targeted release of the active ingredient. This can be achieved by providing a single layer that not only contains the active pharmaceutical ingredient but is also mucoadhesive, or by providing the preparation in multi-layer form, at least one, preferably the outermost layer, is mucoadhesive.

[0064] In a preferred embodiment, the pharmaceutical dosage form according to the invention is adapted to be administered orally.

[0065] The capsule device is made of or consists essentially of a material that is essentially insoluble in the fluids present along the route of delivery of the capsule device to the site of administration, specifically the gastrointestinal tract. Such materials are known in the art and are described in WO 2016 / 102067. Specific examples include known gastric juice-resistant polymers, such as polymethacrylic acid (Eudragit), HPMCAS, shellac, gelatin, and the like. These may be formulated with known additives that improve processability, such as plasticizers, flavors, and flavorings.

[0066] The preparation is diagnostic substances, such as dyes or stains, painkillers, preferably NSAIDs, such as ibuprofen or flurbiprofen; local anesthetics, such as benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, or novocaine; Antibiotics, such as penicillin, amoxicillin or vancomycin; disinfectants, such as 2,4-dichlorobenzyl alcohol, amylmetacresol or cetylpyridinium chloride; steroids, such as corticosteroids, glucocorticoids, fluticasone, budesonide, clocortolone, perdesonide, hydrocortisone, clobetasone butyrate, flumethasone, fluprednidene, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone-17-butyrate, triamcinolone acetonide, amcinonide, betamethasone-17,21-dipropionate, betamethasone-17-valerate, desoximethasone, diflucortolone-21-valerate, fluocinolone acetonide, fluocinonide, fluticasone-17-propionate, methylprednisolone aceponate, mometasone furoate, prednylcarbate, or clobetasol-17-propionate; Parasiticides, also called parasizides, such as mebendazole, albendazole, thiabendazole, diethylcarbamazine, diaminodiphenylsulfone, benznidazole, ivermectin, pyrantel, praziquantel, Fungicides, such as nystatin, imidazoles, triazoles, thiazoles, clotrimazole, ketoconazole, or undecylenic acid; Hexamethylpararosaniline chloride, amphotericin B, botulinum toxin, sucralfate, nitric oxide or nitric oxide formers such as isosorbide dinitrate or nitroglycerin, furanocoumarins, benzoic acid, citric acid, lactic acid, pH buffers, antacids, calcium carbonate, magnesium carbonate or aluminum carbonate The pharmaceutical compositions contain at least one active pharmaceutical ingredient selected from the group consisting of:

[0067] Additionally or alternatively, the preparation may contain, inter alia, an inflammatory regulator, such as montelukast, an interleukin receptor, or an interleukin antibody. Additionally or alternatively, the sheet-form preparation may contain, inter alia, beclomethasone dipropionate, budesonide, or ciclesonide, which are particularly advantageous for the treatment of asthma. Additionally or alternatively, the sheet-form preparation may contain, inter alia, mesalazine, sulfasalazine, or olsalazine, which are particularly advantageous for the treatment of inflammatory bowel disease.

[0068] The active pharmaceutical ingredient contained in the sheet-like preparation of the pharmaceutical dosage form according to the present invention may be selected from the group including proteins and peptides, specifically insulin, buserelin, desmopressin, calcitonin, and estrogen, and drugs produced by biotechnology, such as antibodies, for example, rituximab. It should be understood that proteins and peptides, specifically insulin, buserelin, desmopressin, calcitonin, and estrogen, may show low bioavailability under certain circumstances, specifically low oral bioavailability, and therefore are promising candidates for the application of the dosage form according to the present invention.

[0069] Substances from the groups of drugs acting on the skeleton 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 the sensory organs, dermatological drugs, vitamins and micronutrients, peptide drugs and proteins, analgesics, anti-infectives and parasiticides may be used as active pharmaceutical ingredients.

[0070] In one embodiment, the active ingredient is selected from corticosteroids, illustratively including budesonide, mometasone, fluticasone, and ciclesonide, and pharma- ceutically acceptable salts thereof.

[0071] Exemplary conditions to be treated include conditions relating to the gastrointestinal mucosa, preferably the esophagus, such as GERD, NERD, and eosinophilic esophagitis, which are particularly well treated with the above-mentioned groups of steroids and the mentioned nitric oxide or nitric oxide forming agents.

[0072] The pharmaceutical preparations contain an amount of the active pharmaceutical ingredient known to be effective for the condition to be treated, depending on the site of administration and the active ingredient, e.g., the concentration / amount of budesonide in the dosage form is considerably higher compared to mometasone-containing dosage forms.

[0073] Additionally or alternatively, in certain embodiments of the capsule device according to the invention, the string or strip preparation is adapted to dissolve, e.g. biologically denature, preferably in a time-controlled manner, e.g. within 1 hour, or within 1-2 hours, or within 1-5 hours, or within 1-12 hours, or within 1-24 hours, thereby improving user convenience, since there is no need to remove the sheet preparation.

[0074] The method for preparing the preparation containing these active ingredients is not particularly limited and is known to those skilled in the art. Furthermore, in relation to the pharmaceutical dosage form of the present invention, reference is made to WO 2016 / 102067.

[0075] Specifically, the preparation in the form of a string or strip can be prepared by a person skilled in the art by basically known methods, for example by coating an inert support with a liquid composition comprising a polymer, an active pharmaceutical ingredient, and optionally additives, and a solvent, for example by a method involving a doctor blade, a spray processor, or an extrusion processor.The thin film layer thus obtained is dried.In the preparation in the form of a multi-layered sheet, one or more coatings can be applied to an existing film layer in the same manner, or can be produced separately and then laminated.

[0076] The shape of the gap preferably corresponds to the outer contour of the elongated preparation in a plane perpendicular to the longitudinal axis of the elongated preparation. For example, in the case of a strip-shaped preparation, a slit-shaped gap is preferred, and in the case of a string-shaped preparation, a circular gap may be provided, where the gap provides an essentially rectangular passage cross-section and the cross-section of the strip-shaped preparation is also essentially rectangular. In the case of a string-shaped preparation, the gap may provide a circular passage cross-section and the cross-section of the strip-shaped preparation may also be essentially circular. In this way, the movement of the elongated preparation relative to the capsule device is guided by the gap, and the relative positions of the preparation and the capsule device are stable during the extraction of the preparation from the capsule device.

[0077] Preferably, the string-like or strip-like preparation is bendable, in particular so that it can be transformed from a compressed form to an expanded form by a folded, disassembled, rolled, rolled or coiled sheet-like preparation, which may preferably have a string-like, cord-like, strip-like or tubular shape. For example, such a sheet-like preparation is exemplarily described in WO 2020 / 183005.

[0078] In a preferred embodiment of the capsule device, the preparation is expandable from a compressed form to an expanded form in order to extract the preparation stored in the capsule from the hollow space of the capsule to the surrounding area of ​​the capsule device. The preparation is therefore preferably provided with a retaining device. When the retaining device is fixed, the preparation can be extracted from the capsule device by a pulling action and / or a pulling force. The fixing of the retaining device is preferably obtained by connecting the retaining device to a fixing device. Such a fixing device may be a string member, e.g. a cord, a string, a rope. In that case, the fixing device for example prevents the retaining device from moving together with the capsule device, thereby generating a pulling force. The fixing is for example achieved by connecting the retaining device to one end of a cord and fixing the other end of the cord to an applicator. Thus, when the cord of the fixing device is subjected to a pull by moving the capsule from the applicator, the retaining device establishes a pulling force, whereby the preparation is extracted from the capsule device. If the retaining device is preferably part of the preparation or attached to the preparation, the retaining device may be a handle, a sling or an adhesive tape, or may include an adhesive area. The retaining device is adapted to strengthen and maintain a connection capable of transmitting forces between the retaining device and the area to which it is attached. Moreover, this connection may be strengthened or maintained while the dosage form and / or the sheet-like preparation is in a compressed and / or expanded form. Preferably, the retaining device, and possibly further parts, may be held at a defined position or area by a force fit, in particular by frictional engagement, form-fitting or material engagement, in particular by mucoadhesion, preferably adhesive. For example, such a retaining device is described in WO 2016 / 102067.

[0079] The term "compressed form" as used herein preferably refers to a folded, rolled, rolled, coiled or disassembled form.Specifically, in compressed form, the string-like or strip-like preparation has a smaller spatial extent and / or exposes a smaller amount of surface than in non-compressed form, specifically in uncompressed form.Preferably, the string-like or strip-like preparation in compressed form is folded, disassembled, rolled, rolled, coiled, pressed, packed together or otherwise made into a smaller form.Specifically, when in compressed form, the string-like or strip-like preparation can have a certain size or spatial extent.

[0080] The term "unfolded form" as used herein preferably refers to an unfolded form, an unfolded form, an unfolded form, an elongated form, an extended form, or a rectangular form. Specifically, in unfolded form, the string-like or strip-like preparation has a larger spatial extent and / or exposes a larger amount of surface than in unfolded form, specifically in compressed form. Preferably, the string-like or strip-like preparation in unfolded form is unfolded, unfolded, unrolled, stretched, unfolded, elongated, stretched, unfolded, or otherwise made into a larger form. Specifically, when in unfolded form, the string-like or strip-like preparation can have a predetermined size or spatial extent. Alternatively, the size or spatial extent of the string-like or strip-like preparation depends on the existing conditions and the site of action or application, and therefore may not be predetermined.

[0081] In a particularly preferred embodiment, the preparation is wrapped around the outside of the capsule device. In such a case, it is intended, for example, to place the preparation in compressed form in a first half capsule shell and only afterwards to connect the second half capsule shell to the first half capsule shell to form the capsule device.

[0082] However, alternatively, the preparation is wound inside the capsule device. When wound inside the capsule device, the preparation is advantageously provided in an unfolded state from outside the preparation and is fed into the capsule device during rolling, for example through an opening and / or a gap in the capsule device. In such a case, the capsule device is preferably provided with a first half capsule shell having a hollow cylindrical wall including an opening, and the wall of the second half capsule shell overlaps the cross section of the opening. However, the two halves do not necessarily overlap so that the gap is ultimately formed. Alternatively, the wall part used to cover the opening and form the gap is preferably provided after the completion of the rolling, not during.

[0083] Preferably, the rolling of the preparation is performed mechanically, for example by means of a winding device or winding unit. Alternatively, the preparation can be rolled manually. During manual and mechanical rolling of the preparation, an end section of the preparation is clamped, for example between two holding jaws, or, if an essentially continuous preparation is used, a section of the preparation is clamped and the part outside the clamped section is cut off, whereby the clamped section of the preparation forms the end section of the rolled preparation. More illustratively, the clamped section of the preparation is braided into a fork or U-shaped end of a winding pin, whereby the preparation is rolled around the pin end by rotating the pin. The pin around which the preparation is wound is then placed, for example through an opening, in the capsule device, and the pin is pulled out of the rolled preparation. In a particularly preferred embodiment, the rolled preparation is placed into the first half capsule shell through the opening.

[0084] Alternatively, the preparation is fed in an unfolded state into the pressing chamber by a conveyor, e.g. a conveyor belt. A number of surfaces, preferably rotating in a common direction, are arranged in the pressing chamber, which rotate the pulled, but not yet folded, preparation. Furthermore, the rotational movement of the preparation can be assisted by rollers. The principle is similar to that of a hay baler. The rotational movement of the rotating surfaces in the pressing chamber is transmitted to the preparation, which then undergoes a rotational movement itself and thus begins to be rolled up. As soon as the preparation has a predetermined size and / or weight, the rotational movement stops and the rolled preparation is pushed out of the pressing chamber, e.g. directly into the opening of a capsule device.

[0085] The machine that rolls the preparation into a compressed form has a scale, which allows the amount of active substance contained in the preparation to be determined by measuring the weight during the rolling process, or by measuring the weight of a section of the preparation to be rolled. Alternatively, a device can be used that measures the length, or width, or thickness, or any combination of these quantities, such as the volume, of the part of the preparation to be rolled. In a further alternative, it should be possible to determine the concentration of the active ingredient of the preparation in the compressed state.

[0086] The invention also relates to a machine for producing pharmaceutical dosage forms according to the invention, in particular by carrying out the method of the invention, which machine comprises a positioning device for positioning a first half capsule shell in a mounting position.

[0087] The connecting device has a movable element configured to connect the second half capsule shell and the first half capsule shell at a joining position by moving the first half capsule shell and the second half capsule shell towards each other, whereby a wall of the second half capsule shell overlaps the opening cross-section by an amount controlled by the movement of the movable element, thereby forming a gap in the capsule device at the joining position.

[0088] The positioning device preferably comprises one or more holding members for holding one or more of the first and / or second half capsule shells in a fixed position. The holding member preferably comprises a fixing space shaped to fix the first and / or second half capsule shells by form-fitting. The positioning device, in particular the holding member, may be configured to hold a plurality of the first and / or second half capsule shells in a fixed position in parallel. In this way, the throughput of the manufacturing method can be increased. A positioning device may be provided for positioning one or more of the first and / or second half capsule shells in two or more mounting positions. Thereby, several manufacturing steps of the pharmaceutical dosage form can be performed in parallel using a plurality of mounting positions, in particular working stations.

[0089] The positioning device preferably comprises a movable platform carrying one or more work stations. The work stations preferably comprise at least one or more holding members. The movable platform may be rotatably arranged on a base member rotating about an axis configured to rotate the respective work stations to the work positions of the manufacturing machine. At the first work position a feeder may be arranged for providing at least one first half capsule shell to at least one mounting position provided by at least one holding member. At the second work position a feeder may be arranged for providing at least one second half capsule shell to at least one mounting position provided by at least one holding member. At the third work position a mounting device may be arranged for mounting the preparation, preferably in a compressed state, on the first half capsule shell. The mounting device may comprise a conveying device, possibly for conveying at least part or the whole of the preparation to the mounting position, and / or a compressing device, particularly a winding device, for transitioning the preparation from an elongated state to a compressed state, particularly a rolled or rolled state. At the fourth work position a receiving station may be provided for receiving the prepared manufactured pharmaceutical dosage form and possibly for sending the pharmaceutical dosage form to a storage or conveyor system.

[0090] Preferably, the manufacturing machine comprises a conveying device for conveying an end of the preparation having an elongated shape and comprising an active pharmaceutical ingredient from a preparation storage location to a mounting location, where the preparation is arranged to be inserted into a hollow space of the first half capsule shell in the mounting location, in particular through an opening. In a preferred embodiment, the conveying device comprises a rotatable conveying member configured to receive at least a part of the preparation or the entire preparation at the first location, in particular from a preparation storage device, and convey said part of the preparation to the mounting location by rotating. The rotatable conveying member may be a rotatable rod member or a disk member. The movement or rotation of the conveying device may be controlled by an electronic control device of the manufacturing machine. The manufacturing machine and / or the rotatable conveying member comprises a winding device for winding the preparation from an elongated state to a compressed position. The rotatable conveying member may comprise a winding device for winding the preparation in an elongated state to form a wound state. The winding device may comprise one or two or more rotatable shafts configured to be electrically driven and controlled by an electronic control device of the manufacturing machine. One or two or more rotatable shafts may be arranged at a position offset from the axis of rotation of the rotatable conveying member. The rotatable conveying member and / or the winding device are configured to wind up the preparation in an elongated state in the mounting position, in particular when the rotatable shaft is arranged in front of or within the opening, so that forming of the preparation in a compressed state may take place in the compressed position when the first half capsule shell is in the mounting position. This is preferably arranged in front of or even within the opening, thereby at least partially directly inside the hollow space of the first half capsule shell. This significantly facilitates the transfer of the preparation into the capsule. The winding of the preparation is preferably performed by means of a winding pin. The winding device therefore preferably comprises a winding pin.

[0091] Preferably, the manufacturing machine and / or the conveying device includes a compression device, in particular a winding device, for winding the preparation from an elongated state to a compressed position, or a folding device for folding the preparation from an elongated state to a compressed position, the compression preferably being performed in the compression position of the manufacturing machine.

[0092] Preferably, the machine comprises a cutting device for cutting the preparation inserted into the hollow space of the first half capsule shell to form the preparation.

[0093] Preferably, the machine comprises an actuator for moving the compressed preparation from the compression position to a final position within the hollow space of the first half capsule shell.

[0094] Preferably, the machine further comprises a pressing device for pressing the weighting material, e.g. a powder, to obtain a weighting device. Preferably, the pressing device is configured to feed the obtained weighting device to a further processing device for producing the pharmaceutical dosage form.

[0095] In one embodiment, an applicator may be used for administration, which aids in swallowing the capsule device in combination with a drinking cup. For example, such an applicator is described in WO 2020 / 183003. This is particularly advantageous when the dosage form is administered on a regular basis, in particular daily, since administration of the capsule device is possible without professional assistance.

[0096] The applicator comprises a housing configured to accommodate the capsule device and a capsule retainer. The applicator preferably further comprises 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 arranged between the drinking cup and the applicator. The spacer thereby reduces the risk of moisture from the drinking cup, for example, before residual moisture in the drinking cup gets into the applicator, rendering the dosage form unusable before use. The spacer preferably has a tube shape or has an annular shape and is preferably screwed onto the opening of the applicator and the drinking cup, respectively, after the corresponding cap is removed. The spacer preferably has a length of 1-10 mm, preferably 2-8 mm, most preferably 5 mm.

[0097] The present invention also relates to a retainer. The retainer is part of the applicator in that the applicator further comprises a retainer. In a preferred embodiment, the retainer consists of or comprises a string element. The retainer is wound around the capsule-holding device. The capsule-holding device thus comprises a wall structure. The retainer is preferably attached to or fixed to the capsule-holding device, so that the retainer can transmit forces, e.g. mechanical traction forces, to the capsule-holding device and thus to the applicator. The retainer is preferably made of or comprises a thread, or fiber, or string, or twisted thread, having a first end and a second end. The retainer is connected at its first end to one end of the preparation, e.g. the holding device of the preparation, which extends through the gap of the capsule device. The retainer is connected at its second end to the capsule-holding device of the applicator, e.g. the wall structure of the capsule-holding device. When the retainer is connected to the preparation, it unwinds from the capsule-holding device when the capsule moves from the applicator and the retainer is subjected to tension. When the patient swallows the capsule, the capsule moves away from the capsule retainer, thereby unwinding the retainer from the capsule retainer. As the patient swallows the capsule, the retainer will at some point completely unwind from the capsule retainer, increasing the tensile stress, which will pull the preparation out of the capsule. Thus, advantageously the retainer, e.g. the string member, allows for the release of the active pharmaceutical ingredient, particularly to the mucous membrane surrounding a rather small lumen or cavity, e.g. the esophageal cavity or the nasal cavity.

[0098] Prior to use of the applicator, the retainer is wrapped around the wall structure of the retainer. Wrapping the retainer around the retainer prevents knots from forming in the retainer. Once the patient swallows the dosage form, the retainer is unwound from the retainer.

[0099] Winding the fastener around the structure of the holding device and / or bonding the fastener to the preparation, e.g. a string containing the preparation, or a holding device for the preparation, is preferably carried out by a machine, e.g. a winding machine and / or bonding machine, in particular in the bonding area of ​​the machine.

[0100] In a first step of winding the fastener around the holding device, the fastener is mechanically fixed to the machine and for example clamped by the support jaws. In a second step, the fastener is tensioned. In a third step, the fastener is placed along the tensioned fastener (meaning the mechanical clutch) and the fastener is clamped in a groove in the wall structure of the holding device. In a fourth step, the support jaws that clamp the fastener are opened. In a fifth step, the holding device is rotated by rotating the clutch that fixes and supports the holding device, thereby winding the fastener around the holding device. A rotational movement of the coupling is superimposed on a vertical translational movement, whereby the fastener is wound around the holding device in a parallel position. In a sixth step, the support jaws clamp the fastener again and in a seventh step, one end of the fastener is cut off by a knife-like part of the machine and connected to the preparation in a further step. In an eighth step, the retainer around which the fastener is wound is placed, in particular by a machine, over an opening in the applicator housing, which opening is preferably pressed onto an axis extending through the housing placed in the machine, for example an auxiliary tube, and the cut end of the fastener is placed over one end of the preparation, which is subsequently pulled out of the capsule.

[0101] In a ninth step, the fixture is coupled to one end of the preparation at a clamp coupling region. As described, the fixture can be wound around the holding fixture by rotating the holding fixture about the winding axis, or alternatively, the fixture can be rotated around the fixed holding fixture to wind the fixture.

[0102] In a preferred embodiment of the applicator, the cap of the applicator, which is removed before use to cover the opening of the applicator and allow the dosage form to exit the applicator body, includes a lid and a number of springs configured to press the support element against the capsule, which preferably touches one end of the capsule placed in the holding device, which preferably faces the cap. For example, the cap is similar to a cap for an effervescent tablet.

[0103] Thus, in a preferred embodiment, the capsule is placed vertically in the holding device and the support element is pressed towards one end of the capsule that faces the lid. The lid preferably further comprises a desiccant, for example to prevent humidity from rendering the dosage form unusable during storage.

[0104] The springs can be made of plastic or any elastic material, so that when the springs apply pressure to the support element, they mechanically secure the capsule in the holding device by forcing the support element towards the capsule surface. The support element preferably has a shape complementary to the contour of the capsule, such that the contour of the capsule fits into the support element.

[0105] In a preferred embodiment, the pharmaceutical dosage form comprises a pharmaceutical preparation for application to a mucous membrane, preferably the mucous membrane of the esophagus, and a capsule device comprising a weight, the preparation being connected to a retainer of an applicator configured to withdraw the preparation when the dosage form is swallowed, after which the retainer dissolves after a period of time in the mouth, the preparation adhering in particular to the mucous membrane of the esophagus, and the weight and capsule device dissolving in the stomach.

[0106] In a preferred embodiment, the pharmaceutical dosage form is manufactured, connected to a retainer and loaded into an applicator by the following process steps.

[0107] In a first step, a capsule device is inserted into the machine by an insertion case, the capsule device including first and second half capsule shells joined by overlapping the first half capsule shell and the second half capsule shell at a joining location.

[0108] In a second step, the second half capsule shell is grasped by an insertion case and separated from the first half capsule shell, and the applicator housing is placed in the machine.

[0109] In a third step, the piston moves the first half capsule shell towards the punch tool, whereby the insertion pin of the punch tool enters the hollow, in particular the cylindrical hollow of the first half capsule shell, so that the insertion pin holds the first half capsule shell, whereby a part of the punch tool moving transversely to the movement direction of the insertion pin punches an opening and / or a recess out of the wall of the first half capsule shell.

[0110] In a fourth step, the insertion pin is pulled out of the hollow of the first half capsule shell. The first half capsule shell is positioned such that the punched opening is preferably facing the applicator housing. The punch tool conveys the material punched from the capsule wall out of the first half capsule shell using negative pressure.

[0111] In a fifth step, the preparation is clamped between two holding jaws and stretched slightly by increasing the distance between the two clamping jaws. On one side of one of the two holding jaws, the preparation extending beyond this holding jaw is cut flush with the holding jaw, thereby creating a cut end of the preparation while it is still stretched. This cut end of the preparation serves as a starting point for winding the preparation. Thus, a winding mandrel is passed through the preparation stretched between the two jaws. One of the holding jaws used for cutting is opened, as the end portion of the preparation is now also held by the winding mandrel. After or while opening the jaw, the winding mandrel rotates so that the cut end of the preparation already clamped by the holding jaw is wound on the winding mandrel, thereby creating the first winding.

[0112] In a sixth step, the other of the two holding jaws is opened and the winding mandrel rotates. In this process, further preparations are wound on the rotating winding mandrel. After a certain length of preparation is wound, the rotational movement of the winding mandrel is stopped. This length is preferably determined so that an end section of the preparation is not wound, i.e. the preparation is not completely rolled up. This end section of the preparation is used to connect the preparation to a fixture, i.e. the end section of the fixture.

[0113] In a seventh step, the preparation wound on the winding mandrel is placed in front of the punched opening in the first half capsule shell. The wound preparation can also partially protrude into the punched opening or recess. The unwound end section of the preparation is left outside the first half capsule shell.

[0114] In an eighth step, the winding mandrel is pulled from the rolled preparation and the rolled preparation is disposed inside the first half capsule shell through the opening in the first half capsule shell by mechanically forcing the rolled preparation into the first half capsule shell through the opening.

[0115] In a ninth step, the insertion pin is moved into the first half capsule shell, specifically into the hollow cylindrical opening, and the rolled preparation placed in the first half capsule shell in step 8 is positioned deeper into the first half capsule shell. The end section of the unrolled preparation is placed into the docking area of ​​the machine.

[0116] In a tenth step, the fastener is configured to be wrapped around a holding device of the applicator. Also, step 10 can be performed simultaneously with, earlier than, or after other manufacturing steps. To wrap the fastener around the holding device, the fastener is mechanically fixed to the machine by a clamping and cutting unit. The clamping and cutting unit includes clamping jaws between which the fastener can be clamped to provide tension to the fastener. The clamping and cutting unit further includes a cutter to cut the fastener and the guide block to ensure a smooth cut of the fastener. In a tenth step, the fastener is tensioned by moving the clamping jaws.

[0117] In an eleventh step, the retainer is placed in a winding unit and placed alongside the tensioned fastener, and the fastener is attached to the wall structure of the retainer, such that as the retainer rotates, the fastener is wound around the retainer.

[0118] In a twelfth step, one of the clamping jaws of the clamping and cutting unit is opened so that the fastener can be guided and slid through the clamping jaw for winding, while the other clamping jaw of the unit, which further includes a cutter, remains closed.

[0119] In a thirteenth step, the winding unit starts to rotate by rotating the clutch that holds and supports the holding device, thereby winding the holding device around the holding device. Ideally, a rotational motion is superimposed on a vertical translational motion, thereby winding the holding device around the holding device in a parallel position.

[0120] In a fourteenth step, after a predetermined length of the fastener has been wound around the holding device, the clamping jaws of the winding unit further clamp the fastener, so that it remains clamped by the clamping jaws of the winding unit even when the fastener is cut by the cutter of the still closed clamping jaws of the clamping and cutting unit. The fastener is then cut by the cutter. However, the fastener is not cut directly by the clamping jaws of the winding unit, but away from said unit. Thus, after cutting, a short section of the fastener still remains outside the clamping jaws of the winding unit. This short section of the fastener is used to connect the fastener to the preparation in a further processing step. The winding unit further comprises a robotic gripper.

[0121] In a fifteenth step, the robot gripper of the winding unit transports the holding device (with the fastener wound around it) and the fastener (clamped at one end by the clamp jaws of the winding unit) to the machine part on which the first half capsule shell is positioned and on which the housing of the applicator rests. The robot gripper positions the holding device on the axis by pushing it on the axis that is located inside the housing. In doing so, the holding device is pushed on the axis only to such an extent that a short section of the fastener used to connect the fastener with the preparation can be positioned in a joining area that is located outside the housing. The joining area extends through the opening of the first half capsule shell when both half shells are joined in the joining position, i.e. extends through the gap of the capsule device, and further includes an end section of the unwound preparation.

[0122] In a sixteenth step, the fixture and / or the preparation are moistened, preferably by means of a nozzle of a sprayer. Moistening takes place in the bonding area.

[0123] In a seventeenth step, the fixation device is pressed against the preparation by the stamp in order to connect the preparation to the fixation device, the connection being made such that a pulling force can be transmitted between the fixation device and the preparation.

[0124] In the 18th step, weights are produced and inserted into the second half capsule shell. Also, step 18 can be performed simultaneously with other production steps, earlier or later. The weights are preferably pressed from the powder by using a press pin. A robotic rotating arm can move to the powder, pick up a predetermined amount of powder and press the powder. The robotic rotating arm then moves from the powder and rotates above the second half capsule shell. Here, the pressed powder is preferably inserted directly into the second half capsule shell as a weight. The step of producing the weights can be performed independently from the other processing steps. That is, the weights can be produced prior to or in parallel with further processing steps, and the robotic arm can only grip the finished pressed weight or the weight produced in another way. It is also conceivable that there are no weights in the capsule device at all and the 18th process step can be omitted.

[0125] In a nineteenth step, the second half capsule shell is placed above the first half capsule shell by the insert case, with or without a weight. After the capsule halves are resting on top of each other, the second half capsule shell is pressed from the insert case onto or into the first half capsule shell, thereby obtaining a pharmaceutical dosage form in which the second half capsule shell has a wall that overlaps with the cross section of the opening, thereby forming a gap in the capsule device at the joining location. The end section of the preparation is then unrolled and extends from the gap into the joining area and connected to the end section of the fastener.

[0126] In a twentieth step, the capsule device of the pharmaceutical dosage form is grasped using a grasping tool, positioned on the retainer, and then placed into the retainer.

[0127] In a twenty-first step, the housing is pushed towards and onto the retainer. An end cap is placed onto the housing, thereby closing the housing containing the retainer now wrapped around the retainer and the pharmaceutical dosage form disposed within the retainer, while connecting the end section of the retainer to the end section of the preparation, such that the retainer is completely unwound and pulls the preparation from the capsule device, e.g., when the patient swallows the dosage form.

[0128] 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 of a pharmaceutical dosage form according to the invention can be understood from the description of the invention and its embodiments, as well as the description of the embodiments by the drawings.

[0129] Exemplary embodiments of the invention are described in more detail below with reference to the accompanying drawings and examples from which further features, advantages and embodiments can be learned. [Brief description of the drawings]

[0130] [Figure 1a] FIG. 1 shows a schematic side view of a dosage form according to a first embodiment of the present invention. [Figure 1b] 1 shows a detail of the area marked "X" in FIG. 1a. [Figure 1c] 1 shows an alternative configuration for the area marked "X" in FIG. 1a. [Figure 2a] FIG. 2 illustrates a top view of first and second half capsule shells aligned with one another to form a capsule device of a pharmaceutical dosage form according to another preferred embodiment of the present invention. [Figure 2b] FIG. 2 illustrates a top view of first and second half capsule shells aligned with one another to form a capsule device of a pharmaceutical dosage form according to another preferred embodiment of the present invention. [Figure 2c] 2b shows a top view of the first and second half capsule shells of FIG. 2a attached together along the direction of movement M. [Figure 2d]2b shows a top view of the capsule device formed by joining the first and second half capsule shells of FIG. 2a. FIG. [Figure 2e] Corresponding to FIG. 2d, the second half capsule shell is shown as transparent to show the area of ​​the wall of the second half capsule shell which overlaps the opening, thereby forming a gap. [Figure 3a] FIG. 2b is a side view of the situation in FIG. 2a. [Figure 3b] A pharmaceutical preparation in compressed form is shown being inserted into the opening of a first half capsule device forming an exemplary step of a method according to the present invention for producing a pharmaceutical dosage form. [Figure 3c] 1 shows a pharmaceutical preparation in compressed form being inserted into the hollow space of the first half capsule device forming another exemplary step of a method according to the present invention for producing a pharmaceutical dosage form. [Figure 3d] 2c shows a pharmaceutical dosage form according to an embodiment of the present invention using the capsule device of FIG. 2d. [Figure 3e] FIG. 3d shows the pharmaceutical dosage form, with the second half capsule shell shown as transparent. [Figure 4a] FIG. 1 shows a first and second half capsule shell of a pharmaceutical preparation and also shows an axis of rotation X disposed within the opening to which a strip of preparation is connected, forming an exemplary step of a method according to the invention for producing a pharmaceutical dosage form. [Figure 4b] It is shown that the first and second half capsule shells of the pharmaceutical preparation according to Fig. 3d comprise an axis of rotation X which is arranged in the opening and the strip-shaped preparation is partially wound around said axis by rotation (R), forming an exemplary step of the method according to the invention for producing a pharmaceutical dosage form. [Figure 4c] It is shown that the first and second half capsule shells of the pharmaceutical preparation according to Fig. 3d comprise an axis of rotation X which is located in the opening and the strip-shaped preparation is completely wound around said axis by rotation (R), forming an exemplary step of the method according to the invention for producing a pharmaceutical dosage form. [Figure 4d]FIG. 3d shows that the second half capsule shell of the pharmaceutical preparation comprises a weighting element that is inserted into the hollow space of the second half capsule shell, forming an exemplary step of a method according to the invention for producing a pharmaceutical dosage form. [Figure 5a] 1 illustrates a first step of using the kit to facilitate administration of a pharmaceutical dosage form prior to the patient swallowing the dosage form. [Figure 5b] 1 illustrates a second step of using the kit to facilitate administration of the pharmaceutical dosage form after the patient has swallowed the dosage form. [Figure 6a] 1 illustrates steps of a method for attaching a retainer to a wall structure of a retention device in conjunction with a kit. [Figure 6b] In relation to the kit, method steps are illustrated for wrapping the retainer around the retainer of the applicator after the retainer is attached to the wall structure of the retainer. [Figure 6c] In the context of a kit, method steps for connecting a fixing device to a holding device of a preparation are illustrated. [Figure 6d] 1 illustrates, in relation to a kit, method steps for joining a first half capsule shell with a second half capsule shell while a retainer is connected to the preparation. [Figure 6e] 1 illustrates method steps for assembling a capsule device to an applicator while a retainer is connected to a preparation in relation to a kit. [Figure 7] 1 illustrates an end portion of the preparation connected to a retainer of the applicator. [Figure 8] There is shown by way of example a machine according to the invention for producing pharmaceutical dosage forms according to the invention, in particular by carrying out a method according to the invention. [Figure 9a] 1 shows an exemplary mounting device of a manufacturing machine for mounting the preparation onto a first half capsule shell in a first step, in which an elongated preparation is wound up at a mounting position. [Figure 9b] FIG. 9a exemplarily illustrates the mounting device of FIG. 9a in a second step, where the elongated preparation is easily wound up and immediately cut by the cutting device. [Figure 9c]The mounting device of FIG. 9b is exemplarily shown in a third step, where, by actuation of the actuation device, the elongated preparation is easily wound up, cut from the storage roll, and inserted into the hollow space of the first half capsule shell through the opening. [Figure 10a] 1 shows a schematic cross-section of an applicator with a pharmaceutical dosage form disposed within the bottom of an applicator holding device and covered by an applicator cap. [Figure 10b] 1 shows a schematic cross-section of an applicator having a pharmaceutical dosage form disposed therein and an improved applicator cap. [Figure 11] FIG. 2 shows a schematic side view of a pharmaceutical dosage form according to a further embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0131] Figure 1a shows a capsule device 1 for application to the mucous membrane. The capsule device 1 has an elongated shape and contains a preparation 2 containing an active pharmaceutical ingredient. The preparation 2 is shown in a compressed state. Assuming that the preparation has a strip-like shape, Figure 1a shows a side view of the strip-like preparation wound as a spiral around an imaginary axis perpendicular to the drawing sheet. In the unfolded state, where the preparation is pulled out of the slit-like gap 5 of the capsule 3, the strip-like preparation will have the elongated shape of a substantially straight strip.

[0132] The capsule device 3 has a capsule shape and comprises a hollow space 4. The hollow space 4 contains the preparation 2 in a compressed state. The capsule is made of thin walls having a thickness of about 50 μm to 200 μm and is made of a biodegradable or non-biodegradable material.

[0133] The capsule device has a gap 5 forming a planar curved slit.

[0134] The width of the gap 5 formed as a curved slit is defined by measuring the distance between the facing surfaces 5a of the capsule walls of the first and second half capsule shells 3a, 3b in a direction parallel to the longitudinal axis A. The distance "a" may be a constant value, for example between 200 μm and 600 μm. The thickness t of the preparation may be a constant value, for example between 20 μm and 150 μm.

[0135] With regard to the outer dimensions of the capsule device, for example, the height H of the capsule 3 may be 8 mm and the width W of the capsule may be 4 mm, however, other dimensions of the capsule device are generally contemplated, taking into account the desired administration site on the patient.

[0136] The first end 2a of the preparation 2 extends through the gap 5 in a compressed state of the preparation, allowing for gripping and pulling the preparation from the hollow space into the surrounding area of ​​the capsule device, thereby moving the preparation 2 from the compressed state to the expanded state. Pulling of the preparation, i.e. the pulling movement P (see Fig. 1b), may result from fixing the end 2a of the preparation 2 and pulling the capsule device in a direction M opposite to P. This is the case for example with a process of administering the capsule device by swallowing the capsule device and connecting the end 2a of the preparation to a fixing device of an applicator including a drinking cup, as shown in Figs. 5a, 5b.

[0137] The first end 2a may have an end portion (see FIG. 1c) having a different shape than the strip 2. For example, the end portion may form a seal suitable for placement in the gap 5 to seal the gap 5 before the end portion is pulled out of the gap. Furthermore, the end portion may be configured to be connected to a retainer of an applicator by providing a bonding region.

[0138] In Fig. 1b, an enlarged view of the gap area 5 is shown. As shown in Fig. 1b, 1c, the gap 5 originates from the second half capsule shell 3b, which is fitted onto the first half capsule shell 3a, thereby overlapping the opening 6 of the first half capsule shell and forming a slit-like gap 5. The slit-like gap 5 and the strip-like preparation 2 are dimensioned such that when the preparation is pulled out of the gap, a gap (S1, S2) is provided (measured at the gap cross section CS of the gap 5 between the preparation 2 and the surface 5a of the capsule device that defines the gap 5). Here, the central longitudinal axis A of the capsule extends parallel to the gap cross section CS. The capsule device 3 shown in Fig. 1a includes a first half capsule shell 3a and a second half capsule shell 3b. When the first and second half capsule shells 3a, 3b are fitted relative to each other to form the capsule device 3, the opening 6 of the first half capsule shell 3a is partially covered by the second half capsule shell 3b to form a slit-like gap 5. Such an opening 6 may be made by milling the capsule material with a plate-shaped milling tool, e.g. a plate-shaped saw blade. The overlapping position, i.e. the joining position between the two half capsule shells 3a, 3b, is indicated by the dotted line marked B in Fig. 1a.

[0139] As shown in FIG. 1b, the thickness t of the strip 2 is significantly smaller than the width a of the planar curved slit 5. For example, the thickness t may be a constant value between 20 μm and 150 μm. The spacing S=S1=S2 is measured by placing the preparation 2 in the center of the gap 5 and in a centered position on the strip surface parallel to and facing the surface 5a of the capsule. The spacing S may be present and, on average, substantially constant while the preparation 2 is pulled out of the gap. This means that it is substantially along the entire length of the elongated preparation. However, the scope of the present invention may also encompass embodiments of dosage forms in which the spacing between the preparation and the surface 5a (defining the gap) varies due to a variation in the thickness t of the preparation 2, or the spacing is partially blocked due to a partial variation in the dimensions a and t (including the partial dimension a=t).

[0140] If the preparation has a string-like shape, the dimensions may be measured by analogy, in the case of irregularly shaped preparations the dimensions may be determined by average.

[0141] As shown in FIG. 1c, the first end 2a may have an end portion forming an enlargement, which may be configured to avoid the preparation being lost in the capsule 3. This may make it different for the patient or the person to pull the strip and retrieve the end portion 2a to apply the dosage form in a predetermined manner. The end portion 2a may also be configured to be placed in the gap 5 to seal the gap 5 before pulling the end portion 2a out of the gap. A portion 7 may be provided in the end portion and configured to connect a line, for example a retainer of an applicator, to the end portion 2a. The width a' of the gap 5 in a direction extending perpendicular to the axis A and showing the elongated shape of the capsule 3 is measured between the opposing faces 5a' of the second half capsule shell. The width a' may be dimensioned in the same way as the width of the preparation end portion 2a.

[0142] 2a shows a top view of a first half capsule shell 11 and a second half capsule shell 12 aligned with each other to form a capsule device 13 of a pharmaceutical dosage form 10 according to another preferred embodiment of the present invention. The first half capsule shell 11 has a first end closed by a spheroidal cap 11a and a second end which is a hollow cylindrical wall 11b where the opening of the first half capsule shell 11 is provided. The second half capsule shell 12 has a first end closed by a spheroidal cap 12a and a second end which is a hollow cylindrical wall 12b where the opening of the second half capsule shell 12 is provided. The first half capsule shell 11 has a hollow cylindrical wall 11c completely surrounding an opening 16. The opening 16 is essentially a hole in the wall 11c. Stability is provided by the wall frame 11c around the opening 16.

[0143] Fig. 2b shows a top view of a first half capsule shell 11' and a second half capsule shell 12' aligned with each other to form a capsule device of a pharmaceutical dosage form according to another preferred embodiment of the present invention. The first half capsule shell 11' has a first end closed by a spheroidal cap 11a' and a second end which is a hollow cylindrical wall 11b' in which the opening of the first half capsule shell 11' is provided. The second half capsule shell 12' has a first end closed by a spheroidal cap 12a' and a second end which is a hollow cylindrical wall 12b' in which the opening of the second half capsule shell 12' is provided. The hollow cylindrical wall section 11c' does not completely surround the opening 16, specifically the recess 16'. The recess 16' extends from the wall boundary of the second end 11b' towards the first end 11a'. The recess provides sufficient space within the hollow space of the first half capsule shell 11' for handling the preparation, in particular for the insertion of the preparation 2 in compressed form either along a direction perpendicular to the drawing plane and / or along the direction M.

[0144] Fig. 2c shows a top view of the first and second half capsule shells of Fig. 2a attached together by a sliding movement along the direction of movement M. The cylindrical portion of the second half capsule shell 12 may have a slightly larger diameter than the cylindrical portion of the first half capsule shell 11 to facilitate engagement of the first half capsule shell 11 with the second half capsule shell 12.

[0145] Fig. 2d shows a top view of the capsule device 13 formed by the joining position of the first half capsule shell 11 and the second half capsule shell 12 of Fig. 2a. The gap 15 is a slit extending circumferentially and tangentially around the axis a in the capsule wall. The cross section A_o of the gap is significantly smaller than the cross section A_a of the opening 16, for example by a factor f=0.05-0.2, i.e. A_o=f*A_a. In this way, the preparation easily inserted through the opening 16 at the joining position of the first half capsule shell 11 and the second half capsule shell 12 cannot get out of the gap 15 in a compressed state, but can be easily pulled out of the gap 15 in an elongated position when unwound from a rolled state during swallowing (see Fig. 9b).

[0146] FIG. 2e corresponds to FIG. 2d and shows the second half capsule shell as transparent to show that region 12c of wall 12b of the second half capsule shell overlaps with opening 16, thereby forming gap 15.

[0147] Figure 3a is a side view of the situation in figure 2a. When projected on a plane, the opening 16 has a rectangular shape, but follows the cylindrical shape of the wall 11b in the circumferential direction. The opening 16 essentially opens the cylinder along approximately the entire width W (see figure 1b) and allows the preparation in compressed state to be inserted through the opening 16 into the hollow space 14 of the capsule device or of the first half capsule shell, respectively, along a direction N perpendicular to the axis A (see figure 3b).

[0148] FIG. 3 b shows the pharmaceutical preparation in compressed form being inserted into the opening 16 of the first half capsule shell 11 .

[0149] FIG. 3c shows that the compressed form of the pharmaceutical preparation is fully inserted into the hollow space 14 of the first half capsule shell 11 while the end 2a of the compressed form of the preparation extends through the opening 16 even as the second half capsule shell 12 moves into engagement with the first half capsule shell 11, thereby continually reducing the free cross-section of the opening 16 until the joining position of FIG. 3d is reached, showing the finished pharmaceutical dosage form 10.

[0150] Figure 3d shows a pharmaceutical dosage form 10 using the capsule device of Figure 2d. Figure 3e shows the pharmaceutical dosage form 10. The second half capsule shell 12 is shown as transparent to show the position of the compressed preparation within the hollow space 14.

[0151] FIG. 4a shows a first half capsule shell 11 and a second half capsule shell 12 of a pharmaceutical preparation and illustrates that the axis of rotation X is positioned in the opening 16 to which the strip-shaped preparation 2 is connected, forming an exemplary step of the method of manufacturing a capsule device and assembling a pharmaceutical dosage form according to the invention.

[0152] Fig. 4b shows that the first half capsule shell 11 and the second half capsule shell 12 of the pharmaceutical preparation according to Fig. 3d comprise an axis of rotation R, which is located in or in front of the opening, around which the strip-shaped preparation 2 is partially wound by rotation (R), forming an exemplary step of the method according to the invention for producing a capsule device and assembling a pharmaceutical dosage form. The direction of rotation (R) in Fig. 4b is chosen as an example and may therefore be opposite to the direction of rotation (R) shown.

[0153] FIG. 4c shows that the first half capsule shell 11 and the second half capsule shell 12 of the pharmaceutical preparation according to FIG. 3d include an axis of rotation X that is located in the opening, around which the strip-shaped preparation is completely wound by rotation (R), forming an exemplary step of the method of manufacturing a capsule device and assembling a pharmaceutical dosage form according to the present invention.

[0154] FIG. 4d shows the second half capsule shell of the pharmaceutical preparation according to FIG. 3d, comprising a weight element 60 inserted into the hollow space of the second half capsule shell 12, forming an exemplary step of the method according to the invention for manufacturing a capsule device and assembling a pharmaceutical dosage form.

[0155] 5a illustrates administration of a pharmaceutical dosage form comprising a capsule device, represented herein by a patient. A drinking cup 901 is filled with liquid and an applicator 902 is attached to the cup 901. The applicator 902 contains a pharmaceutical dosage form comprising a capsule device 903 and a retainer 904. The retainer 904 is connected to the preparation contained in the capsule device 903.

[0156] 5b illustrates the procedure as a patient swallows capsule device 903, which travels down the esophagus to the stomach. Retainer 904 pulls preparation 905 from capsule device 903. Preparation 905 then spreads along the esophagus, thereby delivering the active ingredient of preparation 905 to the mucosa of the esophagus.

[0157] Fig. 6a relates to a method of winding a fastener 101 around a holding device 102 of an applicator 103 by means of a machine 100. Thus, as shown in Fig. 6a, in a first step of winding the fastener 101 around the holding device 102, the fastener 101 is mechanically fixed to the machine 100 with a clamping and cutting unit 110. The cutting unit 110 comprises a clamping jaw 106, a cutter 108 and a guiding means 107. In a second step, the fastener 101 is tensioned by moving the clamping jaw 106. In a third step, the holding device 102 is positioned along the tensioned fastener 101 by means of a material clutch 109 and the fastener 101 and clamped in a groove of the wall structure of the holding device 102.

[0158] Figure 6b describes how the retainer is wrapped around the applicator's retainer after it has been attached to the retainer wall structure. In a first step, the jaws 106 clamping the retainer 101 are opened as shown in Figure 6b.

[0159] In a second step, the holding device 102 is rotated with a winding unit, for example by rotating the clutch 109 which holds and supports the holding device 102, thereby winding the fastener 101 around the holding device 102. A rotational movement is superimposed on a vertical translational movement, whereby the fastener 101 is wound around the holding device 102 in a parallel position, while the clamp jaws re-secure the fastener 101 in a sixth step after the fastener is fully wound around the holding device 102.

[0160] In a third step, the knife-like element 108 of the machine 100 cuts off one end of the fastener 101, which is then connected to the preparation 104 in a further step.

[0161] 6c relates to a method for further assembling the kit by a machine, while connecting the fastener 101 to a holding device of a preparation means which joins the fastener 101 with the preparation 104. In a first step, the positioning of the holding device 102 above the opening 110 of the applicator housing 111 and the fastener 101 wrapped around the holding device 102 is specifically performed by a machine. The holding device 102 is thus pressed by its opening 110 onto the axis 112, for example an auxiliary tube. Thereby, the axis 112 extends through the housing 111 already positioned in the machine 100. The first half capsule shell 105a of the capsule device 105 is further positioned in the machine 100 and is placed next to the applicator housing 111, whereby the preparation 104 extends at least partially from the first half 105a into the joining area 113 of the machine 100. The cut end 101a of the fastener 101 is further placed in the joining area 113 of the machine 100. The preparation 104 is then pulled from the capsule device 103 by the cut end 101a.

[0162] Fig. 6d describes a method of joining a first half capsule shell with a second half capsule shell while the fastener is connected to the preparation. As shown in a first step, the end portion 101a of the fastener is joined to one end of the preparation 104 in the clamping joining area 113. Thereby, the support 114 moves downwards towards the joining area 113 and presses against the overlapping preparation 104 and the end portion 101a of the fastener. The joining is further explained in Fig. 10. In a second step, the second half capsule shell 105b is positioned above the first half 105a with a weight element 115. In a third machine step, the two halves 105a, 105b are fitted, joined or slid against each other, thereby partially closing the opening and forming the gap of the capsule device 105, while the end portion of the preparation 104 can be pulled through the gap by the now finally connected or joined fastener 101.

[0163] Fig. 6e relates to a method of assembling the capsule device to the applicator while the fixing device is connected to the preparation. Thus, in Fig. 6e, a step of assembling a pharmaceutical dosage form, i.e. capsule device 105, comprising a preparation 104 and in the illustrated case a weight element 115, with an applicator 103 is shown. Thus, in a first step, a gripping element 116, which holds the capsule device 103, for example by negative pressure, is positioned above the capsule device 103 to grip the device 103 and transport it above the housing 111 of the applicator 105. In a second step, the capsule device 103 is placed in the housing 111. The housing 111 is further wrapped around the holding device 102 and contains the fixing device 101 positioned in the opening 110 of the housing 111, as already explained in relation to Figs. 6c and 6d. In a third step, the housing 111 of the applicator 105 is closed by an end cap 117.

[0164] 7 shows an end portion of a preparation 701 connected to a fastener 702, for example an end portion of a fastener of an applicator. In a first step, the fastener 702 is immersed in a pure water solution to connect it to the end portion of the preparation 701. In this embodiment, water acts as the adhesive. However, other embodiments are envisaged in which substances other than water can be used as the adhesive.

[0165] The fixture 702 is preferably immersed in the aqueous solution for a period of 1-10 seconds or 1-5 seconds or for about 1 second. In a second step, the immersed fixture 702 is positioned on the water-wetted end portion 701, whereby the fixture 702 overlaps the end portion of the preparation 701 over an overlap distance d in the range of 0.5-2 cm or 0.5-1.5 cm or 0.5-1 cm or preferably 1 cm. After positioning the fixture 702, the fixture 702 is pressed against the end portion of the preparation 701, while the end portion 701 is still water-wetted. The pressing is preferably performed for a period of 1-10 seconds, or 1-5 seconds, or 2-3 seconds. The pressing is performed by using a contact pressure stamp. In a further third step, the joined fixture 702-preparation 701 is dried for a period of 1-10 minutes or 2-8 minutes or preferably 5 minutes before a further step of processing the joined parts. Alternatively, the fixture 702 is placed on the end portion 701 in a dry state without immersion, so that the fixture 702 overlaps the end portion of the preparation 701 over an overlap distance d, and is pressed after spraying pure water on the fixture together with the end portion 701. The spraying can be performed with the aid of a nozzle, for example a spray nozzle or a mist nozzle, to mist the liquid onto the surface to be sprayed. The nozzle is used to facilitate dispersing the liquid in the spray, whereby the nozzle distributes the liquid over an area that includes at least the overlap distance d, increasing the liquid surface area and generating an inertial forward force on the solid surface.

[0166] 8 exemplarily shows a manufacturing machine according to the invention for producing pharmaceutical dosage forms according to the invention, in particular by carrying out the method according to the invention. The manufacturing machine 200 is configured to produce pharmaceutical dosage forms according to the invention, in particular by carrying out the method according to the invention, and comprises a positioning device 240 for positioning a first half capsule shell in a mounting position. The connecting device 260 has a movable element 261 configured to connect the second half capsule shell and the first half capsule shell in a joining position by moving the first half capsule shell 11, 11' and the second half capsule shell 12, 12' towards each other, so that the wall 12c of the second half capsule shell overlaps the cross section of the opening 16, 16' by an amount controlled by the movement of the movable element 261, thereby forming the gap 5, 15 of the capsule device 3, 13 in the joining position.

[0167] The positioning device 240 comprises four holding members 243.1, 243.2, 243.3, 243.4 for holding one or more of the first and / or second half capsule shells in a fixed position. The holding members provide a shaped fixing space for fixing the first and / or second half capsule shells in a fixed position by a form-fit. The holding members of the positioning device 240 may be configured to hold a plurality of the first and / or second half capsule shells in a fixed position in parallel, where only one capsule is produced in each mounting position. In this way, the throughput of the manufacturing method can be increased. The positioning device 240 provides for the positioning of the four first and four second half capsule shells in four mounting positions, each provided by a holding member 243.1, 243.2, 243.3, 243.4. Thereby, several manufacturing steps of the pharmaceutical dosage form can be performed in parallel using a plurality of mounting positions, in particular working stations defined by the holding members.

[0168] The positioning device 240 comprises a rotatable platform 241 carrying the work stations. Each work station comprises one holding member arranged along a radially outer area of ​​the rotating platform. The mobile platform 241 is rotatably arranged on a base member (not shown) which rotates about an axis 242 and is configured to rotate each work station to a work position of the manufacturing machine. In the first work position (in FIG. 11 the holding member 243.1 is shown) a feeder 251 is arranged which feeds at least one first half capsule shell 11, 11' to a mounting position provided by the holding member 243.1. In the second work position (in FIG. 11 the holding member 243.2 is shown) a feeder 252 is arranged which feeds the second half capsule shell 12, 12' to a mounting position provided by the holding member 243.2.

[0169] In a third working position (retaining member 243.3 is shown in FIG. 8) an attachment device 201 may be arranged for attaching the preparation 2, preferably in a compressed state, to the first half capsule shells 11, 11'. The attachment device 201 comprises a conveying device 220 for conveying the ends 212a, 2a of the preparation to the attachment position and a compression device 223.1, 223.2, in particular a winding device, for transferring the preparation 212,2 from an elongated state to a compressed state, in particular a folded or rolled state.

[0170] A fourth working position (shown in FIG. 8 as holding member 243.4) may be provided with a receiving station 270 for receiving already manufactured pharmaceutical dosage forms 10 and, in some cases, for storing or delivering the pharmaceutical dosage forms 10 to a conveyor system (not shown).

[0171] The machine is preferably provided with an electronic control device 280 each time, which controls the respective operations. The respective operations are performed automatically in the machine by controlling in particular the operation and parameters of at least one drive driving the rotation of the positioning device around the axis 242, the supply of capsule parts by the devices 252 and 251, the conveying of the preparation by the conveying device, the operation of the compression device, in particular the rotation of the winding device, the cutting operation of the cutting device, the actuating operation of the actuating device, the connecting operation of the connecting device 260, as well as any further devices. The electronic control device 280 may comprise a user interface which allows a user to control the machine and / or the control software controlling the machine, in particular a computer program programmed to implement the respective steps of the method according to the invention, including all possible preferred steps described herein.

[0172] The manufacturing machine comprises a preparation storage device 210. The preparation storage device 210 provides a storage roll 212 of the preparation. The preparation is released from the roll by rotating the roll 212 about an axis 211, which allows the elongated preparation to be moved along a direction towards the cutting device 230 and the holding member 243.3. The holding member 243.3 provides a working position, the movement of the elongated preparation 212 being guided by a guide unit 213, which also comprises a roll 214. A portion 212a of the preparation 212 (which then forms the first end 2a of the elongated preparation 2) is gripped by a rotating shaft 223.1. The rotating shaft 223.1 is moved by rotating the rotating disk 222 about the axis R1 into the mounting position of the holding member 243.3. See FIG. 9a.

[0173] FIG. 9a exemplarily shows a mounting device 201 of a manufacturing machine 200 for mounting the preparation 2 on the first half capsule shells 11, 11' in a first step, in which the elongated preparation 212 is wound up at the mounting location of the holding member 243.3.

[0174] The manufacturing machine 200 comprises a conveying device 220 having an elongated shape and adapted to convey an end of the preparation 212a containing an active pharmaceutical ingredient from a preparation storage position to a mounting position. The preparation is positioned to be inserted into the hollow space 14 of the first half capsule shell 11, 11'. The first half capsule shell 11, 11' is inserted at the mounting position 243.3, specifically through the opening 16. Here, the conveying device has a rotatable conveying member 222. The rotatable conveying member 222 is adapted to receive at least a portion 212a of the preparation 212 at a first position 223.2, specifically after being released from the preparation storage device 210, and to convey said portion of the preparation 212a to the mounting position 243.3 by a rotation R1. The movement or rotation of the conveying device 222 may be controlled by an electronic control device 280 of the manufacturing machine 200.

[0175] The rotatable conveying member 222 may be provided with a winding device 223.1, 223.2 for winding the preparation in the elongated state and forming a wound state. The winding device has two rotatable shafts 223.1, 223.2 configured to be electrically driven and controlled by the electronic control device 280 of the manufacturing machine. The two rotatable shafts are arranged at a position offset from the rotation axis R1 of the rotatable conveying member 222. In particular, when the rotatable shaft 223.1 is positioned in front of and within the opening 16, the rotatable conveying member 222 and / or the winding device are configured to wind the preparation 212 in the elongated state at the mounting position 243.3, so that when the first half capsule shell is in the mounting position 243.3, the formation of the preparation 2 in the compressed state takes place in the compression position in front of the opening and further within the opening 16 (thereby at least partially directly inside the hollow space 14 of the first half capsule shell 11, 11') as shown in Figures 9a and 9b. This greatly facilitates the transfer of the preparation into the capsule.

[0176] FIG. 9b exemplarily illustrates the mounting device 201 of FIG. 9a in a second step, where the elongated preparation 212 is readily wound up and immediately cut by a cutting device 230. In FIG.

[0177] The machine comprises a cutting device 230 for cutting the preparation to form the preparation to be inserted into the hollow space of the first half capsule shell. The cutting device comprises a first part 231 having a first cutting edge and a second part 232 having a second cutting edge.

[0178] Fig. 9c exemplarily shows the mounting device 201 of Fig. 9b in a third step, where, by actuation of an actuating device 233, which in this case is part of the second part 232, the elongated preparation 2 is easily wound up, cut from the storage roll 212 and inserted into the hollow space 14 of the first half capsule shell 11 through the opening 16. The manufacturing machine comprises an actuating device 233 which moves the compressed preparation 2 from the compressed position to a final position within the hollow space 14 of the first half capsule shell 11.

[0179] 10a shows a schematic cross-section of an applicator 1000 including a pharmaceutical dosage form 1002, with preparation 1013 placed in the bottom part 1005 of an applicator holding device 1007, covered by an applicator cap 1003 including a lid 1004. The bottom part 1005 is shown by a dotted line separating it from the top part, i.e. the cap 1003, both parts forming the housing 1006 of the applicator 1000. The dosage form 1002 is arranged inside the housing 1006, in particular inside the holding device 1007. The dosage form 1002 is therefore arranged inside the holding device 1007 vertically, thus along an axis showing an elongated shape. The holding device 1007 comprises a bar 1007a, which extends along the dosage form 1002 and serves to support the dosage form 1002, i.e. the capsule device, in a vertical position within the holding device structure 1007. The retainer 1008 is wrapped around the rod 1007a. A weight element 1009 is further housed within the dosage form 1002. The rod structure of the retainer 1007 allows the dosage form 1002 to move vertically as indicated by the arrow.

[0180] Fig. 10b shows a schematic cross-section of the applicator shown in Fig. 10a. To inhibit vertical movement of the dosage form 1002, in case the applicator 1000 is inverted or vibrated, a curved retainer 1010 is placed on the spherically shaped cap of the dosage form 1002. Therefore, the retainer 1010 preferably has an external profile similar to that of the end cap of the dosage form 1002. Furthermore, the retainer 1010 is fixed by a spring 1011. The spring 1011 also presses the retainer 1010 against the cap of the dosage form 1002. Thus, the dosage form 1002 cannot move vertically. Furthermore, the lid 1004 of the applicator 1000 contains a desiccant 1012 to prevent the dosage form 1002 from becoming unusable.

[0181] 11 illustrates a semi-transparent view of a pharmaceutical dosage form 1100. The dosage form 1100 includes a first half capsule shell 1102 and a second half capsule shell 1101 nested against each other. A gap 1106 is obtained by sliding the first half 1102 and the second half 1101 against each other such that the opening 1104 of the first half 1102 is partially covered to form the gap 1106. The preparation 1105 is shown in a compressed form while an end 1107 of the preparation extends from the gap 1106 to the outside of the dosage form 1100. The dosage form 1100 further includes a weight element 1103 depicted on top of the preparation 1105. The weight element 1103 is secured by a notch 1108 to prevent vertical movement of the element 1103 along the long axis of the dosage form 1100. Preferably, a plurality of notches 1108 are distributed on the wall of the dosage form 1100 . [Explanation of symbols]

[0182] Figure 1a to Figure 1c 1. Drug Form 2 Preparations 2a End portion of the preparation 3 Capsule device 3a First half capsule shell 3b Second half capsule shell 4 Hollow space 5. Gap 5a,5a' Capsule wall surface 6 Opening of first half capsule shell 7. Part of the edge of the preparation Figures 2a to 2e, 3a to 3e, and 4a to 4d 10 Drug dosage forms 11 First half capsule shell 11a Spherical Cap 11b Hollow cylindrical wall 11c Capsule Wall 12 Second half capsule shell 12a Spherical Cap 12b Hollow cylindrical wall 12c Capsule wall area 13 Capsule Device 14 Hollow space 15. Gap 16 Opening 17 Hollow cylindrical wall parts 18 small flag 60 Weight elements Figure 5a, Figure 5b 901 Drinking Cup 902 Applicator 903 Capsule Device 904 Fixtures 905 Preparations Figures 6a to 6e 100 machines 101 Fixtures 101a End portion of fixing device 102 Applicator holder 105a first half capsule shell 105b Second half capsule shell 106 Clamp Jaw 107 Guidance means 108 Cutter 109 Support Clutch 110 Cutting unit 111 Applicator housing 112 axis 113 Combined area 114 Support 115 Weight Element 116 Gripping element 117 End Cap Figure 7 701 Preparations 702 Fixtures Figures 8 and 9a to 9c 200 manufacturing machine 201 Installation Equipment 210 Storage device 211 axis 212 Preparation storage roll 212a End parts of preparations 213 Guidance unit 214 rolls 220 Transport Equipment 222 Rotating Disk 223.1 Compression devices 223.2 Compression devices 230 Cutting device 231 First part of the cutting device 232 Second part of the cutting device having a cutting edge 233 Actuator 240 Positioning device 241 Rotatable Platform 242 axis 243.1 Retaining members 243.2 Retaining members 243.3 Retaining members 243.4 Retaining members 251 Feeding device 251 Equipment 252 Equipment 260 Connection Device 261 Moving Elements 270 Pick-up Station 280 Control Device Figure 10a, Figure 10b 1000 Applicator 1002 Pharmaceutical dosage forms 1003 Applicator Cap 1004 Lid 1005 Applicator bottom 1006 Case 1007 Holding device 1008 Fixtures 1009 Weight element 1010 Curved retaining device 1011 Spring 1012 Desiccant 1013 Preparations Figure 11 1100 Pharmaceutical dosage forms 1101 Second half capsule shell 1102 First half capsule shell 1103 Weight element 1104 Opening 1105 Preparations 1106 Gap 1107 End parts of preparations 1108 Cutout

Claims

1. A capsule device (13) adapted for application to a mucous membrane, in particular the buccal or gastrointestinal, in particular the esophageal, mucous membrane, having an elongated shape, containing an active pharmaceutical ingredient and adapted to contain a pharmaceutical preparation (2) capable of being placed in a compressed and an expanded state, a hollow space (14) for containing the preparation (2) in the compressed state, a gap (15) configured to allow a first end (2a) of the preparation in the compressed state to extend through the gap (15) and thereby to transition the preparation from the compressed state in the hollow space (14) to the expanded state in the surrounding area of ​​the capsule device (13); a first half capsule shell (11, 11') and a second half capsule shell (12), the first half capsule shell (11, 11') and the second half capsule shell (12) being joined by overlapping the first half capsule shell (11, 11') and the second half capsule shell (12) at a joining position; The first half capsule shell (11, 11') has a hollow cylindrical wall (11c, 11c') containing an opening (16, 16'), The second half capsule shell (12) has a wall (12c) that overlaps with a cross section of the opening (16, 16'), thereby forming the gap (15) of the capsule device (13) at the joining position.

2. 2. The capsule device of claim 1, wherein the hollow cylindrical wall (11c) of the first half capsule shell (11) is closed at a first end (11a) and open at a second end (11b), and the opening (16) is completely surrounded by the material of the hollow cylindrical wall (11c).

3. 2. The capsule device of claim 1, wherein the hollow cylindrical wall (11c') of the first half capsule shell (11) is closed at a first end (11a) and open at a second end (11b), and the opening (16') is formed as a recess starting at the second end (11b) and extending towards the first end (11a).

4. 4. A capsule device according to any one of claims 1 to 3, wherein the cross-section of the opening (16, 16') is dimensioned to accommodate the preparation (2) in the compressed state prior to joining the first half capsule shell (11, 11') and the second half capsule shell (12, 12'), preferably in the joining position, the gap (15) defined by the opening (16) and the walls (12b, 12c) of the second half capsule shell (12, 12') has a cross-section dimensioned to prevent the preparation (2) in the compressed state from passing through the gap (15).

5. A capsule device as claimed in any one of claims 1 to 3, wherein the cross-sectional size of the gap (15) is a fraction f of the cross-sectional size A_a of the opening (16, 16'), where A_o = f * A_a, and preferably 0.0010 < f < 0.7500.

6. The capsule device according to any one of claims 1 to 3, wherein in the joining position, the first half capsule shell (11, 11') is inserted into the second half capsule shell (12, 12').

7. A capsule device as described in any one of claims 1 to 3, wherein the gap (15) is a slit-like opening configured to allow the preparation (2) to pass through the gap (15), and a cross-section (CS) of the gap (15) is larger than a cross-section of the strip-shaped preparation (2) when the strip-shaped preparation (2) extends through the gap (15).

8. The capsule device of any one of claims 1 to 3, wherein the capsule device (13) is adapted to be swallowed by a patient.

9. The capsule device of any one of claims 1 to 3, comprising a weight device (60) occupying a portion of the hollow space and providing additional weight to the capsule device.

10. A method (100) for manufacturing a capsule device (1, 10, 51) for containing a pharmaceutical preparation according to claim 1, comprising the steps of: a) providing said first half capsule shell (11, 11') and said second half capsule shell (12, 12') having a hollow cylindrical wall (11c, 11c') including an opening (16, 16'); and b) sliding the second half capsule shell (12, 12') and the first half capsule shell (11, 11') into a joining position, such that the walls (12b, 12c) of the second half capsule shell (12, 12') overlap a cross-section of the opening (16, 16') of the first half capsule shell (12, 12'), thereby forming the gap (15) of the capsule device (13) at the joining position.

11. The step a) further comprises: a) providing materials for forming the capsule device (13), in particular the first half capsule shell and the second half capsule shell; and b) creating an opening (16, 16'), in particular a rectangular opening (16, 16'), in the material of the first half capsule shell and / or the second half capsule shell.

12. The method according to claim 11, wherein the opening (16, 16') is created in the material of the formed hollow cylindrical wall of the first half capsule shell and / or the second half capsule shell.

13. 13. A pharmaceutical dosage form comprising a capsule device (13) according to claim 1 and a pharmaceutical preparation (2) having an elongated shape, containing an active pharmaceutical ingredient and capable of being arranged in a compressed 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 (13) according to claim 10, a) providing said preparation having an elongated shape and comprising an active pharmaceutical ingredient; b) providing said first and second half capsule shells having a hollow cylindrical wall including an opening (16, 16'); c) placing said preparation, preferably in a compressed state, in said first half capsule shell through said opening (16, 16') such that a part or an end of said preparation extends through said opening (16, 16'); and d) sliding the second half capsule shell onto the first half capsule shell into said joining position or sliding the first half capsule shell onto the second half capsule shell into said joining position until the opening (16, 16') forms the gap (15) of the capsule device (13) at the joining position of the first and second half capsule shells, thereby reducing the cross-section of the opening (16, 16') and the end of the preparation extends through the opening (16, 16').

15. 15. The method according to claim 14, further comprising the step of providing a rotating axis (X) after step a) or step b), preferably positioning said rotating axis (X) in front of said opening (16, 16') or within the cross section of said opening (16, 16') and rotating said rotating axis until said preparation reaches a compressed state, thereby preferably winding said preparation in an elongated state using said opening (16, 16') to guide and / or align said preparation.

16. 15. The method of claim 14, further comprising, after step b) or step c), disposing a weight device in at least a portion of the hollow space of the first half capsule shell and / or the second half capsule shell.

17. 14. A kit comprising the pharmaceutical dosage form of claim 13, a drinking cup, and an applicator for administering said pharmaceutical dosage form to a patient, said applicator being in fluid communication with said drinking cup and containing said pharmaceutical dosage form, said preparation of said pharmaceutical dosage form being connected to said applicator by a retainer for withdrawing said preparation from the capsule device after administration to the patient.

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