PHARMACEUTICAL DOSAGE FORM FOR APPLICATION TO MUCOUS MEMBRANES

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 sheet like, in particular film shaped, foil shaped or wafer shaped preparation comprising the active pharmaceutical ingredient, a release mechanism, and a trigger mechanism, wherein the trigger mechanism is adapted to trigger, at a predetermined site of action, in particular of the gastrointestinal tract, of the rectum or of the vagina, the release of the sheet like preparation by the release mechanism.

Claims

1. A pharmaceutical dosage form (1) for the application to a mucous membrane, comprising at least one sheet like, preparation (3) comprising an active pharmaceutical ingredient, a release mechanism (4) and a trigger mechanism (5), wherein the trigger mechanism (5) is adapted to trigger, at a predetermined site of action, the release of the sheet like preparation (3) by the release mechanism (4), and wherein the pharmaceutical dosage form (1) further comprises a shell (2), wherein the shell (2) contains the preparation (3), characterized in that the release mechanism (4) is an expansion mechanism (4).

2. The pharmaceutical dosage form (1) according to claim 1, wherein the expansion mechanism (4) is selected from the group consisting of a mechanical expansion system, a gas driven expansion system, compressed foam and compressed tissue.

3. (canceled)

4. The pharmaceutical dosage form (1) according to claim 1, wherein an expansion of the expansion mechanism (4) results in an opening of the shell (2).

5. The pharmaceutical dosage form (1) according to claim 1, wherein the dosage form (1) contains the preparation (3) in a folded form.

6. The pharmaceutical dosage form (1) according to claim 1, wherein the shell (2) contains a gas-forming agent as the release mechanism (4) and the gas-forming agent is arranged in a part of the shell (2) that is opposed to the part of the shell (2) containing the preparation (3).

7. The pharmaceutical dosage form (1) according to claim 1, wherein the expansion mechanism (4) is a mechanical expansion system comprising at least a first joint or lever element (13), and/or wherein the expansion mechanism (4) is a mechanical expansion system comprising at least one spring element (10).

8. The pharmaceutical dosage form (1) according to claim 1, wherein the preparation (3) comprises a swelling agent (11).

9. The pharmaceutical dosage form (1) according to claim 1, wherein the shell (2) at least comprises a first tube element (11).

10. The pharmaceutical dosage form (1) according to claim 1, wherein the expansion mechanism (4), comprises at least a first joint or lever element (13) and a second joint or lever element (14).

11. The pharmaceutical dosage form (1) according to claim 10, wherein: a) the first joint or lever element (13) and/or the second joint or lever element (14) is at least partially covered by the trigger mechanism (5); and/or b) the at least one first joint or lever element (13) or the at least one second joint or lever element (14) is arranged such that the at least one first joint or lever element (13) or the at least a second joint or lever element (14) of one end is arranged adjacent to a respective joint or lever element of the other end.

12.-17. (canceled)

18. The pharmaceutical dosage form of claim 1, wherein: a) the mucous membrane is a buccal, intestinal, rectal or vaginal mucous membrane; b) the sheet like preparation is a film shaped, foil shaped or wafer shaped preparation; or c) the predetermined site of action is the gastrointestinal tract, the rectum or the vagina.

19. The pharmaceutical dosage form of claim 5, wherein expansion of the expansion mechanism (4) results in an unfolding of the preparation (3).

20. The pharmaceutical dosage form of claim 6, wherein the shell contains a gas-forming agent as the expansion mechanism (4).

21. The pharmaceutical dosage form of claim 7, wherein: a) the mechanical expansion system comprises a hinge; or b) the spring element (10) is a compression spring.

22. The pharmaceutical dosage form of claim 8, wherein the swelling agent (11) is selected from the group consisting of a sponge and fibers.

23. The pharmaceutical dosage form of claim 9, wherein the shell (2) further comprises at least a second tube element (12).

24. The pharmaceutical dosage form of claim 23, wherein the second tube element (12) has a smaller tube diameter than the first tube element (11).

25. The pharmaceutical dosage form of claim 24, wherein the second tube element (12) is arranged at least partially in the first tube element (11).

26. The pharmaceutical dosage form of claim 23, wherein the mechanical expansion system comprises at least one spring element (10), wherein the spring element (10) is arranged such that the spring element (10) can move the second tube element (12) longitudinally relative to the first tube element (11).

27. The pharmaceutical dosage form of claim 10, wherein: a) the first joint or lever element (13) and/or the second joint or lever element (14) is arranged at a free end of the shell (2); or b) the first joint or lever element (13) is a lever and/or the second joint or lever element (14) is a lever.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0239] FIG. 1 shows a schematic perspective illustration of a pharmaceutical dosage form according to the invention in accordance with a first embodiment of the invention in an initial state;

[0240] FIG. 2 shows a schematic perspective illustration of a pharmaceutical dosage form according to the invention in accordance with the first embodiment of the invention in a state after the release of the sheet-like preparation by the release mechanism;

[0241] FIG. 3 shows a schematic perspective illustration of a pharmaceutical dosage form according to the invention in accordance with a second embodiment of the invention in an initial state;

[0242] FIG. 4 shows a schematic perspective illustration of a pharmaceutical dosage form according to the invention in accordance with the second embodiment of the invention in a state after the release of the sheet-like preparation by the release mechanism;

[0243] FIG. 5a, 5b show a schematic perspective illustration of a pharmaceutical dosage form according to the invention in accordance with a third embodiment of the invention in an initial state;

[0244] FIG. 5c shows a photograph of a pharmaceutical dosage form according to the invention in accordance with the third embodiment of the invention in an initial state;

[0245] FIG. 6a, 6b show a schematic perspective illustration of a pharmaceutical dosage form according to the invention in accordance with a fourth embodiment of the invention in an initial state;

[0246] FIG. 6c shows a photograph of a pharmaceutical dosage form according to the invention in accordance with the fourth embodiment of the invention in an initial state;

[0247] FIG. 7 shows the schematic structure of an example of a three-layered film-shaped preparation of the present invention;

[0248] FIG. 8a, 8b show a schematic illustration of a pharmaceutical dosage form according to the invention in accordance with a fourth embodiment of the invention; and

[0249] FIG. 8c illustrates the enveloping cross-sectional areas of the fourth embodiment of the invention.

[0250] In FIG. 1 a schematic perspective illustration of the pharmaceutical dosage form 1 according to the invention in accordance with a first embodiment of the invention in an initial state is shown. FIG. 2 shows the pharmaceutical dosage form 1 from FIG. 1 in a state after the release of the sheet-like preparation 3 by the release mechanism 4. In FIGS. 1 and 2 it can be seen that the illustrated pharmaceutical dosage form 1 comprises, in particular for the oral administration, a capsule-shaped shell 2, the shell contains a sheet-like, in particular film-shaped, foil-shaped or wafer-shaped preparation 3 comprising the active pharmaceutical ingredient in form of a folded, respectively unfoldable wafer 3, as well as a release mechanism 4 and a trigger mechanism 5 that is adapted to trigger the release of the sheet-like preparation 3 by the release mechanism 4 at a predetermined site of action, in particular of the gastrointestinal tract. The shell 2 comprises an aperture 6a on the one side an aperture 6b on the opposite side of the dosage form 1, in particular the aperture 6b is formed as a slit. The aperture 6a is covered by a trigger mechanism 5. When this aperture, at the site of action, is contacted with fluid surrounding the dosage form there, it dissolved and fluid can come into contact with the inner space 7 of the shell 2. The aperture 6a is at least partially covered by the trigger mechanism 5, e.g. a soluble polymer, which is adapted to trigger the release of the sheet-like preparation 3 by the release mechanism 4 after contacting the pharmaceutical dosage form 1, in particular the trigger mechanism 5, with a key stimulus. Here, a predetermined change of a physical or chemical parameter or a fluid surrounding the dosage form 1, in particular gastric juice in the stomach, or alternatively also fluid of the small intestine, which has a substantially lower pH value compared to the oral cavity and pharyngeal cavity, serves as a key stimulus to trigger the trigger mechanism 5. The trigger mechanism 5 is made of a substance whose solubility and/or solidity depends on the pH value that is present in the stomach.

[0251] In FIG. 2 the trigger mechanism 5 is not shown any more because it has already dissolved. The shell 2 is made of a material that is essentially insoluble in the gastric juice, e.g. hard gelatin or starch that is additionally coated with other polymers in order to remain stable in the gastric juice, which are stable on their own (e.g. Eudragit etc.). The release mechanism 4 is embodied as an expansion mechanism 4 that comprises a wick system, more specifically the gas driven expansion system, to which fluid is directed through the wick system by capillary forces. An expansion of the expansion mechanism 4 can result in an opening of the shell 2 at the predetermined breaking point 8 or is alternatively suitable to rupture a coating sealing the aperture 6b. This coating protects the dosage form 1 from an unwanted entry of fluid through the aperture 6b in an initial state. The latter can be seen in the interplay between FIG. 1 and FIG. 2. Preparation 3 is contained in the shell 2 in a folded form that is shown in FIG. 1, whereinas shown in FIG. 2the expansion of the expansion mechanism 4 results in an unfolding of the preparation 3, wherein the preparation 3 escapes through the slit 6b and inflates like a balloon. For this purpose, a gas-forming agent, e.g. a powder that optionally can be incorporated into a wick system, in particular comprising capillaries e.g. fibers, that can absorb a fluid, is arranged in the area of the shell 2, that is shown in FIGS. 1 and 2 on the left hand side, as a release mechanism 4 and expansion mechanism 4. For example, sodium hydrogen carbonate or citric acid or alternatively a pressurized gas is suitable as a gas-forming agent, here.

[0252] In particular, a release mechanism and the expansion mechanism is formed in such a way that the formed gas is directed only into the wafer respectively balloon 3 and cannot escape at another place. At the time of release, the powdery gas-forming agent and the wick system 4 are kept in contact. Therefore it is beneficial when the gas-forming agent is incorporated into the wick system.

[0253] In case of a liquid or partial liquid gas-forming agent, a separated compartment may contain the gas-forming agent, that compartment is at least partially formed out of the outer shell 2 of the dosage form. Thus, the gas-forming agent is arranged in a part of the shell 2 that is opposed to the part of the shell by containing the preparation 3arranged at the right hand side of the shell in the figures. The gas-tight shell 2 which can be filled with a gas comprises a central aperture 6a that is circumferentially attached at an inner edge of the shell 2. After triggering of the release mechanism, liquid is directed to the release mechanism in form of a gas-forming agent through the wick system 4 and gas is formed by the gas-forming agent and is directed into an inner space of the sheet-like preparation 3. For this purpose, this preparation is formed as a gas-tight shell that can be filled with a gas, in particular a balloon, as in particular shown in FIG. 2.

[0254] In FIG. 1 the preparation 3 formed as a gas-tight gas-fillable shell is present in folded form. Furthermore, it can be seen from FIG. 1 that the shell is divided at its periphery. It is also seen from FIG. 1, that the shell comprises at least one predetermined breaking point. It is to be understood that, depending on the actual embodiment, it can be sufficient that the balloon 3 protrudes through the slit 6b only. However, further experiments have shown that in order to completely unfold the balloon a predetermined breaking point 8 at the shell 2 may completely rupture or fold open, in particular by the gas pressure developed in the balloon 3. In particular, such a mechanism can be held together by a coating of the slit 6b in the initial state. Such a coating may also be chosen such that itin particular when it is chosen from a similar or from the same material as the trigger mechanism 5, this coating is etched or dissolved at the trigger site, respectively site of action, such that gas pressure can open up the capsule 2. For this purpose, it may be beneficial, that the coating of the slit 6b dissolves more slowly than the trigger mechanism 5. It is to be understood that just one predetermined breaking point 8 or a folding mechanism at this position may be provided or just a slit 6b or a combination thereof may be provided in different actual further embodiments. The actual embodiment may be chosen by a person skilled in the art depending on the size and scope of application and depending on the actually used materials.

[0255] Gastric juice or intestinal fluid enters at the predetermined trigger site, here e.g. in a stomach or in the intestine, the inner space 7 of the shell through the aperture 6a and results in a formation of gas by the gas-forming agent. Along with this gas is directed into the inner space of the wafer 3 which inflates like a balloon at the site of application and expands. Along with this the capsule-shaped shell 2 is opened at one of itshere right endby e.g. the breaking of the predetermined breaking point 8 by the pressure of the expanding balloon 3 and/or by protruding of the balloon 3 through the aperture 6b. In this way, a complete unfolding and release of the wafer 3 of the capsule 2 is possible. In particular, such a construction allows forming a relatively large wafer surface which can rest over a relatively large area of the gastric wall in order to release the active pharmaceutical ingredient. Alternatively and in particular, such a construction allows forming a relatively large wafer surface which can rest over a relatively large area of the intestinal wall in order to release the active pharmaceutical ingredient. It is also to be understood that a part of the wick system 4 may stick out of the shell and direct the fluid into the inner space of the shell 2. The portion of the wick system 4, which is located outside the shell, is expediently covered by the release mechanism 5 in an initial state, and released upon activation.

[0256] FIG. 3 shows a schematic perspective illustration of a pharmaceutical dosage form 1 according to the invention in accordance with a second embodiment of the invention in initial state. Again, the pharmaceutical dosage form 1, which is, in particular, suitable for oral application, comprises a shell 2 wherein the shell 2 contains a sheet-like, in particular film-shaped, foil-shaped, or wafer-shaped preparation 3 comprising the active pharmaceutical ingredient in form of a folded wafer 3 as well as a release mechanism 4 and a trigger mechanism 5 that is adapted to trigger the release of the wafer 3 by the release mechanism 4 at a predetermined site of action, e.g. the gut. The shell 2 comprises a central aperture 6a, respectively 6b, at both sides that are closed by a coating, e.g. a dissolvable coating or something similar. After the application, the apertures 6a and 6b are covered, whereby the trigger mechanism 5 can come into contact with a fluid. However, an aperture does not have to be present, because the trigger mechanism may also be located at the circumference of the dosage form 1. The fluid of the gastrointestinal tract or the small intestine surrounding the shell 2 comes into contact with the inner space 7 of the shell after dissolution of the coating. The trigger mechanism 5 is adapted to trigger the release of the sheet-like preparation 3 by the release mechanism after contacting the pharmaceutical dosage form, in particular of the trigger mechanism 5, with a key stimulus. For example, in the illustrated embodiment, an action of pressure caused by an intestinal peristalsis or a specific pH value usually prevailing or occurring at the site of action serves as a key stimulus. In the illustrated embodiment, the trigger mechanism is formed by a soluble polymer that is located at the inside of the tube elements 11 and 12. In particular, an action of pressure can serve as a key influence if the levers of the capsule are held together with a material that breaks upon action of pressure. The release mechanism 4 is constructed as an expansion mechanism 4, specifically as a mechanical expansion system, wherein an expansion of the expansion mechanism 4 results in an unfolding of the wafer 3.

[0257] FIG. 4 shows the embodiment illustrated in FIG. 3 in an unfolded state. The shown embodiment comprises, as part of the mechanical expansion system, a plurality of joint or lever elements 13, which are arranged at both free ends of the shell 2 in the area of the central aperture 6, as well as a spring element 10 that is arranged within the tube elements 11 and 12 that are slit into each other. In particular, the joint or lever elements 13a of the first tube 11 and the joint or lever elements 13b in in tube 12 are arranged alternately in a closed initial state of the dosage form 1 as shown in FIG. 3 such that in the closed state as shown in FIG. 3 the joint or lever elements 13a of the first tube 11 and the joint or lever elements 13b of the second tube form a shell 2, respectively a cladding, that is flipped open upon release and that opens up the preparation 3.

[0258] In particular, the length of the lever of the joint or lever elements 13a of the first tube 11 and of the joint or lever elements 13b of the second tube 12 have the whole length of the folded dosage form 1 in this arrangement. It is to be understood that in the case, in which the lever or joint elements 13a and 13b are arranged opposing each other, the maximum length of the lever is limited to half of the length of the dosage form 1. In this case, the first and the second tube element 11 and 12 as well as the lever and joint elements 13a and 13b are arranged such that the lever and/or joint elements 13a, respectively 13b, form a wreath structure and the lever and joint elements 13a at the tube element 11 and the lever and joint elements 13b at the tube element 12 are respectively attached in a slit at the tube element 11, respectively 12, when the dosage form 1 is viewed from the rear or from the front, thus looking on the smallest surface area of a dosage form 1. The resilient force of the spring 10 pushes the lever and joint elements 13a and 13b through this slit 16 to the outside, and the wafer 3 is unfolded as the cladding or shell parts 17 that are pivotally attached at the lever and joint elements 13a and 13 b, respectively, swing outwards. In this context it is to be understood that the pivotally attached cladding or shell parts 17 may also form lever or joint elements and may be understood as such.

[0259] In such an arrangement, it is beneficial if, as shown in FIG. 3, in a closed state of the dosage form 1 the cladding or shell parts 17 of the first tube 11 forming joint or lever elements and the cladding or shell parts 17 of a second tube 12 forming joint or lever elements are arranged alternately such that preferably in a closed state, the cladding or shell parts 17 of a first tube 11 forming joint or lever elements and the cladding or shell parts 17 of the second tube 12 forming joint or lever elements form the shell and/or the cladding 2. The wreath structure at a first end of the dosage form 1, in particular at an end of the first tube element 11, and the wreath structure at a second end of the dosage form 1, in particular at an end of the second tube element 12, are offset in a rotationally symmetric manner. A joint or lever movement of the joint elements 13a and 13b cause an unfolding of a sheet-like preparation 3, that is folded in an initial state in the dosage form 1, by the spring force driven movement in the slit 16 to the outside as the cladding or shell parts 17 swing outwards such that the sheet-like preparation 3 unfolds at a predetermined site of action in a particular advantageous manner, and preferably can contact a mucous membrane or the intestinal wall.

[0260] The shell 2 comprises the tube elements 11 and 12 that are pushed into each other by a spring 16 arranged in the tube elements 11 and 12 in such a way that they can move relatively to each other and that are centrally arranged in the main longitudinal axis of the dosage form 1. By the action of pressure of the intestinal peristalsis or the dissolution of a coating and the subsequent entry of fluid to trigger the release mechanism the mechanical expansion system is triggered and by means of the spring driven joint or lever elements 13a, 13b in combination with the shell or cladding elements 17 the unfolding of the wafer 3 and thus its release out of the shell is effectuated. In particular, this expansion thus can be assisted or directed by providing at least a further joint or lever element.

[0261] FIG. 5a, 5b show a schematic perspective illustration of a pharmaceutical dosage form 1 according to the invention in accordance with a third embodiment of the invention in an initial state and FIG. 5c shows a photograph of the pharmaceutical dosage form according to the invention in accordance with a third embodiment of the invention in an initial state. FIG. 5a shows the embodiment in a side view and FIG. 5b shows a view to the tip of the embodiment. This pharmaceutical dosage form 1 according to the invention is adapted for the application onto a mucous membrane, in particular onto a vaginal mucous membrane, but also onto a rectal mucous membrane, and comprises the sheet-like, in particular film-shaped, foil-shaped or wafer-shaped preparation 3 that comprises the active pharmaceutical ingredient in form of a wafer 3 which is circumferentially arranged at a longitudinal section of the cylindrical main body of the dosage form 1 that tapers on one side. In particular, the main body may be a tampon that is essentially formed out of a swellable material. This swellable material may form both, the release mechanism 4 and the trigger mechanism 5, which swells upon contact of the dosage form 1 with a fluid, in particular a vaginal fluid, and thus unfolds the preparation 3. Because of the increase of the diameter of the dosage form 1 due to the swelling, also the circumference of the preparation 3 increases. This is the case because the preparation 3 may be folded into grooves or depressions of the main body of the dosage form.

[0262] FIGS. 6a, 6b, and 6c show an alternative embodiment that defer from the embodiment shown in the FIGS. 5a, 5b, 5c in that here the preparation 3 is partially folded outwards. Due to swelling of the main body of the dosage form at a predetermined site of action, here, in particular, the rectum or preferably the vagina, the release of the sheet-like preparation 3 by the release mechanism 4 is triggered.

[0263] It is to be understood that the main body of the dosage form 1 may comprise grooves or may not comprise grooves depending on the embodiment.

[0264] In particular, however, a polymer being a glue can serve as a further trigger mechanism 5, wherein the polymer dissolves at least partially or completely upon contact with the fluid at the trigger site. In particular, such a polymer may attach the preparation 3 to the main body or may, additionally or alternatively, glue the foldings of the wafer 3 together. In particular, this may result in that the wafer 3 does not unfold as the polymer acting as a trigger mechanism 5 is not or is at least partially not dissolved. In the context of the embodiments shown in FIG. 5 and FIG. 6, it is also to be understood that these are particularly suited for embodiments in which a rapid and immediate release and dissolution and thus a relatively fast and immediate contacting of the wafer with the site of application, in particular of the vaginal mucous membrane, is intended.

[0265] FIG. 7 shows the schematic structure of a three-layered sheet-like preparation. A sheet-like preparation, like it is contained in the pharmaceutical dosage form 1 according to the invention, may have a thickness of 0.01 mm to 2 mm, preferably 0.03 mm to 1 mm, preferably 0.05 mm to 0.1 mm, wherein the sheet-like preparation 3 has an area between 0.5 and 20 cm.sup.2, preferably between 1 and 10 cm.sup.2. In particular, a sheet-like preparation 3 comprises at least one layer comprising an active pharmaceutical ingredient. The sheet-like, in particular film-shaped, foil-shaped or wafer-shaped preparation 3, which preferably has the shape of a wafer 3, contains an active pharmaceutical ingredient with an active ingredient content of 0.5 to 40% by weight, preferably 1 to 30% by weight, and more preferred 5 to 20% by weight. A sheet-like preparation 3 may have a single-layered or a multi-layered structure out of one or more layers 9, wherein at least one first layer 9a contains an active pharmaceutical ingredient. FIG. 7 shows the exemplary structure of a three-layered wafer 3 with a single layer containing an active substance 9a.

[0266] The dosage form according to the invention is further elucidated by the following examples.

EXAMPLE 1

[0267] The single-layered or multi-layered preparation according to the present invention preferably has a paper-like form.

[0268] 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.

[0269] 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.

[0270] 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.

Development and Testing

[0271] 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.

[0272] In this way, preparations are obtained that meet the requirements which arise, in particular, for a usage in connection with the dosage form.

[0273] 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.

[0274] 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.

[0275] 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 2SINGLE-LAYERED PREPARATION

[0276] Single-layered preparations, in particular wafers, that are suitable for the usage according to the invention, may, in particular, comprise the following formulations: [0277] A 10% PVA [0278] 20% PEG 400 [0279] 5% HPMC [0280] x % active pharmaceutical ingredient [0281] ad 100% demineralized water [0282] B 5% PVA [0283] 15% Kollicoat IR [0284] x % active pharmaceutical ingredient [0285] ad 100% demineralized water [0286] or [0287] C 5% PVA [0288] 15% Kollicoat IR [0289] 8% Glycerol 85% [0290] x % active pharmaceutical ingredient [0291] ad 100% demineralized water

EXAMPLE 3TWO-LAYERED PREPARATION

[0292] 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.

[0293] 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.

[0294] Table 1 which follows shows various exemplary compositions of layers of a two-layered wafer 3 according to the present invention.

TABLE-US-00001 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 g 400 g 500 g 750 g 5000 g (4% solution in acetone) EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 Ethyl cellulose 45 300 g 400 g 500 g 750 g 5000 g (4% solution in acetone EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2

[0295] The sheet-like, in particular film-shaped, foil-shaped, wafer-shaped preparation 3 comprising the active pharmaceutical ingredient comprises at least one first layer 9a containing the active substance. The layer 9a containing the active substance preferably comprises a polymer, more preferably a film-forming polymer, wherein the polymer fraction in the layer 9a 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 9a, and wherein the polymer is a water-dispersible and/or water-decomposable and/or water-disintegrable film-forming polymer.

[0296] Furthermore, the sheet-like, in particular film-shaped or wafer-shaped preparation 3 comprising the active pharmaceutical ingredient comprises at least one active substance free layer 9c, that does not contain an active pharmaceutical ingredient. In a three-layered wafer 3 the wafer 3 comprises a further active substance-free layer 9d that also does not contain an active pharmaceutical ingredient. Such a first active substance free layer 9c and/or such a further active substance free layer 9d is preferably a water-insoluble layer, e.g. made of or comprising ethyl cellulose. An active substance free layer 9c and/or a further active substance free layer 9d may be formed as an adhesive layer, in particular in a two-layered wafer 3, wherein the layer consists of or comprises e.g. hydroxypropyl methylcellulose. In a multi-layered, in particular three-layered wafer 3 layer 9a containing the active substance is preferably arranged between two active substance free layers 9c, 9d., wherein a layer 9a containing the active substance may be arranged between a first active substance free layer 9c and a further active substance free layer 9d and wherein preferably the first active substance free layer 9c 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 4THREE-LAYERED PREPARATION

[0297] 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.

[0298] Table 2 which follows shows various exemplary compositions of layers of such a three-layered wafer 3.

TABLE-US-00002 TABLE 2 Adhesive protective layer HPMC 50-100 m 50-100 m 50-100 m 50-100 m (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 x % x % x % x % ingredients Water ad 100% ad 100% ad 100% ad 100% Water-impermeable layer (backing layer) Ethyl cellulose 10 300 g 400 g 500 g 750 g (4% solution in acetone) EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 Ethyl cellulose 45 300 g 400 g 500 g 750 g (4% solution in acetone EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2 EC/cm.sup.2

[0299] 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

Regarding the Calculation of the Amount of Active Ingredient Per Wafer:

[0300] 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]$m\left(\mathrm{active}\mathrm{pharmaceutical}\mathrm{ingredient}\right)=\frac{m\left(\mathrm{formulation}\right)*m\left(\frac{\mathrm{active}\mathrm{pharmaceutical}\mathrm{ingredient}}{\mathrm{wafer}}\right)*10000}{p\left(\mathrm{polymer}\mathrm{mass}\right)*A\left(\mathrm{wafer}\right)*h\left(\mathrm{doctor}\mathrm{blade}\right)}$ [0301] wherein [0302] m mass [g] [0303] p density [g/cm.sup.3] [0304] A area [cm.sup.2] [0305] h height [m]

[0306] 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 [0307] 35% for sodium fluorescein [0308] 40% for quinine [0309] 35% for sodium diclofenac

[0310] 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]$m\left(\mathrm{active}\mathrm{pharmaceutical}\mathrm{ingredient}\right)=\frac{m\left(\mathrm{formulation}\right)*m\left(\frac{\mathrm{active}\mathrm{pharmaceutical}\mathrm{ingredient}}{\mathrm{wafer}}\right)*10000}{p\left(\mathrm{polymer}\mathrm{mass}\right)*A\left(\mathrm{wafer}\right)*h\left(\mathrm{doctor}\mathrm{blade}\right)}*\mathrm{drug}\mathrm{specific}\mathrm{factor}$

EXAMPLE 6MANUFACTURE OF SINGLE-LAYERED WAFERS

[0311] 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.

[0312] In the following, the manufacturing methods for the preparations mentioned in Example 2 above are described in detail: [0313] 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. [0314] 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. [0315] 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 7MANUFACTURE OF MULTI-LAYERED WAFERS

[0316] 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.

[0317] In the following, the manufacturing methods for the above-mentioned formulations of two- and three-layered wafers are described in detail:

Manufacture of Two-Layered Wafers:

[0318] 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.

[0319] 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.

[0320] 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.

Manufacture of Three-Layered Wafers:

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] In FIG. 8a a schematic illustration of the pharmaceutical dosage form 1 according to the invention in accordance with a fourth embodiment of the invention is shown. In particular, this illustration shows the pharmaceutical dosage form 1, wherein the sheet like preparation 3 is in a compact form. Moreover, without limiting the scope of this example, FIG. 8a shows the pharmaceutical dosage form 1 as a side view. A part of the sheet like preparation 3 is a rolled around a rod 19. This roll of the sheet like preparation 3 and the rod 19 together with the elongated part of the sheet like preparation 3 form the release mechanism. It is to be understood, that in some variants of the fourth embodiment the rod 19 is not necessary for the release mechanism 4, and thus omitted. The shell 2 contains the release mechanism 4 in the inner space 7 of the shell 2. Thus, the sheet like preparation 3 and the release mechanism form is protected. Preferably, the shell 2 is formed as a capsule. This capsule 2 facilitates swallowing the dosage form or, in particular, the part of the dosage form that have to be swallowed for the desired application. Furthermore, the shell 2 comprises an aperture 6, through which the sheet like preparation 3 may leave the shell 2. It is to be understood, that also the aperture 6 may be regarded as a part of the release mechanism 4 as it facilitates the release of the sheet like preparation 3. The trigger mechanism 5 is connected to the sheet like preparation 3 and is outside the shell 2. It is to be understood, that a part of the trigger mechanism 5 may be inside the shell 2 and/or that a part of the sheet like preparation 3 may be outside the shell 2. Moreover, the trigger mechanism 5 may be formed by a sophisticated part of the sheet like preparation 3. Additionally, the shell 2 comprises a sealing 18 that seals the aperture 6, at least in an initial state of the dosage form 1, in particular in a state of the dosage 1 that is particularly suited for storage. Such a manner, the inner space of the shell 7 may be protected from the environment such as humidity, liquids or microbes.

[0327] Especially, the fourth embodiment relates to an orally administrable dosage form for the treatment of the esophageal mucosa. In this case, it can deliver useful substances such as an active pharmaceutical ingredient to the esophageal mucous membrane by unrolling its sheet like preparation 3 while moving along the esophagus when it is swallowed. Thus, active pharmaceutical ingredients contained in the sheet like preparation 3 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 3 to the esophageal mucosa a pharmaceutical dosage form 1 according to the fourth embodiment of the invention the treatment of local diseases of the esophagus can be improved and, in particular, the contact time can be prolonged. When applied to the esophageal mucosa, the sheet like preparation 3 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 3 dissolves and is, preferably swallowed. Moreover, the shell 2 may detach from the sheet like preparation 3 immediately after the release of the sheet like preparation 3 or may dissolve while still attached to the sheet like preparation 3. Preferably, the shell 2 is made of a dissolvable and/or digestible material. Moreover, the trigger mechanism 5 is a holding device 5. In particular, the holding device 5 is adapted to be fixed in the oral cavity. Therefore, the holding device 5 has 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. 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.

[0328] Even more specifically, the fourth embodiment 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 2 is a capsule made out of hard gelatin. In an initial state of the dosage form 1, the sheet like preparation 3 is in a compact form, in particular in form of a coil, and is connected to the trigger mechanism 5. The trigger mechanism 5 is a holding device 5 as described above. On administration, the holding device is attached in the oral cavity, preferably to the buccal mucosa, in particular by gluing it to the mucosa. Next, the dosage form 1 is swallowed, preferably with a beverage or water, and, therefore, the dosage form 1 moves along the esophagus and a force acts on the holding device 5 triggering the release of the sheet like preparation 3 by the release mechanism 4. While the dosage form 1 moves down the esophagus the sheet like preparation 3 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 holding device 5. Afterwards, an oblong region of the esophageal mucosa is covered or at least near to the sheet like preparation 3. Thus, it can be treated with active pharmaceutical ingredients, in particular topic steroids, released by the sheet like preparation 3. Preferably, the sheet like preparation 3 may comprise and release fluticasone or budesonide.

[0329] Preferably, the manufacture of a sheet like preparation 3, in particular according to the fourth embodiment 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.

[0330] 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.

[0331] A sheet like preparation 3 manufactured according to this preferred variant has been experimentally analyzed. For this purpose the sheet like preparation 3 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 1145 m and a mean mass of 9.390.03 mg/cm.sup.2. The disintegration time in water was 76035 s, and greater than 1200 s on alginate gel. The tensile strength was 31.35 MPa. The elongation at break was 7.410.90%.

[0332] Preferably, a pharmaceutical dosage form 1, in particular according to the fourth embodiment of the present invention, may be manufactured as described in the following: [0333] cutting the film resulting from a solvent casting technique to strips of 400 mm by 4 mm; [0334] folding or rolling the resultant sheet like preparations 3; [0335] providing a hard gelatin capsule of size 1 is a shell 2; [0336] cutting an aperture 6 into a part of the hard gelatin capsule 2, specifically, as illustrated, into the upper part; [0337] threading one end of the sheet like preparation 3 through the aperture 6; and [0338] closing the capsule 2.

[0339] Here, the trigger mechanism, in particular holding device 5, is formed by the part of the sheet like preparation 3 that is outside the shell 2 and the release mechanism 4 is formed by the part of the sheet like preparation 3 that is inside the shell 2, and preferably the aperture 6.

[0340] A dosage form 1 manufactured as described above comprising the preferred variant of the sheet like preparation 3, in particular for the fourth embodiment of the present invention, has been experimentally analyzed, as described above. The extraction force of the sheet like preparation 3 from the capsule 2 was 0.310.09 N in case of the rolled sheet like preparation 3, and 0.240.45 N in case of the folded sheet like preparation 3.

[0341] In FIG. 8b a schematic illustration of the pharmaceutical dosage form 1 according to the invention in accordance with the fourth embodiment of the invention is shown. In particular, this illustration shows the pharmaceutical dosage form 1, wherein the sheet like preparation 3 is, at least partially, in an expanded form. Moreover, without limiting the scope of this example, FIG. 8b shows the pharmaceutical dosage form 1 is a top view. The shell 2 contains a rod 19 and a part of the sheet like preparation 3 that is still rolled or coiled, which form the release mechanism 4. The sheet like preparation 3 leaves the shell 2 through the aperture 6. In particular, it is unrolled within the shell 2, i.e. in the inner space of the shell 7, and then elongates into the direction of the aperture 6.

[0342] Furthermore, the sheet like preparation 3 is divided into two regions, a first region of the sheet like preparation 3a and a second region of the sheet like preparation 3b. The first region 3a and the second region 3b may comprise different active pharmaceutical ingredients. Preferably, the first region 3a can comprise local anesthetics such as benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine or novocaine, and the second region 3b 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 3a has a smaller cross-sectional area than the second region 3b. In particular, this beneficially facilitates swallowing the dosage form.

[0343] Furthermore, the holding device 5 is connected to the sheet like preparation 3 or is a broadened part of the sheet like preparation 3 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.

[0344] Additionally, the movement path PM of the dosage form 1 is illustrated.

[0345] Preferably, the preparation 3 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 3a and at least a second region 3b, 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 holding device 5 may be manufactured and/or connected to the sheet like preparation 3 in this way.

[0346] FIG. 8c illustrates the enveloping cross-sectional areas of the fourth embodiment of the invention. The pharmaceutical dosage form 1, in particular the shell 2, and the sheet like preparation 3, in particular the portion of the sheet like preparation 3 that just has been released e.g. a portion of the region 3b, are shown as they viewed in the direction of the movement path. Thus, the movement path in FIG. 8c points into the drawing area. As illustrated, the enveloping cross-sectional area of the dosage form AD is larger than the enveloping cross-sectional area of the released part of the sheet like preparation AP. In particular, this facilitates swallowing an orally administrable pharmaceutical dosage form 1.

[0347] In particular, the FIGS. 8a, b, and c have the same scale. It is to be understood, that the sheet like preparation 3 may be broader or narrower relative to the capsule 2 than illustrated. Preferably, the sheet like preparation may be broader to better utilize the inner space of the shell 7. Alternatively, the sheet like preparation may be rolled, wherein some windings of the sheet like preparation 3 are beneficially offset to each other. Thus, in particular, the inner space 7 is used in a more efficient way. Also preferably, the sheet like preparation 3 can form or can be comprises by a string member that is rolled or coiled. In particular, such a string member can be coiled in an efficient, reliable and/or space efficient way.

LIST OF REFERENCE SYMBOLS

[0348] 1 pharmaceutical dosage form [0349] 2 shell [0350] 3 sheet like preparation [0351] 3a, 3b regions of the sheet like preparation, in particular first and second region [0352] 4 release mechanism [0353] 5 trigger mechanism [0354] 6 aperture [0355] 7 inner space of the shell [0356] 8 predetermined breaking point [0357] 9 layer [0358] 9a, 9b layer containing an active substance [0359] 9c, 9d active substance free layer [0360] 10 spring element [0361] 11 first tube element [0362] 12 further tube element [0363] 13 first joint element [0364] 14 further joint element [0365] 15 central aperture of the wafer balloon [0366] 16 slit [0367] 17 cladding or shell parts [0368] 18 sealing [0369] 19 rod [0370] PM movement path [0371] AD enveloping cross-sectional area of the dosage form [0372] AP enveloping cross-sectional area of the released part of the sheet like preparation