PHARMACEUTICAL DOSAGE FORM FOR APPLICATION TO MUCOUS MEMBRANES AND METHODS FOR PRODUCING SAME

Abstract

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

Claims

1. A pharmaceutical dosage form (1; 51) for the application to a mucous membrane, in particular to a buccal, gastro-intestinal, rectal or vaginal mucous membrane, preferably a gastro-intestinal membrane, more preferably an esophageal membrane comprising at least one preparation (2; 52) having an elongated shape and comprising an active pharmaceutical ingredient, the at least one preparation being capable to be arranged in a compact condition and in an expanded condition, a capsule device (3; 53) comprising a hollow space (4; 54a, 54b) for accommodating the at least one preparation being in the compact condition, the capsule device having an opening (5; 25; 35; 45.1; 45.2; 45.3; 55) and a first end (2a; 52a) of the preparation extending, in the compact condition, through the opening (5; 25; 35; 45.1; 45.2; 45.3; 55) for allowing pulling out the preparation from the hollow space into the surrounding area (6) of the capsule device thereby transferring the preparation from the compact condition to the expanded condition, characterized in that the opening (5; 55) and the preparation (2; 52) being dimensioned such that, when the preparation is pulled out from the opening (5; 25; 35; 45.1; 45.2; 45.3; 55), a spacing (S1, S2) is provided in an opening cross section (CS) of the opening (5; 55) between the preparation (2; 52) and a surface (5a) of the capsule device defining the opening (5; 55).

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

3. A pharmaceutical dosage form (1) according to claim 1 or 2, wherein the opening (5; 25; 35; 45.1; 45.2; 45.3) is a slit-like opening (5; 25; 35; 45.1; 45.2; 45.3) configured for allowing a strip-like preparation (2) to pass through the opening (5; 25; 35; 45.1; 45.2; 45.3), the cross section (CS) of the opening (5; 25; 35; 45.1; 45.2; 45.3) being larger than the cross section of the strip-like preparation (2), when the latter is moving through the opening.

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

5. A pharmaceutical dosage form (1) according to claim 4, wherein 1°<α<=90°.

6. A pharmaceutical dosage form (1) according to claim 4, wherein α=45°.

7. A pharmaceutical dosage form (1) according to claim 4, wherein α=90°.

8. A pharmaceutical dosage form (1) according to claim 3, wherein a width (a) of the slit-like opening (5; 25; 35; 45.1; 45.2; 45.3) is larger than a thickness (t) of the strip-like preparation (2), which is moved out of the capsule device (3) through the slit-like opening (5; 25; 35; 45.1; 45.2; 45.3).

9. A pharmaceutical dosage form (1) according to any of the previous claims, wherein the spacing S is from 100 μm to 2000 μm.

10. A pharmaceutical dosage form (1) according to any of the previous claims, wherein the capsule device (3) comprises at least one guiding member (33c.1; 33c.3), which is arranged inside the inner space of the capsule device (3) to guide the motion of the string-like or sheet like preparation (2) towards the opening (5; 25; 35; 45.1; 45.2; 45.3) of the capsule device (3).

11. A pharmaceutical dosage form (1) according to claim 4, wherein the at least one guiding members (33c.1; 33c.3) form a guiding compartment for accommodating and guiding the preparation (2).

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

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

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

15. A pharmaceutical dosage form (51) according to one of the previous claims 1 to 13, wherein pharmaceutical dosage form comprises a sinker device (60), which occupies a part of the hollow space and which provides an additional weight to the pharmaceutical dosage form.

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

17. Method of producing the pharmaceutical dosage form according to any of claims 1 to 15, comprising the steps of: providing a capsule device (3; 23; 33) including an opening (5; 25; placing a preparation (2) having an elongated shape and comprising the active pharmaceutical ingredient, in a compact condition of the preparation (2), inside a hollow space (4) of the capsule device (3; 23; 33) and let an end portion of the preparation (2) extend through the opening, the opening (5; 25; 35; 45.1; 45.2; 45.3) and the preparation (2) being configured such that, when the preparation (2) is pulled out from the opening (5; 25; 35; 45.1; 45.2; 45.3), a spacing (S1, S2) is provided in the opening cross section (CS) of the opening (5) between the preparation (2) and a surface (5a) of the capsule device (3; 23; 33) defining the opening (5; 25; 35; 45.1; 45.2; 45.3).

Description

[0176] Exemplary embodiments of the present invention will be described in greater detail below with reference to the accompanying drawings and samples, from which further features, advantages, and embodiments can be learned.

[0177] FIG. 1a shows a schematic side view of a dosage form according to a first embodiment of the invention.

[0178] FIG. 1b shows the dosage form of FIG. 1a, rotated by 90° around the central length axis A.

[0179] FIG. 1c shows a detail of the area marked by “X” in FIG. 1a.

[0180] FIG. 1d shows an alternative configuration of the area marked by “X” in FIG. 1a.

[0181] FIG. 2a shows an isometric oblique view of a capsule device being part of a dosage form according to a second embodiment of the invention.

[0182] FIG. 2b shows the capsule device of FIG. 2a, consisting of two parts, before assembly of the capsule device.

[0183] FIG. 2c shows a side view of the arrangement in FIG. 2b.

[0184] FIG. 2d shows a front view of the arrangement in FIG. 2b.

[0185] FIG. 2e shows a front view of the capsule device in FIG. 2a.

[0186] FIG. 3a shows an isometric oblique view of a dosage form according to a third embodiment of the invention.

[0187] FIG. 3b shows the dosage form of FIG. 3a, consisting of two parts of the capsule device and the strip-shaped preparation, before assembly of the capsule device.

[0188] FIG. 3c shows a front view of the dosage form in FIG. 3a.

[0189] FIG. 3d shows a front view of the arrangement in FIG. 3b.

[0190] FIG. 3e shows an oblique bottom view of the dosage form in FIG. 3a.

[0191] FIG. 3f shows a side view of the arrangement form in FIG. 3b.

[0192] FIG. 4a shows a perspective side view of a string-like preparation, in its compact condition, which is suitable for use in a dosage form according to the invention.

[0193] FIG. 4b shows a side view of another string-like preparation, in its compact condition, which is suitable for use in a dosage form according to the invention.

[0194] FIG. 4c shows a side view of a strip-like preparation, in its compact condition, which is suitable for use in a dosage form according to the invention.

[0195] FIG. 4d shows a side view of another strip-like preparation, in its compact condition, which is suitable for use in a dosage form according to the invention.

[0196] FIG. 4e shows a side view of the string-like preparation of FIG. 4a or FIG. 4b, in its expanded condition.

[0197] FIG. 4f shows a side view of the strip-like preparation of FIG. 4c or FIG. 4d, in its expanded condition.

[0198] FIG. 5a shows an oblique isometric side view of a capsule part of a capsule device being part of a dosage form according to a fourth embodiment of the invention.

[0199] FIG. 5b shows an oblique isometric side view of a capsule part of a capsule device being part of a dosage form according to a fifth embodiment of the invention.

[0200] FIG. 5c shows an oblique isometric side view of a capsule part of a capsule device being part of a dosage form according to a sixth embodiment of the invention.

[0201] FIG. 6a shows the capsule part of FIG. 5a, in a top view.

[0202] FIG. 6b shows the capsule part of FIG. 5b, in a top view.

[0203] FIG. 6c shows the capsule part of FIG. 5c, in a top view.

[0204] FIG. 7a shows, in a side view, a schematic cross section of the capsule part of FIG. 5a and a strip-like preparation, in its compact condition, being placed inside the capsule part and extending through the opening of the capsule device.

[0205] FIG. 7b shows, in a side view, a schematic cross section of the capsule part of FIG. 5b and a strip-like preparation, in its compact condition, being placed inside the capsule part and extending through the opening of the capsule device.

[0206] FIG. 7c shows, in a side view, a schematic cross section of the capsule part of FIG. 5c and a strip-like preparation, in its compact condition, being placed inside the capsule part and extending through the opening of the capsule device.

[0207] FIG. 7d shows a modified version of the embodiment of FIG. 7c, wherein the width of the slit-like opening is larger than in FIG. 7c.

[0208] FIG. 7e is a schematic side view of the embodiment of a capsule part in FIG. 5b, describing the position of the opening being a planar curved slit.

[0209] FIG. 8 shows a diagram with results of pulling force experiments performed with dosage forms corresponding to the embodiments shown in FIGS. 7a to 7d, under dry and wet conditions, respectively.

[0210] FIG. 9a shows an illustration explaining a first step of a procedure including the administration of a swallowable dosage form being configured according to the invention.

[0211] FIG. 9b shows an illustration explaining a second step of the procedure starting with FIG. 9a.

[0212] FIG. 9c shows an illustration explaining a third step of the procedure starting with FIG. 9a.

[0213] FIG. 9d shows an illustration explaining a fourth step of the procedure starting with FIG. 9a.

[0214] FIG. 10 shows a schematic side view of a dosage form according to a further embodiment of the invention.

[0215] FIG. 1a shows the pharmaceutical dosage form 1 for the application to a mucous membrane, in particular to a buccal, gastro-intestinal, rectal or vaginal mucous membrane, comprising a preparation 2 having an elongated shape and comprising the active pharmaceutical ingredient. The preparation 2 is shown in a compact condition: assuming that the preparation has a strip-like shape, FIG. 1a shows a side view of the strip-like preparation being wound as a spiral around a virtual axis, which is perpendicular to the drawing sheet. In an expanded condition, when the preparation is pulled out from the slit-like opening 5 of the capsule 3, the strip-like preparation will have an elongated shape of a substantially straight strip, as shown in FIG. 4f.

[0216] The capsule device 3 has the shape of a capsule and comprises a hollow space 4, which accommodates the preparation 2 being in the compact condition. The capsule consists of a thin wall having a thickness of about 50 μm to 200 μm, made from a biodegradable or non-biodegradable material.

[0217] The capsule device has an opening 5, which is a planar curved slit being centered with the central length axis A of the capsule 3. Such a slit may be produced by milling out the capsule material using a plate-shaped milling tool, for example a plate shaped saw blade. The width a of the planar curved slit is defined by measuring the distance of opposing surfaces 5a of the capsule wall in a direction perpendicular to the length axis A. The distance ‘a’ may be a constant value between 200 μm and 600 μm, for example. The thickness t of the preparation may be a constant value between 20 μm and 150 μm, for example.

[0218] As shown FIG. 1b, where the dosage form is turned around the axis A by 90°, the length of an outer edge of a surface 5a is denoted as ‘b’. Since the upper cap of the capsule 3 carrying the slit, has a convex shape, the distance b is larger than the distance ‘c’, which denotes the direct connection between the two opposing end points 5b of a single outer edge of a surface 5a. The rectangular area (not directly shown), which is defined by the four edge points 5b of the slit-like opening and which has a size of a*c, is also referred to as passage cross section, because it limits the area which is available for the strip 2 when passing through the slit 5, the strip 2 having a rectangular cross section small enough to pass by the surfaces 5a in a distance (=spacing).

[0219] Regarding the outer dimensions of a capsule device, for example, the height H of the capsule 3 may be 8 mm, the width W of the capsule may be 4 mm. However, other dimensions of a capsule device are generally possible taking into account the desired administration site of a patient.

[0220] A first end 2a of the preparation 2 extends, in the compact condition of the preparation, through the opening 5 for allowing grabbing and pulling out the preparation from the hollow space into the surrounding area of the capsule device, thereby transferring the preparation 2 from the compact condition to the expanded condition. Pulling out the preparation, i.e. the pull-out movement P (cf. FIG. 1c), may be the result of fixating and end 2a of the preparation 2 and pulling the capsule device in a direction M opposite to P. This is the case for example, by using the process of administering the capsule device by swallowing the same, and fixating the end 2a of the preparation at the teeth of a patient (cf. FIGS. 9a to 9d).

[0221] The first end 2a may have an end portion (cf. FIG. 1d), which has a shape different from the strip 2. For example, the end portion may form a sealing part suitable to be arranged at the opening 5 for sealing the opening 5, before the end portion is pulled out from the opening.

[0222] The slit-like opening 5 and the strip-like preparation 2 are dimensioned such that, when the preparation is pulled out from the opening, a spacing (S1, S2; cf. FIG. 1c) is provided measured in the opening cross section CS of the opening 5 between the preparation 2 and a surface 5a of the capsule device defining the opening 5. Here, the central length axis A of the capsule runs perpendicular to the opening cross section CS.

[0223] As shown in FIG. 1c, the thickness t of the strip 2 is remarkably 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 positioning the preparation 2 in the center of the opening 5 and in a centered-and-aligned position of the strip surfaces being in parallel to and facing the surfaces 5a of the capsule. The spacing S is present and may be—in average-substantially constant while the preparation 2 is pulled out from the opening, which means, substantially along the whole length of the elongated preparation (cf. FIGS. 4e, 4f). However, the scope of the invention also may cover embodiments of dosage forms, where the spacing between the preparation and the surfaces 5a, which define the opening, varies—due to a varying thickness t of the preparation 2—, or where the spacing is partly interrupted—due to a portion-wise variation of dimensions a and t, including the portion-wise dimensioning of a=t.

[0224] In cases, where the preparation has a string-like shape, the dimensions may be measured in analogy, and in case of irregularly shaped preparation, the dimensions may be determined by averaging.

[0225] As shown in FIG. 1d, the first end 2a may have an end portion forming an enlarged part, which may be configured for avoiding that the preparation is lost inside the capsule 3, which would make it different for a patient or applicant to recover the end 2a for pulling out the strip and applying the dosage form in the predetermined way. The end portion 2a may also be configured to be arranged at the opening 5 for sealing the opening 5, before the end portion is pulled out from the opening. A portion 7 may be provided at the end part, being configured to connect a line to the end part, which may be used by a patient or applicant to grab the preparation or manipulate the preparation. The line may be fixated at the teeth of a patient, instead of the end 2a being directly fixated to the patient, in case of the oral administration of the dosage form shown in FIGS. 9a to 9d.

[0226] FIGS. 2a to 2e show different arrangements of a capsule device 23, and the two half-cylinder elements 23a and 23b forming the capsule device. The manufacture of the two half-cylinder elements may use a type of molding process. The setup of the capsule 23 is different compared with the capsules in FIGS. 5a to 5c, which capsules may be traditionally produced by a Colton process, including joining of two tube elements, followed by a step of providing the capsules with an opening. The lower part contains a cuboid recess 25c on one of its rounded end faces. Such a configuration allows to easily assembly the dosage form by arranging the lower part 23a of the capsule 23 horizontally with the hollow space facing upwards, and by placing the compacted preparation inside the hollow space of the lower part 23a and then simply dropping the end portion 2a of a preparation onto the surface 25a.1, which defines the opening 25, followed by a step of placing the upper half part 23b onto the lower half part 23a. The parts may be connected by adhesion, force fit and/or using an adhesive. Positioning of the two half parts 23a, 23b is such that the surfaces 25a.1 and 25a.2 are aligned opposite to each other, thereby defining the opening 25. The opening 25 is arranged offset form the length axis A, which means that the axis A does not cross the center point 25x of the opening 25. The surface 25a.2 is defined by an outer surface of the halve part 23b. The lower half 23a of the capsule device has a (male) connector part 23d.1, here configured to be a protrusion 23d.1 of the connecting side of the halve part 23a, which runs circumferentially around the inner space of the capsule device and thereby forms a ring-shaped protrusion. The upper half has a corresponding connector part 23d.2, here configured to be a recess 23d.2 of the connecting side of the half part 23b, which runs circumferentially around the inner space of the capsule device and thereby forms a ring-shaped recess, configured to receive the protrusion 23d.1 by a form-fit connection, which secures the precise relative positioning of the two half-cylinder elements 23a, 23b.

[0227] Each half-cylinder element 23a, 23b of the capsule device 23 in FIGS. 2a to 2e is made from one wall 23c, which has an inner side 23c.1 and an outer side 23c.2, which sides run in parallel to each other. The resulting hollow space of the capsule device 23 is basically shaped similar to the outer contour of the capsule 23, which means the hollow space is capsule-shaped, including a hollow-cylindrical part, which is capped by a hollo-semi-sphere portion at each end of the cylinder, wherein one of the (hollow) cap parts is connected to the opening 25. Any edges of the opening 25 may be alternatively trimmed to avoid sharp edges.

[0228] FIGS. 3a to 3f show the arrangement of a dosage form 31, which has a capsule device 33. The capsule device 33 has the same features as the capsule device 23 shown in FIGS. 2a to 2e, except from the shaping of the hollow space, or the inner side of the capsule walls, respectively. Moreover, the strip-like preparation 32 is shown here, which is placed in the hollow space of the capsule device 33 and extends through the opening 35. The same preparation 32 may be used to form a dosage form using the capsule device 23 of FIGS. 2a to 2e.

[0229] The inner sides 33c.1, 33c.3 of the capsule walls 33c are shaped to provide a substantially cuboid shaped hollow space. Each side acts as a guiding member 33c.1, 33c.3. Such a cuboid shaped hollow space offers the functionality of a guiding compartment for guiding the position of the winding of the strip-like preparation 2, which may be advantageous in particular during the process of unwinding the compacted preparation 2 during pulling out of the preparation. It was found that the cuboid hollow space, which provides a kind of form-fit casing of the preparation 2 (being in the shape/condition of a cylindrical coil), provides a guiding structure, which stabilizes the preparation against a rotation around the central length axis A. Thereby, twisting of the preparation around the axis A is avoided and the unwinding process becomes more reliable, in particular in cases where the preparation is rather deformable.

[0230] FIGS. 5a to 5c, respectively, show a capsule part 43a, which has the shape of a cylindrical part being capped by a semi-sphere shaped part, which carries a slit-like opening 45.1, 45.2, 45.3, respectively. Such capsule parts may be produced by the known Colton method, and a corresponding cylindrical counter part (not shown) may be used to close the capsule part 43a—after placing a compacted preparation inside the hollow space of the capsule part 43a—and to thereby form a dosage form according to the invention. The slit-like opening 45.1, 45.2, 45.3 may be provided by milling out a plate shaped recess form the capsule material using a plate shaped milling tool, e.g. a saw blade or any tools having a comparable effect.

[0231] FIGS. 7a to 7c correspond to the embodiments of capsule parts 43a shown in FIGS. 5a to 5c and 6a to 6c, respectively, wherein the positioning of the slit like opening is varied. In each case, the position of the opening 45.1, 45.2, 45.3, 45.3′ is offset from a length axis A of the capsule part 43. The opening 45.3 is equal to the opening 45.3′, but the width a.2 of the opening 45.3′ is larger than the width a.1 of the opening 45.3, by about 50%, such that a.2=1.5*a.1. The drawings of FIGS. 7a to 7d are copied in the diagram of FIG. 8.

[0232] The slit-like opening 45.2 is arranged such that the normal N of the main plane of the planar curved slit 45.2 and the central axis A of the capsule part 43a include an angle α=45° (cf. FIG. 7e). For the slit-like opening 45.1, where the slit-like opening is offset from the central axis A of the capsule part, the angle α is Null. In another preferred configuration of the slit-like opening 45.3, 45.3′, the angle α is 90°, respectively. The slit-like openings 45.1, 45.2, 45.3, 45.3′ are, respectively, arranged such that a main plane running through the opening is in parallel to an axis B, which is perpendicular to the central axis A of the capsule device (cf. FIG. 7e). Such a configuration matches to a winding of a strip-like preparation, which is wound around a winding axis being parallel to axis B, and facilitates the unwinding process.

[0233] The diagram of FIG. 8 shows that the maximum pulling force, which occurs when pulling out a strip-shaped preparation 2 from a dosage form having a capsule part 43 a and one of the different types of openings 45.1, 45.2, 45.3, 45.3′, differs depending of the type of opening and depending of the choice of a dry or wet condition. For performing the experiments, a standard setup for measuring tensional forces was used. The dosage form was arranged and fixated in a vertical position, with the central length axis of the capsule part 43a being vertically arranged. The end portion of the strip-like preparation 2, which in each case extended through the opening, was connected to a force sensor. The force sensor with the end portion of the preparation was then vertically raised by a constant velocity of somewhere between 0.01 to 0.05, e.g. 0.02 m/s and the maximum force was determined by continuously monitoring the occurring forces.

[0234] In case of dry conditions, the preparations, which were stored under room temperature 21° C. and standard humidity, were directly transferred to the force measurement apparatus and measured. In case of the wet conditions, the dosage forms were rinsed for 10 seconds with distilled water and then transferred to the force measurement apparatus and measured. Surprisingly, the maximum tension force was generally lower in the case of wet conditions compared to dry conditions, and no rupturing of the preparation was observed during the experiments, either under wet or dry conditions. Enlarging the width of the slit (compare the results for openings 45.3 and 45.3′) results in a lower maximum pulling force.

[0235] FIG. 10 shows a pharmaceutical dosage form 51 for the application to a mucous membrane, in particular to an esophageal membrane comprising a preparation 52 having an elongated shape with an end portion 52a and comprising an active pharmaceutical ingredient, the at least one preparation being capable to be arranged in a compact condition and in an expanded condition and a capsule device 53 comprising a hollow space 54a, 54b for accommodating the preparation 52 being in the compact condition. More specifically, the preparation is located inside the upper half 54a of the hollow space, the “upper half” meaning that said half is oriented towards the upstream direction when the dosage form is swallowed with a stream of water by a patient. Inside the lower half 54b of the hollow space, a sinker element is clamped between opposing sides 53a, 53b of the capsule's inner side. The sinker element 60 is a basically cylindrical part and coaxially arranged with the capsule device along its axis A. The sinker device 60 occupies the larger part of the lower half 54b of the hollow space. The “lower half” meaning that said half is oriented towards the downstream direction when the dosage form is swallowed with a stream of water by a patient. The upper half and the lower half are illustrated also by the virtual line C, which divides the hollow space in the two substantially equally dimensioned volumes 54a, 54b. The presence of the sinker element 60 avoids that the lower half 54b of the hollow space is filled with air. The sinker element is made of a glucose, for example, having a density of about 1.5 g/cm.sup.3, thereby being heavier than water. The weight element 60 will improve the efficiency of the expansion of the compacted strip-like preparation 52 by a gravity driven displacement in downstream direction, when the dosage form is administered by a patient in the presence of a stream of water. The placement of the sinker element 60 in the lower half 54b of the capsule's hollow space will assist to align the capsule with the direction of stream, which may substantially be the direction of gravity.

[0236] The sinker element 60 and the dosage form 51, respectively, were produced by a method according to the invention, using a process of tablet pressing a graular material mixture, which exemplarily comprised the following excipients: Croscarmellose-Na 0,25; Calcium hydrogen phosphate anhydrate 97.75; Magnesium Stearate 1.5; Highly dispersed silica 0.5, all numbers in mol %.

[0237] The physical properties of the sinker element 60 being a pressed tablet, which fits inside the lower half of the capsule, having a diameter of 7.0 mm, are as follows: Density: approx. 1.65 g/cm.sup.3; Mass: 366 mg±5%; Height: 5.3-5.7 mm; Diameter: 6.95 mm.

[0238] The overall density of the dosage for 51 without the sinker element 60 was 0.4 g/cm.sup.3, the overall density of the dosage for 51 with the sinker element 60 was 1.05 g/cm.sup.3.

[0239] The sinker element, alternatively, may also be porous by containing open pores allowing water entering the pores. The porous material may be any absorbent material. In this case, the water entering the pores and displacing the air will contribute to a negative buoyancy provided by the sinker device.

[0240] The capsule device has an opening 55 and a first end 52a of the preparation extending, in the compact condition, through the opening 55 for allowing pulling out the preparation from the hollow space into the surrounding area of the capsule device thereby transferring the preparation from the compact condition to the expanded condition. During administration, the end 52a of the preparation may be fixed to the teeth of the patient. Also here, the opening 55 and the preparation 52 are dimensioned such that, when the preparation is pulled out from the opening 55, a spacing is provided in an opening cross section of the opening between the preparation and a surface of the capsule device defining the opening. The spacing and, in this embodiment, additionally the optional pores 53c extending through the wall of the capsule device, allow water to enter the hollow space, while air leaves the hollow space. In this case, the water entering the pores and the opening, thereby displacing the air, contributes to a negative buoyancy provided by the sinker device.

[0241] The dosage form according to the invention is further elucidated by the following examples.

EXAMPLE 1

[0242] The single-layered or multi-layered preparation according to the present invention preferably has a paper-like form.

[0243] The preparation according to the present invention dissolves preferably within 1 h, more preferably within 30 min, most preferably within 15 min and particularly most preferably within 5 min after contact with the site of action, in particular the mucous membrane.

[0244] They essentially comprise a mucoadhesive, active substance containing layer, which preferably comprises: mucoadhesive polymers such as cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid, and polyacryl derivatives, polyvinylpyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectins, dextrans, lectins, chitosan, pullulan, and mixtures thereof, plasticizers such as polyethylene glycol, glycerol, sorbitol, and mixtures thereof, and solvents such as water, ethanol, methanol, acetone, organic solvents, and mixtures thereof. Furthermore, additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, penetration enhancers, solubilizers, disintegration accelerators, lubricants, and mixtures thereof may be contained.

[0245] In particular, substances out of the following groups are suitable as active pharmaceutical ingredients: drugs acting on the skeleton and the muscles, drugs acting on the nervous system, hormones and drugs acting on the hormonal system, gynecological acting drugs, drugs acting on the cardio-vascular system, drugs acting on the respiratory system, drugs acting on the gastrointestinal tract, diuretics, drugs acting on the sensory organs, dermatics, vitamins and micronutrients, peptide based drugs and proteins, analgesics, anti-infectives, and parasizides.

[0246] Development and Testing

[0247] In order to develop and test a preparation in the form of a wafer suitable for the present invention, testing methods based on the following test and selection protocol 1 have been conducted.

[0248] In this way, preparations are obtained that meet the requirements which arise, in particular, for a usage in connection with the dosage form.

[0249] In particular, the wafers according to the present invention are distinguished over previously known wafers by the fact that they do not dissolve at just a slight contact with fluid already and that they have a relatively high stretchiness and fracture resistance.

[0250] Especially for a vaginal, rectal or intestinal mucous membrane, a tensile strength of less than 3.5 MPa may be beneficial to increase the safety, the user convenience and/or to enable a close but flexible fitting of the sheet like preparation with the respective mucosa.

[0251] Especially for an esophageal mucous membrane and/or for the application to the esophagus, a tensile strength of more than 15 MPa may be beneficial, particularly for avoiding a rupture of the sheet like preparation during its application, especially during swallowing the dosage form.

EXAMPLE 2—SINGLE-LAYERED PREPARATION

[0252] Single-layered preparations, in particular wafers, that are suitable for the usage according to the invention, may, in particular, comprise the following formulations:

TABLE-US-00001 A 10% PVA 20% PEG 400 5% HPMC x % active pharmaceutical ingredient ad 100 % demineralized water B 5% PVA 15% Kollicoat IR x % active pharmaceutical ingredient ad 100 % demineralized water or C 5% PVA 15% Kollicoat IR 8% Glycerol 85 % x % active pharmaceutical ingredient ad 100 % demineralized water

EXAMPLE 3—TWO-LAYERED PREPARATION

[0253] Two-layered preparations, in particular wafers, according to the present invention comprise a mucoadhesive layer containing an active substance and a water-impermeable layer, which is called a backing layer. The mucoadhesive layer containing an active substance is preferably composed of mucoadhesive polymers as cellulose derivates, starch and starch derivates, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylate derivates, polyvinylpyrollidone, Povidone, Copovidone, sodium alginate, gelatin, xanthan gum, guar gum, Carrageenan, pectins, dextrans, lectins, Chitosan, Pullulan an mixtures thereof, plasticizers such as polyethylene glycol, glycerol, sorbitol and mixtures thereof, and the solvent such as water, ethanol, methanol, acetone, organic solvents and mixtures thereof. Furthermore, additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, penetration enhancers, solubilizers, disintegration accelerators, lubricants, and mixtures thereof may be contained. Substances of the following group are suitable as active pharmaceutical ingredients: Drugs acting on the skeleton and on the muscles, drugs acting on the nervous system, hormones and drugs acting on the hormonal system, gynecological acting drugs, drugs acting on the cardio-vascular system, drugs acting on the respiratory system, drugs acting on the gastrointestinal tract, diuretics, drugs acting on the sensory organs, dermatics, vitamins and micronutrients, peptide based drugs and proteins, analgesics, anti-infectives and parasizides.

[0254] The backing layer preferably comprises an ethyl cellulose layer of varying thickness, wherein ethyl cellulose of different viscosities may be used. Furthermore, it is possible to incorporate further additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, solubilizers, pore formers, lubricants, and mixtures thereof.

[0255] Table 1 which follows shows various exemplary compositions of layers of a two-layered wafer 3 according to the present invention.

TABLE-US-00002 TABLE 1 Adhesive layer containing an active substance PVA 10% 10% 10% 10% 10% PEG 400 20% 20% 20% 20% 20% HPMC  5%  5%  5%  5%  5% Active pharmaceutical  x %  x %  x %  x %  x % ingredients Water ad 100%   ad 100%   ad 100%   ad 100%   ad 100%   Water-impermeable layer (backing layer) Ethyl cellulose 10 300 μg 400 μg 500 μg 750 μg 5000 μg (4% solution in acetone) EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm Ethyl cellulose 45 300 μg 400 μg 500 μg 750 μg 5000 μg (4% solution in acetone EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm

[0256] The strip-like, in particular film-shaped, foil-shaped, wafer-shaped preparation 2 comprising the active pharmaceutical ingredient comprises at least one first layer containing the active substance. The layer containing the active substance preferably comprises a polymer, more preferably a film-forming polymer, wherein the polymer fraction in the layer containing the polymer and the active substance is 10 to 90% by weight, preferably 20 to 70% by weight, and more preferred 30 to 60% by weight, and wherein the layer containing the active substance, in particular in a two-layered wafer, is an adhesive layer, and wherein the polymer is a water-dispersible and/or water-decomposable and/or water-disintegrable film-forming polymer.

[0257] Furthermore, the strip-like, in particular film-shaped or wafer-shaped preparation 2 comprising the active pharmaceutical ingredient comprises at least one active substance free layer, that does not contain an active pharmaceutical ingredient. In a three-layered wafer 2 the wafer 2 comprises a further active substance-free layer that also does not contain an active pharmaceutical ingredient. Such a first active substance free layer and/or such a further active substance free layer is preferably a water-insoluble layer, e.g. made of or comprising ethyl cellulose. An active substance free layer and/or a further active substance free layer may be formed as an adhesive layer, in particular in a two-layered wafer 2, wherein the layer consists of or comprises e.g. hydroxypropyl methylcellulose. In a multi-layered, in particular three-layered wafer 2 layer containing the active substance is preferably arranged between two active substance free layers, wherein a layer containing the active substance may be arranged between a first active substance free layer and a further active substance free layer and wherein preferably the first active substance free layer is a water-insoluble layer, which more preferably comprises ethyl cellulose, and wherein the at least one further active substance-free layer 9d is an adhesive layer, which more preferably comprises hydroxypropyl methylcellulose.

EXAMPLE 4—THREE-LAYERED PREPARATION

[0258] Three-layered preparations, in particular wafers, according to the present invention preferably comprise a mucoadhesive layer containing an active substance, a water-impermeable layer, which is called a backing layer, and an adhesive protective layer. The mucoadhesive layer containing the active substance may be composed of mucoadhesive polymers such as cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid, and polyacryl derivatives, polyvinylpyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectins, dextrans, lectins, chitosan, pullulan, and mixtures thereof, plasticizers such as polyethylene glycol, glycerol, sorbitol, and mixtures thereof, and solvents such as water, ethanol, methanol, acetone, organic solvents, and mixtures thereof. Furthermore, additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, penetration enhancers, solubilizers, disintegration accelerators, lubricants, and mixtures thereof may be contained. In particular, substances out of the following groups are suitable as active pharmaceutical ingredients: drugs acting on the skeleton and the muscles, drugs acting on the nervous system, hormones and drugs acting on the hormonal system, gynecological acting drugs, drugs acting on the cardio-vascular system, drugs acting on the respiratory system, drugs acting on the gastrointestinal tract, diuretics, drugs acting on the sensory organs, dermatics, vitamins and micronutrients, peptide based drugs and proteins, analgesics, anti-infectives, and parasizides. The backing layer is made of an ethyl cellulose layer with a varying thickness, wherein ethyl cellulose with various viscosities may be used. Moreover, the incorporation of other additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, solubilizers, pore formers, lubricants, and mixtures thereof is possible. The adhesive protective layer may vary in its thickness and is made of mucoadhesive polymers such as cellulose derivatives, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid, and polyacryl derivatives, polyvinylpyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectins, dextrans, lectins, chitosan, pullulan, and mixtures thereof, and a solvent such as water, ethanol, methanol, acetone, organic solvents, and mixtures thereof. Furthermore, additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, penetration enhancers, solubilizers, disintegration accelerators, pore formers, lubricants, and mixtures thereof may be contained.

[0259] Table 2 which follows shows various exemplary compositions of layers of such a three-layered wafer 3.

TABLE-US-00003 TABLE 2 Adhesive protective layer HPMC 50-100 μm 50-100 μm 50-100 μm 50-100 μm (0.5% solution in water) layer layer layer layer Mucoadhesive layer containing the active substance PVA 10% 10% 10% 10% PEG 400 20% 20% 20% 20% HPMC  5%  5%  5%  5% Active pharmaceutical ingredients  x %  x %  x %  x % Water ad 100%   ad 100%   ad 100%   ad 100%   Water-impermeable layer (backing layer) Ethyl cellulose 10 300 μg 400 μg 500 μg 750 μg (4% solution in acetone) EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 Ethyl cellulose 45 300 μg 400 μg 500 μg 750 μg (4% solution in acetone EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2

[0260] A sheet-like preparation 3 of a pharmaceutical dosage form 1 according to the present invention may also be formed out of one layer or out of multiple layers, in particular out of two layers.

EXAMPLE 5

[0261] Regarding the Calculation of the Amount of Active Ingredient Per Wafer:

[0262] In particular, the amount of active ingredient based on the layer thickness of the wet polymer film can be calculated according to the following formula:

[00001]$m\left(\mathrm{active}\mathrm{pharmaceutical}\mathrm{ingredient}\right)=\frac{m\left(\mathrm{formulation}\right)*m\left(\frac{\mathrm{acti\nu e}\mathrm{pharmaceutical}\mathrm{ingredient}}{wafer}\right)*10000}{p\left(\mathrm{polymer}\mathrm{mass}\right)*A\left(\mathrm{wafer}\right)*h\left(\mathrm{doctor}\mathrm{blade}\right)}$

wherein
m mass [g]
p density [g/cm.sup.3]
A area [cm.sup.2]
h height [μm]

[0263] In this context it is important to keep in mind that the height of the doctor blade is not equal to the layer thickness of the wet wafer. Reasons for this are, for example, the shearing of the polymer film while it is spread out, the flowing apart or flowing together of the polymer composition after spreading out, and the formation of thicker regions at the edges of the polymer film. The extent of these processes is, inter alia, dependent on the viscosity of the polymer solution and on the used active pharmaceutical ingredient. Therefore, for each active pharmaceutical ingredient a specific individual fraction may be added to the calculated amount of active ingredient. This additional fraction is [0264] 35% for sodium fluorescein [0265] 40% for quinine [0266] 35% for sodium diclofenac

[0267] Moreover, one may use a drug specific factor to adjust the calculated amount, wherein, in particular, the drug specific factor is 100%+the additional fraction, and therefore the formula reads:

[00002]$m\left(\mathrm{active}\mathrm{pharmaceutical}\mathrm{ingredient}\right)=\frac{m\left(\mathrm{formulation}\right)*m\left(\frac{\mathrm{acti\nu e}\mathrm{pharmaceutical}\mathrm{ingredient}}{wafer}\right)*10000}{p\left(\mathrm{polymer}\mathrm{mass}\right)*A\left(\mathrm{wafer}\right)*h\left(\mathrm{doctor}\mathrm{blade}\right)}*\mathrm{drug}\mathrm{specific}\mathrm{factor}$

EXAMPLE 6—MANUFACTURE OF SINGLE-LAYERED WAFERS

[0268] The manufacture of single-layered wafers is carried out by a solvent casting method, wherein at first all ingredients are dissolved in the solvent, homogenized, and subsequently spread out on a suitable release liner to the desired thickness using a doctor blade. Then, the resulting film is dried under defined conditions and then cut into pieces of suitable size.

[0269] In the following, the manufacturing methods for the preparations mentioned in Example 2 above are described in detail:

A At first, polyvinyl alcohol (PVA) is dissolved in demineralized water in a beaker at a temperature of 90° C. and at a stirring speed of 400 rpm. Then, polyethylene glycol 400 (PEG 400) and the medical substance or the medical substance solution, respectively, is added and the solution is homogenized. Finally, hydroxypropyl methylcellulose (HPMC) is added with stirring, homogenized, and the evaporation loss is compensated with demineralized water. The polymer solution is covered and left overnight and centrifuged on the next day at 4400 rpm for 50 min in order to remove air bubbles. Then, the solution is evenly spread out onto the release liner by means of a doctor blade and the polymer film is dried for 6 h at 40° C. in a drying cabinet. Before testing and further use, the film is cut into appropriately sized pieces and detached from the release liner. The single-layered wafer is stored on the release liner and is wrapped in aluminum foil.
B At first, polyvinyl alcohol (PVA) and Kollicoat IR are dissolved in demineralized water in a beaker at a temperature of 90° C. and at a stirring speed of 400 rpm. Then, the medical substance or the medical substance solution, respectively, is added, homogenized, and the evaporation loss is compensated with demineralized water. The polymer solution is covered and left overnight and is centrifuged at 4400 rpm for 15 min on the next day in order to remove air bubbles. Then, the polymer solution is evenly spread out onto the release liner by means of a doctor blade and the polymer film is dried for 5 h at 40° C. in a drying cabinet. Before testing and further use, the film is cut into appropriately sized pieces and detached from the release liner. The single-layered wafer is stored on the release liner and is wrapped in aluminum foil.
C At first, polyvinyl alcohol (PVA) and Kollicoat IR are dissolved in demineralized water in a beaker at a temperature of 90° C. and at a stirring speed of 400 rpm. Then, Glycerol 85% and the medical substance or the medical substance solution, respectively, are added, homogenized, and the evaporation loss is compensated with demineralized water. The polymer solution is covered and left overnight and is centrifuged at 4400 rpm for 15 min on the next day in order to remove air bubbles. Then, the polymer solution is evenly spread out onto the release liner by means of a doctor blade and the polymer film is dried for 5 h at 40° C. in a drying cabinet. Before testing and further use, the film is cut into appropriately sized pieces and detached from the release liner. The single-layered wafer is stored on the release liner and is wrapped in aluminum foil.

EXAMPLE 7—MANUFACTURE OF MULTI-LAYERED WAFERS

[0270] For the manufacturing of multi-layered wafers, like those mentioned in Example 3 and Example 4, the individual layers are initially manufactured by the solvent casting method. Therefore, all ingredients of the layer are dissolved in the solvent, homogenized, and subsequently spread out to the desired thickness using a doctor blade. Then, the individual layers are either spread out one above the other or joint together in various ways such as pressure or “gluing”. Thereafter, the resulting film is cut into pieces of appropriate size.

[0271] In the following, the manufacturing methods for the above-mentioned formulations of two- and three-layered wafers are described in detail:

[0272] Manufacture of Two-Layered Wafers:

[0273] 1. At first, the polymer solution for the mucoadhesive layer containing the active substance is manufactured according to “Manufacture of Single-layered Wafers A” and a 4% (w/v) ethyl cellulose solution EC solution in acetone is prepared. Then, the EC solution is evenly sprayed onto the release liner with the desired layer thickness and dried at room temperature for 15 min. Then, the polymer solution is evenly spread out over it by means of the doctor blade and the resulting two-layered film is dried at 40° C. for 6 h in a drying cabinet. Before testing and further use, the film is cut into appropriately sized pieces and detached from the release liner. The two-layered wafer is stored on the release liner and wrapped into aluminum foil.

[0274] 2. At first, the polymer solution for the mucoadhesive, active substance containing layer is prepared according to “Manufacture of a Single-layered Wafer A” and a 4% (w/v) EC solution in acetone is prepared. The, the polymer solution is evenly spread out onto the release liner by means of a doctor blade and the polymer film is dried for 4 h at 40° C. in a drying cabinet. Then, the EC solution is evenly sprayed onto the partly dried, still sticky polymer film in the desired layer thickness. Finally, the resulting two-layered film is, again, dried for 2 h at 40° C. in a drying cabinet such that both layers firmly interconnect. Before testing and further use, the film is cut into appropriately sized pieces and pulled off the release liner. The two-layered wafer is stored on the release liner and wrapped in aluminum foil.

[0275] 3. At first, the polymer solution for the mucoadhesive, active substance containing layer is prepared according to “Manufacture of a Single-layered Wafer A” and a 4% (w/v) EC solution in acetone is prepared. Then, the polymer solution is evenly spread onto the release liner by means of a doctor blade and the polymer film is dried for 4 h at 40° C. in a drying cabinet. In parallel, the EC solution is evenly sprayed onto a second release liner in the desired layer thickness and dried for 15 min at room temperature. Then, the resulting EC film is carefully detached from the release liner and is pressed onto the partly dried, still sticky polymer film by means of a roller. Finally, the now two-layered film is dried for 2 h at 40° C. in a drying cabinet such that both layers firmly interconnect. Before testing and further use, the film is cut into appropriately sized pieces and detached from the release liner. The two-layered wafer is stored on the release liner and wrapped in aluminum foil.

[0276] Manufacture of Three-Layered Wafers:

[0277] 1. At first, the polymer solution for the mucoadhesive, active substance containing layer prepared according to “Manufacture of Single-layered Wafer A”, a 4% (w/v) EC solution in acetone, and a 0.5% (w/v) HPMC solution in cold, demineralized water is prepared. Then, the EC solution is evenly sprayed onto the release liner with a desired layer thickness and dried for 15 min at room temperature. Then, the polymer solution is evenly spread out over it by means of a doctor blade and the resulting two-layered film is dried for 6 h at 40° C. in a drying cabinet. Finally, the HPMC solution is spread out over it as a third layer by means of a doctor blade and the resulting three-layered film is, once again, dried for 2 h at 40° C. in a drying cabinet such that all layers firmly interconnect. Before testing and further use, the film is cut into appropriately sized pieces and detached from the release liner. The three-layered wafer is stored on the release liner and wrapped into aluminum foil.

[0278] 2. At first, the polymer solution for the mucoadhesive layer containing the active ingredient is prepared according to “Manufacture of Single-layered Wafers”, a 4% (w/v) EC solution in acetone is prepared, and a 0.5% (w/v) HPMC solution in cold, demineralized water is prepared. Then, the EC solution is evenly sprayed onto the release liner in the desired layer thickness and dried for 15 min at room temperature. Then, the polymer solution is evenly spread out over it by means of a doctor blade and the resulting two-layered film is dried for 6 h at 40° C. in a drying cabinet. In parallel, the HPMC solution is spread out onto a second release liner with their desired layer thickness and dried for 2 h at 40° C. in a drying cabinet. Then, the HPMC film is carefully pulled off the release liner and glued onto the two-layered film with water as binder. Finally, the resulting two-layered film is dried for 1 h at 40° C. in a drying cabinet such that all layers firmly interconnect. Before testing and further use, the film is cut into appropriately sized pieces and pulled off the release liner. The three-layered wafer is stored on the release liner and wrapped into aluminum foil.

[0279] 3. At first, the polymer solution for the mucoadhesive, active substance containing layer is prepared according to “Manufacture of Single-layered Wafers A”, a 4% (w/v) EC solution in acetone is prepared, and a 0.5% (w/v) HPMC solution in cold, demineralized water is prepared. Then, the polymer solution is evenly spread out onto the release liner by means of a doctor blade and the polymer film is dried for 6 h at 40° C. in a drying cabinet. In parallel, the HPMC solution is spread out onto a second release liner in the desired layer thickness and dried for 1 h at 40° C. in a drying cabinet. Then, the resulting polymer film is carefully pulled off the release liner and pressed onto the partly dried, still sticky HPMC film by means of a roller. Then, the now two-layered film is dried for 1 h at 40° C. in a drying cabinet such that both layers firmly interconnect. Finally, the EC solution is evenly sprayed onto the two-layered film with a desired layer thickness and the resulting three-layered film is dried for 30 min at room temperature. Before testing and further use, the film is cut into appropriately sized pieces and pulled from the release liner. The three-layered wafer is stored on the release liner and wrapped into aluminum foil.

[0280] 4. At first, the polymer solution for the mucoadhesive, active substance containing layer is prepared according to “Manufacture of Single-layered Wafers A”, a 4% (w/v) EC solution in acetone is prepared, and a 0.5% (w/v) HPMC solution in cold, demineralized water is prepared. Then, the HPMC solution is spread out onto the release liner with a desired layer thickness and dried for 2 h at 40° C. in a drying cabinet. Then, the polymer solution is spread out over it by means of a doctor blade and the resulting two-layered film is dried for 4 h at 40° C. in a drying cabinet. In parallel, the EC solution is evenly sprayed onto a second release liner in the desired thickness and dried for 15 min at room temperature. Subsequently, resulting EC film is carefully pulled off the release liner and pressed onto the partly dried, still sticky two-layered film by means of a roller. Finally, the now three-layered film is dried for 2 h at 40° C. in a drying cabinet such that all layers firmly interconnect. Before testing and further use, the film is cut into appropriately sized pieces and pulled off the release liner. The three-layered wafer is stored on the release liner and wrapped into aluminum foil.

[0281] The features of the present invention disclosed in the description above, in the claims, and in the drawings can be essential both individually and also in any combination for implementing the invention in its various embodiments.

[0282] Especially, the exemplary embodiments of the invention relate to an orally administrable dosage form for the treatment of the esophageal mucosa. An exemplary process of administering the dosage form by swallowing the same is shown in FIGS. 9a to 9d. An applicator 100 is used, which contains a pharmaceutical dosage from according to the invention. A coiled string member 2b is connected to the end portion 2a of the preparation 2 of the dosage form (1 or 31). The applicator is connected to a vessel 101 with water. Drinking from the applicator involves rinsing of the applicator by the water inside the vessel and thereby transporting the dosage form into the mouth of the patient, while the string member 2b stays connected to the applicator. After the dosage form is fully swallowed and arrived in the stomach of the patient (FIG. 9c) the patient removes the end portion of the string member 2b and connects the same to the teeth for fixating the string member and the preparation in its expanded condition, where it is located inside the esophagus. In this case, the preparation 2 can deliver useful substances such as an active pharmaceutical ingredient to the esophageal mucous membrane by unrolling its sheet like preparation 2 while moving along the esophagus when it is swallowed (FIG. 9b, c). Thus, active pharmaceutical ingredients contained in the sheet like preparation 2 can be locally released to the mucous membrane of the esophagus. Current treatments for local diseases of the esophagus generally employ swallowing the content of application systems, which were designed for inhalation therapy of the lung, or swallowing a gel containing specific drugs. However, generally the swallowed content of the application systems or the gel only has a short contact time with the esophageal mucosa. Therefore, the local effect is decreased and the systemic effect is increased, in particular, compared to an application form, in which the contact time is prolonged. By applying the sheet like preparation 2 to the esophageal mucosa a pharmaceutical dosage form according to the embodiment of the invention the treatment of local diseases of the esophagus can be improved and, in particular, the contact time can be prolonged and the reliability of the process of pulling out the preparation from the capsule and, thus, the reliability of the overall administration process is improved. When applied to the esophageal mucosa, the sheet like preparation 2 stays in contact with the mucosa whilst providing a controlled release of the active pharmaceutical ingredient in order to achieve a local therapy or diagnosis. Preferably, the controlled release can neither be immediate, sustained or prolonged, also preferably, during or after the release of the active pharmaceutical ingredient or the active pharmaceutical ingredients the sheet like preparation 2 dissolves and is, preferably swallowed. Moreover, the shell (=capsule) 3 may detach from the sheet like preparation 2 immediately after the release of the sheet like preparation 2 (FIG. 9c, d) or may dissolve while still attached to the sheet like preparation 2. Preferably, the shell 3 is made of a dissolvable and/or digestible material. In particular, the end portion 2a may be adapted to be fixed in the oral cavity. Therefore, the end portion 2 may include a mucoadhesive surface, preferably comprising cellulose derivates, starch and starch derivates, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylate derivates, polyvinylpyrollidone, Povidone, Copovidone, sodium alginate, gelatin, xanthan gum, guar gum, Carrageenan, pectins, dextrans, lectins, Chitosan, Pullulan an mixtures thereof.

[0283] So, preferably, the holding device 5 can be attached to the oral mucosa, in particular the buccal mucosa, i.e. the inside of the cheek.

[0284] Even more specifically, the embodiments of the invention may refer to a pharmaceutical dosage form for the treatment of eosinophilic esophagitis. Eosinophilic esophagitis is an inflammatory, immune-mediated disease with increasing relevance in gastrointestinal disorders. This disease can be treated with topic steroids. Preferably, the shell 3 is a capsule made out of hard gelatin. In an initial state of the dosage form, the sheet like preparation 2 is in a compact form, in particular in form of a coil, and is connected to an applicator containing the dosage form and water at an initial phase. On administration, the end portion 2a is attached in the oral cavity, preferably to the buccal mucosa, in particular by gluing it to the mucosa. Next, the dosage form is swallowed, preferably with a beverage or water, and, therefore, the dosage form moves along the esophagus and a force acts on the end portion 2a by conveying the capsule towards the stomach. While the dosage form moves down the esophagus the sheet like preparation 1 is unrolled, and thus released. Preferably, the sheet like preparation is mucoadhesive, and thus may adhere to the mucous membrane of the esophagus. In this case, the contact and/or position of the sheet like preparation is not or is not only dependent on the position o the end portion 2a in the oral cavity. Afterwards, an oblong region of the esophageal mucosa is covered or at least near to the sheet like preparation 2. Thus, it can be treated with active pharmaceutical ingredients, in particular topic steroids, released by the sheet like preparation 2. Preferably, the sheet like preparation 2 may comprise and release fluticasone or budesonide.

[0285] Preferably, the manufacture of a sheet like preparation 2, in particular according to the embodiments of the present invention, is carried out by a solvent casting method, wherein at first all ingredients are dissolved in the solvent, homogenized, and subsequently spread out on a suitable release liner to the desired thickness using a doctor blade. Then, the resulting film is dried under defined conditions and then cut into pieces of suitable size.

[0286] In a preferred variant, the ingredients, particularly the polymer matrix, consists of 10% m/m polyvinyl alcohol (PVA) (Mowiol 40-88) suspended in a 20% m/m Kollicoat IR aqueous solution. Furthermore, the active pharmaceutical ingredient such as fluticasone or budesonide as well as additives such as methylene blue as a visual control is added.

[0287] A sheet like preparation 2 manufactured according to this preferred variant has been experimentally analyzed. For this purpose the sheet like preparation 2 was tested for film thickness and uniformity of mass. Furthermore, disintegration time was tested both and purified water and on wetted are alginate gel (3% m/m) to simulate the mucosa. Fully disintegration was defined as the absence of any solid matrix particle. Tensile strength, elongation and extraction force have been measured using a texture analyzer. All tests were performed triplicate and mean plus/minus standard derivation are reported. The resulting sheet like preparation 3 had a thickness of 114±5 μm and a mean mass of 9.39±0.03 mg/cm.sup.2. The disintegration time in water was 760±35 s, and greater than 1200 s on alginate gel. The tensile strength was 31.35 MPa. The elongation at break was 7.41±0.90%.

[0288] Preferably, a pharmaceutical dosage form, in particular according to the embodiments of the present invention, may be manufactured as described in the following: [0289] cutting the film resulting from a solvent casting technique to strips of 400 mm by 4 mm; [0290] folding or rolling the resultant sheet like preparations 2; [0291] providing a hard gelatin capsule of size 1 is a shell 3; [0292] milling an opening 5 into a part of the hard gelatin capsule 3, specifically, as illustrated, into the upper part; [0293] threading one end of the sheet like preparation 2 through the opening 5; and [0294] closing the capsule.

[0295] A dosage form manufactured as described above comprising the preferred variant of the sheet like preparation 2, in particular for the embodiments of the present invention, has been experimentally analyzed, as described above. The extraction force of the sheet like preparation 2 from the capsule was documented in diagram of FIG. 8.

[0296] Furthermore, as shown in FIG. 4f, the sheet like preparation 2 may optionally comprise two regions, a first region of the sheet like preparation 2c and a second region of the sheet like preparation 2c. The first region 2c is pulled out from the opening, and the second region 2c is pulled out following the first region 2c. The first region 2c and the second region 2d may comprise different active pharmaceutical ingredients. Preferably, the first region 2c can comprise local anesthetics such as benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine or novocaine, and the second region 2d can comprise a steroid such as corticosteroids, glucocorticoids, fluticasone, budesonide or clocortolone. In particular, in this way, when treating the esophagus, a gag reflex can be suppressed by the local anesthetic and the esophageal mucous membrane can be treated with the steroid. Additionally, the first region 2c has a smaller cross-sectional area than the second region 2d. In particular, this beneficially facilitates swallowing the dosage form.

[0297] Furthermore, the end portion 2a is connected to the sheet like preparation 2 or is a broadened part of the sheet like preparation 2 with a mucoadhesive layer preferably comprising: mucoadhesive polymers such as cellulose derivatives, starch and starch derivatives, sodium alginate, gelatin, xanthan gum, guar gum, carrageenan, pectins, dextrans, lectins, and mixtures thereof.

[0298] Preferably, the preparation 2 is manufactured according to one manufacturing method described in here. In particular, the sheet like preparation with multiple regions, especially at least a first region 2c and at least a second region 2d, can be manufactured similarly to a multi-layered preparation, wherein, at least some of, the layers are offset to each other but still partially overlap. Also the end portion 2a may be manufactured and/or connected to the sheet like preparation 2 in this way.