FLOATING PHARMACEUTICAL DOSAGE FORM

Abstract

The invention relates to a pharmaceutical dosage form having a density below the density of gastric fluid, wherein the dosage form comprises a pharmacologically active ingredient and a cavity. The invention also relates to a process for the preparation of said dosage form comprising a three-dimensional printing step.

Claims

1. A gastric-retentive pharmaceutical dosage form, which has been manufactured by three-dimensional printing technology and which has a density below the density of gastric fluid, wherein the dosage form comprises a pharmacologically active ingredient and a cavity, wherein the cavity has a volume of at least 0.1 l; and wherein the balance point of the dosage form is outside the geometrical center of the dosage form.

2. The dosage form according to claim 1, wherein the cavity has a volume of at least 25 l.

3. The dosage form according to claim 1, comprising a floating unit comprising the cavity; and a releasing unit comprising the pharmacologically active ingredient; and optionally, a protecting unit.

4. The dosage form according to claim 3, wherein the floating unit comprises a material which surrounds the cavity and which is insoluble or poorly soluble in gastric fluid.

5. The dosage form according to claim 3, wherein the releasing unit comprises an erodible matrix material in which the pharmacologically active ingredient is embedded.

6. The dosage form according to claim 3, wherein the optionally present protecting unit comprises a material which covers at least a portion of the outer surface of the floating unit and/or at least a portion of the outer surface of the releasing unit and which is soluble in gastric fluid.

7. The dosage form according to claim 1, comprising one or more pockets, which have openings at the outer surface of the pharmaceutical dosage form.

8. The dosage form according to claim 1, which comprises an enteric material.

9. The dosage form according to claim 1, comprising a first segment comprising a first cavity and a second segment comprising a second cavity.

10. The dosage form according to claim 9, wherein the first cavity and/or the second cavity is/are encased by an enteric material.

11. The dosage form according to claim 9, wherein the first cavity and the second cavity have different volumes.

12. The dosage form according to claim 9, comprising one or more pockets, which have openings at the outer surface of the pharmaceutical dosage form, wherein the pockets are positioned between the first segment and the second segment.

13. The dosage form according to claim 1, wherein the dosage form comprises a combination of two or more pharmacologically active ingredients or a combination of two or more derivatives of one and the same pharmacologically active ingredients such as different salts.

14. The dosage form according to claim 1, wherein the one or more cavities and the remainder of the pharmaceutical dosage form are spatially arranged in a non-centro-symmetric manner.

15. A process for the preparation of a dosage form according to claim 1, said process comprising a three-dimensional printing step.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0144] Preferred embodiments of the pharmaceutical dosage form according to the invention are also illustrated by FIGS. 1 to 8.

[0145] FIG. 1A schematically illustrates a cross-section of a comparatively simple embodiment of the pharmaceutical dosage form (1) according to the invention comprising body (2) which contains the pharmacologically active ingredient as well as typically one or more pharmaceutical excipients and a single cavity (3). FIG. 1B schematically illustrates a cross-section of a similar dosage form (1) according to the invention comprising two cavities (3) of about the same size. FIG. 1C schematically illustrates a cross-section of a related pharmaceutical dosage form (1) according to the invention comprising three cavities (3a,b), where cavities (3a) are of about the same size and cavity (3b) is larger.

[0146] FIG. 2A schematically illustrates a cross-section of a preferred embodiment of the pharmaceutical dosage form (1) according to the invention comprising body (2) which contains the pharmacologically active ingredient as well as typically one or more pharmaceutical excipients, cavity (3) and a plurality of pockets (4) thatonce their ends are exposed to gastric fluidsserve as canals allowing the gastric fluid to penetrate from the outside through the pockets into the inner core of the pharmaceutical dosage form (1). FIG. 2B schematically illustrates a cross-section of a variant of the pharmaceutical dosage form of FIG. 2B. FIG. 2C schematically illustrates a cross-section of another variant of the pharmaceutical dosage form of FIGS. 2A and 2B comprising two cavities (3) of about the same size.

[0147] FIG. 3A schematically illustrates a cross-section of a preferred embodiment of the pharmaceutical dosage form (1) according to the invention comprising body (2) which contains the pharmacologically active ingredient as well as typically one or more pharmaceutical excipients and cavity (3), which is located above the geometrical center of the pharmaceutical dosage form (1). In consequence, the balance point of the pharmaceutical dosage form is located below its geometrical center. FIG. 3B schematically illustrates a cross-section of a variant of the pharmaceutical dosage form of FIG. 3B comprising two cavities (3) of about the same size, which are both located above the geometrical center of the pharmaceutical dosage form (1). FIG. 3C schematically illustrates a cross-section of another variant of the pharmaceutical dosage form of FIG. 2A. Cavity (3) is located on the left hand side whereas the right hand side comprises pockets (4). When being contacted with gastric fluid, the pharmaceutical dosage form will turn clockwise and float with cavity (3) upwards and pockets (4) downwards.

[0148] FIG. 4A/B schematically illustrate a cross-section of a preferred embodiment of the pharmaceutical dosage form (1) according to the invention. FIG. 4A schematically illustrates the state before the pharmaceutical dosage form is subjected to gastric fluid. Under these conditions, the pharmaceutical dosage form comprises body (2) which contains the pharmacologically active ingredient as well as typically one or more pharmaceutical excipients and cavity (3), which is located above the geometrical center of the pharmaceutical dosage form (1). Cavity (3) serves as floating unit whereas body (2) serves as releasing unit through its releasing area (5). Floating unit (3) and releasing unit (2) are surrounded by a protecting unit (6). FIG. 4B schematically illustrates the state after the pharmaceutical dosage form has been subjected to gastric fluid and protecting unit (6) has been dissolved thereby exposing releasing area (5) of the releasing unit (2) to the gastric fluid (7). Under these conditions, the pharmaceutical dosage form releases the pharmacologically active ingredient from the releasing unit (2) through the releasing area (5) into the gastric fluid (indicated by arrows).

[0149] FIG. 5A/B schematically illustrate a cross-section of a preferred embodiment of the pharmaceutical dosage form (1) according to the invention. The pharmaceutical dosage form (1) schematically illustrated in FIG. 5A comprises a cavity (3), which is located above the geometrical center of the pharmaceutical dosage form (1). Cavity (3) serves as floating unit whereas body (2) serves as releasing unit through its releasing area (5). The releasing unit (2) has a thickness (b). The wall (a) of the cavity (3) is composed of an erodible material but the thickness of said wall (a) is greater than the thickness (b) of the releasing unit (2). FIG. 5B schematically illustrates a cross-section of the pharmaceutical dosage form (1) after it has been subjected to gastric fluid (7) for a while. Assuming even erosion of the material, the entire releasing unit (2) will be dissolved, i.e. the entire content of the pharmacologically active ingredient will be released into the gastric fluid (7), before the wall of the cavity (3)due to its greater thickness (a)will disappear thereby causing the pharmaceutical dosage form to sink.

[0150] Preferably, independent from the other features depicted in FIG. 5A/B, the wall (a) of the cavity is at least 10% thicker, more preferably at least 20%, or at least 30%, or at least 40%, even more preferred at least 50%, or at least 60%, or at least 70%, or at least 80%, most preferably at least 90% thicker than the thickness (b) of the releasing unit.

[0151] FIG. 6A schematically illustrates a cross-section of an embodiment of the pharmaceutical dosage form (1) according to the invention comprising two parts (2a, 2b) of a body wherein each part contains one pharmacologically active ingredient as well as typically one or more pharmaceutical excipients. The pharmacologically active ingredient in part (2a) may differ from the pharmacologically active ingredient in part (2b). Further, each part (2a, 2b) comprises one cavity (3a, 3b), wherein the cavity (3a) in part (2a) has a bigger volume than the cavity (3b) in part (2b). The dosage form also comprises two pockets (4) that are positioned between the two parts and thatonce their ends are exposed to gastric fluidsserve as canals allowing the gastric fluid to penetrate from the outside through the pockets into the inner core of the pharmaceutical dosage form (1). FIG. 6B schematically illustrates the state after the pharmaceutical dosage form has been subjected to gastric fluid and gastric fluid has penetrated from the outside through the pockets into the inner core of the pharmaceutical dosage form (1). Adjacent to the two pockets (4) the parts (2a, 2b) of the body have been partly dissolved in the gastric fluid such that the dosage form is about to be divided in two separate parts, wherein each separate part contains one cavity (3). FIG. 6C schematically illustrates the state after the body adjacent to the two pockets has been completely dissolved in the gastric fluid and the dosage form is divided in two separate parts (2a) and (2b), wherein each separate part contains one cavity (3a, 3b). Due to the bigger volume of cavity (3a) the separate part (2a) comprising this cavity will have less contact to the gastric fluid and therefore will dissolve more slowly than separate part (2b) which comprises cavity (3b) with the smaller volume and which will have more contact to the gastric fluid than separate part (2a).

[0152] FIG. 7 schematically illustrates a cross-section of a preferred embodiment of the pharmaceutical dosage form (1) according to the invention. The pharmaceutical dosage form (1) comprises a cavity (3), which serves as floating unit, whereas body (2) serves as releasing unit. The cavity (3) is encased by an enteric material (8) on all sides by body (2), i.e. the releasing unit, i.e. the pharmacologically active ingredient is not encased by the enteric material but exposed to gastric fluid and subject to erosion and dissolution. In consequence, the buoyancy provided by the cavity prevents the dosage form from sinking, whereas the release unit is in contact with the gastric fluid as to release the pharmacologically active ingredient into the gastric fluid according to the desired release kinetics.

[0153] FIG. 8 schematically illustrates a variant of the pharmaceutical dosage form illustrated in FIG. 7. The pharmaceutical dosage form (1) comprises a cavity (3), which serves as floating unit whereas body (2) serves as releasing unit, whereas body (2) serves as releasing unit. According to this embodiment, the inner surface of the cavity (3) is formed by a wall (9) which in turn is covered by the enteric material (8) on its outer surface. Thus, the cavity (3) is also encased on all sides by the enteric material (8), but the enteric material (8) does not form the inner surface of the cavity (3). The pharmacologically active ingredient is not encased by the enteric material (8).

[0154] Another aspect of the invention relates to a process for the preparation of a dosage form according to the invention as described above, said process comprising a three-dimensional printing step. It has been surprisingly found that pharmaceutical dosage forms comprising comparatively large cavities can be manufactured by three-dimensional printing technologies.

[0155] Preferably, the three-dimensional printing step involves fused deposition modeling.

[0156] Machines for fused deposition modeling (FDM) are commercially available. The machines may dispense multiple materials to achieve different goals: For example, one material may be used to build up the pharmaceutical dosage form and another material may be used to build up a soluble support structure. The same applies to the materials of the floating unit, the releasing unit and the optionally present protecting unit as described above.

[0157] In FDM the pharmaceutical dosage form is produced by extruding small flattened strings of molten material to form layers as the material hardens immediately after extrusion from the nozzle. A thermoplastic filament is unwound from a coil and supplies material to an extrusion nozzle which can turn the flow on and off. A worm-drive may push the filament into the nozzle at a controlled rate. The nozzle is heated to melt the material. The thermoplastic material is heated above its glass transition temperature and is then deposited by an extrusion die. The nozzle can be moved in both horizontal and vertical directions by a numerically controlled mechanism. The nozzle follows a tool-path controlled by a computer-aided manufacturing (CAM) software package, and the pharmaceutical dosage form is built from the bottom up, one layer at a time. Stepper motors or servo motors are typically employed to move the extrusion die. The mechanism used is often an X-Y-Z rectilinear design, although other mechanical designs such as deltabot have been employed. Myriad materials are commercially available, such as polylactic acid (PLA), polyamide (PA), among many others (see Ursan et al., J Am Pharm Assoc (2003) 2013, 53(2), 136.44; Prasad et al., Drug Dev Ind Pharm 2015, 1-13).

[0158] Pharmaceutical compositions that are suitable to be employed in the three-dimensional printing step according to the invention, preferably in fused deposition modeling, are preferably identical to or at least similar with pharmaceutical compositions that have been known to be suitable for processing by conventional hot melt extrusion technology. Fused deposition modeling has many similarities with conventional hot melt extrusion.

[0159] Preferably, the pharmaceutical dosage form is prepared by three-dimensionally printing at least two different pharmaceutical compositions that preferably are provided each in form of filaments useful for fused deposition modeling. Preferably, one pharmaceutical composition contains one or more pharmacologically active ingredients, whereas the other pharmaceutical composition does not contain pharmacologically active ingredients.

[0160] Preferably, the pharmaceutical composition not containing pharmacologically active ingredients comprises or essentially consists of an enteric material. Enteric materials are known to the skilled person. Preferably, the enteric material is selected from the group consisting of methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, and mixture thereof.

[0161] Preferably, at least one cavity or the single cavity is encased by the pharmaceutical composition comprising or essentially consisting of an enteric material.

[0162] Both compositions preferably contain pharmaceutical excipients that are conventionally employed in the manufacture of pharmaceutical dosage forms, preferably in the course of three-dimensional printing technology, especially fused deposition modeling. The following preferred embodiments apply to both pharmaceutical compositions (in the following referred to as pharmaceutical composition), irrespective of whether they contain a pharmacologically active ingredient or not.

[0163] Preferably, the pharmaceutical composition comprises a plasticizer. Suitable plasticizers are known to the skilled person. Examples include but are not limited to polyethylene glycols, such as PEG 1500 or PEG 4000 or PEG 6000; citrates, phthalates, glycerin, sugar alcohols, various contents of copolymers (e.g. ethylene vinyl acetate (EVA)/vinyl acetate (VA)), and mixtures of any of the foregoing.

[0164] The content of plasticizer is preferably within the range of from 0.1 to 20 wt.-%, more preferably 5.0 to 17.5 wt.-%, still more preferably 7.5 to 15 wt.-%, relative to the total weight of the pharmaceutical composition.

[0165] Preferably, the pharmaceutical composition comprises one or more matrix polymers. Suitable matrix polymers are known to the skilled person. Examples include but are not limited to polylactic acid (PLA); cellulose ethers such as methylcellulose (MC), ethylcellulose (EC), hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC); vinyl polymers such as polyvinylpyrrolidone (e.g. Kollidon PF 12) or blends thereof such as polyvinyl acetate/polyvinylpyrrolidone (e.g. Kollidon SR). Other suitable polymers include ethylene vinyl acetate copolymers (EVA), polyvinyl chloride, polyethylene terephthalate (PET), polyurethanes (PU), polyamides (PA), polyacrylates and mixtures of any of the foregoing. Polylactic acid (PLA) is particularly preferred.

[0166] The pharmaceutical composition may consist of one or more matrix polymers. The total content of matrix polymers is preferably within the range of from 5.0 to 95 wt.-%, more preferably 10 to 90 wt.-%, still more preferably 25 to 85 wt.-%, relative to the total weight of the pharmaceutical composition.

[0167] Representative pharmaceutical compositions that are useful for the purpose of the invention are compiled in the table here below. Composition 1 comprises a pharmacologically active ingredient whereas Composition 2 comprises the same excipients in the same absolute amounts but no pharmacologically active ingredient:

TABLE-US-00003 Composition Composition 1A 2A weight content weight content ingredient [mg] [wt.-%] [mg] [wt.-%] pharmacologically Tramadol 50 25 active ingredient HCl plasticizer PEG 4000 20 10 20 13.3 matrix polymer Ethylcellulose 80 40 80 53.3 matrix polymer Polylactic acid 50 25 50 33.3 Composition Composition 2A 2B weight content weight content ingredient [mg] [wt.-%] [mg] [wt.-%] pharmacologically Tramadol 0.5 0.1 active ingredient HCl plasticizer PEG 4000 49.5 9.9 49.5 9.9 matrix polymer Kollidon 450 90 450 90.1 PF 12 Composition Composition 3A 3B weight content weight content ingredient [mg] [wt.-%] [mg] [wt.-%] pharmacologically Tramadol 204.08 40.8 active ingredient HCl matrix polymer Kollidon SR 255.1 51.0 255.1 86.2 matrix polymer HPMC 40.81 8.2 40.81 13.8

[0168] For filament preparation, a matrix polymer or a mixture of various matrix polymers, e.g. hydroxypropylcellulose (HPC), may be stored 24 h in oven at 40 C.; when required it may be mixed in a mortar with PEG 1500 or PEG 4000 (2%, 5%, 10% by weight calculated with respect to the dry polymer). Hot-melt extrusion (HME) may be carried out in a twin-screw extruder (Haake MiniLab II, Thermo Scientific, USA) equipped with an aluminum rod-shaped die ( 2.00 mm). Extruded rods may be calibrated and rolled up on a spool.

[0169] Another aspect of the invention relates to a pharmaceutical dosage form that is obtainable by the process according to the invention as described above.

EXAMPLES

[0170] Two tablets were manufactured by three-dimensional printing involving fused deposition modeling. A comparative tablet was prepared from solid material, i.e. which did not comprise cavities. An inventive tablet was prepared by printing web layers above one another thereby forming cavities. Both tablets were made from the same material (polylactic acid, polylactate, PLA).

[0171] FIGS. 9 and 10 illustrate the floating behavior of the inventive tablet compared to the sinking comparative tablet.