REINFORCED PHARMACEUTICAL DOSAGE FORM

Abstract

The invention relates to a reinforced pharmaceutical dosage form comprising a pharmacologically active ingredient and fibers. The reinforced pharmaceutical dosage form is tamper-resistant and thus useful for the avoidance of drug abuse or misuse. The invention also relates to the preparation of such dosage forms and their use in therapy.

Claims

1.-87. (canceled)

88. A reinforced pharmaceutical dosage form comprising a pharmacologically active ingredient and fibers; wherein the pharmaceutical dosage form comprises a polymer matrix that is reinforced with the fibers; wherein the polymer matrix comprises a polymer selected from polyether ether ketones; and wherein the pharmaceutical dosage form is a tablet, a capsule or a pill.

89. The pharmaceutical dosage form according to claim 88, wherein the fibers are manufactured by three-dimensional printing technology.

90. The pharmaceutical dosage form according to claim 88, wherein at least a portion of the fibers is oriented in essentially the same direction.

91. The pharmaceutical dosage form according to claim 88, which comprises a plurality of layers, wherein each layer comprises fibers which are oriented in essentially a same direction of orientation, wherein the direction of orientation of adjacent layers differs from one another.

92. The pharmaceutical dosage form according to claim 91, wherein the direction of orientation of all layers differs from one another.

93. The pharmaceutical dosage form according to claim 91, wherein the direction of orientation of each layer lies essentially within the plane of said layer.

94. The pharmaceutical dosage form according to claim 88, wherein the polymer matrix is manufactured by three-dimensional printing technology.

95. The pharmaceutical dosage form according to claim 88, wherein the fibers are selected from the group consisting of glass fibers, carbon fibers, mineral fibers, polymer fibers, and mixtures thereof.

96. The pharmaceutical dosage form according to claim 95, wherein the fibers are polymer fibers comprising a polymer selected from the group consisting of polyesters, polyamides, polyurethanes, cellulose ethers, polyacrylates, vinyl polymers, polyether ether ketones, polyalkylene oxides, and mixtures thereof.

97. The pharmaceutical dosage form according to claim 88, wherein the pharmacologically active ingredient has psychotropic action.

98. The pharmaceutical dosage form according to claim 88, wherein the pharmacologically active ingredient is selected from opioids and stimulants.

99. The pharmaceutical dosage form according to claim 88, which is tamper resistant.

100. The pharmaceutical dosage form according to claim 88, which comprises one or more pockets that serve as canals allowing the release medium to penetrate from the outside through the pockets into the pharmaceutical dosage form.

101. A method for treating a condition in a patient in need thereof, said method comprising orally administering to said patient the pharmaceutical dosage form according to claim 88, wherein the pharmacologically active ingredient is effective for said treating.

102. A process for preparing a dosage form according to claim 88, said process comprising a three-dimensional printing step.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0209] FIG. 1 schematically illustrates a preferred embodiment of a pharmaceutical dosage form (1) according to the invention comprising a plurality of fibers (2) that are oriented arbitrarily, i.e. do not have a common direction of orientation.

[0210] FIG. 2 schematically illustrates another preferred embodiment of a pharmaceutical dosage form (1) according to the invention comprising a plurality of fibers (2) that with respect to layer (3) of the pharmaceutical dosage form are oriented arbitrarily, i.e. do not have a common direction of orientation.

[0211] FIG. 3 schematically illustrates another preferred embodiment of a pharmaceutical dosage form (1) according to the invention comprising a plurality of fibers (2) that with respect to layer (3) of the pharmaceutical dosage form are only aligned along the plane in x-direction and y-direction of the material. This means that essentially no fibers are aligned in the z-direction (see FIG. 3).

[0212] FIG. 4 schematically illustrates a variant of the pharmaceutical dosage form according to FIG. 3, wherein the fibers are of macroscopic size. Preferably, the fibers comprise or essentially consist of one or more polymers. The fibers are arranged essentially in parallel to one another and preferably in contact with one another thereby forming a plane which is preferably layer (3) of the pharmaceutical dosage form according to the invention (see FIG. 4).

[0213] FIGS. 5 and 6 schematically illustrate preferred embodiments of the pharmaceutical dosage form (1) according to the invention comprising layers (3a) and (3b), wherein each layer comprises fibers (2a) and (2b), respectively, which are oriented in essentially a same direction of orientation, wherein the direction of orientation of adjacent layers differs from one another (see FIGS. 5 and 6). Preferably, the angle of the two different directions of orientation of two adjacent layers is a function of the number of layers. When the pharmaceutical dosage form has n layers comprising fibers which are oriented in n different directions of orientation, the angle of the two different directions of orientation of two adjacent layers is preferably (180/n)10. Thus, when the pharmaceutical dosage form has two layers (n=2), the angle of the two different directions of orientation of the two adjacent layers is preferably within the range of 9010, i.e. 80 to 1000. Preferably, the direction of orientation of each layer lies essentially within the plane of said layer.

[0214] According to the embodiment of FIG. 5, the fibers (2a) and (2b) are of microscopic size and embedded in a polymer matrix.

[0215] According to the embodiment of FIG. 6, the fibers (2a) and (2b) are of macroscopic size and preferably comprise or essentially consist of one or more polymers. The fibers (2a) and (2b) are arranged essentially in parallel to one another and preferably in contact with one another thereby forming planes which are preferably layers (3a) and (3b) of the pharmaceutical dosage form according to the invention

[0216] FIG. 7 schematically illustrates another preferred embodiment of the pharmaceutical dosage form (1) according to the invention comprising wherein the fibers (2) in form a woven or nonwoven fabric (4) surrounding an inner core which comprises the pharmacologically active ingredient. The dosage form comprises an outer coating (5) of excipients deposited at the outer surface of the fabric (4) such that it is not visible from the outside.

[0217] FIG. 8 schematically illustrates a variant of the pharmaceutical dosage form according to FIG. 7, wherein the fabric surrounds the core of the pharmaceutical dosage form in a pouf-like arrangement.

[0218] FIG. 9 schematically illustrates a preferred embodiment of a pharmaceutical dosage form (1) according to the invention comprising pockets (6) thatonce their ends are exposed to gastric fluidsserve as canals allowing the release medium, e.g. the gastric fluid, to penetrate from the outside through the pockets (6) into the pharmaceutical dosage form i.e. into its interior and inner core, respectively.

[0219] The pharmaceutical dosage form according to the invention can be manufactured by conventional means, such as direct compression, granulation (dry or wet) or extrusion.

[0220] In a preferred embodiment, the pharmaceutical dosage form according to the invention is thermoformed, e.g. hot-melt extruded.

[0221] The pharmaceutical dosage form according to the invention is preferably produced by mixing the pharmacologically active ingredient, the fibers and all additional excipients and, optionally after granulation, press-forming the resultant mixture to yield the dosage form with preceding, simultaneous, or subsequent exposure to heat.

[0222] A powder mixture may be heated and then subsequently compressed, or it may be heated and simultaneously compressed, or it may be compressed and then subsequently heated.

[0223] Mixing proceeds in a mixer known to the person skilled in the art. The mixer may, for example, be a roll mixer, shaking mixer, shear mixer or compulsory mixer.

[0224] The resultant mixture is preferably formed directly by application of pressure to yield the dosage form according to the invention with preceding, simultaneous or subsequent exposure to heat. The mixture may, for example, be formed into tablets by direct tabletting. In direct tabletting with simultaneous exposure to heat, the tabletting tool, i.e. bottom punch, top punch and die are briefly heated at least to the softening temperature of the polymers that are contained in the polymer matrix and pressed together. In direct tabletting with subsequent exposure to heat, the formed tablets are briefly heated at least to the softening temperature (glass transition temperature, melting temperature; sintering temperature) of the polymers and cooled again. In direct tabletting with preceding exposure to heat, the material to be pressed is heated immediately prior to tabletting at least to the softening temperature of the polymers and then pressed.

[0225] The resultant mixture may also first be granulated and then be formed with preceding, simultaneous, or subsequent exposure to heat to yield the dosage form according to the invention.

[0226] 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.

[0227] Preferably, the three-dimensional printing step involves fused deposition modeling.

[0228] 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.

[0229] 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 XYZ 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).

[0230] 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.

[0231] A representative pharmaceutical composition is summarized in the table here below:

TABLE-US-00002 Constituent mg wt.-% Tramadol 100 40 PEG 4000 30 12 PEEK 100 40 HPMC 20 8

[0232] The pharmacologically active ingredient (here Tramadol) is mixed with the cut-resistant thermoplastic material in an extruder thereby providing a three-dimensionally printable filament having a diameter within the range of e.g. from 1.0 to 5.0 mm.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] Another aspect of the invention relates to a pharmaceutical dosage form that is obtainable by the process according to the invention as described above.